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    Experimental Brain Research

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

    Abstract

    The activity-dependent neuroprotective protein (ADNP) syndrome is an autistic-like disorder, instigated by mutations in ADNP. This syndrome is characterized by developmental delays, impairments in speech, motor function, abnormal hearing, and intellectual disabilities. In the Adnp-haploinsufficient mouse model, many of these impediments are evident, appearing in a sex-dependent manner. In zebra finch songbird (ZF; Taeniopygia guttata), an animal model used for song/language studies, ADNP mRNA most robust expression is observed in the cerebrum of young males, potentially corroborating with male ZF exclusive singing behavior and developed cerebral song system. Herein, we report a similar sex-dependent ADNP expression profile, with the highest expression in the cerebrum (qRT-PCR) in the brain of another songbird, the domesticated canary (Serinus canaria domestica). Additional analyses for the mRNA transcripts of the ADNP regulator, vasoactive intestinal peptide (VIP), sister gene ADNP2, and speech-related Forkhead box protein P2 (FoxP2) revealed multiple sex and brain region–dependent positive correlations between the genes (including ADNP). Parallel transcript expression patterns for FoxP2 and VIP were observed alongside specific FoxP2 increase in males compared with females as well as VIP/ADNP2 correlations. In spatial view, a sexually independent extensive form of expression was found for ADNP in the canary cerebrum (RNA in situ hybridization). The songbird cerebral mesopallium area stood out as a potentially high-expressing ADNP tissue, further strengthening the association of ADNP with sense integration and auditory memory formation, previously implicated in mouse and human.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Retraction Note to: Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model

    The authors have retracted this article [1] because in further experiments, they found that some experimental data cannot be verified repeatedly.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Identification of Hub Genes in Atypical Teratoid/Rhabdoid Tumor by Bioinformatics Analyses

    Abstract

    Atypical teratoid/rhabdoid tumor (ATRT) is a devastating intracranial tumor in children. Currently, its molecular mechanisms cannot be studied effectively because patient samples are limited, and many factors are involved in its pathogenesis. In this study, we analyzed three gene expression profile data sets obtained from the Gene Expression Omnibus (GEO) database to identify genes that participate in ATRT. The datasets were integrated and analyzed using the RobustRankAggreg method to screen for differentially expressed genes (DEGs). We identified 197 DEGs, including 94 downregulated and 103 upregulated genes which were then used for gene set enrichment analysis. The results showed that the downregulated genes were mainly enriched in synaptic vesicle cycle, nicotine addiction, and GABAergic synapse, whereas the upregulated genes were enriched in the cell cycle, p53 signaling pathway, and cellular senescence. Consistent with these results, gene set enrichment analysis showed that E2F targets, G2M checkpoints, and MYC targets were significantly enriched in datasets. Protein-protein interaction (PPI) network revealed that CDK1, CCNA2, BUB1B, CDC20, KIF11, KIF20A, KIF2C, NCAPG, NDC80, NUSAP1, PBK, RRM2, TPX2, TOP2A, and TTK were hub genes. NetworkAnalyst algorithm was used to predict the transcription factor (TF), and the results showed that MYC, SOX2, and KDM5B could regulate these hub genes. In conclusion, the present study brings a new perspective of ATRT pathogenesis and the strategy targeted to cell cycle related gene may be promising treatments for the disease.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Identification of Circular RNA Expression Profiles and their Implication in Spinal Cord Injury Rats at the Immediate Phase

    Abstract

    This study aimed to explore the implication of circular RNA (circRNA) expression profiles in spinal cord injury (SCI) rats at the immediate phase. CircRNA expression profiles in spinal cord samples from five SCI rats at the immediate phase (2 h post SCI) and five sham control (Ctrl) rats were assessed by microarray analysis. Subsequently, ten candidate circRNAs (obtained from microarray analysis) were validated in ten SCI rats at the immediate phase and ten Ctrl rats by the reverse transcription quantitative polymerase chain reaction (RT-qPCR). PCA plots and heatmap analyses revealed that circRNA expression profiles could distinguish SCI rats at the immediate phase from Ctrl rats. Furthermore, 1101 circRNAs were upregulated and 897 circRNAs were downregulated in SCI rats at the immediate phase compared with Ctrl rats. These dysregulated circRNAs distributed on all chromosomes, and most of them located on chromosome 1–10. As for circRNA types, most of these dysregulated circRNAs were exonic. Additionally, enrichment analyses displayed that these dysregulated circRNAs were enriched in multiple signaling pathways related to neuronal signal transduction, immunity, and inflammation, such as the calcium signaling pathway, JAK-STAT signaling pathway, and MAPK signaling pathway. Using RT-qPCR, eight out of ten candidate circRNAs (including rno_circRNA_011690, rno_circRNA_011494, rno_circRNA_005470, rno_circRNA_014301, rno_circRNA_009608, rno_circRNA_016031, rno_circRNA_011497, and rno_circRNA_015152) were dysregulated in SCI rats at the immediate phase compared with Ctrl rats. Our study provides a valuable reference for circRNA expression profiles in SCI rats at the immediate phase, which offers new clues for investigating mechanisms underlying the immediate phase and possible early intervention targets of SCI.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Integrative In Silico Analysis of Genome-Wide DNA Methylation Profiles in Schizophrenia

    Abstract

    Schizophrenia (SZ) is a complex and severe psychiatric disorder, which has a global lifetime prevalence of 0.4% and a heritability of around 0.81. A number of epigenome-wide association studies (EWAS) have been carried out for SZ, with discordant results. The main aim of this study was to carry out an integrative in silico analysis of available genome-wide DNA methylation profiles in schizophrenia. In this work, an integration of multiple lines of evidence (top candidate genes from several EWAS and genome-wide expression and association data) was carried out, in order to identify top differentially methylated (DM) genes for SZ. In addition, functional enrichment and protein-protein interaction analyses were carried out. Several top differentially methylated genes, such as APC, CACNB2, and PRKN, were found, and an enrichment of binding sites for brain-expressed transcription factors, such as FOXO1, MYB, and ZIC3, was also observed. Moreover, a protein-protein interaction network showed a central role for DISC1 and ZNF688 genes, and experimentally validated targets of MIR-137, such as and KCNB2, NRXN1, and SYN2, were identified among DM genes. This is the first integrative in silico analysis of available genome-wide DNA methylation profiles in schizophrenia. This work identified novel candidate genes and pathways for SZ and provides the basis to explore their role in the pathogenesis of SZ in future studies.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Assessment of Association between NINJ2 Polymorphisms and Suicide Attempts in an Iranian Population

    Abstract

    Suicidal behavior as a psychological problem with high public health burden is associated with a number of genetically determined risk factors. In the current study, we investigated the association between two polymorphisms within the NINJ2 gene and risk of suicide in an Iranian population. The study included 295 individuals who attempted suicide with soft suicide methods, 234 suicide victims and 410 normal controls. The rs11833579 SNP was associated with death from suicide in a codominant model in that the AG genotype decreased the risk of death from suicide compared with the GG genotype (OR (95% CI) = 0.49 (0.34–0.71), adjusted P value = 4e−04). This SNP was also associated with death from suicide in dominant (AG + AA versus GG: OR (95% CI) = 0.63 (0.46–0.87), adjusted P value = 0.011) and overdominant (AG versus GG + AA: OR (95% CI) = 0.49 (0.35–0.69), adjusted P value < 0.0001) models. In addition, this SNP was associated with soft suicide attempts in a codominant model (AG versus AA + GG: OR (95% CI) = 0.7 (0.5–0.98), adjusted P value = 0.02). The rs3806263 SNP was associated with death from suicide in allelic (A versus G: OR (95% CI) = 1.48 (1.17–1.88), adjusted P value = 0.002), codominant (AA versus GG: OR (95% CI) = 3.14 (1.89–5.21), adjusted P value < 0.0001), recessive (AA versus GG + AG: OR (95% CI) = 3.47 (2.15–5.61), adjusted P value < 0.0001), overdominant (AG versus AA + GG: OR (95% CI) = 0.62 (0.45–0.87), adjusted P value = 0.0092) and log-additive models (OR (95% CI) = 1.45 (1.15–1.83), adjusted P value = 0.0034). When comparing allele/genotype frequencies of this SNP between suicide victims and soft suicide attempters, significant associations were found in allelic, codominant, recessive and log-additive models. The AG haplotype (rs11833579 and rs3806263, respectively) was significantly less prevalent among suicide victims compared with controls (OR (95% CI) = 0.37 (0.26–0.52), adjusted P value < 0.0001). This haplotype was also less prevalent among suicide victims vs. soft suicide attempters (OR (95% CI) = 0.43 (0.31–0.61), adjusted P value < 0.0001). The GA haplotype (rs11833579 and rs3806263, respectively) was less frequent among suicide victims compared with controls (OR (95% CI) = 0.63 (0.45–0.89), adjusted P value = 0.0156). Finally, the AA haplotype was more prevalent among suicide victims compared with both controls (OR (95% CI) = 2.37 (1.56–3.6), adjusted P value = 0.0002) and soft suicide attempters (OR (95% CI) = 1.92 (1.32–2.78), adjusted P value = 0.0012). Thus, these two SNPs might be regarded as genetic determinants of suicide risk in Iranian populations. Further studies in different populations are needed to verify these results.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Effect of Different Frequencies of Electroacupuncture on Post-Stroke Dysphagia in Mice

    Abstract

    The aim of this study was to determine the optimum frequency of electroacupuncture (EA) for the treatment of dysphagia after stroke. Male C57BL/6 J mice were randomly divided into five groups: normal, model, 2 Hz, 50 Hz, and 100 Hz groups. All mice received a photochemical ischemia, except the normal group. The EA parameters were 1 mA for 15 min, with different frequencies (2, 50, and 100 Hz) applied. After a three day treatment, neuronal activation was detected by the expression of c-Fos. A multi-channel electrophysiological technique was used to assess the discharge of contralateral neurons and the neuron types in each group. The concentration of brain-derived neurotrophic factor (BDNF) in the contralateral neurons was also examined. In addition, the dysfunction of swallowing in mice was calculated according to the lick counts and the lick–lick interval within a certain period of time. The number of c-Fos neurons (P < 0.05) and the expression of BDNF (P < 0.05) increased after the 2 Hz EA treatment. The total frequency of neuron discharge in the 2 Hz group increased compared with the model group (P < 0.05). The pattern of sorted neuron populations was similar between the normal and 2 Hz groups. Consistent with these results, the lick counts increased (P < 0.05) and the lick–lick interval decreased after the 2 Hz EA treatment, which indicated a functional improvement in swallowing. These results indicated that the 2 Hz EA treatment had a good effect on dysphagia after stroke.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    3′UTRs Regulate Mouse Ntrk2 mRNA Distribution in Cortical Neurons

    Abstract

    There are two major isoforms of NTRK2 (neurotrophic receptor tyrosine kinase 2, or TrkB), full-length isoform with tyrosine kinase (TK) domain intact (+) and spliced isoform without tyrosine kinase domain (TK(−)). Within each isoform, there exist subtypes with minor modifications of the protein sequences. In human, the NTRK2 mRNA transcripts encoding TK(+) have same 3′UTRs, while the transcripts encoding subtypes of NTRK2 TK(−) have two completely different 3′UTRs. In mouse, the mRNA transcripts encoding same NTRK2 protein sequence for either TK(+) or TK(−) have long or short 3′UTRs, respectively. The physiological functions of these different 3′UTRs are still unknown. Pilocarpine stimulation increased Ntrk2 mRNA levels in soma, while the increase in synaptosome was smaller. FISH results further showed that mouse Ntrk2 transcripts with different 3′UTRs were distributed differently in cultured cortical neurons. The transcripts with long 3′UTR were distributed more in apical dendrites compared with transcripts with short 3′UTR. Our results provide evidence of non-coding 3′UTR function in regulating mRNA distribution in neurons.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Association of ADH7 Gene Polymorphism with Schizophrenia in the Han Population of Northern China: a Case-Control Study

    Abstract

    Schizophrenia is a serious neurodevelopmental disorder. Genetics is an important factor leading to schizophrenia, but its exact role is still unclear. Many studies have focused on neurotransmitters and regulators that participate in the processes mediated by these neurotransmitters. Alcohol dehydrogenase may not only catalyze the oxidation of retinol and ethanol but also be involved in a variety of neurotransmitter metabolic pathways. Therefore, our study investigated whether ADH7 gene variations in the Chinese Han population were associated with schizophrenia. Genomic DNA was extracted from a cohort of 275 schizophrenic patients (136 men and 139 women) and 313 healthy controls (160 men and 153 women) from the Northern Han Chinese population. The Hardy-Weinberg equilibrium test and linkage disequilibrium analysis were performed. Differences in genotypes, alleles, and haplotypes between the schizophrenic and control groups were determined using the chi-square test and correlation analysis. The distribution of the CC + TT genotype of rs284787 was statistically different between the case and control groups (p = 0.026, OR = 1.448); however, the difference disappeared after Bonferroni correction. Linkage analysis indicated that rs739147, rs284787, rs3805329, rs894369, rs3805331, and rs284786 were closely linked in one block. The haplotype analysis found no association between the composed haplotypes and the occurrence of schizophrenia. Our study showed that the ADH7 gene was not associated with the risk of schizophrenia. Additional studies with larger cohorts of different ethnicities are needed to validate our findings.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Direct Conjugation of Retinoic Acid with Gold Nanoparticles to Improve Neural Differentiation of Human Adipose Stem Cells

    Abstract

    Gold nanoparticles (AuNPs) have been proposed as useful medical carriers in the field of regenerative medicine. This study aimed to assess the direct conjugation ability of retinoic acid (RA) with AuNPs and to develop a strategy to differentiate the human adipose-derived stromal/stem cells (hADSCs) into neurons using AuNPs-RA. The physical properties of this nanocarrier were characterized using FT-IR, TEM, and FE-SEM. Moreover, the efficiency of RA conjugation on AuNPs was determined at 99% using UV-Vis spectroscopy. According to the MTT assay, an RA concentration of 66 μM caused a 50% inhibition of cell viability and AuNPs were not cytotoxic in concentrations below 5 μg/ml. Real-time PCR and immunocytochemistry proved that AuNPs-RA is able to increase the expression of neuronal marker genes and the number of neuronal protein (GFAP and MAP2)-positive cells, 14 days post-induction of hADSCs. Taken together, these results confirmed that the AuNPs-RA promote the neuronal differentiation of hADSCs.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Is Fertility Affected in Women of Childbearing Age with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder?

    Abstract

    Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS), which is more prevalent among women of childbearing age. Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease of the CNS with similar prevalence features to MS and has recently been considered a different entity from MS. Measuring ovarian reserve is one way of evaluating fertility. Anti-Müllerian hormone (AMH) is a peptide hormone produced by ovarian granulosa cells of early follicles and is considered to be a marker for ovarian reserve. With MS and NMOSD predominance in young women, the present study aimed to address the possibility of these diseases affecting fertility by measuring AMH levels in MS and NMOSD patients and comparing it with healthy controls. The present study included 23 relapsing-remitting MS (RRMS) patients, 23 seronegative NMOSD patients, and 23 healthy age-matched controls between 18 and 45 years of age. Serum samples of the three groups were collected, and the AMH levels were measured with AMH Gen II Enzyme-Linked Immunosorbent Assay, Beckman Coulter kit. In the present study, the AMH levels did not differ significantly between the groups (p = 0.996). The mean AMH in the RRMS group was 3.59 ± 0.55 ng/ml compared with the mean of 3.60 ± 0.50 ng/ml in healthy controls. The mean AMH levels in the NMOSD group were 3.66 ± 0.61 ng/ml. Lower levels of AMH were found to be negatively associated with annualized relapse rate (in both groups of patients) and MS severity score. However, the difference was not significant. In NMOSD patients, the serum levels of AMH were negatively associated with disease duration (r = − 0.42, p = 0.023). There had been a significant negative correlation between mean AMH serum levels with Expanded Disability Status Scale (EDSS) at the time of diagnosis and at the time of study in the NMOSD group (r = − 0.402, p = 0.03 and r = − 0.457, p = 0.014, respectively). There was not a significant difference in mean serum AMH levels between RRMS and NMOSD patients compared with that of healthy controls. Further studies with larger sample sizes should be conducted, which take more variables affecting fertility in women with either RRMS or NMOSD into account to put an end to the controversial issue of fertility in this area.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Plasma Erythropoietin, IL-17A, and IFNγ as Potential Biomarkers of Motor Function Recovery in a Canine Model of Spinal Cord Injury

    Abstract

    Traumatic spinal cord injury (SCI) is a devastating neurological disease for which an accurate, cost-effective prediction of motor function recovery is in pressing need. A plethora of neurochemical changes involved in the pathophysiological process of SCI may serve as a new source of biomarkers for patient outcomes. Five dogs were included in this study. We characterized the plasma cytokine profiles in acute phase (0, 1, and 3 days after SCI) and subacute phase (7, 14, and 21 days after SCI) with microarray analysis. The motor function recovery following SCI was monitored by Olby scores. The expression level of differentially expressed proteins (DEPs) was measured with enzyme-linked immunosorbent assay (ELISA). Then, correlations with the Olby scores and receiver operating characteristic curve (ROC) analysis were performed. We identified 12 DEPs including 10 pro-inflammatory and 2 anti-inflammatory cytokines during the 21-day study period. Among those, the expression levels of erythropoietin (EPO), IL-17A, and IFNγ significantly correlated with the Olby scores with R2 values of 0.870, 0.740, and 0.616, respectively. The results of the ROC analysis suggested that plasma EPO, IL-17A, and IFNγ exhibited a significant predictive power with an area under the curve (AUC) of 0.656, 0.848, and 0.800 for EPO, IL-17A, and IFNγ, respectively. Our results provide a longitudinal description of the changes in plasma cytokine expression in the acute and subacute stages of canine SCI. These data reveal novel panels of inflammation-related cytokines which have the potential to be evaluated as biomarkers for predicting motor function prognosis after SCI.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Channels that Cooperate with TRPV4 in the Brain

    Abstract

    Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+-permeable cation channel that is a member of the TRP channel family. It is clear that TRPV4 channels are broadly expressed in the brain. As they are expressed on the plasma membrane, they interact with other channels and play a crucial role in nervous system activity. Under some pathological conditions, TRPV4 channels are upregulated and sensitized via cellular signaling pathways, and this can cause nervous system diseases. In this review, we focus on receptors that cooperate with TRPV4, including large-conductance Ca2+-activated K+(BKca) channels, N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs), inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), aquaporin 4 (AQP4), and other potential cooperative receptors in the brain. The data demonstrate how these channels work together to cause nervous system diseases under pathological conditions. The aim of this review was to discuss the receptors and signaling pathways related to TRPV4 based on recent data on the important physiological functions of TRPV4 channels to provide new clues for future studies and prospective therapeutic targets for related brain diseases.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Quantitative Assessment of Hippocampal Tau Pathology in AD and PART

    Abstract

    To quantitatively assess the distribution pattern of hippocampal tau pathology in Alzheimer’s disease (AD) and primary age-related tauopathy (PART), we investigated the distribution of phosphorylated tau protein (AT8) in 6 anatomically defined subregions of the hippocampal formation and developed a mathematical algorithm to compare the patterns of tau deposition in PART and AD. We demonstrated regional patterns of selective vulnerability as distinguishing features of PART and AD in functionally relevant structures of the hippocampus. In AD cases, tau pathology was high in both CA1 and subiculum, followed by CA2/3, entorhinal cortex (EC), CA4, and dentate gyrus (DG). In PART, the severity of tau pathology in CA1 and subiculum was high, followed by EC, CA2/3, CA4, and DG. There are significant differences between sector DG and CA1, DG and subiculum in both AD and PART.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Effect of Methylene Blue and PI3K-Akt Pathway Inhibitors on the Neurovascular System after Chronic Cerebral Hypoperfusion in Rats

    Abstract

    Methylene blue (MB) has a protective effect on cognitive decline caused by chronic hypoperfusion, but the specific mechanism is not clear. This article aims to determine whether MB protects vascular neurons through PI3K/Akt and plays a role in improving cognitive impairment. Molecular biological methods, the hippocampal neuronal density test, the hippocampal vascular network density test, and dynamic enhanced magnetic resonance imaging (MRI) were used to detect the blood–brain barrier permeability and Evans blue leakage rate in the hippocampus. We also observed and evaluated the changes in the above results after administration of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway protein inhibitor LY294002. There were significant differences for cerebral blood flow (CBF) between the chronic cerebral hypoperfusion (CCH) + MB group (100 ml/100 g/min) and the CCH group (60 ml/100 g/min, P < 0.05). After using LY294002, the CBF of the CCH + MB + LY294002 group dropped to 82 ml/100 g/min. The vascular density in the CCH + MB group was 23%, which is significantly higher than that in the CCH group (15.1%) (P < 0.05). The vascular density (17.5%) in the CCH + MB + LY294002 group was significantly higher than that in the CCH group but lower than that in the CCH + MB group. Western blotting results showed that one week after intraperitoneal injection of MB, the expression of t-Akt and p-Akt in the CCH + MB group was increased after CCH, and LY294002 partially blocked this up-regulation effect (CCH + MB + LY294002 group). MB is a potential therapy for the relief of mild cognitive impairment associated with CCH, vascular dementia, and Alzheimer’s disease.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    A Systematic and Comprehensive Review on Disease-Causing Genes in Amyotrophic Lateral Sclerosis

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and is characterized by degeneration and axon loss from the upper motor neuron, that descends from the lower motor neuron in the brain. Over the period, assorted outcomes from medical findings, molecular pathogenesis, and structural and biophysical studies have abetted in providing thoughtful insights underlying the importance of disease-causing genes in ALS. Consequently, numerous mechanisms were proposed for the pathogenesis of ALS, considering protein mutations, aggregation, and misfolding. Besides, the answers to the majority of ALS cases that happen to be sporadic still remain obscure. The application in discovering susceptibility factors in ALS contemplating the genetic factors is to be further dissevered in the future years with innovation in research studies. Hence, this review targets in revisiting the breakthroughs on the disease-causing genes related with ALS.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Induction of SPARC on Oxidative Stress, Inflammatory Phenotype Transformation, and Apoptosis of Human Brain Smooth Muscle Cells Via TGF-β1-NOX4 Pathway

    Abstract

    Secreted protein acidic and rich in cysteine (SPARC) has a close association with inflammatory response and oxidative stress in tissues and is widely expressed in intracranial aneurysms (IAs), especially in smooth muscle cells. Therefore, it is inferred that SPARC might be involved in the formation and development of IAs through the inflammatory response pathway or oxidative stress pathway. The aim of this study is to investigate the pathological mechanism of SPARC in oxidative stress, inflammation, and apoptosis during the formation of IAs, as well as the involvement of TGF-β1 and NOX4 molecules. Human brain vascular smooth muscle cells (HBVSMCs) were selected as experimental objects. After the cells were stimulated by recombinant human SPARC protein in vitro, the ROS level in the cells was measured using an ID/ROS fluorescence analysis kit combined with fluorescence microscope and flow cytometry. The related protein expression in HBVSMCs was measured using western blotting. The mitochondrial membrane potential change was detected using a mitochondrial membrane potential kit and laser confocal microscope. The mechanism was explored by intervention with reactive oxygen scavengers N-acetylcysteine (NAC), TGF-β1 inhibitor (SD-208), and siRNA knockout. The results showed that SPARC upregulated the expression of NOX4 through the TGF-β1-dependent signaling pathway, leading to oxidative stress and pro-inflammatory matrix behavior and apoptosis in HBVSMCs. These findings demonstrated that SPARC may promote the progression of IAs.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Inhibition of IL-32 Expression Ameliorates Cerebral Ischemia-Reperfusion Injury via the NOD/MAPK/NF-κB Signaling Pathway

    Abstract

    Cerebral ischemia represents a major cause of disability, yet its precise mechanism remains unknown. In addition, ischemia-reperfusion injury which occurs during the blood recovery process increases the risk of mortality, and is not adequately addressed with current treatment. To improve therapeutic options, it is important to explore the vital substances that play a pivotal role in ischemia-reperfusion injury. This study is the first to investigate the role of IL-32, a vital pro-inflammatory factor, in models of cerebral ischemia-reperfusion injury. The results showed that IL-32 was highly expressed in both in vivo and in vitro models. The proteins of the NOD/MAPK/NF-κB pathway were also up-regulated, indicating a potential signaling pathway mechanism. Inhibition of IL-32 and blocking of the NOD/MAPK/NF-κB pathway increased cell survival, decreased the level of inflammatory factors and inflammasomes, and attenuated nitrosative stress. Taken together, the results show that inhibition of IL-32 expression ameliorates cerebral ischemia-reperfusion injury via the NOD/MAPK/NF-κB signaling pathway. The findings in this study reveal that IL-32 is a vital target of ischemia-reperfusion injury, providing a new avenue for treatment development.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Identification of Core Genes and Pathways in Medulloblastoma by Integrated Bioinformatics Analysis

    Abstract

    Medulloblastoma (MB) is one of the most common intracranial malignancies in children. The present study applied integrated bioinformatics to identify potential core genes associated with the pathogenesis of MB and reveal potential molecular mechanisms. Through the integrated analysis of multiple data sets from the Gene Expression Omnibus (GEO), 414 differentially expressed genes (DEGs) were identified. Combining the protein–protein interaction (PPI) network analysis with gene set enrichment analysis (GSEA), eight core genes, including CCNA2, CCNB1, CCNB2, AURKA, CDK1, MAD2L1, BUB1B, and RRM2, as well as four core pathways, including “cell cycle”, “oocyte meiosis”, “p53 pathway” and “DNA replication” were selected. In independent data sets, the core genes showed superior diagnostic values and significant prognostic correlations. Moreover, in the pan-caner data of the cancer genome atlas (TCGA), the core genes were also widely abnormally expressed. In conclusion, this study identified core genes and pathways of MB through integrated analysis to deepen the understanding of the molecular mechanisms underlying the MB and provide potential targets and pathways for diagnosis and treatment of MB.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Neuronal Plasticity: Neuronal Organization is Associated with Neurological Disorders

    Abstract

    Stimuli from stressful events, attention in the classroom, and many other experiences affect the functionality of the brain by changing the structure or reorganizing the connections between neurons and their communication. Modification of the synaptic transmission is a vital mechanism for generating neural activity via internal or external stimuli. Neuronal plasticity is an important driving force in neuroscience research, as it is the basic process underlying learning and memory and is involved in many other functions including brain development and homeostasis, sensorial training, and recovery from brain injury. Indeed, neuronal plasticity has been explored in numerous studies, but it is still not clear how neuronal plasticity affects the physiology and morphology of the brain. Thus, unraveling the molecular mechanisms of neuronal plasticity is essential for understanding the operation of brain functions. In this timeline review, we discuss the molecular mechanisms underlying different forms of synaptic plasticity and their association with neurodegenerative/neurological disorders as a consequence of alterations in neuronal plasticity.

    in Journal of Molecular Neuroscience on November 01, 2020 12:00 AM.

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    Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine

    Abstract

    Neurogenic inflammation including calcitonin gene-related peptide (CGRP) and substance-P (SP) release plays a pivotal role in migraine pathogenesis. Prevalence of migraine is ~ 3 folds higher in women than in men, but its underlying mechanisms remained unclear. We investigated the effects of female sex hormones estrogen and progesterone on CGRP and SP in in-vivo and ex-vivo in rats of both sexes. For in-vivo experiments, male, female and ovariectomized rats were separated into four groups (n = 7) as control, estrogen, progesterone and estrogen + progesterone, respectively. Groups received daily intraperitoneal vehicle, 17β-estradiol, progesterone and 17β-estradiol + progesterone for 5 days, respectively. For ex-vivo experiments in both sexes, isolated trigeminal ganglia and hemiskull preparations were divided into four groups (n = 6 or 8), respectively, as in-vivo groups, and administered the same test substances. CGRP and SP contents in plasma and superfusates were determined using ELISA. In in-vivo experiments, 17β-estradiol decreased CGRP levels in males and SP levels in ovariectomized rats. Progesterone increased both CGRP and SP levels in females. Their combination decreased both CGRP and SP levels in males, and only SP levels in ovariectomized rats. In ex-vivo experiments, 17β-estradiol reduced CGRP release in males and SP release in females in trigeminal ganglia. While progesterone increased CGRP release in trigeminal ganglia, it reduced SP release from hemiskulls in both sexes. Their combination restored progesterone-mediated changes in neuropeptides releases in both trigeminal ganglia and hemiskulls in both sexes. Estrogen alleviates neurogenic inflammation through modulation of CGRP and SP release. Progesterone has dual effects on these neuropeptides in different sites associated with migraine pain.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Local syntactic violations evoke fast mismatch-related neural activity detected by optical neuroimaging

    Abstract

    It remains to be investigated whether syntax-related mismatch activity would be evoked in event-related optical signals by syntactic violations that deviate from our language knowledge and expectations. In the current study, we have employed fast optical neuroimaging with a frequency-domain oximeter to examine whether syntactic violations of English bare infinitives in the non-finite complement clause would trigger syntax-related mismatch effects. Recorded sentences of bare or full infinitive structures (without or with the ‘to’ infinitival marker) with syntactically correct or incorrect versions and non-syntactic lexical items (verbs) were presented to native speakers of English (n = 8) during silent movie viewing as a passive oddball task. The analysis of source strength (i.e., minimum norm current amplitudes) revealed that the syntactic category violations of bare object infinitives led to significantly more robust optical mismatch effects than the other syntactic violation and non-structural, lexical elements. This mismatch response had a peak latency of 186 ms in the left anterior superior temporal gyrus. In combination with our prior MEG report (Kubota et al. in Neurosci Lett 662:195–204, 2018), the present optical neuroimaging findings show that syntactic marking (unmarked-to-marked) violations of the bare object infinitive against the rule of the mental grammar enhance the signal strength exactly in the same manner seen with MEG scanning, including the peak latency of mismatch activity and the activated area of the brain.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Functional brain asymmetry for emotions: psychological stress-induced reversed hemispheric asymmetry in emotional face perception

    Abstract

    Empirical evidence has demonstrated functional (mostly right-biased) brain asymmetry for emotion perception, whereas recent studies indicate that acute stress may modulate left and/or right hemisphere activation. However, it is still unknown whether emotion perception can be influenced by stress-induced hemispheric activation since behavioral studies report inconsistent or even contradictory results. We sought to reevaluate this gap. Eighty-eight healthy Caucasian university students participated in the study. In half of the randomly selected participants, acute psychological stress was induced by displaying a brief stressful movie clip (the stress condition), whereas the other half were shown a neutral movie clip (the non-stress condition). Prior to (the baseline) and following the movie clip display an emotion perception task was applied by presenting an emotional (happy, surprised, fearful, sad, angry, or disgusted) or neutral face to the left or right visual field. We found a more accurate perception of emotional and neutral faces presented to the LVF (the right hemisphere) in the baseline. However, we revealed that after watching a neutral movie clip, behavioral performance in emotional and neutral face perception accuracy became relatively equalized for both visual fields, whereas after watching a stressful movie clip, the RVF (the left hemisphere) even became dominant in emotional face perception. We propose a novel hemispheric functional-equivalence model: the brain is initially right-biased in emotional and neutral face perception by default; however, psychophysiological activation of a distributed brain-network due to watching neutral movie clips redistributes hemispheric performance toward relative equivalence. Moreover, even reversed hemispheric asymmetry may occur.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Functional specialization in human dorsal pathway for stereoscopic depth processing

    Abstract

    Binocular disparity, a primary cue for stereoscopic depth perception, is widely represented in visual cortex. However, the functional specialization in the disparity processing network remains unclear. Using magnetic resonance imaging-guided transcranial magnetic stimulation, we studied the causal contributions of V3A and MT+ to stereoscopic depth perception. Subjects viewed random-dot stereograms forming transparent planes with various interplane disparities. Their smallest detectable disparity and largest detectable disparity were measured in two experiments. We found that the smallest detectable disparity was affected by V3A, but not MT+ , stimulation. On the other hand, the largest detectable disparity was affected by both V3A and MT+ stimulation. Our results suggest different roles of V3A and MT+ in stereoscopic depth processing.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice

    Abstract

    Neuronal dysfunction and loss are thought to be one of the causes of cognitive impairment in Alzheimer's disease (AD), but the specific mechanism of neuronal loss in the pathogenesis of AD remains controversial. This study explored the role of NLRP3 inflammasome-induced neuronal pyroptosis in neuronal loss of AD, and pioneered the use of NLRP3 inhibitor MCC950 to intervene in the treatment of senescence-accelerated mouse prone 8 (SAMP8) mice. In vitro, human primary neurons (HPNs) pretreated with MCC950 were stimulated with amyloid-β1–42 (Aβ1–42), and it was found that MCC950 significantly reduced the neurotoxicity of Aβ1–42 by inhibiting neuronal pyroptosis. In vivo, SAMP8 mice were randomly divided into vehicle-treated group and MCC950-treated group, and it was found that MCC950 also played a positive role in treatment. The intervention of MCC950 improved the spatial memory ability and brain histological morphology of SAMP8 mice, and reduced the deposition of amyloid-β in the brain. Furthermore, MCC950 was found to inhibit the overexpressions of NLRP3, caspase-1, and GSDMD, which were the response factors of pyroptosis in SAMP8 mouse neurons, by immunofluorescence staining. In this study, we found that neuronal pyroptosis induced by the NLRP3/caspase-1/GSDMD axis was an important factor in neuronal loss of AD, and revealed that MCC950 might be a potential AD therapeutic agent.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Pupil diameter as a biomarker of effort in goal-directed gait

    Abstract

    Subjects’ eye movement behavior related to cognitive effort during gait was measured as subjects walked to perform low and high cognitive load tasks. We found that all pupil diameter measures, fixation durations, and the proportion of blink duration changed significantly during gait as a function of task load. In contrast, the number of fixations, saccade durations and travel time did not change significantly as a function of task load. Findings showed that pupil diameter was the best predictor of task load during one’s gait preceding the performance of the task. While other studies have demonstrated the importance of eye fixation characteristics during gait, our findings showed that eye measures related to pupil diameter were better at detecting cognitive load while walking to perform a task compared to eye fixation data. We also found that cognitive effort was not limited to just the performance of the task, but that it was also exerted during one’s gait preceding the performance of the task. Therefore, the additional attention demand caused by an increase in task complexity may result in less attentional resources being available to adequately handle distractions (such as obstacle avoidance) while walking to perform the task. Consequently, this may increase the likelihood of falls in those individuals with lower attentional capacity.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Obesity-related alterations in anticipatory postural mechanisms associated with gait initiation

    Abstract

    Obesity is known to have a detrimental effect on balance and motor performance during daily motor tasks. However, it remains unclear whether these obesity-related impairments are due to deficient anticipatory postural adjustments (APA) that precede voluntary movement. The objective of this study was to examine the effects of obesity on APA and the impacts related on motor performance and mediolateral postural stability during gait initiation. Fifteen obese and ten normal-weight young participants performed a series of gait initiation at their preferred speed. Our results showed that the durations and amplitudes of APA along both anteroposterior and mediolateral directions did not differ between the two groups (P > 0.05). In contrast, compared to normal-weight participants, mechanical effectiveness of APA was reduced in obese participants (P < 0.05). As a result, we observed a decreased motor performance (P < 0.05), in terms of peak anteroposterior center-of-mass velocity at the end of the first step, and a reduced mediolateral stability at swing foot contact in obese participants compared to normal-weight participants (P < 0.05). These findings suggest that APA effectiveness during gait initiation is reduced in obese adults, resulting in a decrease of both mediolateral stability and motor performance compared to their lean counterparts.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Mesenchymal stem cells with modafinil (gold nanoparticles) significantly improves neurological deficits in rats after middle cerebral artery occlusion

    Abstract

    Systemic treatments for ischemic stroke as a disease with high disability and death have been yet unsuccessful. Combined treatments can potentially cause better results in treatment of patients with Stroke. In this study we assessed the neuroprotective effect of modafinil-coated gold nanoparticles (AuNPs) and mesenchymal stem cell (MSC) in ischemic stroke rats. Stem cells and AuNPs offer great promise for new medical treatments. 60 male Wistar rats were randomly divided into five groups (12 in each group): (1) the group that developed middle cerebral artery occlusion (MCAO or ischemia), (2) the normal group (control), (3) the MCAO group that received MSC (C + MCAO), (4) the MCAO group that received MSC and modafinil (CM + MCAO), and (5) the MCAO group that received MSC and modafinil-coated AuNPs (CMN + MCAO). Middle Cerebral Artery Occlusion (MCAO) was performed by inserting a silicone coat filament in the right internal carotid artery via the external carotid artery until it reached the anterior cerebral artery. The filament was located in the internal carotid artery for 60 min and then removed. Modafinil-coated AuNPs (100 mg/kg) or Modafinil (100 mg/kg) were given to the rats as an oral gavage, once a day in the morning time. Finally, infarct volume, BDNF (Brain-derived neurotrophic factor), GDNF (Glial cell-derived neurotrophic factor), NeuN (neuronal nuclear protein) expression, and cell apoptosis in brain were analyzed. The brain infarct volume and apoptosis significantly decreased and BDNF, NeuN, and GDNF increased in C + MCAO, CM + MCAO, and CMN + MCAO groups compared to ischemia. CMN + MCAO groups did not show significant difference in these factors compared to control group. These results demonstrated that the administration of stem cells and Modafinil-coated AuNPs at the same time had a good effect on ischemic brain injuries. It happened through increasing neurotrophic factors and decreasing brain cell apoptosis.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB-NLRP3 inflammation activation

    Abstract

    Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Metformin has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. We used a chronic mild stress model of depression and cultured primary macrophage to investigate the effects of metformin on depression and its underlying mechanisms. We demonstrated that metformin alleviated depressive-like behaviors in the chronic mild stress-induced anhedonia model of depression. We further found that metformin significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central hippocampus. Our findings reveal that metformin confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation. In light of metformin favorable properties, it should be evaluated in the treatment of depression and related neurologic disorders characterized by NLRP3 inflammasome activation.

    in Experimental Brain Research on November 01, 2020 12:00 AM.

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    Modeling psychological measurements with quantum instruments: Combination of question order effect, response replicability effect, and QQ-equality. (arXiv:2010.10444v1 [q-bio.NC])

    We continue to analyze matching of some basic constraints on human's decision making with quantum theory of measurement. As was found, quantum measurement theory based on the projection postulate does not match with combination of the question order effect (QOE) and the response replicability effect (RRE). This was the alarm signal for quantum-like modeling of decision making. Recently, it was shown that this objection to quantum-like modeling can be removed on the basis of the general measurement theory based on quantum instruments. In the present paper, the problem of combination QOE, RRE with the famous QQ-equality is analyzed. This equality was derived by Busemeyer and Wang and it was shown (in the joint paper with Solloway and Shiffrin) that statistical data from many social opinion polls satisfies it. Now, we construct quantum instruments satisfying QQE, RRE, and QQ-inequality. Moreover, we show that this model reproduces the statistics of the famous Clinton-Gore Poll data almost faithfully with a prior belief state independent of the question order. This model successfully removes the order effect from the data to determine the genuine distribution of the opinion to the Poll. Independently of modeling of the concrete psychological effects, the paper provides psychologist-friendly presentation of the theory of quantum instruments - the most general mathematical framework for quantum measurements. We hope that this theory will attract attention of psychologists and generate further psychological applications.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 21, 2020 01:30 AM.

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    Performance of Dual-Augmented Lagrangian Method and Common Spatial Patterns applied in classification of Motor-Imagery BCI. (arXiv:2010.10359v1 [eess.SP])

    Motor-imagery based brain-computer interfaces (MI-BCI) have the potential to become ground-breaking technologies for neurorehabilitation, the reestablishment of non-muscular communication and commands for patients suffering from neuronal disorders and disabilities, but also outside of clinical practice, for video game control and other entertainment purposes. However, due to the noisy nature of the used EEG signal, reliable BCI systems require specialized procedures for features optimization and extraction. This paper compares the two approaches, the Common Spatial Patterns with Linear Discriminant Analysis classifier (CSP-LDA), widely used in BCI for extracting features in Motor Imagery (MI) tasks, and the Dual-Augmented Lagrangian (DAL) framework with three different regularization methods: group sparsity with row groups (DAL-GLR), dual-spectrum (DAL-DS) and l1-norm regularization (DAL-L1). The test has been performed on 7 healthy subjects performing 5 BCI-MI sessions each. The preliminary results show that DAL-GLR method outperforms standard CSP-LDA, presenting 6.9% lower misclassification error (p-value = 0.008) and demonstrate the advantage of DAL framework for MI-BCI.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    Online adaptive group-wise sparse NPLS for ECoG neural signal decoding. (arXiv:2010.10353v1 [eess.SP])

    Objective. Brain-computer interfaces (BCIs) create a new communication pathway between the brain and an effector without neuromuscular activation. BCI experiments highlighted high intra and inter-subjects variability in the BCI decoders. Although BCI model is generally relying on neurological markers generalizable on the majority of subjects, it requires to generate a wide range of neural features to include possible neurophysiological patterns. However, the processing of noisy and high dimensional features, such as brain signals, brings several challenges to overcome such as model calibration issues, model generalization and interpretation problems and hardware related obstacles. Approach. An online adaptive group-wise sparse decoder named Lp-Penalized REW-NPLS algorithm (PREW-NPLS) is presented to reduce the feature space dimension employed for BCI decoding. The proposed decoder was designed to create BCI systems with low computational cost suited for portable applications and tested during offline pseudo-online study based on online closed-loop BCI control of the left and right 3D arm movements of a virtual avatar from the ECoG recordings of a tetraplegic patient.

    Main results. PREW-NPLS algorithm highlight at least as good decoding performance as REW-NPLS algorithm. However, the decoding performance obtained with PREW-NPLS were achieved thanks to sparse models with up to 64% and 75% of the electrodes set to 0 for the left and right hand models respectively using L1-PREW-NPLS.

    Significance. The designed solution proposed an online incremental adaptive algorithm suitable for online adaptive decoder calibration which estimate sparse decoding solutions. The PREW-NPLS models are suited for portable applications with low computational power using only small number of electrodes with degrading the decoding performance.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 21, 2020 01:30 AM.

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    Sparse Gaussian Process Variational Autoencoders. (arXiv:2010.10177v1 [stat.ML])

    Large, multi-dimensional spatio-temporal datasets are omnipresent in modern science and engineering. An effective framework for handling such data are Gaussian process deep generative models (GP-DGMs), which employ GP priors over the latent variables of DGMs. Existing approaches for performing inference in GP-DGMs do not support sparse GP approximations based on inducing points, which are essential for the computational efficiency of GPs, nor do they handle missing data -- a natural occurrence in many spatio-temporal datasets -- in a principled manner. We address these shortcomings with the development of the sparse Gaussian process variational autoencoder (SGP-VAE), characterised by the use of partial inference networks for parameterising sparse GP approximations. Leveraging the benefits of amortised variational inference, the SGP-VAE enables inference in multi-output sparse GPs on previously unobserved data with no additional training. The SGP-VAE is evaluated in a variety of experiments where it outperforms alternative approaches including multi-output GPs and structured VAEs.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    Overlapping neural representations for the position of visible and imagined objects. (arXiv:2010.09932v1 [q-bio.NC])

    Humans can covertly track the position of an object, even if the object is temporarily occluded. What are the neural mechanisms underlying our capacity to track moving objects when there is no physical stimulus for the brain to track? One possibility is that the brain 'fills-in' information about imagined objects using internally generated representations similar to those generated by feed-forward perceptual mechanisms. Alternatively, the brain might deploy a higher order mechanism, for example using an object tracking model that integrates visual signals and motion dynamics. In the present study, we used EEG and time-resolved multivariate pattern analyses to investigate the spatial processing of visible and imagined objects. Participants tracked an object that moved in discrete steps around fixation, occupying six consecutive locations. They were asked to imagine that the object continued on the same trajectory after it disappeared and move their attention to the corresponding positions. Time-resolved decoding of EEG data revealed that the location of the visible stimuli could be decoded shortly after image onset, consistent with early retinotopic visual processes. For processing of unseen/imagined positions, the patterns of neural activity resembled stimulus-driven mid-level visual processes, but were detected earlier than perceptual mechanisms, implicating an anticipatory and more variable tracking mechanism. Encoding models revealed that spatial representations were much weaker for imagined than visible stimuli. Monitoring the position of imagined objects thus utilises similar perceptual and attentional processes as monitoring objects that are actually present, but with different temporal dynamics. These results indicate that internally generated representations rely on top-down processes, and their timing is influenced by the predictability of the stimulus.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 21, 2020 01:30 AM.

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    Smooth activations and reproducibility in deep networks. (arXiv:2010.09931v1 [cs.LG])

    Deep networks are gradually penetrating almost every domain in our lives due to their amazing success. However, with substantive performance accuracy improvements comes the price of \emph{irreproducibility}. Two identical models, trained on the exact same training dataset may exhibit large differences in predictions on individual examples even when average accuracy is similar, especially when trained on highly distributed parallel systems. The popular Rectified Linear Unit (ReLU) activation has been key to recent success of deep networks. We demonstrate, however, that ReLU is also a catalyzer to irreproducibility in deep networks. We show that not only can activations smoother than ReLU provide better accuracy, but they can also provide better accuracy-reproducibility tradeoffs. We propose a new family of activations; Smooth ReLU (\emph{SmeLU}), designed to give such better tradeoffs, while also keeping the mathematical expression simple, and thus training speed fast and implementation cheap. SmeLU is monotonic, mimics ReLU, while providing continuous gradients, yielding better reproducibility. We generalize SmeLU to give even more flexibility and then demonstrate that SmeLU and its generalized form are special cases of a more general methodology of REctified Smooth Continuous Unit (RESCU) activations. Empirical results demonstrate the superior accuracy-reproducibility tradeoffs with smooth activations, SmeLU in particular.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    Anti-Distillation: Improving reproducibility of deep networks. (arXiv:2010.09923v1 [cs.LG])

    Deep networks have been revolutionary in improving performance of machine learning and artificial intelligence systems. Their high prediction accuracy, however, comes at a price of \emph{model irreproducibility\/} in very high levels that do not occur with classical linear models. Two models, even if they are supposedly identical, with identical architecture and identical trained parameter sets, and that are trained on the same set of training examples, while possibly providing identical average prediction accuracies, may predict very differently on individual, previously unseen, examples. \emph{Prediction differences\/} may be as large as the order of magnitude of the predictions themselves. Ensembles have been shown to somewhat mitigate this behavior, but without an extra push, may not be utilizing their full potential. In this work, a novel approach, \emph{Anti-Distillation\/}, is proposed to address irreproducibility in deep networks, where ensemble models are used to generate predictions. Anti-Distillation forces ensemble components away from one another by techniques like de-correlating their outputs over mini-batches of examples, forcing them to become even more different and more diverse. Doing so enhances the benefit of ensembles, making the final predictions more reproducible. Empirical results demonstrate substantial prediction difference reductions achieved by Anti-Distillation on benchmark and real datasets.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    Environmental Adaptation of Robot Morphology and Control through Real-world Evolution. (arXiv:2003.13254v2 [cs.RO] UPDATED)

    Robots operating in the real world will experience a range of different environments and tasks. It is essential for the robot to have the ability to adapt to its surroundings to work efficiently in changing conditions. Evolutionary robotics aims to solve this by optimizing both the control and body (morphology) of a robot, allowing adaptation to internal, as well as external factors. Most work in this field has been done in physics simulators, which are relatively simple and not able to replicate the richness of interactions found in the real world. Solutions that rely on the complex interplay between control, body, and environment are therefore rarely found. In this paper, we rely solely on real-world evaluations and apply evolutionary search to yield combinations of morphology and control for our mechanically self-reconfiguring quadruped robot. We evolve solutions on two distinct physical surfaces and analyze the results in terms of both control and morphology. We then transition to two previously unseen surfaces to demonstrate the generality of our method. We find that the evolutionary search finds high-performing and diverse morphology-controller configurations by adapting both control and body to the different properties of the physical environments. We additionally find that morphology and control vary with statistical significance between the environments. Moreover, we observe that our method allows for morphology and control parameters to transfer to previously-unseen terrains, demonstrating the generality of our approach.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    A Neural Approach to Ordinal Regression for the Preventive Assessment of Developmental Dyslexia. (arXiv:2002.02184v2 [cs.LG] UPDATED)

    Developmental Dyslexia (DD) is a learning disability related to the acquisition of reading skills that affects about 5% of the population. DD can have an enormous impact on the intellectual and personal development of affected children, so early detection is key to implementing preventive strategies for teaching language. Research has shown that there may be biological underpinnings to DD that affect phoneme processing, and hence these symptoms may be identifiable before reading ability is acquired, allowing for early intervention. In this paper we propose a new methodology to assess the risk of DD before students learn to read. For this purpose, we propose a mixed neural model that calculates risk levels of dyslexia from tests that can be completed at the age of 5 years. Our method first trains an auto-encoder, and then combines the trained encoder with an optimized ordinal regression neural network devised to ensure consistency of predictions. Our experiments show that the system is able to detect unaffected subjects two years before it can assess the risk of DD based mainly on phonological processing, giving a specificity of 0.969 and a correct rate of more than 0.92. In addition, the trained encoder can be used to transform test results into an interpretable subject spatial distribution that facilitates risk assessment and validates methodology.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    Deep learning to achieve clinically applicable segmentation of head and neck anatomy for radiotherapy. (arXiv:1809.04430v2 [cs.CV] UPDATED)

    Over half a million individuals are diagnosed with head and neck cancer each year worldwide. Radiotherapy is an important curative treatment for this disease, but it requires manual time consuming delineation of radio-sensitive organs at risk (OARs). This planning process can delay treatment, while also introducing inter-operator variability with resulting downstream radiation dose differences. While auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying and achieving expert performance remain. Adopting a deep learning approach, we demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck OARs commonly segmented in clinical practice. The model was trained on a dataset of 663 deidentified computed tomography (CT) scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus OAR definitions. We demonstrate the model's clinical applicability by assessing its performance on a test set of 21 CT scans from clinical practice, each with the 21 OARs segmented by two independent experts. We also introduce surface Dice similarity coefficient (surface DSC), a new metric for the comparison of organ delineation, to quantify deviation between OAR surface contours rather than volumes, better reflecting the clinical task of correcting errors in the automated organ segmentations. The model's generalisability is then demonstrated on two distinct open source datasets, reflecting different centres and countries to model training. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 21, 2020 01:30 AM.

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    The Cerebellum on Cocaine

    The traditional cerebellum’s role has been linked to the high computational demands for sensorimotor control. However, several findings have pointed to its involvement in executive and emotional functions in the last decades. First in 2009 and then, in 2016, we raised why we should consider the cerebellum when thinking about drug addiction. A decade later, mounting evidence strongly suggests the cerebellar involvement in this disorder. Nevertheless, direct evidence is still partial and related mainly to drug-induced reward memory, but recent results about cerebellar functions may provide new insights into its role in addiction. The present review does not intend to be a compelling revision on available findings, as we did in the two previous reviews. This minireview focuses on specific findings of the cerebellum’s role in drug-related reward memories and the way ahead for future research. The results discussed here provide grounds for involving the cerebellar cortex’s apical region in regulating behavior driven by drug-cue associations. They also suggest that the cerebellar cortex dysfunction may facilitate drug-induced learning by increasing glutamatergic output from the deep cerebellar nucleus (DCN) to the ventral tegmental area (VTA) and neural activity in its projecting areas.

    in Frontiers in Systems Neuroscience on October 21, 2020 12:00 AM.

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    Spinal Cord Imaging Markers and Recovery of Volitional Leg Movement With Spinal Cord Epidural Stimulation in Individuals With Clinically Motor Complete Spinal Cord Injury

    Previous studies have shown that epidural stimulation of the lumbosacral spinal cord (scES) can re-enable lower limb volitional motor control in individuals with chronic, clinically motor complete spinal cord injury (SCI). This observation entails that residual supraspinal connectivity to the lumbosacral spinal circuitry still persisted after SCI, although it was non-detectable when scES was not provided. In the present study, we aimed at exploring further the mechanisms underlying scES-promoted recovery of volitional lower limb motor control by investigating neuroimaging markers at the spinal cord lesion site via magnetic resonance imaging (MRI). Spinal cord MRI was collected prior to epidural stimulator implantation in 13 individuals with chronic, clinically motor complete SCI, and the spared tissue of specific regions of the spinal cord (anterior, posterior, right, left, and total cord) was assessed. After epidural stimulator implantation, and prior to any training, volitional motor control was evaluated during left and right lower limb flexion and ankle dorsiflexion attempts. The ability to generate force exertion and movement was not correlated to any neuroimaging marker. On the other hand, spared tissue of specific cord regions significantly and importantly correlated with some aspects of motor control that include activation amplitude of antagonist (negative correlation) muscles during left ankle dorsiflexion, and electromyographic coordination patterns during right lower limb flexion. The fact that amount and location of spared spinal cord tissue at the lesion site were not related to the ability to generate volitional lower limb movements may suggest that supraspinal inputs through spared spinal cord regions that differ across individuals can result in the generation of lower limb volitional motor output prior to any training when epidural stimulation is provided.

    in Frontiers in Systems Neuroscience on October 21, 2020 12:00 AM.

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    Local Sleep Slow-Wave Activity Colocalizes With the Ictal Symptomatogenic Zone in a Patient With Reflex Epilepsy: A High-Density EEG Study

    Background: Slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep reflects synaptic potentiation during preceding wakefulness. Epileptic activity may induce increases in state-dependent SWA in human brains, therefore, localization of SWA may prove useful in the presurgical workup of epileptic patients. We analyzed high-density electroencephalography (HDEEG) data across vigilance states from a reflex epilepsy patient with a clearly localizable ictal symptomatogenic zone to provide a proof-of-concept for the testability of this hypothesis.

    Methods: Overnight HDEEG recordings were obtained in the patient during REM sleep, NREM sleep, wakefulness, and during a right facial motor seizure then compared to 10 controls. After preprocessing, SWA (i.e., delta power; 1–4 Hz) was calculated at each channel. Scalp level and source reconstruction analyses were computed. We assessed for statistical differences in maximum SWA between the patient and controls within REM sleep, NREM sleep, wakefulness, and seizure. Then, we completed an identical statistical comparison after first subtracting intrasubject REM sleep SWA from that of NREM sleep, wakefulness, and seizure SWA.

    Results: The topographical analysis revealed greater left hemispheric SWA in the patient vs. controls in all vigilance states except REM sleep (which showed a right hemispheric maximum). Source space analysis revealed increased SWA in the left inferior frontal cortex during NREM sleep and wakefulness. Ictal data displayed poor source-space localization. Comparing each state to REM sleep enhanced localization accuracy; the most clearly localizing results were observed when subtracting REM sleep from wakefulness.

    Conclusion: State-dependent SWA during NREM sleep and wakefulness may help to identify aspects of the potential epileptogenic zone. Future work in larger cohorts may assess the clinical value of sleep SWA to help presurgical planning.

    in Frontiers in Systems Neuroscience on October 21, 2020 12:00 AM.

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    Neuronal Activity at Synapse Resolution: Reporters and Effectors for Synaptic Neuroscience

    The development of methods for the activity-dependent tagging of neurons enabled a new way to tackle the problem of engram identification at the cellular level, giving rise to groundbreaking findings in the field of memory studies. However, the resolution of activity-dependent tagging remains limited to the whole-cell level. Notably, events taking place at the synapse level play a critical role in the establishment of new memories, and strong experimental evidence shows that learning and synaptic plasticity are tightly linked. Here, we provide a comprehensive review of the currently available techniques that enable to identify and track the neuronal activity with synaptic spatial resolution. We also present recent technologies that allow to selectively interfere with specific subsets of synapses. Lastly, we discuss how these technologies can be applied to the study of learning and memory.

    in Frontiers in Molecular Neuroscience on October 21, 2020 12:00 AM.

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    Functional Interactions of Tau Phosphorylation Sites That Mediate Toxicity and Deficient Learning in Drosophila melanogaster

    Hyperphosphorylated Tau protein is the main component of the neurofibrillary tangles, characterizing degenerating neurons in Alzheimer’s disease and other Tauopathies. Expression of human Tau protein in Drosophila CNS results in increased toxicity, premature mortality and learning and memory deficits. Herein we use novel transgenic lines to investigate the contribution of specific phosphorylation sites previously implicated in Tau toxicity. These three different sites, Ser238, Thr245, and Ser262 were tested either by blocking their phosphorylation, by Ser/Thr to Ala substitution, or pseudophosphorylation, by changing Ser/Thr to Glu. We validate the hypothesis that phosphorylation at Ser262 is necessary for Tau-dependent learning deficits and a “facilitatory gatekeeper” to Ser238 occupation, which is linked to Tau toxicity. Importantly we reveal that phosphorylation at Thr245 acts as a “suppressive gatekeeper”, preventing phosphorylation of many sites including Ser262 and consequently of Ser238. Therefore, we elucidate novel interactions among phosphosites central to Tau mediated neuronal dysfunction and toxicity, likely driven by phosphorylation-dependent conformational plasticity.

    in Frontiers in Molecular Neuroscience on October 21, 2020 12:00 AM.

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    The Application of MR Spectroscopy and MR Perfusion in Cerebral Syphilitic Gumma: A Case Report

    Cerebral syphilitic gumma is a rare disease and can be misdiagnosed as a common brain tumor when only conventional imaging results are adopted. Differentiating between syphilitic gumma and tumors may be achieved by applying advanced magnetic resonance (MR) techniques, such as MR spectroscopy and MR perfusion. However, the MR perfusion characteristics of cerebral syphilitic gumma have not been reported yet. Here, we report a case of cerebral syphilitic gumma in a 52-year-old woman and discuss the imaging features of conventional MR, MR spectroscopy, and MR perfusion. The results suggest that the application of MR spectroscopy and MR perfusion could provide additional information that contributes to the diagnosis of cerebral syphilitic gumma.

    in Frontiers in Neuroscience: Brain Imaging Methods on October 21, 2020 12:00 AM.

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    Corrigendum: The Shape of Water Stream Induces Differences in P300 and Alpha Oscillation

    in Frontiers in Human Neuroscience on October 21, 2020 12:00 AM.

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    Publication of Study Exit Procedures in Clinical Trials of Deep Brain Stimulation: A Focused Literature Review

    Considerable variability exists in the publication of clinical research study procedures related to study enrollment and participant exit from clinical trials. Despite recent efforts to encourage research data sharing and greater transparency regarding research outcomes, reporting of research procedures remains inconsistent. Transparency about study procedures has important implications for the interpretation of study outcomes and the consistent implementation of best practices in clinical trial design and conduct. This review of publications from clinical trials of deep brain stimulation (DBS) using the MEDLINE database examines the frequency and consistency of publication of research procedures and data related to exit from DBS research. Related considerations, such as device explant or continued use, battery and other device hardware replacements, and post-trial follow-up care are also reviewed. This review finds significant variability in the publication and reporting of study exit procedures. Of the 47 clinical trials included in this review, 19% (9) disclosed procedures related to exit from research. Reporting of other exit-related data and study procedures examined in this review was identified in fewer than half of the included clinical trials. The rate of participant retention and duration of follow-up was reported more than any other category of data included in this review. Results inform efforts to improve consistency in research design, conduct, and publication of results from clinical trials in DBS and related areas of clinical research.

    in Frontiers in Human Neuroscience on October 21, 2020 12:00 AM.

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    Commentary: Probabilistic Representation in Human Visual Cortex Reflects Uncertainty in Serial Decisions

    in Frontiers in Human Neuroscience on October 21, 2020 12:00 AM.

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    Convergent Associative Motor Cortical Plasticity Induced by Conditional Somatosensory and Motor Reaction Afferents

    Objective: Associative motor cortical plasticity can be non-invasively induced by paired median nerve electric stimulation and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1). This study investigates whether a simultaneous motor reaction of the other hand advances the associative plasticity in M1.

    Methods: Twenty-four right-handed subjects received conventional paired associative stimulation (PAS) and PAS with simultaneous motor reaction (PASmr) with at least a 1-week interval. The PASmr protocol additionally included left abductor pollicis brevis muscle movement responding to a digital sound. The motor reaction time was individually measured. The M1 excitability was examined by the motor evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) before and after the PAS protocols.

    Results: The conventional PAS protocol significantly facilitated MEP and suppressed SICI. A negative correlation between the reaction time and the MEP change, and a positive correlation between the reaction time and the ICF change were found in the PASmr protocol. By subgrouping analysis, we further found significant facilitation of MEP and a reduction of ICF in the subjects with fast reaction times but not in those with slow reaction times.

    Conclusion: Synchronized motor reaction ipsilateral to the stimulated M1 induces associative M1 motor plasticity through the spike-timing dependent principle. MEP and ICF change could represent this kind of plasticity. The current findings provide a novel insight into designing rehabilitation programs concerning motor function.

    in Frontiers in Human Neuroscience on October 21, 2020 12:00 AM.

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    The Impact of Medical Complications in Predicting the Rehabilitation Outcome of Patients With Disorders of Consciousness After Severe Traumatic Brain Injury

    In this study, we sought to assess the predictors of outcome in patients with disorders of consciousness (DOC) after severe traumatic brain injury (TBI) during neurorehabilitation stay. In total, 96 patients with DOC (vegetative state, minimally conscious state, or emergence from minimally conscious state) were enrolled (69 males; mean age 43.6 ± 20.8 years) and the improvement of the degree of disability, as assessed by the Disability Rating Scale, was considered the main outcome measure. To define the best predictor, a series of demographical and clinical factors were modeled using a twofold approach: (1) logistic regression to evaluate a possible causal effect among variables; and (2) machine learning algorithms (ML), to define the best predictive model. Univariate analysis demonstrated that disability in DOC patients statistically decreased at the discharge with respect to admission. Genitourinary was the most frequent medical complication (MC) emerging during the neurorehabilitation period. The logistic model revealed that the total amount of MCs is a risk factor for lack of functional improvement. ML discloses that the most important prognostic factors are the respiratory and hepatic complications together with the presence of the upper gastrointestinal comorbidities. Our study provides new evidence on the most adverse short-term factors predicting a functional recovery in DOC patients after severe TBI. The occurrence of medical complications during neurorehabilitation stay should be considered to avoid poor outcomes.

    in Frontiers in Human Neuroscience on October 21, 2020 12:00 AM.

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    Editorial: Brain Organoids: Modeling in Neuroscience

    in Frontiers in Cellular Neuroscience on October 21, 2020 12:00 AM.

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    Inference of Diagnostic Markers and Therapeutic Targets From CSF Proteomics for the Treatment of Hydrocephalus

    in Frontiers in Cellular Neuroscience on October 21, 2020 12:00 AM.

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    Impaired Topographical Organization of Functional Brain Networks in Parkinson’s Disease Patients With Freezing of Gait

    Objective: This study aimed to explore alterations in the topological properties of the functional brain network in primary Parkinson’s disease (PD) patients with freezing of gait (PD-FOG).

    Methods: Resting-state functional magnetic resonance imaging (Rs-fMRI) data were obtained in 23 PD-FOG patients, 33 PD patients without FOG (PD-nFOG), and 24 healthy control (HC) participants. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and topological properties were analyzed by using graph theory approaches. The network-based statistics (NBS) method was used to determine the suprathreshold connected edges (P < 0.05; threshold T = 2.725), and statistical significance was estimated by using the non-parametric permutation method (5,000 permutations). Statistically significant topological properties were further evaluated for their relationship with clinical neurological scales.

    Results: The topological properties of the functional brain network in PD-FOG and PD-nFOG showed no abnormalities at the global level. However, compared with HCs, PD-FOG patients showed decreased nodal local efficiency in several brain regions, including the bilateral striatum, frontoparietal areas, visual cortex, and bilateral superior temporal gyrus, increased nodal local efficiency in the left gyrus rectus. When compared with PD-nFOG patients and HCs, PD-FOG showed increased betweenness centrality in the left hippocampus. Moreover, compared to HCs, both PD-FOG and PD-nFOG patients displayed reduced network connections by using the NBS method, mainly involving the sensorimotor cortex (SM), visual network (VN), default mode network (DMN), auditory network (AN), dorsal attention network (DAN), subcortical regions, and limbic network (LIM). The local node efficiency of the right temporal pole: superior temporal gyrus in PD-FOG patients was positively correlated with the Freezing of Gait Questionnaire (FOGQ) scores.

    Conclusions: This study demonstrates the disrupted regional topological organization in PD-FOG patients, especially associated with damage to the subcortical regions and multiple cortical regions. Our results provide insights into the dysfunctional mechanisms of the relevant networks and indicate potential neuroimaging biomarkers of PD-FOG.

    in Frontiers in Ageing Neuroscience on October 21, 2020 12:00 AM.

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    Rapid prediction of crucial hotspot interactions for icosahedral viral capsid self-assembly by energy landscape atlasing validated by mutagenesis

    by Ruijin Wu, Rahul Prabhu, Aysegul Ozkan, Meera Sitharam

    Icosahedral viruses are under a micrometer in diameter, their infectious genome encapsulated by a shell assembled by a multiscale process, starting from an integer multiple of 60 viral capsid or coat protein (VP) monomers. We predict and validate inter-atomic hotspot interactions between VP monomers that are important for the assembly of 3 types of icosahedral viral capsids: Adeno Associated Virus serotype 2 (AAV2) and Minute Virus of Mice (MVM), both T = 1 single stranded DNA viruses, and Bromo Mosaic Virus (BMV), a T = 3 single stranded RNA virus. Experimental validation is by in-vitro, site-directed mutagenesis data found in literature. We combine ab-initio predictions at two scales: at the interface-scale, we predict the importance (cruciality) of an interaction for successful subassembly across each interface between symmetry-related VP monomers; and at the capsid-scale, we predict the cruciality of an interface for successful capsid assembly. At the interface-scale, we measure cruciality by changes in the capsid free-energy landscape partition function when an interaction is removed. The partition function computation uses atlases of interface subassembly landscapes, rapidly generated by a novel geometric method and curated opensource software EASAL (efficient atlasing and search of assembly landscapes). At the capsid-scale, cruciality of an interface for successful assembly of the capsid is based on combinatorial entropy. Our study goes all the way from resource-light, multiscale computational predictions of crucial hotspot inter-atomic interactions to validation using data on site-directed mutagenesis’ effect on capsid assembly. By reliably and rapidly narrowing down target interactions, (no more than 1.5 hours per interface on a laptop with Intel Core i5-2500K @ 3.2 Ghz CPU and 8GB of RAM) our predictions can inform and reduce time-consuming in-vitro and in-vivo experiments, or more computationally intensive in-silico analyses.

    in PLoS Computational Biology on October 20, 2020 09:00 PM.

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    seekCRIT: Detecting and characterizing differentially expressed circular RNAs using high-throughput sequencing data

    by Mohamed Chaabane, Kalina Andreeva, Jae Yeon Hwang, Tae Lim Kook, Juw Won Park, Nigel G. F. Cooper

    Over the past two decades, researchers have discovered a special form of alternative splicing that produces a circular form of RNA. Although these circular RNAs (circRNAs) have garnered considerable attention in the scientific community for their biogenesis and functions, the focus of current studies has been on the tissue-specific circRNAs that exist only in one tissue but not in other tissues or on the disease-specific circRNAs that exist in certain disease conditions, such as cancer, but not under normal conditions. This approach was conducted in the relative absence of methods that analyze a group of common circRNAs that exist in both conditions, but are more abundant in one condition relative to another (differentially expressed). Studies of differentially expressed circRNAs (DECs) between two conditions would serve as a significant first step in filling this void. Here, we introduce a novel computational tool, seekCRIT (seek for differentially expressed CircRNAs In Transcriptome), that identifies the DECs between two conditions from high-throughput sequencing data. Using rat retina RNA-seq data from ischemic and normal conditions, we show that over 74% of identifiable circRNAs are expressed in both conditions and over 40 circRNAs are differentially expressed between two conditions. We also obtain a high qPCR validation rate of 90% for DECs with a FDR of < 5%. Our results demonstrate that seekCRIT is a novel and efficient approach to detect DECs using rRNA depleted RNA-seq data. seekCRIT is freely downloadable at https://github.com/UofLBioinformatics/seekCRIT. The source code is licensed under the MIT License. seekCRIT is developed and tested on Linux CentOS-7.

    in PLoS Computational Biology on October 20, 2020 09:00 PM.

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    Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

    by M. Latorre, J. D. Humphrey

    Myriad risk factors–including uncontrolled hypertension, aging, and diverse genetic mutations–contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.

    in PLoS Computational Biology on October 20, 2020 09:00 PM.

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    Expression of concern: A chaperonin subunit with unique structures is essential for folding of a specific substrate

    by The PLOS Biology Editors

    in PLoS Biology on October 20, 2020 09:00 PM.

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    Visual detection is locked to the internal dynamics of cortico-motor control

    by Alice Tomassini, Eric Maris, Pauline Hilt, Luciano Fadiga, Alessandro D’Ausilio

    Movements overtly sample sensory information, making sensory analysis an active-sensing process. In this study, we show that visual information sampling is not just locked to the (overt) movement dynamics but to the internal (covert) dynamics of cortico-motor control. We asked human participants to perform continuous isometric contraction while detecting unrelated and unpredictable near-threshold visual stimuli. The motor output (force) shows zero-lag coherence with brain activity (recorded via electroencephalography) in the beta-band, as previously reported. In contrast, cortical rhythms in the alpha-band systematically forerun the motor output by 200 milliseconds. Importantly, visual detection is facilitated when cortico-motor alpha (not beta) synchronization is enhanced immediately before stimulus onset, namely, at the optimal phase relationship for sensorimotor communication. These findings demonstrate an ongoing coupling between visual sampling and motor control, suggesting the operation of an internal and alpha-cycling visuomotor loop.

    in PLoS Biology on October 20, 2020 09:00 PM.

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    Model-free motion control of continuum robots based on a zeroing neurodynamic approach

    Publication date: Available online 19 October 2020

    Source: Neural Networks

    Author(s): Ning Tan, Peng Yu, Xinyu Zhang, Tao Wang

    in Neural Networks on October 20, 2020 06:00 PM.

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    Multiple graphs learning with a new weighted tensor nuclear norm

    Publication date: Available online 20 October 2020

    Source: Neural Networks

    Author(s): Deyan Xie, Quanxue Gao, Siyang Deng, Xiaojun Yang, Xinbo Gao

    in Neural Networks on October 20, 2020 06:00 PM.

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    Correction for Wang et al., Regenerative therapy based on miRNA-302 mimics for enhancing host recovery from pneumonia caused by Streptococcus pneumoniae [Correction]

    MICROBIOLOGY Correction for “Regenerative therapy based on miRNA-302 mimics for enhancing host recovery from pneumonia caused by Streptococcus pneumoniae,” by Yan Wang, Yong Li, Peggy Zhang, Sandy T. Baker, Marla R. Wolfson, Jeffrey N. Weiser, Ying Tian, and Hao Shen, which was first published April 10, 2019; 10.1073/pnas.1818522116 (Proc. Natl....

    in PNAS on October 20, 2020 04:26 PM.

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    Correction for Vogt et al., Intergenerational resource sharing and mortality in a global perspective [Correction]

    SOCIAL SCIENCES Correction for “Intergenerational resource sharing and mortality in a global perspective,” by Tobias Vogt, Fanny Kluge, and Ronald Lee, which was first published August 31, 2020; 10.1073/pnas.1920978117 (Proc. Natl. Acad. Sci. U.S.A. 117, 22793–22799). The editors note that Luis Rosero-Bixby’s affiliation appeared incorrectly as University of California, Berkeley,...

    in PNAS on October 20, 2020 04:26 PM.

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    Correction for Byers-Heinlein et al., Bilingual infants control their languages as they listen [Correction]

    PSYCHOLOGICAL AND COGNITIVE SCIENCES Correction for “Bilingual infants control their languages as they listen,” by Krista Byers-Heinlein, Elizabeth Morin-Lessard, and Casey Lew-Williams, which was first published August 7, 2017; 10.1073/pnas.1703220114 (Proc. Natl. Acad. Sci. U.S.A. 114, 9032–9037). The authors note that, due to a coding error, a portion of Fig....

    in PNAS on October 20, 2020 04:26 PM.

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    Correction for Huang et al., Catalytic prior distributions with application to generalized linear models [Correction]

    STATISTICS Correction for “Catalytic prior distributions with application to generalized linear models,” by Dongming Huang, Nathan Stein, Donald B. Rubin, and S. C. Kou, which was first published May 15, 2020; 10.1073/pnas.1920913117 (Proc. Natl. Acad. Sci. U.S.A. 117, 12004–12010). The authors note that an additional affiliation should be listed for...

    in PNAS on October 20, 2020 04:26 PM.

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    Posttranscriptional regulation of human endogenous retroviruses by RNA-binding motif protein 4, RBM4 [Systems Biology]

    The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts. Most studies of RBPs have concentrated on their action on host protein-encoding mRNAs, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements, termed...

    in PNAS on October 20, 2020 04:26 PM.

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    Evolved differences in energy metabolism and growth dictate the impacts of ocean acidification on abalone aquaculture [Sustainability Science]

    Ocean acidification (OA) poses a major threat to marine ecosystems and shellfish aquaculture. A promising mitigation strategy is the identification and breeding of shellfish varieties exhibiting resilience to acidification stress. We experimentally compared the effects of OA on two populations of red abalone (Haliotis rufescens), a marine mollusc important to...

    in PNAS on October 20, 2020 04:26 PM.

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    Inactivation of rice starch branching enzyme IIb triggers broad and unexpected changes in metabolism by transcriptional reprogramming [Plant Biology]

    Starch properties can be modified by mutating genes responsible for the synthesis of amylose and amylopectin in the endosperm. However, little is known about the effects of such targeted modifications on the overall starch biosynthesis pathway and broader metabolism. Here we investigated the effects of mutating the OsSBEIIb gene encoding...

    in PNAS on October 20, 2020 04:26 PM.

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    An inhibitor of endothelial ETS transcription factors promotes physiologic and therapeutic vessel regression [Physiology]

    During the progression of ocular diseases such as retinopathy of prematurity and diabetic retinopathy, overgrowth of retinal blood vessels results in the formation of pathological neovascular tufts that impair vision. Current therapeutic options for treating these diseases include antiangiogenic strategies that can lead to the undesirable inhibition of normal vascular...

    in PNAS on October 20, 2020 04:26 PM.

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    Fecal transplantation and butyrate improve neuropathic pain, modify immune cell profile, and gene expression in the PNS of obese mice [Physiology]

    Obesity affects over 2 billion people worldwide and is accompanied by peripheral neuropathy (PN) and an associated poorer quality of life. Despite high prevalence, the molecular mechanisms underlying the painful manifestations of PN are poorly understood, and therapies are restricted to use of painkillers or other drugs that do not...

    in PNAS on October 20, 2020 04:26 PM.

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    Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion [Physiology]

    The diversity and near universal expression of G protein-coupled receptors (GPCR) reflects their involvement in most physiological processes. The GPCR superfamily is the largest in the human genome, and GPCRs are common pharmaceutical targets. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential. We previously...

    in PNAS on October 20, 2020 04:26 PM.

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    Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence [Neuroscience]

    Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or “incubates”) during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved...

    in PNAS on October 20, 2020 04:26 PM.

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    Neddylation is critical to cortical development by regulating Wnt/{beta}-catenin signaling [Neuroscience]

    Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show...

    in PNAS on October 20, 2020 04:26 PM.

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    Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria [Neuroscience]

    Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson’s disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like...

    in PNAS on October 20, 2020 04:26 PM.

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    Primary and secondary motoneurons use different calcium channel types to control escape and swimming behaviors in zebrafish [Neuroscience]

    The escape response and rhythmic swimming in zebrafish are distinct behaviors mediated by two functionally distinct motoneuron (Mn) types. The primary (1°Mn) type depresses and has a large quantal content (Qc) and a high release probability (Pr). Conversely, the secondary (2°Mn) type facilitates and has low and variable Qc and...

    in PNAS on October 20, 2020 04:26 PM.

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    Point process temporal structure characterizes electrodermal activity [Neuroscience]

    Electrodermal activity (EDA) is a direct readout of the body’s sympathetic nervous system measured as sweat-induced changes in the skin’s electrical conductance. There is growing interest in using EDA to track physiological conditions such as stress levels, sleep quality, and emotional states. Standardized EDA data analysis methods are readily available....

    in PNAS on October 20, 2020 04:26 PM.

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    Chronicling changes in the somatosensory neurons after peripheral nerve injury [Neuroscience]

    Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using...

    in PNAS on October 20, 2020 04:26 PM.

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    Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance [Psychological and Cognitive Sciences]

    Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons...

    in PNAS on October 20, 2020 04:26 PM.

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    A microstructural neural network biomarker for dystonia diagnosis identified by a DystoniaNet deep learning platform [Computer Sciences]

    Isolated dystonia is a neurological disorder of heterogeneous pathophysiology, which causes involuntary muscle contractions leading to abnormal movements and postures. Its diagnosis is remarkably challenging due to the absence of a biomarker or gold standard diagnostic test. This leads to a low agreement between clinicians, with up to 50% of...

    in PNAS on October 20, 2020 04:26 PM.

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    Agrobacterium-delivered VirE2 interacts with host nucleoporin CG1 to facilitate the nuclear import of VirE2-coated T complex [Microbiology]

    Agrobacterium tumefaciens is the causal agent of crown gall disease. The bacterium is capable of transferring a segment of single-stranded DNA (ssDNA) into recipient cells during the transformation process, and it has been widely used as a genetic modification tool for plants and nonplant organisms. Transferred DNA (T-DNA) has been...

    in PNAS on October 20, 2020 04:26 PM.

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    Experimental infection of domestic dogs and cats with SARS-CoV-2: Pathogenesis, transmission, and response to reexposure in cats [Microbiology]

    The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached nearly every country in the world with extraordinary person-to-person transmission. The most likely original source of the virus was spillover from an animal reservoir and subsequent adaptation to humans sometime during the winter of 2019 in Wuhan...

    in PNAS on October 20, 2020 04:26 PM.

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    Convergent evolution of zoonotic Brucella species toward the selective use of the pentose phosphate pathway [Microbiology]

    Mechanistic understanding of the factors that govern host tropism remains incompletely understood for most pathogens. Brucella species, which are capable of infecting a wide range of hosts, offer a useful avenue to address this question. We hypothesized that metabolic fine-tuning to intrahost niches is likely an underappreciated axis underlying pathogens’...

    in PNAS on October 20, 2020 04:26 PM.

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    Segregation of four Agrobacterium tumefaciens replicons during polar growth: PopZ and PodJ control segregation of essential replicons [Microbiology]

    Agrobacterium tumefaciens C58 contains four replicons, circular chromosome (CC), linear chromosome (LC), cryptic plasmid (pAt), and tumor-inducing plasmid (pTi), and grows by polar growth from a single growth pole (GP), while the old cell compartment and its old pole (OP) do not elongate. We monitored the replication and segregation of...

    in PNAS on October 20, 2020 04:26 PM.

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    Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors [Medical Sciences]

    Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are...

    in PNAS on October 20, 2020 04:26 PM.

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    Estrogen receptor {beta} regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3 [Medical Sciences]

    Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN....

    in PNAS on October 20, 2020 04:26 PM.

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    Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A [Medical Sciences]

    Balanced rearrangements involving the KMT2A gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and...

    in PNAS on October 20, 2020 04:26 PM.

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    The transcription factor C/EBP{beta} orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions [Immunology and Inflammation]

    Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic...

    in PNAS on October 20, 2020 04:26 PM.

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    Rewiring of B cell receptor signaling by Epstein-Barr virus LMP2A [Immunology and Inflammation]

    Epstein–Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis...

    in PNAS on October 20, 2020 04:26 PM.

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    Genome mapping of a LYST mutation in corn snakes indicates that vertebrate chromatophore vesicles are lysosome-related organelles [Genetics]

    Reptiles exhibit a spectacular diversity of skin colors and patterns brought about by the interactions among three chromatophore types: black melanophores with melanin-packed melanosomes, red and yellow xanthophores with pteridine- and/or carotenoid-containing vesicles, and iridophores filled with light-reflecting platelets generating structural colors. Whereas the melanosome, the only color-producing endosome in...

    in PNAS on October 20, 2020 04:26 PM.

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    Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants [Genetics]

    The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor, Sup35p. For known pathogenic prions, such as [PSI+], a single protein can form an array of different amyloid structures (prion variants) each stably inherited and with differing biological properties. The ribosome-associated chaperones, Ssb1/2p (Hsp70s), and RAC (Zuo1p...

    in PNAS on October 20, 2020 04:26 PM.

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    Genomic diversity generated by a transposable element burst in a rice recombinant inbred population [Genetics]

    Genomes of all characterized higher eukaryotes harbor examples of transposable element (TE) bursts—the rapid amplification of TE copies throughout a genome. Despite their prevalence, understanding how bursts diversify genomes requires the characterization of actively transposing TEs before insertion sites and structural rearrangements have been obscured by selection acting over evolutionary...

    in PNAS on October 20, 2020 04:26 PM.

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    Rivastigmine in Parkinson's Disease Dementia with Orthostatic Hypotension

    Objective

    The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD).

    Methods

    We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH‐). The primary end point was the Alzheimer's Disease Assessment Scale ‐ Cognitive subscale (ADAS‐Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention‐to‐treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses.

    Results

    Overall safety was comparable between OH+ (n = 288, 27.5%) and OH‐ (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo‐adjusted effect of rivastigmine on ADAS‐Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH‐ (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs ‐1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476).

    Interpretation

    The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2020

    in Annals of Neurology on October 20, 2020 02:23 PM.

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    The amygdaloid body of two carnivore species: The feliform banded mongoose and the caniform domestic ferret

    The amygdaloid body of two carnivore species: The feliform banded mongoose and the caniform domestic ferret

    Low power photomicrographs of myelin staining in the basolateral amygdala of the banded mongoose (left) and domestic ferret (right). Note the overall lower density of myelin in the domestic ferret, which may relate to either a smaller brain mass or be an effect of the domestication process. Scale bars in each image = 1 mm.


    Abstract

    The current study provides an analysis of the cytoarchitecture, myeloarchitecture, and chemoarchitecture of the amygdaloid body of the banded mongoose (Mungos mungo) and domestic ferret (Mustela putorius furo). Using architectural and immunohistochemical stains, we observe that the organization of the nuclear and cortical portions of the amygdaloid complex is very similar in both species. The one major difference is the presence of a cortex‐amygdala transition zone observed in the domestic ferret that is absent in the banded mongoose. In addition, the chemoarchitecture is, for the most part, quite similar in the two species, but several variances, such as differing densities of neurons expressing the calcium‐binding proteins in specific nuclei are noted. Despite this, certain aspects of the chemoarchitecture, such as the cholinergic innervation of the magnocellular division of the basal nuclear cluster and the presence of doublecortin expressing neurons in the shell division of the accessory basal nuclear cluster, appear to be consistent features of the Eutherian mammal amygdala. The domestic ferret presented with an overall lower myelin density throughout the amygdaloid body than the banded mongoose, a feature that may reflect artificial selection in the process of domestication for increased juvenile‐like behavior in the adult domestic ferret, such as a muted fear response. The shared, but temporally distant, ancestry of the banded mongoose and domestic ferret allows us to generate observations relevant to understanding the relative influence that phylogenetic constraints, adaptive evolutionary plasticity, and the domestication process may play in the organization and chemoarchitecture of the amygdaloid body.

    in Journal of Comparative Neurology on October 20, 2020 12:26 PM.

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    Time‐restricted feeding prevents depressive‐like and anxiety‐like behaviors in male rats exposed to an experimental model of shift‐work

    Time‐restricted feeding prevents depressive‐like and anxiety‐like behaviors in male rats exposed to an experimental model of shift‐work

    In male rats exposed to an experimental model of shift‐work, we reported circadian disruption, depressive and anxiety‐like behaviors as well as neuroinflammation in brain areas associated with mood regulation. Time‐restricted feeding associated with the normal activity phase prevents depressive and anxiety‐like behaviors as well as neuroinflammation.


    Abstract

    Individuals who regularly shift their sleep timing, like night and/or shift‐workers suffer from circadian desynchrony and are at risk of developing cardiometabolic diseases and cancer. Also, shift‐work is are suggested to be a risk factor for the development of mood disorders such as the burn out syndrome, anxiety, and depression. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental health effects associated with circadian disruption. Here, we explored whether adult male Wistar rats exposed to an experimental model of shift‐work (W‐AL) developed depressive and/or anxiety‐like behaviors and whether this was associated with neuroinflammation in brain areas involved with mood regulation. We also tested whether time‐restricted feeding (TRF) to the active phase could ameliorate circadian disruption and therefore would prevent depressive and anxiety‐like behaviors as well as neuroinflammation. In male Wistar rats, W‐AL induced depressive‐like behavior characterized by hypoactivity and anhedonia and induced increased anxiety‐like behavior in the open field test. This was associated with increased number of glial fibrillary acidic protein and IBA‐1‐positive cells in the prefrontal cortex and basolateral amygdala. Moreover W‐AL caused morphological changes in the microglia in the CA3 area of the hippocampus indicating microglial activation. Importantly, TRF prevented behavioral changes and decreased neuroinflammation markers in the brain. Present results add up evidence about the importance that TRF in synchrony with the light–dark cycle can prevent neuroinflammation leading to healthy mood states in spite of circadian disruptive conditions.

    in Journal of Neuroscience Research on October 20, 2020 11:29 AM.

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    SPA: Stochastic Probability Adjustment for System Balance of Unsupervised SNNs. (arXiv:2010.09690v1 [cs.NE])

    Spiking neural networks (SNNs) receive widespread attention because of their low-power hardware characteristic and brain-like signal response mechanism, but currently, the performance of SNNs is still behind Artificial Neural Networks (ANNs). We build an information theory-inspired system called Stochastic Probability Adjustment (SPA) system to reduce this gap. The SPA maps the synapses and neurons of SNNs into a probability space where a neuron and all connected pre-synapses are represented by a cluster. The movement of synaptic transmitter between different clusters is modeled as a Brownian-like stochastic process in which the transmitter distribution is adaptive at different firing phases. We experimented with a wide range of existing unsupervised SNN architectures and achieved consistent performance improvements. The improvements in classification accuracy have reached 1.99% and 6.29% on the MNIST and EMNIST datasets respectively.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    A geometric framework to predict structure from function in neural networks. (arXiv:2010.09660v1 [q-bio.NC])

    Neural computation in biological and artificial networks relies on nonlinear synaptic integration. The structural connectivity matrix of synaptic weights between neurons is a critical determinant of overall network function. However, quantitative links between neural network structure and function are complex and subtle. For example, many networks can give rise to similar functional responses, and the same network can function differently depending on context. Whether certain patterns of synaptic connectivity are required to generate specific network-level computations is largely unknown. Here we introduce a geometric framework for identifying synaptic connections required by steady-state responses in recurrent networks of rectified-linear neurons. Assuming that the number of specified response patterns does not exceed the number of input synapses, we analytically calculate all feedforward and recurrent connectivity matrices that can generate the specified responses from the network inputs. We then use this analytical characterization to rigorously analyze the solution space geometry and derive certainty conditions guaranteeing a non-zero synapse between neurons. Numerical simulations of feedforward and recurrent networks verify our analytical results. Our theoretical framework could be applied to neural activity data to make anatomical predictions that follow generally from the model architecture. It thus provides novel opportunities for discerning what model features are required to accurately relate neural network structure and function.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Neuronal graphs: a graph theory primer for microscopic, functional networks of neurons recorded by Calcium imaging. (arXiv:2010.09601v1 [q-bio.NC])

    Connected networks are a fundamental structure of neurobiology. Understanding these networks will help us elucidate the neural mechanisms of computation. Mathematically speaking these networks are `graphs' - structures containing objects that are connected. In neuroscience, the objects could be regions of the brain, e.g. fMRI data, or be individual neurons, e.g. calcium imaging with fluorescence microscopy. The formal study of graphs, graph theory, can provide neuroscientists with a large bank of algorithms for exploring networks. Graph theory has already been applied in a variety of ways to fMRI data but, more recently, has begun to be applied at the scales of neurons, e.g. from functional calcium imaging. In this primer we explain the basics of graph theory and relate them to features of microscopic functional networks of neurons from calcium imaging - neuronal graphs. We explore recent examples of graph theory applied to calcium imaging and we highlight some areas where researchers new to the field could go awry.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Continuous monitoring of cognitive load using advanced computerized analysis of brain signals during virtual simulator training for laparoscopic surgery, reflects laparoscopic dexterity. A comparative study using a novel wireless device. (arXiv:2010.09588v1 [q-bio.NC])

    Simulation-based training is an effective tool for acquiring practical skills, the question remains as to which methods should be utilized to optimize this process and for a better assessment of improved manual dexterity. Specifically, it is not fully understood which brain processes during simulation-based training will translate to better skill acquisition through practice. As cognitive load decreases with better performance, we used a novel method for brain assessment that enables an extraction of a cognitive load neurological biomarker. 38 participants were assigned into 3 experiments examining their behavioral performance undergoing a task with the Simbionix LAP MENTO simulator, while their brain activity was measured using a single-electrode EEG by Aurora by Neurosteer. Each task was repeated 3 times with difference session setups. Correlations between a cognitive biomarker (VC9) and behavioral performance measurements (e.g. accuracy, economy of movement and time to exceed the task). Exp 1 results exhibited an improvement in behavioral performance with no correlations to VC9. As a result of prolonging session time to three trials, VC9 activity significantly decreased with higher participants performance both in Exp.2 and in Exp. 3. Altogether, VC9 is found to be an effective biological measurement for the assessment of cognitive load while performing laparoscopic tasks using the surgical simulator. As surgical simulations allow to gain important skills and experience needed to perform procedures without any patient risk, it is crucial to fully evaluate and optimize the effect of these simulations on medical staff. This could potentially be expanded to evaluate the efficacy different medical simulations to help medical staff and to measure cognitive and mental load under real laparoscopic surgeries.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Introducing and Applying Newtonian Blurring: An Augmented Dataset of 126,000 Human Connectomes at braingraph.org. (arXiv:2010.09568v2 [q-bio.NC] UPDATED)

    Gaussian blurring is a well-established method for image data augmentation: it may generate a large set of images from a small set of pictures for training and testing purposes for Artificial Intelligence (AI) applications. When we apply AI for non-imagelike biological data, hardly any related method exists. Here we introduce the "Newtonian blurring" in human braingraph (or connectome) augmentation: Started from a dataset of 1053 subjects, we first repeat a probabilistic weighted braingraph construction algorithm 10 times for describing the connections of distinct cerebral areas, then take 7 repetitions in every possible way, delete the lower and upper extremes, and average the remaining 7-2=5 edge-weights for the data of each subject. This way we augment the 1053 graph-set to 120 x 1053 = 126,360 graphs. In augmentation techniques, it is an important requirement that no artificial additions should be introduced into the dataset. Gaussian blurring and also this Newtonian blurring satisfy this goal. The resulting dataset of 126,360 graphs, each in 5 resolutions (i.e., 631,800 graphs in total), is freely available at the site https://braingraph.org/cms/download-pit-group-connectomes/. Augmenting with Newtonian blurring may also be applicable in other non-image related fields, where probabilistic processing and data averaging are implemented.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Altered structural balance of resting-state networks in autism. (arXiv:2010.09441v1 [q-bio.NC])

    What makes a network complex, in addition to its size, is the interconnected interactions between elements, disruption of which inevitably results in dysfunction. Likewise, the brain networks' complexity arises from interactions beyond pair connections, as it is simplistic to assume that in complex networks state of a link is independently determined only according to its two constituting nodes. This is particularly of note in genetically complex brain impairments, such as the autism spectrum disorder (ASD). Accordingly, structural balance theory (SBT) affirms that in the real-world signed networks, a link is remarkably influenced by each of its two nodes' interactions with the third node within a triadic interrelationship. Thus, it is plausible to ask whether ASD is associated with altered structural balance resulting from atypical triadic interactions. In other words, it is the abnormal interplay of positive and negative interactions that matter in ASD, besides and beyond hypo (hyper) pair connectivity. To address this, we explore triadic interactions in the rs-fMRI network of participants with ASD relative to healthy controls (CON). We demonstrate that balanced triads are overrepresented in the ASD and CON networks while unbalanced triads are underrepresented, providing first-time empirical evidence for the strong notion of structural balance on the brain networks. We further analyze the frequency and energy distribution of triads and suggest an alternative description for the reduced functional integration and segregation in the ASD brain networks. Last but not least, we observe that energy of the salient and the default mode networks are lower in autism, which may be a reflection of the difficulty in flexible behaviors. Altogether, these results highlight the potential value of SBT as a new perspective in functional connectivity studies, especially in neurodevelopmental disorders.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Body models in humans, animals, and robots. (arXiv:2010.09325v1 [q-bio.NC])

    Humans and animals excel in combining information from multiple sensory modalities, controlling their complex bodies, adapting to growth, failures, or using tools. These capabilities are also highly desirable in robots. They are displayed by machines to some extent - yet, as is so often the case, the artificial creatures are lagging behind. The key foundation is an internal representation of the body that the agent - human, animal, or robot - has developed. In the biological realm, evidence has been accumulated by diverse disciplines giving rise to the concepts of body image, body schema, and others. In robotics, a model of the robot is an indispensable component that enables to control the machine. In this article I compare the character of body representations in biology with their robotic counterparts and relate that to the differences in performance that we observe. I put forth a number of axes regarding the nature of such body models: fixed vs. plastic, amodal vs. modal, explicit vs. implicit, serial vs. parallel, modular vs. holistic, and centralized vs. distributed. An interesting trend emerges: on many of the axes, there is a sequence from robot body models, over body image, body schema, to the body representation in lower animals like the octopus. In some sense, robots have a lot in common with Ian Waterman - "the man who lost his body" - in that they rely on an explicit, veridical body model (body image taken to the extreme) and lack any implicit, multimodal representation (like the body schema) of their bodies. I will then detail how robots can inform the biological sciences dealing with body representations and finally, I will study which of the features of the "body in the brain" should be transferred to robots, giving rise to more adaptive and resilient, self-calibrating machines.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Sliding Differential Evolution Scheduling for Federated Learning in Bandwidth-Limited Networks. (arXiv:2010.08991v1 [cs.IT])

    Federated learning (FL) in a bandwidth-limited network with energy-limited user equipments (UEs) is under-explored. In this paper, to jointly save energy consumed by the battery-limited UEs and accelerate the convergence of the global model in FL for the bandwidth-limited network, we propose the sliding differential evolution-based scheduling (SDES) policy. To this end, we first formulate an optimization that aims to minimize a weighted sum of energy consumption and model training convergence. Then, we apply the SDES with parallel differential evolution (DE) operations in several small-scale windows, to address the above proposed problem effectively. Compared with existing scheduling policies, the proposed SDES performs well in reducing energy consumption and the model convergence with lower computational complexity.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    On Size Generalization in Graph Neural Networks. (arXiv:2010.08853v1 [cs.LG])

    Graph neural networks (GNNs) can process graphs of different sizes but their capacity to generalize across sizes is still not well understood. Size generalization is key to numerous GNN applications, from solving combinatorial optimization problems to learning in molecular biology. In such problems, obtaining labels and training on large graphs can be prohibitively expensive, but training on smaller graphs is possible.

    This paper puts forward the size-generalization question and characterizes important aspects of that problem theoretically and empirically. We show that even for very simple tasks, GNNs do not naturally generalize to graphs of larger size. Instead, their generalization performance is closely related to the distribution of patterns of connectivity and features and how that distribution changes from small to large graphs. Specifically, we show that in many cases, there are GNNs that can perfectly solve a task on small graphs but generalize poorly to large graphs and that these GNNs are encountered in practice. We then formalize size generalization as a domain-adaption problem and describe two learning setups where size generalization can be improved. First, as a self-supervised learning problem (SSL) over the target domain of large graphs. Second, as a semi-supervised learning problem when few samples are available in the target domain. We demonstrate the efficacy of these solutions on a diverse set of benchmark graph datasets.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    DIFER: Differentiable Automated Feature Engineering. (arXiv:2010.08784v1 [cs.LG])

    Feature engineering, a crucial step of machine learning, aims to extract useful features from raw data to improve data quality. In recent years, great efforts have been devoted to Automated Feature Engineering (AutoFE) to replace expensive human labor. However, existing methods are computationally demanding due to treating AutoFE as a coarse-grained black-box optimization problem over a discrete space. In this work, we propose an efficient gradient-based method called DIFER to perform differentiable automated feature engineering in a continuous vector space. DIFER selects potential features based on evolutionary algorithm and leverages an encoder-predictor-decoder controller to optimize existing features. We map features into the continuous vector space via the encoder, optimize the embedding along the gradient direction induced by the predicted score, and recover better features from the optimized embedding by the decoder. Extensive experiments on classification and regression datasets demonstrate that DIFER can significantly improve the performance of various machine learning algorithms and outperform current state-of-the-art AutoFE methods in terms of both efficiency and performance.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    Understanding Information Processing in Human Brain by Interpreting Machine Learning Models. (arXiv:2010.08715v1 [q-bio.NC])

    The thesis explores the role machine learning methods play in creating intuitive computational models of neural processing. Combined with interpretability techniques, machine learning could replace human modeler and shift the focus of human effort to extracting the knowledge from the ready-made models and articulating that knowledge into intuitive descroptions of reality. This perspective makes the case in favor of the larger role that exploratory and data-driven approach to computational neuroscience could play while coexisting alongside the traditional hypothesis-driven approach.

    We exemplify the proposed approach in the context of the knowledge representation taxonomy with three research projects that employ interpretability techniques on top of machine learning methods at three different levels of neural organization. The first study (Chapter 3) explores feature importance analysis of a random forest decoder trained on intracerebral recordings from 100 human subjects to identify spectrotemporal signatures that characterize local neural activity during the task of visual categorization. The second study (Chapter 4) employs representation similarity analysis to compare the neural responses of the areas along the ventral stream with the activations of the layers of a deep convolutional neural network. The third study (Chapter 5) proposes a method that allows test subjects to visually explore the state representation of their neural signal in real time. This is achieved by using a topology-preserving dimensionality reduction technique that allows to transform the neural data from the multidimensional representation used by the computer into a two-dimensional representation a human can grasp.

    The approach, the taxonomy, and the examples, present a strong case for the applicability of machine learning methods to automatic knowledge discovery in neuroscience.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Optoelectronic Intelligence. (arXiv:2010.08690v1 [cs.ET])

    To design and construct hardware for general intelligence, we must consider principles of both neuroscience and very-large-scale integration. For large neural systems capable of general intelligence, the attributes of photonics for communication and electronics for computation are complementary and interdependent. Using light for communication enables high fan-out as well as low-latency signaling across large systems with no traffic-dependent bottlenecks. For computation, the inherent nonlinearities, high speed, and low power consumption of Josephson circuits are conducive to complex neural functions. Operation at 4\,K enables the use of single-photon detectors and silicon light sources, two features that lead to efficiency and economical scalability. Here I sketch a concept for optoelectronic hardware, beginning with synaptic circuits, continuing through wafer-scale integration, and extending to systems interconnected with fiber-optic white matter, potentially at the scale of the human brain and beyond.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    Generalizable Machine Learning in Neuroscience using Graph Neural Networks. (arXiv:2010.08569v1 [cs.LG])

    Although a number of studies have explored deep learning in neuroscience, the application of these algorithms to neural systems on a microscopic scale, i.e. parameters relevant to lower scales of organization, remains relatively novel. Motivated by advances in whole-brain imaging, we examined the performance of deep learning models on microscopic neural dynamics and resulting emergent behaviors using calcium imaging data from the nematode C. elegans. We show that neural networks perform remarkably well on both neuron-level dynamics prediction, and behavioral state classification. In addition, we compared the performance of structure agnostic neural networks and graph neural networks to investigate if graph structure can be exploited as a favorable inductive bias. To perform this experiment, we designed a graph neural network which explicitly infers relations between neurons from neural activity and leverages the inferred graph structure during computations. In our experiments, we found that graph neural networks generally outperformed structure agnostic models and excel in generalization on unseen organisms, implying a potential path to generalizable machine learning in neuroscience.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    The Lottery Ticket Hypothesis for Pre-trained BERT Networks. (arXiv:2007.12223v2 [cs.LG] UPDATED)

    In natural language processing (NLP), enormous pre-trained models like BERT have become the standard starting point for training on a range of downstream tasks, and similar trends are emerging in other areas of deep learning. In parallel, work on the lottery ticket hypothesis has shown that models for NLP and computer vision contain smaller matching subnetworks capable of training in isolation to full accuracy and transferring to other tasks. In this work, we combine these observations to assess whether such trainable, transferrable subnetworks exist in pre-trained BERT models. For a range of downstream tasks, we indeed find matching subnetworks at 40% to 90% sparsity. We find these subnetworks at (pre-trained) initialization, a deviation from prior NLP research where they emerge only after some amount of training. Subnetworks found on the masked language modeling task (the same task used to pre-train the model) transfer universally; those found on other tasks transfer in a limited fashion if at all. As large-scale pre-training becomes an increasingly central paradigm in deep learning, our results demonstrate that the main lottery ticket observations remain relevant in this context. Codes available at https://github.com/VITA-Group/BERT-Tickets.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    Bidirectional Self-Normalizing Neural Networks. (arXiv:2006.12169v2 [cs.LG] UPDATED)

    The problem of vanishing and exploding gradients has been a long-standing obstacle that hinders the effective training of neural networks. Despite various tricks and techniques that have been employed to alleviate the problem in practice, there still lacks satisfactory theories or provable solutions. In this paper, we address the problem from the perspective of high-dimensional probability theory. We provide a rigorous result that shows, under mild conditions, how the vanishing/exploding gradients problem disappears with high probability if the neural networks have sufficient width. Our main idea is to constrain both forward and backward signal propagation in a nonlinear neural network through a new class of activation functions, namely Gaussian-Poincar\'e normalized functions, and orthogonal weight matrices. Experiments on both synthetic and real-world data validate our theory and confirm its effectiveness on very deep neural networks when applied in practice.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    Deep Learning based Frameworks for Handling Imbalance in DGA, Email, and URL Data Analysis. (arXiv:2004.04812v2 [cs.LG] UPDATED)

    Deep learning is a state of the art method for a lot of applications. The main issue is that most of the real-time data is highly imbalanced in nature. In order to avoid bias in training, cost-sensitive approach can be used. In this paper, we propose cost-sensitive deep learning based frameworks and the performance of the frameworks is evaluated on three different Cyber Security use cases which are Domain Generation Algorithm (DGA), Electronic mail (Email), and Uniform Resource Locator (URL). Various experiments were performed using cost-insensitive as well as cost-sensitive methods and parameters for both of these methods are set based on hyperparameter tuning. In all experiments, the cost-sensitive deep learning methods performed better than the cost-insensitive approaches. This is mainly due to the reason that cost-sensitive approach gives importance to the classes which have a very less number of samples during training and this helps to learn all the classes in a more efficient manner.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    A bio-inspired geometric model for sound reconstruction. (arXiv:2004.02450v2 [eess.AS] UPDATED)

    The reconstruction mechanisms built by the human auditory system during sound reconstruction are still a matter of debate. The purpose of this study is to propose a mathematical model of sound reconstruction based on the functional architecture of the auditory cortex (A1). The model is inspired by the geometrical modelling of vision, which has undergone a great development in the last ten years. There are however fundamental dissimilarities, due to the different role played by the time and the different group of symmetries. The algorithm transforms the degraded sound in an 'image' in the time-frequency domain via a short-time Fourier transform. Such an image is then lifted in the Heisenberg group and it is reconstructed via a Wilson-Cowan differo-integral equation. Preliminary numerical experiments are provided, showing the good reconstruction properties of the algorithm on synthetic sounds concentrated around two frequencies.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Projected Neural Network for a Class of Sparse Regression with Cardinality Penalty. (arXiv:2004.00858v3 [cs.NE] UPDATED)

    In this paper, we consider a class of sparse regression problems, whose objective function is the summation of a convex loss function and a cardinality penalty. By constructing a smoothing function for the cardinality function, we propose a projected neural network and design a correction method for solving this problem. The solution of the proposed neural network is unique, global existent, bounded and globally Lipschitz continuous. Besides, we prove that all accumulation points of the proposed neural network have a common support set and a unified lower bound for the nonzero entries. Combining the proposed neural network with the correction method, any corrected accumulation point is a local minimizer of the considered sparse regression problem. Moreover, we analyze the equivalent relationship on the local minimizers between the considered sparse regression problem and another regression sparse problem. Finally, some numerical experiments are provided to show the efficiency of the proposed neural networks in solving some sparse regression problems in practice.

    in arXiv: Computer Science: Neural and Evolutionary Computing on October 20, 2020 01:30 AM.

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    How old are dense core vesicles residing in en passant boutons: Simulation of the mean age of dense core vesicles in axonal arbors accounting for resident and transiting vesicle populations. (arXiv:1912.12762v4 [q-bio.SC] UPDATED)

    In neurons, neuropeptides are synthesized in the soma and are then transported along the axon in dense core vesicles (DCVs). DCVs are captured in varicosities located along the axon terminal called en passant boutons, which are active terminal sites that accumulate and release neurotransmitters. Recently developed experimental techniques allow for the estimation of the age of DCVs in various locations in the axon terminal. Accurate simulation of the mean age of DCVs in boutons requires the development of a model that would account for resident, transiting-anterograde, and transiting-retrograde DCV populations. In this paper, such a model is developed. The model is applied to simulating DCV transport in Drosophila type II motoneurons. The model simulates DCV transport and capture in the axon terminals and makes it possible to predict the age density distribution of DCVs in en passant boutons as well as DCV's mean age in boutons. The predicted prevalence of older organelles in distal boutons may explain the "dying back" pattern of axonal degeneration observed in dopaminergic neurons in Parkinson's disease. The predicted difference of two hours between the age of older DCVs residing in distal boutons and the age of younger DCVs residing in proximal boutons is consistent with an approximate estimate of age difference deduced from experimental observations. The age density of resident DCVs is found to be bimodal, which is because DCVs are captured from two transiting states: the anterograde transiting state that contains younger DCVs and the retrograde transiting state that contains older DCVs.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Maximum-entropy and representative samples of neuronal activity: a dilemma. (arXiv:1805.09084v2 [q-bio.NC] UPDATED)

    The present work shows that the maximum-entropy method can be applied to a sample of neuronal recordings along two different routes: (1) apply to the sample; or (2) apply to a larger, unsampled neuronal population from which the sample is drawn, and then marginalize to the sample. These two routes give inequivalent results. The second route can be further generalized to the case where the size of the larger population is unknown. Which route should be chosen? Some arguments are presented in favour of the second. This work also presents and discusses probability formulae that relate states of knowledge about a population and its samples, and that may be useful for sampling problems in neuroscience.

    in arXiv: Quantitative Biology: Neurons and Cognition on October 20, 2020 01:30 AM.

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    Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19150-9

    Here, the authors apply genetic fate mapping and temporal clonal analysis to study progenitor recruitment and network morphogenesis of murine cardiac Purkinje fibers. Additionally, they characterize how transcription factor dosage regulates cell fate divergence during distinct phases of this process.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Telomere damage induces internal loops that generate telomeric circles

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19139-4

    Extrachromosomal circular DNA made of telomeric repeats have been found to have an effect on telomere maintenance. By combining electron microscopy with a telomere purification procedure the authors identify damage-induced i-loops as a key intermediate in telomere circle formation.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19115-y

    Telomerase enzymes add telomeric repeats to the end of linear chromosomes. Here the authors reveal mechanisms by which oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19063-7

    In neural development, progenitors transition from a proliferative to a differentiated state. Here, the authors show that cerebellar granule neurons retract primary cilia as they exit their proliferative niche upon decreased ECM engagement, enabling radial migration due to loss of Shh sensitivity.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Electrification at water–hydrophobe interfaces

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19054-8

    Electrification of water upon contact with hydrophobic surfaces is a ubiquitous but poorly understood phenomenon. Here, the authors pinpoint the factors responsible for the excess positive charge carried by water droplets dispensed from hydrophobic capillaries, thereby answering some outstanding questions and raising new ones.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Prosociality predicts labor market success around the world

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-19007-1

    Previous research on the importance of prosociality is based on observations from WEIRD societies, questioning the generalizability of these findings. Here the authors present a global investigation of the relation between prosociality and labor market success and generalize the positive relation to a wide geographical context.

    in Nature Communications on October 20, 2020 12:00 AM.

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    CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-18980-x

    Carboxyl terminus of Hsc70-interacting protein (CHIP) is proteostasis regulator. Here the authors show that CHIP-mediated protein turnover is enhanced by PKG-mediated phosphorylation, which results in attenuated cardiac ischemic proteotoxicity.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity

    Nature Communications, Published online: 20 October 2020; doi:10.1038/s41467-020-18966-9

    How normal cells proliferate without CDK4 and CDK6, two cancer-driving kinases, remains unclear. Here, the authors show that without CDK4/6 activity, cells start the cell cycle with a different signaling order and commitment point, revealing unexpected flexibility in cell-cycle entry mechanisms.

    in Nature Communications on October 20, 2020 12:00 AM.

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    Daily briefing: A popular unproven COVID treatment is hindering drug trials

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02969-z

    Scientists are struggling to run clinical trials for ivermectin in Latin America. Plus: the unsung heroes of a Nobel-winning discovery and Nature has its first open-access agreement.

    in Nature on October 20, 2020 12:00 AM.

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    Nature journals announce first open-access agreement

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02959-1

    The arrangement will allow some researchers in Germany to publish openly — but critics say it comes with a high price.

    in Nature on October 20, 2020 12:00 AM.

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    Latin America’s embrace of an unproven COVID treatment is hindering drug trials

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02958-2

    Unchecked ivermectin use in the region is making it difficult to test the anti-parasite drug’s effectiveness against the coronavirus.

    in Nature on October 20, 2020 12:00 AM.

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    How obesity could create problems for a COVID vaccine

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02946-6

    Researchers fear that vaccines might not be as effective in people who are obese, a population already highly vulnerable to COVID-19.

    in Nature on October 20, 2020 12:00 AM.

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    COVID-19 vaccines: time to talk about the uncertainties

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02944-8

    Plan now for decisions on which vaccines should go to whom, when and how often.

    in Nature on October 20, 2020 12:00 AM.

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    The code-breakers who led the rise of computing

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02937-7

    World wars, cold wars, cyberwars — marking a century of state surveillance at GCHQ.

    in Nature on October 20, 2020 12:00 AM.

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    Question hubris in nations’ COVID-19 responses

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02930-0

    Question hubris in nations’ COVID-19 responses

    in Nature on October 20, 2020 12:00 AM.

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    Commercial antibodies: alternative grading for research

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02929-7

    Commercial antibodies: alternative grading for research

    in Nature on October 20, 2020 12:00 AM.

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    Hunger in Africa: get the costing right

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02928-8

    Hunger in Africa: get the costing right

    in Nature on October 20, 2020 12:00 AM.

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    Non-animal-derived antibodies: pharma companies respond

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02923-z

    Non-animal-derived antibodies: pharma companies respond

    in Nature on October 20, 2020 12:00 AM.

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    Dozens to be deliberately infected with coronavirus in UK ‘human challenge’ trials

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-02821-4

    Proponents of the trials say they can be run safely and help to identify effective vaccines, but others have questioned their value.

    in Nature on October 20, 2020 12:00 AM.

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    COVID research updates: Genomics ties university COVID cases to care-home deaths

    Nature, Published online: 20 October 2020; doi:10.1038/d41586-020-00502-w

    Nature wades through the literature on the new coronavirus — and summarizes key papers as they appear.

    in Nature on October 20, 2020 12:00 AM.

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    Stress Varies Along the Social Density Continuum

    Social stress is ubiquitous in the lives of social animals. While significant research has aimed to understand the specific forms of stress imparted by particular social interactions, less attention has been paid to understanding the behavioral effects and neural underpinnings of stress produced by the presence and magnitude of social interactions. However, in humans and rodents alike, chronically low and chronically high rates of social interaction are associated with a suite of mental health issues, suggesting the need for further research. Here, we review literature examining the behavioral and neurobiological findings associated with changing social density, focusing on research on chronic social isolation and chronic social crowding in rodent models, and synthesize findings in the context of the continuum of social density that can be experienced by social animals. Through this synthesis, we aim to both summarize the state of the field and describe promising avenues for future research that would more clearly define the broad effects of social interaction on the brain and behavior in mammals.

    in Frontiers in Systems Neuroscience on October 20, 2020 12:00 AM.

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    Using Minimal-Redundant and Maximal-Relevant Whole-Brain Functional Connectivity to Classify Bipolar Disorder

    Background

    A number of mental illness is often re-diagnosed to be bipolar disorder (BD). Furthermore, the prefronto-limbic-striatal regions seem to be associated with the main dysconnectivity of BD. Functional connectivity is potentially an appropriate objective neurobiological marker that can assist with BD diagnosis.

    Methods

    Health controls (HC; n = 173) and patients with BD who had been diagnosed by experienced physicians (n = 192) were separated into 10-folds, namely, a ninefold training set and a onefold testing set. The classification involved feature selection of the training set using minimum redundancy/maximum relevance. Support vector machine was used for training. The classification was repeated 10 times until each fold had been used as the testing set.

    Results

    The mean accuracy of the 10 testing sets was 76.25%, and the area under the curve was 0.840. The selected functional within-network/between-network connectivity was mainly in the subcortical/cerebellar regions and the frontoparietal network. Furthermore, similarity within the BD patients, calculated by the cosine distance between two functional connectivity matrices, was smaller than between groups before feature selection and greater than between groups after the feature selection.

    Limitations

    The major limitations were that all the BD patients were receiving medication and that no independent dataset was included.

    Conclusion

    Our approach effectively separates a relatively large group of BD patients from HCs. This was done by selecting functional connectivity, which was more similar within BD patients, and also seems to be related to the neuropathological factors associated with BD.

    in Frontiers in Neuroscience: Brain Imaging Methods on October 20, 2020 12:00 AM.

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    Editorial: Embodying Tool Use: From Cognition to Neurorehabilitation

    in Frontiers in Human Neuroscience on October 20, 2020 12:00 AM.

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    Phosphorylation of the Retinal Ribbon Synapse Specific t-SNARE Protein Syntaxin3B Is Regulated by Light via a Ca2 +-Dependent Pathway

    Neurotransmitter release at retinal ribbon-style synapses utilizes a specialized t-SNARE protein called syntaxin3B (STX3B). In contrast to other syntaxins, STX3 proteins can be phosphorylated in vitro at T14 by Ca2+/calmodulin-dependent protein kinase II (CaMKII). This modification has the potential to modulate SNARE complex formation required for neurotransmitter release in an activity-dependent manner. To determine the extent to which T14 phosphorylation occurs in vivo in the mammalian retina and characterize the pathway responsible for the in vivo phosphorylation of T14, we utilized quantitative immunofluorescence to measure the levels of STX3 and STX3 phosphorylated at T14 (pSTX3) in the synaptic terminals of mouse retinal photoreceptors and rod bipolar cells (RBCs). Results demonstrate that STX3B phosphorylation at T14 is light-regulated and dependent upon the elevation of intraterminal Ca2+. In rod photoreceptor terminals, the ratio of pSTX3 to STX3 was significantly higher in dark-adapted mice, when rods are active, than in light-exposed mice. By contrast, in RBC terminals, the ratio of pSTX3 to STX3 was higher in light-exposed mice, when these terminals are active, than in dark-adapted mice. These results were recapitulated in the isolated eyecup preparation, but only when Ca2+ was included in the external medium. In the absence of external Ca2+, pSTX3 levels remained low regardless of light/dark exposure. Using the isolated RBC preparation, we next showed that elevation of intraterminal Ca2+ alone was sufficient to increase STX3 phosphorylation at T14. Furthermore, both the non-specific kinase inhibitor staurosporine and the selective CaMKII inhibitor AIP inhibited the Ca2+-dependent increase in the pSTX3/STX3 ratio in isolated RBC terminals, while in parallel experiments, AIP suppressed RBC depolarization-evoked exocytosis, measured using membrane capacitance measurements. Our data support a novel, illumination-regulated modulation of retinal ribbon-style synapse function in which activity-dependent Ca2+ entry drives the phosphorylation of STX3B at T14 by CaMKII, which in turn, modulates the ability to form SNARE complexes required for exocytosis.

    in Frontiers in Cellular Neuroscience on October 20, 2020 12:00 AM.

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    Genetically Encoded Calcium Indicators Can Impair Dendrite Growth of Cortical Neurons

    A battery of genetically encoded calcium indicators (GECIs) with different binding kinetics and calcium affinities was developed over the recent years to permit long-term calcium imaging. GECIs are calcium buffers and therefore, expression of GECIs may interfere with calcium homeostasis and signaling pathways important for neuronal differentiation and survival. Our objective was to investigate if the biolistically induced expression of five commonly used GECIs at two postnatal time points (days 14 and 22–25) could affect the morphological maturation of cortical neurons in organotypic slice cultures of rat visual cortex. Expression of GCaMP3 in both time windows, and of GCaMP5G and TN-XXL in the later time window impaired apical and /or basal dendrite growth of pyramidal neurons. With time, the proportion of GECI transfectants with nuclear filling increased, but an only prolonged expression of TN-XXL caused higher levels of neurodegeneration. In multipolar interneurons, only GCaMP3 evoked a transient growth delay during the early time window. GCaMP6m and GCaMP6m-XC were quite “neuron-friendly.” Since growth-impaired neurons might not have the physiological responses typical of age-matched wildtype neurons the results obtained after prolonged developmental expression of certain GECIs might need to be interpreted with caution.

    in Frontiers in Cellular Neuroscience on October 20, 2020 12:00 AM.

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    The lncRNA MALAT1/miR-30/Spastin Axis Regulates Hippocampal Neurite Outgrowth

    Spastin, a microtubule-severing enzyme, is important for neurite outgrowth. However, the mechanisms underlying the post-transcriptional regulation of spastin during microtubule-related processes are largely unknown. We demonstrated that the spastin expression level is controlled by a long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-30 (miR-30) axis during neurite outgrowth. The miR-30 expression level decreased in hippocampal neurons with increasing days in culture, and miR-30 overexpression suppressed while miR-30 inhibition promoted neurite outgrowth in hippocampal neurons. Spastin was validated as a target gene of miR-30 using the luciferase reporter assay. The protein expression, microtubule severing activity, and neurite promoting effect of spastin were suppressed by the overexpression of miR-30 mimics and increased by miR-30 inhibitors. MALAT1 expression increased during neurite outgrowth and MALAT1 silencing impaired neurite outgrowth. miR-30 was a sponge target of MALAT1 and MALAT1/miR-30 altered neurite outgrowth in hippocampal neurons. MALAT1 overexpression reversed the inhibitory effect of miR-30 on the activity of a luciferase reporter construct containing spastin, as well as spastin mRNA and protein expression, indicating that spastin was a downstream effector of MALAT1/miR-30. The MALAT1/miR-30 cascade also modulated spastin-induced microtubule severing, and the MALAT1/miR-30/spastin axis regulated neurite outgrowth in hippocampal neurons. This study suggests a new mechanism governing neurite outgrowth in hippocampal neurons involving MALAT1/miR-30-regulated spastin expression.

    in Frontiers in Cellular Neuroscience on October 20, 2020 12:00 AM.

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    Hindbrain and Spinal Cord Contributions to the Cutaneous Sensory Innervation of the Larval Zebrafish Pectoral Fin

    Vertebrate forelimbs contain arrays of sensory neuron fibers that transmit signals from the skin to the nervous system. We used the genetic toolkit and optical clarity of the larval zebrafish to conduct a live imaging study of the sensory neurons innervating the pectoral fin skin. Sensory neurons in both the hindbrain and the spinal cord innervate the fin, with most cells located in the hindbrain. The hindbrain somas are located in rhombomere seven/eight, laterally and dorsally displaced from the pectoral fin motor pool. The spinal cord somas are located in the most anterior part of the cord, aligned with myomere four. Single cell reconstructions were used to map afferent processes and compare the distributions of processes to soma locations. Reconstructions indicate that this sensory system breaks from the canonical somatotopic organization of sensory systems by lacking a clear organization with reference to fin region. Arborizations from a single cell branch widely over the skin, innervating the axial skin, lateral fin surface, and medial fin surface. The extensive branching over the fin and the surrounding axial surface suggests that these fin sensory neurons report on general conditions of the fin area rather than providing fine location specificity, as has been demonstrated in other vertebrate limbs. With neuron reconstructions that span the full primary afferent arborization from the soma to the peripheral cutaneous innervation, this neuroanatomical study describes a system of primary sensory neurons and lays the groundwork for future functional studies.

    in Frontiers in Neuroanatomy on October 20, 2020 12:00 AM.

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    Detection of Cerebrovascular Loss in the Normal Aging C57BL/6 Mouse Brain Using in vivo Contrast-Enhanced Magnetic Resonance Angiography

    Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide in vivo whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis via vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents.

    in Frontiers in Ageing Neuroscience on October 20, 2020 12:00 AM.

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    Conditional protein tagging methods reveal highly specific subcellular distribution of ion channels in motion-sensing neurons

    Neurotransmitter receptors and ion channels shape the biophysical properties of neurons, from the sign of the response mediated by neurotransmitter receptors to the dynamics shaped by voltage-gated ion channels. Therefore, knowing the localizations and types of receptors and channels present in neurons is fundamental to our understanding of neural computation. Here, we developed two approaches to visualize the subcellular localization of specific proteins in Drosophila: The flippase-dependent expression of GFP-tagged receptor subunits in single neurons and 'FlpTag', a versatile new tool for the conditional labelling of endogenous proteins. Using these methods, we investigated the subcellular distribution of the receptors GluClα, Rdl, and Dα7 and the ion channels para and Ih in motion-sensing T4/T5 neurons of the Drosophila visual system. We discovered a strictly segregated subcellular distribution of these proteins and a sequential spatial arrangement of glutamate, acetylcholine, and GABA receptors along the dendrite that matched the previously reported EM-reconstructed synapse distributions.

    in eLife on October 20, 2020 12:00 AM.

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    3D in situ imaging of female reproductive tract reveals molecular signatures of fertilizing spermatozoa in mice

    Out of millions of ejaculated sperm, only a few reach the fertilization site in mammals. Flagellar Ca2+ signaling nanodomains, organized by multi-subunit CatSper calcium channel complexes, are pivotal for sperm migration in the female tract, implicating CatSper-dependent mechanisms in sperm selection. Here, using biochemical and pharmacological studies, we demonstrate that CatSper1 is an O-linked glycosylated protein, undergoing capacitation-induced processing dependent on Ca2+ and phosphorylation cascades. CatSper1 processing correlates with protein tyrosine phosphorylation (pY) development in sperm cells capacitated in vitro and in vivo. Using 3D in situ molecular imaging and ANN-based automatic detection of sperm distributed along the cleared female tract, we demonstrate that all spermatozoa past the UTJ possess intact CatSper1 signals. Together, we reveal that fertilizing mouse spermatozoa in situ are characterized by intact CatSper channel, lack of pY, and reacted acrosomes. These findings provide molecular insight into sperm selection for successful fertilization in the female reproductive tract.

    in eLife on October 20, 2020 12:00 AM.

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    Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

    Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.

    in eLife on October 20, 2020 12:00 AM.

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    Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase

    The way in which multidomain proteins fold has been a puzzling question for decades. Until now, the mechanisms and functions of domain interactions involved in multidomain protein folding have been obscure. Here, we develop structure-based models to investigate the folding and DNA-binding processes of the multidomain Y-family DNA polymerase IV (DPO4). We uncover shifts in folding mechanism among ordered domain-wise folding, backtracking folding, and cooperative folding, modulated by interdomain interactions. These lead to "U-shaped' folding kinetics. We characterize the effects of interdomain flexibility on the promotion of DPO4-DNA (un)binding, which probably contributes to the ability of DPO4 to bypass DNA lesions, a known biological role of Y-family polymerases. We suggest that the native topology of DPO4 leads to a trade-off between fast, stable folding and tight functional DNA binding. Our approach provides an effective way to quantitatively correlate the roles of protein interactions in conformational dynamics at the multidomain level.

    in eLife on October 20, 2020 12:00 AM.

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    A feedback loop governs the relationship between lipid metabolism and longevity

    The relationship between lipid metabolism and longevity remains unclear. Although fat oxidation is essential for weight loss, whether it remains beneficial when sustained for long periods, and the extent to which it may attenuate or augment lifespan remain important unanswered questions. Here, we develop an experimental handle in the Caenorhabditis elegans model system, in which we uncover the mechanisms that connect long-term fat oxidation with longevity. We find that sustained β-oxidation via activation of the conserved triglyceride lipase ATGL-1, triggers a feedback transcriptional loop that involves the mito-nuclear transcription factor ATFS-1, and a previously unknown and highly conserved repressor of ATGL-1 called HLH-11/AP4. This feedback loop orchestrates the dual control of fat oxidation and lifespan, and shields the organism from life-shortening mitochondrial stress in the face of continuous fat oxidation. Thus, we uncover one mechanism by which fat oxidation can be sustained for long periods without deleterious effects on longevity.

    in eLife on October 20, 2020 12:00 AM.

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    Sex-specific effects of cooperative breeding and colonial nesting on prosociality in corvids

    The investigation of prosocial behavior is of particular interest from an evolutionary perspective. Comparisons of prosociality across non-human animal species have, however, so far largely focused on primates, and their interpretation is hampered by the diversity of paradigms and procedures used. Here we present the first systematic comparison of prosocial behavior across multiple species in a taxonomic group outside the primate order, namely the bird family Corvidae. We measured prosociality in 8 corvid species, which vary in the expression of cooperative breeding and colonial nesting. We show that cooperative breeding is positively associated with prosocial behavior across species. Also, colonial nesting is associated with a stronger propensity for prosocial behavior, but only in males. The combined results of our study strongly suggest that both cooperative breeding and colonial nesting, which may both rely on heightened social tolerance at the nest, are likely evolutionary pathways to prosocial behavior in corvids.

    in eLife on October 20, 2020 12:00 AM.

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    Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

    Cardiac pumping depends on the morphological structure of the heart, but also on its sub-cellular (ultrastructural) architecture, which enables cardiac contraction. In cases of congenital heart defects, localized ultrastructural disruptions that increase the risk of heart failure are only starting to be discovered. This is in part due to a lack of technologies that can image the three dimensional (3D) heart structure, to assess malformations; and its ultrastructure, to assess organelle disruptions. We present here a multiscale, correlative imaging procedure that achieves high-resolution images of the whole heart, using 3D micro-computed tomography (micro-CT); and its ultrastructure, using 3D scanning electron microscopy (SEM). In a small animal model (chicken embryo), we achieved uniform fixation and staining of the whole heart, without losing ultrastructural preservation on the same sample, enabling correlative multiscale imaging. Our approach enables multiscale studies in models of congenital heart disease and beyond.

    in eLife on October 20, 2020 12:00 AM.

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    Functional links between sensory representations, choice activity, and sensorimotor associations in parietal cortex

    Three-dimensional (3D) representations of the environment are often critical for selecting actions that achieve desired goals. The success of these goal-directed actions relies on 3D sensorimotor transformations that are experience-dependent. Here we investigated the relationships between the robustness of 3D visual representations, choice-related activity, and motor-related activity in parietal cortex. Macaque monkeys performed an eight-alternative 3D orientation discrimination task and a visually guided saccade task while we recorded from the caudal intraparietal area using laminar probes. We found that neurons with more robust 3D visual representations preferentially carried choice-related activity. Following the onset of choice-related activity, the robustness of the 3D representations further increased for those neurons. We additionally found that 3D orientation and saccade direction preferences aligned, particularly for neurons with choice-related activity, reflecting an experience-dependent sensorimotor association. These findings reveal previously unrecognized links between the fidelity of ecologically relevant object representations, choice-related activity, and motor-related activity.

    in eLife on October 20, 2020 12:00 AM.

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    Photosynthetic sea slugs induce protective changes to the light reactions of the chloroplasts they steal from algae

    Sacoglossan sea slugs are able to maintain functional chloroplasts inside their own cells, and mechanisms that allow preservation of the chloroplasts are unknown. We found that the slug Elysia timida induces changes to the photosynthetic light reactions of the chloroplasts it steals from the alga Acetabularia acetabulum. Working with a large continuous laboratory culture of both the slugs (>500 individuals) and their prey algae, we show that the plastoquinone pool of slug chloroplasts remains oxidized, which can suppress reactive oxygen species formation. Slug chloroplasts also rapidly build up a strong proton motive force upon a dark-to-light transition, which helps them to rapidly switch on photoprotective non-photochemical quenching of excitation energy. Finally, our results suggest that chloroplasts inside E. timida rely on oxygen-dependent electron sinks during rapid changes in light intensity. These photoprotective mechanisms are expected to contribute to the long-term functionality of the chloroplasts inside the slugs.

    in eLife on October 20, 2020 12:00 AM.

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    Neuronal octopamine signaling regulates mating-induced germline stem cell increase in female Drosophila melanogaster

    Stem cells fuel the development and maintenance of tissues. Many studies have addressed how local signals from neighboring niche cells regulate stem cell identity and their proliferative potential. However, the regulation of stem cells by tissue-extrinsic signals in response to environmental cues remains poorly understood. Here we report that efferent octopaminergic neurons projecting to the ovary are essential for germline stem cell (GSC) increase in response to mating in female Drosophila. The neuronal activity of the octopaminergic neurons is required for mating-induced GSC increase as they relay the mating signal from sex peptide receptor-positive cholinergic neurons. Octopamine and its receptor Oamb are also required for mating-induced GSC increase via intracellular Ca2+ signaling. Moreover, we identified Matrix metalloproteinase-2 as a downstream component of the octopamine-Ca2+ signaling to induce GSC increase. Our study provides a mechanism describing how neuronal system couples stem cell behavior to environmental cues through stem cell niche signaling.

    in eLife on October 20, 2020 12:00 AM.

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    Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

    Chavali et al. demonstrate that oligodendroglial precursor density and their interactions with endothelial tip cells regulate white matter vascular development. In hypoxic brain injury, OPCs activate canonical Wnt signaling in angiogenic endothelial cells. Ablation of OPC-derived Wnt7 ligands results in disrupted white matter tip-cell angiogenesis and myelination defects.

    in Neuron: In press on October 20, 2020 12:00 AM.

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    Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable

    Using astrocyte RNA sequencing, Yu et al. demonstrate context-specific molecular responses of striatal astrocytes to multiple experimental perturbations. They identify reciprocal changes between Huntington’s disease (HD) and activation of the astrocyte Gi-GPCR pathway. Selective stimulation of the striatal astrocyte Gi-GPCR pathway corrects several HD-associated cellular and behavioral phenotypes.

    in Neuron: In press on October 20, 2020 12:00 AM.

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    High-density amplicon sequencing identifies community spread and ongoing evolution of SARS-CoV-2 in the Southern United States

    SARS-CoV-2 is constantly evolving. Prior studies focused on high case-density locations, such as the U.S. Northern and Western metropolitan areas. This study demonstrates continued SARS-CoV-2 evolution in a suburban Southern U.S. region by high-density amplicon sequencing of symptomatic cases. 57% of strains carried the spike D614G variant, which was associated with higher genome copy numbers and its prevalence expanded with time. Four strains carried a deletion in a predicted stem loop of the 3’ untranslated region.

    in Cell Reports: In press on October 20, 2020 12:00 AM.

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    Gastrointestinal Neurons Expressing HCN4 Regulate Retrograde Peristalsis

    (Cell Reports 30, 2879–2888.e1–e3; March 3, 2020)

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway

    Tian et al. show that MYSM1 cleaves STING ubiquitination to suppress the STING pathway. Mysm1-deficient mice exhibit tissue damage and high mortality upon virus infection. MYSM1 treatment represses pro-inflammatory cytokines in PBMCs from patients with systemic lupus erythematosus. Thus, MYSM1 acts a therapeutic agent for infectious and autoimmune diseases.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

    Tlemsani et al. provide a unique resource, SCLC-CellMiner, integrating drug sensitivity and multi-omics data from 118 small cell lung cancer (SCLC) cell lines. They demonstrate that SCLCs have differential transcriptional networks driven by lineage-specific transcription factors (NEUROD1, ASCL1, POU2F3, and YAP1). Furthermore, YAP1-driven SCLCs have distinct drug sensitivity profiles.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

    Landgraf et al. show that the obesity-susceptibility gene TMEM18 is of critical functional importance for adipose tissue biology. TMEM18 promotes adipogenesis by activating PPARG1 and thereby metabolically beneficial hyperplasia. The link between TMEM18 and PPARG1 is dysregulated in obesity and related inflammatory and metabolic parameters in children.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Structural and Functional Insights into an Archaeal Lipid Synthase

    Ren et al. report a member of superfamily UbiA which are transmembrane enzymes for lipophilic molecules biosynthesis. These structures reveal the unique cavity containing two long hydrophobic tunnels for substrates accommodation, and functional assays provide insights into mechanisms of lipid biosynthesis and membrane adaptation.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma

    Through an in vivo epigenome-focused pooled RNAi screen, Maitituoheti et al. identify KMT2D as a tumor suppressor in melanoma. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways by reduction of H3K4me1-marked active enhancers, conferring sensitivity to glycolysis and IGFR inhibitors in melanoma with KMT2D-inactivating mutations.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

    The ER-residing STIM2 protein gates ORAI Ca2+ channels at the plasma membrane. However, the functional relevance of STIM2 is not fully understood. Gibhardt et al. reveal a regulatory mechanism in which oxidation of C313 controls STIM2 function. Oxidative stress-induced C313 sulfonylation hinders STIM2 oligomerization, causing inhibition of store-operated Ca2+ entry.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Dendritic Cells and Microglia Have Non-redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

    CD11c+ dendritic cells infiltrate the brain after ischemic injury and share some features with microglia. Gallizioli et al. show that dendritic cells exhibit a transcriptional profile different from microglia and excel in antigen presentation. Microglia attract different DC subsets via chemokines, especially cDC1 that exert beneficial functions in cerebral ischemia.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

    Kong et al. show that JQ1 affects multiple aspects of B cell function, including survival, proliferation, and as a consequence, antibody production. JQ1-induced apoptosis is solely attributed to the pro-apoptotic protein Bim. JQ1 treatment drives temporal changes in Brd4 displacement, resulting in a specific transcriptional profile.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    MutSβ Stimulates Holliday Junction Resolution by the SMX Complex

    Young et al. show that MSH2 and MSH3, two components of the MutSβ heterodimer, bind SLX4 and are required for the efficient resolution of Holliday junctions by the SMX trinuclease complex. Loss of MutSβ activity leads to an accumulation of unresolved homologous recombination ultrafine bridges at mitosis.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure

    Cibi et al. demonstrate that Prdm16 is dispensable for cardiac development. However, in the adult heart, Prdm16 is required for preserving mitochondrial function and inhibiting hypertrophy. Prdm16 and Ehmts act together to limit reactivation of the fetal gene program by inhibiting the functions of pro-hypertrophic transcription factors such as Myc.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    The 9-1-1 Complex Controls Mre11 Nuclease and Checkpoint Activation during Short-Range Resection of DNA Double-Strand Breaks

    Resection of DNA double-strand breaks is a two-step process that relies on short and long-range nucleases. Gobbini et al. show that the 9-1-1 complex plays a dual function during short-range resection, promoting checkpoint activation by recruiting Rad9 at damaged sites and negatively regulating short-range resection in a Rad9-independent manner by restricting Mre11 nuclease.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

    Balakrishnan et al. identify BMI1 as an oncogenic target using a combinatorial RNAi and drug screen in diffuse intrinsic pontine glioma. Genetic and pharmacological inhibition of BMI1 decreases cell self-renewal by driving senescence in vitro and in vivo. Clearance of these senescent cells prolongs survival in the patient-derived xenograft model.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance

    The role of Hhex in NK cells remains unclear, even though there is a strong correlation between Hhex expression and NK cell numbers. Using conditional knockout mouse models, Goh et al. establish Hhex as a critical regulator of NK cell development by preventing BIM-mediated NK cell death.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis

    He et al. identify NR4A1 as a directly repressed target of YAP/TAZ-TEADs and show that the reciprocal feedback regulation between YAP and NR4A1 enables proper organ size during liver regeneration and constrains tumorigenesis to maintain tissue homeostasis.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    A Small-RNA-Mediated Feedback Loop Maintains Proper Levels of 22G-RNAs in C. elegans

    Rogers and Phillips identify a small-RNA-mediated feedback mechanism that regulates the expression of endogenous siRNAs. By modulating the expression of the endogenous siRNA biogenesis factor ERI-6/7, this feedback mechanism ensures homeostasis of small RNA production and ultimately mRNA expression.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction

    Yin et al. reveal that tumor-derived exosomes (TDEs), as fatty acid carriers, induce a metabolic shift toward oxidative phosphorylation, driving DC immune dysfunction. Transcriptomic analysis identifies PPARα as the fatty acid sensor mediating the immunosuppressive effects of TDEs on DCs. PPARα blockade effectively restores DC function and enhances the efficacy of immunotherapy.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Integrated Proteomic and Glycoproteomic Characterization of Human High-Grade Serous Ovarian Carcinoma

    Hu et al. provide an integrated proteomic and glycoproteomic characterization of high-grade serous ovarian carcinomas and relevant non-tumor tissues, which reveals tumor-specific glycosylation, uncovers different glycosylation associated with three tumor clusters, and identifies glycosylation enzymes correlated with glycosylation alterations.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice

    Although anti-TNF therapies are used to treat colitis, Liu et al. demonstrate that colitis-susceptible mice deficient for TNF receptor 1 (TNFR1) paradoxically develop severe disease shortly after weaning. TNFR1 function can be traced back to its mediation of pro-inflammatory responses during a critical period of immune development in early life.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Integrated Single-Cell Transcriptomics and Chromatin Accessibility Analysis Reveals Regulators of Mammary Epithelial Cell Identity

    Pervolarakis et al. use integrated analysis of single-cell transcriptomics and chromatin accessibility data to reveal the spectrum of heterogeneity of mouse mammary epithelial cell types and states, along with regulatory elements that contribute to these differences. Analysis of secretory luminal cells defines their differentiation trajectory and underlying regulatory factors.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    Motivation and Engagement during Visually Guided Behavior

    Ortiz et al. study performance of mice in a visual task during engagement and disengagement. Mice disengage from the task without reaching satiation. Pupil diameter indicates that reduced alertness is not associated with disengagement. We suggest that areas downstream of visual cortex perform cost-benefit analysis governing response to thirst signals.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    CMTR1-Catalyzed 2′-O-Ribose Methylation Controls Neuronal Development by Regulating Camk2α Expression Independent of RIG-I Signaling

    Lee et al. demonstrate that CMTR1-catalyzed 2′-O-ribose methylation in mRNAs is important for dendritic morphogenesis and brain development. CMTR1 is dispensable for silencing RIG-I-activated innate immunity in neurons. Transcriptomic profiling and rescue experiments show Camk2α as the most downregulated gene in the absence of CMTR1, suggesting a role in dendrite development.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    LPS-Induced Acute Kidney Injury Is Mediated by Nox4-SH3YL1

    Yoo et al. demonstrate that SH3YL1 serves as a cytosolic regulator of Nox4 to mediate LPS-dependent H2O2 generation. The Nox4-SH3YL1 axis stimulates expression of pro-inflammatory cytokines and then triggers apoptosis of tubular cells, leading to AKI. SH3YL1 plays an important role in diseases associated with H2O2 produced by Nox4.

    in Cell Reports: Current Issue on October 20, 2020 12:00 AM.

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    eEF1A2 controls local translation and actin dynamics in structural synaptic plasticity

    Synaptic plasticity involves structural modifications in dendritic spines. Increasing evidence suggests that structural plasticity is modulated by local protein synthesis and actin remodeling in a synapsis-specific manner. However, the precise molecular mechanisms connecting synaptic stimulation to these processes in dendritic spines are still unclear. In the present study, we demonstrate that the configuration of phosphorylation sites in eEF1A2, an essential translation elongation factor in neurons, is a key modulator of structural plasticity in dendritic spines. A mutant that cannot be phosphorylated stimulates translation but reduces actin dynamics and spine density. By contrast, the phosphomimetic variant loosens its association with F-actin and becomes inactive as a translation elongation factor. Metabotropic glutamate receptor signaling triggers a transient dissociation of eEF1A2 from its GEF protein in dendritic spines, in a phospho-dependent manner. We propose that eEF1A2 establishes a crosstalk mechanism that coordinates local translation and actin dynamics during spine remodeling

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Dendritic spines are lost in clusters in patients with Alzheimers disease

    Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau protein in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in patients with AD are still unclear. Here, comparing dendrites with and without tau pathology of AD patients, we show that the presence of tau pathology determines the loss of dendritic spines in blocks, ruling out alternative models where spine loss occurs randomly. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits by altering spine organization.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Neural oscillations track natural but not artificial fast speech: Novel insights from speech-brain coupling using MEG

    Convincing evidence for synchronization of cortical oscillations to normal rate speech and artificially accelerated speech has been offered. However, the case of natural speech rate variations, which are ubiquitous in everyday life, has been largely overlooked. Here, we directly compared changes in the properties of cortico-acoustic coupling when speech naturally shifts from normal to fast rate and when it is artificially accelerated. Neuromagnetic brain signals of 24 normal-hearing adults were recorded with magnetoencephalography (MEG) while they listened to natural normal (~6 syllables/s), natural fast (~9 syllables/s) and time-compressed (~9 syllables/s) sentences, as well as to envelope-matched amplitude-modulated noise. We estimated coherence between the envelope of the acoustic input and MEG source time-series in two frequency bands corresponding to the mean syllable rates of the normal and fast speech stimuli. We found that listening to natural speech at normal and fast rates was associated with coupling between speech signal envelope and neural oscillations in right auditory and (pre)motor cortices. This oscillatory alignment occurred within [5.7-7.7 Hz] for normal rate sentences and shifted up to [8-10 Hz] for naturally-produced fast speech, mirroring the increase in syllable rate between the two conditions. Unexpectedly, despite being generated at the same rate as naturally-produced fast speech, the time-compressed sentences did not lead to significant cortico-acoustic coupling at [8-10 Hz]. In addition, neural activity in articulatory cortex exhibited stronger tuning to natural fast rather than to artificially accelerated speech, reflecting enhanced mapping to articulatory features of natural speech. Finally, we observed no coupling when participants listened to amplitude-modulated noise, which suggests that envelope tracking does not only reflect passive acoustic tracking but is sensitive to linguistic information. Altogether, our findings provide new insights into the oscillatory brain signature underlying the perception of natural speech at different rates and highlight the importance of using naturally-produced speech when probing the dynamics of brain-to-speech coupling.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Large, stable spikes exhibit differential broadening in excitatory and inhibitory neocortical boutons

    Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here we report direct recordings from boutons of neocortical pyramidal neurons and interneurons. Our data reveal rapid and large presynaptic action potentials in layer 5 neurons and fast-spiking interneurons reliably propagating into axon collaterals. For in-depth analyses we validate boutons of mature cultured neurons as models for excitatory neocortical boutons, demonstrating that the presynaptic spike amplitude was unaffected by potassium channels, homeostatic long-term plasticity, and high-frequency firing. In contrast to the stable amplitude, presynaptic spikes profoundly broadened for example during high-frequency firing in layer 5 pyramidal neurons but not in fast-spiking interneurons. Thus, our data demonstrate large presynaptic spikes and fundamental differences between excitatory and inhibitory boutons in the neocortex.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

    The preoptic hypothalamus regulates both NREM and REM sleep. We found that calcium levels in mouse lateral preoptic (LPO) neurons were highest during REM. Deleting the core GluN1 subunit of NMDA receptors from LPO neurons abolished calcium signals during all vigilance states, and the excitatory drive onto LPO neurons was reduced. Mice had less NREM sleep and were incapable of generating conventionally classified REM sleep episodes: cortical theta oscillations were greatly reduced but muscle atonia was maintained. Additionally, mice lacking NMDA receptors in LPO neurons had highly fragmented sleep-wake patterns. The fragmentation persisted even under high sleep pressure produced by sleep deprivation. Nevertheless, the sleep homeostasis process remained intact, with an increase in EEG delta power. The sedative dexmedetomidine and sleeping medication zolpidem could transiently restore consolidated sleep. High sleep-wake fragmentation, but not sleep loss, was also produced by selective GluN1 knock-down in GABAergic LPO neurons. We suggest that NMDA glutamate receptor signalling stabilizes the firing of GABAergic NREM sleep-on neurons and is also essential for the theta rhythm in REM sleep.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Conserved core visual object recognition across simian primates: Marmoset image-by-image behavior mirrors that of humans and macaques

    We report that the marmoset, a 300-gram simian primate with a flat cortex, performs a challenging high-level perceptual task in a strikingly human-like manner. Across the same set of 400 images, marmosets' image-by-image core object recognition behavior was highly similar to that of humans -- and was nearly as human-like as was macaques' (r=0.73 vs. r=0.77). Separately, we found that marmosets' visual abilities far outstripped those of rodents -- marmosets substantially outperformed rats and generalized in a far more robust manner across images. Thus, core aspects of visual perception are conserved across simian primates, and marmosets may be a powerful small model organism for high-level visual neuroscience.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Hierarchical Bayesian Models of Reinforcement Learning: Introduction and comparison to alternative methods

    Reinforcement learning models have been used extensively and with great success to capture learning and decision-making processes in humans and other organisms. One essential goal of these computational models is generalization to new sets of observations. Extracting parameters that can reliably predict out-of-sample data can be difficult, however: reinforcement learning models often face problems of non-identifiability, which can lead to poor predictive accuracy. The use of prior distributions to regularize parameter estimates can be an effective way to remedy this issue. While previous research has suggested that empirical priors estimated from a separate dataset improve identifiability and predictive accuracy, this paper outlines an alternate method for the derivation of empirical priors: hierarchical Bayesian modeling. We provide a detailed introduction to this method, and show that using hierarchical models to simultaneously extract and impose empirical priors leads to better out-of-sample prediction while being more data efficient.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    White matter brain aging In Relationship to Schizophrenia and Its Cognitive Deficit

    We hypothesized that cerebral white matter deficits in schizophrenia (SZ) are driven in part by accelerated white matter aging and are associated with cognitive deficits. We used machine learning model to predict individual age from diffusion tensor imaging features and calculated the delta age ({Delta}age) as the difference between predicted and chronological age. Through this approach, we translated multivariate white matter imaging features into an age-scaled metric and used it to test the temporal trends of accelerated aging-related white matter deficit in SZ and its association with the cognition. Followed feature selection, a machine learning model was trained with fractional anisotropy values in 34 of 43 tracts on a training set consisted of 107 healthy controls (HC). The brain age of 166 SZs and 107 HCs in the testing set were calculated using this model. Then, we examined the SZ-HC group effect on {Delta}age and whether this effect was moderated by chronological age using the regression spline model. The results showed that {Delta}age was significantly elevated in the age >30 group in patients (p < 0.001) but not in age [≤] 30 group (p = 0.364). {Delta}age in patients was significantly and negatively associated with both working memory ({beta} = -0.176, p = 0.007) and processing speed ({beta} = -0.519, p = 0.035) while adjusting sex and chronological age. Overall, these findings indicate that the {Delta}age is elevated in SZs and become significantly from middle life stage; the increase of {Delta}age in SZs is associated with the decline neurocognitive performance.

    in bioRxiv: Neuroscience on October 20, 2020 12:00 AM.

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    Timescales of motor memory formation in dual-adaptation

    by Marion Forano, David W. Franklin

    The timescales of adaptation to novel dynamics are well explained by a dual-rate model with slow and fast states. This model can predict interference, savings and spontaneous recovery, but cannot account for adaptation to multiple tasks, as each new task drives unlearning of the previously learned task. Nevertheless, in the presence of appropriate contextual cues, humans are able to adapt simultaneously to opposing dynamics. Consequently this model was expanded, suggesting that dual-adaptation occurs through a single fast process and multiple slow processes. However, such a model does not predict spontaneous recovery within dual-adaptation. Here we assess the existence of multiple fast processes by examining the presence of spontaneous recovery in two experimental variations of an adaptation-de-adaptation-error-clamp paradigm within dual-task adaptation in humans. In both experiments, evidence for spontaneous recovery towards the initially learned dynamics (A) was found in the error-clamp phase, invalidating the one-fast-two-slow dual-rate model. However, as adaptation is not only constrained to two timescales, we fit twelve multi-rate models to the experimental data. BIC model comparison again supported the existence of two fast processes, but extended the timescales to include a third rate: the ultraslow process. Even within our single day experiment, we found little evidence for decay of the learned memory over several hundred error-clamp trials. Overall, we show that dual-adaptation can be best explained by a two-fast-triple-rate model over the timescales of adaptation studied here. Longer term learning may require even slower timescales, explaining why we never forget how to ride a bicycle.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    PyHIST: A Histological Image Segmentation Tool

    by Manuel Muñoz-Aguirre, Vasilis F. Ntasis, Santiago Rojas, Roderic Guigó

    The development of increasingly sophisticated methods to acquire high-resolution images has led to the generation of large collections of biomedical imaging data, including images of tissues and organs. Many of the current machine learning methods that aim to extract biological knowledge from histopathological images require several data preprocessing stages, creating an overhead before the proper analysis. Here we present PyHIST (https://github.com/manuel-munoz-aguirre/PyHIST), an easy-to-use, open source whole slide histological image tissue segmentation and preprocessing command-line tool aimed at tile generation for machine learning applications. From a given input image, the PyHIST pipeline i) optionally rescales the image to a different resolution, ii) produces a mask for the input image which separates the background from the tissue, and iii) generates individual image tiles with tissue content.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    Predicting antimicrobial resistance using conserved genes

    by Marcus Nguyen, Robert Olson, Maulik Shukla, Margo VanOeffelen, James J. Davis

    A growing number of studies are using machine learning models to accurately predict antimicrobial resistance (AMR) phenotypes from bacterial sequence data. Although these studies are showing promise, the models are typically trained using features derived from comprehensive sets of AMR genes or whole genome sequences and may not be suitable for use when genomes are incomplete. In this study, we explore the possibility of predicting AMR phenotypes using incomplete genome sequence data. Models were built from small sets of randomly-selected core genes after removing the AMR genes. For Klebsiella pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, and Staphylococcus aureus, we report that it is possible to classify susceptible and resistant phenotypes with average F1 scores ranging from 0.80–0.89 with as few as 100 conserved non-AMR genes, with very major error rates ranging from 0.11–0.23 and major error rates ranging from 0.10–0.20. Models built from core genes have predictive power in cases where the primary AMR mechanisms result from SNPs or horizontal gene transfer. By randomly sampling non-overlapping sets of core genes, we show that F1 scores and error rates are stable and have little variance between replicates. Although these small core gene models have lower accuracies and higher error rates than models built from the corresponding assembled genomes, the results suggest that sufficient variation exists in the core non-AMR genes of a species for predicting AMR phenotypes.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    Fibrillarin evolution through the Tree of Life: Comparative genomics and microsynteny network analyses provide new insights into the evolutionary history of Fibrillarin

    by Alejandro Pereira-Santana, Samuel David Gamboa-Tuz, Tao Zhao, M. Eric Schranz, Pablo Vinuesa, Andrea Bayona, Luis C. Rodríguez-Zapata, Enrique Castano

    Fibrillarin (FIB), a methyltransferase essential for life in the vast majority of eukaryotes, is involved in methylation of rRNA required for proper ribosome assembly, as well as methylation of histone H2A of promoter regions of rRNA genes. RNA viral progression that affects both plants and animals requires FIB proteins. Despite the importance and high conservation of fibrillarins, there little is known about the evolutionary dynamics of this small gene family. We applied a phylogenomic microsynteny-network approach to elucidate the evolutionary history of FIB proteins across the Tree of Life. We identified 1063 non-redundant FIB sequences across 1049 completely sequenced genomes from Viruses, Bacteria, Archaea, and Eukarya. FIB is a highly conserved single-copy gene through Archaea and Eukarya lineages, except for plants, which have a gene family expansion due to paleopolyploidy and tandem duplications. We found a high conservation of the FIB genomic context during plant evolution. Surprisingly, FIB in mammals duplicated after the Eutheria split (e.g., ruminants, felines, primates) from therian mammals (e.g., marsupials) to form two main groups of sequences, the FIB and FIB-like groups. The FIB-like group transposed to another genomic context and remained syntenic in all the eutherian mammals. This transposition correlates with differences in the expression patterns of FIB-like proteins and with elevated Ks values potentially due to reduced evolutionary constraints of the duplicated copy. Our results point to a unique evolutionary event in mammals, between FIB and FIB-like genes, that led to non-redundant roles of the vital processes in which this protein is involved.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections

    by Brandon Hollingsworth, Kenichi W. Okamoto, Alun L. Lloyd

    The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control–the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    PyOIF: Computational tool for modelling of multi-cell flows in complex geometries

    by Iveta Jančigová, Kristína Kovalčíková, Rudolf Weeber, Ivan Cimrák

    A user ready, well documented software package PyOIF contains an implementation of a robust validated computational model for cell flow modelling. The software is capable of simulating processes involving biological cells immersed in a fluid. The examples of such processes are flows in microfluidic channels with numerous applications such as cell sorting, rare cell isolation or flow fractionation. Besides the typical usage of such computational model in the design process of microfluidic devices, PyOIF has been used in the computer-aided discovery involving mechanical properties of cell membranes. With this software, single cell, many cell, as well as dense cell suspensions can be simulated. Many cell simulations include cell-cell interactions and analyse their effect on the cells. PyOIF can be used to test the influence of mechanical properties of the membrane in flows and in membrane-membrane interactions. Dense suspensions may be used to study the effect of cell volume fraction on macroscopic phenomena such as cell-free layer, apparent suspension viscosity or cell degradation. The PyOIF module is based on the official ESPResSo distribution with few modifications and is available under the terms of the GNU General Public Licence. PyOIF is based on Python objects representing the cells and on the C++ computational core for fluid and interaction dynamics. The source code is freely available at GitHub repository, runs natively under Linux and MacOS and can be used in Windows Subsystem for Linux. The communication among PyOIF users and developers is maintained using active mailing lists. This work provides a basic background to the underlying computational models and to the implementation of interactions within this framework. We provide the prospective PyOIF users with a practical example of simulation script with reference to our publicly available User Guide.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    BinaryCIF and CIFTools—Lightweight, efficient and extensible macromolecular data management

    by David Sehnal, Sebastian Bittrich, Sameer Velankar, Jaroslav Koča, Radka Svobodová, Stephen K. Burley, Alexander S. Rose

    3D macromolecular structural data is growing ever more complex and plentiful in the wake of substantive advances in experimental and computational structure determination methods including macromolecular crystallography, cryo-electron microscopy, and integrative methods. Efficient means of working with 3D macromolecular structural data for archiving, analyses, and visualization are central to facilitating interoperability and reusability in compliance with the FAIR Principles. We address two challenges posed by growth in data size and complexity. First, data size is reduced by bespoke compression techniques. Second, complexity is managed through improved software tooling and fully leveraging available data dictionary schemas. To this end, we introduce BinaryCIF, a serialization of Crystallographic Information File (CIF) format files that maintains full compatibility to related data schemas, such as PDBx/mmCIF, while reducing file sizes by more than a factor of two versus gzip compressed CIF files. Moreover, for the largest structures, BinaryCIF provides even better compression—factor ten and four versus CIF files and gzipped CIF files, respectively. Herein, we describe CIFTools, a set of libraries in Java and TypeScript for generic and typed handling of CIF and BinaryCIF files. Together, BinaryCIF and CIFTools enable lightweight, efficient, and extensible handling of 3D macromolecular structural data.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    Intuitive physical reasoning about objects’ masses transfers to a visuomotor decision task consistent with Newtonian physics

    by Nils Neupärtl, Fabian Tatai, Constantin A. Rothkopf

    While interacting with objects during every-day activities, e.g. when sliding a glass on a counter top, people obtain constant feedback whether they are acting in accordance with physical laws. However, classical research on intuitive physics has revealed that people’s judgements systematically deviate from predictions of Newtonian physics. Recent research has explained at least some of these deviations not as consequence of misconceptions about physics but instead as the consequence of the probabilistic interaction between inevitable perceptual uncertainties and prior beliefs. How intuitive physical reasoning relates to visuomotor actions is much less known. Here, we present an experiment in which participants had to slide pucks under the influence of naturalistic friction in a simulated virtual environment. The puck was controlled by the duration of a button press, which needed to be scaled linearly with the puck’s mass and with the square-root of initial distance to reach a target. Over four phases of the experiment, uncertainties were manipulated by altering the availability of sensory feedback and providing different degrees of knowledge about the physical properties of pucks. A hierarchical Bayesian model of the visuomotor interaction task incorporating perceptual uncertainty and press-time variability found substantial evidence that subjects adjusted their button-presses so that the sliding was in accordance with Newtonian physics. After observing collisions between pucks, which were analyzed with a hierarchical Bayesian model of the perceptual observation task, subjects transferred the relative masses inferred perceptually to adjust subsequent sliding actions. Crucial in the modeling was the inclusion of a cost function, which quantitatively captures participants’ implicit sensitivity to errors due to their motor variability. Taken together, in the present experiment we find evidence that our participants transferred their intuitive physical reasoning to a subsequent visuomotor control task consistent with Newtonian physics and weighed potential outcomes with a cost functions based on their knowledge about their own variability.

    in PLoS Computational Biology on October 19, 2020 09:00 PM.

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    A novel function for CDK2 activity at meiotic crossover sites

    by Nathan Palmer, S. Zakiah A. Talib, Priti Singh, Christine M. F. Goh, Kui Liu, John C. Schimenti, Philipp Kaldis

    Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1–2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called “late recombination nodules” (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain. Here, we describe the phenotype of 2 Cdk2 point mutants with elevated or decreased activity, respectively. Elevated CDK2 activity was associated with increased numbers of LRN-associated proteins, including CDK2 itself and the MutL homolog 1 (MLH1) component of the MutLγ complex, but did not lead to increased numbers of COs. In contrast, reduced CDK2 activity leads to the complete absence of CO formation during meiotic prophase I. Our data suggest an important role for CDK2 in regulating MLH1 focus numbers and that the activity of this kinase is a key regulatory factor in the formation of meiotic COs.

    in PLoS Biology on October 19, 2020 09:00 PM.

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    NOTCH2NLC Intermediate‐Length Repeat Expansions Are Associated with Parkinson Disease

    NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate‐length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate‐length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho‐alpha‐synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate‐length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate‐length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate‐length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2020

    in Annals of Neurology on October 19, 2020 05:44 PM.

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    Association between migraine and cryptogenic ischemic stroke in young adults

    Objective

    To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).

    Methods

    We prospectively enrolled 347 consecutive patients aged 18‐49 with a recent CIS and 347 age‐ and sex‐matched (±5 years) stroke‐free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache‐neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist‐to‐hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen.

    Results

    The screener performance was excellent (Cohen’s Kappa >0.75) in patients and controls. Compared with non‐migraineurs, any migraine (odds ratio [OR] 2.48, 95% confidence interval 1.63‐3.76) and MA (OR 3.50, 2.19‐5.61) were associated with CIS, whereas MO was not. The association emerged both in women (OR 2.97 for any migraine, 1.61‐5.47; OR 4.32 for MA, 2.16‐8.65) and men (OR 2.47 for any migraine, 1.32‐4.61; OR 3.61 for MA, 1.75‐7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right‐to‐left shunt in patients with PFO.

    Interpretation

    MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on October 19, 2020 04:16 PM.

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    A comparison of cell density and serotonergic innervation of the amygdala among four macaque species

    A comparison of cell density and serotonergic innervation of the amygdala among four macaque species

    A high degree of behavioral variation has been observed among macaque species. To investigate the neural basis of this variation, we used stereological methods to compare neural cell density and serotonin transporter‐immunoreactive axon density in the amygdala among four species that differ in social style. We hypothesized that significantly greater serotonergic innervation would be observed in the amygdala of the most socially tolerant species in our sample, the moor macaque. Instead, the pigtailed macaque, which is considered moderately tolerant, possessed significantly greater serotonergic innervation in the amygdala relative to Japanese and moor macaques. Our findings provide insight on the neural substrates of primate sociality from an evolutionary perspective.


    Abstract

    The genus Macaca is an ideal model for investigating the biological basis of primate social behavior from an evolutionary perspective. A significant amount of behavioral diversity has been reported among the macaque species, but little is known about the neural substrates that support this variation. The present study compared neural cell density and serotonergic innervation of the amygdala among four macaque species using histological and immunohistochemical methods. The species examined included rhesus (Macaca mulatta), Japanese (M. fuscata), pigtailed (M. nemestrina), and moor macaques (M. maura). We anticipated that the more aggressive rhesus and Japanese macaques would have lower serotonergic innervation within the amygdala compared to the more affiliative pigtailed and moor macaques. In contrast to our prediction, pigtailed macaques had higher serotonergic innervation than Japanese and moor macaques in the basal and central amygdala nuclei when controlling for neuron density. Our analysis of neural cell populations revealed that Japanese macaques possess significantly higher neuron and glia densities relative to the other three species, however we observed no glia‐to‐neuron ratio differences among species. The results of this study revealed serotonergic innervation and cell density differences among closely related macaque species, which may play a role in modulating subtle differences in emotional processing and species‐typical social styles.

    in Journal of Comparative Neurology on October 19, 2020 11:41 AM.

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    Coevolution of cooperation and language

    Author(s): Mohammad Salahshour

    As a cooperative act decreases an individual's fitness for others to benefit, it is expected to be selected against by natural selection. That, how contrary to this naive expectation cooperation has evolved, is a fundamental problem in evolutionary biology and social sciences. Here, by introducing a...


    [Phys. Rev. E 102, 042409] Published Mon Oct 19, 2020

    in Physical Review E: Biological physics on October 19, 2020 10:00 AM.

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    Stochastic epigenetic dynamics of gene switching

    Author(s): Bhaswati Bhattacharyya, Jin Wang, and Masaki Sasai

    Epigenetic modifications of histones crucially affect eukaryotic gene activity, while the epigenetic histone state is largely determined by the binding of specific factors such as the transcription factors (TFs) to DNA. Here, the way in which the TFs and the histone state are dynamically correlated ...


    [Phys. Rev. E 102, 042408] Published Mon Oct 19, 2020

    in Physical Review E: Biological physics on October 19, 2020 10:00 AM.

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    Help from peripheral macrophages in ALS?

    Nature Neuroscience, Published online: 19 October 2020; doi:10.1038/s41593-020-00727-y

    Chiot and colleagues investigated whether peripheral macrophages play a role in amyotrophic lateral sclerosis (ALS) pathology, finding that macrophages along peripheral motor neuron axons react to neurodegeneration. Modifying reactive oxygen species (ROS) signaling in peripheral macrophages, using bone marrow cell replacement, reduces both macrophage and microglia inflammatory response, delays pathology and increases survival in ALS mouse models.

    in Nature Neuroscience on October 19, 2020 12:00 AM.

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    Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11.2 microdeletion mouse model

    Nature Neuroscience, Published online: 19 October 2020; doi:10.1038/s41593-020-00720-5

    Donegan et al. show that hippocampal CA2 neurons contribute to social memory by encoding social novelty. Abnormal CA2 coding and social memory in a mouse model of the 22q11.2 microdeletion are rescued by blocking elevated CA2 TREK-1 K+ current.

    in Nature Neuroscience on October 19, 2020 12:00 AM.

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    Edge-centric functional network representations of human cerebral cortex reveal overlapping system-level architecture

    Nature Neuroscience, Published online: 19 October 2020; doi:10.1038/s41593-020-00719-y

    The authors present an edge-centric model of brain connectivity. Edge networks are stable across datasets, and their structure can be modulated by sensory input. When clustered, edge networks yield pervasively overlapping functional modules.

    in Nature Neuroscience on October 19, 2020 12:00 AM.

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    Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival

    Nature Neuroscience, Published online: 19 October 2020; doi:10.1038/s41593-020-00718-z

    Peripheral macrophages located along motor axons react differently to neurodegeneration compared to CNS microglia in ALS mice. Modifying peripheral macrophages suppresses proinflammatory microglial responses, shifting them toward neuronal support.

    in Nature Neuroscience on October 19, 2020 12:00 AM.

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    Smart solutions for automated imaging

    Nature Methods, Published online: 19 October 2020; doi:10.1038/s41592-020-00988-2

    Algorithms trained to interpret microscope data can greatly extend the information that can be derived from the resulting images, or even optimize how imaging experiments are conducted.

    in Nature Methods on October 19, 2020 12:00 AM.

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    Author Correction: Quantitative mapping and minimization of super-resolution optical imaging artifacts

    Nature Methods, Published online: 19 October 2020; doi:10.1038/s41592-020-00983-7

    Author Correction: Quantitative mapping and minimization of super-resolution optical imaging artifacts

    in Nature Methods on October 19, 2020 12:00 AM.

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    A compact Cascade–Cas3 system for targeted genome engineering

    Nature Methods, Published online: 19 October 2020; doi:10.1038/s41592-020-00980-w

    This work repurposes the Type I-C Cascade–Cas3 system from Pseudomonas aeruginosa to achieve large deletions in bacterial genomes.

    in Nature Methods on October 19, 2020 12:00 AM.

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    MARS: discovering novel cell types across heterogeneous single-cell experiments

    Nature Methods, Published online: 19 October 2020; doi:10.1038/s41592-020-00979-3

    MARS uses a meta-learning strategy for annotating known cell types and identifying novel ones across single-cell RNA-seq datasets.

    in Nature Methods on October 19, 2020 12:00 AM.

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    Isotopy and energy of physical networks

    Nature Physics, Published online: 19 October 2020; doi:10.1038/s41567-020-1029-z

    Recently, a framework was introduced to model three-dimensional physical networks, such as brain or vascular ones, in a way that does not allow link crossings. Here the authors combine concepts from knot theory and statistical mechanics to be able to distinguish between physical networks with identical wiring but different layouts.

    in Nature Physics on October 19, 2020 12:00 AM.

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    A free-electron laboratory coherent X-ray source

    Nature Photonics, Published online: 19 October 2020; doi:10.1038/s41566-020-00710-w

    Facilities generating coherent X-rays tend to be large scale and costly. Now researchers have demonstrated a parametric and coherent laboratory-scale X-ray source by passing moderately energetic electrons through van der Waals heterostructures.

    in Nature Photomics on October 19, 2020 12:00 AM.

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    Sub-molecular photoluminescence

    Nature Photonics, Published online: 19 October 2020; doi:10.1038/s41566-020-00706-6

    Photoluminescence spectroscopy using atomic-scale light reveals an optical transition of a single molecule at sub-nanometre resolution.

    in Nature Photomics on October 19, 2020 12:00 AM.

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    Pockels soliton microcomb

    Nature Photonics, Published online: 19 October 2020; doi:10.1038/s41566-020-00704-8

    Photonic-chip-based microcomb solitons driven by Pockels nonlinearity—the quadratic χ(2) effect—instead of the Kerr soliton are demonstrated in an aluminium nitride microring resonator with a conversion efficiency of 17%.

    in Nature Photomics on October 19, 2020 12:00 AM.

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    Transient optical symmetry breaking for ultrafast broadband dichroism in plasmonic metasurfaces

    Nature Photonics, Published online: 19 October 2020; doi:10.1038/s41566-020-00702-w

    Inhomogeneity of the photogenerated carrier spacetime distribution enables transient symmetry breaking in a metasurface. As a result, broadband transient dichroism is demonstrated.

    in Nature Photomics on October 19, 2020 12:00 AM.

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    Directly modulated membrane lasers with 108 GHz bandwidth on a high-thermal-conductivity silicon carbide substrate

    Nature Photonics, Published online: 19 October 2020; doi:10.1038/s41566-020-00700-y

    Directly modulated membrane distributed reflector lasers are fabricated on a silicon carbide platform. The 3 dB bandwidth, four-level pulse-amplitude modulation speed and operating energy for transmitting one bit are 108 GHz, 256 Gbit s−1 and 475 fJ, respectively.

    in Nature Photomics on October 19, 2020 12:00 AM.

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    Probing complex geophysical geometries with chattering dust

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-19087-z

    Chattering dust, or chemically reactive grains of sucrose containing pockets of pressurized carbon dioxide, are used in this experimental approach to study rock fractures. The chattering dust emits acoustic shocks that can be monitored and illuminates fracture geometry.

    in Nature Communications on October 19, 2020 12:00 AM.

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    Pearl millet genomic vulnerability to climate change in West Africa highlights the need for regional collaboration

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-19066-4

    Replacement of local crops with alternative varieties adapted to future conditions may improve food security under climate change. Here the authors apply landscape genomics and ensemble climate modelling to pearl millet in West Africa, supporting the potential of transfrontier assisted seed exchange.

    in Nature Communications on October 19, 2020 12:00 AM.

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    A streamlined pipeline for multiplexed quantitative site-specific N-glycoproteomics

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-19052-w

    Comprehensive quantitative profiling of intact glycopeptides remains technically challenging. To address this, the authors here develop an integrated quantitative glycoproteomic workflow, including optimized sample preparation, multiplexed quantification and a dedicated data processing tool.

    in Nature Communications on October 19, 2020 12:00 AM.

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    Direct C(sp2)–H alkylation of unactivated arenes enabled by photoinduced Pd catalysis

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-19038-8

    Direct catalytic C(sp2)–H alkylation of unactivated arenes with alkyl halides remains elusive despite the progress in C-H functionalization. Here, the authors report the catalytic C(sp2)–H alkylation of unactivated arenes with alkyl bromides via visible-light induced Pd catalysis.

    in Nature Communications on October 19, 2020 12:00 AM.

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    Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-18997-2

    The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.

    in Nature Communications on October 19, 2020 12:00 AM.

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    A pyridinic Fe-N4 macrocycle models the active sites in Fe/N-doped carbon electrocatalysts

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-18969-6

    Iron- and nitrogen-doped carbon materials are effective catalysts for the oxygen reduction reaction whose active sites are poorly understood. Here, the authors establish a new pyridinic iron macrocycle complex as a more effective active site model relative to legacy pyrrolic model complexes.

    in Nature Communications on October 19, 2020 12:00 AM.

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    The structure of a red-shifted photosystem I reveals a red site in the core antenna

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-18884-w

    Cyanobacterial photosystem I has a highly conserved core antenna consisting of eleven subunits and more than 90 chlorophylls. Here via CryoEM and spectroscopy, the authors determine the location of a red-shifted low-energy chlorophyll that allows harvesting of longer wavelengths of light.

    in Nature Communications on October 19, 2020 12:00 AM.

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    Chromosome-level genome assembly of a parent species of widely cultivated azaleas

    Nature Communications, Published online: 19 October 2020; doi:10.1038/s41467-020-18771-4

    Azaleas are one of the most diverse ornamental plants and have cultural and economic importance. Here, the authors report a chromosome-scale genome assembly for the primary ancestor of the azalea cultivar Rhododendro simsi and identify transcription factors that may function in flower coloration at different stages.

    in Nature Communications on October 19, 2020 12:00 AM.

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    Daily briefing: A giant cat was hiding among the Nazca lines

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02961-7

    A 37-metre-long figure of a cat has reappeared among the iconic Peruvian geoglyphs known as the Nazca lines. Plus, how China could be carbon neutral by 2060 and migraine headaches.

    in Nature on October 19, 2020 12:00 AM.

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    How LGBT+ scientists would like to be included and welcomed in STEM workplaces

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02949-3

    Steps that peers and institutions can take to make laboratories, conferences and lecture halls safe and inclusive spaces.

    in Nature on October 19, 2020 12:00 AM.

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    Probing fine-scale connections in the brain

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02947-5

    Artificial intelligence and improved microscopy make it feasible to map the nervous system at ever-higher resolution.

    in Nature on October 19, 2020 12:00 AM.

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    The scientist-gardener who is harnessing tobacco’s power to heal

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02938-6

    Molecular immunologist Audrey Teh is passionate about converting plants into pharmaceutical producers.

    in Nature on October 19, 2020 12:00 AM.

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    The unsung heroes of the Nobel-winning hepatitis C discovery

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02932-y

    A tight-knit team of scientists worked feverishly to identify the deadly virus. Only one of them was awarded the Nobel.

    in Nature on October 19, 2020 12:00 AM.

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    How China could be carbon neutral by mid-century

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02927-9

    Our special report examines the role of renewables, nuclear power and carbon capture in reaching this ambitious goal.

    in Nature on October 19, 2020 12:00 AM.

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    All eyes on a hurdle race for a SARS-CoV-2 vaccine

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02926-w

    Leading COVID-19 vaccine candidates have progressed through laboratory tests at record speed. Two early clinical trials suggest that immunization delivers a favourable immune response and safety profile, but questions remain.

    in Nature on October 19, 2020 12:00 AM.

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    A nanomachine makes light work

    Nature, Published online: 19 October 2020; doi:10.1038/d41586-020-02902-4

    Laser light helps to build a miniature ‘gear’ system and provides energy to turn it.

    in Nature on October 19, 2020 12:00 AM.

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    Repeated Restraint Stress Led to Cognitive Dysfunction by NMDA Receptor-Mediated Hippocampal CA3 Dendritic Spine Impairments in Juvenile Sprague-Dawley Rats

    Although numerous studies have indicated that chronic stress causes cognitive dysfunction with the impairment of synaptic structures and functions, the relationship between cognitive deficits induced by repeated restraint stress and the level of NMDA receptors in the subregion of the hippocampus has been relatively unknown until now. In this study, 3-week-old male Sprague-Dawley rats were exposed to repeated restraint stress for seven consecutive days, their cognitive functions were evaluated through behavioral tests, and then they were sacrificed for electrophysiological, morphological, and biochemical assays. Chronic repeated restraint stress led to cognitive and electrophysiological impairments, with a reduced density of dendritic spines. We also found that the protein level of NMDA receptors only increased in the hippocampal CA3 region. Nevertheless, repeated restraint stress-induced cognitive and synaptic dysfunction were effectively reversed by Ro25-6981, an inhibitor of the GluN2B receptor. These findings suggest that repeated restraint stress-induced synaptic and cognitive deficits are probably mediated through NMDA receptors.

    in Frontiers in Molecular Neuroscience on October 19, 2020 12:00 AM.

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    Transcranial Magnetic Stimulation-Induced Plasticity Mechanisms: TMS-Related Gene Expression and Morphology Changes in a Human Neuron-Like Cell Model

    Transcranial Magnetic Stimulation (TMS) is a form of non-invasive brain stimulation, used to alter cortical excitability both in research and clinical applications. The intermittent and continuous Theta Burst Stimulation (iTBS and cTBS) protocols have been shown to induce opposite after-effects on human cortex excitability. Animal studies have implicated synaptic plasticity mechanisms long-term potentiation (LTP, for iTBS) and depression (LTD, for cTBS). However, the neural basis of TMS effects has not yet been studied in human neuronal cells, in particular at the level of gene expression and synaptogenesis. To investigate responses to TBS in living human neurons, we differentiated human SH-SY5Y cells toward a mature neural phenotype, and stimulated them with iTBS, cTBS, or sham (placebo) TBS. Changes in (a) mRNA expression of a set of target genes (previously associated with synaptic plasticity), and (b) morphological parameters of neurite outgrowth following TBS were quantified. We found no general effects of stimulation condition or time on gene expression, though we did observe a significantly enhanced expression of plasticity genes NTRK2 and MAPK9 24 h after iTBS as compared to sham TBS. This specific effect provides unique support for the widely assumed plasticity mechanisms underlying iTBS effects on human cortex excitability. In addition to this protocol-specific increase in plasticity gene expression 24 h after iTBS stimulation, we establish the feasibility of stimulating living human neuron with TBS, and the importance of moving to more complex human in vitro models to understand the underlying plasticity mechanisms of TBS stimulation.

    in Frontiers in Molecular Neuroscience on October 19, 2020 12:00 AM.

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    Dopamine, Alpha-Synuclein, and Mitochondrial Dysfunctions in Parkinsonian Eyes

    Parkinson’s disease (PD) is characterized by motor dysfunctions including bradykinesia, tremor at rest and motor instability. These symptoms are associated with the progressive degeneration of dopaminergic neurons originating in the substantia nigra pars compacta and projecting to the corpus striatum, and by accumulation of cytoplasmic inclusions mainly consisting of aggregated alpha-synuclein, called Lewy bodies. PD is a complex, multifactorial disorder and its pathogenesis involves multiple pathways and mechanisms such as α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation. Motor symptoms manifest when there is already an extensive dopamine denervation. There is therefore an urgent need for early biomarkers to apply disease-modifying therapeutic strategies. Visual defects and retinal abnormalities, including decreased visual acuity, abnormal spatial contrast sensitivity, color vision defects, or deficits in more complex visual tasks are present in the majority of PD patients. They are being considered for early diagnosis together with retinal imaging techniques are being considered as non-invasive biomarkers for PD. Dopaminergic cells can be found in the retina in a subpopulation of amacrine cells; however, the molecular mechanisms leading to visual deficits observed in PD patients are still largely unknown. This review provides a comprehensive analysis of the retinal abnormalities observed in PD patients and animal models and of the molecular mechanisms underlying neurodegeneration in parkinsonian eyes. We will review the role of α-synuclein aggregates in the retina pathology and/or in the onset of visual symptoms in PD suggesting that α-synuclein aggregates are harmful for the retina as well as for the brain. Moreover, we will summarize experimental evidence suggesting that the optic nerve pathology observed in PD resembles that seen in mitochondrial optic neuropathies highlighting the possible involvement of mitochondrial abnormalities in the development of PD visual defects. We finally propose that the eye may be considered as a complementary experimental model to identify possible novel disease’ pathways or to test novel therapeutic approaches for PD.

    in Frontiers in Neuroscience: Neurodegeneration on October 19, 2020 12:00 AM.

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    Motor Imagery Under Distraction— An Open Access BCI Dataset

    in Frontiers in Neuroscience: Neural Technology on October 19, 2020 12:00 AM.

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    Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER)

    This article provides an overview of the study protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) project, a longitudinal study in which we plan to recruit 60 depressed adolescents (ages 13–18 years) and 30 psychiatrically healthy controls in order to examine the inflammatory and glutamatergic pathways that contribute to the recurrence of depression in adolescents. TIGER is the first study to examine the effects of peripheral inflammation on neurodevelopmental trajectories by assessing changes in cortical glutamate in depressed adolescents. Here, we describe the scientific rationale, design, and methods for the TIGER project. This article is intended to serve as an introduction to this project and to provide details for investigators who may be seeking to replicate or extend these methods for other related research endeavors.

    in Frontiers in Human Neuroscience on October 19, 2020 12:00 AM.

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    Pancreatic Polypeptide but Not Other Members of the Neuropeptide Y Family Shows a Moderate Association With Perceived Anxiety in Obese Men

    Neuropeptide Y (NPY), peptide tyrosine tyrosine (PYY), and pancreatic polypeptide (PP) are important mediators in the bidirectional communication along the gut-brain-axis. Best known for their role in the regulation of appetite and food intake they are considered to play a crucial role in the development of obesity. Additionally, mounting evidence indicates a regulatory function in anxiety, mood and stress resilience with potential sex differences. In the present study, we examined the associations of NPY, PYY, and PP plasma levels with anxiety, depressiveness and perceived stress in obese patients. We analyzed 144 inpatients (90 female, 54 male, BMI mean: 49.4 kg/m2) in a naturalistic treatment setting for obesity and its somatic and mental comorbidities. Fasting blood samples were taken, and patients completed psychometric self-assessment questionnaires (GAD-7, PHQ-9, PSQ-20) within the first week after admission and before discharge. Plasma concentrations of the peptides were measured by ELISA. Women showed significant higher anxiety (GAD-7: 8.13 ± 5.67 vs. 5.93 ± 5.42, p = 0.04) and stress scores (PSQ-20: 52.62 ± 23.5 vs. 41.23 ± 22.53, p = 0.01) than men. In the longitudinal analysis women with a clinically relevant improvement of anxiety (≥ 5 points on GAD-7, p < 0.001) also showed significant improvements in depression (PHQ-9: 38%, p = 0.002) and PSQ-20 scores (23%, p = 0.005) while anxiety-improved male patients only improved in the subscale tension of the PSQ-20 (34%, p = 0.02). In men we observed a positive correlation of PP with anxiety scores (GAD-7: r = 0.41, p = 0.007) and with age (r = 0.49, p = 0.001) on admission while NPY negatively correlated with age (r = -0.38, p = 0.01). In contrast, there were no significant associations (p > 0.05) in female subjects in the cross-sectional as well as in the longitudinal analysis. In conclusion, women suffering from morbid obesity showed greater psychological comorbidity and considerable interactions among them. Despite that we solely observed associations of PP with anxiety and age with NPY and PP in men, suggesting a possible influence of sex hormones on the NPY system. However, improvement of anxiety scores did not lead to significant changes in NPY.

    in Frontiers in Human Neuroscience on October 19, 2020 12:00 AM.

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    Synchronization, Stochasticity, and Phase Waves in Neuronal Networks With Spatially-Structured Connectivity

    Oscillations in the beta/low gamma range (10–45 Hz) are recorded in diverse neural structures. They have successfully been modeled as sparsely synchronized oscillations arising from reciprocal interactions between randomly connected excitatory (E) pyramidal cells and local interneurons (I). The synchronization of spatially distant oscillatory spiking E–I modules has been well-studied in the rate model framework but less so for modules of spiking neurons. Here, we first show that previously proposed modifications of rate models provide a quantitative description of spiking E–I modules of Exponential Integrate-and-Fire (EIF) neurons. This allows us to analyze the dynamical regimes of sparsely synchronized oscillatory E–I modules connected by long-range excitatory interactions, for two modules, as well as for a chain of such modules. For modules with a large number of neurons (> 105), we obtain results similar to previously obtained ones based on the classic deterministic Wilson-Cowan rate model, with the added bonus that the results quantitatively describe simulations of spiking EIF neurons. However, for modules with a moderate (~ 104) number of neurons, stochastic variations in the spike emission of neurons are important and need to be taken into account. On the one hand, they modify the oscillations in a way that tends to promote synchronization between different modules. On the other hand, independent fluctuations on different modules tend to disrupt synchronization. The correlations between distant oscillatory modules can be described by stochastic equations for the oscillator phases that have been intensely studied in other contexts. On shorter distances, we develop a description that also takes into account amplitude modes and that quantitatively accounts for our simulation data. Stochastic dephasing of neighboring modules produces transient phase gradients and the transient appearance of phase waves. We propose that these stochastically-induced phase waves provide an explanative framework for the observations of traveling waves in the cortex during beta oscillations.

    in Frontiers in Computational Neuroscience on October 19, 2020 12:00 AM.

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    Molecular Motor KIF3B Acts as a Key Regulator of Dendritic Architecture in Cortical Neurons

    Neurons require a well-coordinated intercellular transport system to maintain their normal cellular function and morphology. The kinesin family of proteins (KIFs) fills this role by regulating the transport of a diverse array of cargos in post-mitotic cells. On the other hand, in mitotic cells, KIFs facilitate the fidelity of the cellular division machinery. Though certain mitotic KIFs function in post-mitotic neurons, little is known about them. We studied the role of a mitotic KIF (KIF3B) in neuronal architecture. We find that the RNAi mediated knockdown of KIF3B in primary cortical neurons resulted in an increase in spine density; the number of thin and mushroom spines; and dendritic branching. Consistent with the change in spine density, we observed a specific increase in the distribution of the excitatory post-synaptic protein, PSD-95 in KIF3B knockdown neurons. Interestingly, overexpression of KIF3B produced a reduction in spine density, in particular mushroom spines, and a decrease in dendritic branching. These studies suggest that KIF3B is a key determinant of cortical neuron morphology and that it functions as an inhibitory constraint on structural plasticity, further illuminating the significance of mitotic KIFs in post-mitotic neurons.

    in Frontiers in Cellular Neuroscience on October 19, 2020 12:00 AM.

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    Mapping Central Projection of Oxytocin Neurons in Unmated Mice Using Cre and Alkaline Phosphatase Reporter

    Oxytocin, a neuropeptide and peptide hormone, is produced by neurons in the hypothalamus and released by the posterior pituitary to control breastfeeding and labor. Recent studies have revealed that oxytocin in the central nervous system is also involved in modulating social interaction. To understand the potential role and innervation pattern of oxytocin neurons before sexual interaction, here we used transgenic mice which have the Cre recombinase under the control of an endogenous oxytocin promoter and Cre-dependent human placental alkaline phosphatase (AP) reporter to label the oxytocin neurons in the naive mouse brain. Since AP is located on the membrane of oxytocin neurons, AP histochemistry staining enabled us to observe the fine axonal terminals and the innervation pattern of oxytocin neurons in the thick serial coronal brain slices. Here we show that the number of AP-labeled cells varies with staining reaction time and ranges from 30% of the oxytocin immune-positive cell count to slightly higher than the oxytocin immune-positive cell count. Using AP staining with extended reaction time, which may not label all oxytocin neurons, we confirmed many innervation targets of oxytocin neurons from the anterior olfactory nucleus, some cortex regions, the limbic system, the hypothalamus, and the hindbrain, while the cell bodies were exclusively located in the hypothalamus and the bed nucleus of the stria terminalis. Finally, we observe some individual variance at the olfactory area, isocortex, striatum, paraventricular nucleus of thalamus, locus coeruleus, and Barrington’s nucleus.

    in Frontiers in Neuroanatomy on October 19, 2020 12:00 AM.

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    BrainWiki—A Wiki-Style, User Driven, Comparative Brain Anatomy Tool

    The mouse is the most important animal model within neuroscientific research, a position strengthened by the wide-spread use of transgenic mouse models. Discoveries in animals are followed by corroboration in humans, and the interchange between these fields of research is essential to our understanding of the human brain. With the advent of advanced technologies such as single-cell transcriptomics, epigenetic profiling and diffusion MRI, many prominent research institutes and collaborations have emerged, aiming to construct complete human or mouse brain atlases with data on gene expression, connectivity and cell types. These initiatives are indispensable resources, but frequently require extensive, time-consuming development, and rely on updates by the provider. They often come in the shape of applications which require practice or prior technical know-how. Importantly, none of them place the human and the mouse brain next to each other to allow for immediate comparison. We present BrainWiki, a user-friendly, web-based atlas that links the human and the mouse brain together, side-by-side. The platform gives the user a simple overview of brain anatomy along with published articles relating to each brain region that allows the user to delve deeper into the current state of research concerning circuitry, brain functions and pathology. The website relies on interactivity and supports user contributions resulting in a dynamic website that evolves at the pace of neuroscience. It is designed to allow for constant updates and new features in the future which will contain data such as gene expression and neuronal cell types.

    in Frontiers in Neuroanatomy on October 19, 2020 12:00 AM.

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    Large-Scale Convergence of Receptor Cell Arrays Onto Afferent Terminal Arbors in the Lorenzinian Electroreceptors of Polyodon

    Certain sensory receptors contain many transducers, converging onto few afferents. Convergence creates star-topology neural networks, of iterative parallel organization, that may yield special functional properties. We quantitated large-scale convergence in electroreceptors on the rostrum of preadult paddlefish, Polyodon spathula (Acipenseriforme vertebrates), and analyzed the afferent terminal branching underlying the convergence. From neurophysiological mapping, a recorded afferent innervated 23.3 ± 9.1 (range 6–45) ampullary organs, and innervated every ampullary organ within the receptive field’s sharp boundary. Ampullary organs each contained ∼665 Lorenzinian receptor cells, from imaging and modeling. We imaged three serial types of afferent branching at electroreceptors, after immunofluorescent labeling for neurite filaments, glial sheaths, or nodal ion channels, or by DiI tracing. (i) Myelinated tree: Each of 3.08 ± 0.51 (2–4) parallel afferents from a cranial nerve (ALLn) entered a receptive field from deeper tissue, then branched into a laminar tree of large myelinated dendrites, parallel to the skin, that branched radially until ∼9 extremities with heminodes, which were candidate sites of spike encoders. (ii) Inline transition: Each myelinated extremity led distally into local unmyelinated arbors originating at inline branching structures covered by terminal (satellite) glia. The unmyelinated transition zones included globular afferent modules, 4–6 microns wide, from which erupted fine fascicles of parallel submicron neurites, a possibly novel type of neuronal branching. The neurite fascicles formed loose bundles projecting ∼105 microns distally to innervate local groups of ∼3 adjacent ampullary organs. (iii) Radial arbors: Receptor cells in an electrosensory neuroepithelium covering the basal pole of each ampullary organ were innervated by bouton endings of radial neurites, unmyelinated and submicron, forming a thin curviplanar lamina distal to the lectin+ basal lamina. The profuse radial neurites diverged from thicker (∼2 micron) basolateral trunks. Overall, an average Polyodon electroreceptor formed a star topology array of ∼9 sensor groups. Total convergence ratios were 15,495 ± 6,052 parallel receptor cells per afferent per mean receptive field, assuming 100% innervation. Large-scale convergence likely increases the signal-to-noise ratio (SNR) of stimulus encoding into spiking afferent output, increasing receiver sensitivity. Unmyelinated arbors may also regenerate and repair the afferent innervation of ampullary organs.

    LSID:urn:lsid:zoobank.org:act:09BCF04C-3C3C-4B6C-9DC9-A2BF43087369

    in Frontiers in Neuroanatomy on October 19, 2020 12:00 AM.

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    LncRNAs Stand as Potent Biomarkers and Therapeutic Targets for Stroke

    Stroke is a major public health problem worldwide with a high burden of neurological disability and mortality. Long noncoding RNAs (lncRNAs) have attracted much attention in the past decades because of their newly discovered roles in pathophysiological processes in many diseases. The abundance of lncRNAs in the nervous system indicates that they may be part of a complex regulatory network governing physiology and pathology of the brain. In particular, lncRNAs have been shown to play pivotal roles in the pathogenesis of stroke. In this article, we provide a review of the multifaceted functions of lncRNAs in the pathogenesis of ischemic stroke and intracerebral hemorrhage, highlighting their promising use as stroke diagnostic biomarkers and therapeutics. To this end, we discuss the potential of stem cells in aiding lncRNA applications in stroke.

    in Frontiers in Ageing Neuroscience on October 19, 2020 12:00 AM.

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    The Effects of Nordic Walking With Poles With an Integrated Resistance Shock Absorber on Cognitive Abilities and Cardiopulmonary Efficiency in Postmenopausal Women

    Late adulthood is associated with atrophy of brain areas, which contribute to cognitive deterioration and increase the risk of depression. On the other hand, aerobic exercise can improve learning and memory function, ameliorate mood, and prevent neurodegenerative changes. This study demonstrates the effect of Nordic walking (NW) and NW with poles with an integrated resistance shock absorber (NW with RSA) on aerobic capacity and body composition in postmenopausal women. It also measures the brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) serum levels and determines correlations with cognitive functions and depression symptoms. These relationships with the use of NW with RSA as a new form of exercise have not been described thus far. In this study, 31 women (NW – 16, NW with RSA – 15) participated in eight weeks of training. The findings showed that only NW with RSA training caused a significant decrease in body mass and body mass index (p < 0.05). There were no significant changes in GDNF levels between groups studied. Regarding BDNF, a significant decrease (p < 0.05) in the NW group and an increase (not statistically significant) in the NW with RSA group was found. A comparative analysis of cognitive and depression outcomes and changes in BDNF and GDNF concentration showed no significant differences in the efficacy of either form of training. Training loads resulted in a significant increase in VO2max in both the NW (p < 0.01) and NW with RSA (p < 0.05) groups. This indicates an improvement in cardiopulmonary efficiency of the examined women.

    in Frontiers in Ageing Neuroscience on October 19, 2020 12:00 AM.

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    Reliability of P3 Event-Related Potential During Working Memory Across the Spectrum of Cognitive Aging

    Event-related potentials (ERPs) offer unparalleled temporal resolution in tracing distinct electrophysiological processes related to normal and pathological cognitive aging. The stability of ERPs in older individuals with a vast range of cognitive ability has not been established. In this test-retest reliability study, 39 older individuals (age 74.10 (5.4) years; 23 (59%) women; 15 non β-amyloid elevated, 16 β-amyloid elevated, 8 cognitively impaired) with scores on the Montreal Cognitive Assessment (MOCA) ranging between 3 and 30 completed a working memory (n-back) test with three levels of difficulty at baseline and 2-week follow-up. The main aim was to evaluate stability of the ERP on grand averaged task effects for both visits in the total sample (n = 39). Secondary aims were to evaluate the effect of age, group (non β-amyloid elevated; β-amyloid elevated, cognitively impaired), cognitive status (MOCA), and task difficulty on ERP reliability. P3 peak amplitude and latency were measured in predetermined channels. P3 peak amplitude at Fz, our main outcome variable, showed excellent reliability in 0-back (intraclass correlation coefficient (ICC), 95% confidence interval = 0.82 (0.67–0.90) and 1-back (ICC = 0.87 (0.76–0.93), however, only fair reliability in 2-back (ICC = 0.53 (0.09–0.75). Reliability of P3 peak latencies was substantially lower, with ICCs ranging between 0.17 for 2-back and 0.54 for 0-back. Generalized linear mixed models showed no confounding effect of age, group, or task difficulty on stability of P3 amplitude and latency of Fz. By contrast, MOCA scores tended to negatively correlate with P3 amplitude of Fz (p = 0.07). We conclude that P3 peak amplitude, and to lesser extent P3 peak latency, provide a stable measure of electrophysiological processes in older individuals.

    in Frontiers in Ageing Neuroscience on October 19, 2020 12:00 AM.

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    APOE2 is associated with longevity independent of Alzheimer's disease

    Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical database as well as animal models. Notably, APOE2 was associated with preserved physical activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

    in eLife on October 19, 2020 12:00 AM.

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    Feeding state functionally reconfigures a sensory circuit to drive thermosensory behavioral plasticity

    Internal state alters sensory behaviors to optimize survival strategies. The neuronal mechanisms underlying hunger-dependent behavioral plasticity are not fully characterized. Here we show that feeding state alters C. elegans thermotaxis behavior by engaging a modulatory circuit whose activity gates the output of the core thermotaxis network. Feeding state does not alter the activity of the core thermotaxis circuit comprised of AFD thermosensory and AIY interneurons. Instead, prolonged food deprivation potentiates temperature responses in the AWC sensory neurons, which inhibit the postsynaptic AIA interneurons to override and disrupt AFD-driven thermotaxis behavior. Acute inhibition and activation of AWC and AIA, respectively, restores negative thermotaxis in starved animals. We find that state-dependent modulation of AWC-AIA temperature responses requires INS-1 insulin-like peptide signaling from the gut and DAF-16 FOXO function in AWC. Our results describe a mechanism by which functional reconfiguration of a sensory network via gut-brain signaling drives state-dependent behavioral flexibility.

    in eLife on October 19, 2020 12:00 AM.

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    Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

    Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.

    in eLife on October 19, 2020 12:00 AM.

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    Amino acid synthesis loss in parasitoid wasps and other hymenopterans

    Insects utilize diverse food resources which can affect the evolution of their genomic repertoire, including leading to gene losses in different nutrient pathways. Here we investigate gene loss in amino acid synthesis pathways, with special attention to hymenopterans and parasitoid wasps. Using comparative genomics, we find that synthesis capability for tryptophan, phenylalanine, tyrosine and histidine was lost in holometabolous insects prior to hymenopteran divergence, while valine, leucine and isoleucine were lost in the common ancestor of Hymenoptera. Subsequently, multiple loss events of lysine synthesis occurred independently in the Parasitoida and Aculeata. Experiments in the parasitoid Cotesia chilonis confirm that it has lost the ability to synthesize eight amino acids. Our findings provide insights into amino acid synthesis evolution, and specifically can be used to inform the design of parasitoid artificial diets for pest control.

    in eLife on October 19, 2020 12:00 AM.

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    On the objectivity, reliability, and validity of deep learning enabled bioimage analyses

    Bioimage analysis of fluorescent labels is widely used in the life sciences. Recent advances in deep learning (DL) allow automating time-consuming manual image analysis processes based on annotated training data. However, manual annotation of fluorescent features with a low signal-to-noise ratio is somewhat subjective. Training DL models on subjective annotations may be instable or yield biased models. In turn, these models may be unable to reliably detect biological effects. An analysis pipeline integrating data annotation, ground truth estimation, and model training can mitigate this risk. To evaluate this integrated process, we compared different DL-based analysis approaches. With data from two model organisms (mice, zebrafish) and five laboratories, we show that ground truth estimation from multiple human annotators helps to establish objectivity in fluorescent feature annotations. Furthermore, ensembles of multiple models trained on the estimated ground truth establish reliability and validity. Our research provides guidelines for reproducible DL-based bioimage analyses.

    in eLife on October 19, 2020 12:00 AM.

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    NAIP-NLRC4-deficient mice are susceptible to shigellosis

    Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to Shigella and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here we propose that the differential susceptibility of mice and humans to Shigella is due to mouse-specific activation of the NAIP–NLRC4 inflammasome. We find that NAIP–NLRC4-deficient mice are highly susceptible to oral Shigella infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote Shigella pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP–NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.

    in eLife on October 19, 2020 12:00 AM.

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    Neural encoding of task-dependent errors during adaptive learning

    Effective learning requires using errors in a task-dependent manner, for example adjusting to errors that result from unpredicted environmental changes but ignoring errors that result from environmental stochasticity. Where and how the brain represents errors in a task-dependent manner and uses them to guide behavior are not well understood. We imaged the brains of human participants performing a predictive-inference task with two conditions that had different sources of errors. Their performance was sensitive to this difference, including more choice switches after fundamental changes versus stochastic fluctuations in reward contingencies. Using multi-voxel pattern classification, we identified task-dependent representations of error magnitude and past errors in posterior parietal cortex. These representations were distinct from representations of the resulting behavioral adjustments in dorsomedial frontal, anterior cingulate, and orbitofrontal cortex. The results provide new insights into how the human brain represents errors in a task-dependent manner and guides subsequent adaptive behavior.

    in eLife on October 19, 2020 12:00 AM.

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    Intestinal microbiology shapes population health impacts of diet and lifestyle risk exposures in Torres Strait Islander communities

    Poor diet and lifestyle exposures are implicated in substantial global increases in non-communicable disease burden in low-income, remote, and Indigenous communities. This observational study investigated the contribution of the fecal microbiome to influence host physiology in two Indigenous communities in the Torres Strait Islands: Mer, a remote island where a traditional diet predominates, and Waiben a more accessible island with greater access to takeaway food and alcohol. Counterintuitively, disease markers were more pronounced in Mer residents. However, island-specific differences in disease risk were explained, in part, by microbiome traits. The absence of Alistipes onderdonkii, for example, significantly (p=0.014) moderated island-specific patterns of systolic blood pressure in multivariate-adjusted models. We also report mediatory relationships between traits of the fecal metagenome, disease markers, and risk exposures. Understanding how intestinal microbiome traits influence response to disease risk exposures is critical for the development of strategies that mitigate the growing burden of cardiometabolic disease in these communities.

    in eLife on October 19, 2020 12:00 AM.

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    Identification of ubiquitin Ser57 kinases regulating the oxidative stress response in yeast

    Ubiquitination regulates many different cellular processes, including protein quality control, membrane trafficking, and stress responses. The diversity of ubiquitin functions in the cell is partly due to its ability to form chains with distinct linkages that can alter the fate of substrate proteins in unique ways. The complexity of the ubiquitin code is further enhanced by post-translational modifications on ubiquitin itself, the biological functions of which are not well understood. Here, we present genetic and biochemical evidence that serine 57 (Ser57) phosphorylation of ubiquitin functions in stress responses in Saccharomyces cerevisiae, including the oxidative stress response. We also identify and characterize the first known Ser57 ubiquitin kinases in yeast and human cells, and we report that two Ser57 ubiquitin kinases regulate the oxidative stress response in yeast. These studies implicate ubiquitin phosphorylation at the Ser57 position as an important modifier of ubiquitin function, particularly in response to proteotoxic stress.

    in eLife on October 19, 2020 12:00 AM.

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    Replication Study: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs

    As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Phelps et al., 2016) that described how we intended to replicate selected experiments from the paper ‘Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs’ (Tay et al., 2011). Here, we report the results. We found depletion of putative PTEN competing endogenous mRNAs (ceRNAs) in DU145 cells did not impact PTEN 3’UTR regulation using a reporter, while the original study reported decreased activity when SERINC1, VAPA, and CNOT6L were depleted (Figure 3C; Tay et al., 2011). Using the same reporter, we found decreased activity when ceRNA 3’UTRs were overexpressed, while the original study reported increased activity (Figure 3D; Tay et al., 2011). In HCT116 cells, ceRNA depletion resulted in decreased PTEN protein levels, a result similar to the findings reported in the original study (Figure 3G,H; Tay et al., 2011); however, while the original study reported an attenuated ceRNA effect in microRNA deficient (DicerEx5) HCT116 cells, we observed increased PTEN protein levels. Further, we found depletion of the ceRNAs VAPA or CNOT6L did not statistically impact DU145, wild-type HCT116, or DicerEx5 HCT116 cell proliferation. The original study reported increased DU145 and wild-type HCT116 cell proliferation when these ceRNAs were depleted, which was attenuated in the DicerEx5 HCT116 cells (Figure 5B; Tay et al., 2011). Differences between the original study and this replication attempt, such as variance between biological repeats, are factors that might have influenced the results. Finally, we report meta-analyses for each result.

    in eLife on October 19, 2020 12:00 AM.

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    Quantitative dissection of transcription in development yields evidence for transcription factor-driven chromatin accessibility

    Thermodynamic models of gene regulation can predict transcriptional regulation in bacteria, but in eukaryotes chromatin accessibility and energy expenditure may call for a different framework. Here we systematically tested the predictive power of models of DNA accessibility based on the Monod-Wyman-Changeux (MWC) model of allostery, which posits that chromatin fluctuates between accessible and inaccessible states. We dissected the regulatory dynamics of hunchback by the activator Bicoid and the pioneer-like transcription factor Zelda in living Drosophila embryos and showed that no thermodynamic or non-equilibrium MWC model can recapitulate hunchback transcription. Therefore, we explored a model where DNA accessibility is not the result of thermal fluctuations but is catalyzed by Bicoid and Zelda, possibly through histone acetylation, and found that this model can predict hunchback dynamics. Thus, our theory-experiment dialogue uncovered potential molecular mechanisms of transcriptional regulatory dynamics, a key step toward reaching a predictive understanding of developmental decision-making.

    in eLife on October 19, 2020 12:00 AM.

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    Distributional Reinforcement Learning in the Brain

    Learning about rewards and punishments is critical for survival. Classical studies have demonstrated an impressive correspondence between the firing of dopamine neurons in the mammalian midbrain and the reward prediction errors of reinforcement learning algorithms, which express the difference between actual reward and predicted mean reward. However, it may be advantageous to learn not only the mean but also the complete distribution of potential rewards. Recent advances in machine learning have revealed a biologically plausible set of algorithms for reconstructing this reward distribution from experience.

    in Trends in Neurosciences: In press on October 19, 2020 12:00 AM.

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    Fast Recurrent Processing via Ventrolateral Prefrontal Cortex Is Needed by the Primate Ventral Stream for Robust Core Visual Object Recognition

    Kar and DiCarlo show that reversibly inactivating parts of macaque vlPFC results in selective object recognition deficits for specific images that most likely depend on recurrent computations. Their results implicate vlPFC, a recurrently connected circuit node, as critical to producing behaviorally sufficient object representations in the primate ventral visual stream.

    in Neuron: In press on October 19, 2020 12:00 AM.

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    Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex

    Xing et al. uncover a novel role of the serotonin receptor HTR2A distinct from its function in neurotransmission, and that role is to increase basal progenitor proliferation in the embryonic ferret and fetal human neocortex. HTR2A-induced basal progenitor proliferation may therefore have contributed to the evolutionary expansion of human neocortex.

    in Neuron: In press on October 19, 2020 12:00 AM.

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    Dopamine Oppositely Modulates State Transitions in Striosome and Matrix Direct Pathway Striatal Spiny Neurons

    Prager et al. show that dopamine promotes the maintenance of dendritically evoked “up-states” in mouse direct pathway matrix SPNs but opposes it in striosomes. This requires postsynaptic D1 receptors and involves differential engagement of L-type Ca2+ channels. These findings reveal a mechanism where fluctuations in dopamine may constrain compartment-specific striatal output.

    in Neuron: In press on October 19, 2020 12:00 AM.

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    An Open Resource for Non-human Primate Optogenetics

    To accelerate development of optogenetics in non-human primates, Tremblay et al. established an international open science initiative allowing investigators to easily share results of successful and unsuccessful experiments with the community. The resulting database reveals new insights into best practices to maximize success in primate optogenetics and spearhead translational applications.

    in Neuron: In press on October 19, 2020 12:00 AM.

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    A Platform for Brain-wide Volumetric Functional Ultrasound Imaging and Analysis of Circuit Dynamics in Awake Mice

    Brunner, Grillet et al. develop volumetric functional ultrasound imaging (vfUSI) of brain activity in awake mice. vfUSI applies in most experimental conditions used for neuroscience research, and it allows recording of brain-wide activity simultaneously in hundreds of regions with unprecedented spatiotemporal resolution and sensitivity.

    in Neuron: In press on October 19, 2020 12:00 AM.

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    APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

    Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimers disease, as well as in young cognitively normal carriers of the E4 allele of Apolipoprotein E, the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Here, we undertook a multi-omic approach by combining single-cell RNA sequencing and stable isotope resolved metabolomics to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increases in lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the E4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing mice, young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a Warburg like endophenotype that is observable in young humans decades prior to clinically manifest AD.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

    Repeat associated non-AUG (RAN) translation of FMR1 5' UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located just 5' to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation (IP) enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: one beginning with methionine (Ac-MEAPLPGGVR) initiating at an ACG, and a second beginning with threonine (Ac-TEAPLPGGVR), initiating at a GUG. Abundance of the threonine peptide was enhanced relative to the methionine peptide upon activation of the integrated stress response. In addition, loss of the eIF2 alternative factor, eIF2A, or enhanced expression of initiation factor eIF1, preferentially suppressed GUG initiated FMRpolyG synthesis. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates at specific near cognate codons dependent on available initiation factors and cellular environment.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Membrane Ca2+ permeability and IP3R2 dependent Ca2+-induced Ca2+ release are essential for astrocytic intracellular Ca2+ elevation upon neuronal stimulation at the mouse hippocampal CA3 - CA1 excitatory synapses

    Astrocytes are intricately involved in the activity of neural circuits, however, their basic physiology of interacting with neurons remains controversial. Using dual-indicator two-photon imaging of neurons and astrocytes during stimulations of hippocampal CA3 - CA1 Schaffer collateral (Scc) excitatory synapses, we report that under physiological conditions, the increased glutamate released from the higher frequency stimulation of neurons can accelerate local astrocytic Ca2+ levels. As consequences of extracellular glutamate clearance and maintaining of astrocytic intracellular Na+ homeostasis, the increase of astrocytic membrane Ca2+ permeability via Na+/Ca2+ exchanger (NCX) reverse mode is the primary reason of eliciting astrocytic intracellular Ca2+ elevation upon neuronal stimulation. This Ca2+-induced Ca2+ release is dependent on inositol triphosphate receptor type 2 (IP3R2). In addition, ATP released from Scc excitatory synapses can contribute to this molecular mechanism of Ca2+-induced Ca2+ release in astrocytes.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: evidence for an implication of oligodendrocyte progenitor cells

    Child abuse (CA) is a strong predictor of psychopathologies and suicide, and can lastingly alter normal trajectories of brain development, particularly in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which are essential in orchestrating the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons (PV) into neuronal circuits. Using well-characterized post-mortem brain samples, we explored the hypothesis that CA has lasting effects on the development of PNNs in the ventromedial PFC. We found that a history of CA was specifically associated with increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in-situ hybridization, we show that the expression of canonical components of PNNs is highly enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviours by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Testing The Role Of Δ9-Tetrahydrocannabinol During Adolescence As A Gateway Drug: Behavioural, Brain Imaging And Transcriptomic Studies

    Cannabis is widely consumed by adolescents, and is also a potential prior step leading to the use of other drugs later in life (Gateway Hypothesis); however, the evidence for this hypothesis is controversial. This work aimed to increase our understanding of the long-term consequences of adolescent exposure to {Delta}9-tetrahydrocannabinol (THC) and to test the Gateway Hypothesis, experimentally. We exposed rats of both sexes to THC and studied its effects on reward-related processes, brain morphology (MRI), metabolism (1H-MRS), function (PET) and the transcriptomic profiles of the nucleus accumbens (RNASeq). Lastly, we studied cocaine-induced cellular activation (c-Fos) and cocaine addiction-like behaviours. THC exposure increased Pavlovian to instrumental transfer in males, goal-tracking (regardless of the sex) and impulsivity, but did not affect habit formation. Adolescent THC reduced striatal volume (in females), commissural integrity and ventricular volume. Also, there were lower levels of choline compounds in the cortex of THC-exposed rats and cerebellar hypoactivation in THC-females. THC also modified some of the gene expression programs of the nucleus accumbens, which could contribute to the behavioural features observed. Lastly, THC exposure increased cocaine-induced c-Fos levels in cortical and hypothalamic areas and increased the motivation for cocaine, followed by a higher rebound of use in THC-females after reestablishing low-effort conditions. Critically, acquisition of cocaine self-administration, compulsive seeking, intake under extended access or the incubation of seeking were unaltered. These results suggest that adolescent THC exposure alters psychological and brain development and that the Gateway Hypothesis does not entirely pass the test of preclinical enquiry.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Information Confusion Reveals an Innate Limit of the Information Processing by Neurons

    Information experiences complex transformation processes in the brain, involving various errors. A daunting and critical challenge in neuroscience is to understand the origin of these errors and their effects on neural information processing. While previous efforts have made substantial progresses in studying the information errors in bounded, unreliable and noisy transformation cases, it still remains elusive whether the neural system is inherently error-free under an ideal and noise-free condition. This work brings the controversy to an end with a negative answer. We propose a novel neural information confusion theory, indicating the widespread presence of information confusion phenomenon after the end of transmission process, which originates from innate neuron characteristics rather than external noises. Then, we reformulate the definition of zero-error capacity under the context of neuroscience, presenting an optimal upper bound of the zero-error transformation rates determined by the tuning properties of neurons. By applying this theory to neural coding analysis, we unveil the multi-dimensional impacts of information confusion on neural coding. Although it reduces the variability of neural responses and limits mutual information, it controls the stimulus-irrelevant neural activities and improves the interpretability of neural responses based on stimuli. Together, the present study discovers an inherent and ubiquitous precision limitation of neural information transformation, which shapes the coding process by neural ensembles. These discoveries reveal that the neural system is intrinsically error-prone in information processing even in the most ideal cases.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    3D analysis of the synaptic organization in the Entorhinal cortex in Alzheimer's disease

    The entorhinal cortex (EC) is especially vulnerable in the early stages of Alzheimer's disease (AD). In particular, cognitive deficits have been linked to alterations in the upper layers of EC. In the present report, we performed light microscopy analysis and 3D ultrastructural analyses of synapses in the EC using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to examine possible alterations related to AD. We analyzed 5000 synaptic junctions that were 3D reconstructed, representing the largest 3D ultrastructural study of synapses in the EC of the human brain from cases with AD performed to date. Structural differences were found in the AD tissue at the light microscope level and at the ultrastructural level. These differences may play a role in the anatomical basis for the impairment of cognitive functions in AD.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain

    The formation of new blood vessels and the establishment of vascular networks are crucial during brain development, in the adult healthy brain, as well as in various diseases of the central nervous system (CNS). Here, we describe a method that enables hierarchical imaging and computational analysis of vascular networks in postnatal- and adult mouse brains. Resin-based vascular corrosion casting, scanning electron microscopy, synchrotron radiation and desktop uCT imaging, and computational network analysis are used. Combining these methods enables detailed visualization and quantification of the three-dimensional (3D) brain vasculature. Network features such as vascular volume fraction, branch point density, vessel diameter, -length, -tortuosity, and -directionality as well as extravascular distance can be obtained at any developmental stage from the early postnatal to the adult brain. Our method allows characterizing brain vascular networks separately for capillaries and non-capillaries. The entire protocol, from mouse perfusion to vessel network analysis, takes approximately 10 days.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    The Brain Knows enough to take into account Light and Shadow

    Visual perception requires to infer object and light source color to maintain constancy. This study demonstrates the influences of environmental sunlight color trajectory (blue-white-yellow-red), and associated color of scattered light in shadows on color perception. In Adelson's checkerboard shadow illusion, squares of equal luminance appear lighter or darker depending on whether they are inside or outside a cast shadow. In some color variations, illusion magnitude is attenuated by specific colors of the cast shadow. Particularly in the green monotone environment (green checkerboard under green ambient and diffusion light), illusion magnitude reduces down nearly to zero. In contrast, shading by structure is not affected by the color environment. Thus, the cast shadow and shading by structure have distinct effects on surface color constancy. This illusion attenuation may be related to the absence of green in the natural environmental light spectrum, including in cast shadows. The brain may utilize the implicit learned trajectory of natural light to resolve ambiguity in surface reflectance. Our results provide a new formula not only to understand, but also to generate new variations of other illusions such as #The Dress.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease

    Neuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number o neurodegenerative disorders, including Alzheimer's disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation facor 2 (eIF2-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR wit the small molecule compound ISRIB (ISR inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Differential effects of prediction and adaptation along the cortical hierarchy during deviance processing

    Neural mismatch responses have been proposed to rely on different mechanisms, including prediction-related activity and adaptation to frequent stimuli. However, the cortical hierarchical structure of these mechanisms is unknown. To investigate this question, we used functional magnetic resonance imaging (fMRI) and an auditory oddball design with a suited control condition that enabled us to delineate the contributions of prediction- or adaptation-related brain activation during deviance processing. We found that while predictive processes increased with the hierarchical position of the brain area, adaptation declined. This suggests that the relative contribution of different mechanisms in deviance processing varies across the cortical hierarchy.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Temporal regulation of motor behavior on a modified forelimb dexterity test in mice

    Hand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Prenatal Environmental Stressors Impair Postnatal Microglia Function and Adult Behavior in Males

    Gestational exposure to environmental toxins and socioeconomic stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism. We modeled these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activated the maternal immune system. Only male offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminished microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Genetic ablation of microglia during the same critical period mimicked the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.

    in bioRxiv: Neuroscience on October 19, 2020 12:00 AM.

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    Corticocuneate projections are altered after spinal cord dorsal column lesions in New World monkeys

    Corticocuneate projections are altered after spinal cord dorsal column lesions in New World monkeys

    The cuneate nucleus normally receives cortical inputs from the hand regions of sensorimotor cortex in the contralateral and ipsilateral hemispheres. This cortical descending influence remains similar in New World monkeys with the short recoveries from the dorsal column lesion, but is greatly increased after the long recoveries.


    Abstract

    Recovery of responses to cutaneous stimuli in the area 3b hand cortex of monkeys after dorsal column lesions (DCLs) in the cervical spinal cord relies on neural rewiring in the cuneate nucleus (Cu) over time. To examine whether the corticocuneate projections are modified during recoveries after the DCL, we injected cholera toxin subunit B into the hand representation in Cu to label the cortical neurons after various recovery times, and related results to the recovery of neural responses in the affected area 3b hand cortex. In normal New World monkeys, labeled neurons were predominately distributed in the hand regions of contralateral areas 3b, 3a, 1 and 2, parietal ventral (PV), secondary somatosensory cortex (S2), and primary motor cortex (M1), with similar distributions in the ipsilateral cortex in significantly smaller numbers. In monkeys with short‐term recoveries, the area 3b hand neurons were unresponsive or responded weakly to touch on the hand, while the cortical labeling pattern was largely unchanged. After longer recoveries, the area 3b hand neurons remained unresponsive, or responded to touch on the hand or somatotopically abnormal parts, depending on the lesion extent. The distributions of cortical labeled neurons were much more widespread than the normal pattern in both hemispheres, especially when lesions were incomplete. The proportion of labeled neurons in the contralateral area 3b hand cortex was not correlated with the functional reactivation in the area 3b hand cortex. Overall, our findings indicated that corticocuneate inputs increase during the functional recovery, but their functional role is uncertain.

    in Journal of Comparative Neurology on October 18, 2020 05:32 PM.

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    Hippocampal subregional volume changes in elders classified using positron emission tomography‐based Alzheimer's biomarkers of β‐amyloid deposition and neurodegeneration

    Hippocampal subregional volume changes in elders classified using positron emission tomography‐based Alzheimer's biomarkers of β‐amyloid deposition and neurodegeneration

    Volume of hippocampal subregions (presubiculum/subiculum) are reduced in elderly subjects presenting cortical β‐amyloid deposition and signs of neurodegeneration. In elderly subjects with no neurodegeneration, hippocampal subregional volumes are also reduced in those with cognitive decline (dementia or amnestic mild cognitive impairment) compared to cognitively intact individuals.


    Abstract

    Changes in hippocampal subfield volumes (HSV) along the Alzheimer's disease (AD) continuum have been scarcely investigated to date in elderly subjects classified based on the presence of β‐amyloid aggregation and signs of neurodegeneration. We classified patients (either sex) with mild dementia compatible with AD (n = 35) or amnestic mild cognitive impairment (n = 39), and cognitively unimpaired subjects (either sex; n = 26) using [11C]PIB‐PET to assess β‐amyloid aggregation (A+) and [18F]FDG‐PET to account for neurodegeneration ((N)+). Magnetic resonance imaging‐based automated methods were used for HSV and white matter hyperintensity (WMH) measurements. Significant HSV reductions were found in A+(N)+ subjects in the presubiculum/subiculum complex and molecular layer, related to worse memory performance. In both the A+(N)+ and A+(N)− categories, subicular volumes were inversely correlated with the degree of Aβ deposition. The A−(N)+ subgroup showed reduced HSV relative to the A−(N)− subgroup also in the subiculum/presubiculum. Combining all (N)− subjects, HSV were lower in subjects presenting significant cognitive decline irrespective of A+/A− classification (controlling for WMH load); these between‐group differences were detected again in the presubiculum, but also involved the CA4 and granular layer. These findings demonstrate that differential HSV reductions are detectable both in (N)+ and (N)− categories along the AD continuum, and are directly related to the severity of cognitive deficits. HSV reductions are larger both in A+(N)+ and A+(N)− subjects in direct proportion to the degree of Aβ deposition. The meaningful HSV reductions detected in the A−(N)+ subgroup highlights the strength of biomarker‐based classifications outside of the classical AD continuum.

    in Journal of Neuroscience Research on October 18, 2020 04:15 PM.

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    Prespecified-time synchronization of swtiched coupled neural networks via smooth controllers

    Publication date: Available online 16 October 2020

    Source: Neural Networks

    Author(s): Shao Shao, Xiaoyang Liu, Jinde Cao

    in Neural Networks on October 18, 2020 01:00 PM.

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    CEGAN: Classification Enhancement Generative Adversarial Networks for unraveling data imbalance problems

    Publication date: Available online 17 October 2020

    Source: Neural Networks

    Author(s): Sungho Suh, Haebom Lee, Paul Lukowicz, Yong Oh Lee

    in Neural Networks on October 18, 2020 01:00 PM.

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    Genetic risk of Alzheimer’s disease – Sleepless with the enemy

    in Annals of Neurology on October 18, 2020 10:15 AM.

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    Morphological diversity of acoustic and electric communication systems of mochokid catfish

    Morphological diversity of acoustic and electric communication systems of mochokid catfish

    This study provides an anatomical characterization of motor and premotor neurons associated with the muscle producing swim bladder sounds and/or electric discharges in five mochokid catfish. Even though the same muscle and neuronal populations are associated with these behaviors across all species, our results suggest that behavioral differences are associated with quantitative differences, mainly in the size of the protractor muscle and associated skeletal elements, and the number, size and location of motoneurons.


    Abstract

    Mochokid catfish offer a distinct opportunity to study a communication system transitioning to a new signaling channel because some produce sounds and others electric discharges. Both signals are generated using an elastic spring system (ESS), which includes a protractor muscle innervated by motoneurons within the protractor nucleus that also has a motoneuron afferent population. Synodontis grandiops and S. nigriventris produce sounds and electric discharges, respectively, and their ESSs show several morphological and physiological differences. The extent to which these differences explain different signal types remains unclear. Here, we compare ESS morphologies and behavioral phenotypes among five mochokids. Synodontis grandiops and S. nigriventris were compared with S. eupterus that is known to produce both signal types, and representative members of two sister genera, Microsynodontis cf. batesii and Mochokiella paynei, for which no data were available. We provide support for the hypothesis that peripheral and central components of the ESS are conserved among mochokids. We also show that the two non‐synodontids are only sonic, consistent with sound production being an ancestral character for mochokids. Even though the three sound producing‐only species differ in some ESS characters, several are similar and likely associated with only sound production. We propose that the ability of S. eupterus to generate both electric discharges and sounds may depend on a protractor muscle intermediate in morphology between sound producing‐only and electric discharge‐only species, and two separate populations of protractor motoneurons. Our results further suggest that an electrogenic ESS in synodontids is an exaptation of a sound producing ESS.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on October 18, 2020 10:05 AM.

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    Evolutionary and homeostatic changes in morphology of visual dendrites of Mauthner cells in Astyanax blind cavefish

    Evolutionary and homeostatic changes in morphology of visual dendrites of Mauthner cells in Astyanax blind cavefish

    Development and Evolution influence the size and branching of visually targeted Mauthner cell dendrites.


    Abstract

    Mauthner cells are the largest neurons in the hindbrain of teleost fish and most amphibians. Each cell has two major dendrites thought to receive segregated streams of sensory input: the lateral dendrite receives mechanosensory input while the ventral dendrite receives visual input. These inputs, which mediate escape responses to sudden stimuli, may be modulated by the availability of sensory information to the animal. To understand the impact of the absence of visual information on the morphologies of Mauthner cells during developmental and evolutionary time scales, we examined the teleost Astyanax mexicanus. This species of tetra is found in two morphs: a seeing surface fish and a blind cavefish. We compared the structure of Mauthner cells in surface fish raised under daily light conditions, in surface fish raised in constant darkness, and in two independent lineages of cave populations. The length of ventral dendrites of Mauthner cells in dark‐raised surface fish larvae were longer and more branched, while in both cave morphs the ventral dendrites were smaller or absent. The absence of visual input in surface fish with normal eye development leads to a homeostatic increase in dendrite size, whereas over evolution, the absence of light led to the loss of eyes and a reduction in dendrite size.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on October 18, 2020 09:51 AM.

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    Retinal horizontal cells of goldfish (Carassius auratus) display subtype‐specific differences in spontaneous action potentials in situ

    Retinal horizontal cells of goldfish (Carassius auratus) display subtype‐specific differences in spontaneous action potentials in situ

    We measured [Ca2+]i using fura‐2 imaging in all subtypes (H1, H2, H3, H4) of goldfish retinal horizontal cells in isolated cell and tissue slice preparations, and report spontaneous Ca2+‐based action potentials (APs) in every subtype. In both preparations, APs differed by subtype: APs were longer and less frequent in H3/4.


    ABSTRACT

    Horizontal cells (HCs) are neurons of the outer retina, which provide inhibitory feedback onto photoreceptors and contribute to image processing. HCs in teleosts are classified into four subtypes (H1‐H4), each having different roles: H1‐H3 feed back onto different sets of cones, H4 feed back onto rods, and only H1 store and release the inhibitory neurotransmitter, γ‐aminobutyric acid (GABA). Dissociated HCs exhibit spontaneous Ca2+‐based action potentials (APs), yet it is unclear if APs occur in situ, or if all subtypes exhibit APs. We measured intracellular Ca2+ and report APs in slice preparations of the goldfish retina. In HCs furthest from photoreceptors (i.e. H3/H4), APs were less frequent, with greater duration and area under the curve (a measure of Ca2+ flux). Next, we classified acutely‐dissociated HCs into subtypes by integrating the ratio of dendritic field size vs. soma size (r d/s ). H1 and H2 subtypes had low r d/s values (<8); H3/H4 had high r d/s (>12). To verify this model, H1s were identified by immunoreactivity for GABA and 95% of these cells had an r d/s <4. In Ca2+ imaging experiments, as r d/s increased, AP duration and area under the curve increased, while frequency decreased. Our results demonstrate the presence of Ca2+‐based APs in the goldfish retina in situ and show that HC subtypes H1 through H4 exhibit progressively longer and less frequent spontaneous APs. These results suggest that APs may play an important role in inhibitory feedback, and may have implications for understanding the relative contributions of HC subtypes in the outer retina.

    in Journal of Comparative Neurology on October 18, 2020 09:35 AM.

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    Cardiovascular risk factors and APOE‐ε4 status affect memory functioning in aging via changes to temporal stem diffusion

    Cardiovascular risk factors and APOE‐ε4 status affect memory functioning in aging via changes to temporal stem diffusion

    In 125 healthy older adults we highlighted the importance of routinely accounting for factors that impact cognition both directly as well as indirectly via structural brain changes. Temporal stem diffusion changes demonstrated specificity for explaining the differential impacts of a number of cognitive risk factors on memory performance.


    Abstract

    Prior research investigating associations between hypertension, obesity, and apolipoprotein (APOE) genotype status with memory performance among older adults has yielded inconsistent results. This may reflect, in part, a lack of first accounting for the effects these variables have on structural brain changes, that in turn contribute to age‐related memory impairment. The current study sought to clarify the relationships between these factors via path modeling. We hypothesized that higher body mass index (BMI), hypertension, and being an APOE‐ε4 allele carrier would predict poorer memory scores, with much of these effects accounted for by indirect effects operating via differences in the integrity of temporal stem white matter. Participants included 125 healthy older adults who underwent neuropsychological assessment and diffusion‐weighted MRI scanning. Direct effects were found for hypertension and demographic variables including age, sex, and education. Importantly, indirect effects were found for BMI, hypertension, APOE‐ε4 status, age, and sex, where these factors predicted memory scores via their impact on temporal stem diffusion measures. There was also a dual effect of sex, with a direct effect indicating that females had better memory performance overall, and an indirect effect indicating that females with greater temporal stem diffusion had poorer memory performance. Results suggest that changes to the integrity of temporal white matter in aging may underpin reduced memory performance. These results highlight that accounting for variables that not only directly impact cognition, but also for those that indirectly impact cognition via structural brain changes, is crucial for understanding the impact of risk factors on cognition.

    in Journal of Neuroscience Research on October 18, 2020 09:35 AM.

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    Adipose tissue stem cells in peripheral nerve regeneration—In vitro and in vivo

    Abstract

    After peripheral nerve injury, Schwann cells (SCs) are crucially involved in several steps of the subsequent regenerative processes, such as the Wallerian degeneration. They promote lysis and phagocytosis of myelin, secrete numbers of neurotrophic factors and cytokines, and recruit macrophages for a biological debridement. However, nerve injuries with a defect size of >1 cm do not show proper tissue regeneration and require a surgical nerve gap reconstruction. To find a sufficient alternative to the current gold standard—the autologous nerve transplant—several cell‐based therapies have been developed and were experimentally investigated. One approach aims on the use of adipose tissue stem cells (ASCs). These are multipotent mesenchymal stromal cells that can differentiate into multiple phenotypes along the mesodermal lineage, such as osteoblasts, chondrocytes, and myocytes. Furthermore, ASCs also possess neurotrophic features, that is, they secrete neurotrophic factors like the nerve growth factor, brain‐derived neurotrophic factor, neurotrophin‐3, ciliary neurotrophic factor, glial cell‐derived neurotrophic factor, and artemin. They can also differentiate into the so‐called Schwann cell‐like cells (SCLCs). These cells share features with naturally occurring SCs, as they also promote nerve regeneration in the periphery. This review gives a comprehensive overview of the use of ASCs in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo. While the sustainability of differentiation of ASCs to SCLCs in vivo is still questionable, ASCs used with different nerve conduits, such as hydrogels or silk fibers, have been shown to promote nerve regeneration.

    in Journal of Neuroscience Research on October 18, 2020 09:29 AM.

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    Time‐to‐contact perception in the brain

    Time‐to‐contact perception in the brain

    What are the brain areas engaged when estimating the time to contact of an approaching ball? Patients undergoing an awake brain surgery performed the task while various areas were stimulated. The performances were assessed compared to a presurgery baseline. Results showed a direct and causal involvement of areas near the intraparietal sulcus, and indirect involvement of areas related to the language.


    Abstract

    Time‐to‐contact (TTC) perception refers to the ability of an observer to estimate the remaining time before an object reaches a point in the environment, and is of crucial importance in daily life. Noninvasive correlational approaches have identified several brain areas sensitive to TTC information. Here we report the results of two studies, including one during an awake brain surgery, that aimed to identify the specific areas causally engaged in the TTC estimation process. In Study 1, we tested 40 patients with brain tumor in a TTC estimation task. The results showed that four of the six patients with impaired performance had tumors in right upper parietal cortex, although this tumoral location represented only six over 40 patients. In Study 2, 15 patients underwent awake brain surgery electrostimulation mapping to examine the implication of various brain areas in the TTC estimation process. We acquired and normalized to MNI space the coordinates of the functional areas that influenced task performance. Our results seem to demonstrate that the early stage of the TTC estimation process involved specific cortical territories in the ventral region of the right intraparietal sulcus. Downstream processing of TTC could also involve the frontal eye field (middle frontal gyrus) related to ocular search. We also found that deactivating language areas in the left hemisphere interfered with the TTC estimation process. These findings demonstrate a fine grained, cortical representation of TTC processing close to the ventral right intraparietal sulcus and complement those described in other human studies.

    in Journal of Neuroscience Research on October 18, 2020 09:01 AM.

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    Antimicrobial peptides in the gut–brain axis: A straightforward review to unravel some missing links

    Abstract

    Antimicrobial peptides (AMPs) are intriguing molecules, able to directly kill several microorganisms and to regulate multiple aspects of the immune response. Despite the extensive studies on the role of AMPs in the epithelial barrier, placing them as a pivotal line of defense against pathogen invasion, little attention has been directed to their role in the maintenance and modulation of the gut microbiota and, by consequence, of the homeostasis of extra intestinal tissues. Here, we review the recent literature about the microbiome–gut–brain axis, focusing on the role of AMPs in this scenario. We provide a straightforward revision of current data in order to provide an overview of the subject, discussing more in depth some points that, in our opinion, are crucial and have received little attention.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Disrupted brain functional networks in patients with end‐stage renal disease undergoing hemodialysis

    Disrupted brain functional networks in patients with end‐stage renal disease undergoing hemodialysis

    Using graph theory‐based approach, we investigated the topological organization of functional brain networks in patients with end‐stage renal disease (ESRD) undergoing hemodialysis (HD). Disrupted brain functional networks were identified in patients with ESRD, and HD patients showed further disruptions in functional network organization compared with nondialysis patients.


    Abstract

    Patterns of change in whole‐brain functional networks remain poorly understood in patients with end‐stage renal disease (ESRD) undergoing hemodialysis (HD). We conducted a prospective research to investigate the topological properties of whole‐brain functional networks in those patients using a graph‐based network analysis. Resting‐state functional magnetic resonance imaging was performed on 51 ESRD patients (25 HD and 26 nondialysis patients) and 36 healthy controls (HCs). We compared the topological properties of brain functional networks among the three groups, and analyzed the relationships between those significant parameters and clinical variables in ESRD patients. Progressively disrupted global topological organizations were observed from nondialysis patients to HD patients compared with HCs (all p < 0.05 after Bonferroni correction). HD patients, relative to HCs, showed significantly decreased nodal centralities in the left temporal pole: superior temporal gyrus, bilateral median cingulate and paracingulate gyri, bilateral hippocampus, bilateral parahippocampal gyrus, and bilateral amygdala, and showed increased nodal centralities in the orbital part of the bilateral middle frontal gyrus, left cuneus, and left superior occipital gyrus (all p < 0.05 after Bonferroni correction). Furthermore, nodal centralities in the bilateral hippocampus were significantly decreased in HD patients compared with nondialysis patients (p < 0.05 after Bonferroni correction). Dialysis duration negatively correlated with global efficiency in ESRD patients undergoing HD (r = −0.676, FDR q = 0.004). This study indicates that ESRD patients exhibit disruptions in brain functional networks, which are more severe in HD patients, and these alterations are correlated with cognitive performance and clinical markers.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Sex‐specific peripheral and central responses to stress‐induced depression and treatment in a mouse model

    Sex‐specific peripheral and central responses to stress‐induced depression and treatment in a mouse model

    Social defeat stress induces sex‐specific inflammatory cytokine/chemokine responses in the periphery and sex‐specific transcriptional regulation in the prefrontal cortex (PFC). Treatment with dihydrocaffeic acid/malvidin‐glucoside modulates periphery inflammation and gene expression in the prefrontal cortex and alleviates depression‐like phenotype. CSDS, chronic social defeat stress; DHCA, dihydrocaffeic acid.


    Abstract

    Major depressive disorder affects ~20% of the world population and is characterized by strong sexual dimorphism with females being two to three times more likely to develop this disorder. Previously, we demonstrated that a combination therapy with dihydrocaffeic acid and malvidin‐glucoside to synergistically target peripheral inflammation and stress‐induced synaptic maladaptation in the brain was effective in alleviating chronic social defeat stress (CSDS)‐induced depression‐like phenotype in male mice. Here, we test the combination therapy in a female CSDS model for depression and compared sex‐specific responses to stress in the periphery and the central nervous system. Similar to male mice, the combination treatment is also effective in promoting resilience against the CSDS‐induced depression‐like behavior in female mice. However, there are sex‐specific differences in peripheral immune responses and differential gene regulation in the prefrontal cortex to chronic stress and to the treatment. These data indicate that while therapeutic approaches to combat stress‐related disorders may be effective in both sexes, the mechanisms underlying these effects differ, emphasizing the need for inclusion of both sexes in preclinical studies using animal models.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Overt speech feasibility using continuous functional magnetic resonance imaging: Isolation of areas involved in phonology and prosody

    Overt speech feasibility using continuous functional magnetic resonance imaging: Isolation of areas involved in phonology and prosody

    Here we investigated the effects of the functional magnetic resonance imaging (fMRI) performed with natural speaking, on the results of linguistic activations. We found that overt speaking during fMRI induced few artifacts and did not significantly affect the results, allowing the identification of areas involved in primary motor control and prosodic regulation of speech.


    Abstract

    To avoid motion artifacts, almost all speech‐related functional magnetic resonance imagings (fMRIs) are performed covertly to detect language activations. This method may be difficult to execute, especially by patients with brain tumors, and does not allow the identification of phonological areas. Here, we aimed to evaluate overt task feasibility. Thirty‐three volunteers participated in this study. They performed two functional sessions of covert and overt generation of a short sentence semantically linked with a word. Three main contrasts were performed: Covert and Overt for the isolation of language‐activated areas, and Overt > Covert for the isolation of the motor cortical activation of speech. fMRI data preprocessing was performed with and without unwarping, and with and without regression of movement parameters as confounding variables. All types of results were compared to each other. For the Overt contrast, Dice coefficients showed strong overlap between each pair of types of results: 0.98 for the pair with and without unwarping, and 0.9 for the pair with and without movement parameter regression. The Overt > Covert contrast allowed isolation of motor laryngeal activations with high statistical reliability and revealed the right‐lateralized temporal activity related to acoustic feedback. Overt speaking during magnetic resonance imaging induced few artifacts and did not significantly affect the results, allowing the identification of areas involved in primary motor control and prosodic regulation of speech. Unwarping and motion artifact regression in the postprocessing step, seem to not be necessary. Changes in lateralization of cortical activity by overt speech shall be explored before using these tasks for presurgical mapping.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Sex‐specific association between infant caudate volumes and a polygenic risk score for major depressive disorder

    Sex‐specific association between infant caudate volumes and a polygenic risk score for major depressive disorder

    A polygenic risk score for major depressive disorder (MDD) is associated with sex‐specific brain structural alterations in the infant bilateral caudate which is crucially implicated in MDD in adults. Our results suggest that sex‐specific polygenic influences on early caudate volume development might contribute to the sexually dimorphic prevalence of MDD.


    Abstract

    Polygenic risk scores for major depressive disorder (PRS‐MDD) have been identified in large genome‐wide association studies, and recent findings suggest that PRS‐MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS‐MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother–infant dyads (44 female, 11–54 days old) were investigated to reveal how infant PRS‐MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS‐MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex‐specific main effect of PRS‐MDD on bilateral infant caudate volumes was observed. PRS‐MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS‐MDD with the environmental risk factor “prenatal maternal depressive symptoms” (genotype‐by‐environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype‐by‐environment‐by‐sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS‐MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex‐specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Dehydroepiandrosterone for depressive symptoms: A systematic review and meta‐analysis of randomized controlled trials

    Abstract

    Depression is a mental disorder that affects millions of people around the world. However, depressive symptoms can be seen in other psychiatric and medical conditions. Here, we investigate the effect of DHEA treatment on depressive symptoms in individuals with depression and/or other clinical conditions in which depressive symptoms are present. An electronic search was performed until October 2019, with no restrictions on language or year of publication in the following databases: Medline, EMBASE, LILACS, and Cochrane Library. Randomized controlled trials comparing DHEA versus placebo were included if the depressive symptoms were assessed. Fifteen studies with 853 female and male individuals were included in this review. To conduct the meta‐analysis, data were extracted from 14 studies. In comparison with placebo, DHEA improved depressive symptoms (standardized mean difference [SMD] −0.28, 95% (CI) −0.45 to −0.11, p =.001, 12 studies, 742 individuals (375 in the experimental group and 367 in the placebo group), I 2 = 24%), very low quality of evidence, 2 of 14 studies reporting this outcome were removed in a sensitivity analysis as they were strongly influencing heterogeneity between studies. No hormonal changes that indicated any risk to the participants' health were seen. Side effects observed were uncommon, mild, and transient, but commonly related to androgyny. In conclusion, DHEA was associated with a beneficial effect on depressive symptoms compared to placebo. However, these results should be viewed with caution, since the quality of evidence for this outcome was considered very low according to the GRADE criteria.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Polyethylene glycol‐fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses

    Polyethylene glycol‐fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses

    Innate and adaptive immune responses to sciatic nerve allografts treated with a polyethylene glycol (PEG)‐fusion repair protocol were compared to those in negative control allografts untreated by PEG. By 21 days PO, PEG‐fused allografts showed significantly reduced major histocompatibility complex class I expression and T cell (CD3) infiltration. PEG‐fused allografts more closely resembled unoperated nerves.


    Abstract

    Ablation/segmental loss peripheral nerve injuries (PNIs) exhibit poor functional recovery due to slow and inaccurate outgrowth of regenerating axons. Viable peripheral nerve allografts (PNAs) as growth‐guide conduits are immunologically rejected and all anucleated donor/host axonal segments undergo Wallerian degeneration. In contrast, we report that ablation‐type sciatic PNIs repaired by neurorrhaphy of viable sciatic PNAs and a polyethylene glycol (PEG)‐fusion protocol using PEG immediately restored axonal continuity for many axons, reinnervated/maintained their neuromuscular junctions, and prevented much Wallerian degeneration. PEG‐fused PNAs permanently restored many sciatic‐mediated behaviors within 2–6 weeks. PEG‐fused PNAs were not rejected even though host/donors were neither immunosuppressed nor tissue‐matched in outbred female Sprague Dawley rats. Innate and adaptive immune responses to PEG‐fused sciatic PNAs were analyzed using electron microscopy, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction for morphological features, T cell and macrophage infiltration, major histocompatibility complex (MHC) expression, apoptosis, expression of cytokines, chemokines, and cytotoxic effectors. PEG‐fused PNAs exhibited attenuated innate and adaptive immune responses by 14–21 days postoperatively, as evidenced by (a) many axons and cells remaining viable, (b) significantly reduced infiltration of cytotoxic and total T cells and macrophages, (c) significantly reduced expression of inflammatory cytokines, chemokines, and MHC proteins, (d) consistently low apoptotic response. Morphologically and/or biochemically, PEG‐fused sciatic PNAs often resembled sciatic autografts or intact sciatic nerves. In brief, PEG‐fused PNAs are an unstudied, perhaps unique, example of immune tolerance of viable allograft tissue in a nonimmune‐privileged environment and could greatly improve the clinical outcomes for PNIs relative to current protocols.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    A potential entanglement between the spinal cord and hippocampus: Theta rhythm correlates with neurogenesis deficiency following spinal cord injury in male rats

    A potential entanglement between the spinal cord and hippocampus: Theta rhythm correlates with neurogenesis deficiency following spinal cord injury in male rats

    (a) Spatial memory, neurogenesis, apoptosis, and theta power alteration following spinal cord injury in rats. (b) The correlation coefficient of spatial memory and theta power (movement/no‐movement) with receptor (GABAA, NMDA, Muscarinic1) expression, BrdU+ cells, and DCX+ cells.


    Abstract

    Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus‐dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI‐induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y‐maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

    Abstract

    Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of the central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, LC terminals provide dense innervation of brain intraparenchymal arterioles/capillaries, and NA modulates astrocyte functions. The term neurovascular unit (NVU) defines the strict anatomical/functional interaction occurring between neurons, glial cells, and brain vessels. NVU plays a fundamental role in coupling the energy demand of activated brain regions with regional cerebral blood flow, it includes the blood–brain barrier (BBB), plays an active role in neuroinflammation, and participates also to the glymphatic system. NVU alteration is involved in AD pathophysiology through several mechanisms, mainly related to a relative oligoemia in activated brain regions and impairment of structural and functional BBB integrity, which contributes also to the intracerebral accumulation of insoluble amyloid. We review the existing data on the morphological features of LC‐NA innervation of the NVU, as well as its contribution to neurovascular coupling and BBB proper functioning. After introducing the main experimental data linking LC with AD, which have repeatedly shown a key role of neuroinflammation and increased amyloid plaque formation, we discuss the potential mechanisms by which the loss of NVU modulation by LC might contribute to AD pathogenesis. Surprisingly, thus far not so many studies have tested directly these mechanisms in models of AD in which LC has been lesioned experimentally. Clarifying the interaction of LC with NVU in AD pathogenesis may disclose potential therapeutic targets for AD.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Possible routes of SARS‐CoV‐2 invasion in brain: In context of neurological symptoms in COVID‐19 patients

    Abstract

    Manifestation of neurological symptoms in certain patients of coronavirus disease‐2019 (COVID‐19) has warranted for their virus‐induced etiogenesis. SARS‐CoV‐2, the causative agent of COVID‐19, belongs to the genus of betacoronaviruses which also includes SARS‐CoV‐1 and MERS‐CoV; causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS‐CoV‐2 in vivo are still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature. Based on the recent evidence for the presence of SARS‐CoV‐2 host cell entry receptors in specific components of the human nervous and vascular tissue, a neural (olfactory and/or vagal), and a hematogenous—crossing the blood–brain barrier, routes have been proposed. The neurological symptoms in COVID‐19 may also arise as a consequence of the “cytokine storm” (characteristically present in severe disease) induced neuroinflammation, or co‐morbidities. There is also a possibility that, there may be multiple routes of SARS‐CoV‐2 entry into the brain, or multiple mechanisms can be involved in the pathogenesis of the neurological symptoms. In this review article, we have discussed the possible routes of SARS‐CoV‐2 brain entry based on the emerging evidence for this virus, and that available for other betacoronaviruses in literature.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments

    Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments

    In the present study, we identified cannabinoid type 1 (CB1)/dopamine type 2 (D2) heteromers in the globus pallidus of C57BL/J male mice. We found that heteromer formation was differentially influenced by a cannabinoid agonist and different antipsychotics. These CB1/D2 heteromers were also functionally relevant to mouse movement and γ‐aminobutyric acid release in a neuronal cell culture.


    Abstract

    The cannabinoid type 1 (CB1) receptor and the dopamine type 2 (D2) receptor are co‐localized on medium spiny neuron terminals in the globus pallidus where they modulate neural circuits involved in voluntary movement. Physical interactions between the two receptors have been shown to alter receptor signaling in cell culture. The objectives of the current study were to identify the presence of CB1/D2 heteromers in the globus pallidus of C57BL/6J male mice, define how CB1/D2 heteromer levels are altered following treatment with cannabinoids and/or antipsychotics, and determine if fluctuating levels of CB1/D2 heteromers have functional consequences. Using in situ proximity ligation assays, we observed CB1/D2 heteromers in the globus pallidus of C57BL/6J mice. The abundance of the heteromers increased following treatment with the nonselective cannabinoid receptor agonist, CP55,940. In contrast, treatment with the typical antipsychotic haloperidol reduced the number of CB1/D2 heteromers, whereas the atypical antipsychotic olanzapine treatment had no effect. Co‐treatment with CP55,940 and haloperidol had similar effects to haloperidol alone, whereas co‐treatment with CP55,940 and olanzapine had similar effects to CP55,940. The observed changes were found to have functional consequences as the differential effects of haloperidol and olanzapine also applied to γ‐aminobutyric acid release in STHdh Q7/Q7 cells and motor function in C57BL/6J male mice. This work highlights the clinical relevance of co‐exposure to cannabinoids and different antipsychotics over acute and prolonged time periods.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Beyond barrier functions: Roles of pericytes in homeostasis and regulation of neuroinflammation

    Abstract

    Pericytes are contractile cells that extend along the vasculature to mediate key homeostatic functions of endothelial barriers within the body. In the central nervous system (CNS), pericytes are important contributors to the structure and function of the neurovascular unit, which includes endothelial cells, astrocytes and neurons. The understanding of pericytes has been marred by an inability to accurately distinguish pericytes from other stromal cells with similar expression of identifying markers. Evidence is now growing in favor of pericytes being actively involved in both CNS homeostasis and pathology of neurological diseases, including multiple sclerosis, spinal cord injury, and Alzheimer's disease among others. In this review, we discuss the current understanding on the characterization of pericytes, their roles in maintaining the integrity of the blood–brain barrier, and their contributions to neuroinflammation and neurorepair. Owing to its plethora of surface receptors, pericytes respond to inflammatory mediators such as CCL2 (monocyte chemoattractant protein‐1) and tumor necrosis factor‐α, in turn secreting CCL2, nitric oxide, and several cytokines. Pericytes can therefore act as promoters of both the innate and adaptive arms of the immune system. Much like professional phagocytes, pericytes also have the ability to clear up cellular debris and macromolecular plaques. Moreover, pericytes promote the activities of CNS glia, including in maturation of oligodendrocyte lineage cells for myelination. Conversely, pericytes can impair regenerative processes by contributing to scar formation. A better characterization of CNS pericytes and their functions would bode well for therapeutics aimed at alleviating their undesirable properties and enhancing their benefits.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis

    Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis

    The activity of PXT864, a combination of acamprosate and baclofen, was assessed in cellular models relevant for ALS disease. PXT864 protected neuro muscular junctions in co‐cultures of primary rat neurons and human muscle cells, as well as motoneurons derived from SOD1G93A rodents against glutamate toxicity. When combined with riluzole, PXT864 exerted larger protective effects, highlighting the potential use of PXT864 with the standard of care. Importantly, PXT864 reduced TDP‐43 toxic accumulation in cells after insulting stimuli such as glutamate or oxidative stress inducers. An improved maturity of cultured primary SOD1G93A motoneurons was also found after PXT864 treatment.


    Abstract

    There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short‐lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron‐muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP‐43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti‐TDP‐43 aggregation effect was also confirmed in a cell line expressing TDP‐43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Role of glial niche in regulating neural stem cell proliferation in Drosophila central nervous system

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Issue Information

    in Journal of Neuroscience Research on October 18, 2020 08:46 AM.

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    Protect the Antarctic Peninsula — before it’s too late

    Nature, Published online: 18 October 2020; doi:10.1038/d41586-020-02939-5

    Banning fishing in warming coastal waters and limiting tourism and construction on land will help to protect marine mammals and seabirds.

    in Nature on October 18, 2020 12:00 AM.

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    Architectural Affordance Impacts Human Sensorimotor Brain Dynamics

    Action is a medium of collecting sensory information about the environment, which in turn is shaped by architectural affordances. Affordances characterize the fit between the physical structure of the body and capacities for movement and interaction with the environment, thus relying on sensorimotor processes associated with exploring the surroundings. Central to sensorimotor brain dynamics, the attentional mechanisms directing the gating function of sensory signals share neuronal resources with motor-related processes necessary to inferring the external causes of sensory signals. Such a predictive coding approach suggests that sensorimotor dynamics are sensitive to architectural affordances that support or suppress specific kinds of actions for an individual. However, how architectural affordances relate to the attentional mechanisms underlying the gating function for sensory signals remains unknown. Here we demonstrate that event-related desynchronization of alpha-band oscillations in parieto-occipital and medio-temporal regions covary with the architectural affordances. Source-level time-frequency analysis of data recorded in a motor-priming Mobile Brain/Body Imaging experiment revealed strong event-related desynchronization of the alpha band to originate from the posterior cingulate complex and bilateral parahippocampal areas. Our results firstly contribute to the understanding of how the brain resolves architectural affordances relevant to behaviour. Second, our results indicate that the alpha-band originating from the posterior cingulate complex covaries with the architectural affordances before participants interact with the environment. During the interaction, the bilateral parahippocampal areas dynamically reflect the affordable behaviour as perceived through the visual system. We conclude that the sensorimotor dynamics are developed for processing behaviour-relevant features in the designed environment.

    in bioRxiv: Neuroscience on October 18, 2020 12:00 AM.

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    Place cells in head-fixed mice navigating a floating real-world environment

    The hippocampal place cell system in rodents has provided a major paradigm for the scientific investigation of memory function and dysfunction. Place cells have been observed in area CA1 of the hippocampus of both freely moving animals, and of head-fixed animals navigating in virtual reality environments. However, spatial coding in virtual reality preparations has been observed to be impaired. Here we show that the use of a real-world environment system for head-fixed mice, consisting of a track floating on air, provides some advantages over virtual reality systems for the study of spatial memory. We imaged the hippocampus of head-fixed mice injected with the genetically encoded calcium indicator GCaMP6s while they navigated circularly constrained or open environments on the floating platform. We observed consistent place tuning in a substantial fraction of cells, stable over multiple days, with remapping of place fields when the animal entered a different environment. Spatial information rates were within the range observed in freely moving mice. Manifold analysis indicated that spatial information could be extracted from a low-dimensional subspace of the neural population dynamics. This is the first demonstration of place cells in head-fixed mice navigating on an air-lifted real-world platform, validating its use for the study of brain circuits involved in memory and affected by neurodegenerative disorders.

    in bioRxiv: Neuroscience on October 18, 2020 12:00 AM.

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    Retinal INL thickness in multiple sclerosis: a mere marker of neurodegeneration?

    in Annals of Neurology on October 17, 2020 07:20 PM.

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    Scalp ripples can predict development of epilepsy after first unprovoked seizure in childhood

    Objective

    Identification of children at risk of developing epilepsy after a first unprovoked seizure can be challenging. Interictal epileptiform discharges are associated with higher risk but have limited sensitivity and specificity. High frequency oscillations (HFOs) are newer biomarkers for epileptogenesis. We prospectively evaluated the predictive value of HFOs for developing epilepsy in scalp EEG of children after a first unprovoked seizure.

    Methods

    After their first seizure, 56 children were followed prospectively over 12 months and then grouped in “epilepsy” or “no epilepsy”. Initial EEGs were visually analyzed for spikes, spike ripples and ripples. Inter‐group comparisons of spike‐ and HFO‐rates were done by Mann–Whitney U test. Predictive values and optimal thresholds were calculated by ROC curves.

    Results

    In the epilepsy group (n = 26, 46%), mean rates of ripples (0.3 vs. 0.09/min, p < 0.0001) and spike ripples (0.6 vs. 0.06/min, p < 0.05) were significantly higher, with no difference in spike rates (1.7 vs. 3.0/min, p = 0.38). Of those three markers, ripples showed the best predictive value (AUCripples 0.88). The optimal threshold for ripples was calculated to be ≥0.125/min with a sensitivity of 87% and specificity of 85%. Ripple rates were negatively correlated to days passing before epilepsy‐diagnosis (R = −0.59, p < 0.0001) and time to a second seizure (R = −0.64, CI ‐0.77 to 0.43, p < 0.0001).

    Interpretation

    We could show that in a cohort of children with a first unprovoked seizure, ripples predict the development of epilepsy better than spikes or spike ripples and might be useful biomarkers in the estimation of prognosis and question of treatment.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on October 17, 2020 07:00 PM.

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    Blood metal levels and amyotrophic lateral sclerosis risk: a prospective cohort

    Objective

    Metals have been suggested as risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality.

    Methods

    A nested ALS case‐control study was conducted within the prospective EPIC cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium and zinc concentrations were measured by inductively coupled plasma‐mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models.

    Results

    The study population comprised 107 cases (65% female) and 319 controls matched for age, sex and study center. Median time between blood collection and ALS death was 8 years (range 1‐15). Comparing the highest with the lowest tertile, cadmium (odds ratio (OR) 2.04, 95% confidence interval (CI) 1.08‐3.87) and lead (OR 1.89, 95%CI 0.97‐3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR 0.50, 95%CI 0.27‐0.94). Associations for cadmium and lead remained when limiting analyses to non‐current smokers.

    Interpretation

    This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on October 17, 2020 07:00 PM.

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    Prior Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation

    Objective

    The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3‐month outcomes.

    Methods

    This was a cohort study of consecutive patients (2014–2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0–2) at 3 months.

    Results

    Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2–11]) compared with VKA (6, [2–14]) and controls (7, [3–15], p < 0.001; quantile regression: β −2.1, 95% confidence interval [CI] −2.6 to −1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50–0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05–0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6–4.7%) of controls, 9 of 195 (4.6%; 1.9–9.2%; aOR 0.93; 95% CI 0.46–1.90) patients on VKA and 2 of 65 (3.1%; 0.4–10.8%, aOR 0.56; 95% CI 0.28–1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3‐month outcome (aOR 1.24; 1.01–1.51).

    Interpretation

    Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2020

    in Annals of Neurology on October 17, 2020 03:09 PM.

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    Petrous Apex Cholesterol Granuloma Revealed by Facial Palsy

    in Annals of Neurology on October 17, 2020 03:04 PM.

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    Reply to “Retinal INL thickness in multiple sclerosis: a mere marker of neurodegeneration?”

    in Annals of Neurology on October 17, 2020 10:32 AM.

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    Safety and Efficacy of Omaveloxolone in Friedreich's Ataxia (MOXIe Study)

    Objective

    Friedreich's ataxia (FRDA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FRDA. We investigated the safety and efficacy of omaveloxolone in patients with FRDA.

    Methods

    We conducted an international, double‐blind, randomized, placebo‐controlled parallel‐group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015‐002762‐23). Eligible patients, 16 to 40 years of age with genetically confirmed FRDA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150 mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.

    Results

    155 patients were screened and 103 were randomly assigned to receive omaveloxolone (n=51) or placebo (n=52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (–1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of –2.40 ± 0.96; p=0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.

    Interpretation

    In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FRDA.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on October 17, 2020 10:30 AM.

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    Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms

    Objective

    Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here.

    Methods

    In the tetrodotoxin model, we used 16‐channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasms patients.

    Results

    Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow‐wave sleep. In addition, the ensuing interictal up states of slow‐wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations since it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp‐up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasms patients.

    Interpretation

    Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on October 17, 2020 09:58 AM.

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    Rejection in early life is associated with high and long-lasting stress and higher incidence of infections in owl monkeys

    1.BackgroundThe mothers of owl monkeys sometimes reject their new-borns. When this occurs in captive colonies, the rejected infants are manually raised by veterinarians, allowing them to survive. However, maternal rejection can induce chronic stress, which in turn is associated with infectious diseases. Rescued, rejected owl monkeys might experience high rates of stress and infections which go undetected. MethodologyTo test this hypothesis, we evaluated the connection between maternal rejection, stress and infections in owl monkeys (Aotus nancymaae) from the IVITA Center for Conservation and Reproduction of Primates (UNMSM, Peru). Specifically, we compared the stress rates and frequency of infection treatment in juveniles (19-24 months) rejected in the first month of life and controls. To assess stress, we compared cortisol levels in hair using a competitive ELISA and recorded behaviours using cameras. We analysed past medical treatments and medication to compare incidence of infection treatment in subjects. We then studied the correlation between the frequency of infection treatments and cortisol using a linear regression. ResultsRejected owl monkeys showed significantly higher cortisol levels (p=0.0123), a higher incidence of stereotypical behaviour and overeating (pacing p=0.0159; head twirling p=0.0476, eating p=0.0238) compared to controls. Rejected owl monkeys also received significantly more treatment for infections than controls per month lived (p=0.0009). Moreover, infection rates observed in this population were positively although weakly associated with concentration of cortisol in hair (R2=0.307, p=0.0075). ConclusionMaternal rejection in the first month of life is associated with high and long-lasting stress levels and infections in the IVITA owl monkey colony. IVITA owl monkeys will be a useful model for studying the long-term effects of early life stress at the population level.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

    Non-fibrillar oligomers formed via nucleation from amyloid beta (AB) peptides are currently implicated in the neurotoxicity of Alzheimers disease. Thus, shedding light on the molecular mechanisms underlying their formation is important for identifying targets for drug therapies. This is however an enduring challenge due to the inability to detect AB nucleation processes in the lag phase from bulk kinetic assays, while time-course analyses using a series of peptide solutions involve the discontinuous observation of dynamic nucleation processes and pathways. In this study, by adjusting the pH of AB42 peptide samples while simultaneously imaging with high-speed atomic force microscopy (HS-AFM), we show the in-situ, continuous visualization of dynamic AB42 nucleation at the molecular level. The process reveals a pH-induced saturation regime, enabling a critical monomer substrate concentration to initiate the birth of nucleation. A number of key nucleation phases are identified, including pre-nucleation, saturation regime (mass surface adsorption), nucleation and post-nucleation growth, eventually leading to the formation of predominately oligomer species. HS-AFM observations further reveal the distinct, molecular processes associated with each nucleation phase that constitute the path-dependent formation of different AB species, namely an intial monomer "diffuse-like" surface layer, followed by the emergence of nuclei and then subsequent formation and growth of new complexes and oligomers. In particular, the ability of individual nuclei to undergo surface diffusion and establish new complexes via binding interactions with other species encountered in the system was found to be a significant mechanism influencing the growth of oligomers. Herein, the study contributes to current AB nucleation theories by ascribing new molecular mechanisms. More generally, the knowledge gained from single molecule techniques can greatly assist in our current understanding of various biological processes of AB peptide such as nucleation, growth, aggregation and their related kinetic pathways.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Meet me in the middle: brain-behavior mediation analysis for fMRI experiments

    Functional outcomes (e.g., subjective percepts, emotions, memory retrievals, decisions, etc...) are partly determined by external stimuli and/or cues. But they may also be strongly influenced by (trial-by-trial) uncontrolled variations in brain responses to incoming information. In turn, this variability provides information regarding how stimuli and/or cues are processed by the brain to shape behavioral responses. This can be exploited by brain-behavior mediation analysis to make specific claims regarding the contribution of brain regions to functionally-relevant input-output transformations. In this work, we address four challenges of this type of approach, when applied in the context of mass-univariate fMRI data analysis: (i) we quantify the specificity and sensitivity profiles of different variants of mediation statistical tests, (ii) we evaluate their robustness to hemo-dynamic and other confounds, (iii) we identify the sorts of brain mediators that one can expect to detect, and (iv) we disclose possible interpretational issues and address them using complementary information-theoretic approaches. En passant, we propose a computationally efficient algorithmic implementation of the approach that is amenable to whole-brain exploratory analysis. We also demonstrate the strengths and weaknesses of brain-behavior mediation analysis in the context of an fMRI study of decision under risk. Finally, we discuss the limitations and possible extensions of the approach.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Multiple time-scales of decision making in the hippocampus and prefrontal cortex

    Neural activity underlying decision making has been reported in many brain regions in the form of choice-specific neuronal sequences that span entire task periods. In contrast to this behavioral-timescale activity, recent work has raised the possibility of fast-timescale decision-making activity in hippocampal and prefrontal regions. Whether these are distinct or complementary mechanisms is unknown. Here, we examined simultaneous hippocampal and prefrontal ensemble activity during learning of a spatial working-memory decision task. We found that both regions formed choice-specific sequences at the behavioral timescale (~seconds), as well as two fast timescales (~100-200 ms), theta cycles during navigation and sharp-wave ripples in inter-trial periods. Behavioral-timescale sequences maintained representations of current goals during navigation. In contrast, at the fast timescales, hippocampal sequences supported deliberation, whereas prefrontal ensembles predicted actual choices. Error trials resulted from impaired interaction between behavioral- and fast-timescale mechanisms. These results establish cooperative interaction at multiple timescales for memory-guided decision making.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Validation and comparison of three freely available methods for extracting white matter hyperintensities: FreeSurfer, UBO Detector and BIANCA

    White matter hyperintensities of presumed vascular origin (WMH) are frequently found in MRIs of patients with various neurological and vascular disorders, but also in healthy elderly subjects. Although automated methods have been developed to replace the challenging task of manually segmenting the WMH, there is still no consensus on which validated algorithm(s) should be used. In this study, we validated and compared three freely available methods for WMH extraction: FreeSurfer, UBO Detector, and the Brain Intensity AbNormality Classification Algorithm, BIANCA (with the two thresholding options: global thresholding vs. LOCally Adaptive Threshold Estimation (LOCATE)) using a standardized protocol. We applied the algorithms to longitudinal MRI data (2D FLAIR, 3D FLAIR, T1w sMRI) of cognitively healthy older people (baseline N = 231, age range 64 - 87 years) with a relatively low WMH load. As a reference for the segmentation accuracy of the algorithms, completely manually segmented gold standards were used separately for each MR image modality. To validate the algorithms, we correlated the automatically extracted WMH volumes with the Fazekas scores, chronological age, and between the time points. In addition, we analyzed conspicuous percentage WMH volume increases and decreases in the longitudinal data between two measurement points to verify the segmentation reliability of the algorithms. All algorithms showed a moderate correlation with chronological age except BIANCA with the 2D FLAIR image input only showed a weak correlation. FreeSurfer fundamentally underestimated the WMH volume in comparison with the gold standard as well as with the other algorithms, and cannot be considered as an accurate substitute for manual segmentation, as it also scored the lowest value in the DSC compared to the other algorithms. However, its WMH volumes correlated strongly with the Fazekas scores and showed no conspicuous WMH volume increases and decreases between measurement points in the longitudinal data. BIANCA performed well with respect to the accuracy metrics - especially the DSC, H95, and DER. However, the correlations of the WMH volumes with the Fazekas scores compared to the other algorithms were weaker. Further, we identified a significant amount of outlier WMH volumes in the within-person change trajectories with BIANCA. The WMH volumes extracted by UBO Detector achieved the best result in terms of cost-benefit ratio in our study. Although there is room for optimization with respect to segmentation accuracy (especially for the metrics DSC, H95 and DER), it achieved the highest correlations with the Fazekas scores and the highest ICCs. Its performance was high for both input modalities, although it relies on a built-in single-modality training dataset, and it showed reliable WMH volume estimations across measurement points.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Distal CA1 maintains a more coherent spatial representation than proximal CA1 when local and global cues conflict

    Entorhinal cortical projections show segregation along the transverse axis of CA1, with the medial entorhinal cortex (MEC) sending denser projections to proximal CA1 and the lateral entorhinal cortex (LEC) sending denser projections to distal CA1. Previous studies have reported functional segregation along the transverse axis of CA1 correlated with the functional differences in MEC and LEC. Proximal CA1 shows higher spatial selectivity than distal CA1 in these studies. We employ a double rotation paradigm, which creates an explicit conflict between local and global cues, to understand differential contributions of these reference frames to the spatial code in proximal and distal CA1. We show that proximal and distal CA1 respond differently to this local-global cue conflict. Proximal CA1 shows incoherent response consistent with the strong conflicting inputs it receives from MEC and distal CA3. In contrast, distal CA1 shows a more coherent rotation with global cues. In addition, our study fails to show the difference in spatial selectivity between proximal and distal CA1 seen in the previous studies, perhaps due to richer sensory information available in our behavior arena. Together these observations indicate that the functional segregation along proximodistal axis of CA1 is not merely of more or less spatial selectivity but that of the nature of the different inputs utilized to create and anchor spatial representations.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Brain preparedness: The proactive role of the cortisol awakening response

    Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated 'preparation' function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.

    in bioRxiv: Neuroscience on October 17, 2020 12:00 AM.

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    Updated science-wide author databases of standardized citation indicators

    by John P. A. Ioannidis, Kevin W. Boyack, Jeroen Baas

    This Formal Comment presents an update to citation databases of top-cited scientists across all scientific fields, including more granular information on diverse indicators.

    in PLoS Biology on October 16, 2020 09:00 PM.

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    The COVID-19 response illustrates that traditional academic reward structures and metrics do not reflect crucial contributions to modern science

    by Adam J. Kucharski, Sebastian Funk, Rosalind M. Eggo

    The COVID-19 pandemic has motivated many open and collaborative analytical research projects with real-world impact. However, despite their value, such activities are generally overlooked by traditional academic metrics. Science is ultimately improved by analytical work, whether ensuring reproducible and well-documented code to accompany papers, developing and maintaining flexible tools, sharing and curating data, or disseminating analysis to wider audiences. To increase the impact and sustainability of modern science, it will be crucial to ensure these analytical activities—and the people who do them—are valued in academia.

    in PLoS Biology on October 16, 2020 09:00 PM.

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    Adaptive evolution shapes the present-day distribution of the thermal sensitivity of population growth rate

    by Dimitrios—Georgios Kontopoulos, Thomas P. Smith, Timothy G. Barraclough, Samraat Pawar

    Developing a thorough understanding of how ectotherm physiology adapts to different thermal environments is of crucial importance, especially in the face of global climate change. A key aspect of an organism’s thermal performance curve (TPC)—the relationship between fitness-related trait performance and temperature—is its thermal sensitivity, i.e., the rate at which trait values increase with temperature within its typically experienced thermal range. For a given trait, the distribution of thermal sensitivities across species, often quantified as “activation energy” values, is typically right-skewed. Currently, the mechanisms that generate this distribution are unclear, with considerable debate about the role of thermodynamic constraints versus adaptive evolution. Here, using a phylogenetic comparative approach, we study the evolution of the thermal sensitivity of population growth rate across phytoplankton (Cyanobacteria and eukaryotic microalgae) and prokaryotes (bacteria and archaea), 2 microbial groups that play a major role in the global carbon cycle. We find that thermal sensitivity across these groups is moderately phylogenetically heritable, and that its distribution is shaped by repeated evolutionary convergence throughout its parameter space. More precisely, we detect bursts of adaptive evolution in thermal sensitivity, increasing the amount of overlap among its distributions in different clades. We obtain qualitatively similar results from evolutionary analyses of the thermal sensitivities of 2 physiological rates underlying growth rate: net photosynthesis and respiration of plants. Furthermore, we find that these episodes of evolutionary convergence are consistent with 2 opposing forces: decrease in thermal sensitivity due to environmental fluctuations and increase due to adaptation to stable environments. Overall, our results indicate that adaptation can lead to large and relatively rapid shifts in thermal sensitivity, especially in microbes for which rapid evolution can occur at short timescales. Thus, more attention needs to be paid to elucidating the implications of rapid evolution in organismal thermal sensitivity for ecosystem functioning.

    in PLoS Biology on October 16, 2020 09:00 PM.

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    A ‘Marginal’ tale: the development of the neocortical layer 1

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Lorenzo Gesuita, Theofanis Karayannis

    in Current Opinion in Neurobiology on October 16, 2020 06:00 PM.

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    Molecular mechanisms within the dentate gyrus and the perirhinal cortex interact during discrimination of similar nonspatial memories

    Abstract

    Differentiating between similar memories is a crucial cognitive function that enables correct episodic memory formation. The ability to separate the components of memories into distinct representations is thought to rely on a computational process known as pattern separation, by which differences are amplified to disambiguate similar events. Although pattern separation has been localized to the dentate gyrus (DG) of the hippocampus and shown to occur in a spatial domain, this cognitive function takes place also during processing of other types of information. In particular, there is some debate on whether the DG participates in pattern separation of nonspatial representations. Considering the classic role of the Prh in the acquisition and storage of object memories in general and tasks with similar features in particular, this cognitive function could rely more heavily on perirhinal regions when object‐related information is processed. Here we show that two plasticity‐related proteins, BDNF, and Arc, are required in the DG for nonspatial mnemonic differentiation. Moreover, we found that the crucial role of the DG is transient since activity of AMPAR is only required in the Prh but not the DG during differentiated object memory retrieval. Additionally, this memory is not modifiable by postacquisition rhBDNF infusions in the DG that are known to improve memory when given in the Prh. This highlights a differential role of Prh and DG during differentiated object memory consolidation. Additionally, we found that these molecular mechanisms actively interact in the DG and Prh for the formation of distinguishable memories, with infusions of rhBDNF in the Prh being able to rescue mnemonic deficits caused by reduced Arc expression in the DG. These results reveal a complex interaction between plasticity mechanisms in the Prh and DG for nonspatial pattern separation and posit the Prh as the key structure where unique object representations are stored.

    in Hippocampus on October 16, 2020 05:55 PM.

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    Distribution and co‐expression of adrenergic receptor‐encoding mRNA in the mouse inferior colliculus

    Distribution and co‐expression of adrenergic receptor‐encoding mRNA in the mouse inferior colliculus

    The inferior colliculus (IC) is the primary auditory nucleus of the midbrain. We used multi‐channel fluorescent in situ hybridization to detect expression of α1A,B,D, α2A, and β2 encoding mRNA in the mouse IC. We found expression of mRNA encoding these adrenergic receptors in the three subnuclei of the IC in juveniles and adults.


    Abstract

    Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multi‐channel fluorescent in situ hybridization to detect the expression of adrenergic receptor‐encoding mRNA in the inferior colliculus of male and female mice. We found expression of α1, α2A, and β2 receptor‐encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α1 receptor‐encoding mRNA across the subregions of the IC, α2A and β2 receptor‐encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co‐expression of α1, α2A, and β2 receptor‐encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor‐encoding mRNA, α1 and α2A adrenergic receptor‐encoding mRNA, and α1, α2A, and β2 receptor‐encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co‐expression in the subregions of the mouse auditory midbrain.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on October 16, 2020 05:27 PM.

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    Dynamics of perineuronal nets over amphibian metamorphosis

    Dynamics of perineuronal nets over amphibian metamorphosis

    We demonstrate a dramatic, brain‐wide reorganization of perineuronal nets (PNNs) during metamorphosis in an anuran amphibian. A sharp reduction of PNNs precedes the overhaul of amphibian morphology and neural circuitry that transitions the animal from an aquatic to terrestrial lifestyle. In mammals, PNNs regulate neuronal plasticity and maturation. Results suggest PNN temporal dynamics are important to understanding their role in neural development, learning, and memory.


    Abstract

    Extracellular matrix materials known as perineuronal nets (PNNs) have been shown to have remarkable consequences for the maturation of neural circuits and stabilization of behavior. It has been proposed that, due to the possibly long‐lived biochemical nature of their components, PNNs may be an important substrate by which long‐term memories are stored in the central nervous system. However, little empirical evidence exists that shows that PNNs are themselves stable once established. Thus, the question of their temporal dynamics remains unresolved.

    We leverage the dramatic morphological and behavioral transformations that occur during amphibian metamorphosis to show that PNNs can be highly dynamic in nature. We used established lectin histochemistry to show that PNNs undergo drastic reconstruction during the metamorphic transition. Pre‐metamorphic tadpoles have abundant lectin‐labeled pericellular material, which we interpret to be PNNs, surrounding neurons throughout the central nervous system. During the metamorphic transition, these structures degrade, and begin to reform in the months following metamorphosis. We show that PNN sizes and staining intensity further change over metamorphosis, suggesting compositional rearrangement. We found PNNs in brain regions with putative homology to regions in mammals with known PNN function, and in other shared regions where PNN function is unknown.

    Our results suggest that PNNs are susceptible to remodeling by endogenous mechanisms during development. Interpreting the roles of PNNs in circuit maturation and stability requires understanding their temporal relationship with the neurons and synapses they surround. Our work provides further impetus to investigate this relationship in tandem with developmental and behavioral studies.

    in Journal of Comparative Neurology on October 16, 2020 03:39 PM.

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    Moment dynamics for gene regulation with rational rate laws

    Author(s): Yan-Mei Kang and Ruo-Nan Liu

    This aim of this paper is mainly to investigate the performance of two typical moment closure schemes in gene regulatory master equations of rational rate laws. When the reaction rate is polynomial, the error bounds between the authentic and approximate moments obtained by schemes of Gaussian moment...


    [Phys. Rev. E 102, 042407] Published Fri Oct 16, 2020

    in Physical Review E: Biological physics on October 16, 2020 10:00 AM.

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    Additional contributions to elastic energy of lipid membranes: Tilt-curvature coupling and curvature gradient

    Author(s): Konstantin V. Pinigin, Peter I. Kuzmin, Sergey A. Akimov, and Timur R. Galimzyanov

    Lipid bilayer membranes under biologically relevant conditions are flexible thin laterally fluid films consisting of two unimolecular layers (monolayers) each about 2 nm thick. On spatial scales much larger than the bilayer thickness, the membrane elasticity is well determined by its shape. The clas...


    [Phys. Rev. E 102, 042406] Published Fri Oct 16, 2020

    in Physical Review E: Biological physics on October 16, 2020 10:00 AM.

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    Efficacy of N‐acetylcysteine in the prevention of alcohol relapse‐like drinking: Study in long‐term ethanol‐experienced male rats

    Efficacy of N‐acetylcysteine in the prevention of alcohol relapse‐like drinking: Study in long‐term ethanol‐experienced male rats

    In this research, the potential anti‐relapse efficacy of N‐acetylcysteine (NAC), using the alcohol deprivation effect (ADE) model in long‐term experienced male Wistar rats, has been explored. Two different experiments were performed in order to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for the drug. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, was able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose under an intermittent regimen.


    Abstract

    Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N‐acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti‐relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long‐term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini‐osmotic pumps delivering 0 or 1 mg/hr NAC during 14 days. In a second experiment, rats received 0, 60, or 100 mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.

    in Journal of Neuroscience Research on October 16, 2020 08:29 AM.

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    Publisher Correction: A glycolytic shift in Schwann cells supports injured axons

    Nature Neuroscience, Published online: 16 October 2020; doi:10.1038/s41593-020-00731-2

    Publisher Correction: A glycolytic shift in Schwann cells supports injured axons

    in Nature Neuroscience on October 16, 2020 12:00 AM.

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    Author Correction: Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells

    Nature Methods, Published online: 16 October 2020; doi:10.1038/s41592-020-00996-2

    Author Correction: Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells

    in Nature Methods on October 16, 2020 12:00 AM.

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    Publisher Correction: A single-cell transcriptome atlas of marsupial embryogenesis and X inactivation

    Nature, Published online: 16 October 2020; doi:10.1038/s41586-020-2840-5

    Publisher Correction: A single-cell transcriptome atlas of marsupial embryogenesis and X inactivation

    in Nature on October 16, 2020 12:00 AM.

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    Surgery-free optogenetics

    Nature Reviews Neuroscience, Published online: 16 October 2020; doi:10.1038/s41583-020-00400-0

    Surgery-free optogenetics

    in Nature Reviews on October 16, 2020 12:00 AM.

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    Microglia coordinate repair

    Nature Reviews Neuroscience, Published online: 16 October 2020; doi:10.1038/s41583-020-00399-4

    Microglia coordinate repair

    in Nature Reviews on October 16, 2020 12:00 AM.

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    Controlling synaptic spillover

    Nature Reviews Neuroscience, Published online: 16 October 2020; doi:10.1038/s41583-020-00398-5

    Controlling synaptic spillover

    in Nature Reviews on October 16, 2020 12:00 AM.

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    Microglia drive dysfunction in Down syndrome

    Nature Reviews Neuroscience, Published online: 16 October 2020; doi:10.1038/s41583-020-00397-6

    Microglia drive dysfunction in Down syndrome

    in Nature Reviews on October 16, 2020 12:00 AM.

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    Gut microbial molecules in behavioural and neurodegenerative conditions

    Nature Reviews Neuroscience, Published online: 16 October 2020; doi:10.1038/s41583-020-00381-0

    Mounting evidence suggests that the gut microbiome impacts brain function, and mechanistic connections between specific microbial by-products and the brain have begun to emerge. In this Perspective, Mazmanian and colleagues discuss the assortment of microbial molecules currently thought to mediate these gut–brain connections.

    in Nature Reviews on October 16, 2020 12:00 AM.

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    ATP hydrolysis by yeast Hsp104 determines protein aggregate dissolution and size in vivo

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19104-1

    The sequestration of misfolded protein into insoluble aggregates occurs under conditions of proteotoxic stress. Here the authors observe that a reduction in cellular ATP promotes protein sequestration into two separate compartments: Q-bodies and stress granules; and identify Hsp104 as a critical ATP-consuming process that determines those compartments abundance and size.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Non-dispersive infrared multi-gas sensing via nanoantenna integrated narrowband detectors

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19085-1

    Gas sensing based on infrared absorption typically uses narrowband filters paired with detectors to select different gases. Here, the authors propose a multi-gas-sensing platform based on an array of narrowband detectors employing nanoantenna based plasmonic metamaterial absorbers.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19080-6

    COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Metal chalcogenide hollow polar bipyramid prisms as efficient sulfur hosts for Na-S batteries

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19078-0

    Sodium sulfur batteries require efficient sulfur hosts that can capture soluble polysulfides and enable fast reduction kinetics. Here, authors report hollow catalytic bipyramid prism CoS2/C as efficient sulfur carriers, and investigate the reaction mechanism in the sodium sulfur battery.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Analysis of protein-DNA interactions in chromatin by UV induced cross-linking and mass spectrometry

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19047-7

    Cross-linking mass spectrometry (XLMS) allows mapping of protein-protein and protein-RNA interactions, but the analysis of protein-DNA complexes remains challenging. Here, the authors develop a UV light-based XLMS workflow to determine protein-DNA interfaces in reconstituted chromatin and isolated nuclei.

    in Nature Communications on October 16, 2020 12:00 AM.

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    A causal role for frontal cortico-cortical coordination in social action monitoring

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-19026-y

    Social interactions require monitoring others’ actions to optimally organise one’s own actions. Here, the authors show that the pathway from the ventral premotor cortex (PMv) to the medial prefrontal cortex (MPFC) is causally involved in monitoring observed, but not executed, actions.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-18988-3

    Acral melanoma occurs on the soles of the feet, palms of the hands and in nail beds. Here, the authors reports the genomic landscape of 87 acral melanomas and find that some tumors harbor a UV signature and that the tumors are diverse at the levels of mutational signatures, structural aberrations and copy number signatures.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Photon-directed multiplexed enzymatic DNA synthesis for molecular digital data storage

    Nature Communications, Published online: 16 October 2020; doi:10.1038/s41467-020-18681-5

    Writing data in DNA is still a bottleneck due to the reliance on chemical synthesis methods. Here the authors report multiplexed enzymatic DNA synthesis using maskless photolithography.

    in Nature Communications on October 16, 2020 12:00 AM.

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    Daily briefing: Huge COVID trial finds ‘little or no effect’ for remdesivir

    Nature, Published online: 16 October 2020; doi:10.1038/d41586-020-02951-9

    WHO’s global trial appears to show that none of four repurposed antiviral drugs reduce COVID-19 deaths. Plus, NASA’s asteroid mission and rewilding.

    in Nature on October 16, 2020 12:00 AM.

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    Universal assembly instructions for the placenta

    Nature, Published online: 16 October 2020; doi:10.1038/d41586-020-02914-0

    Our understanding of how mammalian embryos develop is based largely on mice. A study now reveals striking similarities and intriguing differences between mouse, cow and human embryos.

    in Nature on October 16, 2020 12:00 AM.

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    NASA ‘fist bumps’ an asteroid to reveal Solar System’s secrets

    Nature, Published online: 16 October 2020; doi:10.1038/d41586-020-02910-4

    OSIRIS-REx spacecraft successfully executes a nail-biting manoeuvre to scoop up rock samples from the asteroid Bennu and send them back to Earth.

    in Nature on October 16, 2020 12:00 AM.

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    Differential Expression of DeltaFosB in Reward Processing Regions Between Binge Eating Prone and Resistant Female Rats

    Binge eating (BE) is characterized by the consumption of large amounts of palatable food in a discrete period and compulsivity. Even though BE is a common symptom in bulimia nervosa (BN), binge eating disorder (BED), and some cases of other specified feeding or eating disorders, little is known about its pathophysiology. We aimed to identify brain regions and neuron subtypes implicated in the development of binge-like eating in a female rat model. We separated rats into binge eating prone (BEP) and binge eating resistant (BER) phenotypes based on the amount of sucrose they consumed following foot-shock stress. We quantified deltaFosB (ΔFosB) expression, a stably expressed Fos family member, in different brain regions involved in reward, taste, or stress processing, to assess their involvement in the development of the phenotype. The number of ΔFosB-expressing neurons was: (1) higher in BEP than BER rats in reward processing areas [medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA)]; (2) similar in taste processing areas [insular cortex, IC and parabrachial nucleus (PBN)]; and (3) higher in the paraventricular nucleus of BEP than BER rats, but not different in the locus coeruleus (LC), which are stress processing structures. To study subtypes of ΔFosB-expressing neurons in the reward system, we performed in situ hybridization for glutamate decarboxylase 65 and tyrosine hydroxylase (TH) mRNA after ΔFosB immunohistochemistry. In the mPFC and Acb, the proportions of γ-aminobutyric acidergic (GABAergic) and non-GABAergic ΔFosB-expressing neurons were similar in BER and BEP rats. In the VTA, while the proportion of dopaminergic ΔFosB-expressing neurons was similar in both phenotypes, the proportion of GABAergic ΔFosB-expressing neurons was higher in BER than BEP rats. Our results suggest that reward processing brain regions, particularly the VTA, are important for the development of binge-like eating.

    in Frontiers in Systems Neuroscience on October 16, 2020 12:00 AM.

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    Degradation and Transmission of Tau by Autophagic-Endolysosomal Networks and Potential Therapeutic Targets for Tauopathy

    Tauopathies are a class of neurodegenerative diseases, including Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and many others where microtubule-associated protein tau (MAPT or tau) is hyperphosphorylated and aggregated to form insoluble paired helical filaments (PHFs) and ultimately neurofibrillary tangles (NFTs). Autophagic-endolysosomal networks (AELN) play important roles in tau clearance. Excessive soluble neurotoxic forms of tau and tau hyperphosphorylated at specific sites are cleared through the ubiquitin-proteasome system (UPS), Chaperon-mediated Autophagy (CMA), and endosomal microautophagy (e-MI). On the other hand, intra-neuronal insoluble tau aggregates are often degraded within lysosomes by macroautophagy. AELN defects have been observed in AD, FTD, CBD, and PSP, and lysosomal dysfunction was shown to promote the cleavage and neurotoxicity of tau. Moreover, several AD risk genes (e.g., PICALM, GRN, and BIN1) have been associated with dysregulation of AELN in the late-onset sporadic AD. Conversely, tau dissociation from microtubules interferes with retrograde transport of autophagosomes to lysosomes, and that tau fragments can also lead to lysosomal dysfunction. Recent studies suggest that tau is not merely an intra-neuronal protein, but it can be released to brain parenchyma via extracellular vesicles, like exosomes and ectosomes, and thus spread between neurons. Extracellular tau can also be taken up by microglial cells and astrocytes, either being degraded through AELN or propagated via exosomes. This article reviews the complex roles of AELN in the degradation and transmission of tau, potential diagnostic/therapeutic targets and strategies based on AELN-mediated tau clearance and propagation, and the current state of drug development targeting AELN and tau against tauopathies.

    in Frontiers in Molecular Neuroscience on October 16, 2020 12:00 AM.

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    Hepcidin Decreases Rotenone-Induced α-Synuclein Accumulation via Autophagy in SH-SY5Y Cells

    Parkinson’s disease (PD) is a neurodegenerative disorder, and the hallmarks of this disease include iron deposition and α-synuclein (α-syn) aggregation. Hepcidin could reduce iron in the central and peripheral nervous systems. Here, we hypothesized that hepcidin could further decrease α-syn accumulation via reducing iron. Therefore, rotenone or α-syn was introduced into human neuroblastoma SH-SY5Y cells to imitate the pathological progress of PD in vitro. This study investigated the clearance effects of hepcidin on α-syn induced by a relatively low concentration of rotenone exposure or α-syn overexpression to elucidate the potential clearance pathway involved in this process. We demonstrated that SH-SY5Y cell viability was impaired after rotenone treatment in a dose-dependent manner. α-syn expression and iron content increased under a low concentration rotenone (25 nM for 3 days) treatment in SH-SY5Y cells. Pre-treatment with hepcidin peptide suppressed the abovementioned effects of rotenone. However, hepcidin did not affect treatment with rotenone under high iron conditions. Hepcidin also played a role in reducing α-syn accumulation in rotenone and α-syn overexpression conditions. We identified that the probable clearance effect of hepcidin on α-syn was mediated by the autophagy pathway using pretreatment with autophagy inhibitors (3-MA and CQ) and detection of autophagy protein markers (LC3II/I and p62). In conclusion, hepcidin eliminated α-syn expression via the autophagy pathway in rotenone-treated and α-syn overexpression SH-SY5Y cells. This study highlights that hepcidin may offer a potential therapeutic perspective in α-syn accumulation diseases.

    in Frontiers in Molecular Neuroscience on October 16, 2020 12:00 AM.

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    On the Organization of the Locomotor CPG: Insights From Split-Belt Locomotion and Mathematical Modeling

    Rhythmic limb movements during locomotion are controlled by central pattern generator (CPG) circuits located in the spinal cord. It is considered that these circuits are composed of individual rhythm generators (RGs) for each limb interacting with each other through multiple commissural and long propriospinal circuits. The organization and operation of each RG are not fully understood, and different competing theories exist about interactions between its flexor and extensor components, as well as about left–right commissural interactions between the RGs. The central idea of circuit organization proposed in this study is that with an increase of excitatory input to each RG (or an increase in locomotor speed) the rhythmogenic mechanism of the RGs changes from “flexor-driven” rhythmicity to a “classical half-center” mechanism. We test this hypothesis using our experimental data on changes in duration of stance and swing phases in the intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) or split-belt treadmills with different left and right belt speeds (asymmetric conditions). We compare these experimental data with the results of mathematical modeling, in which simulated CPG circuits operate in similar symmetric and asymmetric conditions with matching or differing control drives to the left and right RGs. The obtained results support the proposed concept of state-dependent changes in RG operation and specific commissural interactions between the RGs. The performed simulations and mathematical analysis of model operation under different conditions provide new insights into CPG network organization and limb coordination during locomotion.

    in Frontiers in Neuroscience: Systems Biology on October 16, 2020 12:00 AM.

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    Current Status of Stem Cell-Derived Therapies for Parkinson’s Disease: From Cell Assessment and Imaging Modalities to Clinical Trials

    Curative therapies or treatments reversing the progression of Parkinson’s disease (PD) have attracted considerable interest in the last few decades. PD is characterized by the gradual loss of dopaminergic (DA) neurons and decreased striatal dopamine levels. Current challenges include optimizing neuroprotective strategies, developing personalized drug therapy, and minimizing side effects from the long-term prescription of pharmacological drugs used to relieve short-term motor symptoms. Transplantation of DA cells into PD patients’ brains to replace degenerated DA has the potential to change the treatment paradigm. Herein, we provide updates on current progress in stem cell-derived DA neuron transplantation as a therapeutic alternative for PD. We briefly highlight cell sources for transplantation and focus on cell assessment methods such as identification of genetic markers, single-cell sequencing, and imaging modalities used to access cell survival and function. More importantly, we summarize clinical reports of patients who have undergone cell-derived transplantation in PD to better perceive lessons that can be drawn from past and present clinical outcomes. Modifying factors include (1) source of the stem cells, (2) quality of the stem cells, (3) age of the patient, (4) stage of disease progression at the time of cell therapy, (5) surgical technique/practices, and (6) the use of immunosuppression. We await the outcomes of joint efforts in clinical trials around the world such as NYSTEM and CiRA to further guide us in the selection of the most suitable parameters for cell-based neurotransplantation in PD.

    in Frontiers in Neuroscience: Neurodegeneration on October 16, 2020 12:00 AM.

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    The Upper Extremity Flexion Synergy Is Minimally Expressed in Young Individuals With Unilateral Cerebral Palsy Following an Early Brain Injury

    Hemiparetic stroke in adulthood often results in the grouped movement pattern of the upper extremity flexion synergy thought to arise from an increased reliance on cortico-reticulospinal pathways due to a loss of lateral corticospinal projections. It is well established that the flexion synergy induces reaching constraints in individuals with adult-onset hemiplegia. The expression of the flexion synergy in individuals with brain injuries onset earlier in the lifespan is currently unknown. An early unilateral brain injury occurring prior to six months post full-term may preserve corticospinal projections which can be used for independent joint control and thus minimizing the expression of the flexion synergy. This study uses kinematics of a ballistic reaching task to evaluate the expression of the flexion synergy in individuals with pediatric hemiplegia (PH) ages six to seventeen years. Fifteen individuals with brain injuries before birth (n = 8) and around full-term (n = 7) and nine age-matched controls with no known neurological impairment completed a set of reaches in an admittance controlled robotic device. Descending drive, and the possible expression of the upper extremity flexion synergy, was modulated by increasing shoulder abduction loading. Individuals with early-onset PH achieved lower peak velocities when reaching with the paretic arm compared to controls; however, no differences in reaching distance were found between groups. Relative maintenance in reaching seen in individuals with early brain injuries highlights minimal expression of the flexion synergy. We interpret this conservation of independent control of the paretic shoulder and elbow as the use of more direct corticospinal projections instead of indirect cortico-reticulospinal pathways used in individuals with adult-onset hemiplegia.

    in Frontiers in Human Neuroscience on October 16, 2020 12:00 AM.

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    Myelin Water Imaging Demonstrates Lower Brain Myelination in Children and Adolescents With Poor Reading Ability

    Magnetic resonance imaging (MRI) provides a means to non-invasively investigate the neurological links with dyslexia, a learning disability that affects one’s ability to read. Most previous brain MRI studies of dyslexia and reading skill have used structural or diffusion imaging to reveal regional brain abnormalities. However, volumetric and diffusion MRI lack specificity in their interpretation at the microstructural level. Myelin is a critical neural component for brain function and plasticity, and as such, deficits in myelin may impact reading ability. MRI can estimate myelin using myelin water fraction (MWF) imaging, which is based on evaluation of the proportion of short T2 myelin-associated water from multi-exponential T2 relaxation analysis, but has not yet been applied to the study of reading or dyslexia. In this study, MWF MRI, intelligence, and reading assessments were acquired in 20 participants aged 10–18 years with a wide range of reading ability to investigate the relationship between reading ability and myelination. Group comparisons showed markedly lower MWF by 16–69% in poor readers relative to good readers in the left and right thalamus, as well as the left posterior limb of the internal capsule, left/right anterior limb of the internal capsule, left/right centrum semiovale, and splenium of the corpus callosum. MWF over the entire group also correlated positively with three different reading scores in the bilateral thalamus as well as white matter, including the splenium of the corpus callosum, left posterior limb of the internal capsule, left anterior limb of the internal capsule, and left centrum semiovale. MWF imaging from T2 relaxation suggests that myelination, particularly in the bilateral thalamus, splenium, and left hemisphere white matter, plays a role in reading abilities. Myelin water imaging thus provides a potentially valuable in vivo imaging tool for the study of dyslexia and its remediation.

    in Frontiers in Human Neuroscience on October 16, 2020 12:00 AM.

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    Effects of Transcranial Direct Current Stimulation on Brain Networks Related to Creative Thinking

    Human creative thinking is unique and capable of generating novel and valuable ideas. Recent research has clarified the contribution of different brain networks (default mode network, DN; executive control network; salience network) to creative thinking. However, the effects of brain stimulation on brain networks during creative thinking and on creative performance have not been clarified. The present study was designed to examine the changes in functional connectivity (FC) and effective connectivity (EC) of the large-scale brain network, and the ensuing changes in creative performance, induced by transcranial direct current stimulation (tDCS). Fourteen healthy male students underwent two tDCS sessions, one with actual stimulation and one with sham stimulation, on two separate days. Participants underwent tDCS (anode over the left dorsolateral prefrontal cortex, DLPFC; cathode over the right inferior parietal lobule, IPL) for 20 min. Before and after the tDCS session, electroencephalography signals were acquired from 32 electrodes over the whole head during the creative thinking task. On FC analysis, the delta band FC between the posterior cingulate cortex and IPL significantly increased only after real stimulation. We also found that the change of flexibility score was significantly correlated with the change in: (i) delta band FC between mPFC and left lateral temporal cortex (LTC) and (ii) alpha band FC between IPL and right LTC. On EC analysis, decreased flow within the DN (from left LTC to right IPL) was observed. Our results reveal that tDCS could affect brain networks, particularly the DN, during creative thinking and modulate key FC in the generation of flexible creative ideas.

    in Frontiers in Human Neuroscience on October 16, 2020 12:00 AM.

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    C1q Regulates Horizontal Cell Neurite Confinement in the Outer Retina

    During development, neurons generate excess processes which are then eliminated in concert with circuit maturation. C1q is the initiating protein in the complement cascade and has been implicated in this process, but whether C1q-mediated elimination is targeted to particular neural compartments is unclear. Using the murine retina, we identify C1q as a specific regulator of horizontal cell neurite confinement. Subsets of horizontal cell dendritic and axonal neurites extend into the outer retina suggesting that complement achieves both cellular and subcellular selectivity. These alterations emerge as outer retina synapses become mature. C1q expression is restricted to retina microglia, and the loss of C1q results in decreased microglia activation. This pathway appears independent of the C3a receptor (C3aR) and complement receptor 3 (CR3), as horizontal cells are normal when either protein is absent. Together, these data identify a new role for C1q in cell and neurite-specific confinement and implicate microglia-mediated phagocytosis in this process.

    in Frontiers in Neural Circuits on October 16, 2020 12:00 AM.

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    Activity of a vmPFC-DRN Pathway Corresponds With Resistance to Acute Social Defeat Stress

    The ventromedial prefrontal cortex (vmPFC) plays a critical role in stress resilience through top-down inhibition of key stress-sensitive limbic and hindbrain structures, including the dorsal raphe nucleus (DRN). In a model of experience-dependent stress resistance, socially dominant Syrian hamsters display fewer signs of anxiety following acute social defeat when compared to subordinate or control counterparts. Further, dominants activate vmPFC neurons to a greater degree during stress than do subordinates and become stress-vulnerable following pharmacological inhibition of the vmPFC. Dominants also display fewer stress-activated DRN neurons than subordinates do, suggesting that dominance experience gates activation of vmPFC neurons that inhibit the DRN during social defeat stress. To test whether social dominance alters stress-induced activity of a vmPFC-DRN pathway, we injected a retrograde tracer, cholera toxin B (CTB), into the DRN of dominant, subordinate, and control hamsters and used a dual-label immunohistochemical approach to identify vmPFC neurons co-labeled with CTB and the defeat-induced expression of an immediate early gene, cFos. Results indicate that dominant hamsters display more cFos+ and dual-labeled cells in layers V/VI of infralimbic and prelimbic subregions of the vmPFC compared to other animals. Furthermore, vmPFC-DRN activation corresponded directly with proactive behavioral strategies during defeat, which is indicative of stress resilience. Together, results suggest that recruiting the vmPFC-DRN pathway during acute stress corresponds with resistance to the effects of social defeat in dominant hamsters. Overall, these findings indicate that a monosynaptic vmPFC-DRN pathway can be engaged in an experience-dependent manner, which has implications for behavioral interventions aimed at alleviating stress-related psychopathologies.

    in Frontiers in Neural Circuits on October 16, 2020 12:00 AM.

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    Astrocytic Calcium Dynamics Along the Pain Pathway

    Astrocytes, once thought to be passive cells merely filling the space between neurons in the nervous system, are receiving attention as active modulators of the brain and spinal cord physiology by providing nutrients, maintaining homeostasis, and modulating synaptic transmission. Accumulating evidence indicates that astrocytes are critically involved in chronic pain regulation. Injury induces astrocytes to become reactive, and recent studies suggest that reactive astrocytes can have either neuroprotective or neurodegenerative effects. While the exact mechanisms underlying the transition from resting astrocytes to reactive astrocytes remain unknown, astrocytic calcium increase, coordinated by inflammatory molecules, has been suggested to trigger this transition. In this mini review article, we will discuss the roles of astrocytic calcium, channels contributing to calcium dynamics in astrocytes, astrocyte activations along the pain pathway, and possible relationships between astrocytic calcium dynamics and chronic pain.

    in Frontiers in Cellular Neuroscience on October 16, 2020 12:00 AM.

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    Three-Week Treadmill Exercise Enhances Persistent Inward Currents, Facilitates Dendritic Plasticity, and Upregulates the Excitability of Dorsal Raphe Serotonin Neurons in ePet-EYFP Mice

    Exercise plays a key role in preventing or treating mental or motor disorders caused by dysfunction of the serotonergic system. However, the electrophysiological and ionic channel mechanisms underlying these effects remain unclear. In this study, we investigated the effects of 3-week treadmill exercise on the electrophysiological and channel properties of dorsal raphe nucleus (DRN). Serotonin (5-HT) neurons in ePet-EYFP mice, using whole-cell patch clamp recording. Treadmill exercise was induced in ePet-EYFP mice of P21–24 for 3 weeks, and whole-cell patch clamp recording was performed on EYFP-positive 5-HT neurons from DRN slices of P42–45 mice. Experiment data showed that 5-HT neurons in the DRN were a heterogeneous population with multiple firing patterns (single firing, phasic firing, and tonic firing). Persistent inward currents (PICs) with multiple patterns were expressed in 5-HT neurons and composed of Cav1.3 (Ca-PIC) and sodium (Na-PIC) components. Exercise hyperpolarized the voltage threshold for action potential (AP) by 3.1 ± 1.0 mV (control: n = 14, exercise: n = 18, p = 0.005) and increased the AP amplitude by 6.7 ± 3.0 mV (p = 0.031) and firing frequency by more than 22% especially within a range of current stimulation stronger than 70 pA. A 3-week treadmill exercise was sufficient to hyperpolarize PIC onset by 2.6 ± 1.3 mV (control: −53.4 ± 4.7 mV, n = 28; exercise: −56.0 ± 4.7 mV, n = 25, p = 0.050) and increase the PIC amplitude by 28% (control: 193.6 ± 81.8 pA; exercise: 248.5 ± 105.4 pA, p = 0.038). Furthermore, exercise hyperpolarized Na-PIC onset by 3.8 ± 1.8 mV (control: n = 8, exercise: n = 9, p = 0.049) and increased the Ca-PIC amplitude by 23% (p = 0.013). The exercise-induced enhancement of the PIC amplitude was mainly mediated by Ca-PIC and hyperpolarization of PIC onset by Na-PIC. Moreover, exercise facilitated dendritic plasticity, which was shown as the increased number of branch points by 1.5 ± 0.5 (p = 0.009) and dendritic branches by 2.1 ± 0.6 (n = 20, p = 0.001) and length by 732.0 ± 100.1 μm (p < 0.001) especially within the range of 50–200 μm from the soma. Functional analysis suggested that treadmill exercise enhanced Na-PIC for facilitation of spike initiation and Ca-PIC for regulation of repetitive firing. We concluded that PICs broadly existed in DRN 5-HT neurons and could influence serotonergic neurotransmission in juvenile mice and that 3-week treadmill exercise induced synaptic adaptations, enhanced PICs, and thus upregulated the excitability of the 5-HT neurons.

    in Frontiers in Cellular Neuroscience on October 16, 2020 12:00 AM.

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    Cerebrospinal Fluid IgM Levels in Association With Inflammatory Pathways in Multiple Sclerosis Patients

    Background

    Intrathecal immunoglobulin M (IgM) synthesis has been demonstrated in the early disease stages of multiple sclerosis (MS) as a predictor factor of a worsening disease course. Similarly, increased cerebrospinal fluid (CSF) molecules related to B-cell intrathecal activity have been associated with a more severe MS progression. However, whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated.

    Methods

    Using customized Bio-Plex assay, the protein levels of IgG, IgA, IgM, and of 34 other inflammatory molecules, related to B-cell, T-cell, and monocyte/macrophage activity, were analyzed in the CSF of 103 newly diagnosed relapsing–remitting MS patients and 36 patients with other neurological disorders. CSF IgM levels were also correlated with clinical and neuroradiological measures [advanced 3-T magnetic resonance imaging (MRI) parameters], at diagnosis and after 2 years of follow-up.

    Results

    A 45.6% increase in CSF IgM levels was found in MS patients compared to controls (p = 0.013). CSF IgM levels correlated with higher CSF levels of CXCL13 (p = 0.039), CCL21 (p = 0.023), interleukin 10 (IL-10) (p = 0.025), IL-12p70 (p = 0.020), CX3CL1 (p = 0.036), and CHI3L1 (p = 0.048) and were associated with earlier age of patients at diagnosis (p = 0.008), white matter lesion (WML) number (p = 0.039) and disease activity (p = 0.033) after 2 years of follow-up.

    Conclusion

    IgMs are the immunoglobulins mostly expressed in the CSF of naive MS patients compared to other neurological conditions at the time of diagnosis. The association between increased CSF IgM levels and molecules related to both B-cell immunity (IL-10) and recruitment (CXCL13 and CCL21) and to macrophage/microglia activity (IL-12p70, CX3CL1, and CHI3L1) suggests possible correlation between humoral and innate intrathecal immunity in early disease stage. Furthermore, the association of IgM levels with WMLs and MS clinical and MRI activity after 2 years supports the idea of key role of IgM in the disease course.

    in Frontiers in Cellular Neuroscience on October 16, 2020 12:00 AM.

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    Engineering Three-Dimensional Tumor Models to Study Glioma Cancer Stem Cells and Tumor Microenvironment

    Glioblastoma (GBM) is the most common and devastating primary brain tumor, leading to a uniform fatality after diagnosis. A major difficulty in eradicating GBM is the presence of microscopic residual infiltrating disease remaining after multimodality treatment. Glioma cancer stem cells (CSCs) have been pinpointed as the treatment-resistant tumor component that seeds ultimate tumor progression. Despite the key role of CSCs, the ideal preclinical model to study the genetic and epigenetic landmarks driving their malignant behavior while simulating an accurate interaction with the tumor microenvironment (TME) is still missing. The introduction of three-dimensional (3D) tumor platforms, such as organoids and 3D bioprinting, has allowed for a better representation of the pathophysiologic interactions between glioma CSCs and the TME. Thus, these technologies have enabled a more detailed study of glioma biology, tumor angiogenesis, treatment resistance, and even performing high-throughput screening assays of drug susceptibility. First, we will review the foundation of glioma biology and biomechanics of the TME, and then the most up-to-date insights about the applicability of these new tools in malignant glioma research.

    in Frontiers in Cellular Neuroscience on October 16, 2020 12:00 AM.

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    Pharmacological Targeting of CSF1R Inhibits Microglial Proliferation and Aggravates the Progression of Cerebral Ischemic Pathology

    Ischemic stroke can induce rapid activation of the microglia. It has been reported that the microglia’s survival is dependent on colony-stimulating factor 1 receptor (CSF1R) signaling and that pharmacological inhibition of CSF1R leads to morphological changes in the microglia in the healthy brain. However, the impact of CSF1R inhibition on neuronal structures and motor ability after ischemia–reperfusion remains unclear. In this study, we investigated microglial de-ramification, proliferation, and activation after inhibition of CSF1R by a tyrosine kinase inhibitor (ki20227) in a mouse model of global cerebral ischemia induced by bilateral common carotid artery ligation (BCAL). In addition to microglial morphology, we evaluated the mRNA expression of cytokines, chemokines, and inflammatory receptors. Our results show that pharmacological inhibition of CSF1R in ischemic mice resulted in the blockade of microglial proliferation and a shift in microglial morphology reflected by excessive de-ramification and a more activated phenotype accompanied by an enhanced innate immune response. Furthermore, we show that pharmacological inhibition of CSF1R in ischemic mice resulted in the aggravation of neuronal degeneration and behavioral impairment. Intravital two-photon imaging revealed that although pharmacological inhibition of CSF1R did not affect the recovery of dendritic structures, it caused a significant increase in spine elimination during reperfusion in ischemic mice. These findings suggest that pharmacological inhibition of CSF1R induces a blockade of microglial proliferation and causes acute activation of the microglia accompanied by a severe inflammatory response. It aggravates neuronal degeneration, loss of dendritic spines, and behavioral deficits after transient global cerebral ischemia.

    in Frontiers in Cellular Neuroscience on October 16, 2020 12:00 AM.

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    The Relationship Between Cognitive Status and Known Single Nucleotide Polymorphisms in Age-Related Macular Degeneration

    Recent literature has reported a higher occurrence of cognitive impairment among individuals with Age-related Macular Degeneration (AMD) compared to older adults with normal vision. This pilot study explored potential links between single nucleotide polymorphisms (SNPs) in AMD and cognitive status. Individuals with AMD (N = 21) and controls (N = 18) were genotyped for the SNPs CFHY402H, ARMS2A69S and FADS1 rs174547. Cognitive status was evaluated using the Montreal Cognitive Assessment. The two groups differed significantly on which subscales were most difficult. The control group had difficulty with delayed recall while those with AMD had difficulty on delayed recall in addition to abstraction and orientation. Homozygous carriers of the FADS1 rs174547 SNP had significantly lower scores than heterozygotes or non-carriers on the MoCA. The results suggest that the FADS1 SNP may play a role in visual impairment/cognitive impairment comorbidity as reflected in the poorer cognitive scores among homozygotes with AMD compared to those carrying only one, or no copies of the SNP.

    in Frontiers in Ageing Neuroscience on October 16, 2020 12:00 AM.

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    Altered Functional Network Associated With Cognitive Performance in Early Parkinson Disease Measured by Eigenvector Centrality Mapping

    Objective: To investigate relationships between whole-brain functional changes and the performance of multiple cognitive functions in early Parkinson’s disease (PD).

    Methods: In the current study, we evaluated resting-state functional MRI (rsfMRI) data and neuropsychological assessments for various cognitive functions in a cohort with 84 early PD patients from the Parkinson’s Progression Markers Initiative (PPMI). Eigenvector centrality (EC) mapping based on rsfMRI was used to identify the functional connectivity of brain areas correlated with different neuropsychological scores at a whole-brain level.

    Results: Our study demonstrated that in the early PD patients, scores of Letter Number Sequencing (LNS) were positively correlated with EC in the left inferior occipital gyrus (IOG) and lingual gyrus. The immediate recall scores of Hopkins Verbal Learning Test-Revised (HVLT-R) were positively correlated with EC in the left superior frontal gyrus. No correlation was found between the EC and other cognitive performance scores.

    Conclusions: Functional alternations in the left occipital lobe (inferior occipital and lingual gyrus) and left superior frontal gyrus may account for the performance of working memory and immediate recall memory, respectively in early PD. These results may broaden the understanding of the potential mechanism of cognitive impairments in early PD.

    in Frontiers in Ageing Neuroscience on October 16, 2020 12:00 AM.

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    Debunking an old theory

    Recording the neural activity of cells in the brain of patients with Parkinson's disease challenges long-standing assumptions about how this disease manifests at the cellular level.

    in eLife on October 16, 2020 12:00 AM.

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    A natural variant of the essential host gene MMS21 restricts the parasitic 2-micron plasmid in Saccharomyces cerevisiae

    Antagonistic coevolution with selfish genetic elements (SGEs) can drive evolution of host resistance. Here, we investigated host suppression of 2-micron (2m) plasmids, multicopy nuclear parasites that have co-evolved with budding yeasts. We developed SCAMPR (Single-Cell Assay for Measuring Plasmid Retention) to measure copy number heterogeneity and 2m plasmid loss in live cells. We identified three S. cerevisiae strains that lack endogenous 2m plasmids and reproducibly inhibit mitotic plasmid stability. Focusing on the Y9 ragi strain, we determined that plasmid restriction is heritable and dominant. Using bulk segregant analysis, we identified a high-confidence Quantitative Trait Locus (QTL) with a single variant of MMS21 associated with increased 2m instability. MMS21 encodes a SUMO E3 ligase and an essential component of the Smc5/6 complex, involved in sister chromatid cohesion, chromosome segregation, and DNA repair. Our analyses leverage natural variation to uncover a novel means by which budding yeasts can overcome highly successful genetic parasites.

    in eLife on October 16, 2020 12:00 AM.

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    Modular metabolite assembly in C. elegans depends on carboxylesterases and formation of lysosome-related organelles

    Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.

    in eLife on October 16, 2020 12:00 AM.

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    Effects of lifelong testosterone exposure on health and disease: a Mendelian randomization study

    Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased haematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes.

    in eLife on October 16, 2020 12:00 AM.

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    Typical and atypical language brain organization based on intrinsic connectivity and multitask functional asymmetries

    Based on the joint investigation in 287 healthy volunteers (150 Left-Handers (LH)) of language task-induced asymmetries and intrinsic connectivity strength of the sentence-processing supramodal network, we show that individuals with atypical rightward language lateralization (N = 30, 25 LH) do not rely on an organization that simply mirrors that of typical leftward lateralized individuals. Actually, the resting-state organization in the atypicals showed that their sentence processing was underpinned by left and right networks both wired for language processing and highly interacting by strong interhemispheric intrinsic connectivity and larger corpus callosum volume. Such a loose hemispheric specialization for language permits the hosting of language in either the left and/or right hemisphere as assessed by a very high incidence of dissociations across various language task-induced asymmetries in this group.

    in eLife on October 16, 2020 12:00 AM.

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    Postnatal mechanical loading drives adaptation of tissues primarily through modulation of the non-collagenous matrix

    Mature connective tissues demonstrate highly specialised properties, remarkably adapted to meet their functional requirements. Tissue adaptation to environmental cues can occur throughout life and poor adaptation commonly results in injury. However, the temporal nature and drivers of functional adaptation remain undefined. Here, we explore functional adaptation and specialisation of mechanically loaded tissues using tendon; a simple aligned biological composite, in which the collagen (fascicle) and surrounding predominantly non-collagenous matrix (interfascicular matrix) can be interrogated independently. Using an equine model of late development, we report the first phase-specific analysis of biomechanical, structural and compositional changes seen in functional adaptation, demonstrating adaptation occurs postnatally, following mechanical loading, and is almost exclusively localised to the non-collagenous interfascicular matrix. These novel data redefine adaptation in connective tissue, highlighting the fundamental importance of non-collagenous matrix and suggesting that regenerative medicine strategies should change focus from the fibrous to the non-collagenous matrix of tissue.

    in eLife on October 16, 2020 12:00 AM.

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    Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

    Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here, we demonstrated that cardiac Mφs increased expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

    in eLife on October 16, 2020 12:00 AM.

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    High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition

    Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.

    in eLife on October 16, 2020 12:00 AM.

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    Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver

    The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.

    in eLife on October 16, 2020 12:00 AM.

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    Differential Relation between Neuronal and Behavioral Discrimination during Hippocampal Memory Encoding

    How does the brain tell apart similar information during memory storage and recall? Allegra et al. show that the input and output regions of the hippocampus play distinct roles in forming non-overlapping memory representations that are differentially related to an animal’s memory-guided behavioral performance.

    in Neuron: In press on October 16, 2020 12:00 AM.

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    Emergence of Neuronal Diversity during Vertebrate Brain Development

    The complexity and dynamics of vertebrate brain development are poorly understood. Raj et al. have generated a single-cell atlas of zebrafish brain development. They document the expansion of neuronal diversity, analyze the transition from early to late progenitors, and reconstruct cellular trajectories and lineages.

    in Neuron: In press on October 16, 2020 12:00 AM.

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    A model-based evaluation of the efficacy of COVID-19 social distancing, testing and hospital triage policies

    by Audrey McCombs, Claus Kadelka

    A stochastic compartmental network model of SARS-CoV-2 spread explores the simultaneous effects of policy choices in three domains: social distancing, hospital triaging, and testing. Considering policy domains together provides insight into how different policy decisions interact. The model incorporates important characteristics of COVID-19, the disease caused by SARS-CoV-2, such as heterogeneous risk factors and asymptomatic transmission, and enables a reliable qualitative comparison of policy choices despite the current uncertainty in key virus and disease parameters. Results suggest possible refinements to current policies, including emphasizing the need to reduce random encounters more than personal contacts, and testing low-risk symptomatic individuals before high-risk symptomatic individuals. The strength of social distancing of symptomatic individuals affects the degree to which asymptomatic cases drive the epidemic as well as the level of population-wide contact reduction needed to keep hospitals below capacity. The relative importance of testing and triaging also depends on the overall level of social distancing.

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Reduction in social learning and increased policy uncertainty about harmful intent is associated with pre-existing paranoid beliefs: Evidence from modelling a modified serial dictator game

    by Joseph M. Barnby, Vaughan Bell, Mitul A. Mehta, Michael Moutoussis

    Current computational models suggest that paranoia may be explained by stronger higher-order beliefs about others and increased sensitivity to environments. However, it is unclear whether this applies to social contexts, and whether it is specific to harmful intent attributions, the live expression of paranoia. We sought to fill this gap this by fitting a computational model to data (n = 1754) from a modified serial dictator game, to explore whether pre-existing paranoia could be accounted by specific alterations to cognitive parameters characterising harmful intent attributions. We constructed a ‘Bayesian brain’ model of others’ intent, which we fitted to harmful intent and self-interest attributions made over 18 trials, across three different partners. We found that pre-existing paranoia was associated with greater uncertainty about other’s actions. It moderated the relationship between learning rates and harmful intent attributions, making harmful intent attributions less reliant on prior interactions. Overall, the magnitude of harmful intent attributions was directly related to their uncertainty, and importantly, the opposite was true for self-interest attributions. Our results explain how pre-existing paranoia may be the result of an increased need to attend to immediate experiences in determining intentional threat, at the expense of what is already known, and more broadly, they suggest that environments that induce greater probabilities of harmful intent attributions may also induce states of uncertainty, potentially as an adaptive mechanism to better detect threatening others. Importantly, we suggest that if paranoia were able to be explained exclusively by core domain-general alterations we wouldn’t observe differential parameter estimates underlying harmful-intent and self-interest attributions.

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Optimal forgetting: Semantic compression of episodic memories

    by David G. Nagy, Balázs Török, Gergő Orbán

    It has extensively been documented that human memory exhibits a wide range of systematic distortions, which have been associated with resource constraints. Resource constraints on memory can be formalised in the normative framework of lossy compression, however traditional lossy compression algorithms result in qualitatively different distortions to those found in experiments with humans. We argue that the form of distortions is characteristic of relying on a generative model adapted to the environment for compression. We show that this semantic compression framework can provide a unifying explanation of a wide variety of memory phenomena. We harness recent advances in learning deep generative models, that yield powerful tools to approximate generative models of complex data. We use three datasets, chess games, natural text, and hand-drawn sketches, to demonstrate the effects of semantic compression on memory performance. Our model accounts for memory distortions related to domain expertise, gist-based distortions, contextual effects, and delayed recall.

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Reward-predictive representations generalize across tasks in reinforcement learning

    by Lucas Lehnert, Michael L. Littman, Michael J. Frank

    In computer science, reinforcement learning is a powerful framework with which artificial agents can learn to maximize their performance for any given Markov decision process (MDP). Advances over the last decade, in combination with deep neural networks, have enjoyed performance advantages over humans in many difficult task settings. However, such frameworks perform far less favorably when evaluated in their ability to generalize or transfer representations across different tasks. Existing algorithms that facilitate transfer typically are limited to cases in which the transition function or the optimal policy is portable to new contexts, but achieving “deep transfer” characteristic of human behavior has been elusive. Such transfer typically requires discovery of abstractions that permit analogical reuse of previously learned representations to superficially distinct tasks. Here, we demonstrate that abstractions that minimize error in predictions of reward outcomes generalize across tasks with different transition and reward functions. Such reward-predictive representations compress the state space of a task into a lower dimensional representation by combining states that are equivalent in terms of both the transition and reward functions. Because only state equivalences are considered, the resulting state representation is not tied to the transition and reward functions themselves and thus generalizes across tasks with different reward and transition functions. These results contrast with those using abstractions that myopically maximize reward in any given MDP and motivate further experiments in humans and animals to investigate if neural and cognitive systems involved in state representation perform abstractions that facilitate such equivalence relations.

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Ten simple rules to colorize biological data visualization

    by Georges Hattab, Theresa-Marie Rhyne, Dominik Heider

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Finding, visualizing, and quantifying latent structure across diverse animal vocal repertoires

    by Tim Sainburg, Marvin Thielk, Timothy Q. Gentner

    Animals produce vocalizations that range in complexity from a single repeated call to hundreds of unique vocal elements patterned in sequences unfolding over hours. Characterizing complex vocalizations can require considerable effort and a deep intuition about each species’ vocal behavior. Even with a great deal of experience, human characterizations of animal communication can be affected by human perceptual biases. We present a set of computational methods for projecting animal vocalizations into low dimensional latent representational spaces that are directly learned from the spectrograms of vocal signals. We apply these methods to diverse datasets from over 20 species, including humans, bats, songbirds, mice, cetaceans, and nonhuman primates. Latent projections uncover complex features of data in visually intuitive and quantifiable ways, enabling high-powered comparative analyses of vocal acoustics. We introduce methods for analyzing vocalizations as both discrete sequences and as continuous latent variables. Each method can be used to disentangle complex spectro-temporal structure and observe long-timescale organization in communication.

    in PLoS Computational Biology on October 15, 2020 09:00 PM.

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    Modeling human neuronal migration deficits in 3D

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Orly Reiner, Arpan Parichha, Tamar Sapir

    in Current Opinion in Neurobiology on October 15, 2020 06:00 PM.

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    Advanced deep learning methods for biomedical information analysis: An editorial

    Publication date: Available online 15 October 2020

    Source: Neural Networks

    Author(s): Yu-Dong Zhang, Francesco Carlo Morabito, Dinggang Shen, Khan Muhammad

    in Neural Networks on October 15, 2020 06:00 PM.

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    Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease

    Objective

    The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG‐Ab–associated disease (MOGAD).

    Methods

    This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time‐to‐event data and Kaplan–Meier curves for time to antibody negativity were performed for the objectives.

    Results

    Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow‐up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12–1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9–86.5) of nonrelapsing children became MOG‐Ab negative compared to 14.1% (95% CI = 4.7–38.3) of relapsing children (log‐rank p < 0.001), with no differences observed in adults (log‐rank p = 0.280).

    Interpretation

    MOGAD patients differ in the clinical presentation at onset, showing an age‐related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG‐Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2020

    in Annals of Neurology on October 15, 2020 03:10 PM.

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    Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome

    Objective

    The purpose of this study was to infer causal relationships between 22 previously reported risk factors for Alzheimer's disease (AD) and the “AD phenome”: AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of amyloid‐β (Aβ42), tau, and ptau181, and the neuropathological burden of neuritic plaques, neurofibrillary tangles (NFTs), and vascular brain injury (VBI).

    Methods

    Polygenic risk scores (PRS) for the 22 risk factors were computed in 26,431 AD cases/controls and the association with AD was evaluated using logistic regression. Two‐sample Mendelian randomization (MR) was used to infer the causal effect of risk factors on the AD phenome.

    Results

    PRS for increased education and diastolic blood pressure were associated with reduced risk for AD. MR indicated that only education was causally associated with reduced risk of AD, delayed AAOS, and increased cortical surface area and thickness. Total‐ and LDL‐cholesterol levels were causally associated with increased neuritic plaque burden, although the effects were driven by single nucleotide polymorphisms (SNPs) within the APOE locus. Diastolic blood pressure and pulse pressure are causally associated with increased risk of VBI. Furthermore, total cholesterol was associated with decreased hippocampal volume; smoking initiation with decreased cortical thickness; type 2 diabetes with an earlier AAOS; and sleep duration with increased cortical thickness.

    Interpretation

    Our comprehensive examination of the genetic evidence for the causal relationships between previously reported risk factors in AD using PRS and MR supports a causal role for education, blood pressure, cholesterol levels, smoking, and diabetes with the AD phenome. ANN NEUROL 2020

    in Annals of Neurology on October 15, 2020 02:50 PM.

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    Special acoustical role of pinna simplifying spatial target localization by the brown long-eared bat Plecotus auritus

    Author(s): Xin Ma, Sen Zhang, Zheng Dong, Hongwang Lu, Jinke Li, and Weidong Zhou

    Echolocating bats locate a target by sonar. The performance of this system is related to the shape of the binaural conformation in bats. From numerical predictions, it was found that in a central frequency band, the orientation of a strong sidelobe is shifted nearly linearly in the vertical directio...


    [Phys. Rev. E 102, 040401(R)] Published Thu Oct 15, 2020

    in Physical Review E: Biological physics on October 15, 2020 10:00 AM.

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    Author Correction: Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19253-3

    Author Correction: Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis

    in Nature Communications on October 15, 2020 12:00 AM.

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    Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19240-8

    Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease

    in Nature Communications on October 15, 2020 12:00 AM.

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    Author Correction: MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19103-2

    Author Correction: MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists

    in Nature Communications on October 15, 2020 12:00 AM.

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    Observation of phonon trapping in the continuum with topological charges

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19091-3

    Typically, phonon trapping is performed using mechanically suspended structures which have many limitations. Here the authors study a phononic structure that supports mechanical bound states in the continuum (BICs) at microwave frequencies with topological features.

    in Nature Communications on October 15, 2020 12:00 AM.

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    Training high-strength aluminum alloys to withstand fatigue

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19071-7

    The fatigue performance of high strength aluminum alloys is notoriously poor, leading to design limitations for transportation structures. Here the authors design microstructures to exploit the mechanical energy of fatigue to dynamically heal the microstructural weak points and improve the high cycle fatigue life.

    in Nature Communications on October 15, 2020 12:00 AM.

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    Dual redox mediators accelerate the electrochemical kinetics of lithium-sulfur batteries

    Nature Communications, Published online: 15 October 2020; doi:10.1038/s41467-020-19070-8

    The sluggish electrochemical kinetics of sulfur species remains a major hurdle for the broad adoption of lithium-sulfur batteries. Here, the authors construct an energy diagram of sulfur species to unveil their reaction pathways and propose a general strategy to accelerate electrochemical reactions.

    in Nature Communications on October 15, 2020 12:00 AM.

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    Daily briefing: Nobel-winning biochemist Jennifer Doudna on the future of CRISPR

    Nature, Published online: 15 October 2020; doi:10.1038/d41586-020-02933-x

    The next big CRISPR advance, how to retool for rigorous research and satellites could soon map every tree on Earth.

    in Nature on October 15, 2020 12:00 AM.

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    Georgina Mace (1953–2020)

    Nature, Published online: 15 October 2020; doi:10.1038/d41586-020-02931-z

    Pioneer of biodiversity accounting who overhauled the Red List of threatened species.

    in Nature on October 15, 2020 12:00 AM.

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    Why Borneo’s trees are the loftiest on Earth

    Nature, Published online: 15 October 2020; doi:10.1038/d41586-020-02911-3

    Scientists find that strong winds constrain tropical forest height, but island’s gentle breezes allow trees to stretch tall.

    in Nature on October 15, 2020 12:00 AM.

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    Don’t let COVID stop your fieldwork: three tips for successful collaborations

    Nature, Published online: 15 October 2020; doi:10.1038/d41586-020-02903-3

    Christie Sampson and Steven Vamosi were struck by the kindness of co-workers when coronavirus lockdowns began.

    in Nature on October 15, 2020 12:00 AM.

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    What it’s really like to do science amid COVID-19

    Nature, Published online: 15 October 2020; doi:10.1038/d41586-020-02815-2

    From Germany to India, researchers are grappling with how to run labs and lessons under extraordinary restrictions.

    in Nature on October 15, 2020 12:00 AM.

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    Prolonged Targeted Cardiovascular Epidural Stimulation Improves Immunological Molecular Profile: A Case Report in Chronic Severe Spinal Cord Injury

    In individuals with severe spinal cord injury (SCI), the autonomic nervous system (ANS) is affected leading to cardiovascular deficits, which include significant blood pressure instability, with the prevalence of systemic hypotension and orthostatic intolerance resulting in an increased risk of stroke. Additionally, persons with SCI rostral to thoracic vertebral level 5 (T5), where sympathetic nervous system fibers exit the spinal cord and innervate the immune system, have clinically significant systemic inflammation and increased infection risk. Our recent studies show that lumbosacral spinal cord epidural stimulation (scES), applied at the lumbosacral level using targeted configurations that promote cardiovascular stability (CV-scES), can safely and effectively normalize blood pressure in persons with chronic SCI. Herein we present a case report in a female (age 27 years) with chronic clinically motor complete cervical SCI demonstrating that 97-sessions of CV-scES, which increased systemic blood pressure, improved orthostatic tolerance in association with increased cerebral blood flow velocity in the middle cerebral artery, also promoted positive immunological changes in whole-blood gene expression. Specifically, there was evidence of the down-regulation of inflammatory pathways and the up-regulation of adaptative immune pathways. The findings of this case report suggest that the autonomic effects of epidural stimulation, targeted to promote cardiovascular homeostasis, also improves immune system function, which has a significant benefit to long-term cardiovascular and immunologic health in individuals with long-standing SCI.

    Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02307565.

    in Frontiers in Systems Neuroscience on October 15, 2020 12:00 AM.

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    Brain White-Matter Degeneration Due to Aging and Parkinson Disease as Revealed by Double Diffusion Encoding

    Microstructure imaging by means of multidimensional diffusion encoding is increasingly applied in clinical research, with expectations that it yields a parameter that better correlates with clinical disability than current methods based on single diffusion encoding. Under the assumption that diffusion within a voxel can be well described by a collection of diffusion tensors, several parameters of this diffusion tensor distribution can be derived, including mean size, variance of sizes, orientational dispersion, and microscopic anisotropy. The information provided by multidimensional diffusion encoding also enables us to decompose the sources of the conventional fractional anisotropy and mean kurtosis. In this study, we explored the utility of the diffusion tensor distribution approach for characterizing white-matter degeneration in aging and in Parkinson disease by using double diffusion encoding. Data from 23 healthy older subjects and 27 patients with Parkinson disease were analyzed. Advanced age was associated with greater mean size and size variances, as well as smaller microscopic anisotropy. By analyzing the parameters underlying diffusion kurtosis, we found that the reductions of kurtosis in aging and Parkinson disease reported in the literature are likely driven by the reduction in microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in the patients with Parkinson disease. The present results support the use of multidimensional diffusion encoding in clinical studies and are encouraging for its future clinical implementation.

    in Frontiers in Neuroscience: Brain Imaging Methods on October 15, 2020 12:00 AM.

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    Disrupted Patterns of Rich-Club and Diverse-Club Organizations in Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment

    Background

    Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) were considered to be a continuum of Alzheimer’s disease (AD) spectrum. The abnormal topological architecture and rich-club organization in the brain functional network can reveal the pathology of the AD spectrum. However, few studies have explored the disrupted patterns of diverse club organizations and the combination of rich- and diverse-club organizations in SCD and aMCI.

    Methods

    We collected resting-state functional magnetic resonance imaging data of 19 SCDs, 29 aMCIs, and 28 healthy controls (HCs) from the Alzheimer’s Disease Neuroimaging Initiative. Graph theory analysis was used to analyze the network metrics and rich- and diverse-club organizations simultaneously.

    Results

    Compared with HC, the aMCI group showed altered small-world and network efficiency, whereas the SCD group remained relatively stable. The aMCI group showed reduced rich-club connectivity compared with the HC. In addition, the aMCI group showed significantly increased feeder connectivity and decreased local connectivity of the diverse club compared with the SCD group. The overlapping nodes of the rich club and diverse club showed a significant difference in nodal efficiency and shortest path length (Lp) between groups. Notably, the Lp values of overlapping nodes in the SCD and aMCI groups were significantly associated with episodic memory.

    Conclusion

    The present study demonstrates that the network properties of SCD and aMCI have varying degrees of damage. The combination of the rich club and the diverse club can provide a novel insight into the pathological mechanism of the AD spectrum. The altered patterns in overlapping nodes might be potential biomarkers in the diagnosis of the AD spectrum.

    in Frontiers in Neuroscience: Neurodegeneration on October 15, 2020 12:00 AM.

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    Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation

    α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554W associates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro, with peptide modification enhancing its association with aSyn. Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective, as it would eliminate the need to administer the therapy at pre-aggregation stages, which are difficult to diagnose. Taken together the data suggest that 4554W could be a suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregation.

    in Frontiers in Neuroscience: Neurodegeneration on October 15, 2020 12:00 AM.

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    In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila

    The endoplasmic reticulum (ER) is a highly dynamic network whose shape is thought to be actively regulated by membrane resident proteins. Mutation of several such morphology regulators cause the neurological disorder Hereditary Sp astic Paraplegia (HSP), suggesting a critical role of ER shape maintenance in neuronal activity and function. Human Atlastin-1 mutations are responsible for SPG3A, the earliest onset and one of the more severe forms of dominant HSP. Atlastin has been initially identified in Drosophila as the GTPase responsible for the homotypic fusion of ER membrane. The majority of SPG3A-linked Atlastin-1 mutations map to the GTPase domain, potentially interfering with atlastin GTPase activity, and to the three-helix-bundle (3HB) domain, a region critical for homo-oligomerization. Here we have examined the in vivo effects of four pathogenetic missense mutations (two mapping to the GTPase domain and two to the 3HB domain) using two complementary approaches: CRISPR/Cas9 editing to introduce such variants in the endogenous atlastin gene and transgenesis to generate lines overexpressing atlastin carrying the same pathogenic variants. We found that all pathological mutations examined reduce atlastin activity in vivo although to different degrees of severity. Moreover, overexpression of the pathogenic variants in a wild type atlastin background does not give rise to the loss of function phenotypes expected for dominant negative mutations. These results indicate that the four pathological mutations investigated act through a loss of function mechanism.

    in Frontiers in Neuroscience: Neurodegeneration on October 15, 2020 12:00 AM.

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    A Systemic Review of Available Low-Cost EEG Headsets Used for Drowsiness Detection

    Drowsiness is a leading cause of traffic and industrial accidents, costing lives and productivity. Electroencephalography (EEG) signals can reflect awareness and attentiveness, and low-cost consumer EEG headsets are available on the market. The use of these devices as drowsiness detectors could increase the accessibility of safety and productivity-enhancing devices for small businesses and developing countries. We conducted a systemic review of currently available, low-cost, consumer EEG-based drowsiness detection systems. We sought to determine whether consumer EEG headsets could be reliably utilized as rudimentary drowsiness detection systems. We included documented cases describing successful drowsiness detection using consumer EEG-based devices, including the Neurosky MindWave, InteraXon Muse, Emotiv Epoc, Emotiv Insight, and OpenBCI. Of 46 relevant studies, ~27 reported an accuracy score. The lowest of these was the Neurosky Mindwave, with a minimum of 31%. The second lowest accuracy reported was 79.4% with an OpenBCI study. In many cases, algorithmic optimization remains necessary. Different methods for accuracy calculation, system calibration, and different definitions of drowsiness made direct comparisons problematic. However, even basic features, such as the power spectra of EEG bands, were able to consistently detect drowsiness. Each specific device has its own capabilities, tradeoffs, and limitations. Widely used spectral features can achieve successful drowsiness detection, even with low-cost consumer devices; however, reliability issues must still be addressed in an occupational context.

    in Frontiers in Neuroinformatics on October 15, 2020 12:00 AM.

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    Mental Effort When Playing, Listening, and Imagining Music in One Pianist’s Eyes and Brain

    We investigated “musical effort” with an internationally renowned, classical, pianist while playing, listening, and imagining music. We used pupillometry as an objective measure of mental effort and fMRI as an exploratory method of effort with the same musical pieces. We also compared a group of non-professional pianists and non-musicians by the use of pupillometry and a small group of non-musicians with fMRI. This combined approach of psychophysiology and neuroimaging revealed the cognitive work during different musical activities. We found that pupil diameters were largest when “playing” (regardless of whether there was sound produced or not) compared to conditions with no movement (i.e., “listening” and “imagery”). We found positive correlations between pupil diameters of the professional pianist during different conditions with the same piano piece (i.e., normal playing, silenced playing, listen, imagining), which might indicate similar degrees of load on cognitive resources as well as an intimate link between the motor imagery of sound-producing body motions and gestures. We also confirmed that musical imagery had a strong commonality with music listening in both pianists and musically naïve individuals. Neuroimaging provided evidence for a relationship between noradrenergic (NE) activity and mental workload or attentional intensity within the domain of music cognition. We found effort related activity in the superior part of the locus coeruleus (LC) and, similarly to the pupil, the listening and imagery engaged less the LC–NE network than the motor condition. The pianists attended more intensively to the most difficult piece than the non-musicians since they showed larger pupils for the most difficult piece. Non-musicians were the most engaged by the music listening task, suggesting that the amount of attention allocated for the same task may follow a hierarchy of expertise demanding less attentional effort in expert or performers than in novices. In the professional pianist, we found only weak evidence for a commonality between subjective effort (as rated measure-by-measure) and the objective effort gauged with pupil diameter during listening. We suggest that psychophysiological methods like pupillometry can index mental effort in a manner that is not available to subjective awareness or introspection.

    in Frontiers in Human Neuroscience on October 15, 2020 12:00 AM.

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    Examining Sodium and Potassium Channel Conductances Involved in Hyperexcitability of Chemotherapy-Induced Peripheral Neuropathy: A Mathematical and Cell Culture-Based Study

    Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent, painful side effect which arises due to a number of chemotherapy agents. CIPN can have a prolonged effect on quality of life. Chemotherapy treatment is often reduced or stopped altogether because of the severe pain. Currently, there are no FDA-approved treatments for CIPN partially due to its complex pathogenesis in multiple pathways involving a variety of channels, specifically, voltage-gated ion channels. One aspect of neuropathic pain in vitro is hyperexcitability in dorsal root ganglia (DRG) peripheral sensory neurons. Our study employs bifurcation theory to investigate the role of voltage-gated ion channels in inducing hyperexcitability as a consequence of spontaneous firing due to the common chemotherapy agent paclitaxel. Our mathematical investigation of a reductionist DRG neuron model comprised of sodium channel Nav1.7, sodium channel Nav1.8, delayed rectifier potassium channel, A-type transient potassium channel, and a leak channel suggests that Nav1.8 and delayed rectifier potassium channel conductances are critical for hyperexcitability of small DRG neurons. Introducing paclitaxel into the model, our bifurcation analysis predicts that hyperexcitability is highest for a medium dose of paclitaxel, which is supported by multi-electrode array (MEA) recordings. Furthermore, our findings using MEA reveal that Nav1.8 blocker A-803467 and delayed rectifier potassium enhancer L-alpha-phosphatidyl-D-myo-inositol 4,5-diphosphate, dioctanoyl (PIP2) can reduce paclitaxel-induced hyperexcitability of DRG neurons. Our approach can be readily extended and used to investigate various other contributors of hyperexcitability in CIPN.

    in Frontiers in Computational Neuroscience on October 15, 2020 12:00 AM.

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    Reconfigurable Filtering of Neuro-Spike Communications Using Synthetically Engineered Logic Circuits

    High-frequency firing activity can be induced either naturally in a healthy brain as a result of the processing of sensory stimuli or as an uncontrolled synchronous activity characterizing epileptic seizures. As part of this work, we investigate how logic circuits that are engineered in neurons can be used to design spike filters, attenuating high-frequency activity in a neuronal network that can be used to minimize the effects of neurodegenerative disorders such as epilepsy. We propose a reconfigurable filter design built from small neuronal networks that behave as digital logic circuits. We developed a mathematical framework to obtain a transfer function derived from a linearization process of the Hodgkin-Huxley model. Our results suggest that individual gates working as the output of the logic circuits can be used as a reconfigurable filtering technique. Also, as part of the analysis, the analytical model showed similar levels of attenuation in the frequency domain when compared to computational simulations by fine-tuning the synaptic weight. The proposed approach can potentially lead to precise and tunable treatments for neurological conditions that are inspired by communication theory.

    in Frontiers in Computational Neuroscience on October 15, 2020 12:00 AM.

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    Activity-Dependent Remodeling of Synaptic Protein Organization Revealed by High Throughput Analysis of STED Nanoscopy Images

    The organization of proteins in the apposed nanodomains of pre- and postsynaptic compartments is thought to play a pivotal role in synaptic strength and plasticity. As such, the alignment between pre- and postsynaptic proteins may regulate, for example, the rate of presynaptic release or the strength of postsynaptic signaling. However, the analysis of these structures has mainly been restricted to subsets of synapses, providing a limited view of the diversity of synaptic protein cluster remodeling during synaptic plasticity. To characterize changes in the organization of synaptic nanodomains during synaptic plasticity over a large population of synapses, we combined STimulated Emission Depletion (STED) nanoscopy with a Python-based statistical object distance analysis (pySODA), in dissociated cultured hippocampal circuits exposed to treatments driving different forms of synaptic plasticity. The nanoscale organization, characterized in terms of coupling properties, of presynaptic (Bassoon, RIM1/2) and postsynaptic (PSD95, Homer1c) scaffold proteins was differently altered in response to plasticity-inducing stimuli. For the Bassoon - PSD95 pair, treatments driving synaptic potentiation caused an increase in their coupling probability, whereas a stimulus driving synaptic depression had an opposite effect. To enrich the characterization of the synaptic cluster remodeling at the population level, we applied unsupervised machine learning approaches to include selected morphological features into a multidimensional analysis. This combined analysis revealed a large diversity of synaptic protein cluster subtypes exhibiting differential activity-dependent remodeling, yet with common features depending on the expected direction of plasticity. The expanded palette of synaptic features revealed by our unbiased approach should provide a basis to further explore the widely diverse molecular mechanisms of synaptic plasticity.

    in Frontiers in Neural Circuits on October 15, 2020 12:00 AM.

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    Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation

    Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer’s disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation. We provided details on how stimulation of α7 nicotinic acetylcholine (α7nACh) receptors can be neuroprotective by increasing amyloid-β phagocytosis, decreasing inflammation and reducing oxidative stress by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and decreasing the release of pro-inflammatory cytokines. There is also evidence for astroglial α7nACh receptor stimulation mediating anti-inflammatory and antioxidant effects by inhibiting the nuclear factor-κB (NF-κB) pathway and activating the Nrf2 pathway respectively. We conclude that targeting cholinergic glial interactions between neurons and glial cells via α7nACh receptors could regulate neuroinflammation and oxidative stress, relevant to the treatment of several neurodegenerative diseases.

    in Frontiers in Cellular Neuroscience on October 15, 2020 12:00 AM.

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    Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

    Schizophrenia is a psychiatric disorder affecting ∼1% of humans worldwide. It is earlier and more frequently diagnosed in men than woman, and men display more pronounced negative symptoms together with greater gray matter reductions. Our previous findings utilizing a maternal immune activation (mIA) mouse model of schizophrenia revealed exacerbated anxiety-like behavior and sensorimotor gating deficits in adult male offspring that were associated with increased microglial reactivity and inflammation in the hippocampal dentate gyrus (DG). However, both male and female adult offspring displayed stereotypy and impairment of sociability. We hypothesized that mIA may lead to sex-specific alterations in microglial pruning activity, resulting in abnormal synaptic connectivity in the DG. Using the same mIA model, we show in the current study sex-specific differences in microglia and synapses within the DG of adult offspring. Specifically, microglial levels of cluster of differentiation (CD)68 and CD11b were increased in mIA-exposed females. Sex-specific differences in excitatory and inhibitory synapse densities were also observed following mIA. Additionally, inhibitory synaptic tone was increased in DG granule cells of both males and females, while changes in excitatory synaptic transmission occurred only in females with mIA. These findings suggest that phagocytic and complement pathways may together contribute to a sexual dimorphism in synaptic pruning and neuronal dysfunction in mIA, and may propose sex-specific therapeutic targets to prevent schizophrenia-like behaviors.

    in Frontiers in Cellular Neuroscience on October 15, 2020 12:00 AM.

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    Axonal Degeneration in AD: The Contribution of Aβ and Tau

    Alzheimer’s disease (AD) represents the most common age-related neurodegenerative disorder, affecting around 35 million people worldwide. Despite enormous efforts dedicated to AD research over decades, there is still no cure for the disease. Misfolding and accumulation of Aβ and tau proteins in the brain constitute a defining signature of AD neuropathology, and mounting evidence has documented a link between aggregation of these proteins and neuronal dysfunction. In this context, progressive axonal degeneration has been associated with early stages of AD and linked to Aβ and tau accumulation. As the axonal degeneration mechanism has been starting to be unveiled, it constitutes a promising target for neuroprotection in AD. A comprehensive understanding of the mechanism of axonal destruction in neurodegenerative conditions is therefore critical for the development of new therapies aimed to prevent axonal loss before irreversible neuronal death occurs in AD. Here, we review current evidence of the involvement of Aβ and tau pathologies in the activation of signaling cascades that can promote axonal demise.

    in Frontiers in Ageing Neuroscience on October 15, 2020 12:00 AM.

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    Gait Progression Over 6 Years in Parkinson’s Disease: Effects of Age, Medication, and Pathology

    Background: Gait disturbance is an early, cardinal feature of Parkinson’s disease (PD) associated with falls and reduced physical activity. Progression of gait impairment in Parkinson’s disease is not well characterized and a better understanding is imperative to mitigate impairment. Subtle gait impairments progress in early disease despite optimal dopaminergic medication. Evaluating gait disturbances over longer periods, accounting for typical aging and dopaminergic medication changes, will enable a better understanding of gait changes and inform targeted therapies for early disease. This study aimed to describe gait progression over the first 6 years of PD by delineating changes associated with aging, medication, and pathology.

    Methods: One-hundred and nine newly diagnosed PD participants and 130 controls completed at least two gait assessments. Gait was assessed at 18-month intervals for up to 6 years using an instrumented walkway to measure sixteen spatiotemporal gait characteristics. Linear mixed-effects models assessed progression.

    Results: Ten gait characteristics significantly progressed in PD, with changes in four of these characteristics attributable to disease progression. Age-related changes also contributed to gait progression; changes in another two characteristics reflected both aging and disease progression. Gait impairment progressed irrespective of dopaminergic medication change for all characteristics except step width variability.

    Conclusions: Discrete gait impairments continue to progress in PD over 6 years, reflecting a combination of, and potential interaction between, disease-specific progression and age-related change. Gait changes were mostly unrelated to dopaminergic medication adjustments, highlighting limitations of current dopaminergic therapy and the need to improve interventions targeting gait decline.

    in Frontiers in Ageing Neuroscience on October 15, 2020 12:00 AM.

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    Modeling the Interaction between the Microenvironment and Tumor Cells in Brain Tumors

    In this review, Pasqualini et al. describe the tumor microenvironment in brain cancers and its impact on tumor behavior. They discuss how, compared to current preclinical models, humanized animals and organoids will allow more accurate evaluations of these complex interactions.

    in Neuron: In press on October 15, 2020 12:00 AM.

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    Refractory density model of cortical direction selectivity: Lagged-nonlagged, transient-sustained, and On-Off thalamic neuron-based mechanisms and intracortical amplification

    by Anton Chizhov, Natalia Merkulyeva

    A biophysically detailed description of the mechanisms of the primary vision is still being developed. We have incorporated a simplified, filter-based description of retino-thalamic visual signal processing into the detailed, conductance-based refractory density description of the neuronal population activity of the primary visual cortex. We compared four mechanisms of the direction selectivity (DS), three of them being based on asymmetrical projections of different types of thalamic neurons to the cortex, distinguishing between (i) lagged and nonlagged, (ii) transient and sustained, and (iii) On and Off neurons. The fourth mechanism implies a lack of subcortical bias and is an epiphenomenon of intracortical interactions between orientation columns. The simulations of the cortical response to moving gratings have verified that first three mechanisms provide DS to an extent compared with experimental data and that the biophysical model realistically reproduces characteristics of the visual cortex activity, such as membrane potential, firing rate, and synaptic conductances. The proposed model reveals the difference between the mechanisms of both the intact and the silenced cortex, favoring the second mechanism. In the fourth case, DS is weaker but significant; it completely vanishes in the silenced cortex.DS in the On-Off mechanism derives from the nonlinear interactions within the orientation map. Results of simulations can help to identify a prevailing mechanism of DS in V1. This is a step towards a comprehensive biophysical modeling of the primary visual system in the frameworks of the population rate coding concept.

    in PLoS Computational Biology on October 14, 2020 09:00 PM.

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    Forecasting influenza in Europe using a metapopulation model incorporating cross-border commuting and air travel

    by Sarah C. Kramer, Sen Pei, Jeffrey Shaman

    Past work has shown that models incorporating human travel can improve the quality of influenza forecasts. Here, we develop and validate a metapopulation model of twelve European countries, in which international translocation of virus is driven by observed commuting and air travel flows, and use this model to generate influenza forecasts in conjunction with incidence data from the World Health Organization. We find that, although the metapopulation model fits the data well, it offers no improvement over isolated models in forecast quality. We discuss several potential reasons for these results. In particular, we note the need for data that are more comparable from country to country, and offer suggestions as to how surveillance systems might be improved to achieve this goal.

    in PLoS Computational Biology on October 14, 2020 09:00 PM.

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    A functional context for heterogeneity of the circadian clock in cells

    by Martha Merrow, Mary Harrington

    Characterization of circadian systems at the organism level—a top-down approach—has led to definition of unifying properties, a hallmark of the science of chronobiology. The next challenge is to use a bottom-up approach to show how the molecular workings of the cellular circadian clock work as building blocks of those properties. We review new studies, including a recently published PLOS Biology paper by Nikhil and colleagues, that show how programmed but also stochastic generation of variation in cellular circadian period explain important adaptive features of entrained circadian phase.

    in PLoS Biology on October 14, 2020 09:00 PM.

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    The hippocampal formation of two carnivore species: The feliform banded mongoose and the caniform domestic ferret

    The hippocampal formation of two carnivore species: The feliform banded mongoose and the caniform domestic ferret

    Immunohistochemical staining for calbindin reveals a variety regions of the ventral hippocampus within the brain of the banded mongoose. These regions include the dentate gyrus (DG), cornu Ammonis regions 3 (CA3) and 1 (CA1), the ventral subiculum (VS), presubiculum (PrS), and parasubiculum (PaS). Scale bar = 1 mm.


    ABSTRACT

    Employing cyto‐, myelo‐, and chemoarchitectural staining techniques, we analyzed the structure of the hippocampal formation in the banded mongoose and domestic ferret, species belonging to the two carnivoran superfamilies, which have had independent evolutionary trajectories for the past 55 million years. Our observations indicate that, despite the time since sharing a last common ancestor, these species show extensive similarities. The four major portions of the hippocampal formation (cornu Ammonis, dentate gyrus, subicular complex, and entorhinal cortex) were readily observed, contained the same internal subdivisions, and maintained the topological relationships of these subdivisions that could be considered typically mammalian. In addition, adult hippocampal neurogenesis was observed in both species, occurring at a rate similar to that observed in other mammals. Despite the overall similarities, several differences to each other, and to other mammalian species, were observed. We could not find evidence for the presence of the CA2 and CA4 fields of the cornu Ammonis region. In the banded mongoose the dentate gyrus appears to be comprised of up to seven lamina, through the sublamination of the molecular and granule cell layers, which is not observed in the domestic ferret. In addition, numerous subtle variations in chemoarchitecture between the two species were observed. These differences may contribute to an overall variation in the functionality of the hippocampal formation between the species, and in comparison to other mammalian species. These similarities and variations are important to understanding to what extent phylogenetic affinities and constraints affect potential adaptive evolutionary plasticity of the hippocampal formation.

    in Journal of Comparative Neurology on October 14, 2020 09:32 AM.

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    Lin Tian

    Nature Methods, Published online: 14 October 2020; doi:10.1038/s41592-020-00991-7

    Neurochemistry sensors for brain research and life with a collaborative frame of mind.

    in Nature Methods on October 14, 2020 12:00 AM.

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    Changes in Day/Night Activity in the 6-OHDA-Induced Experimental Model of Parkinson’s Disease: Exploring Prodromal Biomarkers

    The search for experimental models mimicking an early stage of Parkinson’s disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD. Twenty male Sprague-Dawley rats were unilaterally injected with 6-OHDA (n = 10) or saline solution (n = 10) into the right striatum and placed in enriched environment cages where the activity was monitored. After 2 weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Home-cage monitoring revealed behavioral changes in response to 6-OHDA administration including significant hyperactivity and hypoactivity during the light and dark phase, respectively, turning out in a change of the circadian timing. A preclinical stage of PD was functionally confirmed with the amphetamine test. Moreover, the loss of tyrosine hydroxylase expression was significantly correlated with the motor results, and 6-OHDA induced early proapoptotic events. Our findings provide evidence for a novel prodromal 6-OHDA model following a customized monitoring system that could give insights to detect non-motor deficits and molecular targets to test neuroprotective/neurorestorative agents.

    in Frontiers in Neuroscience: Neurodegeneration on October 14, 2020 12:00 AM.

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    Investigating the Relationship Between Neuronal Cell Death and Early DNA Methylation After Ischemic Injury

    Cerebral ischemia induces neuronal cell death and causes various kinds of brain dysfunction. Therefore, prevention of neuronal cell death is most essential for protection of the brain. On the other hand, it has been reported that epigenetics including DNA methylation plays a pivotal role in pathogenesis of some diseases such as cancer. Accumulating evidences indicate that aberrant DNA methylation is related to cell death. However, DNA methylation after cerebral ischemia has not been fully understood yet. The aim of this present study was to investigate the relationships between DNA methylation and neuronal cell death after cerebral ischemia. We examined DNA methylation under the ischemic condition by using transient middle cerebral artery occlusion and reperfusion (MCAO/R) model rats and N-methyl-D-aspartate (NMDA)–treated cortical neurons in primary culture. In this study, we demonstrated that DNA methylation increased in these neurons 24 h after MCAO/R and that DNA methylation, possibly through activation of DNA methyltransferases (DNMT) 3a, increased in such neurons immediately after NMDA treatment. Furthermore, NMDA-treated neurons were protected by treatment with a DNMT inhibitor that were accompanied by inhibition of DNA methylation. Our results showed that DNA methylation would be an initiation factor of neuronal cell death and that inhibition of such methylation could become an effective therapeutic strategy for stroke.

    in Frontiers in Neuroscience: Neurodegeneration on October 14, 2020 12:00 AM.

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    Current Techniques for Investigating the Brain Extracellular Space

    The brain extracellular space (ECS) is a continuous reticular compartment that lies between the cells of the brain. It is vast in extent relative to its resident cells, yet, at the same time the nano- to micrometer dimensions of its channels and reservoirs are commonly finer than the smallest cellular structures. Our conventional view of this compartment as largely static and of secondary importance for brain function is rapidly changing, and its active dynamic roles in signaling and metabolite clearance have come to the fore. It is further emerging that ECS microarchitecture is highly heterogeneous and dynamic and that ECS geometry and diffusional properties directly modulate local diffusional transport, down to the nanoscale around individual synapses. The ECS can therefore be considered an extremely complex and diverse compartment, where numerous physiological events are unfolding in parallel on spatial and temporal scales that span orders of magnitude, from milliseconds to hours, and from nanometers to centimeters. To further understand the physiological roles of the ECS and identify new ones, researchers can choose from a wide array of experimental techniques, which differ greatly in their applicability to a given sample and the type of data they produce. Here, we aim to provide a basic introduction to the available experimental techniques that have been applied to address the brain ECS, highlighting their main characteristics. We include current gold-standard techniques, as well as emerging cutting-edge modalities based on recent super-resolution microscopy. It is clear that each technique comes with unique strengths and limitations and that no single experimental method can unravel the unknown physiological roles of the brain ECS on its own.

    in Frontiers in Neuroscience: Brain Imaging Methods on October 14, 2020 12:00 AM.

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    Cross-Subject Commonality of Emotion Representations in Dorsal Motion-Sensitive Areas

    Emotion perception is a crucial question in cognitive neuroscience and the underlying neural substrates have been the subject of intense study. One of our previous studies demonstrated that motion-sensitive areas are involved in the perception of facial expressions. However, it remains unclear whether emotions perceived from whole-person stimuli can be decoded from the motion-sensitive areas. In addition, if emotions are represented in the motion-sensitive areas, we may further ask whether the representations of emotions in the motion-sensitive areas can be shared across individual subjects. To address these questions, this study collected neural images while participants viewed emotions (joy, anger, and fear) from videos of whole-person expressions (contained both face and body parts) in a block-design functional magnetic resonance imaging (fMRI) experiment. Multivariate pattern analysis (MVPA) was conducted to explore the emotion decoding performance in individual-defined dorsal motion-sensitive regions of interest (ROIs). Results revealed that emotions could be successfully decoded from motion-sensitive ROIs with statistically significant classification accuracies for three emotions as well as positive versus negative emotions. Moreover, results from the cross-subject classification analysis showed that a person’s emotion representation could be robustly predicted by others’ emotion representations in motion-sensitive areas. Together, these results reveal that emotions are represented in dorsal motion-sensitive areas and that the representation of emotions is consistent across subjects. Our findings provide new evidence of the involvement of motion-sensitive areas in the emotion decoding, and further suggest that there exists a common emotion code in the motion-sensitive areas across individual subjects.

    in Frontiers in Neuroscience: Brain Imaging Methods on October 14, 2020 12:00 AM.

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    Simulation of Large Scale Neural Models With Event-Driven Connectivity Generation

    Accurate simulations of brain structures is a major problem in neuroscience. Many works are dedicated to design better models or to develop more efficient simulation schemes. In this paper, we propose a hybrid simulation scheme that combines time-stepping second-order integration of Hodgkin-Huxley (HH) type neurons with event-driven updating of the synaptic currents. As the HH model is a continuous model, there is no explicit spike events. Thus, in order to preserve the accuracy of the integration method, a spike detection algorithm is developed that accurately determines spike times. This approach allows us to regenerate the outgoing connections at each event, thereby avoiding the storage of the connectivity. Consequently, memory consumption is significantly reduced while preserving execution time and accuracy of the simulations, especially the spike times of detailed point neuron models. The efficiency of the method, implemented in the SiReNe software1, is demonstrated by the simulation of a striatum model which consists of more than 106 neurons and 108 synapses (each neuron has a fan-out of 504 post-synaptic neurons), under normal and Parkinson's conditions.

    in Frontiers in Neuroinformatics on October 14, 2020 12:00 AM.

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    Editorial: Wayfinding and Navigation: Strengths and Weaknesses in Atypical and Clinical Populations

    in Frontiers in Human Neuroscience on October 14, 2020 12:00 AM.

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    A Neural Network Model With Gap Junction for Topological Detection

    Visual information processing in the brain goes from global to local. A large volume of experimental studies has suggested that among global features, the brain perceives the topological information of an image first. Here, we propose a neural network model to elucidate the underlying computational mechanism. The model consists of two parts. The first part is a neural network in which neurons are coupled through gap junctions, mimicking the neural circuit formed by alpha ganglion cells in the retina. Gap junction plays a key role in the model, which, on one hand, facilitates the synchronized firing of a neuron group covering a connected region of an image, and on the other hand, staggers the firing moments of different neuron groups covering disconnected regions of the image. These two properties endow the network with the capacity of detecting the connectivity and closure of images. The second part of the model is a read-out neuron, which reads out the topological information that has been converted into the number of synchronized firings in the retina network. Our model provides a simple yet effective mechanism for the neural system to detect the topological information of images in ultra-speed.

    in Frontiers in Computational Neuroscience on October 14, 2020 12:00 AM.

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    Unsupervised Few-Shot Feature Learning via Self-Supervised Training

    Learning from limited exemplars (few-shot learning) is a fundamental, unsolved problem that has been laboriously explored in the machine learning community. However, current few-shot learners are mostly supervised and rely heavily on a large amount of labeled examples. Unsupervised learning is a more natural procedure for cognitive mammals and has produced promising results in many machine learning tasks. In this paper, we propose an unsupervised feature learning method for few-shot learning. The proposed model consists of two alternate processes, progressive clustering and episodic training. The former generates pseudo-labeled training examples for constructing episodic tasks; and the later trains the few-shot learner using the generated episodic tasks which further optimizes the feature representations of data. The two processes facilitate each other, and eventually produce a high quality few-shot learner. In our experiments, our model achieves good generalization performance in a variety of downstream few-shot learning tasks on Omniglot and MiniImageNet. We also construct a new few-shot person re-identification dataset FS-Market1501 to demonstrate the feasibility of our model to a real-world application.

    in Frontiers in Computational Neuroscience on October 14, 2020 12:00 AM.

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    Variational Online Learning of Neural Dynamics

    New technologies for recording the activity of large neural populations during complex behavior provide exciting opportunities for investigating the neural computations that underlie perception, cognition, and decision-making. Non-linear state space models provide an interpretable signal processing framework by combining an intuitive dynamical system with a probabilistic observation model, which can provide insights into neural dynamics, neural computation, and development of neural prosthetics and treatment through feedback control. This brings with it the challenge of learning both latent neural state and the underlying dynamical system because neither are known for neural systems a priori. We developed a flexible online learning framework for latent non-linear state dynamics and filtered latent states. Using the stochastic gradient variational Bayes approach, our method jointly optimizes the parameters of the non-linear dynamical system, the observation model, and the black-box recognition model. Unlike previous approaches, our framework can incorporate non-trivial distributions of observation noise and has constant time and space complexity. These features make our approach amenable to real-time applications and the potential to automate analysis and experimental design in ways that testably track and modify behavior using stimuli designed to influence learning.

    in Frontiers in Computational Neuroscience on October 14, 2020 12:00 AM.

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    Transducin Partners Outside the Phototransduction Pathway

    Transducin mediates signal transduction in a classical G protein-coupled receptor (GPCR) phototransduction cascade. Interactions of transducin with the receptor and the effector molecules had been extensively investigated and are currently defined at the atomic level. However, partners and functions of rod transducin α (Gαt1) and βγ (Gβ1γ1) outside the visual pathway are not well-understood. In particular, light-induced redistribution of rod transducin from the outer segment to the inner segment and synaptic terminal (IS/ST) allows Gαt1 and/or Gβ1γ1 to modulate synaptic transmission from rods to rod bipolar cells (RBCs). Protein-protein interactions underlying this modulation are largely unknown. We discuss known interactors of transducin in the rod IS/ST compartment and potential pathways leading to the synaptic effects of light-dispersed Gαt1 and Gβ1γ1. Furthermore, we show that a prominent non-GPCR guanine nucleotide exchange factor (GEF) and a chaperone of Gα subunits, resistance to inhibitors of cholinesterase 8A (Ric-8A) protein, is expressed throughout the retina including photoreceptor cells. Recent structures of Ric-8A alone and in complexes with Gα subunits have illuminated the structural underpinnings of the Ric-8A activities. We generated a mouse model with conditional knockout of Ric-8A in rods in order to begin defining the functional roles of the protein in rod photoreceptors and the retina. Our analysis suggests that Ric-8A is not an obligate chaperone of Gαt1. Further research is needed to investigate probable roles of Ric-8A as a GEF, trafficking chaperone, or a mediator of the synaptic effects of Gαt1.

    in Frontiers in Cellular Neuroscience on October 14, 2020 12:00 AM.

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    Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging

    Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan. Our data showed that while the number and morphological features of I-S3 cells remained unchanged, their firing and synaptic properties were significantly altered in old animals. In particular, the action potential duration and the level of steady-state depolarization were significantly increased in old animals in parallel with a significant decrease in the maximal firing frequency. Reducing the fast-delayed rectifier potassium or transient sodium conductances in I-S3 cell computational models could reproduce the age-related changes in I-S3 cell firing properties. However, experimental data revealed no difference in the activation properties of the Kv3.1 and A-type potassium currents, indicating that transient sodium together with other ion conductances may be responsible for the observed phenomena. Furthermore, I-S3 cells in aged mice received a stronger inhibitory drive due to concomitant increase in the amplitude and frequency of spontaneous inhibitory currents. These age-associated changes in the I-S3 cell properties occurred in parallel with an increased inhibition of their target interneurons and were associated with spatial memory deficits and increased anxiety. Taken together, these data indicate that VIP+/CR+ interneurons responsible for local circuit disinhibition survive during aging but exhibit significantly altered physiological properties, which may result in the increased inhibition of hippocampal interneurons and distorted mnemonic functions.

    in Frontiers in Cellular Neuroscience on October 14, 2020 12:00 AM.

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    Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

    Neural stimulation modulates the depolarization of neurons, thereby triggering activity-associated mechanisms of neuronal plasticity. Activity-associated mechanisms in turn play a major role in post-mitotic structure and function of adult neurons. Our understanding of the interactions between neuronal behavior, patterns of neural activity, and the surrounding environment is evolving at a rapid pace. Brain derived neurotrophic factor is a critical mediator of activity-associated plasticity, while multiple immediate early genes mediate plasticity of neurons following bouts of neural activity. New research has uncovered genetic mechanisms that govern the expression of DNA following changes in neural activity patterns, including RNAPII pause-release and activity-associated double stranded breaks. Discovery of novel mechanisms governing activity-associated plasticity of neurons hints at a layered and complex molecular control of neuronal response to depolarization. Importantly, patterns of depolarization in neurons are shown to be important mediators of genetic expression patterns and molecular responses. More research is needed to fully uncover the molecular response of different types of neurons-to-activity patterns; however, known responses might be leveraged to facilitate recovery after neural damage. Physical rehabilitation through passive or active exercise modulates neurotrophic factor expression in the brain and spinal cord and can initiate cortical plasticity commensurate with functional recovery. Rehabilitation likely relies on activity-associated mechanisms; however, it may be limited in its application. Electrical and magnetic stimulation direct specific activity patterns not accessible through passive or active exercise and work synergistically to improve standing, walking, and forelimb use after injury. Here, we review emerging concepts in the molecular mechanisms of activity-derived plasticity in order to highlight opportunities that could add value to therapeutic protocols for promoting recovery of function after trauma, disease, or age-related functional decline.

    in Frontiers in Cellular Neuroscience on October 14, 2020 12:00 AM.

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    A Systematic Review on Predictors of Working Memory Training Responsiveness in Healthy Older Adults: Methodological Challenges and Future Directions

    Background: Research on predictors of working memory training responsiveness, which could help tailor cognitive interventions individually, is a timely topic in healthy aging. However, the findings are highly heterogeneous, reporting partly conflicting results following a broad spectrum of methodological approaches to answer the question “who benefits most” from working memory training.

    Objective: The present systematic review aimed to systematically investigate prognostic factors and models for working memory training responsiveness in healthy older adults.

    Method: Four online databases were searched up to October 2019 (MEDLINE Ovid, Web of Science, CENTRAL, and PsycINFO). The inclusion criteria for full texts were publication in a peer-reviewed journal in English/German, inclusion of healthy older individuals aged ≥55 years without any neurological and/or psychiatric diseases including cognitive impairment, and the investigation of prognostic factors and/or models for training responsiveness after targeted working memory training in terms of direct training effects, near-transfer effects to verbal and visuospatial working memory as well as far-transfer effects to other cognitive domains and behavioral variables. The study design was not limited to randomized controlled trials.

    Results: A total of 16 studies including n = 675 healthy older individuals with a mean age of 63.0–86.8 years were included in this review. Within these studies, five prognostic model approaches and 18 factor finding approaches were reported. Risk of bias was assessed using the Quality in Prognosis Studies checklist, indicating that important information, especially regarding the domains study attrition, study confounding, and statistical analysis and reporting, was lacking throughout many of the investigated studies. Age, education, intelligence, and baseline performance in working memory or other cognitive domains were frequently investigated predictors across studies.

    Conclusions: Given the methodological shortcomings of the included studies, no clear conclusions can be drawn, and emerging patterns of prognostic effects will have to survive sound methodological replication in future attempts to promote precision medicine approaches in the context of working memory training. Methodological considerations are discussed, and our findings are embedded to the cognitive aging literature, considering, for example, the cognitive reserve framework and the compensation vs. magnification account. The need for personalized cognitive prevention and intervention methods to counteract cognitive decline in the aging population is high and the potential enormous.

    Registration: PROSPERO, ID CRD42019142750.

    in Frontiers in Ageing Neuroscience on October 14, 2020 12:00 AM.

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    Compromised Behavior and Gamma Power During Working Memory in Cognitively Healthy Individuals With Abnormal CSF Amyloid/Tau

    Research shows that gamma activity changes in Alzheimer’s disease (AD), revealing synaptic pathology and potential therapeutic applications. We aim to explore whether cognitive challenge combined with quantitative EEG (qEEG) can unmask abnormal gamma frequency power in healthy individuals at high risk of developing AD. We analyzed low (30–50 Hz) and high gamma (50–80 Hz) power over six brain regions at EEG sensor level (frontal/central/parietal/left temporal/right temporal/occipital) in a dataset collected from an aging cohort during N-back working memory (WM) testing at two different load conditions (N = 0 or 2). Cognitively healthy (CH) study participants (≥60 years old) of both sexes were divided into two subgroups: normal amyloid/tau ratios (CH-NAT, n = 10) or pathological amyloid/tau (CH-PAT, n = 14) in cerebrospinal fluid (CSF). During low load (0-back) challenge, low gamma is higher in CH-PATs than CH-NATs over frontal and central regions (p = 0.014∼0.032, effect size (Cohen’s d) = 0.95∼1.11). However, during high load (2-back) challenge, low gamma is lower in CH-PATs compared to CH-NATs over the left temporal region (p = 0.045, Cohen’s d = −0.96), and high gamma is lower over the parietal region (p = 0.035, Cohen’s d = −1.02). Overall, our studies show a medium to large negative effect size across the scalp (Cohen’s d = −0.51∼−1.02). In addition, low gamma during 2-back is positively correlated with 0-back accuracy over all regions except the occipital region only in CH-NATs (r = 0.69∼0.77, p = 0.0098∼0.027); high gamma during 2-back correlated positively with 0-back accuracy over all regions in CH-NATs (r = 0.68∼0.78, p = 0.007∼0.030); high gamma during 2-back negatively correlated with 0-back response time over parietal, right temporal, and occipital regions in CH-NATs (r = −0.70∼−0.66, p = 0.025∼0.037). We interpret these preliminary results to show: (1) gamma power is compromised in AD-biomarker positive individuals, who are otherwise cognitively healthy (CH-PATs); (2) gamma is associated with WM performance in normal aging (CH-NATs) (most significantly in the frontoparietal region). Our pilot findings encourage further investigations in combining cognitive challenges and qEEG in developing neurophysiology-based markers for identifying individuals in the prodromal stage, to help improving our understanding of AD pathophysiology and the contributions of low- and high-frequency gamma oscillations in cognitive functions.

    in Frontiers in Ageing Neuroscience on October 14, 2020 12:00 AM.

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    Integrated Neurophotonics: Toward Dense Volumetric Interrogation of Brain Circuit Activity—at Depth and in Real Time

    Moreaux et al. describe a new paradigm for dense functional imaging of brain activity that surmounts limitations of present methodologies. It enables functional imaging from within the brain, permitting dense, large-scale brain circuit interrogation with cellular resolution at arbitrary depths.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Spotlight on Neurotechnology: Reading Networks

    This special issue of Neuron continues our series on neurotechnology. In the first part of this series, we explored approaches to building and mapping neuronal networks. Now, we focus on the tools for reading the activity of these networks. The reviews and perspectives included here discuss methods used to measure neurophysiological data, ranging from the synapse to the whole organism. Some of the articles also describe integrated technologies employed to manipulate these networks—a theme that will be further developed in the next and final chapter of our special issue series.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Imaging Neurotransmitter and Neuromodulator Dynamics In Vivo with Genetically Encoded Indicators

    Sabatini and Tian review recent progress in developing genetically encoded neurotransmitter indicators. They also discuss practical considerations for both sensor developers and end users in terms of sensor design, optimization, characterization, and implementation for in vivo studies.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Mesoscopic Imaging: Shining a Wide Light on Large-Scale Neural Dynamics

    In this Primer, Cardin, Crair, and Higley discuss widefield, mesoscopic fluorescence imaging. This rapidly developing modality combines high spatiotemporal resolution with large fields of view, capable of monitoring neuronal circuit dynamics across the neocortical surface of behaving rodents.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Advancing Neuroscience through Wearable Devices

    Faster, more reliable, and comfortably wearable personal devices are producing data from biosensors on an unprecedented scale. Combined with context and analytics, these signals hold great promise to advance neuroscience via real-world data. Johnson and Picard discuss wearable technology broadly and provide specific examples of activity patterns from electrodermal sensors found during sleep, stress, and seizures.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    A Primer on Motion Capture with Deep Learning: Principles, Pitfalls, and Perspectives

    Mathis et al. provide a timely introduction to deep learning tools for motion capture, highlighting their core principles and potential pitfalls.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Endothelial Tip Cell Finds Its Way with Piezo1

    Like axon guidance, the tuning of vascular tip cells during angiogenesis is an intriguing but puzzling developmental process. A new study in zebrafish (Liu et al., 2020) now demonstrates a critical role of the Piezo1 mechanosensitive ion channel in guiding vascular tip cells in pathfinding.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Marking Time: Colorful New Insights into Master Clock Circuits

    A neural clock controls what we do each day, and understanding its circuitry is important for health. In this issue of Neuron, Shan et al. visualize molecular rhythms in subtypes of master clock neurons to test principles of cell identity and network wiring.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Ultrasound Technologies for Imaging and Modulating Neural Activity

    The physics of ultrasound provides noninvasive access to the intact brain and the potential for large-scale imaging and control of neural activity. This article reviews the current state of ultrasound applications in neuroscience, building from fundamental principles to established techniques for functional imaging and neuromodulation and highlighting ongoing technology development to connect ultrasound to neural activity at the molecular level.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    John P. Donoghue

    In an interview with Neuron, John Donoghue talks about his journey, from basic science investigating movement in primates to multidisciplinary collaborations that led to the development of implantable devices that support movement and communication in impaired individuals, and he discusses ideas to foster neurotechnology development.

    in Neuron: Current Issue on October 14, 2020 12:00 AM.

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    Exploring the sequence fitness landscape of a bridge between protein folds

    by Pengfei Tian, Robert B. Best

    Most foldable protein sequences adopt only a single native fold. Recent protein design studies have, however, created protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the folds of the GA and GB binding domains of streptococcal protein G. To obtain further insight into the design of sequences which can switch folds, we have used a computational model for the fitness landscape of a single fold, built from the observed sequence variation of protein homologues. We have recently shown that such coevolutionary models can be used to design novel foldable sequences. By appropriately combining two of these models to describe the joint fitness landscape of GA and GB, we are able to describe the propensity of a given sequence for each of the two folds. We have successfully tested the combined model against the known series of designed GA/GB hybrids. Using Monte Carlo simulations on this landscape, we are able to identify pathways of mutations connecting the two folds. In the absence of a requirement for domain stability, the most frequent paths go via sequences in which neither domain is stably folded, reminiscent of the propensity for certain intrinsically disordered proteins to fold into different structures according to context. Even if the folded state is required to be stable, we find that there is nonetheless still a wide range of sequences which are close to the transition region and therefore likely fold switches, consistent with recent estimates that fold switching may be more widespread than had been thought.

    in PLoS Computational Biology on October 13, 2020 09:00 PM.

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    Visually guided homing of bumblebees in ambiguous situations: A behavioural and modelling study

    by Charlotte Doussot, Olivier J. N. Bertrand, Martin Egelhaaf

    Returning home is a crucial task accomplished daily by many animals, including humans. Because of their tiny brains, insects, like bees or ants, are good study models for efficient navigation strategies. Bees and ants are known to rely mainly on learned visual information about the nest surroundings to pinpoint their barely visible nest-entrance. During the return, when the actual sight of the insect matches the learned information, the insect is easily guided home. Occasionally, modifications to the visual environment may take place while the insect is on a foraging trip. Here, we addressed the ecologically relevant question of how bumblebees’ homing is affected by such a situation. In an artificial setting, we habituated bees to be guided to their nest by two constellations of visual cues. After habituation, these cues were displaced during foraging trips into a conflict situation. We recorded bumblebees’ return flights in such circumstances and investigated where they search for their nest entrance following the degree of displacement between the two visually relevant cues. Bumblebees mostly searched at the fictive nest location as indicated by either cue constellation, but never at a compromise location between them. We compared these experimental results to the predictions of different types of homing models. We found that models guiding an agent by a single holistic view of the nest surroundings could not account for the bumblebees’ search behaviour in cue-conflict situations. Instead, homing models relying on multiple views were sufficient. We could further show that homing models required fewer views and got more robust to height changes if optic flow-based spatial information was encoded and learned, rather than just brightness information.

    in PLoS Computational Biology on October 13, 2020 09:00 PM.

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    Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

    by Travis B. Thompson, Pavanjit Chaggar, Ellen Kuhl, Alain Goriely, for the Alzheimer’s Disease Neuroimaging Initiative

    Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.

    in PLoS Computational Biology on October 13, 2020 09:00 PM.

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    Systematic modelling of the development of laminar projection origins in the cerebral cortex: Interactions of spatio-temporal patterns of neurogenesis and cellular heterogeneity

    by Sarah F. Beul, Claus C. Hilgetag

    The architectonic type principle conceptualizes structural connections between brain areas in terms of the relative architectonic differentiation of connected areas. It has previously been shown that spatio-temporal interactions between the time and place of neurogenesis could underlie multiple features of empirical mammalian connectomes, such as projection existence and the distribution of projection strengths. However, so far no mechanistic explanation for the emergence of typically observed laminar patterns of projection origins and terminations has been tested. Here, we expand an in silico model of the developing cortical sheet to explore which factors could potentially constrain the development of laminar projection patterns. We show that manipulations which rely solely on spatio-temporal interactions, namely the relative density of laminar compartments, a delay in the neurogenesis of infragranular layers relative to layer 1, and a delay in the neurogenesis of supragranular layers relative to infragranular layers, do not result in the striking correlation between supragranular contribution to projections and the relative differentiation of areas that is typically observed in the mammalian cortex. In contrast, we find that if we introduce systematic variation in cell-intrinsic properties, coupling them with architectonic differentiation, the resulting laminar projection patterns closely mirror the empirically observed patterns. We also find that the spatio-temporal interactions posited to occur during neurogenesis are necessary for the formation of the characteristic laminar patterns. Hence, our results indicate that the specification of the laminar patterns of projection origins may result from systematic variation in a number of cell-intrinsic properties, superimposed on the previously identified spatio-temporal interactions which are sufficient for the emergence of the architectonic type principle on the level of inter-areal connectivity in silico.

    in PLoS Computational Biology on October 13, 2020 09:00 PM.

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    Correction: A kinase-dependent checkpoint prevents escape of immature ribosomes into the translating pool

    by Melissa D. Parker, Jason C. Collins, Boguslawa Korona, Homa Ghalei, Katrin Karbstein

    in PLoS Biology on October 13, 2020 09:00 PM.

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    High-throughput mapping of the phage resistance landscape in <i>E</i>. <i>coli</i>

    by Vivek K. Mutalik, Benjamin A. Adler, Harneet S. Rishi, Denish Piya, Crystal Zhong, Britt Koskella, Elizabeth M. Kutter, Richard Calendar, Pavel S. Novichkov, Morgan N. Price, Adam M. Deutschbauer, Adam P. Arkin

    Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage-specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and high-throughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phage-mediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.

    in PLoS Biology on October 13, 2020 09:00 PM.

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    Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia–thalamic communication

    by Bettina C. Schwab, Daisuke Kase, Andrew Zimnik, Robert Rosenbaum, Marcello G. Codianni, Jonathan E. Rubin, Robert S. Turner

    Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.

    in PLoS Biology on October 13, 2020 09:00 PM.

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    Subthalamic Nucleus Deep Brain Stimulation Modulates 2 Distinct Neurocircuits

    Objective

    Current understanding of the neuromodulatory effects of deep brain stimulation (DBS) on large‐scale brain networks remains elusive, largely due to the lack of techniques that can reveal DBS‐induced activity at the whole‐brain level. Using a novel 3T magnetic resonance imaging (MRI)‐compatible stimulator, we investigated whole‐brain effects of subthalamic nucleus (STN) stimulation in patients with Parkinson disease.

    Methods

    Fourteen patients received STN‐DBS treatment and participated in a block‐design functional MRI (fMRI) experiment, wherein stimulations were delivered during “ON” blocks interleaved with “OFF” blocks. fMRI responses to low‐frequency (60Hz) and high‐frequency(130Hz) STN‐DBS were measured 1, 3, 6, and 12 months postsurgery. To ensure reliability, multiple runs (48 minutes) of fMRI data were acquired at each postsurgical visit. Presurgical resting‐state fMRI (30 minutes) data were also acquired.

    Results

    Two neurocircuits showed highly replicable, but distinct responses to STN‐DBS. A circuit involving the globus pallidus internus (GPi), thalamus, and deep cerebellar nuclei was significantly activated, whereas another circuit involving the primary motor cortex (M1), putamen, and cerebellum showed DBS‐induced deactivation. These 2 circuits were dissociable in terms of their DBS‐induced responses and resting‐state functional connectivity. The GPi circuit was frequency‐dependent, selectively responding to high‐frequency stimulation, whereas the M1 circuit was responsive in a time‐dependent manner, showing enhanced deactivation over time. Finally, activation of the GPi circuit was associated with overall motor improvement, whereas M1 circuit deactivation was related to reduced bradykinesia.

    Interpretation

    Concurrent DBS‐fMRI using 3T revealed 2 distinct circuits that responded differentially to STN‐DBS and were related to divergent symptoms, a finding that may provide novel insights into the neural mechanisms underlying DBS. ANN NEUROL 2020

    in Annals of Neurology on October 13, 2020 07:57 PM.

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    Extraneuronal Phenotypes of Spinal Muscular Atrophy

    in Annals of Neurology on October 13, 2020 07:00 PM.

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    Structural plasticity on an accelerated analog neuromorphic hardware system

    Publication date: January 2021

    Source: Neural Networks, Volume 133

    Author(s): Sebastian Billaudelle, Benjamin Cramer, Mihai A. Petrovici, Korbinian Schreiber, David Kappel, Johannes Schemmel, Karlheinz Meier

    in Neural Networks on October 13, 2020 06:00 PM.

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    An improved Lyapunov functional with application to stability of Cohen–Grossberg neural networks of neutral-type with multiple delays

    Publication date: December 2020

    Source: Neural Networks, Volume 132

    Author(s): Ozlem Faydasicok

    in Neural Networks on October 13, 2020 06:00 PM.

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    Radiographic Improvement of Larval Cysts in Neurocysticercosis

    in Annals of Neurology on October 13, 2020 03:48 PM.

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    In Memoriam: Kenneth Fred Swaiman (11/19/1931 to 9/18/2020)

    in Annals of Neurology on October 13, 2020 11:45 AM.

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    GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma

    (Cell Reports 22, 2455–2468; February 27, 2018)

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    Molecular Fingerprint and Developmental Regulation of the Tegmental GABAergic and Glutamatergic Neurons Derived from the Anterior Hindbrain

    Morello et al. show how different types of neurons are generated among multipotent neuronal precursors in a specific region of the embryonic brainstem. As these neuronal precursors differentiate, they give rise to the neurons in tegmental nuclei that are highly important for the regulation of mood, motivation, movement, and memory.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression

    Bruschetta et al., show that MC4R neurons in the dorsal raphe nucleus are inhibited by α-MSH. Inhibition of melanocortin signaling decreases feeding and increases 5-HT turnover, resulting in increased anxiety and depression-like behavior.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    FMRP-PKA Activity Negative Feedback Regulates RNA Binding-Dependent Fibrillation in Brain Learning and Memory Circuitry

    FMRP is required for brain cAMP induction and cAMP-dependent PKA activation, but the FMRP mechanism is uncharacterized. Sears and Broadie test FXS patient-derived and FMRP domain-deficient mutants to reveal conserved FMRP functions regulating PKA activation, subcellular localization, and reversible partitioning into elongated fibrillar assemblies in brain learning/memory circuit neurons.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    Prostaglandin E2-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance

    Fasting and cold stress are well-known facilitators of lipolysis in WAT, but it remains unclear whether there are other physiological mechanisms that regulate lipolysis. Inazumi et al. find that the adipocyte prostaglandin E2-EP4 receptor axis controls basal lipolysis, fat distribution, and collagen deposition upon feeding and insulin stimuli.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    Activation of the CARD8 Inflammasome Requires a Disordered Region

    Inflammasomes are multiprotein complexes that detect intracellular danger signals and stimulate powerful immune responses. DPP8/9 inhibitors activate the CARD8 inflammasome through an unknown mechanism. Here, Chui et al. show that DPP8/9 inhibitors induce the degradation of many disordered and misfolded proteins. CARD8 has an N-terminal disordered region that is degraded upon DPP8/9 inhibition, triggering inflammasome formation.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    Single-Cell Transcriptomics of Parkinson’s Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses

    Fernandes et al. identify and characterize cellular heterogeneity in human iPSC dopamine neurons using single-cell RNA-seq. The different subtypes of dopamine neurons illustrate distinct transcriptional profiles in response to toxic and genetic stressors. Furthermore, PD GWAS associated gene expression analysis is performed at the single-cell level.

    in Cell Reports: Current Issue on October 13, 2020 12:00 AM.

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    The synergy of damage repair and retention promotes rejuvenation and prolongs healthy lifespans in cell lineages

    by Barbara Schnitzer, Johannes Borgqvist, Marija Cvijovic

    Damaged proteins are inherited asymmetrically during cell division in the yeast Saccharomyces cerevisiae, such that most damage is retained within the mother cell. The consequence is an ageing mother and a rejuvenated daughter cell with full replicative potential. Daughters of old and damaged mothers are however born with increasing levels of damage resulting in lowered replicative lifespans. Remarkably, these prematurely old daughters can give rise to rejuvenated cells with low damage levels and recovered lifespans, called second-degree rejuvenation. We aimed to investigate how damage repair and retention together can promote rejuvenation and at the same time ensure low damage levels in mother cells, reflected in longer health spans. We developed a dynamic model for damage accumulation over successive divisions in individual cells as part of a dynamically growing cell lineage. With detailed knowledge about single-cell dynamics and relationships between all cells in the lineage, we can infer how individual damage repair and retention strategies affect the propagation of damage in the population. We show that damage retention lowers damage levels in the population by reducing the variability across the lineage, and results in larger population sizes. Repairing damage efficiently in early life, as opposed to investing in repair when damage has already accumulated, counteracts accelerated ageing caused by damage retention. It prolongs the health span of individual cells which are moreover less prone to stress. In combination, damage retention and early investment in repair are beneficial for healthy ageing in yeast cell populations.

    in PLoS Computational Biology on October 12, 2020 09:00 PM.

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    Time varying methods to infer extremes in dengue transmission dynamics

    by Jue Tao Lim, Yi Ting Han, Borame Sue Lee Dickens, Lee Ching Ng, Alex R. Cook

    Dengue is an arbovirus affecting global populations. Frequent outbreaks occur, especially in equatorial cities such as Singapore, where year-round tropical climate, large daily influx of travelers and population density provide the ideal conditions for dengue to transmit. Little work has, however, quantified the peaks of dengue outbreaks, when health systems are likely to be most stretched. Nor have methods been developed to infer differences in exogenous factors which lead to the rise and fall of dengue case counts across extreme and non-extreme periods. In this paper, we developed time varying extreme mixture (tvEM) methods to account for the temporal dependence of dengue case counts across extreme and non-extreme periods. This approach permits inference of differences in climatic forcing across non-extreme and extreme periods of dengue case counts, quantification of their temporal dependence as well as estimation of thresholds with associated uncertainties to determine dengue case count extremities. Using tvEM, we found no evidence that weather affects dengue case counts in the near term for non-extreme periods, but that it has non-linear and mixed signals in influencing dengue through tvEM parameters in the extreme periods. Using the most appropriate tvEM specification, we found that a threshold at the 70th (95% credible interval 41.1, 83.8) quantile is optimal, with extreme events of 526.6, 1052.2 and 1183.6 weekly case counts expected at return periods of 5, 50 and 75 years. Weather parameters at a 1% scaled increase was found to decrease the long-run expected case counts, but larger increases would lead to a drastic expected rise from the baseline correspondingly. The tvEM approach can provide valuable inference on the extremes of time series, which in the case of infectious disease notifications, allows public health officials to understand the likely scale of outbreaks in the long run.

    in PLoS Computational Biology on October 12, 2020 09:00 PM.

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    Dynamical persistence in high-diversity resource-consumer communities

    by Itay Dalmedigos, Guy Bunin

    We show how highly-diverse ecological communities may display persistent abundance fluctuations, when interacting through resource competition and subjected to migration from a species pool. These fluctuations appear, robustly and predictably, in certain regimes of parameter space. Their origin is closely tied to the ratio of realized species diversity to the number of resources. This ratio is set by competition, through the balance between species being pushed out and invading. When this ratio is smaller than one, dynamics will reach stable equilibria. When this ratio is larger than one, the competitive exclusion principle dictates that fixed-points are either unstable or marginally stable. If they are unstable, the system is repelled from fixed points, and abundances forever fluctuate. While marginally-stable fixed points are in principle allowed and predicted by some models, they become structurally unstable at high diversity. This means that even small changes to the model, such as non-linearities in how resources combine to generate species’ growth, will result in persistent abundance fluctuations.

    in PLoS Computational Biology on October 12, 2020 09:00 PM.

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    The covariance perceptron: A new paradigm for classification and processing of time series in recurrent neuronal networks

    by Matthieu Gilson, David Dahmen, Rubén Moreno-Bote, Andrea Insabato, Moritz Helias

    Learning in neuronal networks has developed in many directions, in particular to reproduce cognitive tasks like image recognition and speech processing. Implementations have been inspired by stereotypical neuronal responses like tuning curves in the visual system, where, for example, ON/OFF cells fire or not depending on the contrast in their receptive fields. Classical models of neuronal networks therefore map a set of input signals to a set of activity levels in the output of the network. Each category of inputs is thereby predominantly characterized by its mean. In the case of time series, fluctuations around this mean constitute noise in this view. For this paradigm, the high variability exhibited by the cortical activity may thus imply limitations or constraints, which have been discussed for many years. For example, the need for averaging neuronal activity over long periods or large groups of cells to assess a robust mean and to diminish the effect of noise correlations. To reconcile robust computations with variable neuronal activity, we here propose a conceptual change of perspective by employing variability of activity as the basis for stimulus-related information to be learned by neurons, rather than merely being the noise that corrupts the mean signal. In this new paradigm both afferent and recurrent weights in a network are tuned to shape the input-output mapping for covariances, the second-order statistics of the fluctuating activity. When including time lags, covariance patterns define a natural metric for time series that capture their propagating nature. We develop the theory for classification of time series based on their spatio-temporal covariances, which reflect dynamical properties. We demonstrate that recurrent connectivity is able to transform information contained in the temporal structure of the signal into spatial covariances. Finally, we use the MNIST database to show how the covariance perceptron can capture specific second-order statistical patterns generated by moving digits.

    in PLoS Computational Biology on October 12, 2020 09:00 PM.

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    Estimating effective population size changes from preferentially sampled genetic sequences

    by Michael D. Karcher, Luiz Max Carvalho, Marc A. Suchard, Gytis Dudas, Vladimir N. Minin

    Coalescent theory combined with statistical modeling allows us to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. When sequences are sampled serially through time and the distribution of the sampling times depends on the effective population size, explicit statistical modeling of sampling times improves population size estimation. Previous work assumed that the genealogy relating sampled sequences is known and modeled sampling times as an inhomogeneous Poisson process with log-intensity equal to a linear function of the log-transformed effective population size. We improve this approach in two ways. First, we extend the method to allow for joint Bayesian estimation of the genealogy, effective population size trajectory, and other model parameters. Next, we improve the sampling time model by incorporating additional sources of information in the form of time-varying covariates. We validate our new modeling framework using a simulation study and apply our new methodology to analyses of population dynamics of seasonal influenza and to the recent Ebola virus outbreak in West Africa.

    in PLoS Computational Biology on October 12, 2020 09:00 PM.

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    Optimising risk-based surveillance for early detection of invasive plant pathogens

    by Alexander J. Mastin, Timothy R. Gottwald, Frank van den Bosch, Nik J. Cunniffe, Stephen Parnell

    Emerging infectious diseases (EIDs) of plants continue to devastate ecosystems and livelihoods worldwide. Effective management requires surveillance to detect epidemics at an early stage. However, despite the increasing use of risk-based surveillance programs in plant health, it remains unclear how best to target surveillance resources to achieve this. We combine a spatially explicit model of pathogen entry and spread with a statistical model of detection and use a stochastic optimisation routine to identify which arrangement of surveillance sites maximises the probability of detecting an invading epidemic. Our approach reveals that it is not always optimal to target the highest-risk sites and that the optimal strategy differs depending on not only patterns of pathogen entry and spread but also the choice of detection method. That is, we find that spatial correlation in risk can make it suboptimal to focus solely on the highest-risk sites, meaning that it is best to avoid ‘putting all your eggs in one basket’. However, this depends on an interplay with other factors, such as the sensitivity of available detection methods. Using the economically important arboreal disease huanglongbing (HLB), we demonstrate how our approach leads to a significant performance gain and cost saving in comparison with conventional methods to targeted surveillance.

    in PLoS Biology on October 12, 2020 09:00 PM.

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    Pharmacological evidence for the implication of noradrenaline in effort

    by Nicolas Borderies, Pauline Bornert, Sophie Gilardeau, Sebastien Bouret

    The trade-off between effort and reward is one of the main determinants of behavior, and its alteration is at the heart of major disorders such as depression or Parkinson’s disease. Monoaminergic neuromodulators are thought to play a key role in this trade-off, but their relative contribution remains unclear. Rhesus monkeys (Macaca mulatta) performed a choice task requiring a trade-off between the volume of fluid reward and the amount of force to be exerted on a grip. In line with a causal role of noradrenaline in effort, decreasing noradrenaline levels with systemic clonidine injections (0.01 mg/kg) decreased exerted force and enhanced the weight of upcoming force on choices, without any effect on reward sensitivity. Using computational modeling, we showed that a single variable (“effort”) could capture the amount of resources necessary for action and control both choices (as a variable for decision) and force production (as a driving force). Critically, the multiple effects of noradrenaline manipulation on behavior could be captured by a specific modulation of this single variable. Thus, our data strongly support noradrenaline’s implication in effort processing.

    in PLoS Biology on October 12, 2020 09:00 PM.

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    Sex‐specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors

    Sex‐specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors

    Sex‐specific role of dopamine D1 and D2 receptors in cocaine effects on adult neurogenesis has been studied. Results indicate that: 1) Cocaine hyperactivity decreases neurogenesis (males) or neuronal maturity (females), and correlates with BDNF. 2) Cocaine does not increase hyperactivity in D1ko females, but increases neuronal maturity and BDNF. 3) Cocaine increases hypoactivity in D2ko males, and increases neurogenesis and BDNF in D2ko females. 4) SCH23390 reduces cocaine hyperactivity, and correlates with BDNF. 5) Raclopride increases cocaine hyperactivity in females, and neurogenesis and BDNF in both sexes. Sex‐specific D1 and D2 signaling on proliferation and neuronal maturity is differentially perturbed by cocaine, and BDNF may contribute to D2 neuroplasticity in cocaine addiction.


    ABSTRACT

    Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex‐specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in a) cell proliferation (BrdU), b) neural precursor (nestin), c) neuronal phenotype (BrdU/β3‐tubulin), and d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1‐/‐, D2‐/‐) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 h later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1‐/‐ mice and reduced in SCH23390‐treated mice. Activity responses to cocaine were reduced in D2‐/‐ males, but absent in D2‐/‐ females and increased in Raclopride‐treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine‐exposed D1‐/‐ males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2‐/‐ mice had lower proliferative and neural precursor responses. Cocaine in D2‐/‐ females or co‐administered with Raclopride in WT females improved SVZ cell proliferation, an effect that positively correlated with plasma brain‐derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex‐specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on October 12, 2020 03:16 PM.

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    Enhanced diffusion and the eigenvalue band structure of Brownian motion in tilted periodic potentials

    Author(s): N. J. López-Alamilla, M. W. Jack, and K. J. Challis

    We consider enhanced diffusion for Brownian motion on a tilted periodic potential. Expressing the effective diffusion in terms of the eigenvalue band structure, we establish a connection between band gaps in the eigenspectrum and enhanced diffusion. We explain this connection for a simple cosine pot...


    [Phys. Rev. E 102, 042405] Published Mon Oct 12, 2020

    in Physical Review E: Biological physics on October 12, 2020 10:00 AM.

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    Neural mechanisms of aggression across species

    Nature Neuroscience, Published online: 12 October 2020; doi:10.1038/s41593-020-00715-2

    Aggression is an instinctive behavior supported by hardwired neural circuits. Julieta Lischinsky and Dayu Lin review our current understanding of the neural circuits of aggression across species and their modulation by internal state.

    in Nature Neuroscience on October 12, 2020 12:00 AM.

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    A systematic evaluation of the design and context dependencies of massively parallel reporter assays

    Nature Methods, Published online: 12 October 2020; doi:10.1038/s41592-020-0965-y

    Massively parallel reporter assays (MPRAs) enable high-throughput assessments of regulatory elements in single experiments. This work compares nine MPRA designs and reports how differences in reporter assays influence the results of MPRAs.

    in Nature Methods on October 12, 2020 12:00 AM.

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    vLUME: 3D virtual reality for single-molecule localization microscopy

    Nature Methods, Published online: 12 October 2020; doi:10.1038/s41592-020-0962-1

    vLUME is a complete virtual reality environment for visualizing, analyzing and interacting with three-dimensional single-molecule localization microscopy data.

    in Nature Methods on October 12, 2020 12:00 AM.

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    DeepC: predicting 3D genome folding using megabase-scale transfer learning

    Nature Methods, Published online: 12 October 2020; doi:10.1038/s41592-020-0960-3

    DeepC uses transfer learning-based deep neural networks for predicting genome folding from megabase-scale DNA sequence.

    in Nature Methods on October 12, 2020 12:00 AM.

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    Predicting 3D genome folding from DNA sequence with Akita

    Nature Methods, Published online: 12 October 2020; doi:10.1038/s41592-020-0958-x

    Akita enables three-dimensional genome folding predictions from DNA sequence using a convolutional neural network.

    in Nature Methods on October 12, 2020 12:00 AM.

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    Quantify and control reproducibility in high-throughput experiments

    Nature Methods, Published online: 12 October 2020; doi:10.1038/s41592-020-00978-4

    INTRIGUE is a statistical framework based on the directional consistency criterion for quantifying and controlling reproducibility in high-throughput experiments.

    in Nature Methods on October 12, 2020 12:00 AM.

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    Myelin plasticity: sculpting circuits in learning and memory

    Nature Reviews Neuroscience, Published online: 12 October 2020; doi:10.1038/s41583-020-00379-8

    Oligodendrocyte lineage cells have recently been shown to exhibit plasticity in response to sensory experience and learning. In this Review, Xin and Chan outline the evidence for and the possible mechanisms underlying the contribution of oligodendrocyte and myelin plasticity to memory acquisition and maintenance.

    in Nature Reviews on October 12, 2020 12:00 AM.

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    Electrically tunable correlated and topological states in twisted monolayer–bilayer graphene

    Nature Physics, Published online: 12 October 2020; doi:10.1038/s41567-020-01062-6

    Stacking a monolayer and bilayer of graphene, with a small twist angle between them, creates a tunable platform where the physics of both twisted bilayer graphene and twisted double bilayer graphene can be realized.

    in Nature Physics on October 12, 2020 12:00 AM.

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    Directional self-locomotion of active droplets enabled by nematic environment

    Nature Physics, Published online: 12 October 2020; doi:10.1038/s41567-020-01055-5

    Active matter particles self-propel but controlling their direction of motion can be challenging. Here the authors place motile bacteria inside microdroplets and control their propulsion by exploiting the asymmetric director structure of the surrounding liquid crystal.

    in Nature Physics on October 12, 2020 12:00 AM.

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    Resonant phase-matching between a light wave and a free-electron wavefunction

    Nature Physics, Published online: 12 October 2020; doi:10.1038/s41567-020-01042-w

    Energy–momentum phase-matching enables strong interactions between free electrons and light waves. As a result, the wavefunction of the electron exhibits a comb structure, which was observed using photon-induced near-field electron microscopy.

    in Nature Physics on October 12, 2020 12:00 AM.

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    Publisher Correction: Vectorized optoelectronic control and metrology in a semiconductor

    Nature Photonics, Published online: 12 October 2020; doi:10.1038/s41566-020-00713-7

    Publisher Correction: Vectorized optoelectronic control and metrology in a semiconductor

    in Nature Photomics on October 12, 2020 12:00 AM.

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    Broadband Mie driven random quasi-phase-matching

    Nature Photonics, Published online: 12 October 2020; doi:10.1038/s41566-020-00701-x

    Enhanced second-harmonic gene