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Abstract
Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of microdissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphogenetic protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wild-type mice. These findings indicate that performance in DG-dependent cognitive tasks is largely determined by differences in levels BMP signaling in the dentate gyrus.
in eNeuro on 2023-01-10 17:30:23 UTC.
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The purpose of the investigation was to analyze the experiences and perspectives on violence against women in the Apurímac region, Peru. The analysis was carried out through interviews with women in each of the provinces of Apurimac. The aim was to learn about the status of women's rights and the effectiveness of provisions and regulations for their protection. The article will also explore the vast cultural and social diversity present in the interviews themselves, in contrast to the current normative system. As a general conclusion, it became evident that women in Apurimac-Peru suffered different types of abuse and mistreatment just because they were women and that they did not feel any kind of support from the authorities, showing a lack of interest from the state in improving the current situation of women in Peruvian society.
in F1000Research on 2023-01-10 16:22:35 UTC.
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Background: This study examines Muhammad Shahrur's theory of limits and women’s issues. This theory adjusts the muhkamat verses to remain relevant to sociocultural conditions while remining within the jurisdiction of Allah SWT. Shahrur's approach conveyed women as different from traditional ulema, and controversial. Therefore, it is necessary to describe Shahrur's theory and interpretation on women issues. Methods: This was an exploratory bibliographic study using descriptive-hermeneutic analysis. Two of Shahrur's books were selected and five chapters from Al-Kitāb wa Al-Qur’ān, Qirā’ah Mu’āshirah and five chapters from Nahw Ushūl al-Jadīdah Li al-Fiqh al-Islāmy; Fiqh al-Mar'ah . Results: Shahrur’s interpretations on women issues are: a) relationships between teenagers of the opposite sex without marriage or living together is "halal" if it follows their will, without a contract, being accompanied by syecih or permission, b) The maximum limit of hijab is to cover the entire body except the face and palms. In contrast, the minimum limit covers the juyūb, including cleavage under the armpits, body parts, genitals, and buttocks. Apart from these, it does not include intimate parts and adapts to the community. c) women's intimate parts are shown only to the seven groups; brothers, fathers, children of a sibling, parents of one's wives and their children, d) Polygamy has both an upper limit and lower limit. Shahrur allows polygamy under two conditions: widows with children whose husbands left them to protect them, polygamy has two limitations, limit for quantity and limit for quality, e) the law of adultery has a lower and upper limit. Conclusion: According to Shahrur, women's issues are divided into four limits, sometimes they are at the upper limit and sometimes at the lower limit. Shahrur's linguistic approach finally led him to draw a conclusion that the product of Islamic law is highly dependent on the sociocultural context.
in F1000Research on 2023-01-10 16:08:44 UTC.
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A systematic literature review was conducted to summarize the overall thermal performance of different gasified cooking stoves from the available literature. For this purpose, available studies from the last 14 years (2008 to 2022) were searched using different search strings. After screening, a total of 28 articles were selected for this literature review. Scopus, Google Scholar, and Web of Science databases were used as search strings by applying “Gasifier cooking stove” AND “producer gas cooking stove” AND “thermal performance” keywords. This review uncovers different gasified cooking stoves, cooking fuels, and fabrication materials besides overall thermal performances. The result shows that the overall thermal performance of different gasified cooking stoves was 5.88% to 91% depending on the design and burning fuels. The premixed producer gas burner with a swirl vane stove provided the highest overall thermal performance range, which was 84% to 91%, and the updraft gasified stove provided the lowest performance, which was 5.88% to 8.79%. The result also demonstrates that the wood pellets cooking fuel provided the highest thermal performance and corn straw briquette fuel provided the lowest for gasified cooking stoves. The overall thermal performance of wood pellets was 38.5% and corn straw briquette was 10.86%.
in F1000Research on 2023-01-10 16:07:42 UTC.
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Background: Dermatoglyphics is the study of various dermal configurations on the fingers, palms, and soles. These appear during the 12th week of intrauterine life and develop completely by the 24th week. It is said that they remain constant thereafter. The aim of the present study was to compare and assess the association of dermatoglyphic patterns between skeletal class I and skeletal class III malocclusion. Methods: Finger and palm prints were collected using the ink and roller method from 604 subjects who were divided into skeletal class I, class III with maxillary retrognathism and class III with mandibular prognathism based on lateral cephalogram assessment. Results: Loop pattern was more predominant in skeletal class I malocclusion subjects and whorl pattern was more frequent in the other two groups. Total finger ridge count and atd angle also showed significant difference between the study groups. Conclusions: The present study attempted in assessing the association between dermatoglyphic patterns and skeletal malocclusion. Analysing dermal configurations may aid in indicating the type of developing malocclusion and thus help in interceptive and preventive orthodontics.
in F1000Research on 2023-01-10 16:06:43 UTC.
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by Noga Mosheiff, Bard Ermentrout, Chengcheng Huang
Neural activity in the cortex is highly variable in response to repeated stimuli. Population recordings across the cortex demonstrate that the variability of neuronal responses is shared among large groups of neurons and concentrates in a low dimensional space. However, the source of the population-wide shared variability is unknown. In this work, we analyzed the dynamical regimes of spatially distributed networks of excitatory and inhibitory neurons. We found chaotic spatiotemporal dynamics in networks with similar excitatory and inhibitory projection widths, an anatomical feature of the cortex. The chaotic solutions contain broadband frequency power in rate variability and have distance-dependent and low-dimensional correlations, in agreement with experimental findings. In addition, rate chaos can be induced by globally correlated noisy inputs. These results suggest that spatiotemporal chaos in cortical networks can explain the shared variability observed in neuronal population responses.
in PLoS Computational Biology on 2023-01-10 14:00:00 UTC.
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by Ivan Lazarevich, Ilya Prokin, Boris Gutkin, Victor Kazantsev
Modern well-performing approaches to neural decoding are based on machine learning models such as decision tree ensembles and deep neural networks. The wide range of algorithms that can be utilized to learn from neural spike trains, which are essentially time-series data, results in the need for diverse and challenging benchmarks for neural decoding, similar to the ones in the fields of computer vision and natural language processing. In this work, we propose a spike train classification benchmark, based on open-access neural activity datasets and consisting of several learning tasks such as stimulus type classification, animal’s behavioral state prediction, and neuron type identification. We demonstrate that an approach based on hand-crafted time-series feature engineering establishes a strong baseline performing on par with state-of-the-art deep learning-based models for neural decoding. We release the code allowing to reproduce the reported results.
in PLoS Computational Biology on 2023-01-10 14:00:00 UTC.
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by Artem S. Kasianov, Anna V. Klepikova, Alexey V. Mayorov, Gleb S. Buzanov, Maria D. Logacheva, Aleksey A. Penin
Interspecific gene comparisons are the keystones for many areas of biological research and are especially important for the translation of knowledge from model organisms to economically important species. Currently they are hampered by the low resolution of methods based on sequence analysis and by the complex evolutionary history of eukaryotic genes. This is especially critical for plants, whose genomes are shaped by multiple whole genome duplications and subsequent gene loss. This requires the development of new methods for comparing the functions of genes in different species. Here, we report ISEEML (Interspecific Similarity of Expression Evaluated using Machine Learning)–a novel machine learning-based algorithm for interspecific gene classification. In contrast to previous studies focused on sequence similarity, our algorithm focuses on functional similarity inferred from the comparison of gene expression profiles. We propose novel metrics for expression pattern similarity–expression score (ES)–that is suitable for species with differing morphologies. As a proof of concept, we compare detailed transcriptome maps of Arabidopsis thaliana, the model species, Zea mays (maize) and Fagopyrum esculentum (common buckwheat), which are species that represent distant clades within flowering plants. The classifier resulted in an AUC of 0.91; under the ES threshold of 0.5, the specificity was 94%, and sensitivity was 72%.
in PLoS Computational Biology on 2023-01-10 14:00:00 UTC.
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by Ashish B. George, Kirill S. Korolev
Assembling optimal microbial communities is key for various applications in biofuel production, agriculture, and human health. Finding the optimal community is challenging because the number of possible communities grows exponentially with the number of species, and so an exhaustive search cannot be performed even for a dozen species. A heuristic search that improves community function by adding or removing one species at a time is more practical, but it is unknown whether this strategy can discover an optimal or nearly optimal community. Using consumer-resource models with and without cross-feeding, we investigate how the efficacy of search depends on the distribution of resources, niche overlap, cross-feeding, and other aspects of community ecology. We show that search efficacy is determined by the ruggedness of the appropriately-defined ecological landscape. We identify specific ruggedness measures that are both predictive of search performance and robust to noise and low sampling density. The feasibility of our approach is demonstrated using experimental data from a soil microbial community. Overall, our results establish the conditions necessary for the success of the heuristic search and provide concrete design principles for building high-performing microbial consortia.
in PLoS Computational Biology on 2023-01-10 14:00:00 UTC.
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by Jiani Chen, Swan Tan, Vasanthi Avadhanula, Leonard Moise, Pedro A. Piedra, Anne S. De Groot, Justin Bahl
Human respiratory syncytial virus (RSV) is a major cause of lower respiratory infection. Despite more than 60 years of research, there is no licensed vaccine. While B cell response is a major focus for vaccine design, the T cell epitope profile of RSV is also important for vaccine development. Here, we computationally predicted putative T cell epitopes in the Fusion protein (F) and Glycoprotein (G) of RSV wild circulating strains by predicting Major Histocompatibility Complex (MHC) class I and class II binding affinity. We limited our inferences to conserved epitopes in both F and G proteins that have been experimentally validated. We applied multidimensional scaling (MDS) to construct T cell epitope landscapes to investigate the diversity and evolution of T cell profiles across different RSV strains. We find the RSV strains are clustered into three RSV-A groups and two RSV-B groups on this T epitope landscape. These clusters represent divergent RSV strains with potentially different immunogenic profiles. In addition, our results show a greater proportion of F protein T cell epitope content conservation among recent epidemic strains, whereas the G protein T cell epitope content was decreased. Importantly, our results suggest that RSV-A and RSV-B have different patterns of epitope drift and replacement and that RSV-B vaccines may need more frequent updates. Our study provides a novel framework to study RSV T cell epitope evolution. Understanding the patterns of T cell epitope conservation and change may be valuable for vaccine design and assessment.
in PLoS Computational Biology on 2023-01-10 14:00:00 UTC.
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by Salomé Fromonteil, Lucas Marie-Orleach, Lennart Winkler, Tim Janicke
Over the last decades, the field of sexual selection underwent a paradigm shift from sexual-stereotype thinking of “eager” males and “coy” females towards a more nuanced perspective acknowledging that not only males but also females can benefit from multiple mating and compete for mating partners. Yet, sexual selection in females is still considered a peculiarity, and the evolution of polyandry is often viewed to result from a higher mating interest of males. Here, we present meta-analytic evidence from 77 species across a broad range of animal taxa to demonstrate that female reproductive success is overall positively correlated with mating success, suggesting that females typically benefit from multiple mating. Importantly, we found that these fitness gains likely promote the evolution of polyandry. Our findings offer support for the idea that sexual selection is widespread in females and to play a key role for the evolution of animal mating systems. Thereby, our results extend our understanding of the evolutionary consequences of sexual reproduction and contribute to a more balanced view of how sexual selection operates in males and females.
in PLoS Biology on 2023-01-10 14:00:00 UTC.
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Background: Doxorubicin is a crucial anticancer medication, however, cardiotoxicity is a severe adverse effect of doxorubicin therapy. Various mechanisms, including inflammation, have been postulated to account for this negative effect. The omega-7 fatty acid is a polyunsaturated fatty acid with anti-inflammatory and antioxidant properties. Therefore, the study's objective was to see whether omega-7 had any possible protective benefits against doxorubicin-induced cardiotoxicity in male rats. Methods: 28 male Wister rats were split into four groups (seven per group). Group 1 (negative control): healthy animals received normal saline orally as the vehicle for eight successive days and were sacrificed on day nine. Group 2 (positive control): animals that received a single dose of doxorubicin hydrochloride (IP 15mg/kg) were sacrificed the next day. Group 3: the animals were administered omega-7 orally at a 100 mg/kg/day dose for eight days. A single injection of doxorubicin IP (15 mg/kg) was given on day nine. The animals were sacrificed on day 10. Group 4: the animal was administered omega-7 orally at a 300 mg/kg/day dose for eight days. A single injection of doxorubicin IP (15 mg/kg) was given on day nine. The animals were sacrificed on day 10. Serum was collected and used to measure lactate dehydrogenase, creatinine kinase-MB, tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta. Results: Lactate dehydrogenase and creatinine kinase-MB levels in group 3 (100mg/kg) were significantly lower than in group 2 (p>0.05) and significantly lower in group 4 (300mg/kg) than in group 2. Tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta levels were considerably lower in the omega-7-treated groups (100 and 300mg/kg) than in the positive control group (p<0.05). Conclusion: Through a mechanism involving the reduction of inflammation, omega-7 may preserve the cardiac tissue against doxorubicin-induced damage.
in F1000Research on 2023-01-10 11:39:09 UTC.
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Background: The results of the 2020 population census in Indonesia showed that the population has reached 270.020.000 million. This number shows that the population in Indonesia during the last 10 years has increased by around 32,56 million people. One of the BKKBN's efforts to reduce the birth rate in Indonesia is to urge people to marry at the ideal age, 21 years for women and 25 years for men. Methods: This study used GPAS/ SKAP data for the period 2017, 2018, and 2019 using the module for women aged (15-49) and the sample used was all women aged 40-49. This analysis used secondary data from the 2017, 2018, and 2019 government performance and accountability surveys. Results: The age at first marriage for women should be encouraged to be 25 years old, not 21 years old, which has always been echoed and socialized. Age at first marriage is the most dominant factor in women aged (40-49) to have more than two children (2017 SOR: 4.17 95% CI [1.85-17.31], (2018 SOR: 57.14 99% [4.12-793.67]) (2019 SOR 21.22 99% CI [2.28-197.45]), while only in 2019 the AFM variable after controlling for it remained significant in influencing having children more than 2 (AOR 27.64 99% [2.88-265.20]). Conclusion: Women aged (40-49) who have a younger age at first marriage (10-24) have a longer reproductive age range, so they have relatively more children than women who married at the age of 25 and over. After controlling for other factors, the characteristics of women who have a tendency to have more than two children. Therefore, it is necessary to design a health strategy that is more suitable to the needs, characteristics, and capacity of women to reduce the birth rate in Indonesia is to urge people to marry at the ideal age.
in F1000Research on 2023-01-10 11:21:34 UTC.
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Background: Coronavirus disease 2019 (COVID-19) is a global pandemic. Coagulopathy is one of the most common complications characterized by increased D-dimer level. We aimed to investigate the dose-response relationship between elevated D-dimer level and mortality in critically ill COVID-19 patients. Methods: This was a retrospective observational study in 259 critically ill COVID-19 patients requiring intensive care unit admission between March and December 2020. We compared the mortality rate between patients with and without elevated D-dimer. Receiver operating characteristic (ROC) curve analysis, Fagan’s nomogram, and dose-response relationship were performed to determine the association between D-dimer level and mortality. Results: Overall mortality rate was 40.9% (106 patients). Median D-dimer level was higher in non-survivor group (10,170 ng/mL vs 4,050 ng/mL, p=0.028). The association remained significant after multivariate logistic regression analysis (p=0.046). The optimal cut-off for D-dimer level to predict mortality from ROC curve analysis was 9,020 ng/mL (OR (odds ratio) 3.73 [95% CI (confidence interval) 1.91 – 7.28], p<0.001). D-dimer level >9,020 ng/mL confers 67% posterior probability of mortality and D-dimer level <9,020 ng/mL had 35% probability of mortality. Conclusions: There was a non-linear dose-response relationship between D-dimer level and mortality with Pnonlinearity of 0.004. D-dimer level was associated with mortality in critically ill COVID-19 patients in the non-linear dose-response relationship.
in F1000Research on 2023-01-10 09:52:45 UTC.
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Background: Many studies have demonstrated the utility of machine learning (ML) methods for genomic prediction (GP) of various plant traits, but a clear rationale for choosing ML over conventionally used, often simpler parametric methods, is still lacking. Predictive performance of GP models might depend on a plethora of factors including sample size, number of markers, population structure and genetic architecture. Methods: Here, we investigate which problem and dataset characteristics are related to good performance of ML methods for genomic prediction. We compare the predictive performance of two frequently used ensemble ML methods (Random Forest and Extreme Gradient Boosting) with parametric methods including genomic best linear unbiased prediction (GBLUP), reproducing kernel Hilbert space regression (RKHS), BayesA and BayesB. To explore problem characteristics, we use simulated and real plant traits under different genetic complexity levels determined by the number of Quantitative Trait Loci (QTLs), heritability (h2 and h2e), population structure and linkage disequilibrium between causal nucleotides and other SNPs. Results: Decision tree based ensemble ML methods are a better choice for nonlinear phenotypes and are comparable to Bayesian methods for linear phenotypes in the case of large effect Quantitative Trait Nucleotides (QTNs). Furthermore, we find that ML methods are susceptible to confounding due to population structure but less sensitive to low linkage disequilibrium than linear parametric methods. Conclusions: Overall, this provides insights into the role of ML in GP as well as guidelines for practitioners.
in F1000Research on 2023-01-10 09:33:50 UTC.
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Traumatic brain injury (TBI) is experienced during complex conditions. As an extreme example of this point, military personnel have experienced multiple blast and impact head injury exposures under stressful conditions. This complexity may confound attribution of common TBI symptoms. Our longitudinal modeling studies identify stress exposures as inducing sleep–wake dysfunction.
Abstract
Traumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can inform evaluation and care to prevent persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild stress and head injury exposures. We assessed anxiety, depression, and sleep–wake dysfunction as symptoms that impact long-term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a varied sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on 5 days at 24-h intervals. In males and females, UCMS induced anxiety without depressive behavior. A major finding was reproducible sleep–wake dysfunction through 6- to 12-month time points in male mice that received UCMS with repetitive blast plus TBI events, or surprisingly after just UCMS alone. Specifically, male mice exhibited hypersomnia with increased sleep during the active/dark phase and fragmentation of longer wake bouts. Sleep–wake dysfunction was not found with TBI events alone, and hypersomnia was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep–wake dysfunction. Furthermore, this reproducible hypersomnia with impaired wakefulness is similar to the excessive daytime sleepiness reported in patients, including patients with TBI, which warrants further clinical screening, care, and treatment development.
in Journal of Neuroscience Research on 2023-01-10 06:19:11 UTC.
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Abstract
The hippocampus contains rich oscillatory activity, with continuous ebbs and flows of rhythmic currents that constrain its ability to integrate inputs. During associative learning, the hippocampus must integrate inputs from a range of sources carrying information about events and the contexts in which they occur. Under these circumstances, temporal coordination of activity between sender and receiver is likely essential for successful communication. Previously, it has been shown that the coordination of rhythmic activity between the lateral entorhinal cortex (LEC) and the CA1 region of the hippocampus is tightly correlated with the onset of learning in an associative learning task. We aimed to examine whether rhythmic inputs from the LEC in specific frequency ranges were sufficient to enhance the temporal coordination of activity in downstream CA1. In urethane-anesthetized rats, we applied extracellular low-intensity alternating current stimulation across the length of the LEC. Using this method, we aimed to phase-bias ongoing neuronal activity in LEC at a range of different frequencies (from 1.25 to 55 Hz). Rhythmic stimulation of LEC at both 35 and 50 Hz increased the proportion of CA1 neurons significantly entrained to the phase of the applied stimulation current. A subset of stimulation frequencies modified CA1 spiking relationships to the phase of local ongoing CA1 oscillations, with each stimulation frequency exerting a unique influence upon downstream CA1, often in frequency ranges outside the target stimulation frequency. These results suggest there are optimal frequencies for LEC–CA1 communication, and that different profiles of LEC rhythms likely have distinct outcomes upon CA1 processing.
in Hippocampus on 2023-01-10 06:01:26 UTC.
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Abstract
Neural stem cells (NSCs) in the hippocampus generate new neurons throughout life, which functionally contribute to cognitive flexibility and mood regulation. Yet adult hippocampal neurogenesis substantially declines with age and age-related impairments in NSC activity underlie this reduction. Particularly, increased NSC quiescence and consequently reduced NSC proliferation are considered to be major drivers of the low neurogenesis levels in the aged brain. Epigenetic regulators control the gene expression programs underlying NSC quiescence, proliferation and differentiation and are hence critical to the regulation of adult neurogenesis. Epigenetic alterations have also emerged as central hallmarks of aging, and recent studies suggest the deterioration of the NSC-specific epigenetic landscape as a driver of the age-dependent decline in adult neurogenesis. In this review, we summarize the recently accumulating evidence for a role of epigenetic dysregulation in NSC aging and propose perspectives for future research directions.
in Hippocampus on 2023-01-10 05:59:03 UTC.
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Journal of Neurophysiology, Volume 129, Issue 1, Page 115-130, January 2023.
in Journal of Neurophysiology on 2023-01-10 05:08:12 UTC.
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Journal of Neurophysiology, Volume 129, Issue 1, Page 184-190, January 2023.
in Journal of Neurophysiology on 2023-01-10 05:08:11 UTC.
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The neuromodulator DA is firmly established as a key regulator of learning, motivation, and movement under both physiological and pathological conditions [1,2]. Over the last several decades, significant efforts have been devoted to revealing how DA contributes to behavior in mammals by characterizing the activity of DA-releasing neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in vivo, and by dissecting the effects of DA on target cells in vitro. These studies provide the foundations upon which current models of DA function are built.
in Trends in Neurosciences: In press on 2023-01-10 00:00:00 UTC.
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Mitochondria are double membrane-bound organelles present in almost all eukaryotic cells. They possess an inner and outer membrane separated by the intermembrane space, with their central compartment termed the matrix. Some cellular subtypes of high-metabolic demand (e.g., neurons and cardiomyocytes) have a particularly large number of mitochondria. While the reticular nature of these organelles that undergo dynamic fission and fusion events has been recognised since the beginning of the 20th century [1], mitochondria were principally studied as autonomous structures whose major function was to generate ATP via the tricarboxylic acid (TCA) (see Glossary) cycle and oxidative phosphorylation (OXPHOS).
in Trends in Neurosciences: In press on 2023-01-10 00:00:00 UTC.
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Although we experience the world as a continuous stream of information, our knowledge about the visual brain stems primarily from its responses to brief and isolated stimuli. Here, we show in the macaque object pathway that selectivity to natural movie content is strongly determined by visual continuity and temporal context.
in Neuron: In press on 2023-01-10 00:00:00 UTC.
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DePasquale et al. introduce a method for building artificial spiking neural networks using latent factors, a powerful concept in data analysis not yet grounded in neurophysiological terms. Factors are computationally central, enabling robust, flexible learning. Networks clarify that “factor” and firing rate are concretely defined and crucial to understanding computation.
in Neuron: In press on 2023-01-10 00:00:00 UTC.
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Jiao et al. find that protease expression declines during skeletal muscle aging in Drosophila and that this undermines proteostasis. They identify the transcription factor Ptx1/PITX as a repressor of protease expression and show that Ptx1/PITX knockdown improves muscle protein quality control during aging in a protease-dependent manner and extends lifespan.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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5-oxoETE is an inflammatory lipid derived from arachidonic acid. 5-oxoETE’s physiological functions are little understood, partly because its G protein-coupled receptor, OXER1, has no known rodent orthologs. Here, Ma et al. use zebrafish, which express OXER1 orthologs, to illuminate the pathway’s essential physiological functions in rapid innate immune defense against bacterial infection.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Kim-Muller et al. demonstrate that, in addition to body mass restoration, GDF15 neutralization improves muscle function and physical performance in a TOV21G cancer cachexia model in mice, implicating GDF15 neutralization as a potentially effective therapy for enhancing physical performance in patients with cachexia.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Myeloid cells accumulate in glioblastomas. Ochocka et al. dissect myeloid populations in experimental gliomas and show distinct functions using single-cell RNA and protein sequencing. Microglia attract immune cells, while inflammatory monocytes differentiate to immunosuppressive macrophages in TME. The data also show sex disparity in myeloid cell composition and functionality in glioblastomas.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Why some individuals recover better than others from stressful situations is unclear. Swaminathan et al. show that resilience to stress is established during zebrafish development as a stable and heritable trait. Resilience is augmented by brain-derived neuropeptides and attenuated by innate immune complement factors specifically expressed in the liver.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Biomolecular condensates, such as stress granules and processing bodies, rapidly form in response to stress. Zhang et al. discover a stress-induced membraneless condensate called D-granule in the current work, which forms via DIAPH3 LLPS and functions as a regulatory hub for actin cytoskeletal reorganization when cells are subjected to stress.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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In budding yeast, rDNA stability can impact cellular senescence. Yokoyama et al. report that the transcription elongation factor Spt4 activates transcription of non-coding RNA in the rDNA, which induces rDNA instability and accelerates cellular senescence.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Digit tip regeneration rebuilds amputated structures in some mammals if the nail organ is preserved. In recently published Cell Reports papers, Castilla-Ibeas et al., Johnson et al., and Mahmud et al. define the patterning function and regenerative capacity of the dorsal nail mesenchyme in this process.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Cognitive control involves flexibly routing information according to current goals. Xiao et al. demonstrate that the neural mechanisms underlying cognitive control generalize across different conditions within a task but are not task invariant. Instead, the neural signatures of conflict monitoring reflect task-dependent combinations of sensory inputs and motor outputs.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Jiang et al. find SLC7A14 as a GABA transporter, resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)’s activity. These results establish a causal link between lysosomal amino acids and insulin sensitivity and provide drug targets for insulin-resistance-related diseases.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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In this study, Laumaea et al. characterize CD4 downregulation, Env conformation, and ADCC responses in infected macrophages and autologous CD4+ T cells. They report that Nef and Vpu protect infected macrophages from ADCC responses mediated by HIV+ plasma and that small CD4 mimetics sensitize them to ADCC.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Vondra et al. report the accumulation of CD163+CD206+CD11chiHLA-DRlo macrophages termed decidua basalis-associated macrophages (decBAMs). decBAMs proliferate, secrete pregnancy-sustaining factors, and induce Tregs but show diminished phagocytosis and T cell activation efficiency. The secretome of placenta-derived trophoblasts partly induces this phenotype, suggesting that placentation co-regulates macrophage polarization during human pregnancy.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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Guo et al. show that transient episodes of hypoglycemia enhance the nuclear accumulation of HIF-1α, resulting in increased expression of GLUT1 in retinal glial cells. In the presence of hypoxia, this physiologic response results in a pathologic increase in the secretion of HIF-dependent angiogenic mediators that worsen diabetic eye disease.
in Cell Reports: Current Issue on 2023-01-10 00:00:00 UTC.
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The circadian clock governs rhythmic cellular functions by driving the expression of a substantial fraction of the genome and thereby significantly contributes to the adaptation to changing environmental conditions. Using the circadian model organism Neurospora crassa, we show that molecular timekeeping is robust even under severe limitation of carbon sources, however, stoichiometry, phosphorylation and subcellular distribution of the key clock components display drastic alterations. Protein kinase A, protein phosphatase 2 A and glycogen synthase kinase are involved in the molecular reorganization of the clock. RNA-seq analysis reveals that the transcriptomic response of metabolism to starvation is highly dependent on the positive clock component WC-1. Moreover, our molecular and phenotypic data indicate that a functional clock facilitates recovery from starvation. We suggest that the molecular clock is a flexible network that allows the organism to maintain rhythmic physiology and preserve fitness even under long-term nutritional stress.
in eLife on 2023-01-10 00:00:00 UTC.
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Alpha-synuclein (α-syn), a major component of Lewy bodies found in Parkinson's disease (PD) patients, has been found exported outside of cells and may mediate its toxicity via cell-to-cell transmission. Here, we reconstituted soluble, monomeric a-syn secretion by the expression of DnaJ homolog subfamily C member 5 (DNAJC5) in HEK293T cells. DNAJC5 undergoes palmitoylation and anchors on the membrane. Palmitoylation is essential for DNAJC5-induced α-syn secretion, and the secretion is not limited by substrate size or unfolding. Cytosolic α-syn is actively translocated and sequestered in an endosomal membrane compartment in a DNAJC5-dependent manner. Reduction of α-syn secretion caused by a palmitoylation-deficient mutation in DNAJC5 can be reversed by a membrane-targeting peptide fusion-induced oligomerization of DNAJC5. The secretion of endogenous α-syn mediated by DNAJC5 is also found in a human neuroblastoma cell line, SH-SY5Y, differentiated into neurons in the presence of retinoic acid, and in human induced pluripotent stem cell-derived midbrain dopamine neurons. We propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.
in eLife on 2023-01-10 00:00:00 UTC.
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Broadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest1. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through vaccination remains challenging, in part due to our limited understanding of how antibodies evolve breadth2. Here, we analyze the landscape by which an anti-influenza receptor binding site (RBS) bnAb, CH65, evolved broad affinity to diverse H1 influenza strains3,4. We do this by generating an antibody library of all possible evolutionary intermediates between the unmutated common ancestor (UCA) and the affinity-matured CH65 antibody and measure the affinity of each intermediate to three distinct H1 antigens. We find that affinity to each antigen requires a specific set of mutations - distributed across the variable light and heavy chains - that interact non-additively (i.e., epistatically). These sets of mutations form a hierarchical pattern across the antigens, with increasingly divergent antigens requiring additional epistatic mutations beyond those required to bind less divergent antigens. We investigate the underlying biochemical and structural basis for these hierarchical sets of epistatic mutations and find that epistasis between heavy chain mutations and a mutation in the light chain at the VH-VL interface is essential for binding a divergent H1. Collectively, this work is the first to comprehensively characterize epistasis between heavy and light chain mutations and shows that such interactions are both strong and widespread. Together with our previous study analyzing a different class of anti-influenza antibodies5, our results implicate epistasis as a general feature of antibody sequence-affinity landscapes that can potentiate and constrain the evolution of breadth.
in eLife on 2023-01-10 00:00:00 UTC.
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Virus-based tumour vaccines offer many advantages compared to other antigen-delivering systems. They generate concerted innate and adaptive immune response, and robust CD8+ T cell responses. We engineered a non-replicating pseudotyped influenza virus (S-FLU) to deliver the well-known cancer testis antigen, NY-ESO-1 (NY-ESO-1 S-FLU). Intranasal or intramuscular immunization of NY-ESO-1 S-FLU virus in mice elicited a strong NY-ESO-1-specific CD8+ T cell response in lungs and spleen that resulted in the regression of NY-ESO-1-expressing lung tumour and subcutaneous tumour, respectively. Combined administration with anti-PD-1 antibody, NY-ESO-1 S-FLU virus augmented the tumour protection by reducing the tumour metastasis. We propose that the antigen delivery through S-FLU is highly efficient in inducing antigen-specific CD8+ T cell response and protection against tumour development in combination with PD-1 blockade.
in eLife on 2023-01-10 00:00:00 UTC.
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With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockout with mouse Ehd2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.
in eLife on 2023-01-10 00:00:00 UTC.
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A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains imperative. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single-nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years.
in eLife on 2023-01-10 00:00:00 UTC.
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The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here we report that DNA G-quadruplex (G4-DNA) accumulates in neurons in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to play a role in human perception and decision-making, but the nature of our presumed preference for simplicity is not understood. Here we use preregistered behavioral experiments informed by formal theories of statistical model selection to show that, when faced with uncertain evidence, human subjects exhibit preferences for particular, theoretically grounded forms of simplicity of the alternative explanations. These forms of simplicity can be understood in terms of geometrical features of statistical models treated as manifolds in the space of the probability distributions, in particular their dimensionality, boundaries, volume, and curvature. The simplicity preferences driven by these features, which are also exhibited by artificial neural networks trained to optimize performance on comparable tasks, generally improve decision accuracy, because they minimize over-sensitivity to noisy observations (i.e., overfitting). However, unlike for artificial networks, for human subjects these preferences persist even when they are maladaptive with respect to the task training and instructions. Thus, these preferences are not simply transient optimizations for particular task conditions but rather a more general feature of human decision-making. Taken together, our results imply that principled notions of statistical model complexity have direct, quantitative relevance to human and machine decision-making and establish a new understanding of the computational foundations, and behavioral benefits, of our predilection for inferring simplicity in the latent properties of our complex world.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Human learning is a complex phenomenon that varies greatly among individuals and is related to the microstructure of major white matter tracts in several learning domains, yet the impact of the existing myelination of major white matter tracts on future learning outcomes remains unclear. We employed a machine-learning model selection framework to evaluate whether existing microstructure might predict individual differences in the potential for learning a sensorimotor task, and further, if the mapping between the microstructure of major white matter tracts and learning was selective for learning outcomes. We used diffusion tractography to measure the mean fractional anisotropy (FA) of major white matter tracts in 60 adult participants who then underwent training and subsequent testing to evaluate learning. During training, participants practiced drawing a set of 40 novel symbols repeatedly using a digital writing tablet. For testing, we measured drawing learning as the slope of draw duration over the practice session; we measured visual recognition learning as the performance accuracy in an old/new 2-AFC recognition task. We performed two separate analyses, one that assessed the relationship between pre-training FA and learning to draw novel symbols and a second that assessed the relationship between pre-training FA and learning to visually recognize symbols after training. Both analyses focused on the microstructure of white matter tracts that connect dorsal and ventral cortices, the posterior vertical pathway (PVP), as well as tracts within the dorsal motor system and within the ventral perceptual system. Results demonstrated that the microstructure of major white matter tracts selectively predicted learning outcomes, with left hemisphere pArc and SLF 3 tracts predicting drawing learning and the left hemisphere MDLFspl predicting visual recognition learning. These results were replicated in a repeat, held-out data set and supported with complementary analyses. Overall, results suggest that individual differences in the microstructure of human white matter tracts may be selectively related to future learning outcomes that arise from a single experience and open avenues of inquiry concerning the impact of existing tract myelination and individual differences in the potential for learning.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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All life must solve how to allocate limited energy resources to maximise benefits from scarce opportunities. Economic theory posits decision makers optimise choice by maximising the subjective benefit (utility) of reward minus the subjective cost (disutility) of the required effort. While successful in many settings, this model does not fully account for how experience can alter reward-effort trade-offs. Here we test how well the subtractive model of effort disutility explains the behavior of two non-human primates (Macaca mulatta) in a binary choice task in which reward quantity and physical effort to obtain were varied. Applying random utility modelling to independently estimate reward utility and effort disutility, we show the subtractive effort model better explains out-of-sample choice behavior when compared to parabolic and exponential effort discounting. Furthermore, we demonstrate that effort disutility is dependent on previous experience of effort: in analogy to work from behavioral labour economics, we develop a model of reference-dependent effort disutility to explain the increased willingness to expend effort following previous experience of effortful options in a session. The result of this analysis suggests that monkeys discount reward by an effort cost that is measured relative to an expected effort learned from previous trials. When this subjective cost of effort, a function of context and experience, is accounted for, trial-by-trial choice behavior can be explained by the subtractive cost model of effort. Therefore, in searching for net utility signals that may underpin effort-based decision-making in the brain, careful measurement of subjective effort costs is an essential first step.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Experiential decision-making could be explained as a result of either memory-based or reinforcement-based processes. Here, for the first time, we show that individual preferences between a memory-based and a reinforcement-based strategy, even when the two are functionally equivalent in terms of expected payoff, are adaptively shaped by individual differences in resting-state brain connectivity between the corresponding brain regions. Using computational cognitive models to identify which mechanism was most likely used by each participant, we found that individuals with comparatively stronger connectivity between memory regions prefer a memory-based strategy, while individuals with comparatively stronger connectivity between sensorimotor and habit-formation regions preferentially rely on a reinforcement-based strategy. These results suggest that human decision-making is adaptive and sensitive to the neural costs associated with different strategies.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Recognizing spelling errors is important for correct writing and reading, and develops over an extended period. The neural bases of the development of orthographic sensitivity remain poorly understood. We investigated event-related potentials (ERPs) associated with spelling error recognition when performing the orthographic decision task with correctly spelled and misspelled words in children aged 8-10 years old, early adolescents aged 11-14 years old, and adults. Spelling processing in adults included an early stage associated with the initial recognition of conflict between orthography and phonology (reflected in the N400 time window) and a later stage (reflected in the P600 time window) related to re-checking the spelling. In children 8-10 years old, there were no differences in ERPs to correct and misspelled words; in addition, their behavioral scores were worse than those of early adolescents, implying that the ability to quickly recognize the correct spelling is just beginning to develop at this age. In early adolescents, spelling recognition was reflected only at the later stage, corresponding to the P600 component. At the behavioral level, they were worse than adults at recognizing misspelled words. Our data suggest that orthographic sensitivity can develop beyond 14 years.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. In order to develop novel therapies, it is necessary to better understand the neurobiological mechanisms underlying SCD pain. There are many barriers to gaining mechanistic insight into pathogenic SCD pain processes, such as differential gene expression and function of sensory neurons between humans and mice with SCD, as well as the limited availability of patient samples. These can be overcome by utilizing SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs). Here, we characterize the key gene expression and function of SCD iSNs to establish a model for higher-throughput investigation of intrinsic and extrinsic factors that may contribute to increased SCD patient pain. Importantly, identified roles for C-C Motif Chemokine Ligand 2 (CCL2) and endothelin 1 (ET1) in SCD pain can be recapitulated in SCD iSNs. Further, we find that plasma taken from SCD patients during acute pain increases SCD iSN calcium response to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at baseline or healthy control plasma samples. Together, these data provide the framework necessary to utilize iSNs as a powerful tool to investigate the neurobiology of SCD and identify potential intrinsic mechanisms of SCD pain which may extend beyond a blood-based pathology.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Many cognitive functions are represented as cell assemblies. For example, the population activity of place cells in the hippocampus and grid cells in the entorhinal cortex represent self-location in the environment. The brain cannot directly observe self-location information in the environment. Instead, it relies on sensory information and memory to estimate self-location. Therefore, estimating low-dimensional dynamics, such as the movement trajectory of an animal exploring its environment, from only the high-dimensional neural activity is important in deciphering the information represented in the brain. Most previous studies have estimated the low-dimensional dynamics behind neural activity by unsupervised learning with dimensionality reduction using artificial neural networks or Gaussian processes. This paper shows theoretically and experimentally that these previous research approaches fail to estimate well when the nonlinearity between high-dimensional neural activity and low-dimensional dynamics becomes strong. We estimate the animal's position in 2-D and 3-D space from the activity of grid cells using an unsupervised method based on persistent cohomology. The method using persistent cohomology estimates low-dimensional dynamics from the phases of manifolds created by neural activity. Much cognitive information, including self-location information, is expressed in the phases of the manifolds created by neural activity. The persistent cohomology may be useful for estimating these cognitive functions from neural population activity in an unsupervised manner.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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The role of the vertebrate retina in early vision is generally described by the efficient coding theory, which predicts that the retina discards spatiotemporal correlations in natural scenes. It is unclear, however, whether the predicted decorrelation in the activity of ganglion cells, the retina's output neurons, holds under gaze shifts, which dominate the natural visual input. We here show that species-specific gaze patterns in natural stimuli can drive strong and correlated spiking responses both within and across distinct types of ganglion cells in marmoset as well as mouse retina. These concerted responses violate efficient coding and signal fixation periods with locally high spatial contrast. Finally, novel model-based analyses of ganglion cell responses to natural stimuli reveal that the observed response correlations follow from nonlinear pooling of ganglion cell inputs. Our results reveal how concerted population activity can surpass efficient coding to detect gaze-related stimulus features.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disease, which occurs when the cellular prion protein (PrPC) spontaneously misfolds into disease-associated forms, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation time and prion-related neuropathology. Homozygous (Stx6-/-) and heterozygous (Stx6+/-) knockout of Stx6 expression extended survival by 12 days following inoculation with RML prions relative to wildtype controls. Similarly, in Stx6-/- mice, disease incubation time following inoculation with ME7 prions was extended by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide confirmatory evidence for a pathological role of Stx6 expression in prion disease and support further exploration of syntaxin-6 lowering as a potential therapeutic strategy.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Spatial learning is critical for survival and its underlying neuronal mechanisms have been studied extensively. These studies have revealed a wealth of information about the neural representations of space, such as place cells and boundary cells. While many studies have focused on how these representations emerge in the brain, their functional role in driving spatial learning and navigation has received much less attention. We extended an existing computational modeling tool-chain to study the functional role of spatial representations using closed-loop simulations of spatial learning. At the heart of the model agent was a spiking neural network that formed a ring attractor. This network received inputs from place and boundary cells and the location of the activity bump in this network was the output. This output determined the movement directions of the agent. We found that the navigation performance depended on the parameters of the place cell input, such as their number, the place field sizes, and peak firing rate, as well as, unsurprisingly, the size of the goal zone. The dependence on the place cell parameters could be accounted for by just a single variable, the overlap index, but this dependence was nonmonotonic. By contrast, performance scaled monotonically with the Fisher information of the place cell population. Our results therefore demonstrate that efficiently encoding spatial information is critical for navigation performance.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Ca2+/calmodulin-dependent protein kinase II (CaMKII) has long been central in synaptic plasticity research. CaMKII is a dodecameric serine/threonine kinase that has been essentially conserved across metazoans for over a million years. While the mechanisms of CaMKII activation are well studied, its "behavior" at the molecular level has remained unobserved. Here, high-speed atomic force microscopy was used to visualize the activity-dependent structural dynamics of rat/hydra/C. elegans CaMKII in various states at nanometer resolution. Among the species, rat CaMKII underwent internal kinase domain aggregation in an activity-dependent manner and showed a higher tolerance to dephosphorylation by phosphatase. Our findings suggest that mammalian CaMKII has evolutionarily acquired a new structural form and a tolerance to phosphatase to maintain robust CaMKII activity for proper neuronal function.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Overall balance of excitation and inhibition in cortical networks is central to their functionality and normal operation. Such orchestrated temporal co-evolution of excitation and inhibition is established through local connections, and is homeostatically regulated to keep the networks in a vigilant state, so that they readily respond to their inputs and rapidly transition between different states without losing their stability. Several homeostatic plasticity mechanisms have been identified that adjust the strength and kinetics of synaptic activity in cortical networks to restore their balance when it is perturbed from a normal level. However, it is not yet well-understood how a balanced state is established, how it is dynamically regulated, and how it can accurately be measured, partially due to lack of a universally accepted definition of excitation-inhibition balance. Here, we use biologically plausible mathematical models to demonstrate how some of the key physiological factors that control the kinetics of synapses and structural factors that determine the overall topology of a cortical network contribute to establishment of an overall balance of excitation and inhibition throughout the network. We characterize a network's baseline balanced state by a set of functional properties, and show that deviations from this reference state can be continuously quantified by measuring the ratio between mean excitatory and mean inhibitory synaptic conductances in the network. We show how variations in physiological and structural parameters of a network dynamically change the level of excitation-inhibition balance and result in transitions in the spontaneous activity of the network to high-amplitude slow oscillatory regimes. Our results particularly show that the commonly observed ratio between the number of inhibitory and excitatory neurons in local cortical networks is nearly optimal, and the values of inhibitory synaptic decay time constants and the density of inhibitory-to-inhibitory connectivity are critical to network balance and stability.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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COVID-19 has impacted billions of people in the world since 2019 and unfolded a major healthcare crisis. With an increasing number of deaths and the emergence of more transmissible variants, it is crucial to better understand the biology of the disease-causing virus, the SARS-CoV-2. Peripheral neuropathies appeared as a specific COVID-19 symptom occurring at later stages of the disease. In order to understand the impact of SARS-CoV-2 on the peripheral nervous system, we generated human sensory neurons from induced pluripotent stem cells that we infected with the SARS-CoV-2 strain WA1/2020 and the variants delta and omicron. Using single cell RNA sequencing, we found that human sensory neurons can be infected by SARS-CoV-2 but are unable to produce new viruses. Our data suggests that sensory neurons can be infected by the original WA1/2020 strain of SARS-CoV-2 as well as the delta and omicron variants.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Foxb1-expressing neurons are located in the dorsal premammillary nucleus (PMd) and further rostrally in the parvafox nucleus, a longitudinal cluster of neurons in the lateral hypothalamus of rodents. The descending projection of these Foxb1+ neurons end in the dorsolateral part of the periaqueductal gray (dlPAG). The functional role of the Foxb1+ neuronal subpopulation in the PMd and the parvafox nucleus remains elusive. In this study, the activity of the Foxb1+ neurons and of their terminal endings in the dlPAG was selectively altered by employing chemo- and optogenetic tools. Our results show that in whole-body barometric plethysmography, hM3Dq-mediated, global Foxb1+ neuron excitation activates respiration. Time-resolved optogenetic gain-of-function manipulation of the terminal endings of Foxb1+ neurons in the rostral third of the dlPAG leads to abrupt immobility and bradycardia. Chemogenetic activation of Foxb1+ cell bodies and ChR2-mediated excitation of their axonal endings in the dlPAG led to a phenotypical presentation congruent with a freezing-like situation during innate defensive behavior.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. We developed viral vectors to express both endogenous GABAA or GABAB receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABAB receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABAB receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Mammalian sleep is regulated by a homeostatic process that increases sleep drive and intensity as a function of prior wake time. Sleep homeostasis has traditionally been thought to be a product of neurons, but recent findings demonstrate that this process is also modulated by glial astrocytes. The precise role of astrocytes in the accumulation and discharge of sleep drive is unknown. We investigated this question by selectively activating basal forebrain (BF) astrocytes using designer receptors exclusively activated by designer drugs (DREADDs). Activation of the Gq-protein-coupled pathway in BF astrocytes produced long and continuous periods of wakefulness that paradoxically did not cause the expected homeostatic response to sleep loss (e.g., increases in sleep time or intensity). Further investigations showed that this was not due to indirect effects of the ligand that activated DREADDs. These findings suggest that the need for sleep is not driven by wakefulness per se, but specific neuronal-glial circuits that are differentially activated in wakefulness.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. LBD Asyn fibrils comprise two protofilaments with pseudo-21 helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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A crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the readiness of newborn infants for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs to proliferate. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory.
in bioRxiv: Neuroscience on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 119: Neuroplasticity Elicited by Modified Pharyngeal Electrical Stimulation: A Pilot Study
Brain Sciences doi: 10.3390/brainsci13010119
Authors:
Xue Zhang
Xiaolu Wang
Yunxiao Liang
Yilong Shan
Rong Song
Xin Li
Zulin Dou
Hongmei Wen
Modified pharyngeal electrical stimulation (mPES) is a novel therapeutic method for patients with neurogenic dysphagia and tracheostomy. However, the underlying neural mechanisms are still unclear. This study aims to investigate the impact of mPES on swallowing-related neural networks and involuntary swallowing frequency using functional near-infrared spectroscopy (fNIRS). 20 healthy volunteers participated in this study, including two separate experimental paradigms. Experiment 1: Immediate effect observation, 20 participants (10 female; mean age 47.65 &plusmn; 10.48) were delivered with real and sham mPES in random order for 8 repetitions. fNIRS signals were collected during the whole period of Experiments 1. Swallowing frequency was assessed during sham/real mPES. Experiment 2: Prolonged effect observation, 7 out of the 20 participants (4 female; mean age 49.71 &plusmn; 6.26) completed real mPES for 5 sessions (1 session/day). 13 of the 20 participants withdrew for personal reasons. Hemodynamic changes were recorded by fNIRS on day 1 and 5. Results show that mPES evoked cortical activation over a distributed network in bilateral primary somatosensory, primary motor, somatosensory association cortex, pre-motor and supplementary motor area, dorsolateral prefrontal cortex, Broca&rsquo;s area, and supramarginal gyrus part of Wernicke&rsquo;s area. Meanwhile, the increased frequency of involuntary swallowing was associated with decreased frontopolar activation (frontopolar cortex: Channel 6, p = 0.024, r = &minus;0.529; Channel 23, p = 0.019, r = &minus;0.545). Furthermore, after five days of mPES, decreased cortical activations were observed in the right dorsolateral prefrontal and supramarginal gyrus part of Wernicke&rsquo;s area, and left frontopolar and M1 areas. Overall, these results might suggest that mPES could elicit changes in neuroplasticity that could reorganize the swallowing-related neural network and increase involuntary swallow frequency.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 124: Short-Term Benefits of Continuous Positive Airway Pressure Treatment on Cognition in the Obstructive Sleep Apnea Syndrome: A Retrospective Study
Brain Sciences doi: 10.3390/brainsci13010124
Authors:
Giulia Vaioli
Sofia Tagini
Federica Scarpina
Riccardo Cremascoli
Lorenzo Priano
Mauro Cornacchia
Paolo Fanari
Alessandro Mauro
The Obstructive Sleep Apnea Syndrome (OSAS) significantly impacts cognitive functioning. The prolonged use (more than 3 months) of ventilotherapy with continuous positive airway pressure (CPAP) seems to have positive effects in restoring cognitive difficulties. However, there is poor evidence about its possible short-term effect. We investigated whether the short use (less than 15 days at testing) of CPAP improved the cognitive functioning in fifty individuals with OSAS by collecting retrospective neuropsychological measures about verbal memory and learning, information processing speed, attention (i.e., alerting, orienting, and executive system), and executive functions (i.e., strategic reasoning, problem-solving, and mental planning). The predictive role of days of CPAP use on the neuropsychological scores was assessed by hierarchical multiple linear regression analyses, over and above the possible role of demographics, body mass index, level of OSAS severity, and the level of anxiety and depression. The average number of days since CPAP adaptation was 4.70 (SD = 3.90; range = 0&ndash;15). As the days of CPAP adaptation increased, verbal learning and long-term memory significantly improved, contrary to the other assessed domains. Our results show a significant improvement in some cognitive functions even after a short treatment with CPAP, pointing to the importance of the early use of ventilotherapy to rapidly improve cognitive functioning. Identifying which cognitive functions can or cannot be restored with CPAP use may enable the design of complementary neuropsychological interventions focused on those residual difficulties, possibly enhancing patients&rsquo; compliance to the treatment.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 123: Carbamazepine for Chronic Muscle Pain: A Retrospective Assessment of Indications, Side Effects, and Treatment Response
Brain Sciences doi: 10.3390/brainsci13010123
Authors:
Tabea M. Dyong
Burkhard Gess
Christina Dumke
Roman Rolke
Maike F. Dohrn
Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic (n = 5) and other hereditary (n = 9) to acquired (n = 2) myopathies and myotonia syndromes (n = 22). Under carbamazepine (daily dose 254 &plusmn; 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (&minus;1.9 &plusmn; 1.8, p &lt; 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of A&delta;-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional A&delta;-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 122: Eyes-Open and Eyes-Closed Resting State Network Connectivity Differences
Brain Sciences doi: 10.3390/brainsci13010122
Authors:
Junrong Han
Liwei Zhou
Hang Wu
Yujuan Huang
Mincong Qiu
Likai Huang
Chia Lee
Timothy Joseph Lane
Pengmin Qin
Resting state networks comprise several brain regions that exhibit complex patterns of interaction. Switching from eyes closed (EC) to eyes open (EO) during the resting state modifies these patterns of connectivity, but precisely how these change remains unclear. Here we use functional magnetic resonance imaging to scan healthy participants in two resting conditions (viz., EC and EO). Seven resting state networks were chosen for this study: salience network (SN), default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), visual network (VN), motor network (MN) and auditory network (AN). We performed functional connectivity (FC) analysis for each network, comparing the FC maps for both EC and EO. Our results show increased connectivity between most networks during EC relative to EO, thereby suggesting enhanced integration during EC and greater modularity or specialization during EO. Among these networks, SN is distinctive: during the transition from EO to EC it evinces increased connectivity with DMN and decreased connectivity with VN. This change might imply that SN functions in a manner analogous to a circuit switch, modulating resting state relations with DMN and VN, when transitioning between EO and EC.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 121: Recent Studies on the Development of Nicotine Abuse and Behavioral Changes Induced by Chronic Stress Depending on Gender
Brain Sciences doi: 10.3390/brainsci13010121
Authors:
Karolina Grabowska
Wojciech Ziemichód
Grażyna Biała
Nowadays, stressful situations are an unavoidable element of everyday life. Stressors activate a number of complex mental and physiological reactions in the organism, thus affecting the state of health of an individual. Stress is the main risk factor in the development of mental disorders, such as depression and other disorders developing as a result of addiction. Studies indicate that women are twice as likely as men to develop anxiety, depression and therefore addiction, e.g., to nicotine. Even though the data presented is indicative of significant differences between the sexes in the prevalence of these disorders, the majority of preclinical animal models for investigating stress-induced disorders use predominantly male subjects. However, the recent data indicates that this type of studies has also been launched in female rodents. Therefore, conducting research on both sexes allows for a more accurate understanding and assessment of the impact of stress on stress-induced behavioral, peripheral and molecular changes in the body and brain. In this manuscript we have gathered the data from 41 years (from 1981&ndash;2022) on the influence of stress on the development of depression and nicotine addiction in both sexes.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 120: Play with Me: How Fathers and Mothers Play with Their Preschoolers with Autism
Brain Sciences doi: 10.3390/brainsci13010120
Authors:
Silvia Perzolli
Arianna Bentenuto
Giulio Bertamini
Paola Venuti
(1) Background: Children can develop cognitive and social skills during play. Most research has focused on mothers, but the paternal features in interaction with children with autism spectrum disorder (ASD) are mainly unexplored. This study aimed to compare fathers&rsquo; and mothers&rsquo; interactive behaviors with their children with ASD to identify similarities and differences during playful exchanges. (2) Methods: A total of 72 mothers and 72 fathers of paired children with ASD (chronological age: M = 44.61 months; SD = 13.37) took part in this study. Data were collected during 10 min of video-recorded semi-structured interactions with mothers and fathers separately in interaction with their children. (3) Results: Mothers showed more symbolic play (W = 3537; p &lt; 0.001) than fathers, who displayed higher levels of exploratory play (t(139.44) = &minus;2.52; p = 0.013) compared to mothers. However, child cognitive functioning impacts maternal play but not the father&rsquo;s play characteristics. (4) Conclusions: Highlighting mother&ndash;child and father&ndash;child features may have important service delivery implications for implementing personalized parental-based interventions based on the strengths and weaknesses of both caregivers in a complementary system.
in Brain Sciences on 2023-01-10 00:00:00 UTC.
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Background: The telecommunication industry was one of the Indonesian government's priorities in the national development plan 2015-2035. “Primary Industry” was the term for the priority industries with the central role as the prime mover in the future national economy. Various natural, human, technological, innovative, and creative resources were imperative in supporting the underlining national industry development plan. Strategic innovation management refers to the entire sequence of innovation practices, including competition mechanism analysis, such as creating an innovative vision, business strategy alignment, disseminating strategy at an entire organizational level, market tendency, technology, and competitor’s action. Firm innovation performance refers to the measurement of innovation efficiency (the number of new products, product novelty, new product development speed, and new product success rate) and innovation profitability (new product revenue proportion, quality enhancement, cost reduction, and value improvement) conducted by the firm. This study investigates the effect of Innovation Strategy, Organizational Structure, Innovation Culture, Technological Capability, and Customer-Supplier Relationship (these were the practice of Strategic Innovation Management mentioned in various literature) on Firm Innovation Performance. Methods: A quantitative method, from a practical perspective, was employed to investigate the causal relationship between strategic innovation management and firm innovation performance. Data was gathered through a validated and reliable questionnaire disseminated to 90 respondents. It included a representative from the four sub-sectors of the telecommunication industry, namely fixed networks, wireless networks, telecommunication services, and special telecommunication. Results: The survey found that firms within the telecommunication industry already employed Strategic Innovation Management practices. Moreover, this study also found that Innovation Culture, Technological Capability, and Customer-Suppler Relationship significantly influence Firm Innovation Performance. Conclusion: The implementation of Strategic Innovation Management in the mid-size companies within Indonesia's telecommunication industry appears to be relatively high. It indicates that firms within the industry were able to strategically compete by implementing Strategic Innovation Management.
in F1000Research on 2023-01-09 17:33:50 UTC.
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Individuals with a diagnosis of schizophrenia face a myriad of obstacles to wellness, beginning with diagnostic discrepancies including over- and misdiagnoses on the schizophrenia spectrum. People with schizophrenia experience profound amounts of stigmatization from the general population, their healthcare providers, and even themselves. Such stigmatization creates a barrier for wellness, poorer prognoses, and often limits adherence to physical and mental healthcare. Moreover, it can exacerbate the already stifling symptomatology of their diagnoses, including specific bodily-related symptomatology. Oftentimes, a diagnosis of schizophrenia disrupts one’s relationship with their body including a diminished mind-body connection, decreased interoceptive awareness, and thus unsuccessful intra- and interpersonal relationships. Some recent research suggests the use of mind-body therapies, however, if these practices are internalizing, they may not be appropriate for people with schizophrenia experiencing more acute symptomatology excluding them from treatment. Dance/movement therapy (DMT) is an embodied psychotherapeutic treatment option that can support participants in improving mind-body connection, social relationships, and self-regulatory skill development. Research on DMT has shown promising results for people with schizophrenia, however such research is limited and would benefit from increased studies that particularly measure the effects of DMT on mind-body connection and increased interoception for people with schizophrenia. Moreover, integrative and collaborative treatment models that couple DMT and biofeedback may further our understanding of the physiological and neurological effects of DMT interventions for people with schizophrenia and beyond. This review will examine the recent literature on health inequities for people with schizophrenia, their specific body-based disruptions and needs, and DMT as a promising treatment model, particularly when coupled with biofeedback.
in F1000Research on 2023-01-09 17:31:08 UTC.
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Abstract
A central question in neuroscience is how sensory inputs are transformed into percepts. At this point, it is clear that this process is strongly influenced by prior knowledge of the sensory environment. Bayesian ideal observer models provide a useful link between data and theory that can help researchers evaluate how prior knowledge is represented and integrated with incoming sensory information. However, the statistical prior employed by a Bayesian observer cannot be measured directly, and must instead be inferred from behavioral measurements. Here, we review the general problem of inferring priors from psychophysical data, and the simple solution that follows from assuming a prior that is a Gaussian probability distribution. As our understanding of sensory processing advances, however, there is an increasing need for methods to flexibly recover the shape of Bayesian priors that are not well approximated by elementary functions. To address this issue, we describe a novel approach that applies to arbitrary prior shapes, which we parameterize using mixtures of Gaussian distributions. After incorporating a simple approximation, this method produces an analytical solution for psychophysical quantities that can be numerically optimized to recover the shapes of Bayesian priors. This approach offers advantages in flexibility, while still providing an analytical framework for many scenarios. We provide a MATLAB toolbox implementing key computations described herein.
in eNeuro on 2023-01-09 17:30:19 UTC.
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Abstract
Accurate and efficient quantification of animal behavior facilitates the understanding of the brain. An emerging approach within machine learning (ML) field is to combine multiple ML-based algorithms to quantify animal behavior. These so-called hybrid models have emerged because of limitations associated with supervised [e.g., random forest (RF)] and unsupervised [e.g., hidden Markov model (HMM)] ML models. For example, RF models lack temporal information across video frames, and HMM latent states are often difficult to interpret. We sought to develop a hybrid model, and did so in the context of a study of mouse risk assessment behavior. We used DeepLabCut to estimate the positions of mouse body parts. Positional features were calculated using DeepLabCut outputs and were used to train RF and HMM models with equal number of states, separately. The per-frame predictions from RF and HMM models were then passed to a second HMM model layer ("reHMM"). The outputs of the reHMM layer showed improved interpretability over the initial HMM output. Finally, we combined predictions from RF and HMM models with selected positional features to train a third HMM model ("reHMM+"). This reHMM+ layered hybrid model unveiled distinctive temporal and human-interpretable behavioral patterns. We applied this workflow to investigate risk assessment to trimethylthiazoline and snake feces odor, finding unique behavioral patterns to each that were separable from attractive and neutral stimuli. We conclude that this layered, hybrid ML workflow represents a balanced approach for improving the depth and reliability of ML classifiers in chemosensory and other behavioral contexts.
in eNeuro on 2023-01-09 17:30:19 UTC.
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Abstract
Huntington disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod and beam walking, less is known about forelimb deficits. We develop a high-throughput alternating reward/nonreward water-reaching task and training protocol conducted daily over approximately two months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wild-type (WT) littermate mice, starting at ~5.5 months. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as wild-type mice, take longer to learn the alternating event sequence as evident by impulsive (noncued) reaches and initially display reduced cortical activity associated with successful reaches. At this age gross motor defects determined by tapered beam assessment were not apparent. Although wild-type mice displayed no significant changes in cortical activity and reaching trajectory throughout the testing period, HD mice exhibited an increase in cortical activity, especially in the secondary motor and retrosplenial cortices, over time, as well as longer and more variable reaching trajectories by approximately seven months. HD mice also experienced a progressive reduction in successful performance. Tapered beam and rotarod tests as well as reduced DARPP-32 expression (striatal medium spiny neuron marker) after water-reaching assessment confirmed HD pathology. The water-reaching task can be used to inform on a daily basis, HD and other movement disorder onset and manifestation, therapeutic intervention windows, and test drug efficacy.
in eNeuro on 2023-01-09 17:30:19 UTC.
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Background and Aim: The Kacang goat (Capra hircus) is an indigenous livestock species in Indonesia that is at risk of extinction due to cross-breeding. Artificial insemination (AI) techniques are expected to increase the population of these goats. This study aimed to determine the addition of epigallocatechin-3-gallate chitosan nanoparticles (EGCG CNPs) to skim milk–egg yolk (SM–EY) extender to obtain the best possible quality of post-thawed Kacang buck semen for AI. Materials and Methods: Fresh Kacang buck semen was diluted in SM–EY without or with the addition of 0.5, 1.0, 1.5, or 2.0 µg of EGCG CNPs/mL extender. Extended semen was packaged in French mini straws, frooze, and stored in liquid nitrogen at −196℃ for 24 hours. Six replicates from each treatment group were thawed for catalase, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, malondialdehyde (MDA), sperm intact plasma membrane (IPM), viability and motility analyses. Results: Post-thawed semen that was previously frozen without EGCG CNPs in the extender (control group) exhibited the lowest levels of catalase, DPPH, sperm viability, sperm motility, IPM, and the highest levels of MDA. However, the addition of EGCG CNPs at doses of 1.5 µg/mL extender increased post-thawed catalase, DPPH, sperm IPM, viability, and sperm motility and decreased MDA levels (p < 0.05) than those of control group. Conclusion: This study was the first in which EGCG CNPs were used in SM–EY extender, and the addition of only 1.0 µg/mL of EGCG CNPs in this extender increased the antioxidant capacity and post-thawed quality of Kacang buck semen.
in F1000Research on 2023-01-09 17:28:26 UTC.
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Background The coronavirus disease 2019 (COVID-19) pandemic has caused uncertainty in many economic sectors. An entrepreneurial leadership style can become an alternative method of leadership for facing uncertainty. Methods This study uses secondary data from the Scopus website as samples. The samples are papers from Indonesia, China, and the USA. Data were collected through the Scopus website, using keywords entrepreneurial and leadership, saved into a CSV file, and processed using VOSviewer. The findings were analyzed using a systematic search. Results Entrepreneurial leadership as a topic was more prevalent in China than Indonesia and the USA. There were 101 papers from Chinese authors, 28 from Indonesian authors, and 575 from USA authors. However, there was no topic of entrepreneurial leadership connected to the strings of the topic of COVID-19. This study also found that inclusive leadership was used in China and local government leadership was used by the USA government to anticipate the impact of COVID-19. Conclusions Entrepreneurial leadership was not used for COVID-19 pandemic management in USA, China, and Indonesia as a research trend.
in F1000Research on 2023-01-09 17:06:07 UTC.
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Background: The research focused on evaluating the biological and reproductive parameters of the species Spodoptera sunia with the introduction of field genetic material, in the Noctuid Insect Breeding Laboratory. Methods: The study was pre-experimental using three treatments with 30 individuals and three repetitions. The individuals were collected from the field, transferred to the laboratory under semi-controlled conditions of temperature and humidity, later they were quarantined for up to three generations for the assembly of the test where the crossing was carried out. In the measurement of the biological and reproductive parameters. Results: The results of the treatments showed that the biological and reproductive parameters in relation to the number of pupae were T2 34 males and 26 females, T3 was 33 males, and 27 females, T1 obtained 27 males and 33 females. The average weight in female T1 was 0.2112 mg and T2 was 0.2401 mg. The number of eggs in T1 in nine days oviposited 196 egg masses, in T2 in seven days 59 egg masses were oviposited, and in T3 160 egg masses were oviposited. In the length parameter in mm T3 obtained 30 mm in larval development, T1 and T2 obtained 27 mm. Finally, in the development stages, the number of days was for T1 and T2, 24 days and for T3 18 days. In the adult stages T1 and T2 it was 12 days and for T3 10 days. In the egg stage in the three treatments it was three days and the pupal stage was eight days. Conclusions: It is concluded that T2 and T3 presented the most optimal results. It is recommended to introduce genetic material every six months to maintain a good production of larvae of the species under study in laboratories for the production and reproduction of insect breeding.
in F1000Research on 2023-01-09 17:03:15 UTC.
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Background and aims: Natural compounds extracted from medicinal plants have recently gained attention in therapeutics as they are considered to have lower toxicity and higher tolerability relative to chemically synthesized compounds. Bakuchiol is one such compound; it is a type of meroterpene derived from the leaves and seeds of Psoralea corylifolia plants. Natural sources of bakuchiol have been used in traditional Chinese and Indian medicine for centuries due to its preventive benefits against tumors and inflammation. It plays a strong potential role as an antioxidant with impressive abilities to remove Reactive Oxygen Species (ROS). This review has focused on bakuchiol's extraction, therapeutic applications, and pharmacological benefits. Methods: A search strategy has been followed to retrieve the relevant newly published literature on the pharmacological benefits of bakuchiol. After an extensive study of the retrieved articles and maintaining the inclusion and exclusion criteria, 106 articles were finally selected for this review. Results: Strong support of primary research on the protective effects via antitumorigenic, anti-inflammatory, antioxidative, antimicrobial, and antiviral activities are delineated. Conclusions: From ancient to modern life, medicinal plants have always been drawing the attention of human beings to alleviate ailments for a healthy and balanced lifestyle. This review is a comprehensive approach to highlighting bona fide essential pharmacological benefits and mechanism of action of therapeutic implications.
in F1000Research on 2023-01-09 16:58:01 UTC.
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DNA samples are often used to identify fish before they are utilised in other experiments. Our recent research has shown that skin swabbing can be used to collect DNA for genotyping, and that swabbing causes less harm to fish than fin clipping, another common technique. In this study we investigated potential refinements to the skin swabbing protocol by pre-treating fish with the analgesic lidocaine. We could not detect any differences in cortisol release, behaviour or expression of stress axis marker genes in skin swabbed sticklebacks or zebrafish regardless of lidocaine application. In contrast, fin clipping caused changes in cortisol release, gene expression and behaviour when analgesia was not used. These changes were rescued by pre-treatment with lidocaine confirming that analgesia was effective. The results demonstrates that skin swabbing is a refined technique for DNA collection that does not require analgesia.
in F1000Research on 2023-01-09 16:30:10 UTC.
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Background: The majority of Indonesians believe and act as if the only people who can learn and be taught Arabic are Muslims. This fact goes against the basic idea that language is a way to communicate. So, the goal of this study is to find out what opportunities and plans there are for non-Muslims in Indonesia to learn Arabic. The goal of this study is to get language back to its basic function of being a way to communicate. It can also be the basis for putting Wasathiyah Islam into practise in Indonesia. Methods: This study was carried out in accordance with the official guidelines for research ethics established by the Ministry of Higher Education Research in the Republic of Indonesia. Between June 11 and August 30, 2022, the research was done. The research was carried out with two approaches, namely quantitative first and followed by qualitative. After collecting and analysing data for a study, researchers submit their findings to reviewers appointed by Indonesia's Ministry of Research and Technology. Results: A total of 64 participants were surveyed, and based on their responses, the following was determined; Researchers conduct interviews directly with informants who are considered to have the ability to provide information related to research themes. Therefore, researchers conducted interviews with 24. First, non-Muslims in Indonesia should study Arabic since language is a communication instrument. This includes religion, ethnicity, and race not limiting language acquisition. Second, teaching non-Muslims Arabic in Indonesia will help to implement Wasathiyah Islam there. Non-Indonesian Muslims who know Arabic will be more tolerant. Third, because Arabic is a communication tool, there is no big challenge for non-Muslims to learn Arabic. Conclusion: However, in terms of obstacles, of course, there are many big obstacles, namely the unsupportive Arabic learning.
in F1000Research on 2023-01-09 16:28:15 UTC.
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Background: Glutamate signaling in the brain is regulated by release, reuptake, and receptor responsiveness. In diseased conditions, glutamate signaling can exceed normal regulatory processes, giving rise to a condition called excitotoxicity. Although regional differences in the excitotoxic effects of glutamate in the brain have been reported, the extent and characteristics of these potential differences are not clear. Here we compared the excitotoxic resiliency of the suprachiasmatic nucleus (SCN), anterior hypothalamus (AH) and cortex. Methods: We treated acute brain slices containing either the SCN and AH or the cortex from adult male mice at different times across the diurnal cycle with varying concentrations of N-methyl-D-aspartate (NMDA), NMDA+ α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or control medium. The extent of cell damage was assessed using propidium iodide (PI), a cell death marker. Results: The results indicate that all three brain regions exhibited increasing cell damage/death when treated with increasing concentrations of NMDA. However, higher concentrations of NMDA were needed to significantly increase cell damage in the SCN compared to the cortex and AH. All three brain regions also exhibited greater cell death/damage when treated in the nighttime compared to the daytime, although the SCN exhibited increased cell death during a more restricted time interval compared to the AH and cortex. Conclusions: Together, these data confirm previous studies showing excitotoxic resiliency in the SCN, while extending them in two ways. First, we demonstrate a dose-dependency in excitotoxic susceptibility that differentiates the SCN from the surrounding AH and the cortex using a brain slice preparation. Second, we demonstrate a diurnal rhythm in excitotoxic susceptibility with a broadly similar phase across all three brain regions. These data increase our understanding of the extent and nature of the SCN excitotoxic resiliency, which will inform future studies on the cellular mechanisms underlying this phenomenon.
in F1000Research on 2023-01-09 16:16:15 UTC.
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Background: Rhizocephalan barnacles stand out in the diverse world of metazoan parasites. The body of a rhizocephalan female is modified beyond revealing any recognizable morphological features, consisting of the interna, a system of rootlets, and the externa, a sac-like reproductive body. Moreover, rhizocephalans have an outstanding ability to control their hosts, literally turning them into “zombies”. Despite all these amazing traits, there are no genomic or transcriptomic data about any Rhizocephala. Methods: We collected transcriptomes from four body parts of an adult female rhizocephalan Peltogaster reticulata: the externa, and the main, growing, and thoracic parts of the interna. We used all prepared data for the de novo assembly of the reference transcriptome. Next, a set of encoded proteins was determined, the expression levels of protein-coding genes in different parts of the parasite’s body were calculated and lists of enriched bioprocesses were identified. We also in silico identified and analyzed sets of potential excretory / secretory proteins. Finally, we applied phylostratigraphy and evolutionary transcriptomics approaches to our data. Results: The assembled reference transcriptome included transcripts of 12,620 protein-coding genes and was the first for any rhizocephalan. Based on the results obtained, the spatial heterogeneity of protein-coding gene expression in different regions of the adult female body of P. reticulata was established. The results of both transcriptomic analysis and histological studies indicated the presence of germ-like cells in the lumen of the interna. The potential molecular basis of the interaction between the nervous system of the host and the parasite's interna was also determined. Given the prolonged expression of development-associated genes, we suggest that rhizocephalans “got stuck in their metamorphosis”, even at the reproductive stage. Conclusions: The results of the first comparative transcriptomic analysis for Rhizocephala not only clarified but also expanded the existing ideas about the biology of these extraordinary parasites.
in F1000Research on 2023-01-09 16:10:36 UTC.
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Background: The datafication scenario of the current communicative ecosystem poses a challenge to media and digital literacy, especially in terms of participation and civic and democratic engagement of youth. Methods: For this purpose, through a survey with a representative sample of 600 young people in Spain, between 16 and 18 years old, we observed their level of digital literacy through three variables: technical competencies, informational competencies, and critical knowledge. This dataset also collects information on the reasons why young people use digital technology such as video games, consoles, computers or mobile phones. On the other hand, we also offer information on the types of social networks or applications and the time and types of uses by youngsters of different digital technologies and social media platforms. The survey includes socio-demographic factors such as gender including (male, female, and others). Conclusions: This survey offers researchers relevant data on the digital skills of Spanish youth and on the perceptions of the use of different digital technologies. This paper also reports the main descriptive data that can be expanded by researchers accessing the database.
in F1000Research on 2023-01-09 16:08:10 UTC.
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Abortion is defined as the termination of pregnancy which is a crucial issue to be addressed by multiple regulating systems such as health care providers and policy makers. The main aim of the study was to assess the attitudes of medical students in Imam Abdulrahman bin Faisal university towards abortion in different circumstances. This is a descriptive cross-sectional study in which a 20-items online questionnaire was distributed through social media platforms to medical students. The results of the study showed that the majority of the students believe abortion should be determined by law, religion and spousal consent. The majority as well support abortion in cases of endangered mother’s life, fetal life compromise and rape victims. However, they were against abortion in cases of financial incapacity of the parents and cases of unplanned pregnancy. The results of the study can be applied to improve medical education of abortion. More studies in this field of research are recommended for the purpose of providing more inclusive assessment of abortion attitudes in different medical education settings.
in F1000Research on 2023-01-09 16:08:09 UTC.
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Background: Stem cell therapy shows applications potential for malnutrition-induced ovarian failure in rat models. However, it is ineffective because of the lack of viability and differentiation of transplanted stem cells, resulting in low adaptation and survival rates. We aimed to determine whether stem cells cultured under low oxygen (O2) tension improves the adaptability and viability of stem cells, as well as ovarian failure. Methods: After four days of culturing mesenchymal stem cells (MSCs) in 21% oxygen (normoxia) as the T2 group and 1% oxygen (low O2 or hypoxia) as the T1 group, 200 million bone marrow-derived MSCs per rat were transplanted into female rats with ovarian failure (15 rats per treatment group). A total of 15 fertile and 15 infertile rats were categorized as the C+ and C− groups, respectively. Results: The slight increase in cells expressing HSP70 (C+, T2, T1, and C− groups were 0.5a±0.53, 1.7a±0.82, 6.2b±1.5, and 9.6c±1.3, respectively), decrease in cells expressing caspase-3 as an apoptotic inhibitor (C+, T2, T1, and C− groups were 0.2a±0.42, 0.6a±0.52, 4.8b±1.03, and 7.3c±1.42, respectively), and increase in cells expressing VEGF-1 (C+, T2, T1, and C− groups were 10.8c±1.55, 8.7b±0.48, 0.4a±0.52, and 0.2a±0.42, respectively) and GDF-9 (C+, T2, T1, and C− groups were 5.8c±1.47, 4.6b±0.97, 0.5a±0.53, and 0.3a±0.48, respectively) were used as markers for viability and differentiation in ovarian tissue, indicating that MSCs cultured under low O2 tension were more effective than those cultured under normoxic conditions as a treatment for female rats with ovarian failure. Furthermore, infertile female rats treated with MSCs cultivated under low O2 tension had an enhanced ovarian tissue shape, as indicated by the increasing Graafian follicle count (C+, T2, T1, and C− groups were 8.9c±0.74, 4.5b±0.71, 0.5a±0.53, and 0.4a±0.52, respectively). Conclusions: MSCs cultured under low O2 tension are an effective treatment for malnourished rats with ovarian failure.
in F1000Research on 2023-01-09 16:00:37 UTC.
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Background: The number of children with complex medical conditions has increased in recent decades. In this context, a complex chronic condition is characterized by multiple morbidities that require intensive or continuous health care according to the level of severity. Given their various health conditions, it is challenging to provide special education to these children, but there is still insufficient evidence regarding the practical experiences of educators. The aim of this study was to investigate special education teacher’s perceptions, experiences, and challenges while developing interpersonal relationships and communicating with children who have complex chronic conditions. Methods: We recruited and interviewed 21 special education school teachers. The transcripts of the interviews were analyzed using thematic analysis. Results: Our analysis revealed four themes, including “searching for the meaning,” “complex chronic conditions as a difficult reality,” “widening experience for the future,” and “priority for interacting with children.” These themes reflect the perceptions, experiences, and challenges of the special education teachers. Conclusions: In cases where children have severe functional limitations, it is more challenging to understand child-teacher interactions. This highlights the importance of searching for meaning in educational practices used among children with complex chronic conditions. Our findings may provide helpful insight into the experiences and challenges faced by special educators who engage with these children.
in F1000Research on 2023-01-09 15:02:19 UTC.
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Background: Gastritis is an inflammation of the stomach lining often caused by Helicobacter pylori infection. Among three H. pylori genes coding for hemolytic toxins, the clinical outcome of hp0499 and hp1490 is unclear. We conducted molecular and histological analyses to evaluate the correlation between these genes and gastritis severity. Methods: We analyzed the hp0499 and hp1490 variants of 116 Indonesian samples using next generation sequencing and validated them using polymerase chain reaction (PCR). The updated Sydney system was used to grade gastritis through histological analyses. We then calculated the influence of hp0499 and hp1490 on the gastritis severity, using multivariate analysis and cagA and vacA as major H. pylori virulence factors. Results: Two variants of each gene were identified and named hp0499-1 and -2, and hp1490-1 and -2. We noted that hp0499 expression was significantly correlated with corporal atrophy (p = 0.037). H. pylori hp1490 significantly correlated with antral acute and chronic inflammation as well as corporal density (p = 0.025, p = 0.07, p = 0.010, respectively). After adjusting for age and sex, we found that vacA s1m1 was an independent risk factor for acute antral inflammation (p = 0.032). hp1490 and vacA s1m1 were independent risk factors for chronic antral inflammation (p = 0.030 and p = 0.031, respectively). Conclusions: We identified the variants hp0499-1 and -2 and hp1490-1 and -2 and demonstrated that hp0499 plays a significant role in the severity of corporal atrophy. Moreover, hp1490 was characterized as an independent risk factor for chronic inflammation in the antral region. Therefore, hp0499 and hp1490 are new potential targets for therapeutics.
in F1000Research on 2023-01-09 14:44:11 UTC.
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by Saskia Hiltemann, Helena Rasche, Simon Gladman, Hans-Rudolf Hotz, Delphine Larivière, Daniel Blankenberg, Pratik D. Jagtap, Thomas Wollmann, Anthony Bretaudeau, Nadia Goué, Timothy J. Griffin, Coline Royaux, Yvan Le Bras, Subina Mehta, Anna Syme, Frederik Coppens, Bert Droesbeke, Nicola Soranzo, Wendi Bacon, Fotis Psomopoulos, Cristóbal Gallardo-Alba, John Davis, Melanie Christine Föll, Matthias Fahrner, Maria A. Doyle, Beatriz Serrano-Solano, Anne Claire Fouilloux, Peter van Heusden, Wolfgang Maier, Dave Clements, Florian Heyl, Galaxy Training Network , Björn Grüning, Bérénice Batut
There is an ongoing explosion of scientific datasets being generated, brought on by recent technological advances in many areas of the natural sciences. As a result, the life sciences have become increasingly computational in nature, and bioinformatics has taken on a central role in research studies. However, basic computational skills, data analysis, and stewardship are still rarely taught in life science educational programs, resulting in a skills gap in many of the researchers tasked with analysing these big datasets. In order to address this skills gap and empower researchers to perform their own data analyses, the Galaxy Training Network (GTN) has previously developed the Galaxy Training Platform (https://training.galaxyproject.org), an open access, community-driven framework for the collection of FAIR (Findable, Accessible, Interoperable, Reusable) training materials for data analysis utilizing the user-friendly Galaxy framework as its primary data analysis platform. Since its inception, this training platform has thrived, with the number of tutorials and contributors growing rapidly, and the range of topics extending beyond life sciences to include topics such as climatology, cheminformatics, and machine learning. While initially aimed at supporting researchers directly, the GTN framework has proven to be an invaluable resource for educators as well. We have focused our efforts in recent years on adding increased support for this growing community of instructors. New features have been added to facilitate the use of the materials in a classroom setting, simplifying the contribution flow for new materials, and have added a set of train-the-trainer lessons. Here, we present the latest developments in the GTN project, aimed at facilitating the use of the Galaxy Training materials by educators, and its usage in different learning environments.
in PLoS Computational Biology on 2023-01-09 14:00:00 UTC.
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Background: Delivery of safe and reliable healthcare to patients and the healthcare workforce shortage amidst growing demand has been major challenge to the healthcare system. Addressing this challenge calls for designing or redesigning of healthcare work system. Work system design which is usually associated with productivity in manufacturing offers a wide spectrum of applicability in addressing this challenge of healthcare system. Despite the availability of primary studies on work system design in healthcare, there are sparse published reviews in specific contexts. This scoping review explores the existing evidence to understand the state of the art of work system design in healthcare. Methods: The scoping review adopts the methodology of Joanna Briggs Institute for scoping review which is based on the methodological framework of Arksey and O’Malley. The search will be done on PubMed, Scopus, and Web of Science for the identification of eligible studies. A grey literature search will also be performed. A two-phase screening and extraction of data will be done by two independent reviewers. Data extraction will be done on a pre-piloted data extraction form. The findings will be presented in tables, figures, and a narrative summary. The scoping review will highlight the state of the art, gaps in knowledge and provide directions for future research. Ethics and dissemination: This is a scoping review of primary studies and therefore ethical approval is not required. The report of the findings will be presented in line with the PRISMA reporting guidelines for scoping reviews (PRISMA-ScR). The results will be submitted to a peer-reviewed scientific journal for publication and presented at relevant conferences.
in F1000Research on 2023-01-09 09:39:30 UTC.
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hPSC-derived migratory cINs show lasting efficacy to treat seizures and comorbid behavioral deficits, as well as safety without uncontrolled growth. Host inhibition did not increase with increasing grafted cIN densities, and their closed-loop optogenetic activation aborted seizure activity. Monosynaptic tracing showed their extensive and specific synaptic connections with host neurons.
in Neuron: In press on 2023-01-09 00:00:00 UTC.
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Wolff et al. provide an overview of the impact of chronological age on mRNA circadian rhythms in multiple tissues from male mice. Across the organs, there are age-related declines in the number of genes exhibiting circadian expression patterns.
in Cell Reports: Current Issue on 2023-01-09 00:00:00 UTC.
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Tan et al. show that SGS3 undergoes liquid-liquid phase separation that drives RDR6, RNAs, RNA-binding proteins, and other siRNA processing components to form siRNA bodies in cytoplasm. The formation of SGS3/RDR6-containing condensates is necessary and sufficient for siRNA-mediated gene silencing, which is regulated by translation, mRNA decay, and DCL2/4 function.
in Cell Reports: Current Issue on 2023-01-09 00:00:00 UTC.
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Meyers et al. uncover a non-canonical role of mitochondrial pyruvate dehydrogenase kinase (PDHK) in promoting mitochondrial stress and activating the NLRP3 inflammasome during acute inflammation. Pharmacological inhibition or genetic ablation of PDHK significantly improves mitochondrial fitness and attenuates NLRP3 inflammasome activation in murine or human macrophages and septic mice.
in Cell Reports: Current Issue on 2023-01-09 00:00:00 UTC.
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Tauzin et al. report that while the third dose of mRNA vaccine induces poor humoral responses against new Omicron subvariants in naïve people, better responses are observed in individuals with hybrid immunity. They also observe that BA.4/5 and BQ.1.1 are less recognized and neutralized than other Omicron subvariants.
in Cell Reports: In press on 2023-01-09 00:00:00 UTC.
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Meyer et al identify peptide sequences from SARS-CoV-2 that are commonly recognized by CD8 T cells in convalescents. They demonstrate that these sequences are conserved in variants of concern (VOC). Thus, emergence of VOC is not driven by escape from T-cell immunity.
in Cell Reports: In press on 2023-01-09 00:00:00 UTC.
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Chondrosarcomas are primary cancers of cartilaginous tissue and capable of alteration to highly aggressive, metastatic, and treatment-refractory states, leading to a poor prognosis with a five-year survival rate at 11 months for dedifferentiated subtype. At present, the surgical resection of chondrosarcoma is the only effective treatment, and no other treatment options including targeted therapies, conventional chemotherapies, or immunotherapies are available for these patients. Here, we identify a signal pathway way involving EZH2/SULF1/cMET axis that contributes to malignancy of chondrosarcoma and provides a potential therapeutic option for the disease. A non-biased chromatin immunoprecipitation sequence, cDNA microarray analysis, and validation of chondrosarcoma cell lines identified sulfatase 1 (SULF1) as the top EZH2-targeted gene to regulate chondrosarcoma progression. Overexpressed EZH2 resulted in downregulation of SULF1 in chondrosarcoma cell lines, which in turn activated cMET pathway. Pharmaceutical inhibition of cMET or genetically silenced cMET pathway significantly retards the chondrosarcoma growth and extends mice survival. The regulation of EZH2/SULF1/cMET axis were further validated in patient samples with chondrosarcoma. The results not only established a signal pathway promoting malignancy of chondrosarcoma but also provided a therapeutic potential for further development of effective target therapy to treat chondrosarcoma.
in eLife on 2023-01-09 00:00:00 UTC.
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Respiratory complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from NADH oxidation by ubiquinone to drive protons across an energy-transducing membrane. Drosophila melanogaster is a candidate model organism for complex I due to its high evolutionary conservation with the mammalian enzyme, well-developed genetic toolkit, and complex physiology for studies in specific cell types and tissues. Here, we isolate complex I from Drosophila and determine its structure, revealing a 43-subunit assembly with high structural homology to its 45-subunit mammalian counterpart, including a hitherto unknown homologue to subunit NDUFA3. The major conformational state of the Drosophila enzyme is the mammalian-type 'ready-to-go' active resting state, with a fully ordered and enclosed ubiquinone-binding site, but a subtly altered global conformation related to changes in subunit ND6. The mammalian-type 'deactive' pronounced resting state is not observed: in two minor states the ubiquinone-binding site is unchanged, but a deactive-type p-bulge is present in ND6-TMH3. Our detailed structural knowledge of Drosophila complex I provides a foundation for new approaches to disentangle mechanisms of complex I catalysis and regulation in bioenergetics and physiology.
in eLife on 2023-01-09 00:00:00 UTC.
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Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in E. coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block occurred while sister replisomes were still in a factory configuration - blocking one fork had no significant effect on the other replisome when sister replisomes were physically separate. Disruption of factory replication also led to increased fork stalling and requirement of fork restart mechanisms. These results suggest that physical association between sister replisomes is important for establishing an efficient and uninterrupted replication program. We discuss the implications of our findings on mechanisms of replication factory structure and function, and cellular strategies of replicating problematic DNA such as highly transcribed segments.
in eLife on 2023-01-09 00:00:00 UTC.
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Background: WHO has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct acting antiviral (DAA) therapy for Hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome.
in eLife on 2023-01-09 00:00:00 UTC.
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The hippocampus is thought to enable the encoding and retrieval of ongoing experience, the organization of that experience into structured representations like contexts, maps, and schemas, and the use of these structures to plan for the future. A central goal is to understand what the core computations supporting these functions are, and how these computations are realized in the collective action of single neurons. A potential access point into this issue is provided by ‘splitter cells’, hippocampal neurons that fire differentially on the overlapping segment of trajectories that differ in their past and/or future. However, the literature on splitter cells has been fragmented and confusing, owing to differences in terminology, behavioral tasks, and analysis methods across studies. In this review, we synthesize consistent findings from this literature, establish a common set of terms, and translate between single-cell and ensemble perspectives. Most importantly, we examine the combined findings through the lens of two major theoretical ideas about hippocampal function: representation of temporal context and latent state inference. We find that unique signature properties of each of these models are necessary to account for the data, but neither theory, by itself, explains all of its features. Specifically, the temporal gradedness of the splitter signal is strong support for temporal context, but is hard to explain using state models, while its flexibility and task-dependence is naturally accounted for using state inference, but poses a challenge otherwise. These theories suggest a number of avenues for future work, and we believe their application to splitter cells is a timely and informative domain for testing and refining theoretical ideas about hippocampal function.
in eLife on 2023-01-09 00:00:00 UTC.
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Optical report of neurotransmitter release allows visualization of excitatory synaptic transmission. Sensitive genetically-encoded glutamate reporters operating with a range of affinities and emission wavelengths are available. However, without targeting to synapses, the specificity of the fluorescent signal is uncertain, compared to sensors directed at vesicles or other synaptic markers. We fused the state-of-the-art reporter iGluSnFR to glutamate receptor auxiliary proteins in order to target it to postsynaptic sites. Chimeras of Stargazin and gamma-8 that we named SnFR-γ2 and SnFR-γ8, were enriched at synapses, retained function and reported spontaneous glutamate release in rat hippocampal cells, with apparently diffraction-limited spatial precision. In autaptic mouse neurons cultured on astrocytic micro islands, evoked neurotransmitter release could be quantitatively detected at tens of synapses in a field of view whilst evoked currents were recorded simultaneously. These experiments revealed a specific postsynaptic deficit from Stargazin overexpression, resulting in synapses with normal neurotransmitter release but without postsynaptic responses. This defect was reverted by delaying overexpression. By working at different calcium concentrations, we determined that SnFR-γ2 is a linear reporter of the global quantal parameters and short-term synaptic plasticity, whereas iGluSnFR is not. On average, half of iGluSnFR regions of interest showing evoked fluorescence changes had intense rundown, whereas less than 5% of SnFR-γ2 ROIs did. We provide an open-source analysis suite for extracting quantal parameters including release probability from fluorescence time series of individual and grouped synaptic responses. Taken together, postsynaptic targeting improves several properties of iGluSnFR and further demonstrates the importance of subcellular targeting for optogenetic actuators and reporters.
in eLife on 2023-01-09 00:00:00 UTC.
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Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss. Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.
in eLife on 2023-01-09 00:00:00 UTC.
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Focal Cortical Dysplasias (FCDs) are a common subtype of malformation of cortical development, which frequently present with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. FCD type II is typically caused by somatic mutations resulting in mTOR hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe FCD. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established FCD model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human RHEB plasmid, an activator of mTOR Complex 1. First, we further characterised this by quantifying electrocorticograms and behavioural abnormalities, both in mice developing spontaneous generalised seizures and in mice only exhibiting abnormal interictal discharges. Then, using continuous video-electrocorticogram recordings from epileptic mice before and after injection of AAV9-CAMK2A-EKC in the dysplastic region, we observed a robust decrease in the frequency of seizures and in interictal activity, compared to mice injected with a control viral vector. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal activity or behaviour in non-epileptic mice. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons and they co-express the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single nuclear RNA sequencing (FANS-snRNAseq). Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb co-express markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder (MDD), which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein Netrin-G2 as a marker of LHb GAD2+/VGLUT+ neurons and a gene product that may contribute to their target projections. These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Background: The Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. Methods: We isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. Results: We determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. Conclusions: Our findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Cre/LoxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. The field of microglial biology has particularly benefited from this technology as microglia have historically been difficult to transduce with virus or electroporation methods for gene delivery. Here, we interrogate four of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency and spontaneous recombination, depending on the Cre line and loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency in microglia, which could be extended to other cell types. There is increasing evidence that microglia are key regulators of neural circuit structure and function. Microglia are also major drivers of a broad range of neurological diseases. Thus, reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field of microglial biology and the development of microglia-based therapeutics.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Human neuroimaging studies have shown that the contents of episodic memories are represented in distributed patterns of neural activity. However, these studies have mostly been limited to decoding simple, unidimensional properties of stimuli. Semantic encoding models, in contrast, offer a means for characterizing the rich, multidimensional information that comprises episodic memories. Here, we extensively sampled four human fMRI subjects to build semantic encoding models and then applied these models to reconstruct content from natural scene images as they were viewed and recalled from memory. First, we found that multidimensional semantic information was successfully reconstructed from activity patterns across visual and lateral parietal cortices, both when viewing scenes and when recalling them from memory. Second, whereas visual cortical reconstructions were much more accurate when images were viewed versus recalled from memory, lateral parietal reconstructions were comparably accurate across visual perception and memory. Third, by applying natural language processing methods to verbal recall data, we showed that fMRI-based reconstructions reliably matched subjects' verbal descriptions of their memories. In fact, reconstructions from ventral temporal cortex more closely matched subjects' own verbal recall than other subjects' verbal recall of the same images. Fourth, encoding models reliably transferred across subjects: memories were successfully reconstructed using encoding models trained on data from entirely independent subjects. Together, these findings provide evidence for successful reconstructions of multidimensional and idiosyncratic memory representations and highlight the differential sensitivity of visual cortical and lateral parietal regions to information derived from the external visual environment versus internally-generated memories.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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There is renewed interest in electrical activity that extends beyond the typical electrophysiological 100 Hz bandwidth. This activity, often in the anterior temporal lobe, has been attributed to processes ranging from memory consolidation to epileptiform activity. Here, using an open-access resting state magnetoencephalography (MEG) dataset (n = 89), and a second task-based MEG dataset, we could reliably localise high-frequency power to the temporal lobes across multiple bands up to 300-400 Hz. A functional connectivity analysis of this activity revealed a robust resting state bilateral network between the temporal lobes. However, we also found robust coherence in the 100-200 and 200-300 Hz bands between source reconstructed MEG data and the electrooculography (EOG) localised to within the temporal poles. Additional denoising schemes applied to the data could reduce power localisation to the temporal poles but the topography of the functional network did not drastically alter. Whilst it is clear that this network is biological and robust to established denoising methods, we cannot definitively rule yet on whether this is of neural or myogenic origin.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Although the pathophysiology of pain has been investigated tremendously, there are still many open questions, especially with regard to specific pain entities and their pain-related symptoms. To increase the translational impact of (preclinical) animal pain neuroimaging studies, the use of disease-specific pain models, as well as relevant stimulus modalities, are critical. Yet, the challenges of identifying neuroimaging signatures at a pain entity- and modality-specific level are manifold. Therefore, we developed a comprehensive framework for brain network analysis in disease-specific pain models combining functional MRI with graph-theory and data classification by linear discriminant analysis. This enabled us to expand our knowledge of stimulus (mechanical vs. electrical) modality processing under incisional (INC) and pathogen-induced inflammatory (CFA) pain entities compared to acute pain conditions. In short, graph-theoretical analyses revealed distinct Network Signatures of Pain Hypersensitivity (NSPH) for INC and CFA, resulting in impaired discrimination of stimulus modalities in both pain models compared to control conditions (CTR). Such specific neuroimaging signatures are an important step toward identifying novel pain biomarkers for certain diseases and relevant outcomes to evaluate target engagement of novel therapeutic options, which ultimately can be translated to the clinic.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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The task of directional hearing faces most of the animals that possess ears. They approach this task in different ways, but the common trait is the usage of the binaural cues to find the direction to the source of sound. In insects, the task is further complicated by their small size and, hence, minute temporal and level differences between two ears. A way to overcome this problem is to receive the particle velocity component of sound rather than the pressure, as the former naturally involves directionality. However, even in this case, one ear is not enough for directional hearing: a single symmetric flagellar particle velocity receiver cannot discriminate between the two opposite directions along the vector of the sound wave. Insects that use flagellar auditory organs, and mosquitoes in particular, possess a pair of receivers, which presumes the usage of binaural hearing. Its mechanisms are expected to be significantly different from the ones typical for the pressure receivers. However, the directionality of flagellar auditory organs has received little attention. Here we measured the in-flight orientation of a female mosquito antennae and obtained detailed physiological mapping of the Johnston's organ directionality at the level of individual sensory units. By combining these data, we provided a three-dimensional model of the mosquito's auditory space. The natural orientation of the antennae together with angular distribution of sensory units in each of the Johnston's organs was found to be optimal for binaural hearing focused primarily in front of, above and below a flying mosquito.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Reactively canceling movements is a vital feature of the motor system to ensure safety. This behavior can be studied in the laboratory using the stop signal task. There remains ambiguity about whether a point-of-no-return exists, after which a response cannot be aborted. A separate question concerns whether motor system inhibition associated with attempted stopping persists when stopping is unsuccessful. We address these two questions using electromyography (EMG) in two stop signal task experiments. Experiment 1 (n = 24) involved simple right and left index finger responses in separate task blocks. Experiment 2 (n = 28) involved a response choice between the right index and pinky fingers. To evaluate the approximate point-of-no-return, we measured EMG in responding fingers during the 100 ms preceding the stop signal and observed significantly greater EMG amplitudes during failed than successful stop trials in both experiments. Thus, EMG differentiated failed from successful stopping prior to the stop signal, regardless of whether there was a response choice. To address whether motor inhibition persists after failed stopping, we assessed EMG peak-to-offset durations and slopes (i.e., the rate of EMG decline) for go, failed stop, and successful stop (partial response EMG) trials. EMG peak-to-offset was shorter and steeper in failed stop trials compared to go and successful stop partial response EMG trials, suggesting motor inhibition persists even when failing to stop. These findings indicate EMG is sensitive to a point at which participants can no longer successfully stop an ongoing movement and suggest the peak-to-offset time of response-related EMG activity during failed stopping reflects stopping-related inhibition.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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The inhibitory neuron population of the cortex can be subdivided into multiple cell classes with highly specialized local circuitry, gene expression, and response properties. PV and SOM neurons are two nonoverlapping cell classes with distinct but interacting functional roles, that depend on brain state. Here, we have applied a simple approach to identify PV, SOM, and putative pyramidal (Pyr) neurons within the same mice. We imaged their spike-related calcium activity in the posterior parietal cortex (PPC) while mice voluntarily ran on a spherical treadmill. We then related the activity of the simultaneously imaged neurons to each other, revealing that the activity of all inhibitory neurons was positively correlated compared to the activity within the Pyr population, and correlations were strongest among neurons of the same type. Furthermore, these activity relationships decayed with distance when comparing Pyr and inhibitory neurons, but not PV and SOM neurons. Finally, we identified coordinated activity events that were mostly restricted to either the PV or the SOM population, and used dimensionality reduction tools to reveal that these PV and SOM events were associated with different activity states in the Pyr population. This methodology will be useful to study population-level interactions across cell types in cortical circuits, and how they depend on behavioral state and task engagement.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin's pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory formation are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 by extracellular perineuronal nets which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Quantifying neural activity in natural conditions (i.e. conditions comparable to the standard clinical patient experience) during the administration of psychedelics may further our scientific understanding of the effects and mechanisms of action. This data may facilitate the discovery of novel biomarkers enabling more personalized treatments and improved patient outcomes. In this single-blind, placebo-controlled study with a non-randomized design, we use time-domain functional near-infrared spectroscopy (TD-fNIRS) to measure acute brain dynamics after intramuscular subanesthetic ketamine (0.75 mg/kg) and placebo (saline) administration in healthy participants (n = 15, 8 females, 7 males, age 32.4 +/- 7.5 years) in a clinical setting. We found that the ketamine administration caused an altered state of consciousness and changes in systemic physiology (e.g. increase in pulse rate and electrodermal activity). Furthermore, ketamine led to a brain-wide reduction in the fractional amplitude of low frequency fluctuations (fALFF), and a decrease in the global brain connectivity of the prefrontal region. Lastly, we provide preliminary evidence that a combination of neural and physiological metrics may serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Overall, our studies demonstrated the successful application of fNIRS neuroimaging to study the physiological effects of the psychoactive substance ketamine and can be regarded as an important step toward larger scale clinical fNIRS studies that can quantify the impact of psychedelics on the brain in standard clinical settings.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys (n=12 adolescents [6 male/6 female] ~2.5 years and n=15 adults [7 male/8 female] ~9.5 years) were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 Tesla scanner. Group level independent component (IC) analysis (30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward (e.g., basal ganglia), and cognitive processes were identified in both adolescent and adult monkeys. Significant age-related differences between the adult and adolescent subjects (adult > adolescent) were found in two networks of interest: (1) the right upper occipital region with an OFC IC and (2) the left temporal cortex, bilateral visual areas, and cerebellum with the cingulate IC. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Neuronal information conductance depends on transmission of action potentials. The conductance of action potentials is based on three physical parameters: The axial resistance of the axon, the axonal insulation by glial membranes, and the positioning of voltage-gated ion channels. In vertebrates, myelin and channel clustering allow fast saltatory conductance. Here we show that in Drosophila melanogaster voltage-gated sodium and potassium channels, Para and Shal, co-localize and cluster in an area of motor axons resembling the axon initial segment. Para but not Shal localization depends on peripheral glia. In larvae, relatively low levels of Para channels are needed to allow proper signal transduction and nerves are simply wrapped by glial cells. In adults, the concentration of Para at the axon initial segment increases. Concomitantly, these axon domains are covered by a mesh of glial processes forming a lacunar structure that serves as an ion reservoir. Directly flanking the voltage-gated ion channel rich axon segment, the lacunar structures collapse forming a myelin-like insulation. Thus, Drosophila development may reflect the evolution of myelin which forms in response to increased levels of clustered voltage-gated ion channels.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic Gi signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and schema memory is not clear. Here, using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic Gi pathway activation in ACC causes significant impairment in flavor-place paired associates (PA) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments were mediated by decreased L-lactate in ACC due to astrocytic Gi activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation was associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in ACC upon Gi activation. Our study also reveals that L-lactate mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 and NMDA receptor activity - discovering a previously unrecognized signaling role of L-lactate. These findings expand our understanding of the role of astrocytes and L-lactate in brain functions.
in bioRxiv: Neuroscience on 2023-01-09 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 115: Frontal Encephalocele Plus Epilepsy: A Case Report and Review of the Literature
Brain Sciences doi: 10.3390/brainsci13010115
Authors:
Ken Yamazaki
Kohei Kanaya
Takehiro Uda
Tetsuhiro Fukuyama
Makoto Nishioka
Yumi Hoshino
Tomoki Kaneko
Ridzky Firmansyah Hardian
Daisuke Yamazaki
Haruki Kuwabara
Kohei Funato
Tetsuyoshi Horiuchi
An encephalocele is a pathological brain herniation caused by osseous dural defects. Encephaloceles are known to be regions of epileptogenic foci. We describe the case of a 44-year-old woman with refractory epilepsy associated with a frontal skull base encephalocele. Epilepsy surgery for encephalocele resection was performed; however, the epilepsy was refractory. A second epilepsy surgery for frontal lobectomy using intraoperative electroencephalography was required to achieve adequate seizure control. Previous reports have shown that only encephalocele resection can result in good seizure control, and refractory epilepsy due to frontal lobe encephalocele has rarely been reported. To the best of our knowledge, this is the first report of frontal encephalocele plus epilepsy in which good seizure control using only encephalocele resection was difficult to achieve. Herein, we describe the possible mechanisms of encephalocele plus epilepsy and the surgical strategy for refractory epilepsy with encephalocele, including a literature review.
in Brain Sciences on 2023-01-09 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 114: Inter-Task Transfer of Prism Adaptation through Motor Imagery
Brain Sciences doi: 10.3390/brainsci13010114
Authors:
Lisa Fleury
Léa Dreyer
Rola El Makkaoui
Elise Leroy
Yves Rossetti
Christian Collet
Prism adaptation (PA) is a useful method to investigate short-term sensorimotor plasticity. Following active exposure to prisms, individuals show consistent after-effects, probing that they have adapted to the perturbation. Whether after-effects are transferable to another task or remain specific to the task performed under exposure, represents a crucial interest to understand the adaptive processes at work. Motor imagery (MI, i.e., the mental representation of an action without any concomitant execution) offers an original opportunity to investigate the role of cognitive aspects of motor command preparation disregarding actual sensory and motor information related to its execution. The aim of the study was to test whether prism adaptation through MI led to transferable after-effects. Forty-four healthy volunteers were exposed to a rightward prismatic deviation while performing actual (Active group) versus imagined (MI group) pointing movements, or while being inactive (inactive group). Upon prisms removal, in the MI group, only participants with the highest MI abilities (MI+ group) showed consistent after-effects on pointing and, crucially, a significant transfer to throwing. This was not observed in participants with lower MI abilities and in the inactive group. However, a direct comparison of pointing after-effects and transfer to throwing between MI+ and the control inactive group did not show any significant difference. Although this interpretation requires caution, these findings suggest that exposure to intersensory conflict might be responsible for sensory realignment during prism adaptation which could be transferred to another task. This study paves the way for further investigations into MI&rsquo;s potential to develop robust sensorimotor adaptation.
in Brain Sciences on 2023-01-09 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 118: First Trimester Ultrasound Detection of Fetal Central Nervous System Anomalies
Brain Sciences doi: 10.3390/brainsci13010118
Authors:
Delia Roxana Ungureanu
Roxana Cristina Drăgușin
Răzvan Grigoraș Căpitănescu
Lucian Zorilă
Anca Maria Istrate Ofițeru
Cristian Marinaș
Ciprian Laurențiu Pătru
Alexandru Cristian Comănescu
Maria Cristina Comănescu
Ovidiu Costinel Sîrbu
Maria-Sidonia Vrabie
Lorena Anda Dijmărescu
Ioana Streață
Florin Burada
Mihai Ioana
Alice Nicoleta Drăgoescu
Dominic Gabriel Iliescu
Objective: To evaluate the potential of the first-trimester ultrasound (US) features for the detection of central nervous system (CNS) anomalies. Methods/Methodology: This is a prospective one-center three-year study. Unselected singleton pregnant women were examined using an extended first-trimester anomaly scan (FTAS) that included the CNS assessment: the calvaria shape, the septum (falx cerebri), the aspect of the lateral ventricles, the presence of the third ventricle and aqueduct of Sylvius (AS) and the posterior brain morphometry: the fourth ventricle, namely intracranial translucency (IT), brain stem/brain stem&ndash;occipital bone ratio (BS/BSOB) and cisterna magna (CM). The spine and underlying skin were also evaluated. The cases were also followed during the second and third trimesters of pregnancy and at delivery. FTAS efficiency to detect major CNS abnormalities was calculated. Results: We detected 17 cases with CNS major abnormalities in a population of 1943 first-trimester (FT) fetuses, including spina bifida with myelomeningocele, exencephaly-anencephaly, holoprosencephaly, hydrocephaly, cephalocele and Dandy-Walker malformation. The CNS features in the abnormal group are presented. In the second trimester (ST), we further diagnosed cases of corpus callosum agenesis, cerebellar hypoplasia, vein of Galen aneurysm and fetal infection features (ventriculomegaly, intraventricular bands, intraventricular cyst and hyperechoic foci), all declared normal at the FTAS. During the third trimester (TT) scan we identified a massive fetal cerebral haemorrhage absent at previous investigations. We report a detection rate of 72.7% of fetal brain anomalies in the FT using the proposed CNS parameters. The sensitivity of the examination protocol was 72.7%, and the specificity was 100%. Conclusion: A detailed FT CNS scan is feasible and efficient. The majority of cases of major CNS abnormalities can be detected early in pregnancy. The visualization rates of the CNS parameters in the FT are great with short, if any, additional investigation time. FT cerebral disorders such as haemorrhage or infections were missed in the FT even when an extended evaluation protocol was used.
in Brain Sciences on 2023-01-09 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 117: The Impact of Affective Temperaments on Suicidal Ideation and Behaviors: Results from an Observational Multicentric Study on Patients with Mood Disorders
Brain Sciences doi: 10.3390/brainsci13010117
Authors:
Mario Luciano
Gaia Sampogna
Bianca Della Rocca
Alessio Simonetti
Pasquale De Fazio
Marco Di Nicola
Giorgio Di Lorenzo
Maria Pepe
Fabio Sambataro
Maria Salvina Signorelli
Alexia Emilia Koukopoulos
Roberto Delle Chiaie
Gabriele Sani
Andrea Fiorillo
Suicide ideation and behaviors are major health issues in the field of mental health. Several psychological and psychosocial factors have been taken into account as possible predictors of suicidality. Only recently affective temperaments have been considered as possible factors linked to suicide. This study aims to investigate the relationship between affective temperaments and suicidality, including the lifetime onset of suicide ideation, lifetime presence of suicide attempts and the total number of lifetime suicide attempts. This is a naturalistic multicentric observational study, involving outpatient units of seven University sites in Italy. Patients were administered with the short version of TEMPS-M and the Columbia Suicide Severity Rating Scale. A total of 653 participants were recruited, with a diagnosis of bipolar (55.7%), unipolar (35.8%) and cyclothymic disorder (8.4%). Regression models showed that the presence of lifetime suicide behaviors was increased in patients presenting trait related impulsivity (p &lt; 0.0001), poor free-interval functioning (p &lt; 0.05), higher number of affective episodes (p &lt; 0.01), higher number of hospitalizations (p &lt; 0.0001), cyclothymic and irritable affective temperaments (p &lt; 0.05 and p &lt; 0.05, respectively). Conversely, the presence of hyperthymic affective disposition reduced the likelihood of having suicidal behaviors (p &lt; 0.01). Lifetime suicidal ideation was associated with trait-related impulsivity (p &lt; 0.001), poor free-interval functioning (p &lt; 0.05), higher number of affective episodes (p &lt; 0.001) and of hospitalizations (p &lt; 0.001). Depressive temperaments increased the likelihood of presenting suicidal ideation (p &lt; 0.05), along with irritable temperaments (p &lt; 0.01), contrary to hyperthymic affective (p &lt; 0.05). Results of the present study confirm that affective disposition has a significant impact on the onset of suicidal ideation and behaviors, and that affective dispositions should be assessed in clinical settings to identify people at risk of suicide. Moreover, a wider clinical evaluation, including different clinical psychopathological dimensions, should be taken into consideration to develop effective preventive interventions.
in Brain Sciences on 2023-01-09 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 116: Mapping Brain Motor Functions Using Transcranial Magnetic Stimulation with a Volume Conductor Model and Electrophysiological Experiments
Brain Sciences doi: 10.3390/brainsci13010116
Authors:
Keigo Hikita
Jose Gomez-Tames
Akimasa Hirata
Transcranial magnetic stimulation (TMS) activates brain cells in a noninvasive manner and can be used for mapping brain motor functions. However, the complexity of the brain anatomy prevents the determination of the exact location of the stimulated sites, resulting in the limitation of the spatial resolution of multiple targets. The aim of this study is to map two neighboring muscles in cortical motor areas accurately and quickly. Multiple stimuli were applied to the subject using a TMS stimulator to measure the motor-evoked potentials (MEPs) in the corresponding muscles. For each stimulation condition (coil location and angle), the induced electric field (EF) in the brain was computed using a volume conductor model for an individualized head model of the subject constructed from magnetic resonance images. A post-processing method was implemented to determine a TMS hotspot using EF corresponding to multiple stimuli, considering the amplitude of the measured MEPs. The dependence of the computationally estimated hotspot distribution on two target muscles was evaluated (n = 11). The center of gravity of the first dorsal interosseous cortical representation was lateral to the abductor digiti minimi by a minimum of 2 mm. The localizations were consistent with the putative sites obtained from previous EF-based studies and fMRI studies. The simultaneous cortical mapping of two finger muscles was achieved with only several stimuli, which is one or two orders of magnitude smaller than that in previous studies. Our proposal would be useful in the preoperative mapping of motor or speech areas to plan brain surgery interventions.
in Brain Sciences on 2023-01-09 00:00:00 UTC.
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Past work has shown that chronic exposure of Drosophila to intense monomolecular odors in early life leads to homeostatic adaptation of olfactory neural responses and behavioral habituation to the familiar odor. Here, we found that, in contrast, persistent exposure to natural odors in early life increases behavioral attraction selectively to familiar odors. Odor experience increases the attractiveness of natural odors that are innately attractive and decreases the aversiveness of natural odors that are innately aversive. These changes in olfactory behavior are unlikely to arise from changes in the sensitivity of olfactory neurons at the first stages of olfactory processing: odor-evoked output from antennal lobe projection neurons was unchanged by chronic exposure to natural odors in terms of olfactory sensitivity, relational distances between odors, or response dynamics. We reveal a requirement for additional features of the environment beyond the odor in establishing odor experience-dependent behavioral plasticity. Passive odor exposure in a featureless environment lacking strong reinforcing cues was insufficient to elicit changes in olfactory preference; however, the same odor exposure resulted in behavioral plasticity when food was present in the environment. Together, these results indicate that behavioral plasticity elicited by persistent exposure to natural odors in early life is mediated by an associative process. In addition, they highlight the importance of using naturalistic odor stimuli for investigating olfactory function.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Cortical astrocytes encode sensory information through their calcium dynamics, but it remains unclear if modulation of astrocyte calcium transients can change somatosensory circuits and behaviour in vivo. Here, we used a novel knockdown approach to selectively reduce astrocyte N-methyl-D-aspartate receptors (NMDAR). We found that these ionotropic receptors contribute to astrocyte Ca2+ transients encoding sensory information. This was essential for the optimal processing of sensory information in nearby neurons, since a reduction in astrocyte NMDARs caused circuit dysfunction and impaired neuronal responses to stimulation. This led to sensory discrimination deficits in the animal. Overall, our findings show that astrocytes can rapidly respond to glutamatergic transmission via their NMDAR and these receptors are an important component for astrocyte-neuron interactions that regulate cortical sensory discrimination in vivo.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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RNAi targeting the electron transport chain has been proven to prolong life span in many different species, and experiments specifically with Drosophila melanogaster and Caenorhabditis elegans have shown a distinct role for neurons. To determine which subset of neurons is implicated in this life span extension, we used the GAL4/UAS system to activate RNAi against genes of Complex I and Complex V. We found life span extension of 18 -- 24% with two glutamate neuron (D42 and VGlut) GAL4 lines. We used the GAL80 system to determine if the overlapping set of glutamate neurons in these two GAL4 lines imparts the life span extension. Limiting GAL4 activity to non-VGlut glutamate neurons in the D42 background failed to extend life span, suggesting that glutamate neurons have a unique role in aging. Interestingly, RNAi of the electron transport chain in D42 glutamate neurons also caused an increase in daytime and nighttime sleep and a decrease in nighttime locomotor activity. Changes to sleep patterns and prolonged life span were not accompanied by any changes in female fertility or response to starvation. Our findings demonstrate that a small subset of neurons can control life span, and further studies exploring the role of the electron transport chain in aging can be focused on the activity of glutamate neurons.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Dendritic spines are considered a morphological proxy for excitatory synapses, rendering them a target of many different lines of research. Over recent years, it has become possible to image simultaneously large numbers of dendritic spines in 3D volumes of neural tissue. In contrast, currently no automated method for spine detection exists that comes close to the detection performance reached by human experts. However, exploiting such datasets requires new tools for the fully automated detection and analysis of large numbers of spines. Here, we developed an efficient analysis pipeline to detect large numbers of dendritic spines in volumetric fluorescence imaging data. The core of our pipeline is a deep convolutional neural network, which was pretrained on a general-purpose image library, and then optimized on the spine detection task. This transfer learning approach is data efficient while achieving a high detection precision. To train and validate the model we generated a labelled dataset using five human expert annotators to account for the variability in human spine detection. The pipeline enables fully automated dendritic spine detection and reaches a near human-level detection performance. Our method for spine detection is fast, accurate and robust, and thus well suited for large-scale datasets with thousands of spines. The code is easily applicable to new datasets, achieving high detection performance, even without any retraining or adjustment of model parameters.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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In nervous system development, disease and injury, neurons undergo programmed cell death, leaving behind cell corpses that are removed by phagocytic glia. Altered glial phagocytosis has been implicated in several neurological diseases including Alzheimer's disease, Parkinson's disease, and traumatic brain injury. To untangle the links between glial phagocytosis and neurodegeneration, we investigated Drosophila mutants lacking the phagocytic receptor Draper. Loss of Draper leads to persistent neuronal cell corpses and age-dependent neurodegeneration. Here we investigate whether the phagocytic defects observed in draper mutants lead to chronic increased immune activation that promotes neurodegeneration. A major immune response in Drosophila is the activation of two NF{kappa}B signaling pathways that produce antimicrobial peptides, primarily in the fat body. We found that the antimicrobial peptide Attacin-A is highly upregulated in the fat body of aged draper mutants and that inhibition of the Immune deficiency (Imd) pathway in the glia and fat body of draper mutants led to reduced neurodegeneration, indicating that immune activation promotes neurodegeneration in draper mutants. Taken together, these findings indicate that phagocytic defects lead to neurodegeneration via increased immune signaling, both systemically and locally in the brain.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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The default mode network (DMN) is a collection of brain regions including midline frontal and parietal structures, medial and lateral temporal lobes, and lateral parietal cortex. Although there is evidence that the network can be subdivided into at least two subcomponents, the network reliably exhibits highly correlated activity both at rest and during task performance. Current understanding regarding the function of the DMN rests on a large body of research indicating that activity in the network decreases during task epochs of experimental paradigms relative to inter-trial intervals. A seeming contradiction arises when the experimental paradigm includes tasks involving autobiographical memory, thinking about one's self, planning for the future, or social cognition. In such cases, the DMN's activity increases and is correlated with attentional networks. Some have therefore concluded that the DMN supports advanced human cognitive abilities such as interoceptive processing and theory of mind. This conclusion may be called into question by evidence of correlated activity in homologous brain regions in other, even non-primate, species. Thus, there are contradictory findings related to the function of the DMN that have been difficult to integrate into a coherent theory regarding its function. Using data from the Human Connectome Project, we explore the temporal dynamics of activity in different regions of the DMN in relation to stimulus presentation. We show that generally the dorsal portion of the network exhibits only a transient initial decrease in activity at the start of trials that increases over trial duration. The ventral component often has more similarity in its time course to that of task-activated areas. We propose that task-associated ramping dynamics in the network are incompatible with a task-negative view of the DMN and propose the dorsal and ventral sub-components of network may rather work together to support bottom-up salience detection and subsequent top-down voluntary action. In this context, we re-interpret the body of anatomical and neurophysiological experimental evidence, arguing that this interpretation can accommodate the seeming contradictions regarding DMN function in the extant literature.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Learning and plasticity rely on fine-tuned regulation of neuronal circuits during offline periods. An unresolved puzzle is how the sleeping brain - in the absence of external stimulation or conscious effort - controls neuronal firing rates (FRs) and communication within and across circuits, supporting synaptic and systems consolidation. Using intracranial Electroencephalography (iEEG) combined with multiunit activity (MUA) recordings from the human hippocampus and surrounding medial temporal lobe (MTL) areas, we here show that governed by slow oscillation (SO) up-states, sleep spindles set a timeframe for ripples to occur. This sequential coupling leads to a stepwise increase in (i) neuronal FRs, (ii) short-latency cross-correlations among local neuronal assemblies and (iii) cross-regional MTL interactions. Triggered by SOs and spindles, ripples thus establish optimal conditions for spike-timing dependent plasticity and systems consolidation. These results unveil how the coordinated coupling of specific sleep rhythms orchestrates neuronal processing and communication during human sleep.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Autism spectrum disorders (ASDs) include a range of developmental disorders that share a core of neurobehavioral deficits manifested by abnormalities in social interactions, deficits in communication, restricted interests, and repetitive behaviors. Several reports showed that mutations in different high-risk ASD genes, including SHANK3 and CNTNAP2, lead to ASD. However, to date, the underlying molecular mechanisms have not been deciphered, and no effective pharmacological treatment has been established for ASD. Recently, we reported a dramatic increase of nitric oxide (NO) in ASD mouse models. NO is a multifunctional neurotransmitter that plays a key role in different neurological disorders. However, its role in ASD has not yet been investigated. To reveal the novel molecular, cellular, and behavioral role of NO in ASD, we conducted multidisciplinary experiments using cellular and mouse models as well as clinical samples. First, we treated WT mice with an NO donor, which led to an autism-like phenotype. Next, we measured and found high levels of nitrosative stress biomarkers in both the Shank3 and Cntnap2 ASD mouse models. Treating both mouse models with a selective neuronal NO synthase (nNOS) inhibitor led to a reversal in the molecular, synaptic, and behavioral ASD phenotypes. Using a primary neuronal cell culture, we confirmed that NO is specifically involved in neurons in ASD pathology. Next, using genetic manipulations in the human SH-SY5Y cell line, we found that nNOS plays a key role in the pathology. Finally, we examined human plasma samples from 19 low-functioning ASD patients, compared to 20 typically developed volunteers, and found a significant elevation in the NO levels in the ASD patients. Furthermore, using the SNOTRAP technology, which is an innovative mass spectrometric method to identify the SNO-proteome (SNO: NO-mediated post-translational modification), we revealed that the complement systems in the synaptic and neuronal development processes are enriched in the ASD group. This work indicates, for the first time, that NO plays a pathological role in ASD development. Our findings will open future and novel directions to examine NO in diverse mutations on the autism spectrum as well as other neurodevelopmental disorders and psychiatric diseases. Most importantly, it suggests a novel treatment strategy for ASD.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of non-invasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1, was studied through a conditional knockout mouse model as a major molecule for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement and muscle EMG responses. We also detected higher Piezo1 in the central amygdala (CEA) which were found more sensitive to ultrasound stimulation than that of cortex. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation while knocking out astrocytic Piezo1 showed no obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions, and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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cAMP is a pivotal second messenger regulated by various upstream pathways including Ca2+ and G protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, an ultrasensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a highly sensitive new red Ca2+ indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca2+ and cAMP in hundreds of neurons. We identified Ca2+-induced cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-induced cAMP responses. Overall, our multicolor suite revealed that information encoded in Ca2+ and GPCRs signaling is integrated and stored as cAMP transients for longer periods in vivo.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Purpose: To investigate the age-dependence of metabolite T1 relaxation times at 3T in both gray- and white-matter-rich voxels. Methods: This manuscript analyzes publicly available metabolite and metabolite-nulled (single inversion recovery TI = 600 ms) spectra acquired at 3T using PRESS localization. Voxels were placed in posterior cingulate cortex and centrum semiovale in 102 healthy volunteers across 5 decades of life (20s to 60s). All spectra were analyzed in Osprey v2.4.0. To estimate T1 relaxation times for tNAA2.0 and tCr3.0, the ratio of modeled metabolite residual amplitudes in the metabolite-nulled spectrum to the full metabolite signal was calculated using the single inversion recovery signal equation. Correlations between T1 and subject age were evaluated. Results: Spearman correlations revealed that estimated T1 relaxation times of tNAA2.0 (rs = -0.43; p < 0.001) and tCr3.0 (rs = -0.23; p = 0.021) decreased significantly with age in white-matter-rich CSO, and less steeply (and not significantly) for tNAA2.0 (rs = -0.15; p = 0.136) and tCr3.0 (rs = -0.10; p = 0.319) in gray-matter-rich PCC. Conclusion: The analysis harnessed a large publicly available cross-sectional dataset to test an important hypothesis, that metabolite T1 relaxation times change with age. This preliminary study stresses the importance of further work to measure age-normed metabolite T1 relaxation times for accurate quantification of metabolite levels in studies of aging.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Three-dimensional (3D) neural cell cultures inherently lend themselves to high-throughput network electrophysiology studies addressing brain function in health and disease in a more realistic architectural complexity than two-dimensional neural networks. Epilepsy is the emblem of brain network disorders, as it reflects aberrant circuit reorganization and hyper-synchronization, resulting in sudden and uncontrolled electrical discharges (seizures). Modeling the features of epilepsy has so far relied on pharmacological, ionic or genetic manipulation of cells, ex-vivo brain tissue or intact animals, failing to recapitulate most of the epilepsies, which are triggered by unknown causes. Here, we report the spontaneous emergence of epileptiform patterns in spheroids of rodent primary hippocampal cells cultured in physiological condition, i.e., in the absence of a known initiating insult, detected by microelectrode array electrophysiology. Three distinct electrical phenotypes, i.e. interictal (between seizures), ictal (seizure) or mixed, arise from DIV10 to DIV35. In particular, the tonic-clonic ictal discharges become the most prominent at DIV28-35. These patterns exhibit electrographic and spectral features that strikingly resemble those observed in the hippocampus of in vitro and in vivo rodent epilepsy models, as well as of drug-resistant epileptic humans. Remarkably, not all spheroids exhibit full-blown ictal activity, bringing parallelism with the yet unanswered question of why a brain becomes epileptic and a seizure is generated. This evidence warrants caution against hippocampal cell-based therapies for regenerative purposes, as they may initiate epileptogenesis; at the same time, hippocampal spheroids lend themselves as reductionist model supporting high-throughput pre-clinical research on epileptic syndromes involving the hippocampus.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ~250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue ([≥]1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo. We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. However, the precise relationship between synaptic input patterns and spiking output of individual neurons remains unresolved during spontaneous network activity. Here, using whole-network high-density microelectrode array (HD-MEA) recordings and patch clamping, we developed a novel experimental approach and analytical tools that provide a comprehensive long-term input-output characterization of individual neurons in cortical cell cultures. We found that, during in vivo-like network activity with excitation(E)-inhibition(I) balance, postsynaptic spiking coincided with the maxima of rapid, network state-dependent fluctuations in the input E/I ratio. Our approach also uncovered the underlying circuit architecture and we identified a few key inhibitory inputs -- often from special hub neurons -- that were instrumental in mediating these E/I ratio changes. Balanced network theory predicts dynamical regimes governed by input fluctuation and featuring a fast neuronal responsiveness. Our findings -- obtained in self-organized neuronal cultures -- suggest that the emergence of these favorable regimes and associated network architectures is an inherent property of all cortical networks.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Episodic memory is thought to be preferentially encoded by sparsely distributed memory-eligible "primed" neurons with high excitability in memory-related regions. Based on in vivo calcium imaging on freely behaving mice, we developed an analytical method to determine the neuronal activity hierarchy and establish hippocampal primed neurons. Neurons with high activity and memory-associated burst synchronization are identified as primed neurons. When a trace fear memory is being formed or retrieved, the major pattern of the calcium dynamics is predominantly mediated by primed neurons and highly correlated with mouse freezing behaviors. In cilia knockout mice that exhibit severe learning deficits, the percentage of their primed neurons is drastically reduced, and any burst synchronization is strongly suppressed. Consistently, the first principal pattern of cilia knockout neurons does not fully distinguish itself from other minor components or correlate with mouse freezing behaviors. To reveal how a portion of neurons get primed, we developed a numerical model of a neural network that incorporates simulations of linear and non-linear weighting synaptic components, modeling AMPAR- and NMDAR-mediated conductances respectively. Moderate NMDAR to AMPAR ratios can naturally lead to the emergence of primed neurons. In such cases, the neuronal firing averages show a right-skewed log-distribution, similar to the distributions of hippocampal c-Fos expression and the activity levels measured by in vivo calcium imaging. In addition, High basal neuronal activity levels speed up the development of activity hierarchy during iterative computation. Together, this study reveals a novel method to measure neuronal activity hierarchy. Our simulation suggests that the accumulation of biased synaptic transmission mediated by the non-linear weighting synaptic component represents an important mechanism for neuronal priming.
in bioRxiv: Neuroscience on 2023-01-08 00:00:00 UTC.
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Zubeidat et al. report that while early life is defined by the induction of a microbiota-independent salivary immunity, adult salivary immunity develops during weaning and is controlled by the microbiota. They further propose the salivary gland as a barrier site in which adaptive immunity is induced.
in Cell Reports: Current Issue on 2023-01-07 00:00:00 UTC.
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Inflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the beta2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Multiple neurodegenerative disorders, including Parkinson,s disease (PD) and Alzheimer,s disease-associated dementia (ADAD), are linked with dopaminergic (DA) neuron death and a resulting reduction in dopamine levels in the brain. DA neuron degeneration and the risk of developing PD is connected to genetic mutations affiliated with lysosomal function and protein degradation. Accessible human cellular models for PD-relevant genetic mutations are needed to investigate mechanisms of DA cell death and define points of therapeutic intervention. Human induced pluripotent stem cell (iPSC)-derived midbrain DA neurons offer a developmentally and physiologically relevant in vitro model for investigating PD pathogenic mechanisms across genetic backgrounds. In this study, we generated DA neurons using iPSCs from two clinically diagnosed PD patients, one harboring an inherited GBAN370S mutation and the other a mutation in LRRK2G2019S and compared pathophysiology against DA neurons from genetically engineered SNCAA53T iPSCs and its isogenic apparently healthy normal (AHN) iPSCs. Our results present a novel phenotype for GBAN370S and LRRK2G2019S derived DA neurons, showing that they produced and released significantly more dopamine compared to the AHN and SNCAA53T mutant DA neurons. All mutant DA neurons developed deficient glucocerebrosidase (GCase) activity, increased mitochondrial stress, aberrant neuronal activity patterns, and increased -synuclein accumulation. Together these data suggest potentially divergent origins of PD pathogenesis in GBAN370S and LRRK2G2019S DA neurons. In addition, compound screening confirmed that GCase modulators can rescue enzyme activity and impact neural activity across all DA mutant neurons, to varying degrees. These data demonstrate unique in vitro phenotypes associated with PD and suggest a diversity of underlying mechanisms across different genetic backgrounds. Together, the cell lines used in this study present a valuable tool for new therapeutic discovery.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Rationale: Acute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability. Objectives: Identify individual factors (e.g., genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH). Methods: Associations of individual factors with the magnitude of AIHH (15, 1-min O2=9.5%, CO2=5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P0.1) were evaluated in 17 healthy individuals (age=27{+/-}5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E, APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoE knock-in rats were performed to test causality. Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met (all p>0.05). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P0.1 within the limited age range studied (p=0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (p<0.05). Conclusions: APOE4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Locomotor movements cause visual images to be displaced across the eye, a retinal slip that is counteracted by stabilizing reflexes in many animals. In insects, optomotor turning causes the animal to turn in the direction of rotating visual stimuli, thereby reducing retinal slip and stabilizing trajectories through the world. This behavior has formed the basis for extensive dissections of motion vision. Here, we report that under certain stimulus conditions, two Drosophila species, including the widely studied D. melanogaster, can suppress and even reverse the optomotor turning response over several seconds. Such 'anti-directional turning' is most strongly evoked by long-lasting, high-contrast, slow-moving visual stimuli that are distinct from those that promote syn-directional optomotor turning. Anti-directional turning, like the syn-directional optomotor response, requires the local motion detecting neurons T4 and T5; a subset of lobula plate tangential cells, CH cells, show involvement in these responses. Imaging from a variety of direction-selective cells in the lobula plate shows no evidence of dynamics that match the behavior, suggesting that the observed inversion in turning direction emerges downstream of the lobula plate. Further, anti-directional turning declines with age and exposure to light. These results show that Drosophila optomotor turning behaviors contain rich, stimulus-dependent dynamics that are inconsistent with simple reflexive stabilization responses.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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The detection and signaling of prediction errors is central to the theory of predictive processing. Experiments that alter the sensory outcome of an animal's behavior reveal enhanced neural responses to unexpected self-generated stimuli, including many neurons that do not respond to the same stimulus heard passively. These neurons may reflect the violation of a learned sensory-motor prediction, but could also emerge due to a combination of sound and movement in a way that is independent from expectation. Here, we train mice to expect the outcome of a simple sound-generating lever behavior and record neural responses to the expected sound and sounds that deviate from expectation in multiple distinct dimensions. Our data reveal suppression of expected sound responses that is specific across multiple stimulus dimensions simultaneously and stimulus-specific prediction error neurons that depend on sensory-motor expectations.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Spike sorting is the computational process of extracting the firing times of single neurons from recordings of local electrical fields. This is an important but hard problem in neuroscience, complicated by the non-stationarity of the recordings and the dense overlap in electrical fields between nearby neurons. To solve the spike sorting problem, we have continuously developed over the past eight years a framework known as Kilosort. This paper describes the various algorithmic steps introduced in different versions of Kilosort, which have not been described before. We also report the development of Kilosort4, a new version with substantially improved performance due to new clustering algorithms inspired by graph-based approaches. To test the performance of Kilosort, we developed a realistic simulation framework which uses densely sampled electrical fields from real experiments to generate non-stationary spike waveforms and realistic noise. We find that nearly all versions of Kilosort outperform other algorithms on a variety of simulated conditions, and Kilosort4 performs best in all cases, correctly identifying even neurons with low amplitudes and small spatial extents in high drift conditions.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor adenosine monophosphate-activated protein kinase (AMPK), along with subsequent neurodegeneration in RGCs differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated variant of Optineurin (OPTN-E50K). Similarly, the microbead occlusion model of glaucoma resulting in ocular hypertension also exhibited autophagy disruption and mTORC1 downregulation. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN-E50K RGCs. Taken together, these results highlight an important balance between autophagy and mTORC1 signaling essential for RGC homeostasis, while disruption to these pathways contributes to neurodegenerative features in glaucoma, providing a potential therapeutic target to prevent neurodegeneration.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Background: The aim of this study was to investigate the effects of walking in reduced lighting with or without performing a secondary cognitive task on gait dynamics in middle-aged adults and to compare them with young and old adults. Methods: Twenty young (age 28.8{+/-}4.1), 20 middle-aged (age 50.2{+/-}4.4), and 19 elderly (age 70.7{+/-}4.2) subjects participated in the study. Subjects walked on an instrumented treadmill at a self-determined pace under four conditions in randomized order: (1) walking in usual lighting (1000 lumens); (2) walking in near-darkness (5 lumens); (3) walking in usual lighting with a serial-7 subtraction dual-task; and (4) walking in near-darkness with a serial-7 subtraction dual-task. Variability in stride time and variability in the trajectory of the center of pressure in the sagittal and frontal planes (anterior/posterior and lateral variability) were measured. Repeated measures ANOVA and post hoc analysis were used to determine the effects of age, lighting conditions, and cognitive task on each gait outcome. Results: Under usual lighting, stride time variability and anterior/posterior variability of the middle-aged subjects were similar to those of the young and lower than those of the old. The lateral variability of the middle-aged subjects was higher than that of young adults under both lighting conditions. Similar to the older adults, the middle-aged participants increased their stride time variability and anterior/posterior variability when walking in near-darkness, but they were the only ones to exhibit increased lateral variability in near-darkness. Young adult gait was not affected by lighting, and concurrent performance of a cognitive task while walking did not affect gait stability in all groups under any of the lighting conditions. Conclusions: Gait stability decreases in middle age when walking in the dark. Recognition of functional deficits in middle age could promote appropriate interventions to optimize aging and reduce fall risk.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases enzymes catalyzing the transition of 5mC to 5hmC in DNA and have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila because Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by determining Tet DNA-binding sites throughout the genome and by mapping the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC-modified sites can be found along the entire transcript and are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are frequently involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and are sensitized to reduced levels of slit. Both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs, primarily in developing nerve cells.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Balance and movement are impaired in a wide variety of neurological disorders. Recent advances in behavioral monitoring provide unprecedented access to posture and locomotor kinematics, but without the throughput and scalability necessary to screen candidate genes / potential therapeutics. We present a powerful solution: a Scalable Apparatus to Measure Posture and Locomotion (SAMPL). SAMPL includes extensible imaging hardware and low-cost open-source acquisition software with real-time processing. We first demonstrate that SAMPL's hardware and acquisition software can acquire data from three species (flies, worms, and zebrafish) as they move vertically. Next, we leverage SAMPL's throughput to rapidly (two weeks) gather a new zebrafish dataset. We use SAMPL's analysis and visualization tools to replicate and extend our current understanding of how zebrafish balance as they navigate through a vertical environment. Next, we discover (1) that key kinematic parameters vary systematically with genetic background, and (2) that such background variation is small relative to the changes that accompany early development. Finally, we simulate SAMPL's ability to resolve differences in posture or vertical navigation as a function of affect size and data gathered -- key data for screens. Taken together, our apparatus, data, and analysis provide a powerful solution for labs using small animals to investigate balance and locomotor disorders at scale. More broadly, SAMPL is both an adaptable resource for labs looking process videographic measures of behavior in real-time, and an exemplar of how to scale hardware to enable the throughput necessary for screening.
in bioRxiv: Neuroscience on 2023-01-07 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 113: Speech and Nonspeech Parameters in the Clinical Assessment of Dysarthria: A Dimensional Analysis
Brain Sciences doi: 10.3390/brainsci13010113
Authors:
Wolfram Ziegler
Theresa Schölderle
Bettina Brendel
Verena Risch
Stefanie Felber
Katharina Ott
Georg Goldenberg
Mathias Vogel
Kai Bötzel
Lena Zettl
Stefan Lorenzl
Renée Lampe
Katrin Strecker
Matthis Synofzik
Tobias Lindig
Hermann Ackermann
Anja Staiger
Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral&ndash;facial movements and maximum phonation times were compared with auditory&ndash;perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain&ndash;general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD.
in Brain Sciences on 2023-01-07 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 112: The Photic Stimulation Has an Impact on the Reproduction of 10 s Intervals Only in Healthy Controls but Not in Patients with Schizophrenia: The EEG Study
Brain Sciences doi: 10.3390/brainsci13010112
Authors:
Galina V. Portnova
Aleksandra V. Maslennikova
Schizophrenia is a mental disorder characterized by both abnormal time perception and atypical relationships with external factors. Here we compare the influence of external photic stimulation on time production between healthy subjects (n = 24) and patients with schizophrenia (n = 22). To delve into neuropsychological mechanisms of such a relationship, the EEG was recorded during variable conditions: during production of 10 s intervals; during photic stimulation of 4, 9, 16, and 25 Hz; and during combinations of these conditions. We found that the higher frequency of photic stimulation influenced the production of time intervals in healthy volunteers, which became significantly longer and were accompanied by corresponding EEG changes. The impact of photic stimulation was absent in patients with schizophrenia. In addition, the time production was characterized by less accuracy and the absence of EEG dynamics typical for healthy controls that included an increase in alpha2 power and envelope frequency. Our findings indicated that the time perception was not adjusted by external factors in patients with schizophrenia and might have involved cognitive and mental processes different from those of healthy volunteers.
in Brain Sciences on 2023-01-07 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 111: The Role of the Left Inferior Frontal Gyrus in Introspection during Verbal Communication
Brain Sciences doi: 10.3390/brainsci13010111
Authors:
Ayumi Yoshioka
Hiroki C. Tanabe
Eri Nakagawa
Motofumi Sumiya
Takahiko Koike
Norihiro Sadato
Conversation enables the sharing of our subjective experiences through verbalizing introspected thoughts and feelings. The mentalizing network represents introspection, and successful conversation is characterized by alignment through imitation mediated by the mirror neuron system (MNS). Therefore, we hypothesized that the interaction between the mentalizing network and MNS mediates the conversational exchange of introspection. To test this, we performed hyperscanning functional magnetic resonance imaging during structured real-time conversations between 19 pairs of healthy participants. The participants first evaluated their preference for and familiarity with a presented object and then disclosed it. The control was the object feature identification task. When contrasted with the control, the preference/familiarity evaluation phase activated the dorso-medial prefrontal cortex, anterior cingulate cortex, precuneus, left hippocampus, right cerebellum, and orbital portion of the left inferior frontal gyrus (IFG), which represents introspection. The left IFG was activated when the two participants&rsquo; statements of introspection were mismatched during the disclosure. Disclosing introspection enhanced the functional connectivity of the left IFG with the bilateral superior temporal gyrus and primary motor cortex, representing the auditory MNS. Thus, the mentalizing system and MNS are hierarchically linked in the left IFG during a conversation, allowing for the sharing of introspection of the self and others.
in Brain Sciences on 2023-01-07 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 110: Health-Related Quality of Life in Spinal Muscular Atrophy Patients and Their Caregivers—A Prospective, Cross-Sectional, Multi-Center Analysis
Brain Sciences doi: 10.3390/brainsci13010110
Authors:
Camilla Wohnrade
Ann-Kathrin Velling
Lucas Mix
Claudia D. Wurster
Isabell Cordts
Benjamin Stolte
Daniel Zeller
Zeljko Uzelac
Sophia Platen
Tim Hagenacker
Marcus Deschauer
Paul Lingor
Albert C. Ludolph
Dorothée Lulé
Susanne Petri
Alma Osmanovic
Olivia Schreiber-Katz
Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient&rsquo;s health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value &lt;0.259 or &gt;0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients&rsquo; motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.
in Brain Sciences on 2023-01-07 00:00:00 UTC.
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Brain Sciences, Vol. 13, Pages 109: Sacrifice of Involved Nerve Root during Surgical Resection of Foraminal and/or Dumbbell Spinal Neurinomas
Brain Sciences doi: 10.3390/brainsci13010109
Authors:
Alberto Vandenbulcke
Ginevra Federica D’Onofrio
Gabriele Capo
Wassim Baassiri
Cédric Y. Barrey
Even if usually needed to achieve the gross total resection (GTR) of spinal benign nerve sheath tumors (NSTs), nerve root sacrifice remains controversial regarding the risk of neurological deficit. For foraminal NSTs, we hypothesize that the involved root is poorly functional and thus can be safely sacrificed. All spinal benign NSTs with foraminal extension that underwent surgery from 2013 to 2021 were reviewed. The impacts of preoperative clinical status and patient and tumor characteristics on long-term outcomes were analyzed. Twenty-six patients were included, with a mean follow-up (FU) of 22.4 months. Functional motor roots (C5-T1, L3-S1) were involved in 14 cases. The involved nerve root was routinely sacrificed during surgery and GTR was obtained in 84.6% of cases. In the functional root subgroup, for patients with a pre-existing deficit (n = 5/14), neurological aggravation persisted in one case at last FU (n = 1/5), whereas for those with no preop deficit (n = 9/14), a postoperative deficit persisted in one patient only (n = 1/9). Preoperative radicular pain was the only characteristic significantly associated with an immediate postoperative motor deficit (p = 0.03). The sacrifice of an involved nerve root in foraminal NSTs seems to represent a reasonable and relevant option to resect these tumors, permitting one to achieve tumor resection in an oncologic fashion with a high rate of GTR.
in Brain Sciences on 2023-01-07 00:00:00 UTC.
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The tuning properties of neurons in the visual system can be contextually modulated by the statistics of the area surrounding their receptive field (RF), particularly when the surround contains natural features. However, stimuli presented in specific egocentric locations may have greater behavioral relevance, raising the possibility that the extent of contextual modulation may vary with position in visual space. To explore this possibility, we utilized the small size and optical transparency of the larval zebrafish to describe the form and spatial arrangement of contextually modulated cells throughout an entire tectal hemisphere. We found that the spatial tuning of tectal neurons to a prey-like stimulus sharpens when the stimulus is presented against a background with the statistics of complex natural scenes, relative to a featureless background. These neurons are confined to a spatially restricted region of the tectum and have receptive fields centered within a region of visual space in which the presence of prey preferentially triggers hunting behavior. Our results suggest that contextual modulation of tectal neurons by complex backgrounds may facilitate prey-localization in cluttered visual environments.
in eNeuro on 2023-01-06 17:30:23 UTC.
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Abstract
Sleep facilitates memory storage and even brief periods of sleep loss lead to impairments in memory, particularly memories that are hippocampus dependent. In previous studies, we have shown that the deficit in memory seen after sleep loss is accompanied by deficits in synaptic plasticity. Our previous work has also found that sleep deprivation (SD) is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus and that the reduction of cAMP mediates the diminished memory observed in sleep-deprived animals. Based on these findings, we hypothesized that cAMP acts as a mediator for not only the cognitive deficits caused by sleep deprivation, but also the observed deficits in synaptic plasticity. In this study, we expressed the heterologous Drosophila melanogaster Gαs-protein-coupled octopamine receptor (DmOctβ1R) in mouse hippocampal neurons. This receptor is selectively activated by the systemically injected ligand (octopamine), thus allowing us to increase cAMP levels in hippocampal neurons during a 5-h sleep deprivation period. Our results show that chemogenetic enhancement of cAMP during the period of sleep deprivation prevents deficits in a persistent form of long-term potentiation (LTP) that is induced at the Schaffer collateral synapses in the hippocampal CA1 region. We also found that elevating cAMP levels in either the first or second half of sleep deprivation successfully prevented LTP deficits. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation at the synaptic level. Targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss.
in eNeuro on 2023-01-06 17:30:23 UTC.
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Abstract
The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.
in eNeuro on 2023-01-06 17:30:23 UTC.
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Background: Post-prostatectomy urinary incontinence (PPI) is a bothersome complication affecting patients undergoing prostate surgery that in up 10% of cases will require an invasive treatment with fixed slings or artificial urinary sphincters (AUS). Although fixed slings have several advantages over AUS, failure rates after slings range between 15% and 45% while current knowledge of predictors of sling efficacy remains limited. By systematically combining and summarizing all relevant literature, the present review and meta-analysis aim to address this research need assessing the association between preoperative risk factors and sling failure. Methods: Studies pertaining to fixed synthetic male perineal slings as treatment for adult male suffering from PPI, will be included. A systematic search will be conducted in PubMED, Scopus, Web of Science and Cochrane databases, and in the reference lists of retrieved articles. Independent reviewers will conduct study selection and data extraction. Outcomes will include failure to achieve the continence cure and overall success (cure plus improvement), measured as per included studies. Exposures will include any preoperative variables evaluated for association with sling failure. The QUIPS tool will be used for study quality assessment and a random-effects DerSimonian-Laird model, with Hartung-Knapp adjustment, will be used to pool adjusted and unadjusted odds ratios separately. Sensitivity analysis will be performed using the leave-one-out methodology and subgroup meta-analyses based on pre-specified studies’ characteristics will be conducted to explain the heterogeneity. Certainty of evidence will be assessed according to GRADE methodology and review reporting will comply with the PRISMA-P statement. Discussion: By summarising all relevant literature in the field, our results will help to incorporate available evidence into clinical practice assisting healthcare professionals managing PPI patients in treatment decision-making. The present review will also provide researchers with the necessary, evidence-based groundwork to perform future high-quality prognostic studies in the field. Registration: CRD42022307160.
in F1000Research on 2023-01-06 14:55:45 UTC.
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Background: Empathy in the context of healthcare is an immersion experience to comprehend patients' viewpoints, feelings, and emotions, without passing judgment, to ensure they receive the necessary treatment to feel comfortable. Empathy for others must be possessed by healthcare professionals and healthcare students as healthcare professionals’ candidates, including the pharmacy student. This study aimed to identify and assess the determinants related to pharmacy students' empathy. Methods: Three electronic databases were used for the first searches. We used peer-reviewed original papers, full text, must assess determinants that are associated with pharmacy students' empathy, and only be focused on pharmacy students (first to the fourth year) as healthcare professionals candidates. We utilized Joanna Briggs Institute Critical Appraisal Checklists to observe the quality of published publications and reduce bias. Results: This review examined 14 papers that reported on determinants connected to pharmacy students' empathy. Nine studies evaluated the association between sex and the level of empathy, seven studies reported educational intervention, four studies discussed the year of study, two studies explained the type of school, four studies evaluated experience, and others determinants that discussed in the included studies were career preference, intercultural sensitivity, stigma, altruism, grit, self-awareness, marital status, and family income Conclusions: Educational intervention, experience, gender or sex, type of school, year of study, intercultural sensitivity, career preference, altruism, grit, self-awareness, marital status, and family income, can all have a positive impact on increased empathy among pharmacy students. We acknowledge that the included studies are heterogeneous, indicating that additional studies are necessary before reaching any firm conclusions. More research is needed to properly understand how empathy can be improved with the most effective pharmacy educational strategies. Higher levels of evidence are also required in studies to address the potential bias caused using self-report questionnaires, as well as other potential biases and inaccuracies.
in F1000Research on 2023-01-06 14:52:22 UTC.
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Background: The University of Rwanda is the only African residency to have implemented the pediatric International In-Training Examination (I-ITE) as a tool to monitor resident knowledge acquisition. The objective of this study was to better understand the acceptance and relevance of this exam to residents from this setting and their perceptions regarding this assessment tool. Methods: A retrospective, survey-study was undertaken to describe candidate feedback. Immediately on completing the I-ITE residents provided feedback by filling in an electronic questionnaire comprised of four closed Likert questions and an open text box for free-text feedback. Participants were pediatric residents from the University of Rwanda, the only university in Rwanda with a pediatric residency program. Quantitative analysis of the Likert questions was undertaken descriptively using SPSS. Free-text feedback was coded and analysed employing a phenomenological approach, with coding and analysis undertaken by two researchers. Results: Eighty-four residents completed a total of 213 I-ITE sittings during the five exam cycles undertaken during the study period. The survey was completed after 206 of the 213 exam sittings, giving a response rate of 97%. Five themes emerged from the qualitative analysis; 1) undertaking the I-ITE was a positive experience; 2) exam content; 3) formative nature of the assessment; 4) challenges to completing the exam; 5) practicalities to undertaking the exam. Conclusion: Qualitative feedback demonstrates that the I-ITE, a standardized, and independent exam, produced by the American Board of Pediatrics, was valued and well accepted by Rwanda pediatric residents. Its formative nature and the breadth and quality of the questions were reported to positively contribute to the residents' formative development.
in F1000Research on 2023-01-06 14:30:42 UTC.
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Introduction and importance: This report details the clinical features and management in a case of Descemet stripping automated endothelial keratoplasty (DSAEK) which had primary graft failure (PGF) due to an inverted yet attached lenticule. Presentation of case: A 66-year-old gentleman had poor visual recovery in the right eye after undergoing cataract surgery 12 years prior to presentation. The visual acuity was counting fingers and examination revealed endothelial decompensation. The patient underwent a DSAEK and postoperatively had a well attached lenticule. However, the cornea was edematous three weeks after the surgery and optical coherence tomography (OCT) revealed a reversed lenticule. The patient underwent a repeat DSAEK and had an uneventful postoperative course. The visual acuity was 20/40 after 7 months with a clear cornea and a well attached graft. Discussion: PGF is a rare complication following DSAEK which occurs due to poor endothelial function of the donor graft. Insertion of a reversed lenticule may get overlooked as a cause of PGF unless the graft edge profile is examined on an OCT scan. The graft in the current case was well attached despite its inverted position suggesting that graft adherence is perhaps not a function of the corneal endothelial pumps in isolation and may be driven by factors such as the intraocular pressure. Conclusion: A reversed DSAEK lenticule may have normal adherence to the host stroma and must be considered in cases with PGF. OCT of the graft edge is required for diagnosis before performing a repeat keratoplasty.
in F1000Research on 2023-01-06 14:11:16 UTC.
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by Lujun Shen, Jinqing Mo, Changsheng Yang, Yiquan Jiang, Liangru Ke, Dan Hou, Jingdong Yan, Tao Zhang, Weijun Fan
Summary The survival path mapping approach has been proposed for dynamic prognostication of cancer patients using time-series survival data. The SurvivalPath R package was developed to facilitate building personalized survival path models. The package contains functions to convert time-series data into time-slices data by fixed interval based on time information of input medical records. After the pre-processing of data, under a user-defined parameters on covariates, significance level, minimum bifurcation sample size and number of time slices for analysis, survival paths can be computed using the main function, which can be visualized as a tree diagram, with important parameters annotated. The package also includes function for analyzing the connections between exposure/treatment and node transitions, and function for screening patient subgroup with specific features, which can be used for further exploration analysis. In this study, we demonstrate the application of this package in a large dataset of patients with hepatocellular carcinoma, which is embedded in the package. The SurvivalPath R package is freely available from CRAN, with source code and documentation hosted at https://github.com/zhangt369/SurvivalPath.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Gian Luca Lancia, Mattia Eluchans, Marco D’Alessandro, Hugo J. Spiers, Giovanni Pezzulo
When faced with navigating back somewhere we have been before we might either retrace our steps or seek a shorter path. Both choices have costs. Here, we ask whether it is possible to characterize formally the choice of navigational plans as a bounded rational process that trades off the quality of the plan (e.g., its length) and the cognitive cost required to find and implement it. We analyze the navigation strategies of two groups of people that are firstly trained to follow a "default policy" taking a route in a virtual maze and then asked to navigate to various known goal destinations, either in the way they want ("Go To Goal") or by taking novel shortcuts ("Take Shortcut"). We address these wayfinding problems using InfoRL: an information-theoretic approach that formalizes the cognitive cost of devising a navigational plan, as the informational cost to deviate from a well-learned route (the "default policy"). In InfoRL, optimality refers to finding the best trade-off between route length and the amount of control information required to find it. We report five main findings. First, the navigational strategies automatically identified by InfoRL correspond closely to different routes (optimal or suboptimal) in the virtual reality map, which were annotated by hand in previous research. Second, people deliberate more in places where the value of investing cognitive resources (i.e., relevant goal information) is greater. Third, compared to the group of people who receive the "Go To Goal" instruction, those who receive the "Take Shortcut" instruction find shorter but less optimal solutions, reflecting the intrinsic difficulty of finding optimal shortcuts. Fourth, those who receive the "Go To Goal" instruction modulate flexibly their cognitive resources, depending on the benefits of finding the shortcut. Finally, we found a surprising amount of variability in the choice of navigational strategies and resource investment across participants. Taken together, these results illustrate the benefits of using InfoRL to address navigational planning problems from a bounded rational perspective.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Hongxuan Zhai, Julia Fukuyama
k-mer-based distances are often used to describe the differences between communities in metagenome sequencing studies because of their computational convenience and history of effectiveness. Although k-mer-based distances do not use information about taxon abundances, we show that one class of k-mer distances between metagenomes (the Euclidean distance between k-mer spectra, or EKS distances) are very closely related to a class of phylogenetically-informed β-diversity measures that do explicitly use both the taxon abundances and information about the phylogenetic relationships among the taxa. Furthermore, we show that both of these distances can be interpreted as using certain features of the taxon abundances that are related to the phylogenetic tree. Our results allow practitioners to perform phylogenetically-informed analyses when they only have k-mer data available and provide a theoretical basis for using k-mer spectra with relatively small values of k (on the order of 4-5). They are also useful for analysts who wish to know more of the properties of any method based on k-mer spectra and provide insight into one class of phylogenetically-informed β-diversity measures.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Theresa Ullmann, Stefanie Peschel, Philipp Finger, Christian L. Müller, Anne-Laure Boulesteix
In recent years, unsupervised analysis of microbiome data, such as microbial network analysis and clustering, has increased in popularity. Many new statistical and computational methods have been proposed for these tasks. This multiplicity of analysis strategies poses a challenge for researchers, who are often unsure which method(s) to use and might be tempted to try different methods on their dataset to look for the “best” ones. However, if only the best results are selectively reported, this may cause over-optimism: the “best” method is overly fitted to the specific dataset, and the results might be non-replicable on validation data. Such effects will ultimately hinder research progress. Yet so far, these topics have been given little attention in the context of unsupervised microbiome analysis. In our illustrative study, we aim to quantify over-optimism effects in this context. We model the approach of a hypothetical microbiome researcher who undertakes four unsupervised research tasks: clustering of bacterial genera, hub detection in microbial networks, differential microbial network analysis, and clustering of samples. While these tasks are unsupervised, the researcher might still have certain expectations as to what constitutes interesting results. We translate these expectations into concrete evaluation criteria that the hypothetical researcher might want to optimize. We then randomly split an exemplary dataset from the American Gut Project into discovery and validation sets multiple times. For each research task, multiple method combinations (e.g., methods for data normalization, network generation, and/or clustering) are tried on the discovery data, and the combination that yields the best result according to the evaluation criterion is chosen. While the hypothetical researcher might only report this result, we also apply the “best” method combination to the validation dataset. The results are then compared between discovery and validation data. In all four research tasks, there are notable over-optimism effects; the results on the validation data set are worse compared to the discovery data, averaged over multiple random splits into discovery/validation data. Our study thus highlights the importance of validation and replication in microbiome analysis to obtain reliable results and demonstrates that the issue of over-optimism goes beyond the context of statistical testing and fishing for significance.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Sebastian Sten, Henrik Podéus, Nicolas Sundqvist, Fredrik Elinder, Maria Engström, Gunnar Cedersund
Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied both experimentally and using mathematical models; various combinations of blood volume and flow, local field potential (LFP), hemoglobin level, blood oxygenation level-dependent response (BOLD), and optogenetics have been measured and modeled in rodents, primates, or humans. However, these data have not been brought together into a unified quantitative model. We now present a mathematical model that describes all such data types and that preserves mechanistic behaviors between experiments. For instance, from modeling of optogenetics and microscopy data in mice, we learn cell-specific contributions; the first rapid dilation in the vascular response is caused by NO-interneurons, the main part of the dilation during longer stimuli is caused by pyramidal neurons, and the post-peak undershoot is caused by NPY-interneurons. These insights are translated and preserved in all subsequent analyses, together with other insights regarding hemoglobin dynamics and the LFP/BOLD-interplay, obtained from other experiments on rodents and primates. The model can predict independent validation-data not used for training. By bringing together data with complementary information from different species, we both understand each dataset better, and have a basis for a new type of integrative analysis of human data.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Nicola Catenacci Volpi, Martin Greaves, Dari Trendafilov, Christoph Salge, Giovanni Pezzulo, Daniel Polani
The mastery of skills, such as balancing an inverted pendulum, implies a very accurate control of movements to achieve the task goals. Traditional accounts of skilled action control that focus on either routinization or perceptual control make opposite predictions about the ways we achieve mastery. The notion of routinization emphasizes the decrease of the variance of our actions, whereas the notion of perceptual control emphasizes the decrease of the variance of the states we visit, but not of the actions we execute. Here, we studied how participants managed control tasks of varying levels of difficulty, which consisted of controlling inverted pendulums of different lengths. We used information-theoretic measures to compare the predictions of alternative accounts that focus on routinization and perceptual control, respectively. Our results indicate that the successful performance of the control task strongly correlates with the decrease of state variability and the increase of action variability. As postulated by perceptual control theory, the mastery of skilled pendulum control consists in achieving stable control of goals by flexible means.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Jason Asher, Annabelle Lemenuel-Diot, Matthew Clay, David P. Durham, Luis Mier-y-Teran-Romero, Carlos J. Arguello, Sebastien Jolivet, Diana Y. Wong, Klaus Kuhlbusch, Barry Clinch, Jean-Eric Charoin
To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic–viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose–response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12–24 hours post symptom onset, the predicted transmission mitigation was 39.9–56.4% for baloxavir and 26.6–38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36–48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8–28.3% for baloxavir and 0.8–19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Connor Brennan, Adeeti Aggarwal, Rui Pei, David Sussillo, Alex Proekt
The relationship between neuronal activity and computations embodied by it remains an open question. We develop a novel methodology that condenses observed neuronal activity into a quantitatively accurate, simple, and interpretable model and validate it on diverse systems and scales from single neurons in C. elegans to fMRI in humans. The model treats neuronal activity as collections of interlocking 1-dimensional trajectories. Despite their simplicity, these models accurately predict future neuronal activity and future decisions made by human participants. Moreover, the structure formed by interconnected trajectories—a scaffold—is closely related to the computational strategy of the system. We use these scaffolds to compare the computational strategy of primates and artificial systems trained on the same task to identify specific conditions under which the artificial agent learns the same strategy as the primate. The computational strategy extracted using our methodology predicts specific errors on novel stimuli. These results show that our methodology is a powerful tool for studying the relationship between computation and neuronal activity across diverse systems.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Junping Li, Lin Gao, Yusen Ye
Structural variations (SVs) play an essential role in the evolution of human genomes and are associated with cancer genetics and rare disease. High-throughput chromosome capture (Hi-C) technology probed all genome-wide crosslinked chromatin to study the spatial architecture of chromosomes. Hi-C read pairs can span megabases, making the technology useful for detecting large-scale SVs. So far, the identification of SVs from Hi-C data is still in the early stages with only a few methods available. Especially, no algorithm has been developed that can detect SVs without control samples. Therefore, we developed HiSV (Hi-C for Structural Variation), a control-free method for identifying large-scale SVs from a Hi-C sample. Inspired by the single image saliency detection model, HiSV constructed a saliency map of interaction frequencies and extracted saliency segments as large-scale SVs. By evaluating both simulated and real data, HiSV not only detected all variant types, but also achieved a higher level of accuracy and sensitivity than existing methods. Moreover, our results on cancer cell lines showed that HiSV effectively detected eight complex SV events and identified two novel SVs of key factors associated with cancer development. Finally, we found that integrating the result of HiSV helped the WGS method to identify a total number of 94 novel SVs in two cancer cell lines.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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by Souvik Seal, Qunhua Li, Elle Butler Basner, Laura M. Saba, Katerina Kechris
Inferring gene co-expression networks is a useful process for understanding gene regulation and pathway activity. The networks are usually undirected graphs where genes are represented as nodes and an edge represents a significant co-expression relationship. When expression data of multiple (p) genes in multiple (K) conditions (e.g., treatments, tissues, strains) are available, joint estimation of networks harnessing shared information across them can significantly increase the power of analysis. In addition, examining condition-specific patterns of co-expression can provide insights into the underlying cellular processes activated in a particular condition. Condition adaptive fused graphical lasso (CFGL) is an existing method that incorporates condition specificity in a fused graphical lasso (FGL) model for estimating multiple co-expression networks. However, with computational complexity of O(p2K log K), the current implementation of CFGL is prohibitively slow even for a moderate number of genes and can only be used for a maximum of three conditions. In this paper, we propose a faster alternative of CFGL named rapid condition adaptive fused graphical lasso (RCFGL). In RCFGL, we incorporate the condition specificity into another popular model for joint network estimation, known as fused multiple graphical lasso (FMGL). We use a more efficient algorithm in the iterative steps compared to CFGL, enabling faster computation with complexity of O(p2K) and making it easily generalizable for more than three conditions. We also present a novel screening rule to determine if the full network estimation problem can be broken down into estimation of smaller disjoint sub-networks, thereby reducing the complexity further. We demonstrate the computational advantage and superior performance of our method compared to two non-condition adaptive methods, FGL and FMGL, and one condition adaptive method, CFGL in both simulation study and real data analysis. We used RCFGL to jointly estimate the gene co-expression networks in different brain regions (conditions) using a cohort of heterogeneous stock rats. We also provide an accommodating C and Python based package that implements RCFGL.
in PLoS Computational Biology on 2023-01-06 14:00:00 UTC.
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Background: The number of Tuberculosis (TB) cases or deaths is declining, however, the rate of decline is not adequate to meet the World Health Organization's (WHO's) mitigation. TB remains a public health problem in Ghana with a significant economic and health burden on its citizens and health care system. Consequently, there is a need for further studies about the disease aimed at accelerating the rate of decline in cases. Methods: The spatio-temporal characteristics of TB in Ghana using Bayesian spatial and spatio-temporal regression models was analysed in this study. Data were obtained from Ghana National Tuberculosis Programme (NTP) for the 10 regions of Ghana, collected over a six-year period. The study also examines some baseline predictors of TB infections to ascertain their effects on the TB risk across the ten regions in Ghana. Results: Hot-spots of TB cases are observed in the Upper East, Upper West, Volta, Western, and Central regions and low risk in the Northern, Ashanti, Greater Accra, Brong Ahafo, Eastern and Western regions. The results indicated a clustering of risk between neighboring regions. TB cure rate, TB success rate, knowledge about TB, awareness that TB is airborne, HIV prevalence, percentage of literacy, and high income are important predictors of detection for this disease across the ten regions of Ghana. Conclusion: Most regions in Ghana have similar TB risks. A substantial reduction in TB cases requires measures that will increase detection, success and cure rates, awareness, knowledge about how this disease spreads as well adequate health facilities with easy access.
in F1000Research on 2023-01-06 13:50:07 UTC.
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Identification of synaptic partners is an essential task for systems neuroscience. Here we present a tool for cell-type specific anterograde monosynaptic tracing utilizing the predominantly anterograde HSV strain H129. The knockout of the capsid portal protein UL6 from a previously derived cre-dependent version of HSV H129 prohibits genome packaging and production of infectious particles. Rescue of this knockout by expression of UL6 from a cre-dependent AAV allows for production of infectious HSV particles that travel to downstream synaptic partners, but no further. We detail the application of this system in five non-reciprocal neural circuits and caveats important for perspective users.
Abstract
Identification of synaptic partners is a fundamental task for systems neuroscience. To date, few reliable techniques exist for whole brain labeling of downstream synaptic partners in a cell-type-dependent and monosynaptic manner. Herein, we describe a novel monosynaptic anterograde tracing system based on the deletion of the gene UL6 from the genome of a cre-dependent version of the anterograde Herpes Simplex Virus 1 strain H129. Given that this knockout blocks viral genome packaging and thus viral spread, we reasoned that co-infection of a HSV H129 ΔUL6 virus with a recombinant adeno-associated virus expressing UL6 in a cre-dependent manner would result in monosynaptic spread from target cre-expressing neuronal populations. Application of this system to five nonreciprocal neural circuits resulted in labeling of neurons in expected projection areas. While some caveats may preclude certain applications, this system provides a reliable method to label postsynaptic partners in a brain-wide fashion.
in Journal of Comparative Neurology on 2023-01-06 12:44:09 UTC.
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Background: 3D-printing has shown potential in several medical advances because of its ability to create patient-specific surgical models and instruments. In fact, this technology makes it possible to acquire and study physical models that accurately reproduce patient-specific anatomy. The challenge is to apply 3D-printing to reproduce the porous structure of a bone tissue, consisting of compact bone, spongy bone and bone marrow. Methods: An interesting approach is presented here for reproducing the structure of a bone tissue of a femur by 3D-printing porous structure. Through the process of CT segmentation, the distribution of bone density was analysed. In 3D-printing, the bone density was compared with the density of infill. Results: The zone of compact bone, the zone of spongy bone and the zone of bone marrow can be recognized in the 3D printed model by a porous density additive manufacturing method. Conclusions: The application of 3D-printing to reproduce a porous structure, such as that of a bone, makes it possible to obtain physical anatomical models that likely represent the internal structure of a bone tissue. This process is low cost and easily reproduced.
in F1000Research on 2023-01-06 12:38:41 UTC.
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Background: Migration is a milestone event in a person’s life, bringing with it the challenges of settling down in an unfamiliar environment. The age at which migration takes place and the way migrants negotiate their old and new world significantly impacts their mental health. Thus, this systematic review seeks to analyse and summarize existing research detailing the contexts in which people migrate later in life and the associations between these contexts and social determinants of their mental health and well-being. Methods: Seven databases including PsycINFO, Web of Science, PubMed, Applied Social Sciences Index, Abstracts: ASSIA, Ageline, CINAHL, and Informit will be searched systematically for original journal articles published in English. In the first screening stage, the first reviewer (PB) will screen all titles and abstracts and mark all potentially eligible texts for full-text screening. The second reviewer (HM) will review the decisions made. Any potential conflicts will be resolved with discussion. Afterward, full texts of potentially eligible studies will be assessed for eligibility by two reviewers (PB and HM). The methodological quality (or risk of bias) of individual studies will be appraised using the Mixed Method Appraisal Tool. The thematic synthesis of the data will be performed using a hybrid approach incorporating deductive (framed against the social determinants of health using intersectionality as a lens) and inductive data-driven processes. The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Reg: CRD42022359881).
in F1000Research on 2023-01-06 11:56:34 UTC.
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Objective
For decades it has been suggested that small dense low-density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke.
Methods
This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow-up time was 3.1 years. We observed 302 and 74 ischemic and haemorrhagic strokes from baseline in 2013-2017 to end of follow-up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol.
Results
Higher levels of sdLDL cholesterol were log-linearly associated with increased risk of ischemic stroke. Compared to individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/L; ≤23 mg/dL) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95%confidence interval: 1.31-2.43) for the highest tertile (≥0.86 mmol/L; ≥33 mg/dL). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/L (38.7 mg/dL) higher levels were 1.69 (1.28-2.22) for sdLDL cholesterol, 0.95 (0.78-1.16) for large buoyant LDL cholesterol, and 1.08 (0.93-1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for BMI and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins.
Interpretation
Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke.
This article is protected by copyright. All rights reserved.
in Annals of Neurology on 2023-01-06 10:43:19 UTC.
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Author(s): Garrett Zills, Trinanjan Datta, and Abdul Naseer Malmi-Kakkada
Cells are dynamic systems characterized by temporal variations in biophysical properties such as stiffness and contractility. Recent studies show that the recruitment and release of actin filaments into and out of the cell cortex—a network of proteins underneath the cell membrane—leads to cell stiff…
[Phys. Rev. E 107, 014401] Published Fri Jan 06, 2023
in Physical Review E: Biological physics on 2023-01-06 10:00:00 UTC.
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Author(s): Lee Jinwoo
When a system is in equilibrium, external perturbations yield a time series of nonequilibrium distributions, and recent experimental techniques give access to the nonequilibrium data that may contain critical information. Jinwoo and Tanaka [Sci. Rep. 5, 7832 (2015)] have provided mathematical proof …
[Phys. Rev. E 107, 014402] Published Fri Jan 06, 2023
in Physical Review E: Biological physics on 2023-01-06 10:00:00 UTC.
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Science, Volume 379, Issue 6627, January 2023.
in Science on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.
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Science Advances, Volume 9, Issue 1, January 2023.
in Science Advances on 2023-01-06 08:00:00 UTC.