• #### Journal of Neurology

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Contribution of multi-modal imaging to our understanding of dystonia pathogenesis

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Correction to: DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

A correction to this paper has been published: https://doi.org/10.1007/s00415-021-10644-0

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Correction to: Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

A correction to this paper has been published: https://doi.org/10.1007/s00415-021-10634-2

in Journal of Neurology on August 01, 2021 12:00 AM.

### Abstract

Many neuropsychological disorders, especially attentional abnormality, are present in patients with myotonic dystrophy type 1 (DM1), but the underlying mechanisms remain unclear. This study aimed to evaluate attention function by auditory event-related potential (ERP) P3a (novelty paradigm) in DM1 patients. A total of 10 young DM1 patients (mean age 30.4 years) and 14 age-matched normal controls participated in this study. ERPs were recorded using an auditory novel paradigm, consisting of three types of stimuli, i.e., standard sound (70%), target sound (20%), and various novel sounds (10%), and participants pressed buttons to the target sounds. ERP components P3b after the target stimuli and P3a following the novel stimuli were analyzed. Correlations of neuropsychological evaluations with the amplitudes and latencies of P3b and P3a were analyzed in DM1 patients. We found that P3a latency was significantly delayed in patients with DM1 compared with normal controls, although the latency and amplitude of P3b in DM1 patients were comparable with those in normal controls. The achievement rates of both the Symbol Digit Modality Test and the Paced Auditory Serial Addition Test were significantly correlated with P3a amplitude, as well as P3b amplitude. These results suggest that ERPs, including P3a and P3b, provide important insights into the physiological basis of neuropsychological abnormalities in patients with DM1, especially from the viewpoint of the frontal lobe and attention function.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Abstract

Previous studies have reported an association between anti-tumor necrosis factor alpha (anti-TNFα) treatment and central nervous system (CNS) events. We described eight patients presenting with demyelinating CNS events while on treatment with anti-TNFα for autoimmune diseases and followed up for a medium period of 4 years. Four patients presented with isolated demyelinating events, three patients fulfilled the criteria for multiple sclerosis (MS), and one patient showed worsening of pre-existing MS after anti-TNF therapy initiation. All patients except one, showed a good medium-term prognosis. Our observation supports an association between anti-TNFα treatment and demyelinating events and suggests that a prompt discontinuation of the drug may lead to a favorable demyelinating disease outcome.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Background

Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS).

### Objective

Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL).

### Methods

We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL.

### Results

In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5–18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5–1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (p = 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (r = 0.56, p = 0.028), but not in the PCNSL group (r = 0.3, p = 0.13).

We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (p < 0.001).

### Discussion and conclusions

Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Abstract

We report a 57-year-old man with recurrent meningoencephalitis resulting in bouts of altered consciousness, encephalopathy, tremors, focal seizures, and paraparesis. The neurological manifestations were accompanied by fever and leukocytosis in the absence of other systemic manifestations. MRI abnormalities of the brain, brainstem, spinal cord and meninges and CSF pleocytosis and elevated protein were observed. Exhaustive studies failed to reveal an etiology. Brain biopsy revealed nodules of neutrophils and macrophages, but no vasculitis. The lesions were not vasocentric as would be expected with neuro-Behcet’s disease and neuro-Sweet’s disease. The disorder was responsive to high-dose corticosteroid therapy and, ultimately, to anakinra, an IL-1α and IL-1β receptor antagonist.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Abstract

The prolonged mechanical ventilation that is often required by patients with severe COVID-19 is expected to result in significant intensive care unit-acquired weakness (ICUAW) in many of the survivors. However, in our post-COVID-19 follow-up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to multiple axonal mononeuropathies. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such a mononeuritis multiplex. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to relate simply to “critical illness neuromyopathy”. While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are surprisingly frequent and often disabling in patients recovering from severe COVID-19.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Background and purpose

During the COVID-19 outbreak, the presence of extensive white matter microhemorrhages was detected by brain MRIs. The goal of this study was to investigate the origin of this atypical hemorrhagic complication.

### Methods

Between March 17 and May 18, 2020, 80 patients with severe COVID-19 infections were admitted for acute respiratory distress syndrome to intensive care units at the University Hospitals of Strasbourg for whom a brain MRI for neurologic manifestations was performed. 19 patients (24%) with diffuse microhemorrhages were compared to 18 control patients with COVID-19 and normal brain MRI.

### Results

The first hypothesis was hypoxemia. The latter seemed very likely since respiratory failure was longer and more pronounced in patients with microhemorrhages (prolonged endotracheal intubation (p = 0.0002), higher FiO2 (p = 0.03), increased use of extracorporeal membrane oxygenation (p = 0.04)). A relevant hypothesis, the role of microangiopathy, was also considered, since patients with microhemorrhages presented a higher increase of the D-Dimers (p = 0.01) and a tendency to more frequent thrombotic events (p = 0.12). Another hypothesis tested was the role of kidney failure, which was more severe in the group with diffuse microhemorrhages (higher creatinine level [median of 293 µmol/L versus 112 µmol/L, p = 0.04] and more dialysis were introduced in this group during ICU stay [12 versus 5 patients, p = 0.04]).

### Conclusions

Blood–brain barrier dysfunction secondary to hypoxemia and high concentration of uremic toxins seems to be the main mechanism leading to critical illness-associated cerebral microbleeds, and this complication remains to be frequently described in severe COVID-19 patients.

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Myasthenic crisis following SARS-CoV-2 infection and delayed virus clearance in a patient treated with rituximab: clinical course and 6-month follow-up

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### COVID-19 in cladribine-treated relapsing-remitting multiple sclerosis patients: a monocentric experience

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Ludwig Horn (1897–1935)

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Hans Joachim Scherer (1906–1945)

in Journal of Neurology on August 01, 2021 12:00 AM.

### Objective

To perform an updated review of the literature on the neurological manifestations of COVID-19-infected patients

### Methods

A PRISMA-guideline-based systematic review was conducted on PubMed, EMBASE, and SCOPUS. Series reporting neurological manifestations of COVID-19 patients were studied.

### Results

39 studies and 68,361 laboratory-confirmed COVID-19 patients were included. Up to 21.3% of COVID-19 patients presented neurological symptoms. Headache (5.4%), skeletal muscle injury (5.1%), psychiatric disorders (4.6%), impaired consciousness (2.8%), gustatory/olfactory dysfunction (2.3%), acute cerebrovascular events (1.4%), and dizziness (1.3%), were the most frequently reported neurological manifestations. Ischemic stroke occurred among 1.3% of COVID-19 patients. Other less common neurological manifestations were cranial nerve impairment (0.6%), nerve root and plexus disorders (0.4%), epilepsy (0.7%), and hemorrhagic stroke (0.15%). Impaired consciousness and acute cerebrovascular events were reported in 14% and 4% of patients with a severe disease, respectively, and they were significantly higher compared to non-severe patients (p < 0.05). Individual patient data from 129 COVID-19 patients with acute ischemic stroke (AIS) were extracted: mean age was 64.4 (SD ± 6.2), 78.5% had anterior circulation occlusions, the mean NIHSS was 15 (SD ± 7), and the intra-hospital mortality rate was 22.8%. Admission to the intensive care unit (ICU) was required among 63% of patients.

### Conclusion

This updated review of literature, shows that headache, skeletal muscle injury, psychiatric disorders, impaired consciousness, and gustatory/olfactory dysfunction were the most common neurological symptoms of COVID-19 patients. Impaired consciousness and acute cerebrovascular events were significantly higher among patients with a severe infection. AIS patients required ICU admission in 63% of cases, while intra-hospital mortality rate was close to 23%.

in Journal of Neurology on August 01, 2021 12:00 AM.

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Janina Hurynowicz (1894–1967)

in Journal of Neurology on August 01, 2021 12:00 AM.

### Objective

To report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.

### Methods

We retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.

### Results

Five patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1–10 days). No adverse events related to IVIg were observed.

### Conclusions

Our preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Correction to: Heritable and non-heritable uncommon causes of stroke

The original version of this article unfortunately contained a mistake. Figure 3 caption is incorrect and co-author name should be E.Tournier-Lasserve.

in Journal of Neurology on August 01, 2021 12:00 AM.

### Abstract

Valproate is a broad-spectrum antiepileptic drug (AED) of particular interest in pediatric epilepsy syndromes and idiopathic generalized epilepsy, as it is relatively more effective in these syndromes than other AEDs. In 2018, the European Medicines Agency introduced new restrictions on the use of valproate in girls and women of childbearing potential to avoid exposure during pregnancy. The strengthening of existing restrictions sparked controversy and debate among patients and the medical community. The high prevalence of epilepsy syndromes amenable to valproate treatment in women of childbearing age and the little information available on the teratogenic potential of alternative treatments have created uncertainty on how to manage these patients. In this consensus statement, based on a review of the literature and the clinical experience of a panel of European epilepsy experts, we present general recommendations for the optimal clinical management of AED treatment in girls, women of childbearing potential, and pregnant women across the different epilepsy syndromes.

in Journal of Neurology on August 01, 2021 12:00 AM.

• #### Into Summarization Techniques for IoT Data Discovery Routing. (arXiv:2107.09558v1 [cs.NI])

In this paper, we consider the IoT data discovery data objects to specific nodes in the network. They are very problem in very large and growing scale networks. Specifically, we investigate in depth the routing table summarization techniques to support effective and space-efficient IoT data discovery routing. Novel summarization algorithms, including alphabetical based, hash based, and meaning based summarization and their corresponding coding schemes are proposed. The issue of potentially misleading routing due to summarization is also investigated. Subsequently, we analyze the strategy of when to summarize in order to balance the tradeoff especially in handling MAA based lookups. between the routing table compression rate and the chance of Unstructured discovery routing approaches, such as [4] [5], causing misleading routing. For experimental study, we have collected 100K IoT data streams from various IoT databases as the input dataset. Experimental results show that our summarization solution can reduce the routing table size by 20 to 30 folds with 2-5% increase in latency when compared with similar peer-to-peer discovery routing algorithms without summarization. Also, our approach outperforms DHT based approaches by 2 to 6 folds in terms of latency and traffic.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### EEG-based Cross-Subject Driver Drowsiness Recognition with Interpretable CNN. (arXiv:2107.09507v1 [eess.SP])

In the context of electroencephalogram (EEG)-based driver drowsiness recognition, it is still a challenging task to design a calibration-free system, since there exists a significant variability of EEG signals among different subjects and recording sessions. As deep learning has received much research attention in recent years, many efforts have been made to use deep learning methods for EEG signal recognition. However, existing works mostly treat deep learning models as blackbox classifiers, while what have been learned by the models and to which extent they are affected by the noise from EEG data are still underexplored. In this paper, we develop a novel convolutional neural network that can explain its decision by highlighting the local areas of the input sample that contain important information for the classification. The network has a compact structure for ease of interpretation and takes advantage of separable convolutions to process the EEG signals in a spatial-temporal sequence. Results show that the model achieves an average accuracy of 78.35% on 11 subjects for leave-one-out cross-subject drowsiness recognition, which is higher than the conventional baseline methods of 53.4%-72.68% and state-of-art deep learning methods of 63.90%-65.61%. Visualization results show that the model has learned to recognize biologically explainable features from EEG signals, e.g., Alpha spindles, as strong indicators of drowsiness across different subjects. In addition, we also explore reasons behind some wrongly classified samples and how the model is affected by artifacts and noise in the data. Our work illustrates a promising direction on using interpretable deep learning models to discover meaning patterns related to different mental states from complex EEG signals.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### Predicting Friction System Performance with Symbolic Regression and Genetic Programming with Factor Variables. (arXiv:2107.09484v1 [cs.LG])

Friction systems are mechanical systems wherein friction is used for force transmission (e.g. mechanical braking systems or automatic gearboxes). For finding optimal and safe design parameters, engineers have to predict friction system performance. This is especially difficult in real-world applications, because it is affected by many parameters. We have used symbolic regression and genetic programming for finding accurate and trustworthy prediction models for this task. However, it is not straight-forward how nominal variables can be included. In particular, a one-hot-encoding is unsatisfactory because genetic programming tends to remove such indicator variables. We have therefore used so-called factor variables for representing nominal variables in symbolic regression models. Our results show that GP is able to produce symbolic regression models for predicting friction performance with predictive accuracy that is comparable to artificial neural networks. The symbolic regression models with factor variables are less complex than models using a one-hot encoding.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### Using Shape Constraints for Improving Symbolic Regression Models. (arXiv:2107.09458v1 [cs.NE])

We describe and analyze algorithms for shape-constrained symbolic regression, which allows the inclusion of prior knowledge about the shape of the regression function. This is relevant in many areas of engineering -- in particular whenever a data-driven model obtained from measurements must have certain properties (e.g. positivity, monotonicity or convexity/concavity). We implement shape constraints using a soft-penalty approach which uses multi-objective algorithms to minimize constraint violations and training error. We use the non-dominated sorting genetic algorithm (NSGA-II) as well as the multi-objective evolutionary algorithm based on decomposition (MOEA/D). We use a set of models from physics textbooks to test the algorithms and compare against earlier results with single-objective algorithms. The results show that all algorithms are able to find models which conform to all shape constraints. Using shape constraints helps to improve extrapolation behavior of the models.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### An induction proof of the backpropagation algorithm in matrix notation. (arXiv:2107.09384v1 [stat.ML])

Backpropagation (BP) is a core component of the contemporary deep learning incarnation of neural networks. Briefly, BP is an algorithm that exploits the computational architecture of neural networks to efficiently evaluate the gradient of a cost function during neural network parameter optimization. The validity of BP rests on the application of a multivariate chain rule to the computational architecture of neural networks and their associated objective functions. Introductions to deep learning theory commonly present the computational architecture of neural networks in matrix form, but eschew a parallel formulation and justification of BP in the framework of matrix differential calculus. This entails several drawbacks for the theory and didactics of deep learning. In this work, we overcome these limitations by providing a full induction proof of the BP algorithm in matrix notation. Specifically, we situate the BP algorithm in the framework of matrix differential calculus, encompass affine-linear potential functions, prove the validity of the BP algorithm in inductive form, and exemplify the implementation of the matrix form BP algorithm in computer code.

in arXiv: Quantitative Biology: Neurons and Cognition on July 21, 2021 01:30 AM.

• #### A biophysical network model reveals the link between deficient inhibitory cognitive control and major neurotransmitter and neural connectivity hypotheses in schizophrenia. (arXiv:2107.09360v1 [q-bio.NC])

We address a biophysical network dynamical model to study how the modulation of dopamine (DA) activity and related N-methyl-d-aspartate (NMDA) glutamate receptor activity as well as the emerging Pre-Frontal Cortex (PFC) functional connectivity network (FCN) affect inhibitory cognitive function in schizophrenia in an antisaccade task. The values of the model parameters and the topology of the PFC-FCN were estimated by minimizing the differences between simulations and the observed distributions of reaction times (RT) during the performance of the antisaccade task in 30 patients with schizophrenia and 30 healthy controls. We show that the proposed model approximates remarkably well the predicted prefrontal cortical DA hypo-activity and the related NMDA receptor hypo-function as well as the FCN dysconnection pattern that are considered as the major etio-pathological hypotheses to explain cognitive deficits in schizophrenia.

in arXiv: Quantitative Biology: Neurons and Cognition on July 21, 2021 01:30 AM.

• #### LENS: Layer Distribution Enabled Neural Architecture Search in Edge-Cloud Hierarchies. (arXiv:2107.09309v1 [cs.LG])

Edge-Cloud hierarchical systems employing intelligence through Deep Neural Networks (DNNs) endure the dilemma of workload distribution within them. Previous solutions proposed to distribute workloads at runtime according to the state of the surroundings, like the wireless conditions. However, such conditions are usually overlooked at design time. This paper addresses this issue for DNN architectural design by presenting a novel methodology, LENS, which administers multi-objective Neural Architecture Search (NAS) for two-tiered systems, where the performance objectives are refashioned to consider the wireless communication parameters. From our experimental search space, we demonstrate that LENS improves upon the traditional solution's Pareto set by 76.47% and 75% with respect to the energy and latency metrics, respectively.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### Rethinking the limiting dynamics of SGD: modified loss, phase space oscillations, and anomalous diffusion. (arXiv:2107.09133v1 [cs.LG])

In this work we explore the limiting dynamics of deep neural networks trained with stochastic gradient descent (SGD). We find empirically that long after performance has converged, networks continue to move through parameter space by a process of anomalous diffusion in which distance travelled grows as a power law in the number of gradient updates with a nontrivial exponent. We reveal an intricate interaction between the hyperparameters of optimization, the structure in the gradient noise, and the Hessian matrix at the end of training that explains this anomalous diffusion. To build this understanding, we first derive a continuous-time model for SGD with finite learning rates and batch sizes as an underdamped Langevin equation. We study this equation in the setting of linear regression, where we can derive exact, analytic expressions for the phase space dynamics of the parameters and their instantaneous velocities from initialization to stationarity. Using the Fokker-Planck equation, we show that the key ingredient driving these dynamics is not the original training loss, but rather the combination of a modified loss, which implicitly regularizes the velocity, and probability currents, which cause oscillations in phase space. We identify qualitative and quantitative predictions of this theory in the dynamics of a ResNet-18 model trained on ImageNet. Through the lens of statistical physics, we uncover a mechanistic origin for the anomalous limiting dynamics of deep neural networks trained with SGD.

in arXiv: Quantitative Biology: Neurons and Cognition on July 21, 2021 01:30 AM.

• #### Quality Evolvability ES: Evolving Individuals With a Distribution of Well Performing and Diverse Offspring. (arXiv:2103.10790v2 [cs.NE] UPDATED)

One of the most important lessons from the success of deep learning is that learned representations tend to perform much better at any task compared to representations we design by hand. Yet evolution of evolvability algorithms, which aim to automatically learn good genetic representations, have received relatively little attention, perhaps because of the large amount of computational power they require. The recent method Evolvability ES allows direct selection for evolvability with little computation. However, it can only be used to solve problems where evolvability and task performance are aligned. We propose Quality Evolvability ES, a method that simultaneously optimizes for task performance and evolvability and without this restriction. Our proposed approach Quality Evolvability has similar motivation to Quality Diversity algorithms, but with some important differences. While Quality Diversity aims to find an archive of diverse and well-performing, but potentially genetically distant individuals, Quality Evolvability aims to find a single individual with a diverse and well-performing distribution of offspring. By doing so Quality Evolvability is forced to discover more evolvable representations. We demonstrate on robotic locomotion control tasks that Quality Evolvability ES, similarly to Quality Diversity methods, can learn faster than objective-based methods and can handle deceptive problems.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### Network community structure and resilience to localized damage: application to brain microcirculation. (arXiv:2103.08587v2 [physics.bio-ph] UPDATED)

In cerebrovascular networks, some vertices are more connected to each other than with the rest of the vasculature, defining a community structure. Here, we introduce a class of model networks built by rewiring Random Regular Graphs, which enables to reproduce this community structure and other topological properties of cerebrovascular networks. We use these model networks to study the global flow reduction induced by the removal of a single edge. We analytically show that this global flow reduction can be expressed as a function of the initial flow rate in the removed edge and of a topological quantity, both of which display probability distributions following Cauchy laws, i.e. with large tails. As a result, we show that the distribution of blood flow reductions is strongly influenced by the community structure. In particular, the probability of large flow reductions increases substantially when the community structure is stronger, weakening the network resilience to single capillary occlusions. We discuss the implications of these findings in the context of Alzheimer's Disease, in which the importance of vascular mechanisms, including capillary occlusions, is beginning to be uncovered.

in arXiv: Quantitative Biology: Neurons and Cognition on July 21, 2021 01:30 AM.

• #### A Biologically Plausible Audio-Visual Integration Model for Continual Learning. (arXiv:2007.08855v2 [cs.NE] UPDATED)

The problem of catastrophic forgetting has a history of more than 30 years and has not been completely solved yet. Since the human brain has natural ability to perform continual lifelong learning, learning from the brain may provide solutions to this problem. In this paper, we propose a novel biologically plausible audio-visual integration model (AVIM) based on the assumption that the integration of audio and visual perceptual information in the medial temporal lobe during learning is crucial to form concepts and make continual learning possible. Specifically, we use multi-compartment Hodgkin-Huxley neurons to build the model and adopt the calcium-based synaptic tagging and capture as the model's learning rule. Furthermore, we define a new continual learning paradigm to simulate the possible continual learning process in the human brain. We then test our model under this new paradigm. Our experimental results show that the proposed AVIM can achieve state-of-the-art continual learning performance compared with other advanced methods such as OWM, iCaRL and GEM. Moreover, it can generate stable representations of objects during learning. These results support our assumption that concept formation is essential for continuous lifelong learning and suggest the proposed AVIM is a possible concept formation mechanism.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 21, 2021 01:30 AM.

• #### Inflammation clock, mini vaccine dose and genome editing

Nature, Published online: 21 July 2021; doi:10.1038/d41586-021-01965-1

The latest science news, in brief.

in Nature on July 21, 2021 12:00 AM.

• #### Differences in Alzheimer’s Disease and Related Dementias Pathology Among African American and Hispanic Women: A Qualitative Literature Review of Biomarker Studies

Introduction

The population of older adults with Alzheimer’s disease and Related Dementias (ADRD) is growing larger and more diverse. Prevalence of ADRD is higher in African American (AA) and Hispanic populations relative to non-Hispanic whites (nHW), with larger differences for women compared to men of the same race. Given the public health importance of this issue, we sought to determine if AA and Hispanic women exhibit worse ADRD pathology compared to men of the same race and nHW women. We hypothesized that such differences may explain the discrepancy in ADRD prevalence.

Methods

We evaluated 932 articles that measured at least one of the following biomarkers of ADRD pathology in vivo and/or post-mortem: beta-amyloid (Aß), tau, neurodegeneration, and cerebral small vessel disease (cSVD). Criteria for inclusion were: (1) mean age of participants >65 years; (2) inclusion of nHW participants and either AA or Hispanics or both; (3) direct comparison of ADRD pathology between racial groups.

Results

We included 26 articles (Aß = 9, tau = 6, neurodegeneration = 16, cSVD = 18), with seven including sex-by-race comparisons. Studies differed by sampling source (e.g., clinic or population), multivariable analytical approach (e.g., adjusted for risk factors for AD), and cognitive status of participants. Aß burden did not differ by race or sex. Tau differed by race (AA < nHW), and by sex (women > men). Both severity of neurodegeneration and cSVD differed by race (AA > nHW; Hispanics < nHW) and sex (women < men). Among the studies that tested sex-by-race interactions, results were not significant.

Conclusion

Few studies have examined the burden of ADRD pathology by both race and sex. The higher prevalence of ADRD in women compared to men of the same race may be due to both higher tau load and more vulnerability to cognitive decline in the presence of similar Aß and cSVD burden. AA women may also exhibit more neurodegeneration and cSVD relative to nHW populations. Studies suggest that between-group differences in ADRD pathology are complex, but they are too sparse to completely explain why minority women have the highest ADRD prevalence. Future work should recruit diverse cohorts, compare ADRD biomarkers by both race and sex, and collect relevant risk factor and cognitive data.

in Frontiers in Systems Neuroscience on July 21, 2021 12:00 AM.

• #### Presence of Vessel Wall Hyperintensity in Unruptured Arteriovenous Malformations on Vessel Wall Magnetic Resonance Imaging: Pilot Study of AVM Vessel Wall “Enhancement”

Purpose: High-resolution vessel wall magnetic resonance imaging (VW-MRI) could provide a way to identify high risk arteriovenous malformation (AVM) features. We present the first pilot study of clinically unruptured AVMs evaluated by high-resolution VW-MRI.

Methods: A retrospective review of clinically unruptured AVMs with VW-MRI between January 1, 2016 and December 31, 2018 was performed documenting the presence or absence of vessel wall “hyperintensity,” or enhancement, within the nidus as well as perivascular enhancement and evidence of old hemorrhage (EOOH). The extent of nidal vessel wall “hyperintensity” was approximated into five groups: 0, 1–25, 26–50, 51–75, and 76–100%.

Results: Of the nine cases, eight demonstrated at least some degree of vessel wall nidus “hyperintensity.” Of those eight cases, four demonstrated greater than 50% of the nidus with hyperintensity at the vessel wall, and three cases had perivascular enhancement adjacent to nidal vessels. Although none of the subjects had prior clinical hemorrhage/AVM rupture, of the six patients with available susceptibility weighted imaging to assess for remote hemorrhage, only two had subtle siderosis to suggest prior sub-clinical bleeds.

Conclusion: Vessel wall “enhancement” occurs in AVMs with no prior clinical rupture. Additional studies are needed to further investigate the implication of these findings.

in Frontiers in Neuroscience: Brain Imaging Methods on July 21, 2021 12:00 AM.

• #### The Effect of Social Distance on Intertemporal Choice of Reward Processing: An Event-Related Potentials Study

Social factors can affect the processing of intertemporal choice, but the influence of social distance on the rewarding process of intertemporal choice is unclear. Therefore, by designing a novel cognitive resource competition paradigm for undifferentiated intertemporal choice, this article aims to explore the influence of social distance on intertemporal choice reward processing at the electrophysiological level. It was found that compared with the stranger condition, P3a is greater in the friend condition, which means social distance is evaluated in the early stage. In addition, different brain regions in the early stages are taking charge of processing the soon-but-small (SS) and later-but-lager (LL) reward in intertemporal choice. There is an interaction effect between social distance (friend vs. stranger) and intertemporal choice (SS reward vs. LL reward) on P3b. Under friend conditions, the P3b induced by LL reward is more positive than SS reward. Under the condition of choosing the LL reward, the P3b induced by friend is more positive than stranger. This result shows that in the latter stage of reward processing, the evaluation process of time discounting is less sensitive in LL reward for friend caused by lack of cognitive resources which is occupied when dealing with social distance in advance, and thus the degree of time discount was reduced. These findings demonstrate that P3b is the key index of time discounting and immediate and delayed rewards are valued in different brain regions.

in Frontiers in Human Neuroscience on July 21, 2021 12:00 AM.

• #### In Patients With Parkinson’s Disease in an OFF-Medication State, Does Bilateral Electrostimulation of Tibialis Anterior Improve Anticipatory Postural Adjustments During Gait Initiation?

A complete lack of bilateral activation of tibialis anterior (TA) during gait initiation (GI), along with bradykinetic anticipatory postural adjustments (APAs), often occurs in patients with Parkinson’s disease (PD) in their OFF-medication state. Functional electrical stimulation (FES) is a non-pharmacological method frequently used in neurorehabilitation to optimize the effect of L-DOPA on locomotor function in this population. The present study tested the potential of bilateral application of FES on TA to improve GI in PD patients. Fourteen PD patients (OFF-medication state, Hoehn and Yahr state 2-3) participated in this study. They performed series of 10 GI trials on a force-plate under the following experimental conditions: (1) GI without FES (control group), (2) GI with 2Hz-FES (considered as a very low FES frequency condition without biomechanical effect; placebo group) and (3) GI with 40Hz-FES (test group). In (2) and (3), FES was applied bilaterally to the TA during APAs (300 mA intensity/300 μs pulse width). Main results showed that the peak of anticipatory backward center of pressure shift, the forward center of mass (COM) velocity and shift at foot off were significantly larger in the 40 Hz FES condition than in the control condition, while the duration of step execution was significantly shorter. In contrast, the capacity of participants to brake the fall of their COM remained unchanged across conditions. Globally taken, these results suggest that acute application of 40-Hz FES to the TA may improve the capacity of PD patients to generate APAs during GI, without altering their balance capacity. Future studies are required before considering that TA FES application might be a valuable tool to improve GI in PD patients and be relevant to optimize the effects of L-DOPA medication on locomotor function.

in Frontiers in Human Neuroscience on July 21, 2021 12:00 AM.

• #### A Deep Learning-Based Approach to Video-Based Eye Tracking for Human Psychophysics

Real-time gaze tracking provides crucial input to psychophysics studies and neuromarketing applications. Many of the modern eye-tracking solutions are expensive mainly due to the high-end processing hardware specialized for processing infrared-camera pictures. Here, we introduce a deep learning-based approach which uses the video frames of low-cost web cameras. Using DeepLabCut (DLC), an open-source toolbox for extracting points of interest from videos, we obtained facial landmarks critical to gaze location and estimated the point of gaze on a computer screen via a shallow neural network. Tested for three extreme poses, this architecture reached a median error of about one degree of visual angle. Our results contribute to the growing field of deep-learning approaches to eye-tracking, laying the foundation for further investigation by researchers in psychophysics or neuromarketing.

in Frontiers in Human Neuroscience on July 21, 2021 12:00 AM.

• #### From Visual Perception to Aesthetic Appeal: Brain Responses to Aesthetically Appealing Natural Landscape Movies

During aesthetically appealing visual experiences, visual content provides a basis for computation of affectively tinged representations of aesthetic value. How this happens in the brain is largely unexplored. Using engaging video clips of natural landscapes, we tested whether cortical regions that respond to perceptual aspects of an environment (e.g., spatial layout, object content and motion) were directly modulated by rated aesthetic appeal. Twenty-four participants watched a series of videos of natural landscapes while being scanned using functional magnetic resonance imaging (fMRI) and reported both continuous ratings of enjoyment (during the videos) and overall aesthetic judgments (after each video). Although landscape videos engaged a greater expanse of high-level visual cortex compared to that observed for images of landscapes, independently localized category-selective visual regions (e.g., scene-selective parahippocampal place area and motion-selective hMT+) were not significantly modulated by aesthetic appeal. Rather, a whole-brain analysis revealed modulations by aesthetic appeal in ventral (collateral sulcus) and lateral (middle occipital sulcus, posterior middle temporal gyrus) clusters that were adjacent to scene and motion selective regions. These findings suggest that aesthetic appeal per se is not represented in well-characterized feature- and category-selective regions of visual cortex. Rather, we propose that the observed activations reflect a local transformation from a feature-based visual representation to a representation of “elemental affect,” computed through information-processing mechanisms that detect deviations from an observer’s expectations. Furthermore, we found modulation by aesthetic appeal in subcortical reward structures but not in regions of the default-mode network (DMN) nor orbitofrontal cortex, and only weak evidence for associated changes in functional connectivity. In contrast to other visual aesthetic domains, aesthetically appealing interactions with natural landscapes may rely more heavily on comparisons between ongoing stimulation and well-formed representations of the natural world, and less on top-down processes for resolving ambiguities or assessing self-relevance.

in Frontiers in Human Neuroscience on July 21, 2021 12:00 AM.

• #### Learning Invariant Object and Spatial View Representations in the Brain Using Slow Unsupervised Learning

First, neurophysiological evidence for the learning of invariant representations in the inferior temporal visual cortex is described. This includes object and face representations with invariance for position, size, lighting, view and morphological transforms in the temporal lobe visual cortex; global object motion in the cortex in the superior temporal sulcus; and spatial view representations in the hippocampus that are invariant with respect to eye position, head direction, and place. Second, computational mechanisms that enable the brain to learn these invariant representations are proposed. For the ventral visual system, one key adaptation is the use of information available in the statistics of the environment in slow unsupervised learning to learn transform-invariant representations of objects. This contrasts with deep supervised learning in artificial neural networks, which uses training with thousands of exemplars forced into different categories by neuronal teachers. Similar slow learning principles apply to the learning of global object motion in the dorsal visual system leading to the cortex in the superior temporal sulcus. The learning rule that has been explored in VisNet is an associative rule with a short-term memory trace. The feed-forward architecture has four stages, with convergence from stage to stage. This type of slow learning is implemented in the brain in hierarchically organized competitive neuronal networks with convergence from stage to stage, with only 4-5 stages in the hierarchy. Slow learning is also shown to help the learning of coordinate transforms using gain modulation in the dorsal visual system extending into the parietal cortex and retrosplenial cortex. Representations are learned that are in allocentric spatial view coordinates of locations in the world and that are independent of eye position, head direction, and the place where the individual is located. This enables hippocampal spatial view cells to use idiothetic, self-motion, signals for navigation when the view details are obscured for short periods.

in Frontiers in Computational Neuroscience on July 21, 2021 12:00 AM.

• #### Circuit Organization Underlying Optic Flow Processing in Zebrafish

Animals’ self-motion generates a drifting movement of the visual scene in the entire field of view called optic flow. Animals use the sensation of optic flow to estimate their own movements and accordingly adjust their body posture and position and stabilize the direction of gaze. In zebrafish and other vertebrates, optic flow typically drives the optokinetic response (OKR) and optomotor response (OMR). Recent functional imaging studies in larval zebrafish have identified the pretectum as a primary center for optic flow processing. In contrast to the view that the pretectum acts as a relay station of direction-selective retinal inputs, pretectal neurons respond to much more complex visual features relevant to behavior, such as spatially and temporally integrated optic flow information. Furthermore, optic flow signals, as well as motor signals, are represented in the cerebellum in a region-specific manner. Here we review recent findings on the circuit organization that underlies the optic flow processing driving OKR and OMR.

in Frontiers in Neural Circuits on July 21, 2021 12:00 AM.

• #### Persistent Activity During Working Memory From Front to Back

Working memory (WM) extends the duration over which information is available for processing. Given its importance in supporting a wide-array of high level cognitive abilities, uncovering the neural mechanisms that underlie WM has been a primary goal of neuroscience research over the past century. Here, we critically review what we consider the two major “arcs” of inquiry, with a specific focus on findings that were theoretically transformative. For the first arc, we briefly review classic studies that led to the canonical WM theory that cast the prefrontal cortex (PFC) as a central player utilizing persistent activity of neurons as a mechanism for memory storage. We then consider recent challenges to the theory regarding the role of persistent neural activity. The second arc, which evolved over the last decade, stemmed from sophisticated computational neuroimaging approaches enabling researchers to decode the contents of WM from the patterns of neural activity in many parts of the brain including early visual cortex. We summarize key findings from these studies, their implications for WM theory, and finally the challenges these findings pose. Our goal in doing so is to identify barriers to developing a comprehensive theory of WM that will require a unification of these two “arcs” of research.

in Frontiers in Neural Circuits on July 21, 2021 12:00 AM.

• #### Murine GRXCR1 Has a Different Function Than GRXCR2 in the Morphogenesis of Stereocilia

Mutations in human glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1) and its paralog GRXCR2 have been linked to hearing loss in humans. Although both GRXCR1 and GRXCR2 are required for the morphogenesis of stereocilia in cochlear hair cells, a fundamental question that remains unclear is whether GRXCR1 and GRXCR2 have similar functions in hair cells. Previously, we found that GRXCR2 is critical for the stereocilia morphogenesis by regulating taperin localization at the base of stereocilia. Reducing taperin expression level rescues the morphological defects of stereocilia and hearing loss in Grxcr2-deficient mice. So far, functions of GRXCR1 in mammalian hair cells are still unclear. Grxcr1-deficient hair cells have very thin stereocilia with less F-actin content inside, which is different from Grxcr2-deficient hair cells. In contrast to GRXCR2, which is concentrated at the base of stereocilia, GRXCR1 is diffusely distributed throughout the stereocilia. Notably, GRXCR1 interacts with GRXCR2. In Grxcr1-deficient hair cells, the expression level of GRXCR2 and taperin is reduced. Remarkably, different from that in Grxcr2-deficient mice, reducing taperin expression level does not rescue the morphological defects of stereocilia or hearing loss in Grxcr1-deficient mice. Thus, our findings suggest that GRXCR1 has different functions than GRXCR2 during the morphogenesis of stereocilia.

in Frontiers in Cellular Neuroscience on July 21, 2021 12:00 AM.

• #### Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer’s disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers.

Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals.

Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc.

Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.

in Frontiers in Ageing Neuroscience on July 21, 2021 12:00 AM.

• #### A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report

The pathogenesis of Alzheimer's disease is complex, and early-onset Alzheimer's disease (EOAD) is mostly influenced by genetic factors. Presenilin-1, presenilin-2 (PSEN2), and amyloid precursor protein are currently known as the three main causative genes for autosomal dominant EOAD, with the PSEN2 mutation being the rarest. In this study, we reported a 56-year-old Chinese Han proband who presented with prominent progressive amnesia, aphasia, executive function impairment, and depression 5 years ago. The 3-year follow-up showed that the patient experienced progressive brain atrophy displayed on magnetic resonance imaging (MRI) and dramatic cognitive decline assessed by neuropsychological evaluation. This patient was clinically diagnosed as EOAD based on established criteria. A heterozygous variant (NM_000447.2: c.1106T>C) of PSEN2 was identified for the first time in this patient and her two daughters. This mutation causing a novel missense mutation (p.Phe369Ser) in transmembrane domain 7 encoded by exon 11 had not been reported previously in 1000Genomes, ExAC, or ClinVar databases. This mutation was predicted by four in silico prediction programs, which all strongly suggested that it was damaging. Our results suggest that this novel PSEN2 Phe369Ser mutation may alter PSEN2 protein function and associate with EOAD.

in Frontiers in Ageing Neuroscience on July 21, 2021 12:00 AM.

• #### WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice

Anesthesia/surgery has been reported to be associated with perioperative neurocognitive disorder (PND) in patients and induces cognitive impairment in mice. Previous studies demonstrate cyclosporine A (CsA) attenuates the anesthesia/surgery-induced cognitive impairment in mice. However, CsA has immunosuppressive effects and may not be routinely used to prevent or treat PND in patients. WS635 is a nonimmunosuppressive CsA analog. We, therefore, set out to determine whether WS635 could mitigate the anesthesia/surgery-induced cognitive impairment in mice. We performed abdominal surgery under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h in 9 month-old wild-type (WT) mice. We treated the mice with CsA (10 mg/kg) or different doses (13.2 mg/kg, 26.4 mg/kg and 52.8 mg/kg) of WS635 before and after the anesthesia/surgery. Barnes maze and fear conditioning system (FCS) were employed to evaluate the cognitive function in mice. We measured the amounts of postsynaptic density (PSD)-95, synaptophysin, and ATP in the hippocampus and cortex of the mice using western blot and ATP Colorimetric/Fluorometric Assay, respectively. We found that the treatment with 52.8 mg/kg, but not 13.2 mg/kg or 26.4 mg/kg, of WS635 attenuated the anesthesia/surgery-induced cognitive impairment in mice and the reductions in the amounts of PSD-95, synaptophysin, and ATP in the mice brain tissues. These results have established a system to study WS635 further and suggest that we need to perform more experiments to determine whether WS635 can ultimately be used as one of the interventions for PND in patients.

in Frontiers in Ageing Neuroscience on July 21, 2021 12:00 AM.

• #### Alterations of Regional Homogeneity in the Mild and Moderate Stages of Parkinson’s Disease

Objectives: This study aimed to investigate alterations in regional homogeneity (ReHo) in early Parkinson’s disease (PD) at different Hoehn and Yahr (HY) stages and to demonstrate the relationships between altered brain regions and clinical scale scores.

Methods: We recruited 75 PD patients, including 43 with mild PD (PD-mild; HY stage: 1.0–1.5) and 32 with moderate PD (PD-moderate; HY stage: 2.0–2.5). We also recruited 37 age- and sex-matched healthy subjects as healthy controls (HC). All subjects underwent neuropsychological assessments and a 3.0 Tesla magnetic resonance scanning. Regional homogeneity of blood oxygen level-dependent (BOLD) signals was used to characterize regional cerebral function. Correlative relationships between mean ReHo values and clinical data were then explored.

Results: Compared to the HC group, the PD-mild group exhibited increased ReHo values in the right cerebellum, while the PD-moderate group exhibited increased ReHo values in the bilateral cerebellum, and decreased ReHo values in the right superior temporal gyrus, the right Rolandic operculum, the right postcentral gyrus, and the right precentral gyrus. Reho value of right Pre/Postcentral was negatively correlated with HY stage. Compared to the PD-moderate group, the PD-mild group showed reduced ReHo values in the right superior orbital gyrus and the right rectus, in which the ReHo value was negatively correlated with cognition.

Conclusion: The right superior orbital gyrus and right rectus may serve as a differential indicator for mild and moderate PD. Subjects with moderate PD had a greater scope for ReHo alterations in the cortex and compensation in the cerebellum than those with mild PD. PD at HY stages of 2.0–2.5 may already be classified as Braak stages 5 and 6 in terms of pathology. Our study revealed the different patterns of brain function in a resting state in PD at different HY stages and may help to elucidate the neural function and early diagnosis of patients with PD.

in Frontiers in Ageing Neuroscience on July 21, 2021 12:00 AM.

• #### Reply to Klein: Ysterfontein 1 shell midden (South Africa) and the antiquity of coastal adaptation [Social Sciences]

Klein (1) challenges two interpretations in Niespolo et al. (2). Regarding his first point, we maintain that Ysterfontein 1 (YFT1) does provide the oldest known example of full coastal adaptation as indicated by the presence of shell middens (cf. ref. 3). Klein inaccurately characterizes the age of the deepest shell...

in PNAS on July 20, 2021 06:25 PM.

• #### Middle Stone Age marine resource exploitation at Ysterfontein 1 rockshelter, South Africa [Social Sciences]

Niespolo et al. (1) report 230Th/238U “burial ages” for ostrich eggshell fragments from a 3.8-m-thick Middle Stone Age (MSA) sequence at Ysterfontein 1 shelter, west coast of South Africa (2). The ages are in expected stratigraphic order and imply that the entire 3.8-m sequence accumulated in as little as 2,300...

in PNAS on July 20, 2021 06:25 PM.

• #### Quantifying COVID-19 importation risk in a dynamic network of domestic cities and international countries [Environmental Sciences]

Since its outbreak in December 2019, the novel coronavirus 2019 (COVID-19) has spread to 191 countries and caused millions of deaths. Many countries have experienced multiple epidemic waves and faced containment pressures from both domestic and international transmission. In this study, we conduct a multiscale geographic analysis of the spread...

in PNAS on July 20, 2021 06:25 PM.

• #### Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [Immunology and Inflammation]

Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found...

in PNAS on July 20, 2021 06:25 PM.

• #### Grain boundary formation through particle detachment during coarsening of nanoporous metals [Engineering]

Grain boundary formation during coarsening of nanoporous gold (NPG) is investigated wherein a nanocrystalline structure can form by particles detaching and reattaching to the structure. MicroLaue and electron backscatter diffraction measurements demonstrate that an in-grain orientation spread develops as NPG is coarsened. The volume fraction of the NPG sample is...

in PNAS on July 20, 2021 06:25 PM.

Cytoskeletal active nematics exhibit striking nonequilibrium dynamics that are powered by energy-consuming molecular motors. To gain insight into the structure and mechanics of these materials, we design programmable clusters in which kinesin motors are linked by a double-stranded DNA linker. The efficiency by which DNA-based clusters power active nematics depends...

in PNAS on July 20, 2021 06:25 PM.

• #### Termite gas emissions select for hydrogenotrophic microbial communities in termite mounds [Earth, Atmospheric, and Planetary Sciences]

Organoheterotrophs are the dominant bacteria in most soils worldwide. While many of these bacteria can subsist on atmospheric hydrogen (H2), levels of this gas are generally insufficient to sustain hydrogenotrophic growth. In contrast, bacteria residing within soil-derived termite mounds are exposed to high fluxes of H2 due to fermentative production...

in PNAS on July 20, 2021 06:25 PM.

• #### Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies [Immunology and Inflammation]

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T...

in PNAS on July 20, 2021 06:25 PM.

• #### Glucocorticoid receptor condensates link DNA-dependent receptor dimerization and transcriptional transactivation [Biochemistry]

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA-binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that...

in PNAS on July 20, 2021 06:25 PM.

• #### Reward-specific satiety affects subjective value signals in orbitofrontal cortex during multicomponent economic choice [Economic Sciences]

Sensitivity to satiety constitutes a basic requirement for neuronal coding of subjective reward value. Satiety from natural ongoing consumption affects reward functions in learning and approach behavior. More specifically, satiety reduces the subjective economic value of individual rewards during choice between options that typically contain multiple reward components. The unconfounded...

in PNAS on July 20, 2021 06:25 PM.

• #### COVID-19 pandemic reveals persistent disparities in nitrogen dioxide pollution [Sustainability Science]

The unequal spatial distribution of ambient nitrogen dioxide (NO2), an air pollutant related to traffic, leads to higher exposure for minority and low socioeconomic status communities. We exploit the unprecedented drop in urban activity during the COVID-19 pandemic and use high-resolution, remotely sensed NO2 observations to investigate disparities in NO2...

in PNAS on July 20, 2021 06:25 PM.

• #### Microbe-dependent heterosis in maize [Plant Biology]

Hybrids account for nearly all commercially planted varieties of maize and many other crop plants because crosses between inbred lines of these species produce first-generation [F1] offspring that greatly outperform their parents. The mechanisms underlying this phenomenon, called heterosis or hybrid vigor, are not well understood despite over a century...

in PNAS on July 20, 2021 06:25 PM.

• #### Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis

Objective In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting. Methods Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4–positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow‐up (n = 176). Results CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere–Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing–remitting and control groups (receiver operator characteristic curve, area under the curve = 0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing–remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing–remitting patients (hazard ratio [HR] = 1.967, 95% confidence interval [CI] = 1.147–3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR = 10.767, 95% CI = 1.335–86.812). Interpretation Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021

in Annals of Neurology on July 20, 2021 03:26 PM.

• #### Performance and scaling behavior of bioinformatic applications in virtualization environments to create awareness for the efficient use of compute resources

by Maximilian Hanussek, Felix Bartusch, Jens Krüger

The large amount of biological data available in the current times, makes it necessary to use tools and applications based on sophisticated and efficient algorithms, developed in the area of bioinformatics. Further, access to high performance computing resources is necessary, to achieve results in reasonable time. To speed up applications and utilize available compute resources as efficient as possible, software developers make use of parallelization mechanisms, like multithreading. Many of the available tools in bioinformatics offer multithreading capabilities, but more compute power is not always helpful. In this study we investigated the behavior of well-known applications in bioinformatics, regarding their performance in the terms of scaling, different virtual environments and different datasets with our benchmarking tool suite BOOTABLE. The tool suite includes the tools BBMap, Bowtie2, BWA, Velvet, IDBA, SPAdes, Clustal Omega, MAFFT, SINA and GROMACS. In addition we added an application using the machine learning framework TensorFlow. Machine learning is not directly part of bioinformatics but applied to many biological problems, especially in the context of medical images (X-ray photographs). The mentioned tools have been analyzed in two different virtual environments, a virtual machine environment based on the OpenStack cloud software and in a Docker environment. The gained performance values were compared to a bare-metal setup and among each other. The study reveals, that the used virtual environments produce an overhead in the range of seven to twenty-five percent compared to the bare-metal environment. The scaling measurements showed, that some of the analyzed tools do not benefit from using larger amounts of computing resources, whereas others showed an almost linear scaling behavior. The findings of this study have been generalized as far as possible and should help users to find the best amount of resources for their analysis. Further, the results provide valuable information for resource providers to handle their resources as efficiently as possible and raise the user community’s awareness of the efficient usage of computing resources.

in PLoS Computational Biology on July 20, 2021 02:00 PM.

• #### Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts

by Kaiyi Zhu, Lingyi Cai, Chenqian Cui, Juan R. de los Toyos, Dimitris Anastassiou

During the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with poor prognosis, invasiveness, metastasis and resistance to therapy in multiple cancer types, characterized by a gene expression signature with prominent presence of genes COL11A1, THBS2 and INHBA. Identifying the underlying biological mechanisms responsible for their creation may facilitate the discovery of targets for potential pan-cancer therapeutics. Using a novel computational approach for single-cell gene expression data analysis identifying the dominant cell populations in a sequence of samples from patients at various stages, we conclude that these fibroblasts are produced by a pan-cancer cellular transition originating from a particular type of adipose-derived stromal cells naturally present in the stromal vascular fraction of normal adipose tissue, having a characteristic gene expression signature. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profiles of cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transition. These results also provide an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression.

in PLoS Computational Biology on July 20, 2021 02:00 PM.

• #### Rigid-body fitting to atomic force microscopy images for inferring probe shape and biomolecular structure

by Toru Niina, Yasuhiro Matsunaga, Shoji Takada

Atomic force microscopy (AFM) can visualize functional biomolecules near the physiological condition, but the observed data are limited to the surface height of specimens. Since the AFM images highly depend on the probe tip shape, for successful inference of molecular structures from the measurement, the knowledge of the probe shape is required, but is often missing. Here, we developed a method of the rigid-body fitting to AFM images, which simultaneously finds the shape of the probe tip and the placement of the molecular structure via an exhaustive search. First, we examined four similarity scores via twin-experiments for four test proteins, finding that the cosine similarity score generally worked best, whereas the pixel-RMSD and the correlation coefficient were also useful. We then applied the method to two experimental high-speed-AFM images inferring the probe shape and the molecular placement. The results suggest that the appropriate similarity score can differ between target systems. For an actin filament image, the cosine similarity apparently worked best. For an image of the flagellar protein FlhAC, we found the correlation coefficient gave better results. This difference may partly be attributed to the flexibility in the target molecule, ignored in the rigid-body fitting. The inferred tip shape and placement results can be further refined by other methods, such as the flexible fitting molecular dynamics simulations. The developed software is publicly available.

in PLoS Computational Biology on July 20, 2021 02:00 PM.

• #### Spatially resolved simulations of the spread of COVID-19 in three European countries

by Andrea Parisi, Samuel P. C. Brand, Joe Hilton, Rabia Aziza, Matt J. Keeling, D. James Nokes

We explore the spatial and temporal spread of the novel SARS-CoV-2 virus under containment measures in three European countries based on fits to data of the early outbreak. Using data from Spain and Italy, we estimate an age dependent infection fatality ratio for SARS-CoV-2, as well as risks of hospitalization and intensive care admission. We use them in a model that simulates the dynamics of the virus using an age structured, spatially detailed agent based approach, that explicitly incorporates governmental interventions and changes in mobility and contact patterns occurred during the COVID-19 outbreak in each country. Our simulations reproduce several of the features of its spatio-temporal spread in the three countries studied. They show that containment measures combined with high density are responsible for the containment of cases within densely populated areas, and that spread to less densely populated areas occurred during the late stages of the first wave. The capability to reproduce observed features of the spatio-temporal dynamics of SARS-CoV-2 makes this model a potential candidate for forecasting the dynamics of SARS-CoV-2 in other settings, and we recommend its application in low and lower-middle income countries which remain understudied.

in PLoS Computational Biology on July 20, 2021 02:00 PM.

• #### Heteroresistance to beta-lactam antibiotics may often be a stage in the progression to antibiotic resistance

by Victor I. Band, David S. Weiss

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation and that when this occurs, all the cells in the bacterial population are phenotypically resistant. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we provide evidence that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by resistance. This suggests the possibility that HR may often develop before resistance and frequently be a stage in its progression, potentially representing a major shift in our understanding of the evolution of antibiotic resistance.

in PLoS Biology on July 20, 2021 02:00 PM.

• #### Trojan horses and tunneling nanotubes enable α-synuclein pathology to spread in Parkinson disease

by Santhanasabapathy Rajasekaran, Stephan N. Witt

In Parkinson disease (PD), Lewy bodies (LBs) form in the gut or nose and spread into the midbrain. A study in this issue indicates that the spread is due to lysosomes “infected” with prion-like alpha-synuclein (α-syn) transmitting from cell to cell via tunneling nanotubes (TNTs). In Parkinson’s disease, Lewy bodies form in the gut or nose and spread into the midbrain. This Primer explores the implications of a study indicating that this spread is due to lysosomes “infected” with prion-like α-synuclein transmitting from cell-to-cell via tunneling nanotubes.

in PLoS Biology on July 20, 2021 02:00 PM.

• #### α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

by Aysegul Dilsizoglu Senol, Maura Samarani, Sylvie Syan, Carlos M. Guardia, Takashi Nonaka, Nalan Liv, Patricia Latour-Lambert, Masato Hasegawa, Judith Klumperman, Juan S. Bonifacino, Chiara Zurzolo

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

in PLoS Biology on July 20, 2021 02:00 PM.

• #### Automated Annotation of Epileptiform Burden and Its Association with Outcomes

Objective This study was undertaken to determine the dose–response relation between epileptiform activity burden and outcomes in acutely ill patients. Methods A single center retrospective analysis was made of 1,967 neurologic, medical, and surgical patients who underwent >16 hours of continuous electroencephalography (EEG) between 2011 and 2017. We developed an artificial intelligence algorithm to annotate 11.02 terabytes of EEG and quantify epileptiform activity burden within 72 hours of recording. We evaluated burden (1) in the first 24 hours of recording, (2) in the 12‐hours epoch with highest burden (peak burden), and (3) cumulatively through the first 72 hours of monitoring. Machine learning was applied to estimate the effect of epileptiform burden on outcome. Outcome measure was discharge modified Rankin Scale, dichotomized as good (0–4) versus poor (5–6). Results Peak epileptiform burden was independently associated with poor outcomes (p < 0.0001). Other independent associations included age, Acute Physiology and Chronic Health Evaluation II score, seizure on presentation, and diagnosis of hypoxic–ischemic encephalopathy. Model calibration error was calculated across 3 strata based on the time interval between last EEG measurement (up to 72 hours of monitoring) and discharge: (1) <5 days between last measurement and discharge, 0.0941 (95% confidence interval [CI] = 0.0706–0.1191); 5 to 10 days between last measurement and discharge, 0.0946 (95% CI = 0.0631–0.1290); >10 days between last measurement and discharge, 0.0998 (95% CI = 0.0698–0.1335). After adjusting for covariates, increase in peak epileptiform activity burden from 0 to 100% increased the probability of poor outcome by 35%. Interpretation Automated measurement of peak epileptiform activity burden affords a convenient, consistent, and quantifiable target for future multicenter randomized trials investigating whether suppressing epileptiform activity improves outcomes. ANN NEUROL 2021

in Annals of Neurology on July 20, 2021 12:26 PM.

• #### Aerobic exercise, cardiorespiratory fitness, and the human hippocampus

Abstract The hippocampus is particularly susceptible to neurodegeneration. Physical activity, specifically increasing cardiorespiratory fitness via aerobic exercise, shows promise as a potential method for mitigating hippocampal decline in humans. Numerous studies have now investigated associations between the structure and function of the hippocampus and engagement in physical activity. Still, there remains continued debate and confusion about the relationship between physical activity and the human hippocampus. In this review, we describe the current state of the physical activity and exercise literature as it pertains to the structure and function of the human hippocampus, focusing on four magnetic resonance imaging measures: volume, diffusion tensor imaging, resting‐state functional connectivity, and perfusion. We conclude that, despite significant heterogeneity in study methods, populations of interest, and scope, there are consistent positive findings, suggesting a promising role for physical activity in promoting hippocampal structure and function throughout the lifespan.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Neural evidence for recognition of naturalistic videos in monkey hippocampus

Abstract The role of the hippocampus in recognition memory has long been a source of debate. Tasks used to study recognition that typically require an explicit probe, where the participant must make a response to prove they remember, yield mixed results on hippocampal involvement. Here, we tasked monkeys to freely view naturalistic videos, and only tested their memory via looking times for two separate novel versus repeat video conditions on each trial. Notably, a large proportion (>30%) of hippocampal neurons differentiated these videos via changes in firing rates time‐locked to the duration of their presentation on screen, and not during the delay period between them as would be expected for working memory. Many of these single neurons (>15%) contributed to both retrieval conditions, and differentiated novel from repeat videos across trials with trial‐unique content, suggesting they detect familiarity. The majority of neurons contributing to the classifier showed an enhancement in firing rate on repeat compared with novel videos, a pattern which has not previously been shown in hippocampus. These results suggest the hippocampus contributes to recognition memory via familiarity during free‐viewing.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Hippocampal subfield‐specific Homer1a expression is triggered by learning‐facilitated long‐term potentiation and long‐term depression at medial perforant path synapses

Abstract Learning about general aspects, or content details, of space results in differentiated neuronal information encoding within the proximodistal axis of the hippocampus. These processes are tightly linked to long‐term potentiation (LTP) and long‐term depression (LTD). Here, we explored the precise sites of encoding of synaptic plasticity in the hippocampus that are mediated by information throughput from the perforant path. We assessed nuclear Homer1a‐expression that was triggered by electrophysiological induction of short and long forms of hippocampal synaptic plasticity, and compared it to Homer1a‐expression that was triggered by LTP and LTD enabled by different forms of spatial learning. Plasticity responses were induced by patterned stimulation of the perforant path and were recorded in the dentate gyrus (DG) of freely behaving rats. We used fluorescence in situ hybridization to detect experience‐dependent nuclear encoding of Homer1a in proximodistal hippocampal subfields. Induction of neither STP nor STD resulted in immediate early gene (IEG) encoding. Electrophysiological induction of robust LTP, or LTD, resulted in highly significant and widespread induction of nuclear Homer1a in all hippocampal subfields. LTP that was facilitated by novel spatial exploration triggered similar widespread Homer1a‐expression. The coupling of synaptic depression with the exploration of a novel configuration of landmarks resulted in localized IEG expression in the proximal CA3 region and the lower (infrapyramidal) blade of the DG. Our findings support that synaptic plasticity induction via perforant path inputs promotes widespread hippocampal information encoding. Furthermore, novel spatial exploration promotes the selection of a hippocampal neuronal network by means of LTP that is distributed in an experience‐dependent manner across all hippocampus subfields. This network may be modified during spatial content learning by LTD in specific hippocampal subfields. Thus, long‐term plasticity‐inducing events result in IEG expression that supports establishment and/or restructuring of neuronal networks that are necessary for long‐term information storage.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Object and object‐memory representations across the proximodistal axis of CA1

Abstract Episodic memory requires information about objects to be integrated into a spatial framework. Place cells in the hippocampus encode spatial representations of objects that could be generated through signaling from the entorhinal cortex. Projections from lateral (LEC) and medial entorhinal cortex (MEC) to the hippocampus terminate in distal and proximal CA1, respectively. We recorded place cells in distal and proximal CA1 as rats explored an environment that contained objects. Place cells in distal CA1 demonstrated higher measures of spatial tuning, stability, and closer proximity of place fields to objects. Furthermore, remapping to object displacement was modulated by place field proximity to objects in distal, but not proximal CA1. Finally, representations of previous object locations were closer to those locations in distal CA1 than proximal CA1. Our data suggest that in cue‐rich environments, LEC inputs to the hippocampus support spatial representations with higher spatial tuning, closer proximity to objects, and greater stability than those receiving inputs from MEC. This is consistent with functional segregation in the entorhinal–hippocampal circuits underlying object‐place memory.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Reduced anterior hippocampal and ventromedial prefrontal activity when repeatedly retrieving autobiographical memories

Abstract Research has reported that repeatedly retrieving a novel or imagined event representation reduces activity within brain regions critical for constructing mental scenarios, namely the anterior hippocampus and ventromedial prefrontal cortex (vmPFC). The primary aim of this investigation was to test if this pattern reported for imagined events would be found when repeatedly recollecting autobiographical memories. Twenty‐four participants retrieved 12 pre‐selected autobiographical memories four times while undergoing an fMRI scan. We used a region of interest approach to investigate how the anterior and posterior hippocampus as well as cortical regions critical for memory retrieval—the vmPFC and the posterior cingulate cortex (PCC)—are affected by repeated retrievals. This analysis revealed an effect in the bilateral anterior hippocampi and vmPFC, but not the posterior hippocampus nor the PCC, with activity decreasing in these regions as a function of repeated retrievals. A multivariate analytic approach (Partial Least Squares) was used to assess whole‐brain patterns of neural activity associated with repeated retrievals. This analysis revealed one pattern of neural activity associated with the initial retrieval of a memory (e.g., inferior frontal and temporal lobe regions) and a separate pattern of activity associated with later retrievals that was distributed primarily across the lateral parietal cortices. These findings suggest that the anterior hippocampus and the vmPFC support the episodic construction of an autobiographical memory the first time it is retrieved and that alternate nonconstructive processes support its subsequent retrieval shortly thereafter.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Structural differences in the hippocampus and amygdala of behaviorally inhibited macaque monkeys

Abstract Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in the hippocampus and amygdala. However, few studies have investigated the structural differences that may underlie these functional abnormalities. In this exploratory study, we evaluated rhesus monkeys exhibiting a phenotype consistent with human behavioral inhibition. We performed quantitative neuroanatomical analyses that cannot be performed in humans including estimates of the volume and neuron number of distinct hippocampal regions and amygdala nuclei in behaviorally inhibited and control rhesus monkeys. Behaviorally inhibited monkeys had larger volumes of the rostral third of the hippocampal field CA3, smaller volumes of the rostral third of CA2, and smaller volumes of the accessory basal nucleus of the amygdala. Furthermore, behaviorally inhibited monkeys had fewer neurons in the rostral third of CA2. These structural differences may contribute to the functional abnormalities in the hippocampus and amygdala of behaviorally inhibited individuals. These structural findings in monkeys are consistent with a reduced modulation of amygdala activity via prefrontal cortex projections to the accessory basal nucleus. Given the putative roles of the amygdala in affective processing, CA3 in associative learning and CA2 in social memory, increased amygdala and CA3 activity, and diminished CA2 structure and function, may be associated with increased social anxiety and the heritability of behavioral inhibition. The findings from this exploratory study compel follow‐up investigations with larger sample sizes and additional analyses to provide greater insight and more definitive answers regarding the neurobiological bases of behavioral inhibition.

in Hippocampus on July 20, 2021 12:17 PM.

• #### APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults

Abstract Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task‐related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task‐free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Issue Information ‐ TOC

Hippocampus, Volume 31, Issue 8, Page C4-C4, August 2021.

in Hippocampus on July 20, 2021 12:17 PM.

• #### Issue Information ‐ Editorial Board

Hippocampus, Volume 31, Issue 8, Page 815-815, August 2021.

in Hippocampus on July 20, 2021 12:17 PM.

• #### The ependymal cell cytoskeleton in the normal and injured spinal cord of mice

The cytoskeleton of the cells lining the central canal of the mouse spinal cord undergoes important modifications following injury. Ependymal cells change their pronounced apicobasal polarity with a striking rearrangement of key cytoskeletal proteins (F‐actin, vimentin, and glial fibrillary acidic protein) that may be key events in the response of these progenitor‐like cells. Abstract The cytoskeleton of ependymal cells is fundamental to organize and maintain the normal architecture of the central canal (CC). However, little is known about the plasticity of cytoskeletal components after spinal cord injury. Here, we focus on the structural organization of the cytoskeleton of ependymal cells in the normal and injured spinal cord of mice (both females and males) using immunohistochemical and electron microscopy techniques. We found that in uninjured animals, the actin cytoskeleton (as revealed by phalloidin staining) was arranged following the typical pattern of polarized epithelial cells with conspicuous actin pools located in the apical domain of ependymal cells. Transmission electron microscopy images showed microvilli tufts, long cilia, and characteristic intercellular membrane specializations. After spinal cord injury, F‐actin rearrangements paralleled by fine structural modifications of the apical domain of ependymal cells were observed. These changes involved disruptions of the apical actin pools as well as fine structural modifications of the microvilli tufts. When comparing the control and injured spinal cords, we also found modifications in the expression of vimentin and glial fibrillary acidic protein (GFAP). After injury, vimentin expression disappeared from the most apical domains of ependymal cells but the number of GFAP‐expressing cells within the CC increased. As in other polarized epithelia, the plastic changes in the cytoskeleton may be critically involved in the reaction of ependymal cells following a traumatic injury of the spinal cord.

in Journal of Neuroscience Research on July 20, 2021 12:11 PM.

• #### Lewy‐body Like Inclusions in Human Midbrain Organoid Carrying Glucocerebrosidase and Alpha Synuclein Mutations

Objective We utilized human midbrain‐like organoids (hMLOs) generated from human pluripotent stem cells (hPSCs) carrying glucocerebrosidase gene (GBA1) and α‐synuclein (SNCA) perturbations to investigate genotype‐to‐phenotype relationships in Parkinson’s disease, with the particular aim of recapitulating α‐syn and Lewy body‐related pathologies and the process of neurodegeneration in the hMLO model. Method We generated and characterized hMLOs from GBA1‐/‐ and SNCA O/E isogenic embryonic stem cells (ESCs) and also generated Lewy body‐like inclusions (LBLIs) in GBA1/SNCA dual perturbation hMLOs and conduritol‐b‐epoxide‐treated SNCA triplication hMLOs. Results We identified for the first time that the loss of glucocerebrosidase, coupled with wild‐type α‐synuclein overexpression, results in a substantial accumulation of detergent‐resistant, β‐sheet‐rich α‐synuclein aggregates and Lewy body‐like inclusions in human midbrain‐like organoids. These Lewy body‐like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α‐synuclein with ubiquitin and can also be formed in Parkinson’s disease patient‐derived midbrain‐like organoids. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body‐like inclusions in human midbrain‐like organoids derived from patients carrying the SNCA triplication. Interpretation Taken together, the data indicate that our midbrain‐like organoids harboring two major risk factors (GCase deficiency and wild‐type α‐synuclein overproduction) of Parkinson’s disease provides a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. This article is protected by copyright. All rights reserved.

in Annals of Neurology on July 20, 2021 07:04 AM.

• #### Changing Gears – DBS For Dopaminergic Desensitization in Parkinson's Disease?

In Parkinson's disease, both motor and neuropsychiatric complications unfold as a consequence of both incremental striatal dopaminergic denervation and intensifying long‐term dopaminergic treatment. Together, this leads to ‘dopaminergic sensitization’ steadily increasing motor and behavioral responses to dopaminergic medication that result in the detrimental sequalae of long‐term dopaminergic treatment. We review the clinical presentations of ‘dopaminergic sensitization’, including rebound off and dyskinesia in the motor domain, and neuropsychiatric fluctuations and behavioral addictions with impulse control disorders and dopamine dysregulation syndrome in the neuropsychiatric domain. We summarize state‐of‐the‐art deep brain stimulation, and show that STN‐DBS allows dopaminergic medication to be tapered, thus supporting dopaminergic desensitization. In this framework, we develop our integrated debatable viewpoint of “changing gears”, that is we suggest rethinking earlier use of subthalamic nucleus deep brain stimulation, when the first clinical signs of dopaminergic motor or neuropsychiatric complications emerge over the steadily progressive disease course. In this sense, subthalamic deep brain stimulation may help reduce longitudinal motor and neuropsychiatric symptom expression – importantly, not by neuroprotection but by supporting dopaminergic desensitization through postoperative medication reduction. Therefore, we suggest considering STN‐DBS early enough before patients encounter potentially irreversible psychosocial consequences of dopaminergic complications, but importantly not before a patient shows first clinical signs of dopaminergic complications. We propose to consider neuropsychiatric dopaminergic complications as a new inclusion criterion in addition to established motor criteria, but this concept will require validation in future clinical trials. ANN NEUROL 2021

in Annals of Neurology on July 20, 2021 07:00 AM.

• #### Genetics of Cluster Headache Takes a Leap

Annals of Neurology, EarlyView.

in Annals of Neurology on July 20, 2021 07:00 AM.

• #### COVID‐19 vaccine‐associated cerebral venous thrombosis in Germany

in Annals of Neurology on July 20, 2021 06:45 AM.

• #### Dynamic Cat Swarm Optimization Algorithm for Backboard Wiring Problem. (arXiv:2107.08908v1 [cs.NE])

This paper presents a powerful swarm intelligence meta-heuristic optimization algorithm called Dynamic Cat Swarm Optimization. The formulation is through modifying the existing Cat Swarm Optimization. The original Cat Swarm Optimization suffers from the shortcoming of 'premature convergence', which is the possibility of entrapment in local optima which usually happens due to the off-balance between exploration and exploitation phases. Therefore, the proposed algorithm suggests a new method to provide a proper balance between these phases by modifying the selection scheme and the seeking mode of the algorithm. To evaluate the performance of the proposed algorithm, 23 classical test functions, 10 modern test functions (CEC 2019) and a real world scenario are used. In addition, the Dimension-wise diversity metric is used to measure the percentage of the exploration and exploitation phases. The optimization results show the effectiveness of the proposed algorithm, which ranks first compared to several well-known algorithms available in the literature. Furthermore, statistical methods and graphs are also used to further confirm the outperformance of the algorithm. Finally, the conclusion as well as future directions to further improve the algorithm are discussed.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Wave-based extreme deep learning based on non-linear time-Floquet entanglement. (arXiv:2107.08564v1 [cs.ET])

Wave-based analog signal processing holds the promise of extremely fast, on-the-fly, power-efficient data processing, occurring as a wave propagates through an artificially engineered medium. Yet, due to the fundamentally weak non-linearities of traditional wave materials, such analog processors have been so far largely confined to simple linear projections such as image edge detection or matrix multiplications. Complex neuromorphic computing tasks, which inherently require strong non-linearities, have so far remained out-of-reach of wave-based solutions, with a few attempts that implemented non-linearities on the digital front, or used weak and inflexible non-linear sensors, restraining the learning performance. Here, we tackle this issue by demonstrating the relevance of Time-Floquet physics to induce a strong non-linear entanglement between signal inputs at different frequencies, enabling a power-efficient and versatile wave platform for analog extreme deep learning involving a single, uniformly modulated dielectric layer and a scattering medium. We prove the efficiency of the method for extreme learning machines and reservoir computing to solve a range of challenging learning tasks, from forecasting chaotic time series to the simultaneous classification of distinct datasets. Our results open the way for wave-based machine learning with high energy efficiency, speed, and scalability.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Synaptic balancing: a biologically plausible local learning rule that provably increases neural network noise robustness without sacrificing task performance. (arXiv:2107.08530v1 [q-bio.NC])

We introduce a novel, biologically plausible local learning rule that provably increases the robustness of neural dynamics to noise in nonlinear recurrent neural networks with homogeneous nonlinearities. Our learning rule achieves higher noise robustness without sacrificing performance on the task and without requiring any knowledge of the particular task. The plasticity dynamics -- an integrable dynamical system operating on the weights of the network -- maintains a multiplicity of conserved quantities, most notably the network's entire temporal map of input to output trajectories. The outcome of our learning rule is a synaptic balancing between the incoming and outgoing synapses of every neuron. This synaptic balancing rule is consistent with many known aspects of experimentally observed heterosynaptic plasticity, and moreover makes new experimentally testable predictions relating plasticity at the incoming and outgoing synapses of individual neurons. Overall, this work provides a novel, practical local learning rule that exactly preserves overall network function and, in doing so, provides new conceptual bridges between the disparate worlds of the neurobiology of heterosynaptic plasticity, the engineering of regularized noise-robust networks, and the mathematics of integrable Lax dynamical systems.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### Classification of Upper Arm Movements from EEG signals using Machine Learning with ICA Analysis. (arXiv:2107.08514v1 [eess.SP])

The Brain-Computer Interface system is a profoundly developing area of experimentation for Motor activities which plays vital role in decoding cognitive activities. Classification of Cognitive-Motor Imagery activities from EEG signals is a critical task. Hence proposed a unique algorithm for classifying left/right-hand movements by utilizing Multi-layer Perceptron Neural Network. Handcrafted statistical Time domain and Power spectral density frequency domain features were extracted and obtained a combined accuracy of 96.02%. Results were compared with the deep learning framework. In addition to accuracy, Precision, F1-Score, and recall was considered as the performance metrics. The intervention of unwanted signals contaminates the EEG signals which influence the performance of the algorithm. Therefore, a novel approach was approached to remove the artifacts using Independent Components Analysis which boosted the performance. Following the selection of appropriate feature vectors that provided acceptable accuracy. The same method was used on all nine subjects. As a result, intra-subject accuracy was obtained for 9 subjects 94.72%. The results show that the proposed approach would be useful to classify the upper limb movements accurately.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### A Novel Evolutionary Algorithm for Hierarchical Neural Architecture Search. (arXiv:2107.08484v1 [cs.NE])

In this work, we propose a novel evolutionary algorithm for neural architecture search, applicable to global search spaces. The algorithm's architectural representation organizes the topology in multiple hierarchical modules, while the design process exploits this representation, in order to explore the search space. We also employ a curation system, which promotes the utilization of well performing sub-structures to subsequent generations. We apply our method to Fashion-MNIST and NAS-Bench101, achieving accuracies of $93.2\%$ and $94.8\%$ respectively in a relatively small number of generations.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### GoTube: Scalable Stochastic Verification of Continuous-Depth Models. (arXiv:2107.08467v1 [cs.LG])

We introduce a new stochastic verification algorithm that formally quantifies the behavioral robustness of any time-continuous process formulated as a continuous-depth model. The algorithm solves a set of global optimization (Go) problems over a given time horizon to construct a tight enclosure (Tube) of the set of all process executions starting from a ball of initial states. We call our algorithm GoTube. Through its construction, GoTube ensures that the bounding tube is conservative up to a desired probability. GoTube is implemented in JAX and optimized to scale to complex continuous-depth models. Compared to advanced reachability analysis tools for time-continuous neural networks, GoTube provably does not accumulate over-approximation errors between time steps and avoids the infamous wrapping effect inherent in symbolic techniques. We show that GoTube substantially outperforms state-of-the-art verification tools in terms of the size of the initial ball, speed, time-horizon, task completion, and scalability, on a large set of experiments. GoTube is stable and sets the state-of-the-art for its ability to scale up to time horizons well beyond what has been possible before.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Multi-objective Test Case Selection Through Linkage Learning-based Crossover. (arXiv:2107.08454v2 [cs.SE] UPDATED)

Test Case Selection (TCS) aims to select a subset of the test suite to run for regression testing. The selection is typically based on past coverage and execution cost data. Researchers have successfully used multi-objective evolutionary algorithms (MOEAs), such as NSGA-II and its variants, to solve this problem. These MOEAs use traditional crossover operators to create new candidate solutions through genetic recombination. Recent studies in numerical optimization have shown that better recombinations can be made using machine learning, in particular link-age learning. Inspired by these recent advances in this field, we propose a new variant of NSGA-II, called L2-NSGA, that uses linkage learning to optimize test case selection. In particular, we use an unsupervised clustering algorithm to infer promising patterns among the solutions (subset of test suites). Then, these patterns are used in the next iterations of L2-NSGA to create solutions that preserve these inferred patterns. Our results show that our customizations make NSGA-II more effective for test case selection. The test suite sub-sets generated by L2-NSGA are less expensive and detect more faults than those generated by MOEAs used in the literature for regression testing.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### A method for estimating the entropy of time series using artificial neural network. (arXiv:2107.08399v1 [cs.LG])

Measuring the predictability and complexity of time series is an essential tool in designing and controlling the nonlinear system. There exist different entropy measures in the literature to analyze the predictability and complexity of time series. However, these measures have some drawbacks especially in short time series. To overcome the difficulties, this paper proposes a new method for estimating the entropy of a time series using the LogNNet 784:25:10 neural network model. The LogNNet reservoir matrix consists of 19625 elements which is filled with the time series elements. After that, the network is trained on MNIST-10 dataset and the classification accuracy is calculated. The accuracy is considered as the entropy measure and denoted by NNetEn. A more complex transformation of the input information by the time series in the reservoir leads to higher NNetEn values. Many practical time series data have less than 19625 elements. Some duplicating or stretching methods are investigated to overcome this difficulty and the most successful method is identified for practical applications. The epochs number in the training process of LogNNet is considered as the input parameter. A new time series characteristic called time series learning inertia is introduced to investigate the effect of epochs number in the efficiency of neural network. To show the robustness and efficiency of the proposed method, it is applied on some chaotic, periodic, random, binary and constant time series. The NNetEn is compared with some existing entropy measures. The results show that the proposed method is more robust and accurate than existing methods.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Otimizacao de Redes Neurais atraves de Algoritmos Geneticos Celulares. (arXiv:2107.08326v1 [cs.NE])

This works proposes a methodology to searching for automatically Artificial Neural Networks (ANN) by using Cellular Genetic Algorithm (CGA). The goal of this methodology is to find compact networks whit good performance for classification problems. The main reason for developing this work is centered at the difficulties of configuring compact ANNs with good performance rating. The use of CGAs aims at seeking the components of the RNA in the same way that a common Genetic Algorithm (GA), but it has the differential of incorporating a Cellular Automaton (CA) to give location for the GA individuals. The location imposed by the CA aims to control the spread of solutions in the populations to maintain the genetic diversity for longer time. This genetic diversity is important for obtain good results with the GAs.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### A computational theory for the production of limb movements. (arXiv:2107.00814v2 [q-bio.NC] UPDATED)

Motor control is a fundamental process that underlies all voluntary behavioral responses. Several different theories based on different principles (task dynamics, equilibrium-point theory, passive-motion paradigm, active inference, optimal control) account for specific aspects of how actions are produced, but fail to provide a unified view on this problem. Here we propose a concise theory of motor control based on three principles: optimal feedback control, control with a receding time horizon, and task representation by a series of via-points updated at fixed frequency. By construction, the theory provides a suitable solution to the degrees-of-freedom problem, i.e. trajectory formation in the presence of redundancies and noise. We show through computer simulations that the theory also explains the production of discrete, continuous, rhythmic and temporally-constrained movements, and their parametric and statistical properties (scaling laws, power laws, speed/accuracy tradeoffs). The theory has no free parameters and only limited variations in its implementation details and in the nature of noise are necessary to guarantee its explanatory power.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### Exploration and preference satisfaction trade-off in reward-free learning. (arXiv:2106.04316v2 [cs.AI] UPDATED)

Biological agents have meaningful interactions with their environment despite the absence of immediate reward signals. In such instances, the agent can learn preferred modes of behaviour that lead to predictable states -- necessary for survival. In this paper, we pursue the notion that this learnt behaviour can be a consequence of reward-free preference learning that ensures an appropriate trade-off between exploration and preference satisfaction. For this, we introduce a model-based Bayesian agent equipped with a preference learning mechanism (pepper) using conjugate priors. These conjugate priors are used to augment the expected free energy planner for learning preferences over states (or outcomes) across time. Importantly, our approach enables the agent to learn preferences that encourage adaptive behaviour at test time. We illustrate this in the OpenAI Gym FrozenLake and the 3D mini-world environments -- with and without volatility. Given a constant environment, these agents learn confident (i.e., precise) preferences and act to satisfy them. Conversely, in a volatile setting, perpetual preference uncertainty maintains exploratory behaviour. Our experiments suggest that learnable (reward-free) preferences entail a trade-off between exploration and preference satisfaction. Pepper offers a straightforward framework suitable for designing adaptive agents when reward functions cannot be predefined as in real environments.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### Improving Entropic Out-of-Distribution Detection using Isometric Distances and the Minimum Distance Score. (arXiv:2105.14399v3 [cs.LG] UPDATED)

Current out-of-distribution detection approaches usually present special requirements (e.g., collecting outlier data and hyperparameter validation) and produce side effects (classification accuracy drop and slow/inefficient inferences). Recently, entropic out-of-distribution detection has been proposed as a seamless approach (i.e., a solution that avoids all the previously mentioned drawbacks). The entropic out-of-distribution detection solution comprises the IsoMax loss for training and the entropic score for out-of-distribution detection. The IsoMax loss works as a SoftMax loss drop-in replacement because swapping the SoftMax loss with the IsoMax loss requires no changes in the model's architecture or training procedures/hyperparameters. In this paper, we propose to perform what we call an isometrization of the distances used in the IsoMax loss. Additionally, we propose to replace the entropic score with the minimum distance score. Our experiments showed that these simple modifications increase out-of-distribution detection performance while keeping the solution seamless. Code available at $\href{https://github.com/dlmacedo/entropic-out-of-distribution-detection}{\text{entropic out-of-distribution detection}}$.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Simple and Cheap Setup for Timing Tapping Responses Synchronized to Auditory Stimuli. (arXiv:2105.01570v2 [q-bio.NC] UPDATED)

Measuring human capabilities to synchronize in time, adapt to perturbations to timing sequences or reproduce time intervals often require experimental setups that allow recording response times with millisecond precision. Most setups present auditory stimuli using either MIDI devices or specialized hardware such as Arduino and are often expensive or require calibration and advanced programming skills. Here, we present in detail an experimental setup that only requires an external sound card and minor electronic skills, works on a conventional PC, is cheaper than alternatives and requires almost no programming skills. It is intended for presenting any auditory stimuli and recording tapping response times with within 2 milliseconds precision (up to -2ms lag). This paper shows why desired accuracy in recording response times against auditory stimuli is difficult to achieve in conventional computer setups, presents an experimental setup to overcome this and explains in detail how to set it up and use the provided code. Finally, the code for analyzing the recorded tapping responses was evaluated, showing that no spurious or missing events were found in 94% of the analyzed recordings.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### The Connection Between Approximation, Depth Separation and Learnability in Neural Networks. (arXiv:2102.00434v2 [cs.LG] UPDATED)

Several recent works have shown separation results between deep neural networks, and hypothesis classes with inferior approximation capacity such as shallow networks or kernel classes. On the other hand, the fact that deep networks can efficiently express a target function does not mean that this target function can be learned efficiently by deep neural networks. In this work we study the intricate connection between learnability and approximation capacity. We show that learnability with deep networks of a target function depends on the ability of simpler classes to approximate the target. Specifically, we show that a necessary condition for a function to be learnable by gradient descent on deep neural networks is to be able to approximate the function, at least in a weak sense, with shallow neural networks. We also show that a class of functions can be learned by an efficient statistical query algorithm if and only if it can be approximated in a weak sense by some kernel class. We give several examples of functions which demonstrate depth separation, and conclude that they cannot be efficiently learned, even by a hypothesis class that can efficiently approximate them.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Sensitivity -- Local Index to Control Chaoticity or Gradient Globally. (arXiv:2012.13134v2 [cs.NE] UPDATED)

Here, we introduce a fully local index named "sensitivity" for each neuron to control chaoticity or gradient globally in a neural network (NN). We also propose a learning method to adjust it named "sensitivity adjustment learning (SAL)". The index is the gradient magnitude of its output with respect to its inputs. By adjusting its time average to 1.0 in each neuron, information transmission in the neuron changes to be moderate without shrinking or expanding for both forward and backward computations. That results in moderate information transmission through a layer of neurons when the weights and inputs are random. Therefore, SAL can control the chaoticity of the network dynamics in a recurrent NN (RNN). It can also solve the vanishing gradient problem in error backpropagation (BP) learning in a deep feedforward NN or an RNN. We demonstrate that when applying SAL to an RNN with small and random initial weights, log-sensitivity, which is the logarithm of RMS (root mean square) sensitivity over all the neurons, is equivalent to the maximum Lyapunov exponent until it reaches 0.0. We also show that SAL works with BP or BPTT (BP through time) to avoid the vanishing gradient problem in a 300-layer NN or an RNN that learns a problem with a lag of 300 steps between the first input and the output. Compared with manually fine-tuning the spectral radius of the weight matrix before learning, SAL's continuous nonlinear learning nature prevents loss of sensitivities during learning, resulting in a significant improvement in learning performance.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Using noise to probe recurrent neural network structure and prune synapses. (arXiv:2011.07334v2 [q-bio.NC] UPDATED)

Many networks in the brain are sparsely connected, and the brain eliminates synapses during development and learning. How could the brain decide which synapses to prune? In a recurrent network, determining the importance of a synapse between two neurons is a difficult computational problem, depending on the role that both neurons play and on all possible pathways of information flow between them. Noise is ubiquitous in neural systems, and often considered an irritant to be overcome. Here we suggest that noise could play a functional role in synaptic pruning, allowing the brain to probe network structure and determine which synapses are redundant. We construct a simple, local, unsupervised plasticity rule that either strengthens or prunes synapses using only synaptic weight and the noise-driven covariance of the neighboring neurons. For a subset of linear and rectified-linear networks, we prove that this rule preserves the spectrum of the original matrix and hence preserves network dynamics even when the fraction of pruned synapses asymptotically approaches 1. The plasticity rule is biologically-plausible and may suggest a new role for noise in neural computation.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Reservoir Memory Machines as Neural Computers. (arXiv:2009.06342v2 [cs.LG] UPDATED)

Differentiable neural computers extend artificial neural networks with an explicit memory without interference, thus enabling the model to perform classic computation tasks such as graph traversal. However, such models are difficult to train, requiring long training times and large datasets. In this work, we achieve some of the computational capabilities of differentiable neural computers with a model that can be trained very efficiently, namely an echo state network with an explicit memory without interference. This extension enables echo state networks to recognize all regular languages, including those that contractive echo state networks provably can not recognize. Further, we demonstrate experimentally that our model performs comparably to its fully-trained deep version on several typical benchmark tasks for differentiable neural computers.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 20, 2021 01:30 AM.

• #### Transient chaotic dimensionality expansion by recurrent networks. (arXiv:2002.11006v4 [cond-mat.dis-nn] UPDATED)

Neurons in the brain communicate with spikes, which are discrete events in time and value. Functional network models often employ rate units that are continuously coupled by analog signals. Is there a qualitative difference implied by these two forms of signaling? We develop a unified mean-field theory for large random networks to show that first- and second-order statistics in rate and binary networks are in fact identical if rate neurons receive the right amount of noise. Their response to presented stimuli, however, can be radically different. We quantify these differences by studying how nearby state trajectories evolve over time, asking to what extent the dynamics is chaotic. Chaos in the two models is found to be qualitatively different. In binary networks we find a network-size-dependent transition to chaos and a chaotic submanifold whose dimensionality expands stereotypically with time, while rate networks with matched statistics are nonchaotic. Dimensionality expansion in chaotic binary networks aids classification in reservoir computing and optimal performance is reached within about a single activation per neuron; a fast mechanism for computation that we demonstrate also in spiking networks. A generalization of this mechanism extends to rate networks in their respective chaotic regimes.

in arXiv: Quantitative Biology: Neurons and Cognition on July 20, 2021 01:30 AM.

• #### Reply to: Managing the high: developing legislation and detection methods for cannabis impairment

Nature Reviews Neuroscience, Published online: 20 July 2021; doi:10.1038/s41583-021-00501-4

Reply to: Managing the high: developing legislation and detection methods for cannabis impairment

in Nature Reviews on July 20, 2021 12:00 AM.

• #### Managing the high: developing legislation and detection methods for cannabis impairment

Nature Reviews Neuroscience, Published online: 20 July 2021; doi:10.1038/s41583-021-00500-5

Managing the high: developing legislation and detection methods for cannabis impairment

in Nature Reviews on July 20, 2021 12:00 AM.

• #### Author Correction: PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24848-5

Author Correction: PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

in Nature Communications on July 20, 2021 12:00 AM.

• #### Sedimentary pyrite sulfur isotopes track the local dynamics of the Peruvian oxygen minimum zone

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24753-x

To explore the importance of local vs. global sulfur-cycle controls on variations in pyrite sulfur isotopes, the authors couple carbon-nitrogen-sulfur concentrations and stable isotopes of sediments from the Peruvian oxygen minimum zone, identifying a major role for the local organic carbon loading.

in Nature Communications on July 20, 2021 12:00 AM.

• #### TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24703-7

Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis

in Nature Communications on July 20, 2021 12:00 AM.

• #### Evidence for higher order topology in Bi and Bi0.92Sb0.08

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24683-8

The experimental realization of higher order topological insulator (HOTI) in solid state materials remains elusive. Here, Aggarwal et al. reveal hinge states on three edges of both Bi and Bi0.92Sb0.08 (110) islands, supporting them as a class of HOTI.

in Nature Communications on July 20, 2021 12:00 AM.

• #### A synthetic tubular molecular transport system

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24675-8

DNA origami can be used to control the movement of nanoscale assemblies. Here the authors construct multiple-micrometer-long hollow DNA filaments through which DNA pistons move with micrometer-per-second speeds.

in Nature Communications on July 20, 2021 12:00 AM.

• #### Temperature heterogeneity correlates with intraspecific variation in physiological flexibility in a small endotherm

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24588-6

Theory predicts that organisms in varied environments should evolve to be more phenotypically flexible. Evidence combining genetic and physiological variation with thermal acclimation experiments shows that the thermogenic flexibility of wild juncos is greatest in populations where temperatures are most variable.

in Nature Communications on July 20, 2021 12:00 AM.

• #### Early-life social experience affects offspring DNA methylation and later life stress phenotype

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24583-x

Early social experience can alter epigenetic patterns and stress responses later in life. A study on wild spotted hyenas finds that maternal care and social connections after leaving the den influence DNA methylation and contribute to a developmentally plastic stress response.

in Nature Communications on July 20, 2021 12:00 AM.

• #### Reversible electroadhesion of hydrogels to animal tissues for suture-less repair of cuts or tears

Nature Communications, Published online: 20 July 2021; doi:10.1038/s41467-021-24022-x

The authors demonstrate strong adhesion of cationic hydrogels to bovine tissues under a DC electric field. Such electroadhesion can be reversed by switching the polarity of the field. This approach could enable simpler surgeries, where sutures are not needed.

in Nature Communications on July 20, 2021 12:00 AM.

• #### How to manage the uncertainty of a remote PhD

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-02001-y

Satheesh Kumar has found ways to be productive without ever visiting his supervisor or lab.

in Nature on July 20, 2021 12:00 AM.

• #### The parenting penalties faced by scientist mothers

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01993-x

Starting a family at a key career stage comes at a cost to birthing parents — and many end up leaving the profession as a result.

in Nature on July 20, 2021 12:00 AM.

• #### Vulnerable nations lead by example on Sustainable Development Goals research

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01992-y

A United Nations study of world science is a wake-up call that richer countries must also shift science towards the SDGs.

in Nature on July 20, 2021 12:00 AM.

• #### China launches world’s largest carbon market: but is it ambitious enough?

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01989-7

Experts welcome the trading scheme, but question whether it is up to the task of helping China achieve its climate goals.

in Nature on July 20, 2021 12:00 AM.

• #### The guts of a ‘bog body’ reveal sacrificed man’s final meal

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01984-y

Tollund Man, who lived more than 2,000 years ago, ate well before he was hanged.

in Nature on July 20, 2021 12:00 AM.

• #### Private immune protection at the border of the central nervous system

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01962-4

At the outer border of the brain and spinal cord, immune cells have been observed that originate from the bone marrow of the adjacent skull and vertebrae. They reach this site through special bone channels, without passing through the blood.

in Nature on July 20, 2021 12:00 AM.

• #### Six years as university rector changed how I do genetics

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01960-6

Six years as university rector changed how I do genetics

in Nature on July 20, 2021 12:00 AM.

• #### ISSCR guidelines uphold human right to science for benefit of all

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01959-z

ISSCR guidelines uphold human right to science for benefit of all

in Nature on July 20, 2021 12:00 AM.

• #### Andes foothills protected by carbon-offset fund

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01958-0

Andes foothills protected by carbon-offset fund

in Nature on July 20, 2021 12:00 AM.

• #### Solar geoengineering research needs formal global debate

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01957-1

Solar geoengineering research needs formal global debate

in Nature on July 20, 2021 12:00 AM.

• #### From the archive

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01946-4

Nature’s pages feature a discussion of global warming in 1971 and report that astronomy captured the imagination of world leaders in 1871.

in Nature on July 20, 2021 12:00 AM.

• #### Should children get COVID vaccines? What the science says

Nature, Published online: 20 July 2021; doi:10.1038/d41586-021-01898-9

With vaccination campaigns underway in some countries while others weigh the options, Nature looks at the evidence for vaccinating younger people.

in Nature on July 20, 2021 12:00 AM.

• #### Experimental Brain Research

in Experimental Brain Research on July 20, 2021 12:00 AM.

### Abstract

Phoenixin-14 (PNX-14) has a wide bioactivity in the central nervous system. Its role in the hypothalamus has been investigated, and it has been reported that it is involved in the regulation of excitability in hypothalamic neurons. However, its role in the regulation of excitability in entorhinal cortex and the hippocampus is unknown. In this study, we investigated whether i. PNX-14 induces any synchronous discharges or epileptiform activity and ii. PNX-14 has any effect on already initiated epileptiform discharges. We used 350 µm thick acute horizontal hippocampal–entorhinal cortex slices obtained from 30- to 35-day-old mice. Extracellular field potential recordings were evaluated in the entorhinal cortex and hippocampus CA1 region. Bath application of PNX-14 did not initiate any epileptiform activity or abnormal discharges. 4-Aminopyridine was applied to induce epileptiform activity in the slices. We found that 200 nM PNX-14 reduced the frequency of interictal-like events in both the entorhinal cortex and hippocampus CA1 region which was induced by 4-aminopyridine. Furthermore, PNX-14 led to a similar suppression in the total power of local field potentials of 1–120 Hz. The frequency or the duration of the ictal events was not affected. These results exhibited for the first time that PNX-14 has a modulatory effect on synchronized neuronal discharges which should be considered in future therapeutic approaches.

in Experimental Brain Research on July 20, 2021 12:00 AM.

### Abstract

Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aβ plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid β modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of β-amyloid (Aβ) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and β-amyloid (Aβ) plaque load and inhibition of neuronal death.

in Experimental Brain Research on July 20, 2021 12:00 AM.

• #### Increasing Serotonin to Reduce Parkinsonian Tremor

While current dopamine-based drugs seem to be effective for most Parkinson's disease (PD) motor dysfunctions, they produce variable responsiveness for resting tremor. This lack of consistency could be explained by considering recent evidence suggesting that PD resting tremor can be divided into different partially overlapping phenotypes based on the dopamine response. These phenotypes may be associated with different pathophysiological mechanisms produced by a cortical-subcortical network involving even non-dopaminergic areas traditionally not directly related to PD. In this study, we propose a bio-constrained computational model to study the neural mechanisms underlying a possible type of PD tremor: the one mainly involving the serotoninergic system. The simulations run with the model demonstrate that a physiological serotonin increase can partially recover dopamine levels at the early stages of the disease before the manifestation of overt tremor. This result suggests that monitoring serotonin concentration changes could be critical for early diagnosis. The simulations also show the effectiveness of a new pharmacological treatment for tremor that acts on serotonin to recover dopamine levels. This latter result has been validated by reproducing existing data collected with human patients.

in Frontiers in Systems Neuroscience on July 20, 2021 12:00 AM.

• #### Long Non-coding RNA T-uc.189 Modulates Neural Progenitor Cell Fate by Regulating Srsf3 During Mouse Cerebral Cortex Development

Neurogenesis is a complex process that depends on the delicate regulation of spatial and temporal gene expression. In our previous study, we found that transcribed ultra-conserved regions (T-UCRs), a class of long non-coding RNAs that contain UCRs, are expressed in the developing nervous systems of mice, rhesus monkeys, and humans. In this study, we first detected the full-length sequence of T-uc.189, revealing that it was mainly concentrated in the ventricular zone (VZ) and that its expression decreased as the brain matured. Moreover, we demonstrated that knockdown of T-uc.189 inhibited neurogenesis. In addition, we found that T-uc.189 positively regulated the expression of serine-arginine-rich splicing factor 3 (Srsf3). Taken together, our results are the first to demonstrate that T-uc.189 regulates the expression of Srsf3 to maintain normal neurogenesis during cortical development.

in Frontiers in Neuroscience: Neurogenesis on July 20, 2021 12:00 AM.

• #### Parietal Lobe Reorganization and Widespread Functional Connectivity Integration in Upper-Limb Amputees: A rs-fMRI Study

The right parietal lobe plays an important role in body image, and disorders of body image emerge after lesions in the parietal lobe or with parietal lobe epilepsy. Body image disorder also often accompanies upper-limb amputation, in which the patient misperceives that their missing limb is still part of their body. Cortical reorganization is known to occur after upper-limb amputation, but it is not clear how widespread and to what degree functional connectivity (FC) is reorganized post-amputation, nor whether such changes might be related to misperceptions of body image. Twenty-four subjects who had a traumatically upper-limb amputees (ULAs) and 24 age-matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. Regions of interest (ROIs) in the right superior parietal gyrus (SPG_R) and right inferior parietal lobule (IPL_R) were defined using BrainNet Viewer. We calculated the amplitude of low-frequency fluctuations (ALFF) in ROIs and correlated the ROI mean amplitude of low-frequency fluctuations (mALFF) and mean scores on the phantom limb sensation (PLS) scale and beck depression index (BDI). We also calculated ROIs and whole-brain FC. Compared to the HC group, we observed significantly increased activation (mALFF) in ROIs of the ULA group. Moreover, correlation analyses revealed a significant positive correlation between ROI mALFF and scores on the PLS. There was a significant negative correlation between the SPG_R mALFF and BDI scores. Seed-based, whole-brain FC analysis revealed that FC in the ULA group significantly decreased in many brain regions across the entire brain. The right parietal lobe appears to be involved in some aspect of body awareness and depression in amputation patients. Upper-limb amputation results not only in reorganization in the local brain area formerly representing the missing limb, but also results in more widespread reorganization through FC changes in whole brain.

in Frontiers in Neuroscience: Brain Imaging Methods on July 20, 2021 12:00 AM.

• #### Altered Spontaneous Neural Activity and Functional Connectivity in Parkinson’s Disease With Subthalamic Microlesion

Background

Transient improvement in motor symptoms are immediately observed in patients with Parkinson’s disease (PD) after an electrode has been implanted into the subthalamic nucleus (STN) for deep brain stimulation (DBS). This phenomenon is known as the microlesion effect (MLE). However, the underlying mechanisms of MLE is poorly understood.

Purpose

We utilized resting state functional MRI (rs-fMRI) to evaluate changes in spontaneous brain activity and networks in PD patients during the microlesion period after DBS.

Method

Overall, 37 PD patients and 13 gender- and age-matched healthy controls (HCs) were recruited for this study. Rs-MRI information was collected from PD patients three days before DBS and one day after DBS, whereas the HCs group was scanned once. We utilized the amplitude of low-frequency fluctuation (ALFF) method in order to analyze differences in spontaneous whole-brain activity among all subjects. Furthermore, functional connectivity (FC) was applied to investigate connections between other brain regions and brain areas with significantly different ALFF before and after surgery in PD patients.

Result

Relative to the PD-Pre-DBS group, the PD-Post-DBS group had higher ALFF in the right putamen, right inferior frontal gyrus, right precentral gyrus and lower ALFF in right angular gyrus, right precuneus, right posterior cingulate gyrus (PCC), left insula, left middle temporal gyrus (MTG), bilateral middle frontal gyrus and bilateral superior frontal gyrus (dorsolateral). Functional connectivity analysis revealed that these brain regions with significantly different ALFF scores demonstrated abnormal FC, largely in the temporal, prefrontal cortices and default mode network (DMN).

Conclusion

The subthalamic microlesion caused by DBS in PD was found to not only improve the activity of the basal ganglia-thalamocortical circuit, but also reduce the activity of the DMN and executive control network (ECN) related brain regions. Results from this study provide new insights into the mechanism of MLE.

in Frontiers in Neuroscience: Neurodegeneration on July 20, 2021 12:00 AM.

• #### Dysfunctional Brain Dynamics of Parkinson's Disease and the Effect of Acute Deep Brain Stimulation

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and deep brain stimulation (DBS) can effectively alleviate PD symptoms. Although previous studies have detected network features of PD and DBS, few studies have considered their dynamic characteristics.

Objective: We tested two hypotheses. (1) Reduced brain dynamics, as evidenced by slowed microstate dynamic change, is a characteristic of PD and is related to the movement disorders of patients with PD. (2) Therapeutic acute DBS can partially reverse slow brain dynamics in PD to healthy levels.

Methods: We used electroencephalography (EEG) microstate analysis based on high density (256-channel) EEG to detect the effects of PD and DBS on brain dynamic changes on a sub-second timescale. We compared 21 healthy controls (HCs) with 20 patients with PD who were in either DBS-OFF or DBS-ON states. Assessment of movement disorder using the Unified Parkinson's Disease Rating Scale III was correlated with microstate parameters.

Results: Compared with HCs, patients with PD displayed a longer mean microstate duration with reduced occurrence per second, which were significantly associated with movement disorders. In patients with PD, some parameters of microstate analysis were restored toward healthy levels after DBS.

Conclusions: Resting-state EEG microstate analysis is an important tool for investigating brain dynamic changes in PD and DBS. PD can slow down brain dynamic change, and therapeutic acute DBS can partially reverse this change toward a healthy level.

in Frontiers in Neuroscience: Neurodegeneration on July 20, 2021 12:00 AM.

• #### Squamous and Respiratory Metaplasia After Olfactory Mucosal Resection

Resection of the olfactory mucosa (OM) is sometimes unavoidable during surgery; however, it is not known whether the OM can completely recover thereafter. The aim of this study was to uncover whether the OM fully recovers after mucosal resection and describe the process of OM regeneration. 8-week-old male Sprague–Dawley rats (n = 18) were subjected to OM resection at the nasal septum; six rats were euthanized for histological examination 0, 30, and 90 days after surgery. Immunohistochemistry was performed to identify olfactory receptor neuron (ORN) lineage cells [mature and immature ORNs and ORN progenitors, and olfactory ensheathing cells (OECs)], as well as dividing and apoptotic cells. Squamous and respiratory metaplasia and inflammatory cell infiltration were also assessed. On day 30 after resection, the mucosa had regenerated, and mainly contained thin nerve bundles, basal cells, and immature ORNs, with a few mature ORNs and OECs. On day 90, the repaired nasal mucosa had degenerated into stratified squamous or ciliated pseudostratified columnar epithelia, with reducing ORNs. The lamina propria contained numerous macrophages. Partial regeneration was observed within 1 month after OM resection, whereas subsequent degeneration into squamous and respiratory epithelia occurred within 3 months. Given the poor persistence of ORNs and OECs, OM resection is likely to result in olfactory impairment. Overall, surgeons should be cautious not to injure the OM during surgery.

in Frontiers in Neuroscience: Neurodegeneration on July 20, 2021 12:00 AM.

• #### Emotional Modulation of Frontal Alpha Asymmetry - a Novel Biomarker of Mild Traumatic Brain Injury

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck’s depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI.

in Frontiers in Human Neuroscience on July 20, 2021 12:00 AM.

• #### Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson’s disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.

in Frontiers in Human Neuroscience on July 20, 2021 12:00 AM.

• #### Children With Dyscalculia Show Hippocampal Hyperactivity During Symbolic Number Perception

Dyscalculia is a learning disability affecting the acquisition of arithmetical skills in children with normal intelligence and age-appropriate education. Two hypotheses attempt to explain the main cause of dyscalculia. The first hypothesis suggests that a problem with the core mechanisms of perceiving (non-symbolic) quantities is the cause of dyscalculia (core deficit hypothesis), while the alternative hypothesis suggests that dyscalculics have problems only with the processing of numerical symbols (access deficit hypothesis). In the present study, the symbolic and non-symbolic numerosity processing of typically developing children and children with dyscalculia were examined with functional magnetic resonance imaging (fMRI). Control (n = 15, mean age: 11.26) and dyscalculia (n = 12, mean age: 11.25) groups were determined using a wide-scale screening process. Participants performed a quantity comparison paradigm in the fMRI with two number conditions (dot and symbol comparison) and two difficulty levels (0.5 and 0.7 ratio). The results showed that the bilateral intraparietal sulcus (IPS), left dorsolateral prefrontal cortex (DLPFC) and left fusiform gyrus (so-called “number form area”) were activated for number perception as well as bilateral occipital and supplementary motor areas. The task difficulty engaged bilateral insular cortex, anterior cingulate cortex, IPS, and DLPFC activation. The dyscalculia group showed more activation in the left orbitofrontal cortex, left medial prefrontal cortex, and right anterior cingulate cortex than the control group. The dyscalculia group showed left hippocampus activation specifically for the symbolic condition. Increased left hippocampal and left-lateralized frontal network activation suggest increased executive and memory-based compensation mechanisms during symbolic processing for dyscalculics. Overall, our findings support the access deficit hypothesis as a neural basis for dyscalculia.

in Frontiers in Human Neuroscience on July 20, 2021 12:00 AM.

• #### Visuospatial Attention Allocation as an Indicator of Cognitive Deficit in Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Traumatic Brain Injury (TBI) is defined by changes in brain function resulting from external forces acting on the brain and is typically characterized by a host of physiological and functional changes such as cognitive deficits including attention problems. In the present study, we focused on the effect of TBI on the ability to allocate attention in vision (i.e., the use of endogenous and exogenous visual cues) by systematically reviewing previous literature on the topic. We conducted quantitative synthesis of 16 selected studies of visual attention following TBI, calculating 80 effect size estimates. The combined effect size was large (g = 0.79, p < 0.0001) with medium heterogeneity (I2 = 68.39%). Subgroup analyses revealed an increase in deficit with moderate-to-severe and severe TBI as compared to mild TBI [F(2, 76) = 24.14, p < 0.0001]. Task type was another key source of variability and subgroup analyses indicated that higher order attention processes were severely affected by TBI [F(2, 77) = 5.66, p = 0.0051). Meta-regression analyses revealed significant improvement in visual attention deficit with time [p(mild) = 0.031, p(moderate-to-severe) = 0.002, p(severe) < 0.0001]. Taken together, these results demonstrate that visual attention is affected by TBI and that regular assessment of visual attention, using a systematic attention allocation task, may provide a useful clinical measure of cognitive impairment and change after TBI.

in Frontiers in Human Neuroscience on July 20, 2021 12:00 AM.

• #### SyNC, a Computationally Extensive and Realistic Neural Net to Identify Relative Impacts of Synaptopathy Mechanisms on Glutamatergic Neurons and Their Networks in Autism and Complex Neurological Disorders

Synaptic function and experience-dependent plasticity across multiple synapses are dependent on the types of neurons interacting as well as the intricate mechanisms that operate at the molecular level of the synapse. To understand the complexity of information processing at synaptic networks will rely in part on effective computational models. Such models should also evaluate disruptions to synaptic function by multiple mechanisms. By co-development of algorithms alongside hardware, real time analysis metrics can be co-prioritized along with biological complexity. The hippocampus is implicated in autism spectrum disorders (ASD) and within this region glutamatergic neurons constitute 90% of the neurons integral to the functioning of neuronal networks. Here we generate a computational model referred to as ASD interrogator (ASDint) and corresponding hardware to enable in silicon analysis of multiple ASD mechanisms affecting glutamatergic neuron synapses. The hardware architecture Synaptic Neuronal Circuit, SyNC, is a novel GPU accelerator or neural net, that extends discovery by acting as a biologically relevant realistic neuron synapse in real time. Co-developed ASDint and SyNC expand spiking neural network models of plasticity to comparative analysis of retrograde messengers. The SyNC model is realized in an ASIC architecture, which enables the ability to compute increasingly complex scenarios without sacrificing area efficiency of the model. Here we apply the ASDint model to analyse neuronal circuitry dysfunctions associated with autism spectral disorder (ASD) synaptopathies and their effects on the synaptic learning parameter and demonstrate SyNC on an ideal ASDint scenario. Our work highlights the value of secondary pathways in regard to evaluating complex ASD synaptopathy mechanisms. By comparing the degree of variation in the synaptic learning parameter to the response obtained from simulations of the ideal scenario we determine the potency and time of the effect of a particular evaluated mechanism. Hence simulations of such scenarios in even a small neuronal network now allows us to identify relative impacts of changed parameters and their effect on synaptic function. Based on this, we can estimate the minimum fraction of a neuron exhibiting a particular dysfunction scenario required to lead to complete failure of a neural network to coordinate pre-synaptic and post-synaptic outputs.

in Frontiers in Cellular Neuroscience on July 20, 2021 12:00 AM.

• #### Pancreas-Brain Crosstalk

The neural regulation of glucose homeostasis in normal and challenged conditions involves the modulation of pancreatic islet-cell function. Compromising the pancreas innervation causes islet autoimmunity in type 1 diabetes and islet cell dysfunction in type 2 diabetes. However, despite the richly innervated nature of the pancreas, islet innervation remains ill-defined. Here, we review the neuroanatomical and humoral basis of the cross-talk between the endocrine pancreas and autonomic and sensory neurons. Identifying the neurocircuitry and neurochemistry of the neuro-insular network would provide clues to neuromodulation-based approaches for the prevention and treatment of diabetes and obesity.

in Frontiers in Neuroanatomy on July 20, 2021 12:00 AM.

• #### Preserved Thermal Pain in 3xTg-AD Mice With Increased Sensory-Discriminative Pain Sensitivity in Females but Affective-Emotional Dimension in Males as Early Sex-Specific AD-Phenotype Biomarkers

The increase of the aging population, where quite chronic comorbid conditions are associated with pain, draws growing interest across its investigation and the underlying nociceptive mechanisms. Burn injuries associated problems might be of relevance in the older adult’s daily life, but in people with dementia, exposure to high temperatures and heat sources poses a significantly increased risk of burns. In this brief report, the hind paws and tail pain withdrawal reflexes and the emotional responses to thermal nociception in 3xTg-AD mice were characterized for the first time in the plantar test and compared to their non-transgenic (NTg) counterparts. We studied a cohort of male and female 3xTg-AD mice at asymptomatic (2 months), early (6 months), middle (9 months), and advanced (12 and 15 months) stages of the disease and as compared to sex- and age-matched NTg control mice with normal aging. At 20 and 40W intensities, the sensorial-discriminative thresholds eliciting the withdrawal responses were preserved from asymptomatic to advanced stages of the disease compared to NTg counterparts. Moreover, 3xTg-AD females consistently showed a greater sensory-discriminative sensitivity already at premorbid ages, whereas increased emotionality was shown in males. False-negative results were found in “blind to sex and age” analysis, warning about the need to study sexes independently. The current results and previous report in cold thermal stimulation provide two paradigms unveiling sex-specific early AD-phenotype nociceptive biomarkers to study the mechanistic underpinnings of sex-, age- and AD-disease-dependent thermal pain sensitivity.

in Frontiers in Ageing Neuroscience on July 20, 2021 12:00 AM.

• #### An actin-related protein that is most highly expressed in Drosophila testes is critical for embryonic development

Most actin-related proteins (Arps) are highly conserved and carry out well-defined cellular functions in eukaryotes. However, many lineages like Drosophila and mammals encode divergent non-canonical Arps whose roles remain unknown. To elucidate the function of non-canonical Arps, we focus on Arp53D, which is highly expressed in testes and retained throughout Drosophila evolution. We show that Arp53D localizes to fusomes and actin cones, two germline-specific actin structures critical for sperm maturation, via a unique N-terminal tail. Surprisingly, we find that male fertility is not impaired upon Arp53D loss, yet population cage experiments reveal that Arp53D is required for optimal fitness in Drosophila melanogaster. To reconcile these findings, we focus on Arp53D function in ovaries and embryos where it is only weakly expressed. We find that under heat stress Arp53D-knockout (KO) females lay embryos with reduced nuclear integrity and lower viability; these defects are further exacerbated in Arp53D-KO embryos. Thus, despite its relatively recent evolution and primarily testis-specific expression, non-canonical Arp53D is required for optimal embryonic development in Drosophila.

in eLife on July 20, 2021 12:00 AM.

• #### Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8+ T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8+ T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8+ T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8+ T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.

in eLife on July 20, 2021 12:00 AM.

• #### Pak1 kinase controls cell shape through ribonucleoprotein granules

Fission yeast cells maintain a rod shape due to conserved signaling pathways that organize the cytoskeleton for polarized growth. We discovered a mechanism linking the conserved protein kinase Pak1 with cell shape through the RNA-binding protein Sts5. Pak1 (also called Shk1 and Orb2) prevents Sts5 association with P bodies by directly phosphorylating its intrinsically disordered region (IDR). Pak1 and the cell polarity kinase Orb6 both phosphorylate the Sts5 IDR but at distinct residues. Mutations preventing phosphorylation in the Sts5 IDR cause increased P body formation and defects in cell shape and polarity. Unexpectedly, when cells encounter glucose starvation, PKA signaling triggers Pak1 recruitment to stress granules with Sts5. Through retargeting experiments, we reveal that Pak1 localizes to stress granules to promote rapid dissolution of Sts5 upon glucose addition. Our work reveals a new role for Pak1 in regulating cell shape through ribonucleoprotein granules during normal and stressed growth conditions.

in eLife on July 20, 2021 12:00 AM.

• #### Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease

in eLife on July 20, 2021 12:00 AM.

• #### Linking plasmid-based beta-lactamases to their bacterial hosts using single-cell fusion PCR

The horizonal transfer of plasmid-encoded genes allows bacteria to adapt to constantly shifting environmental pressures, bestowing functional advantages to their bacterial hosts such as antibiotic resistance, metal resistance, virulence factors, and polysaccharide utilization. However, common molecular methods such as short- and long-read sequencing of microbiomes cannot associate extrachromosomal plasmids with the genome of the host bacterium. Alternative methods to link plasmids to host bacteria are either laborious, expensive or prone to contamination. Here we present the One-step Isolation and Lysis PCR (OIL-PCR) method, which molecularly links plasmid encoded genes with the bacterial 16S rRNA gene via fusion PCR performed within an emulsion. After validating this method, we apply it to identify the bacterial hosts of three clinically relevant beta-lactamases within the gut microbiomes of neutropenic patients, as they are particularly vulnerable multidrug-resistant infections. We successfully detect the known association of a multi-drug resistant plasmid with Klebsiella pneumoniae, as well as the novel associations of two low-abundance genera, Romboutsia and Agathobacter. Further investigation with OIL-PCR confirmed that our detection of Romboutsia is due to its physical association with Klebsiella as opposed to directly harboring the genes. Here we put forth a robust, accessible, and high-throughput platform for sensitively surveying the bacterial hosts of mobile genes, as well as detecting physical bacterial associations such as those occurring within biofilms and complex microbial communities.

in eLife on July 20, 2021 12:00 AM.

• #### Conserved visual capacity of rats under red light

Recent studies examine the behavioral capacities of rats and mice with and without visual input, and the neuronal mechanisms underlying such capacities. These animals are assumed to be functionally blind under red light, an assumption that might originate in the fact that they are dichromats who possess ultraviolet and green but not red cones. But the inability to see red as a color does not necessarily rule out form vision based on red light absorption. We measured Long-Evans rats' capacity for visual form discrimination under red light of various wavelength bands. Upon viewing a black and white grating, they had to distinguish between two categories of orientation, horizontal and vertical. Psychometric curves plotting judged orientation versus angle demonstrate the conserved visual capacity of rats under red light. Investigations aiming to explore rodent physiological and behavioral functions in the absence of visual input should not assume red-light blindness.

in eLife on July 20, 2021 12:00 AM.

• #### Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles

Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in Xenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND in humans. In Xenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.

in eLife on July 20, 2021 12:00 AM.

• #### Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons

Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously-encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Accordingly, our findings establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis, but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the prenatal human hypothalamus

The hypothalamus is critically important for regulating most autonomic, metabolic, and behavioral functions essential for life and species propagation, yet a comprehensive understanding of neuronal subtypes and their development in the human brain is lacking. Here, we characterized the prenatal human hypothalamus by sequencing the transcriptomes of 45,574 single-cells from 12 embryos, spanning gestational weeks 4 through 25. These cells describe a temporal trajectory from proliferative stem cell populations to maturing neurons and glia, including 38 distinct excitatory and inhibitory neuronal subtypes. Merging these data with paired samples from the cortex and ganglionic eminences (GE) revealed two distinct neurogenesis pathways, one shared between GE and hypothalamus and a second unique to cortex. Gene regulatory network modeling predicted that these distinct maturation trajectories involve the activation of region- and cell type-specific transcription factor networks. These results provide the first comprehensive transcriptomic view of human hypothalamus development at cellular resolution.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Postsynaptic neuroligin-1 mediates presynaptic endocytosis during neuronal activity

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn-1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Deficient thalamo-cortical networks dynamics and sleep homeostatic processes in a redox dysregulation model relevant to schizophrenia.

A growing body of evidence implicates thalamo-cortical oscillations with the neuropathophysiology of schizophrenia (SZ) in both mice and humans. Yet, the precise mechanisms underlying sleep perturbations in SZ remain unclear. Here, we characterised the dynamics of thalamo-cortical networks across sleep-wake states in a mouse model carrying a mutation in the enzyme glutathione synthetase gene (Gclm-/-) associated with SZ in humans. We hypothesised that deficits in parvalbumin immunoreactive cells in the thalamic reticular nucleus (TRN) and the anterior cingulate cortex (ACC) -caused by oxidative stress - impact thalamocortical dynamics, thus affecting non-rapid eye movement (NREM) sleep and sleep homeostasis. Using polysomnographic recordings in mice, we showed that KO mice exhibited a fragmented sleep architecture, similar to SZ patients and altered sleep homeostasis responses revealed by an increase in NREM latency and slow wave activities during the recovery period (SR). Although NREM sleep spindle rate during spontaneous sleep was similar in Gclm-/- and Gcml +/+, KO mice lacked a proper homeostatic response during SR. Interestingly, using multisite electrophysiological recordings in freely-moving mice, we found that high order thalamic network dynamics showed increased synchronisation, that was exacerbated during the sleep recovery period subsequent to extended wakefulness (SD), possibly due to lower bursting activity in TRN-antero dorsal thalamus circuit in KO compared to WT littermates. Collectively, these findings provide a mechanism for SZ associated deficits of thalamo-cortical neuron dynamics and perturbations of sleep architecture.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Dendrite regeneration in C. elegans is controlled by the RAC GTPase CED-10 and the RhoGEF TIAM-1

Neurons are vulnerable to physical insults which compromise the integrity of both dendrites and axons. Although several molecular pathways of axon regeneration are identified, our knowledge of dendrite regeneration is limited. To understand the mechanisms of dendrite regeneration, we used PVD neurons in C. elegans having stereotyped branched dendrites. Using femtosecond laser, we severed the primary dendrites and axon of this neuron. After severing the primary dendrites near the cell body, we observed sprouting of new branches from the proximal site within 6 hours, which regrew further with time in an unstereotyped manner. This was accompanied by reconnection between the proximal and distal dendrites as well as the fusion among the higher-order branches as reported before. We quantified the regeneration pattern in three aspects territory length, number of branches and fusion phenomena. Axonal injury causes a retraction of the severed end followed by a Dual leucine zipper kinase-1 (DLK-1) dependent regrowth from the severed end. We tested the roles of the major axon regeneration signaling hubs such as DLK-1-RPM-1, cAMP elevation, let-7 miRNA, AKT-1, Phosphatidyl serine exposure/PS in dendrite regeneration. We found that neither regrowth nor fusion is affected by the axon injury pathway molecules. Surprisingly, we found that the RAC GTPase CED-10 and its upstream GEF TIAM-1 play a cell-autonomous role in dendrite regeneration. Additionally, function of CED-10 in epidermal cell is critical for post-dendrotomy fusion phenomena. This work describes a novel regulatory mechanism of dendrite regeneration and provides a framework for understanding the cellular mechanism of dendrite regeneration using PVD neuron as a model system.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Fast grip force adaptation to friction relies on localized fingerpad strains

Humans can quickly adjust their grip force to a change in friction at the object-skin interface during dexterous manipulation in a precision grip. To perform this adjustment, they rely on the feedback of the mechanoreceptive afferents innervating the fingertip skin. Because these tactile afferents encode information related to skin deformation, the nature of the feedback signaling a change in friction must somehow originate from a difference in the way the skin deforms when manipulating objects of different frictions. To better characterize the origin of the underlying sensory events, we asked human participants to perform a grip-lifting task with a manipulandum equipped with an optical imaging system. This system enabled to monitor fingertip skin strains through transparent plates of glass that had different levels of friction. We observed that, following an unexpected change in friction, participants adapted their grip force within 370ms after contact with the surface. By comparing the deformation patterns when unexpectedly switching from a high to a low friction condition, we found a significant increase in skin deformation inside the contact area arising over 100ms before the motor response, during the loading phase, suggesting that local and partial deformation patterns prior to lift-off are used in the nervous system to adjust the grip force as a function of the frictional condition.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Don't think, feel: basal ganglia-cortical connectivity underlies self-regulation of brain oscillations in humans

Brain-computer interfaces (BCIs) provide an artificial link by which the brain can directly interact with the environment. To achieve fine BCI control, participants must modulate the patterns of the cortical oscillations generated from the motor and somatosensory cortices. However, it remains unclear how humans regulate cortical oscillations, the controllability of which substantially varies across individuals. Here, we performed simultaneous electroencephalography (to assess BCI control) and functional magnetic resonance imaging (to measure brain activity) in healthy participants. Self-regulation of cortical oscillations induced activity in the basal ganglia-cortical network (BgCN) and the neurofeedback control network (NfCN). Successful self-regulation correlated with striatal activity in the BgCN, through which patterns of cortical oscillations were likely modulated. Moreover, BgCN and NfCN connectivity correlated with strong and weak self-regulation, respectively. The findings indicate that the BgCN is important for self-regulation, the understanding of which should help advance BCI technology.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Specialized neurons in the right habenula mediate response to aversive olfactory cues

Hemispheric specializations are well studied at the functional level but less is known about the underlying neural mechanisms. We identified a small cluster of cholinergic neurons in the right dorsal habenula (dHb) of zebrafish, defined by their expression of the lecithin retinol acyltransferase domain containing 2a (lratd2a) gene and their efferent connections with a subregion of the ventral interpeduncular nucleus (vIPN). The unilateral lratd2a-expressing neurons are innervated by a subset of mitral cells from both the left and right olfactory bulb and are activated upon exposure of adult zebrafish to the aversive odorant cadaverine that provokes avoidance behavior. Using an intersectional strategy to drive expression of the botulinum neurotoxin specifically in these neurons, we find that adults no longer show protracted avoidance to cadaverine. Mutants with left-isomerized dHb that lack these neurons are less repelled by cadaverine and their behavioral response to alarm substance, a potent aversive cue, is diminished. However mutants in which both dHb have right identity appear more reactive to alarm substance. The results implicate an asymmetric dHb-vIPN neural circuit in processing of aversive olfactory cues and modulating resultant behavioral responses.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Residual dynamics resolves recurrent contributions to neural computation

Relating neural activity to behavior requires an understanding of how neural computations arise from the coordinated dynamics of distributed, recurrently connected neural populations. However, inferring the nature of recurrent dynamics from partial recordings of a neural circuit presents significant challenges. Here, we show that some of these challenges can be overcome by a fine-grained analysis of the dynamics of neural residuals, i.e. trial-by-trial variability around the mean neural population trajectory for a given task condition. Residual dynamics in macaque pre-frontal cortex (PFC) in a saccade-based perceptual decision-making task reveals recurrent dynamics that is time-dependent, but consistently stable, and implies that pronounced rotational structure in PFC trajectories during saccades are driven by inputs from upstream areas. The properties of residual dynamics restrict the possible contributions of PFC to decision-making and saccade generation, and suggest a path towards fully characterizing distributed neural computations with large-scale neural recordings and targeted causal perturbations.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Typical and disrupted brain circuitry for conscious awareness in full-term and preterm infants

One of the great frontiers of consciousness science is understanding how early consciousness arises in the development of the human infant. The reciprocal relationship between the default mode network (DMN) and frontoparietal networks -- the dorsal attention network (DAN) and executive control network (ECN) -- is thought to facilitate integration of information across the brain and its availability for conscious access to a wide set of mental operations. It remains unknown whether the brain mechanism of conscious awareness is instated in infants from birth. To address this gap, we asked what the impact of prematurity and neonate age is on the development the default mode and fronto-parietal networks, and of their reciprocal relationship. To address these questions, we used the Developing Human Connectome Project (dHCP), a unique Open Science project which provides a large sample of neonatal functional Magnetic Resonance Imaging (fMRI) data with high temporal and spatial resolution. Resting state fMRI data for full-term neonates (N = 282, age 41.2 w {+/-} 12 d), and preterm neonates scanned at term-equivalent age (TEA) (N = 73, 40.9 w {+/-} 14.5 d), or before TEA (N = 73, 34.6 w {+/-} 13.4 d) were obtained from the dHCP, and for a reference adult group (N = 176, 22 - 36 years), from the Human Connectome Project. For the first time, we show that the reciprocal relationship between the DMN and DAN was present at full-term birth or TEA. Although different from the adult networks, the DMN, DAN and ECN were present as distinct networks at full-term birth or TEA, but premature birth disrupted network development. By contrast, neonates before TEA showed dramatic underdevelopment of high-order networks. Only the DAN was present as a distinct network and the reciprocal network relationship was not yet formed. Our results suggest that, at full-term birth or by term-equivalent age, infants possess key features of the neural circuitry that enables integration of information across diverse sensory and high-order functional modules, giving rise to conscious access. Conversely, they suggest that this brain infrastructure is not present before infants reach term-equivalent age. These findings improve understanding of the ontogeny of high-order network dynamics that support conscious awareness, and of their disruption by premature birth.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology

To better define roles that astrocytes and microglia play in Alzheimers disease (AD), we used single-nuclei RNA sequencing to comprehensively characterize transcriptomes in astrocyte and microglia nuclei isolated post mortem from neuropathologically-defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid and pTau expression. Astrocytes were enriched for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, proteostasis and autophagy were highly enriched in microglia and perivascular macrophages. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Losartan shifts social reward motivation and punishment feedback sensitivity via modulating midbrain-striato-frontal circuits

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that modulating interactions between the dopamine and renin-angiotensin system with the angiotensin receptor antagonist Losartan (LT) can modulate learning and reward-related processes. We have therefore determined the behavioral and neural effects of LT on social reward and punishment processing in humans. A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of LT (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation, connectivity and social feedback prediction errors were modelled. Relative to placebo, LT switched reaction times and arousal away from prioritizing punishment towards social reward. On the neural level the LT-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation and attenuated activity in the ventral tegmental area (VTA) and associated connectivity with the bilateral insula in response to punishment during the outcome phase. Computational modelling further revealed an LT-enhanced social reward prediction error signal in VTA and dorsal striatum. LT shifted motivational and emotional salience away from social punishment towards social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Plasticity of the dopaminergic phenotype and of locomotion in larval zebrafish induced by changes in brain excitability during the embryonic period.

Neuronal communication starts before the establishment of the synapses with forms of neuronal excitability occurring during the embryonic period, we called here Embryonic Neuronal Excitability (ENE). ENE has been shown to modulate the correct unfolding of development transcriptional programs but the global consequences for the developing organisms are not all understood. Here we monitored calcium transients as a proxy for ENE in zebrafish to assess the efficacy of transient pharmacological treatments applied by balneation during the embryonic period to modulate ENE. We also report lasting effects of 24h treatments, performed at the end of the embryonic development, on morphology and behavior of larval zebrafish. The post-mitotic differentiation of the dopaminergic phenotype is modulated by ENE in the forebrain. The plasticity of the dopaminergic specification occurs within a stable population of vMAT2 immuno-reactive cells, hence identifying an unanticipated biological marker for this reserve pool. We also report an effect of ENE on locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted an hyperlocomotion in 6dpf zebrafish larvae which is an endophenotype for Attention Deficit with Hyperactivity Disorders and schizophrenia in zebrafish. These results provide a convenient framework to identify environmental factors that could regulate ENE and to study further the molecular mechanisms linking ENE to the neurotransmitters specification, with clinical relevance for the pathogenesis of neurodevelopmental disorders.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Diet modifies allele-specific phenotypes in Drosophila carrying epilepsy-associated PNPO variants

Pyridox(am)ine 5'-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters GABA and monoamines. Pathogenic variants in PNPO have been repeatedly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities, including developmental impairment and intellectual disability. It is unclear how seizure types and associated comorbidities are linked to specific PNPO alleles and to what degree diet can modify their expression. Furthermore, the molecular characteristics of PNPO variants have not been examined in model systems. Using CRISPR/Cas9, we generated four knock-in Drosophila alleles, hWT, hR116Q, hD33V, and hR95H, in which the endogenous Drosophila PNPO (sugarlethal) was replaced by wild-type human PNPO cDNA and epilepsy-associated variants corresponding to R116Q, D33V, and R95H, respectively. We examined these knock-in flies at the molecular, circuitry, and behavioral levels. Collectively, we found a wide range of phenotypes in an allele- and diet-dependent manner. Specifically, the D33V mutation reduces the mRNA level, R95H reduces the protein stability, and R116Q alters the protein localization of PNPO in the brain. D33V and R95H mutations lead to partial and complete lethality during development, respectively and R116Q and D33V mutations shorten lifespan. At the behavioral level, hD33V/hR95H trans-heterozygous flies are hypoactive on all tested diets whereas hR116Q flies show diet-dependent locomotor activities. At the circuitry level, hD33V homozygotes show rhythmic burst firing and hD33V/hR95H trans-heterozygotes exhibit spontaneous seizure discharges. In hR95H homozygotes rescued with PLP supplementation, we uncovered that PLP deficiency abolishes development and causes extreme seizures in adults. Lastly, genetic and electrophysiological analyses demonstrate that hWT/hR95H heterozygous flies are prone to seizures due to a dominant-negative effect of hR95H on hWT, highlighting the possibility that human R95H carriers may also be susceptible to epilepsy. Together, this study demonstrates that human PNPO variants interact with diet to contribute to phenotypic variations; and that the knock-in Drosophila model offers a powerful approach to systematically examine clinical manifestations and the underlying mechanisms of human PNPO deficiency.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Prenatal androgen treatment does not alter the firing activity of hypothalamic arcuate kisspeptin neurons in female mice

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome, who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational D16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in 3wk-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin, aka KNDy neurons. We hypothesized PNA treatment changes firing rates of KNDy neurons in a similar age-dependent manner as GnRH neurons. We conducted targeted extracellular recordings (0.5-2h) of Tac2-identified KNDy neurons from control and PNA mice at 3wks of age and in adulthood. About half of neurons were quiescent (<0.005Hz). Long-term firing rates of active cells varied, suggestive of episodic activity, but were not different among groups. Short-term burst firing was also similar. We thus reject the hypothesis that PNA alters the firing rate of KNDy neurons. This does not preclude altered neurosecretory output of KNDy neurons, involvement of other neuronal populations, or in-vivo networks as critical drivers of altered GnRH firing rates in PNA mice.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Emergence and fragmentation of the alpha-band driven by neuronal network dynamics

Rhythmic neuronal network activity underlies brain oscillations. To investigate how connected neuronal networks contribute to the emergence of the -band and the regulation of Up and Down states, we study a model based on synaptic short-term depression-facilitation with afterhyperpolarization (AHP). We found that the -band is generated by the network behavior near the attractor of the Up-state. Coupling inhibitory and excitatory networks by reciprocal connections leads to the emergence of a stable -band during the Up states, as reflected in the spectrogram. To better characterize the emergence and stability of thalamocortical oscillations containing and {delta} rhythms during anesthesia, we model the interaction of two excitatory with one inhibitory networks, showing that this minimal network topology leads to a persistent -band in the neuronal voltage characterized by dominant Up over Down states. Finally, we show that the emergence of the -band appears when external inputs are suppressed, while the fragmentation occurs at small synaptic noise or with increasing inhibitory inputs. To conclude, interaction between excitatory neuronal networks with and without AHP seems to be a general principle underlying changes in network oscillations that could apply to other rhythms.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Connectivity and dynamics in the olfactory bulb

Dendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the probability of synapse between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. It in turn predicts testable relations between network structure, lateral inhibition, and odor pattern decorrelation; between the density of granule cell activity and LFP oscillation frequency; how cortical feedback to granule cells affects mitral cell activity; and how cortical feedback to mitral cells is modulated by the network embedding. Additionally, the methodology we describe here provides a tractable tool for other researchers.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Distinct but cooperating brain networks supporting semantic cognition

Semantic cognition is a complex brain function involving multiple processes from sensory systems, semantic systems, to domain-general cognitive systems, reflecting its multifaceted nature. However, it remain unclear how these systems cooperate with each other to achieve effective semantic cognition. Here, we investigated the neural networks involved in semantic cognition using independent component analysis (ICA). We used a semantic judgement task and a pattern matching task as a control task with two levels of difficulty to disentangle task-specific networks from domain-general networks and to delineate task-specific involvement of these networks. ICA revealed that semantic processing recruited two task-specific networks (semantic network [SN] and extended semantic network [ESN]) as well as domain general networks including the frontoparietal network (FPN) and default mode network (DMN). Specifically, two distinct semantic networks were differently modulated by task difficulty. The SN was coupled with the extended semantic network and FPN but decoupled with the DMN, whereas the ESN was synchronised with the FPN and DMN. Furthermore, the degree of decoupling between the SN and DMN was associated with semantic performance. Our findings suggest that human higher cognition is achieved by the neural dynamics of brain networks, serving distinct and shared cognitive functions depending on task demands.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons

Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of the triggering receptor expressed myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer's disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease associated microglial (DAM) signature proteins, and were less able to promote outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from TREM2 common variant iPS-Mg. Taken together these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer's disease associated with this variant.

in bioRxiv: Neuroscience on July 20, 2021 12:00 AM.

• #### Invader removal triggers competitive release in a threatened avian predator [Ecology]

Changes in the distribution and abundance of invasive species can have far-reaching ecological consequences. Programs to control invaders are common but gauging the effectiveness of such programs using carefully controlled, large-scale field experiments is rare, especially at higher trophic levels. Experimental manipulations coupled with long-term demographic monitoring can reveal the...

in PNAS on July 19, 2021 07:07 PM.

• #### Correction for Canher et al., Rocks in the auxin stream: Wound-induced auxin accumulation and ERF115 expression synergistically drive stem cell regeneration [Corrections]

PLANT BIOLOGY Correction for “Rocks in the auxin stream: Wound-induced auxin accumulation and ERF115 expression synergistically drive stem cell regeneration,” by Balkan Canher, Jefri Heyman, Maria Savina, Ajay Devendran, Thomas Eekhout, Ilse Vercauteren, Els Prinsen, Rotem Matosevich, Jian Xu, Victoria Mironova, and Lieven De Veylder, which was first published June...

in PNAS on July 19, 2021 07:07 PM.

• #### Correction for Dagdeviren et al., Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm [Corrections]

MEDICAL SCIENCES, ENGINEERING Correction for “Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm,” by Canan Dagdeviren, Byung Duk Yang, Yewang Su, Phat L. Tran, Pauline Joe, Eric Anderson, Jing Xia, Vijay Doraiswamy, Behrooz Dehdashti, Xue Feng, Bingwei Lu, Robert Poston, Zain Khalpey, Roozbeh Ghaffari,...

in PNAS on July 19, 2021 07:07 PM.

• #### Achieving industrial ammonia synthesis rates at near-ambient conditions through modified scaling relations on a confined dual site [Chemistry]

The production of ammonia through the Haber–Bosch process is regarded as one of the most important inventions of the 20th century. Despite significant efforts in optimizing the process, it still consumes 1 to 2% of the worldwide annual energy for the high working temperatures and pressures. The design of a...

in PNAS on July 19, 2021 07:07 PM.

• #### Contact with Child Protective Services is pervasive but unequally distributed by race and ethnicity in large US counties [Social Sciences]

This article provides county-level estimates of the cumulative prevalence of four levels of Child Protective Services (CPS) contact using administrative data from the 20 most populous counties in the United States. Rates of CPS investigation are extremely high in almost every county. Racial and ethnic inequality in case outcomes is...

in PNAS on July 19, 2021 07:07 PM.

• #### Tradeoffs for a viral mutant with enhanced replication speed [Microbiology]

RNA viruses exist as genetically heterogeneous populations due to high mutation rates, and many of these mutations reduce fitness and/or replication speed. However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured...

in PNAS on July 19, 2021 07:07 PM.

• #### A method for measuring investigative journalism in local newspapers [Social Sciences]

Major changes to the operation of local newsrooms—ownership restructuring, layoffs, and a reorientation away from print advertising—have become commonplace in the last few decades. However, there have been few systematic attempts to characterize the impact of these changes on the types of reporting that local newsrooms produce. In this paper,...

in PNAS on July 19, 2021 07:07 PM.

• #### Widespread remodeling of the m6A RNA-modification landscape by a viral regulator of RNA processing and export [Microbiology]

N6-methyladenosine (m6A) is the most abundant internal messenger RNA (mRNA) modification, contributing to the processing, stability, and function of methylated RNAs. Methylation occurs in the nucleus during pre-mRNA synthesis and requires a core methyltransferase complex consisting of METTL3, METTL14, and WTAP. During herpes simplex virus (HSV-1) infection, cellular gene expression...

in PNAS on July 19, 2021 07:07 PM.

• #### Integration of signals from different cortical areas in higher order thalamic neurons [Neuroscience]

Higher order thalamic neurons receive driving inputs from cortical layer 5 and project back to the cortex, reflecting a transthalamic route for corticocortical communication. To determine whether or not individual neurons integrate signals from different cortical populations, we combined electron microscopy “connectomics” in mice with genetic labeling to disambiguate layer...

in PNAS on July 19, 2021 07:07 PM.

• #### Genome-scale metabolic network reconstruction of model animals as a platform for translational research [Systems Biology]

Genome-scale metabolic models (GEMs) are used extensively for analysis of mechanisms underlying human diseases and metabolic malfunctions. However, the lack of comprehensive and high-quality GEMs for model organisms restricts translational utilization of omics data accumulating from the use of various disease models. Here we present a unified platform of GEMs...

in PNAS on July 19, 2021 07:07 PM.

• #### A [3Fe-4S] cluster and tRNA-dependent aminoacyltransferase BlsK in the biosynthesis of Blasticidin S [Biochemistry]

Blasticidin S is a peptidyl nucleoside antibiotic. Its biosynthesis involves a cryptic leucylation and two leucylated intermediates, LDBS and LBS, have been found in previous studies. Leucylation has been proposed to be a new self-resistance mechanism during blasticidin S biosynthesis, and the leucyl group was found to be important for...

in PNAS on July 19, 2021 07:07 PM.

• #### Reply to Perez et al.: Experimental duration unlikely to bias global variation in plant thermal tolerances [Biological Sciences]

We recently published a pioneering synthesis study of plant thermal macrophysiology (1), revealing global patterns that are in agreement with the main patterns known from animals, as well as with expectations from theory (2, 3). Perez et al. (4) criticize our study, primarily on the basis that differences in experimental...

in PNAS on July 19, 2021 07:07 PM.

• #### Long-term decrease in Asian monsoon rainfall and abrupt climate change events over the past 6,700 years [Environmental Sciences]

Asian summer monsoon (ASM) variability and its long-term ecological and societal impacts extending back to Neolithic times are poorly understood due to a lack of high-resolution climate proxy data. Here, we present a precisely dated and well-calibrated tree-ring stable isotope chronology from the Tibetan Plateau with 1- to 5-y resolution...

in PNAS on July 19, 2021 07:07 PM.

• #### A large-scale experiment finds no evidence that a seismic survey impacts a demersal fish fauna [Ecology]

Seismic surveys are used to locate oil and gas reserves below the seabed and can be a major source of noise in marine environments. Their effects on commercial fisheries are a subject of debate, with experimental studies often producing results that are difficult to interpret. We overcame these issues in...

in PNAS on July 19, 2021 07:07 PM.

• #### Surviving winter on the Qinghai-Tibetan Plateau: Pikas suppress energy demands and exploit yak feces to survive winter [Ecology]

The Qinghai-Tibetan Plateau, with low precipitation, low oxygen partial pressure, and temperatures routinely dropping below −30 °C in winter, presents several physiological challenges to its fauna. Yet it is home to many endemic mammalian species, including the plateau pika (Ochotona curzoniae). How these small animals that are incapable of hibernation...

in PNAS on July 19, 2021 07:07 PM.

• #### Arabidopsis group C Raf-like protein kinases negatively regulate abscisic acid signaling and are direct substrates of SnRK2 [Plant Biology]

The phytohormone abscisic acid (ABA) plays a major role in abiotic stress responses in plants, and subclass III SNF1-related protein kinase 2 (SnRK2) kinases mediate ABA signaling. In this study, we identified Raf36, a group C Raf-like protein kinase in Arabidopsis, as a protein that interacts with multiple SnRK2s. A...

in PNAS on July 19, 2021 07:07 PM.

• #### Observational evidence that cloud feedback amplifies global warming [Earth, Atmospheric, and Planetary Sciences]

Global warming drives changes in Earth’s cloud cover, which, in turn, may amplify or dampen climate change. This “cloud feedback” is the single most important cause of uncertainty in Equilibrium Climate Sensitivity (ECS)—the equilibrium global warming following a doubling of atmospheric carbon dioxide. Using data from Earth observations and climate...

in PNAS on July 19, 2021 07:07 PM.

• #### Non-Foster acoustic radiation from an active piezoelectric transducer [Applied Physical Sciences]

The quality factor of a passive, linear, small acoustic radiator is fundamentally limited by its volume normalized to the emitted wavelength, imposing severe constraints on the bandwidth and efficiency of compact acoustic sources and of metamaterials composed of arrangements of small acoustic resonators. We demonstrate that these bounds can be...

in PNAS on July 19, 2021 07:07 PM.

• #### A role for T‐cell exhaustion in Long COVID‐19 and severe outcomes for several categories of COVID‐19 patients

Abstract Unusual mortality rate differences and symptoms have been experienced by COVID‐19 patients, and the postinfection symptoms called Long COVID‐19 have also been widely experienced. A substantial percentage of COVID‐19‐infected individuals in specific health categories have been virtually asymptomatic, several other individuals in the same health categories have exhibited several unusual symptoms, and yet other individuals in the same health categories have fatal outcomes. It is now hypothesized that these differences in mortality rates and symptoms could be caused by a SARS‐CoV‐2 virus infection acting together with one or more latent pathogen infections in certain patients, through mutually beneficial induced immune cell dysfunctions, including T‐cell exhaustion. A latent pathogen infection likely to be involved is the protozoan parasite Toxoplasma gondii, which infects approximately one third of the global human population. Furthermore, certain infections and cancers that cause T‐cell exhaustion can also explain the more severe outcomes of other COVID‐19 patients having several disease and cancer comorbidities.

in Journal of Neuroscience Research on July 19, 2021 05:33 PM.

• #### Human Brain Resilience: A Call to Action

At present, resilience refers to a highly heterogeneous concept with ill‐defined determinants, mechanisms, and outcomes. This call for action argues for the need to define resilience as a person‐centered multidimensional metric, informed by a dynamic lifespan perspective and combining observational and interventional experimental studies to identify specific neural markers and correlated behavioral measures. The coronavirus disease 2019 (COVID‐19) pandemic highlights the urgent need of such an effort with the ultimate goal of defining a new vital sign, an individual index of resilience, as a life‐long metric with the capacity to predict an individual's risk for disability in the face of a stressor, insult, injury, or disease. ANN NEUROL 2021

in Annals of Neurology on July 19, 2021 03:51 PM.

• #### Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

by Dheeraj Prakaash, Graham P. Cook, Oreste Acuto, Antreas C. Kalli

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### Hamming-shifting graph of genomic short reads: Efficient construction and its application for compression

by Yuansheng Liu, Jinyan Li

Graphs such as de Bruijn graphs and OLC (overlap-layout-consensus) graphs have been widely adopted for the de novo assembly of genomic short reads. This work studies another important problem in the field: how graphs can be used for high-performance compression of the large-scale sequencing data. We present a novel graph definition named Hamming-Shifting graph to address this problem. The definition originates from the technological characteristics of next-generation sequencing machines, aiming to link all pairs of distinct reads that have a small Hamming distance or a small shifting offset or both. We compute multiple lexicographically minimal k-mers to index the reads for an efficient search of the weight-lightest edges, and we prove a very high probability of successfully detecting these edges. The resulted graph creates a full mutual reference of the reads to cascade a code-minimized transfer of every child-read for an optimal compression. We conducted compression experiments on the minimum spanning forest of this extremely sparse graph, and achieved a 10 − 30% more file size reduction compared to the best compression results using existing algorithms. As future work, the separation and connectivity degrees of these giant graphs can be used as economical measurements or protocols for quick quality assessment of wet-lab machines, for sufficiency control of genomic library preparation, and for accurate de novo genome assembly.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### The effect of natural selection on the propagation of protein expression noise to bacterial growth

by Laurens H. J. Krah, Rutger Hermsen

In bacterial cells, protein expression is a highly stochastic process. Gene expression noise moreover propagates through the cell and adds to fluctuations in the cellular growth rate. A common intuition is that, due to their relatively high noise amplitudes, proteins with a low mean expression level are the most important drivers of fluctuations in physiological variables. In this work, we challenge this intuition by considering the effect of natural selection on noise propagation. Mathematically, the contribution of each protein species to the noise in the growth rate depends on two factors: the noise amplitude of the protein’s expression level, and the sensitivity of the growth rate to fluctuations in that protein’s concentration. We argue that natural selection, while shaping mean abundances to increase the mean growth rate, also affects cellular sensitivities. In the limit in which cells grow optimally fast, the growth rate becomes most sensitive to fluctuations in highly abundant proteins. This causes abundant proteins to overall contribute strongly to the noise in the growth rate, despite their low noise levels. We further explore this result in an experimental data set of protein abundances, and test key assumptions in an evolving, stochastic toy model of cellular growth.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### Neuron tracing and quantitative analyses of dendritic architecture reveal symmetrical three-way-junctions and phenotypes of <i>git-1</i> in <i>C</i>. <i>elegans</i>

by Omer Yuval, Yael Iosilevskii, Anna Meledin, Benjamin Podbilewicz, Tom Shemesh

Complex dendritic trees are a distinctive feature of neurons. Alterations to dendritic morphology are associated with developmental, behavioral and neurodegenerative changes. The highly-arborized PVD neuron of C. elegans serves as a model to study dendritic patterning; however, quantitative, objective and automated analyses of PVD morphology are missing. Here, we present a method for neuronal feature extraction, based on deep-learning and fitting algorithms. The extracted neuronal architecture is represented by a database of structural elements for abstracted analysis. We obtain excellent automatic tracing of PVD trees and uncover that dendritic junctions are unevenly distributed. Surprisingly, these junctions are three-way-symmetrical on average, while dendritic processes are arranged orthogonally. We quantify the effect of mutation in git-1, a regulator of dendritic spine formation, on PVD morphology and discover a localized reduction in junctions. Our findings shed new light on PVD architecture, demonstrating the effectiveness of our objective analyses of dendritic morphology and suggest molecular control mechanisms.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### From reaction kinetics to dementia: A simple dimer model of Alzheimer’s disease etiology

by Michael R. Lindstrom, Manuel B. Chavez, Elijah A. Gross-Sable, Eric Y. Hayden, David B. Teplow

Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the kinetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomer-dimer-trimer kinetics to develop a simple mathematical model linking Aβ assembly to oligomer-induced neuronal degeneration. This model recapitulates the rapid growth of disease incidence with age. It does so through incorporation of age-dependent changes in rates of Aβ monomer production and elimination. The model also describes clinical progression in genetic forms of AD (e.g., Down’s syndrome), changes in hippocampal volume, AD risk after traumatic brain injury, and spatial spreading of the disease due to foci in which Aβ production is elevated. Continued incorporation of clinical and basic science data into the current model will make it an increasingly relevant model system for doing theoretical calculations that are not feasible in biological systems. In addition, terms in the model that have particularly large effects are likely to be especially useful therapeutic targets.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread

by Alexander O. B. Whitlock, Jonathan J. Juliano, Nicole Mideo

Although drug resistance in Plasmodium falciparum typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty (“immune selection”) suppressed the evolution of resistance in high transmission settings. We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of the spread of a resistant lineage. In contrast, in low transmission settings, we observed that resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistant parasites in the population by allowing them to proliferate, even in untreated hosts, when resistance was linked to a novel epitope. Our results suggest that immune selection plays a role in the global pattern of resistance evolution.

in PLoS Computational Biology on July 19, 2021 02:00 PM.

• #### Do psychiatric diseases follow annual cyclic seasonality?

by Hanxin Zhang, Atif Khan, Qi Chen, Henrik Larsson, Andrey Rzhetsky

Seasonal affective disorder (SAD) famously follows annual cycles, with incidence elevation in the fall and spring. Should some version of cyclic annual pattern be expected from other psychiatric disorders? Would annual cycles be similar for distinct psychiatric conditions? This study probes these questions using 2 very large datasets describing the health histories of 150 million unique U.S. citizens and the entire Swedish population. We performed 2 types of analysis, using “uncorrected” and “corrected” observations. The former analysis focused on counts of daily patient visits associated with each disease. The latter analysis instead looked at the proportion of disease-specific visits within the total volume of visits for a time interval. In the uncorrected analysis, we found that psychiatric disorders’ annual patterns were remarkably similar across the studied diseases in both countries, with the magnitude of annual variation significantly higher in Sweden than in the United States for psychiatric, but not infectious diseases. In the corrected analysis, only 1 group of patients—11 to 20 years old—reproduced all regularities we observed for psychiatric disorders in the uncorrected analysis; the annual healthcare-seeking visit patterns associated with other age-groups changed drastically. Analogous analyses over infectious diseases were less divergent over these 2 types of computation. Comparing these 2 sets of results in the context of published psychiatric disorder seasonality studies, we tend to believe that our uncorrected results are more likely to capture the real trends, while the corrected results perhaps reflect mostly artifacts determined by dominantly fluctuating, health-seeking visits across a given year. However, the divergent results are ultimately inconclusive; thus, we present both sets of results unredacted, and, in the spirit of full disclosure, leave the verdict to the reader.

in PLoS Biology on July 19, 2021 02:00 PM.

• #### Assessing the replicability of spatial gene expression using atlas data from the adult mouse brain

by Shaina Lu, Cantin Ortiz, Daniel Fürth, Stephan Fischer, Konstantinos Meletis, Anthony Zador, Jesse Gillis

High-throughput, spatially resolved gene expression techniques are poised to be transformative across biology by overcoming a central limitation in single-cell biology: the lack of information on relationships that organize the cells into the functional groupings characteristic of tissues in complex multicellular organisms. Spatial expression is particularly interesting in the mammalian brain, which has a highly defined structure, strong spatial constraint in its organization, and detailed multimodal phenotypes for cells and ensembles of cells that can be linked to mesoscale properties such as projection patterns, and from there, to circuits generating behavior. However, as with any type of expression data, cross-dataset benchmarking of spatial data is a crucial first step. Here, we assess the replicability, with reference to canonical brain subdivisions, between the Allen Institute’s in situ hybridization data from the adult mouse brain (Allen Brain Atlas (ABA)) and a similar dataset collected using spatial transcriptomics (ST). With the advent of tractable spatial techniques, for the first time, we are able to benchmark the Allen Institute’s whole-brain, whole-transcriptome spatial expression dataset with a second independent dataset that similarly spans the whole brain and transcriptome. We use regularized linear regression (LASSO), linear regression, and correlation-based feature selection in a supervised learning framework to classify expression samples relative to their assayed location. We show that Allen Reference Atlas labels are classifiable using transcription in both data sets, but that performance is higher in the ABA than in ST. Furthermore, models trained in one dataset and tested in the opposite dataset do not reproduce classification performance bidirectionally. While an identifying expression profile can be found for a given brain area, it does not generalize to the opposite dataset. In general, we found that canonical brain area labels are classifiable in gene expression space within dataset and that our observed performance is not merely reflecting physical distance in the brain. However, we also show that cross-platform classification is not robust. Emerging spatial datasets from the mouse brain will allow further characterization of cross-dataset replicability ultimately providing a valuable reference set for understanding the cell biology of the brain.

in PLoS Biology on July 19, 2021 02:00 PM.

• #### Magnetic Resonance Imaging Correlates of Multiple Sclerosis Immunopathological Patterns

Objective Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T‐cell‐ and macrophage‐associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. Methods We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow‐up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). Results A strong association of a ringlike enhancement and a hypointense T2‐weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. Interpretation We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021

in Annals of Neurology on July 19, 2021 01:28 PM.

• #### A neuromimetic realization of hippocampal CA1 for theta wave generation

Publication date: Available online 9 July 2021

Source: Neural Networks

in Neural Networks on July 19, 2021 12:30 PM.

• #### Optimal attention tuning in a neuro-computational model of the visual cortex - basal ganglia - prefrontal cortex loop

Publication date: Available online 14 July 2021

Source: Neural Networks

Author(s): Oliver Maith, Alex Schwarz, Fred Hamker

in Neural Networks on July 19, 2021 12:30 PM.

• #### Generalized two-dimensional linear discriminant analysis with regularization

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Chun-Na Li, Yuan-Hai Shao, Wei-Jie Chen, Zhen Wang, Nai-Yang Deng

in Neural Networks on July 19, 2021 12:30 PM.

• #### Novel criteria for global robust stability of dynamical neural networks with multiple time delays

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Emel Arslan

in Neural Networks on July 19, 2021 12:30 PM.

• #### A continuous-time neurodynamic approach and its discretization for distributed convex optimization over multi-agent systems

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Xingnan Wen, Linhua Luan, Sitian Qin

in Neural Networks on July 19, 2021 12:30 PM.

• #### Self-spectral learning with GAN based spectral–spatial target detection for hyperspectral image

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Weiying Xie, Jiaqing Zhang, Jie Lei, Yunsong Li, Xiuping Jia

in Neural Networks on July 19, 2021 12:30 PM.

• #### A novel density-based neural mass model for simulating neuronal network dynamics with conductance-based synapses and membrane current adaptation

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Chih-Hsu Huang, Chou-Ching K. Lin

in Neural Networks on July 19, 2021 12:30 PM.

• #### Label propagation via local geometry preserving for deep semi-supervised image recognition

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Yuanyuan Qing, Yijie Zeng, Guang-Bin Huang

in Neural Networks on July 19, 2021 12:30 PM.

• #### Why grid cells function as a metric for space

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Suogui Dang, Yining Wu, Rui Yan, Huajin Tang

in Neural Networks on July 19, 2021 12:30 PM.

• #### Probabilistic learning vector quantization on manifold of symmetric positive definite matrices

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Fengzhen Tang, Haifeng Feng, Peter Tino, Bailu Si, Daxiong Ji

in Neural Networks on July 19, 2021 12:30 PM.

• #### Exponential passivity of discrete-time switched neural networks with transmission delays via an event-triggered sliding mode control

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Jinling Wang, Haijun Jiang, Cheng Hu, Tianlong Ma

in Neural Networks on July 19, 2021 12:30 PM.

• #### Equivalent-input-disturbance estimator-based event-triggered control design for master–slave neural networks

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): P. Selvaraj, O.M. Kwon, S.H. Lee, R. Sakthivel

in Neural Networks on July 19, 2021 12:30 PM.

• #### Anti-transfer learning for task invariance in convolutional neural networks for speech processing

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Eric Guizzo, Tillman Weyde, Giacomo Tarroni

in Neural Networks on July 19, 2021 12:30 PM.

• #### IGAGCN: Information geometry and attention-based spatiotemporal graph convolutional networks for traffic flow prediction

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Jiyao An, Liang Guo, Wei Liu, Zhiqiang Fu, Ping Ren, Xinzhi Liu, Tao Li

in Neural Networks on July 19, 2021 12:30 PM.

• #### Adaptive ensemble perception tracking

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Zikun Zhou, Nana Fan, Kai Yang, Hongpeng Wang, Zhenyu He

in Neural Networks on July 19, 2021 12:30 PM.

• #### An efficient encoder–decoder model for portrait depth estimation from single images trained on pixel-accurate synthetic data

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Faisal Khan, Shahid Hussain, Shubhajit Basak, Joseph Lemley, Peter Corcoran

in Neural Networks on July 19, 2021 12:30 PM.

• #### A brain-inspired computational model for spatio-temporal information processing

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Xiaohan Lin, Xiaolong Zou, Zilong Ji, Tiejun Huang, Si Wu, Yuanyuan Mi

in Neural Networks on July 19, 2021 12:30 PM.

• #### The asymmetric learning rates of murine exploratory behavior in sparse reward environments

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Hiroyuki Ohta, Kuniaki Satori, Yu Takarada, Masashi Arake, Toshiaki Ishizuka, Yuji Morimoto, Tatsuji Takahashi

in Neural Networks on July 19, 2021 12:30 PM.

• #### Effective and direct control of neural TTS prosody by removing interactions between different attributes

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Xiaochun An, Frank K. Soong, Shan Yang, Lei Xie

in Neural Networks on July 19, 2021 12:30 PM.

• #### Low-shot transfer with attention for highly imbalanced cursive character recognition

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Amin Jalali, Swathi Kavuri, Minho Lee

in Neural Networks on July 19, 2021 12:30 PM.

• #### FastGAE: Scalable graph autoencoders with stochastic subgraph decoding

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Guillaume Salha, Romain Hennequin, Jean-Baptiste Remy, Manuel Moussallam, Michalis Vazirgiannis

in Neural Networks on July 19, 2021 12:30 PM.

• #### On the characterization of cognitive tasks using activity-specific short-lived synchronization between electroencephalography channels

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): B. Orkan Olcay, Murat Özgören, Bilge Karaçalı

in Neural Networks on July 19, 2021 12:30 PM.

• #### Arguments for the unsuitability of convolutional neural networks for non-local tasks

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Sebastian Stabinger, David Peer, Antonio Rodríguez-Sánchez

in Neural Networks on July 19, 2021 12:30 PM.

• #### Streaming cascade-based speech translation leveraged by a direct segmentation model

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Javier Iranzo-Sánchez, Javier Jorge, Pau Baquero-Arnal, Joan Albert Silvestre-Cerdà, Adrià Giménez, Jorge Civera, Albert Sanchis, Alfons Juan

in Neural Networks on July 19, 2021 12:30 PM.

• #### Unsupervised multi-sense language models for natural language processing tasks

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Jihyeon Roh, Sungjin Park, Bo-Kyeong Kim, Sang-Hoon Oh, Soo-Young Lee

in Neural Networks on July 19, 2021 12:30 PM.

• #### Finite time convergence of pinning synchronization with a single nonlinear controller

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Tianping Chen, Wenlian Lu, Xiwei Liu

in Neural Networks on July 19, 2021 12:30 PM.

• #### Adaptive neural network asymptotic tracking control for nonstrict feedback stochastic nonlinear systems

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Yongchao Liu, Qidan Zhu

in Neural Networks on July 19, 2021 12:30 PM.

• #### Neural adaptive fault-tolerant finite-time control for nonstrict feedback systems: An event-triggered mechanism

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): K. Sun, J. Qiu, H.R. Karimi

in Neural Networks on July 19, 2021 12:30 PM.

• #### Robust Optimization and Validation of Echo State Networks for learning chaotic dynamics

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Alberto Racca, Luca Magri

in Neural Networks on July 19, 2021 12:30 PM.

• #### A global neural network learning machine: Coupled integer and fractional calculus operator with an adaptive learning scheme

Publication date: November 2021

Source: Neural Networks, Volume 143

Author(s): Huaqing Zhang, Yi-Fei Pu, Xuetao Xie, Bingran Zhang, Jian Wang, Tingwen Huang

in Neural Networks on July 19, 2021 12:30 PM.

• #### Transcription factor encoding of neuron subtype: Strategies that specify arbor pattern

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Yun Jin Pai, Adrian W. Moore

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### A current view on Tau protein phosphorylation in Alzheimer's disease

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Susanne Wegmann, Jacek Biernat, Eckhard Mandelkow

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### From synapse to network: models of information storage and retrieval in neural circuits

Publication date: October 2021

Source: Current Opinion in Neurobiology, Volume 70

Author(s): Johnatan Aljadeff, Maxwell Gillett, Ulises Pereira Obilinovic, Nicolas Brunel

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### APOE signaling in neurodegenerative diseases: an integrative approach targeting APOE coding and noncoding variants for disease intervention

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Xiaopu Zhou, Amy KY Fu, Nancy Y Ip

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### The role of NMDA receptor and neuroligin rare variants in synaptic dysfunction underlying neurodevelopmental disorders

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Marta Mota Vieira, Jaehoon Jeong, Katherine W. Roche

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Dendrite enlightenment

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Gaia Tavosanis

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Wired for insight—recent advances in Caenorhabditis elegans neural circuits

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Dana T. Byrd, Yishi Jin

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Autophagy in axonal and presynaptic development

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Oliver Crawley, Brock Grill

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Measuring and modeling the motor system with machine learning

Publication date: October 2021

Source: Current Opinion in Neurobiology, Volume 70

Author(s): Sebastien B. Hausmann, Alessandro Marin Vargas, Alexander Mathis, Mackenzie W. Mathis

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Three-dimensional chromatin organization in brain function and dysfunction

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Vishnu Dileep, Li-Huei Tsai

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Finding functions of phase separation in the presynapse

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Nathan A. McDonald, Kang Shen

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Imaging neuronal protein signaling dynamics in vivo

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Tal Laviv, Ryohei Yasuda

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Neuronal replacement: Concepts, achievements, and call for caution

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Magdalena Götz, Riccardo Bocchi

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Regulatory roles of mitochondria and metabolism in neurogenesis

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Ryohei Iwata, Pierre Vanderhaeghen

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Regulation of synaptic nanodomain by liquid–liquid phase separation: A novel mechanism of synaptic plasticity

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Pin-Wu Liu, Tomohisa Hosokawa, Yasunori Hayashi

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### SARM1 signaling mechanisms in the injured nervous system

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Shilpa Sambashivan, Marc R. Freeman

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Mariela F. Trinchero, Damiana Giacomini, Alejandro F. Schinder

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Molecular mechanisms of axo-axonic innervation

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Fabrice Ango, Nicholas Biron Gallo, Linda Van Aelst

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Drawing inspiration from biological dendrites to empower artificial neural networks

Publication date: October 2021

Source: Current Opinion in Neurobiology, Volume 70

Author(s): Spyridon Chavlis, Panayiota Poirazi

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Cell adhesion molecules regulating astrocyte–neuron interactions

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Christabel X. Tan, Cagla Eroglu

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### The synaptic life of microtubules

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Clarissa Waites, Xiaoyi Qu, Francesca Bartolini

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Multiple layers of spatial regulation coordinate axonal cargo transport

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Eitan Erez Zahavi, Casper C. Hoogenraad

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Mechanism of synaptic protein turnover and its regulation by neuronal activity

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Tolga Soykan, Volker Haucke, Marijn Kuijpers

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Neurovascular crosstalk coordinates the central nervous system development

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Blanca Peguera, Marta Segarra, Amparo Acker-Palmer

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Applying stem cells and CRISPR engineering to uncover the etiology of schizophrenia

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Peter James Michael Deans, Kristen J. Brennand

in Current Opinion in Neurobiology on July 19, 2021 12:30 PM.

• #### Kinetic assays of DNA polymerase fidelity: A theoretical perspective beyond Michaelis-Menten kinetics

Author(s): Qiu-Shi Li, Yao-Gen Shu, Zhong-Can Ou-Yang, and Ming Li

The high fidelity of DNA polymerase (DNAP) is critical for the faithful replication of DNA. There are several quantitative approaches to measure DNAP fidelity. Directly counting the error frequency in the replication products gives the true fidelity but it turns out very hard to implement in practic...

[Phys. Rev. E 104, 014408] Published Mon Jul 19, 2021

in Physical Review E: Biological physics on July 19, 2021 10:00 AM.

• #### Nonequilibrium model of short-range repression in gene transcription regulation

Author(s): F. E. Garbuzov and V. V. Gursky

Transcription factors are proteins that regulate gene activity by activating or repressing gene transcription. A special class of transcriptional repressors operates via a short-range mechanism, making local DNA regions inaccessible to binding by activators, and thus providing an indirect repressive...

[Phys. Rev. E 104, 014407] Published Mon Jul 19, 2021

in Physical Review E: Biological physics on July 19, 2021 10:00 AM.

• #### Longitudinal changes in hippocampal network connectivity in Alzheimer's disease

Objective The hippocampus is connected to two distinct cortical brain networks, the posterior‐medial and the anterior‐temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these two networks, their changes over time and links to cognition in Alzheimer’s disease. Methods We assessed MTL connectivity in 53 amyloid‐β positive patients with mild cognitive impairment and Alzheimer dementia and 68 healthy elderly controls, using resting‐state functional magnetic resonance imaging, cross‐sectionally and longitudinally. First, we compared the functional connectivity of the posterior‐medial and anterior‐temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18‐months follow‐up in patients. Third, we assessed the association in the connectivity changes between the two networks, and with cognitive performance. Results We found decreased connectivity in patients specifically between the hippocampus and the posterior‐medial network, together with increased connectivity between several MTL subregions and the anterior‐temporal network. Moreover, changes in the posterior‐medial and anterior‐temporal networks were interrelated such that decrease MTL‐posterior‐medial connectivity was associated with increased MTL‐anterior‐temporal connectivity. Finally, both MTL‐posterior‐medial decrease and MTL‐anterior‐temporal increase predicted cognitive decline. Interpretation Our findings demonstrate that longitudinal connectivity changes in the posterior‐medial and anterior‐temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer’s disease. These results shed light on the critical role of the posterior‐medial and anterior‐temporal networks in Alzheimer’s disease pathophysiology and clinical symptoms. This article is protected by copyright. All rights reserved.

in Annals of Neurology on July 19, 2021 09:20 AM.

• #### Medicare should not cover aducanumab as a treatment for Alzheimer's disease

Annals of Neurology, Accepted Article.

in Annals of Neurology on July 19, 2021 08:39 AM.

• #### Genomic insights into myasthenia gravis identify distinct immunological mechanisms in early and late onset disease

Objective To identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis. Methods We used a novel genomic methodology to integrate genome wide association study (GWAS) findings in myasthenia gravis with cell‐type specific information such as gene expression patterns and promotor‐enhancer interactions, in order to identify disease relevant genes. Subsequently, we conducted additional genomic investigations including an expression quantitative analysis of 313 healthy people to provide mechanistic insights. Results We identified genes that were specifically linked to early onset myasthenia gravis based on GWAS associated risk variants including TNIP1, ORMDL3, GSDMB and TRAF3. We showed that regulators of toll‐like receptor 4 signalling were enriched only among the early onset disease genes (fold enrichment = 3.85, p = 6.4 x 10‐3). In contrast, T‐cell regulators CD28 and CTLA4 were exclusively linked to late onset disease. We identified two causal genetic variants (rs231770 and rs231735; posterior probability= 0.98 and 0.91) near the CTLA4 gene. Subsequently, we demonstrated that these causal variants result in low expression of CTLA4 (rho =‐0.66, p = 1.28 x 10‐38 and rho = ‐0.52, p = 7.01 x 10‐22, for rs231735 and rs231770 respectively). Interpretation The disease relevant genes identified in this study are a unique resource for many disciplines including clinicians, scientists and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for drug repurposing opportunities and for future studies of drug development. This article is protected by copyright. All rights reserved.

in Annals of Neurology on July 19, 2021 07:00 AM.

• #### Testing Surrogate-Based Optimization with the Fortified Branin-Hoo Extended to Four Dimensions. (arXiv:2107.08035v1 [math.OC])

Some popular functions used to test global optimization algorithms have multiple local optima, all with the same value, making them all global optima. It is easy to make them more challenging by fortifying them via adding a localized bump at the location of one of the optima. In previous work the authors illustrated this for the Branin-Hoo function and the popular differential evolution algorithm, showing that the fortified Branin-Hoo required an order of magnitude more function evaluations. This paper examines the effect of fortifying the Branin-Hoo function on surrogate-based optimization, which usually proceeds by adaptive sampling. Two algorithms are considered. The EGO algorithm, which is based on a Gaussian process (GP) and an algorithm based on radial basis functions (RBF). EGO is found to be more frugal in terms of the number of required function evaluations required to identify the correct basin, but it is expensive to run on a desktop, limiting the number of times the runs could be repeated to establish sound statistics on the number of required function evaluations. The RBF algorithm was cheaper to run, providing more sound statistics on performance. A four-dimensional version of the Branin-Hoo function was introduced in order to assess the effect of dimensionality. It was found that the difference between the ordinary function and the fortified one was much more pronounced for the four-dimensional function compared to the two dimensional one.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 19, 2021 01:30 AM.

• #### Author Correction: Superior colliculus activates new perspectives on decision-making

Nature Neuroscience, Published online: 19 July 2021; doi:10.1038/s41593-021-00909-2

Author Correction: Superior colliculus activates new perspectives on decision-making

in Nature Neuroscience on July 19, 2021 12:00 AM.

• #### High-throughput and single-cell T cell receptor sequencing technologies

Nature Methods, Published online: 19 July 2021; doi:10.1038/s41592-021-01201-8

This Review discusses methodological advances for high-throughput analysis of the TCR repertoire at bulk and single-cell resolution.

in Nature Methods on July 19, 2021 12:00 AM.

• #### Broad sarbecovirus neutralization by a human monoclonal antibody

Nature, Published online: 19 July 2021; doi:10.1038/s41586-021-03817-4

Broad sarbecovirus neutralization by a human monoclonal antibody

in Nature on July 19, 2021 12:00 AM.

• #### Cleaving arene rings for acyclic alkenylnitrile synthesis

Nature, Published online: 19 July 2021; doi:10.1038/s41586-021-03801-y

Cleaving arene rings for acyclic alkenylnitrile synthesis

in Nature on July 19, 2021 12:00 AM.

• #### Quantum transport in fractal networks

Nature Photonics, Published online: 19 July 2021; doi:10.1038/s41566-021-00845-4

Quantum transport in fractal networks is experimentally investigated by performing continuous-time quantum walks in fractal photonic lattices. Contrarily to classical fractals, anomalous transport governed solely by the fractal dimension is observed.

in Nature Photomics on July 19, 2021 12:00 AM.

• #### Publisher Correction: Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24833-y

Publisher Correction: Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences

in Nature Communications on July 19, 2021 12:00 AM.

• #### Author Correction: AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24770-w

Author Correction: AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines

in Nature Communications on July 19, 2021 12:00 AM.

• #### Combating mosquito-borne diseases using genetic control technologies

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24654-z

Mosquito-borne diseases pose significant global health burdens. In this review, the authors explore Wolbachia and genome engineering approaches to mosquito-borne disease population control.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24643-2

Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Dimensional reduction by geometrical frustration in a cubic antiferromagnet composed of tetrahedral clusters

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24636-1

Dimensionality reduction can occur in magnetically frustrated systems; however, it typically involves lattice distortions. Here, the authors report two- and one-dimensional character of spin correlations in a three-dimensional tetrahedral cluster antiferromagnet, driven purely by geometrical frustration.

in Nature Communications on July 19, 2021 12:00 AM.

• #### The effect of water on colloidal quantum dot solar cells

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24614-7

Surface of colloidal quantum dot is sensitive to water, and the interaction could potentially alter its chemical environments. Here, Shi et al. investigate how the interaction effects the nanostructures and carrier dynamic in CQDs, and subsequently introduce meniscus-guided coating technique to mitigate CQD fusion triggered by water adsorption.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24607-6

Myofibroblasts drive fibrosis in systemic sclerosis (SSc), but the cellular progenitors are unknown. Utilizing single cell RNA-sequencing, the authors show that SSc dermal myofibroblasts arise in a two-step process from SFRP2/DPP4-expressing progenitors and implicate upstream transcription factors.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24584-w

The blood transcriptome of human subjects can be profiled on an almost routine basis in translational research settings. Here the authors show that a fixed and well-characterized repertoire of transcriptional modules can be employed as a reusable framework for the analysis, visualization and interpretation of such data

in Nature Communications on July 19, 2021 12:00 AM.

• #### Insulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24506-w

Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9

Nature Communications, Published online: 19 July 2021; doi:10.1038/s41467-021-24384-2

Extracellular vesicles (EVs) play a role in intercellular communication, however the precise biogenesis of different populations of EVs are not clear. Here, the authors follow the intracellular trafficking of two proteins before their secretion in EVs and report the biogenesis and protein markers of EV subtypes: ectosomes budding from the plasma membrane as well as exosomes from late endosomes.

in Nature Communications on July 19, 2021 12:00 AM.

• #### Daily briefing: Deaf scientists develop better signs for scientific terms

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-02004-9

Science in sign language, huge DNA ‘Borg’ structures perplex scientists, and the hunt for exotic ‘Majorana’ particles.

in Nature on July 19, 2021 12:00 AM.

• #### A monkey researcher fights to protect threatened and endangered primates

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-01995-9

Andie Ang helps to build rope bridges in Singapore and is working to launch primate exchanges with other nations to keep imperilled species safe.

in Nature on July 19, 2021 12:00 AM.

• #### Single-cell analysis enters the multiomics age

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-01994-w

A rapidly growing collection of software tools is helping researchers to analyse multiple huge ‘-omics’ data sets.

in Nature on July 19, 2021 12:00 AM.

• #### Pikas in high places have a winter-time treat: yak poo

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-01978-w

Snacks of faeces help the pocket-sized mammals survive the cold and wind atop a vast plateau that abuts the Himalayas.

in Nature on July 19, 2021 12:00 AM.

• #### Huge gaps in detection networks plague emissions monitoring

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-01967-z

Plug gaps to measure ozone-destroying chemicals and greenhouse gases and verify compliance with Paris and Montreal treaties.

in Nature on July 19, 2021 12:00 AM.

• #### These archaeologists helped quell a COVID surge in Madagascar

Nature, Published online: 19 July 2021; doi:10.1038/d41586-021-01933-9

As a wave of infections threatened rural communities, the scientists stepped in to fund and distribute aid.

in Nature on July 19, 2021 12:00 AM.

• #### Neuroinformatics

in Neuroinformatics on July 19, 2021 12:00 AM.

### Abstract

Simulation of large-scale networks of neurons is an important approach to understanding and interpreting experimental data from healthy and diseased brains. Owing to the rapid development of simulation software and the accumulation of quantitative data of different neuronal types, it is possible to predict both computational and dynamical properties of local microcircuits in a ‘bottom-up’ manner. Simulated data from these models can be compared with experiments and ‘top-down’ modelling approaches, successively bridging the scales. Here we describe an open source pipeline, using the software Snudda, for predicting microcircuit connectivity and for setting up simulations using the NEURON simulation environment in a reproducible way. We also illustrate how to further ‘curate’ data on single neuron morphologies acquired from public databases. This model building pipeline was used to set up a first version of a full-scale cellular level model of mouse dorsal striatum. Model components from that work are here used to illustrate the different steps that are needed when modelling subcortical nuclei, such as the basal ganglia.

in Neuroinformatics on July 19, 2021 12:00 AM.

### Abstract

The cerebral integration of somatosensory inputs from multiple sources is essential to produce adapted behaviors. Previous studies suggest that bilateral somatosensory inputs interact differently depending on stimulus characteristics, including their noxious nature. The aim of this study was to clarify how bilateral inputs evoked by noxious laser stimuli, noxious shocks, and innocuous shocks interact in terms of perception and brain responses. The experiment comprised two conditions (right-hand stimulation and concurrent stimulation of both hands) in which painful laser stimuli, painful shocks and non-painful shocks were delivered. Perception, somatosensory-evoked potentials (P45, N100, P260), laser-evoked potentials (N1, N2 and P2) and event-related spectral perturbations (delta to gamma oscillation power) were compared between conditions and stimulus modalities. The amplitude of negative vertex potentials (N2 or N100) and the power of delta/theta oscillations were increased in the bilateral compared with unilateral condition, regardless of the stimulus type (P < 0.01). However, gamma oscillation power increased for painful and non-painful shocks (P < 0.01), but not for painful laser stimuli (P = 0.08). Despite the similarities in terms of brain activity, bilateral inputs interacted differently for painful stimuli, for which perception remained unchanged, and non-painful stimuli, for which perception increased. This may reflect a ceiling effect for the attentional capture by noxious stimuli and warrants further investigations to examine the regulation of such interactions by bottom–up and top–down processes.

in Experimental Brain Research on July 19, 2021 12:00 AM.

• #### Shifts in Estimated Preferred Directions During Simulated BMI Experiments With No Adaptation

Experiments with brain-machine interfaces (BMIs) reveal that the estimated preferred direction (EPD) of cortical motor units may shift following the transition to brain control. However, the cause of those shifts, and in particular, whether they imply neural adaptation, is an open issue. Here we address this question in simulations and theoretical analysis. Simulations are based on the assumption that the brain implements optimal state estimation and feedback control and that cortical motor neurons encode the estimated state and control vector. Our simulations successfully reproduce apparent shifts in EPDs observed in BMI experiments with different BMI filters, including linear, Kalman and re-calibrated Kalman filters, even with no neural adaptation. Theoretical analysis identifies the conditions for reducing those shifts. We demonstrate that simulations that better satisfy those conditions result in smaller shifts in EPDs. We conclude that the observed shifts in EPDs may result from experimental conditions, and in particular correlated velocities or tuning weights, even with no adaptation. Under the above assumptions, we show that if neurons are tuned differently to the estimated velocity, estimated position and control signal, the EPD with respect to actual velocity may not capture the real PD in which the neuron encodes the estimated velocity. Our investigation provides theoretical and simulation tools for better understanding shifts in EPD and BMI experiments.

in Frontiers in Systems Neuroscience on July 19, 2021 12:00 AM.

• #### From Junk to Function: LncRNAs in CNS Health and Disease

Recent advances in RNA sequencing technologies helped to uncover the existence of tens of thousands of long non-coding RNAs (lncRNAs) that arise from the dark matter of the genome. These lncRNAs were originally thought to be transcriptional noise but an increasing number of studies demonstrate that these transcripts can modulate protein-coding gene expression by a wide variety of transcriptional and post-transcriptional mechanisms. The spatiotemporal regulation of lncRNA expression is particularly evident in the central nervous system, suggesting that they may directly contribute to specific brain processes, including neurogenesis and cellular homeostasis. Not surprisingly, lncRNAs are therefore gaining attention as putative novel therapeutic targets for disorders of the brain. In this review, we summarize the recent insights into the functions of lncRNAs in the brain, their role in neuronal maintenance, and their potential contribution to disease. We conclude this review by postulating how these RNA molecules can be targeted for the treatment of yet incurable neurological disorders.

in Frontiers in Molecular Neuroscience on July 19, 2021 12:00 AM.

• #### Expression Analysis of Ermin and Listerin E3 Ubiquitin Protein Ligase 1 Genes in Autistic Patients

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that involves social interaction defects, impairment of non-verbal and verbal interactions, and limited interests along with stereotypic activities. Its incidence has been increasing rapidly in recent decades. Despite numerous attempts to understand the pathophysiology of ASD, its exact etiology is still unclear. Recent data shows the role of accurate myelination and translational regulation in ASD’s pathogenesis. In this study, we assessed Ermin (ERMN) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) genes expression in Iranian ASD patients and age- and gender-matched healthy subjects’ peripheral blood using quantitative real-time PCR to recognize any probable dysregulation in the expression of these genes and propose this disorder’s mechanisms. Analysis of the expression demonstrated a significant ERMN downregulation in total ASD patients compared to the healthy individuals (posterior beta = −0.794, adjusted P-value = 0.025). LTN1 expression was suggestively higher in ASD patients in comparison with the corresponding control individuals. Considering the gender of study participants, the analysis showed that the mentioned genes’ different expression levels were significant only in male subjects. Besides, a significant correlation was found between expression of the mentioned genes (r = −0.49, P < 0.0001). The present study provides further supports for the contribution of ERMN and LTN1 in ASD’s pathogenesis.

in Frontiers in Molecular Neuroscience on July 19, 2021 12:00 AM.

• #### Surface-Based Falff: A Potential Novel Biomarker for Prediction of Radiation Encephalopathy in Patients With Nasopharyngeal Carcinoma

Radiation encephalopathy (RE) is an important potential complication in patients with nasopharyngeal carcinoma (NPC) who undergo radiotherapy (RT) that can affect the quality of life. However, a functional imaging biomarker of pre-symptomatic RE has not yet been established. This study aimed to assess radiation-induced gray matter functional alterations and explore fractional amplitude of low-frequency fluctuation (fALFF) as an imaging biomarker for predicting or diagnosing RE in patients with NPC. A total of 60 patients with NPC were examined, 21 in the pre-RT cohort and 39 in the post-RT cohort. Patients in the post-RT cohort were further divided into two subgroups according to the occurrence of RE in follow-up: post-RT non−RE (n = 21) and post-RT REprovedinfollow−up (n = 18). Surface-based and volume-based fALFF were used to detect radiation-induced functional alterations. Functional derived features were then adopted to construct a predictive model for the diagnosis of RE. We observed that surface-based fALFF could sensitively detect radiation-induced functional alterations in the intratemporal brain regions (such as the hippocampus and superior temporal gyrus), as well as the extratemporal regions (such as the insula and prefrontal lobe); however, no significant intergroup differences were observed using volume-based fALFF. No significant correlation between fALFF and radiation dose to the ipsilateral temporal lobe was observed. Support vector machine (SVM) analysis revealed that surface-based fALFF in the bilateral superior temporal gyri and left insula exhibited impressive performance (accuracy = 80.49%) in identifying patients likely to develop RE. We conclude that surface-based fALFF may serve as a sensitive imaging biomarker in the prediction of RE.

in Frontiers in Neuroscience: Brain Imaging Methods on July 19, 2021 12:00 AM.

• #### Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms

Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60–70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.

in Frontiers in Neuroscience: Neurodegeneration on July 19, 2021 12:00 AM.

• #### Functional MRI of Native and Non-native Speech Sound Production in Sequential German-English Bilinguals

Bilingualism and multilingualism are highly prevalent. Non-invasive brain imaging has been used to study the neural correlates of native and non-native speech and language production, mainly on the lexical and syntactic level. Here, we acquired continuous fast event-related FMRI during visually cued overt production of exclusively German and English vowels and syllables. We analyzed data from 13 university students, native speakers of German and sequential English bilinguals. The production of non-native English sounds was associated with increased activity of the left primary sensorimotor cortex, bilateral cerebellar hemispheres (lobule VI), left inferior frontal gyrus, and left anterior insula compared to native German sounds. The contrast German > English sounds was not statistically significant. Our results emphasize that the production of non-native speech requires additional neural resources already on a basic phonological level in sequential bilinguals.

in Frontiers in Human Neuroscience on July 19, 2021 12:00 AM.

• #### Diffusional Kurtosis Imaging in the Diffusion Imaging in Python Project

Diffusion-weighted magnetic resonance imaging (dMRI) measurements and models provide information about brain connectivity and are sensitive to the physical properties of tissue microstructure. Diffusional Kurtosis Imaging (DKI) quantifies the degree of non-Gaussian diffusion in biological tissue from dMRI. These estimates are of interest because they were shown to be more sensitive to microstructural alterations in health and diseases than measures based on the total anisotropy of diffusion which are highly confounded by tissue dispersion and fiber crossings. In this work, we implemented DKI in the Diffusion in Python (DIPY) project—a large collaborative open-source project which aims to provide well-tested, well-documented and comprehensive implementation of different dMRI techniques. We demonstrate the functionality of our methods in numerical simulations with known ground truth parameters and in openly available datasets. A particular strength of our DKI implementations is that it pursues several extensions of the model that connect it explicitly with microstructural models and the reconstruction of 3D white matter fiber bundles (tractography). For instance, our implementations include DKI-based microstructural models that allow the estimation of biophysical parameters, such as axonal water fraction. Moreover, we illustrate how DKI provides more general characterization of non-Gaussian diffusion compatible with complex white matter fiber architectures and gray matter, and we include a novel mean kurtosis index that is invariant to the confounding effects due to tissue dispersion. In summary, DKI in DIPY provides a well-tested, well-documented and comprehensive reference implementation for DKI. It provides a platform for wider use of DKI in research on brain disorders and in cognitive neuroscience.

in Frontiers in Human Neuroscience on July 19, 2021 12:00 AM.

• #### An Open Source-Based BCI Application for Virtual World Tour and Its Usability Evaluation

Brain–computer interfaces can provide a new communication channel and control functions to people with restricted movements. Recent studies have indicated the effectiveness of brain–computer interface (BCI) applications. Various types of applications have been introduced so far in this field, but the number of those available to the public is still insufficient. Thus, there is a need to expand the usability and accessibility of BCI applications. In this study, we introduce a BCI application for users to experience a virtual world tour. This software was built on three open-source environments and is publicly available through the GitHub repository. For a usability test, 10 healthy subjects participated in an electroencephalography (EEG) experiment and evaluated the system through a questionnaire. As a result, all the participants successfully played the BCI application with 96.6% accuracy with 20 blinks from two sessions and gave opinions on its usability (e.g., controllability, completeness, comfort, and enjoyment) through the questionnaire. We believe that this open-source BCI world tour system can be used in both research and entertainment settings and hopefully contribute to open science in the BCI field.

in Frontiers in Human Neuroscience on July 19, 2021 12:00 AM.

• #### Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.

in Frontiers in Human Neuroscience on July 19, 2021 12:00 AM.

• #### RNA Is a Double-Edged Sword in ALS Pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

in Frontiers in Cellular Neuroscience on July 19, 2021 12:00 AM.

• #### Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer’s disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood–brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

in Frontiers in Cellular Neuroscience on July 19, 2021 12:00 AM.

• #### The Structural E/I Balance Constrains the Early Development of Cortical Network Activity

Neocortical networks have a characteristic constant ratio in the number of glutamatergic projection neurons (PN) and GABAergic interneurons (IN), and deviations in this ratio are often associated with developmental neuropathologies. Cultured networks with defined cellular content allowed us to ask if initial PN/IN ratios change the developmental population dynamics, and how different ratios impact the physiological excitatory/inhibitory (E/I) balance and the network activity development. During the first week in vitro, the IN content modulated PN numbers, increasing their proliferation in networks with higher IN proportions. The proportion of INs in each network set remained similar to the initial plating ratio during the 4 weeks cultivation period. Results from additional networks generated with more diverse cellular composition, including early-born GABA neurons, suggest that a GABA-dependent mechanism may decrease the survival of additional INs. A large variation of the PN/IN ratio did not change the balance between isolated spontaneous glutamatergic and GABAergic postsynaptic currents charge transfer (E/I balance) measured in PNs or INs. In contrast, the E/I balance of multisynaptic bursts reflected differences in IN content. Additionally, the spontaneous activity recorded by calcium imaging showed that higher IN ratios were associated with increased frequency of network bursts combined with a decrease of participating neurons per event. In the 4th week in vitro, bursting activity was stereotypically synchronized in networks with very few INs but was more desynchronized in networks with higher IN proportions. These results suggest that the E/I balance of isolated postsynaptic currents in single cells may be regulated independently of PN/IN proportions, but the network bursts E/I balance and the maturation of spontaneous network activity critically depends upon the structural PN/IN ratio.

in Frontiers in Cellular Neuroscience on July 19, 2021 12:00 AM.

• #### Acupuncture Can Regulate the Peripheral Immune Cell Spectrum and Inflammatory Environment of the Vascular Dementia Rat, and Improve the Cognitive Dysfunction of the Rats

Objective

The aim of this study is to analyze the effects of acupuncture on peripheral immune function, inflammation, and cognitive impairment in vascular dementia (VD) rats.

Methods

In this study, 2-month-old healthy male Wistar rats (260–280 g) were assigned to the groups as follows: normal group (Gn, n = 10), sham-operated group (Gs, n = 10), and operated group (Go, n = 45). The Go group was established by permanent, bilateral common carotid artery occlusion (BCCAO). Two months after operation, the operated rats were screened by hidden platform trial and the rats with cognitive dysfunction were further randomly divided into impaired group (Gi), acupoint group (Ga), and non-acupoint group (Gna) with 10 rats in each group. The Ga group was given acupuncture treatment for 14 days with a rest for every 7 days. After treatment, the Morris water maze (MWM) test was performed to evaluate the spatial learning and memory abilities of rats. The lymphocyte subsets in peripheral blood and spleen of rats were measured by flow cytometry. The levels of cytokines [i.e., interleukin (IL)-1β, IL-2, IL-4, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ)], chemokines (i.e., macrophage inflammatory protein-2 (MIP-2)), and other inflammatory mediators (i.e., cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS)) in peripheral blood and hippocampus were measured by enzyme linked immunosorbent assay (ELISA).

Results

Compared with the Gn group, the Gi rats presented long escape latencies to find the platform. After acupuncture treatment, the escape latencies of the Ga group were rescued markedly when compared with the Gi group (P < 0.05). The proportion of CD4 + T lymphocytes in both spleen and peripheral blood in the Ga group increased (P < 0.05) in comparison with the Gi group. There is an obvious reduction in IL-1β (P < 0.05), IL-2 (P < 0.05), TNF-α (P < 0.01), INF-γ (P < 0.01), MIP-2 (P < 0.05), and iNOS (P < 0.01), coming along with the increased levels of IL-4 and IL-10 (P < 0.01) in the Ga group when compared with the Gi group. In addition, the hippocampus proinflammatory factors IL-1β (P < 0.01), IL-2 (P < 0.01), TNF-α (P < 0.05), INF-γ (P < 0.05), MIP-2 (P < 0.05), iNOS (P < 0.01), and COX-2 decreased in the Ga group, whereas the anti-inflammatory factors IL-4 and IL-10 (P < 0.01) increased.

Conclusion

There are abnormal immune function and peripheral inflammation in VD rats. Acupuncture can regulate the peripheral immune function and inflammation of the VD rats and can improve the cognitive dysfunction of the rats.

in Frontiers in Ageing Neuroscience on July 19, 2021 12:00 AM.

• #### The Influence of Demographics and Vascular Risk Factors on Glymphatic Function Measured by Diffusion Along Perivascular Space

Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function—Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (β = −0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (β = −0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (β = −0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (β = −0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.

in Frontiers in Ageing Neuroscience on July 19, 2021 12:00 AM.

• #### The Involvement of Lactosylceramide in Central Nervous System Inflammation Related to Neurodegenerative Disease

Neurodegenerative diseases are a class of slow-progressing terminal illnesses characterized by neuronal lesions, such as multiple sclerosis [MS, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)]. Their incidence increases with age, and the associated burden on families and society will become increasingly more prominent with aging of the general population. In recent years, there is growing studies have shown that lactosylceramide (LacCer) plays a crucial role in the progression of neurodegeneration, although these diseases have different pathogenic mechanisms and etiological characteristics. Based on latest research progress, this study expounds the pathogenic role of LacCer in driving central nervous system (CNS) inflammation, as well as the role of membrane microstructure domain (lipid rafts) and metabolite gangliosides, and discusses in detail their links with the pathogenesis of neurodegenerative diseases, with a view to providing new strategies and ideas for the study of pathological mechanisms and drug development for neurodegenerative diseases in the future.

in Frontiers in Ageing Neuroscience on July 19, 2021 12:00 AM.

• #### Prevalence and Predictors of Prolonged Cognitive and Psychological Symptoms Following COVID-19 in the United States

Background/Objectives

Little is known regarding the prevalence and predictors of prolonged cognitive and psychological symptoms of COVID-19 among community-dwellers. We aimed to quantitatively measure self-reported metrics of fatigue, cognitive dysfunction, anxiety, depression, and sleep and identify factors associated with these metrics among United States residents with or without COVID-19.

Methods

We solicited 1000 adult United States residents for an online survey conducted February 3–5, 2021 utilizing a commercial crowdsourcing community research platform. The platform curates eligible participants to approximate United States demographics by age, sex, and race proportions. COVID-19 was diagnosed by laboratory testing and/or by exposure to a known positive contact with subsequent typical symptoms. Prolonged COVID-19 was self-reported and coded for those with symptoms ≥ 1 month following initial diagnosis. The primary outcomes were NIH PROMIS/Neuro-QoL short-form T-scores for fatigue, cognitive dysfunction, anxiety, depression, and sleep compared among those with prolonged COVID-19 symptoms, COVID-19 without prolonged symptoms and COVID-19 negative subjects. Multivariable backwards step-wise logistic regression models were constructed to predict abnormal Neuro-QoL metrics.

Results

Among 999 respondents, the average age was 45 years (range 18–84), 49% were male, 76 (7.6%) had a history of COVID-19 and 19/76 (25%) COVID-19 positive participants reported prolonged symptoms lasting a median of 4 months (range 1–13). Prolonged COVID-19 participants were more often younger, female, Hispanic, and had a history of depression/mood/thought disorder (all P < 0.05). They experienced significantly higher rates of unemployment and financial insecurity, and their symptoms created greater interference with work and household activities compared to other COVID-19 status groups (all P < 0.05). After adjusting for demographics, past medical history and stressor covariates in multivariable logistic regression analysis, COVID-19 status was independently predictive of worse Neuro-QoL cognitive dysfunction scores (adjusted OR 11.52, 95% CI 1.01–2.28, P = 0.047), but there were no significant differences in quantitative measures of anxiety, depression, fatigue, or sleep.

Conclusion

Prolonged symptoms occurred in 25% of COVID-19 positive participants, and NeuroQoL cognitive dysfunction scores were significantly worse among COVID-19 positive subjects, even after accounting for demographic and stressor covariates. Fatigue, anxiety, depression, and sleep scores did not differ between COVID-19 positive and negative respondents.

in Frontiers in Ageing Neuroscience on July 19, 2021 12:00 AM.

• #### Language Disorder in Progressive Supranuclear Palsy and Corticobasal Syndrome: Neural Correlates and Detection by the MLSE Screening Tool

Background: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) affect speech and language as well as motor functions. Clinical and neuropathological data indicate a close relationship between these two disorders and the non-fluent variant of primary progressive aphasia (nfvPPA). We use the recently developed Mini Linguistic State Examination tool (MLSE) to study speech and language disorders in patients with PSP, CBS, and nfvPPA, in combination with structural magnetic resonance imaging (MRI).

Methods: Fifty-one patients (PSP N = 13, CBS N = 19, nfvPPA N = 19) and 30 age-matched controls completed the MLSE, the short form of the Boston Diagnostic Aphasia Examination (BDAE), and the Addenbrooke’s Cognitive Examination III. Thirty-eight patients and all controls underwent structural MRI at 3 Tesla, with T1 and T2-weighted images processed by surface-based and subcortical segmentation within FreeSurfer 6.0.0 to extract cortical thickness and subcortical volumes. Morphometric differences were compared between groups and correlated with the severity of speech and language impairment.

Results: CBS and PSP patients showed impaired MLSE performance, compared to controls, with a similar language profile to nfvPPA, albeit less severe. All patient groups showed reduced cortical thickness in bilateral frontal regions and striatal volume. PSP and nfvPPA patients also showed reduced superior temporal cortical thickness, with additional thalamic and amygdalo-hippocampal volume reductions in nfvPPA. Multivariate analysis of brain-wide cortical thickness and subcortical volumes with MLSE domain scores revealed associations between performance on multiple speech and language domains with atrophy of left-lateralised fronto-temporal cortex, amygdala, hippocampus, putamen, and caudate.

Conclusions: The effect of PSP and CBS on speech and language overlaps with nfvPPA. These three disorders cause a common anatomical pattern of atrophy in the left frontotemporal language network and striatum. The MLSE is a short clinical screening tool that can identify the language disorder of PSP and CBS, facilitating clinical management and patient access to future clinical trials.

in Frontiers in Ageing Neuroscience on July 19, 2021 12:00 AM.

• #### The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development

Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.

in eLife on July 19, 2021 12:00 AM.

• #### Analysis of the PcrA-RNA polymerase complex reveals a helicase interaction motif and a role for PcrA/UvrD helicase in the suppression of R-loops

The PcrA/UvrD helicase binds directly to RNA polymerase (RNAP) but the structural basis for this interaction and its functional significance have remained unclear. In this work we used biochemical assays and hydrogen-deuterium exchange coupled to mass spectrometry to study the PcrA-RNAP complex. We find that PcrA binds tightly to a transcription elongation complex in a manner dependent on protein:protein interaction with the conserved PcrA C-terminal Tudor domain. The helicase binds predominantly to two positions on the surface of RNAP. The PcrA C-terminal domain engages a conserved region in a lineage-specific insert within the β subunit which we identify as a helicase interaction motif present in many other PcrA partner proteins, including the nucleotide excision repair factor UvrB. The catalytic core of the helicase binds near the RNA and DNA exit channels and blocking PcrA activity in vivo leads to the accumulation of R-loops. We propose a role for PcrA as an R-loop suppression factor that helps to minimise conflicts between transcription and other processes on DNA including replication.

in eLife on July 19, 2021 12:00 AM.

• #### Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

in eLife on July 19, 2021 12:00 AM.

• #### Niche partitioning facilitates coexistence of closely related honey bee gut bacteria

Ecological processes underlying bacterial coexistence in the gut are not well understood. Here, we disentangled the effect of the host and the diet on the coexistence of four closely related Lactobacillus species colonizing the honey bee gut. We serially passaged the four species through gnotobiotic bees and in liquid cultures in the presence of either pollen (bee diet) or simple sugars. Although the four species engaged in negative interactions, they were able to stably coexist, both in vivo and in vitro. However, coexistence was only possible in the presence of pollen, and not in simple sugars, independent of the environment. Using metatranscriptomics and metabolomics, we found that the four species utilize different pollen-derived carbohydrate substrates indicating resource partitioning as the basis of coexistence. Our results show that despite longstanding host association, gut bacterial interactions can be recapitulated in vitro providing insights about bacterial coexistence when combined with in vivo experiments.

in eLife on July 19, 2021 12:00 AM.

• #### Cortex cis-regulatory switches establish scale colour identity and pattern diversity in Heliconius

In Heliconius butterflies, wing colour pattern diversity and scale types are controlled by a few genes of large effect that regulate colour pattern switches between morphs and species across a large mimetic radiation. One of these genes, cortex, has been repeatedly associated with colour pattern evolution in butterflies. Here we carried out CRISPR knockouts in multiple Heliconius species and show that cortex is a major determinant of scale cell identity. Chromatin accessibility profiling and introgression scans identified cis-regulatory regions associated with discrete phenotypic switches. CRISPR perturbation of these regions in black hindwing genotypes recreated a yellow bar, revealing their spatially limited activity. In the H. melpomene/timareta lineage, the candidate CRE from yellow-barred phenotype morphs is interrupted by a transposable element, suggesting that cis-regulatory structural variation underlies these mimetic adaptations. Our work shows that cortex functionally controls scale colour fate and that its cis-regulatory regions control a phenotypic switch in a modular and pattern-specific fashion.

in eLife on July 19, 2021 12:00 AM.

• #### High-resolution, genome-wide mapping of positive supercoiling in chromosomes

Supercoiling impacts DNA replication, transcription, protein binding to DNA, and the three-dimensional organization of chromosomes. However, there are currently no methods to directly interrogate or map positive supercoils, so their distribution in genomes remains unknown. Here, we describe a method, GapR-seq, based on the chromatin immunoprecipitation of GapR, a bacterial protein that preferentially recognizes overtwisted DNA, for generating high-resolution maps of positive supercoiling. Applying this method to E. coli and S. cerevisiae, we find that positive supercoiling is widespread, associated with transcription, and particularly enriched between convergently-oriented genes, consistent with the 'twin-domain' model of supercoiling. In yeast, we also find positive supercoils associated with centromeres, cohesin binding sites, autonomously replicating sites, and the borders of R-loops (DNA-RNA hybrids). Our results suggest that GapR-seq is a powerful approach, likely applicable in any organism, to investigate aspects of chromosome structure and organization not accessible by Hi-C or other existing methods.

in eLife on July 19, 2021 12:00 AM.

• #### Structure-guided microbial targeting of antistaphylococcal prodrugs

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of anti-staphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.

in eLife on July 19, 2021 12:00 AM.

• #### Differential conditioning produces merged long-term memory in Drosophila

Multiple spaced trials of aversive differential conditioning can produce two independent long-term memories (LTMs) of opposite valence. One is an aversive memory for avoiding the conditioned stimulus (CS+), and the other is a safety memory for approaching the non-conditioned stimulus (CS-). Here, we show that a single trial of aversive differential conditioning yields one merged LTM (mLTM) for avoiding both CS+ and CS-. Such mLTM can be detected after sequential exposures to the shock-paired CS+ and unpaired CS-, and be retrieved by either CS+ or CS-. The formation of mLTM relies on triggering aversive-reinforcing dopaminergic neurons and subsequent new protein synthesis. Expressing mLTM involves αβ Kenyon cells and corresponding approach-directing mushroom body output neurons (MBONs), in which similar-amplitude long-term depression of responses to CS+ and CS- seems to signal the mLTM. Our results suggest that animals can develop distinct strategies for occasional and repeated threatening experiences.

in eLife on July 19, 2021 12:00 AM.

• #### Highly contiguous assemblies of 101 drosophilid genomes

Over 100 years of studies in Drosophila melanogaster and related species in the genus Drosophila have facilitated key discoveries in genetics, genomics, and evolution. While high-quality genome assemblies exist for several species in this group, they only encompass a small fraction of the genus. Recent advances in long-read sequencing allow high-quality genome assemblies for tens or even hundreds of species to be efficiently generated. Here, we utilize Oxford Nanopore sequencing to build an open community resource of genome assemblies for 101 lines of 93 drosophilid species encompassing 14 species groups and 35 sub-groups. The genomes are highly contiguous and complete, with an average contig N50 of 10.5 Mb and greater than 97% BUSCO completeness in 97/101 assemblies. We show that Nanopore-based assemblies are highly accurate in coding regions, particularly with respect to coding insertions and deletions. These assemblies, along with a detailed laboratory protocol and assembly pipelines, are released as a public resource and will serve as a starting point for addressing broad questions of genetics, ecology, and evolution at the scale of hundreds of species.

in eLife on July 19, 2021 12:00 AM.

• #### Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failure across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.

in eLife on July 19, 2021 12:00 AM.

• #### Distinct skeletal stem cell types orchestrate long bone skeletogenesis

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

in eLife on July 19, 2021 12:00 AM.

• #### Development of antibacterial compounds that constrain evolutionary pathways to resistance

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50-75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.

in eLife on July 19, 2021 12:00 AM.

• #### KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia

The cellular adaptive response to hypoxia, mediated by high HIF1α levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposi's sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1α in normoxia, can also restrict transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1a cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1α levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1α levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.

in eLife on July 19, 2021 12:00 AM.

• #### Granulocyte-colony stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans - several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates expression of granulocyte colony stimulating factor (G-CSF) - a pleiotropic cytokine - in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter - as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to infantile epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to developmental delay and/or autism spectrum disorder with or without co-morbid seizures. One unique case less easily classified using this binary paradigm is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms, and features of autism spectrum disorder. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance, and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model that predicted mixed effects on channel function and neuronal activity. We also generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Dissociated neurons from heterozygous Scn2aK1422E/+ mice exhibited a novel TTX-resistant current with a reversal potential consistent with mixed ion permeation. Cortical slice recordings from Scn2aK1422E/+ tissue demonstrated impaired action potential initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the action potential, suggesting mixed effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal EEG abnormalities, altered response to induced seizures, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from Scn2a knockout models, consistent with mixed effects of K1422E on NaV1.2 channel function.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### The zebra finch auditory cortex reconstructs occluded syllables in conspecific song

Sensory input provides incomplete and often misleading information about the physical world. To compensate, the brain uses internal models to predict what the inputs should be from context, experience, and innate biases. For example, when speech is interrupted by noise, humans perceive the missing sounds behind the noise, a perceptual illusion known as phonemic (or auditory) restoration. The neural mechanisms allowing the auditory system to generate predictions that override ascending sensory information remain poorly understood. Here, we show that the zebra finch (Taeniopygia guttata) exhibits auditory restoration of conspecific song both in a behavioral task and in neural recordings from the equivalent of auditory cortex. Decoding the responses of a population of single units to occluded songs reveals the spectrotemporal structure of the missing syllables. Surprisingly, restoration occurs under anesthesia and for songs that the bird has not heard. These results show that an internal model of the general structure of conspecific vocalizations can bias sensory processing without attention.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### The critical role of spiny stellate cells in seizure onset based on dynamic analysis of a neural mass model

Increasing evidence has shown that excitatory neurons in the brain play a significant role in seizure generation. However, spiny stellate cells are cortical excitatory non-pyramidal neurons in the brain which their basic role in seizure occurrence is not well understood. In the present research, we study the critical role of spiny stellate cells or the excitatory interneurons (EI), for the first time, in epileptic seizure generation using an extended neural mass model introduced originally by Taylor and colleagues in 2014. Applying bifurcation analysis on this modified model, we investigated the rich dynamics corresponding to the epileptic seizure onset and transition between interictal and ictal states due to the EI. Our results indicate that the transition is described by a supercritical Hopf bifurcation which shapes the preictal activity in the model and suggests why before seizure onset, the amplitude and frequency of neural activities increase gradually. Moreover, we showed that 1) the altered function of GABAergic and glutamatergic receptors of EI can cause seizure, and 2) the pathway between the thalamic relay nucleus and EI facilitates the transition from interictal to the ictal activity by decreasing the preictal period. Thereafter, we considered both sensory and cortical periodic inputs to drive the model responses to various harmonic stimulations. Our results from the bifurcation analysis of the model suggest that the initial stage of the brain might be the main cause for the transition between interictal and ictal states as the stimulus frequency changes. The extended thalamocortical model shows also that the amplitude jump phenomenon and nonlinear resonance behavior result from the preictal stage of the brain. These results can be considered as a step forward to a deeper understanding of the mechanisms underlying the transition from brain normal activities to epileptic activities.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### The amplitude of fNIRS hemodynamic response in the visual cortex unmasks autistic traits in typically developing children

Autistic traits represent a continuum dimension across the population, with autism spectrum disorder (ASD) being the extreme end of the distribution. Accumulating evidence shows that neuroanatomical and neurofunctional profiles described in relatives of ASD individuals reflect an intermediate neurobiological pattern between the clinical population and healthy controls. This suggests that quantitative measures detecting autistic traits in the general population represent potential candidates for the development of biomarkers identifying early pathophysiological processes associated with ASD. Functional near-infrared spectroscopy (fNIRS) has been extensively employed to investigate neural development and function. In contrast, the potential of fNIRS to define reliable biomarkers of brain activity has been barely explored. Features of non-invasiveness, portability, ease of administration and low-operating costs make fNIRS a suitable instrument to assess brain function for differential diagnosis, follow-up, analysis of treatment outcomes and personalized medicine in several neurological conditions. Here, we introduce a novel standardized procedure with high entertaining value to measure hemodynamic responses (HDR) in the occipital cortex of adult subjects and children. We found that the variability of evoked HDR correlates with the autistic traits of children, assessed by the Autism-Spectrum Quotient. Interestingly, HDR amplitude was especially linked to social and communication features, representing the core symptoms of ASD. These findings establish a quick and easy strategy for measuring visually-evoked cortical activity with fNIRS that optimize the compliance of young subjects, setting the background for testing the diagnostic value of fNIRS visual measurements in the ASD clinical population.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain

Recent emphasis has been placed on gene transduction mediated through recombinant adeno-associated virus (AAV) vector to manipulate activity of neurons and their circuitry in the primate brain. In the present study, we created a novel AAV vector of which capsid was composed of capsid proteins derived from the serotypes 1 and 2 (AAV1 and AAV2). Following the injection into the frontal cortex of macaque monkeys, this mosaic vector, termed AAV2.1 vector, was found to exhibit the excellence in transgene expression (for the AAV1 vector) and neuron specificity (for the AAV2 vector) simultaneously. To explore its applicability to chemogenetic manipulation and in vivo calcium imaging, the AAV2.1 vector expressing excitatory DREADDs or GCaMP was injected into the striatum or the visual cortex of macaque monkeys, respectively. Our results have defined that such vectors secure intense and stable expression of the target proteins and yield conspicuous modulation and imaging of neuronal activity.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons

Neurons are believed to rely on dendritic localization and translation of mRNAs in order to generate activity-dependent changes in the synaptic plasticity. Here, we develop a strategy combining compartment-specific CLIP and TRAP in conditionally tagged mice to precisely define the ribosome bound dendritic transcriptome of CA1 pyramidal neurons. This revealed transcripts that have differentially localized alternative 3'UTR and splicing isoforms. FMRP targets are overrepresented among dendritic mRNAs, and compartment-specific FMRP-CLIP defined 383 dendritic FMRP targets, and also allowed for segregation of whole-cell FMRP targets into functional modules that are locally regulated by FMRP. In the absence of FMRP, dendritic FMRP targets show increased ribosome association, consistent with reported roles for FMRP in translational repression. Together, the data support a model in which distinct patterns of FMRP localization allow it to differentially regulate the expression of nuclear proteins and synaptic proteins within different compartments of a single neuronal cell type.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### EEG Biomarkers of reduced inhibition in human cortical microcircuits in depression

Major depressive disorder (depression) is a complex condition that involves multiple physiological mechanisms, spanning a range of spatial scales. Altered cortical inhibition is associated with treatment-resistant depression, and reduced dendritic inhibition by somatostatin-expressing (SST) interneurons has been strongly implicated in this aspect of the pathology. However, whether the effects of reduced SST inhibition on microcircuit activity have signatures detectible in electroencephalography (EEG) signals remains unknown. We used detailed models of human cortical layer 2/3 microcircuits with normal or reduced SST inhibition to simulate resting-state activity together with EEG signals in health and depression. We first show that the healthy microcircuit models exhibit emergent key features of resting-state EEG. We then simulated EEG from depression microcircuits and found a significant power increase in theta, alpha and low beta frequencies (4 - 15 Hz). Following spectral decomposition, we show that the power increase involved a combination of aperiodic broadband component, and a periodic theta and low beta components. Neuronal spiking showed a spike preference for the phase preceding the EEG trough, which did not differ between conditions. Our study thus used detailed computational models to identify EEG biomarkers of reduced SST inhibition in human cortical microcircuits in depression, which may serve to improve the diagnosis and stratification of depression subtypes, and in monitoring the effects of pharmacological modulation of inhibition for treating depression.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### Towards on-chip real-time classification of extra-cellular neural recordings

On-line classification of neural recordings can be extremely useful in brain-machine interface, prosthetic applications or therapeutic intervention. In this work we present a feasibility study for developing compact low-power VLSI systems able to classify neural recordings in real-time, using spike-based neuromorphic circuits. We developed a framework for classifying extra-cellular recordings made in rat auditory cortex in response to different auditory stimuli and porting the classification algorithm onto a spiking multi-neuron VLSI chip with programmable synaptic weights. We present recording methods and software classification algorithms; we demonstrate real-time classification in hardware and quantify the system performance; finally, we identify the potential sources of problems in developing such types of systems and propose strategies for overcoming them.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### Common molecular mechanisms underlie the transfer of alpha-synuclein, Tau and huntingtin and modulate spontaneous activity in neuronal cells

The misfolding and accumulation of disease-related proteins are common hallmarks among several neurodegenerative diseases. Alpha-synuclein (aSyn), Tau and huntingtin (wild-type and mutant, 25QHtt and 103QHtt, respectively) were recently shown to be transferred from cell-to-cell through different cellular pathways, thereby contributing to disease progression and neurodegeneration. However, the relative contribution of each of these mechanisms towards the spreading of these different proteins and the overall effect on neuronal function is still unclear. To address this, we exploited different cell-based systems to conduct a systematic comparison of the mechanisms of release of aSyn, Tau and Htt, and evaluated the effects of each protein upon internalization in microglial, astrocytic, and neuronal cells. In the models used, we demonstrate that 25QHtt, aSyn and Tau are released to the extracellular space at higher levels than 103QHtt, and their release can be further augmented with the co-expression of USP19. Furthermore, cortical neurons treated with recombinant monomeric 43QHtt exhibited alterations in neuronal activity that correlated with the toxicity of the polyglutamine expansion. Tau internalization resulted in an increase in neuronal activity, in contrast to slight effects observed with aSyn. Interestingly, all these disease-associated proteins were present at higher levels in ectosomes than in exosomes. The internalization of both types of extracellular vesicles (EVs) by microglial or astrocytic cells elicited the production of pro-inflammatory cytokines and promoted an increase in autophagy markers. Additionally, the uptake of the EVs modulated neuronal activity in cortical neurons. Overall, our systematic study demonstrates the release of neurodegenerative disease-associated proteins through similar cellular pathways. Furthermore, it emphasizes that protein release, both in a free form or in EVs, might contribute to a variety of detrimental effects in receiving cells and to progression of pathology, suggesting they may be exploited as valid targets for therapeutic intervention in different neurodegenerative diseases.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### A Reinforcement Meta-Learning Framework of Executive Function and Information Demand

Gathering information is crucial for maximizing fitness, but requires diverting resources from searching directly for primary rewards to actively exploring the environment. Optimal decision-making thus maximizes information while reducing effort costs, but little is known about the neural implementation of these tradeoffs. We present a Reinforcement Meta-Learning (RML) computational mechanism that solves the trade-offs between the value and costs of gathering information. We implement the RML in a biologically plausible architecture that links catecholaminergic neuromodulators, the medial prefrontal cortex and topographically organized visual maps and show that it accounts for neural and behavioral findings on information demand motivated by instrumental incentives and intrinsic utility. Moreover, the utility function used by the RML, encoded by dopamine, is an approximation of free-energy. Thus, the RML presents a biologically plausible mechanism through which coordinated motivational, executive and sensory systems generate visual information gathering policies that minimize free energy.

in bioRxiv: Neuroscience on July 19, 2021 12:00 AM.

• #### Targeted tDCS Mitigates Dual‐Task Costs to Gait and Balance in Older Adults

Objective Among older adults, the ability to stand or walk while performing cognitive tasks (ie, dual‐tasking) requires coordinated activation of several brain networks. In this multicenter, double‐blinded, randomized, and sham‐controlled study, we examined the effects of modulating the excitability of the left dorsolateral prefrontal cortex (L‐DLPFC) and the primary sensorimotor cortex (SM1) on dual‐task performance “costs” to standing and walking. Methods Fifty‐seven older adults without overt illness or disease completed 4 separate study visits during which they received 20 minutes of transcranial direct current stimulation (tDCS) optimized to facilitate the excitability of the L‐DLPFC and SM1 simultaneously, or each region separately, or neither region (sham). Before and immediately after stimulation, participants completed a dual‐task paradigm in which they were asked to stand and walk with and without concurrent performance of a serial‐subtraction task. Results tDCS simultaneously targeting the L‐DLPFC and SM1, as well as tDCS targeting the L‐DLPFC alone, mitigated dual‐task costs to standing and walking to a greater extent than tDCS targeting SM1 alone or sham (p < 0.02). Blinding efficacy was excellent and participant subjective belief in the type of stimulation received (real or sham) did not contribute to the observed functional benefits of tDCS. Interpretation These results demonstrate that in older adults, dual‐task decrements may be amenable to change and implicate L‐DPFC excitability as a modifiable component of the control system that enables dual‐task standing and walking. tDCS may be used to improve resilience and the ability of older results to walk and stand under challenging conditions, potentially enhancing everyday functioning and reducing fall risks. ANN NEUROL 2021

in Annals of Neurology on July 17, 2021 12:48 PM.

• #### Targeting Inflammasomes to Treat Neurological Diseases

Inflammasomes are multimeric protein complexes that can sense a plethora of microbe‐ and damage‐associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome‐mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL‐18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune‐mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021

in Annals of Neurology on July 17, 2021 12:40 PM.

• #### Impact of Time of Day and Season on Outcome in Acute Ischemic Stroke

Annals of Neurology, EarlyView.

in Annals of Neurology on July 17, 2021 07:00 AM.

• #### Biological Cybernetics

in Biological Cybernetics on July 17, 2021 12:00 AM.

• #### Journal of Molecular Neuroscience

in Journal of Molecular Neuroscience on July 17, 2021 12:00 AM.

### Abstract

CircRNAs belong to a novel class of noncoding RNAs that are generated by exons of genes by alternative mRNA splicing and involved in pathophysiological processes of ischemic stroke by regulating neuro-inflammation. A total of 982 patients were enrolled in our study for stroke recovery analysis. The aim of our study was to first explore the association between the inflammation-related circRNA polymorphism and functional outcome 3 months after ischemic stroke by using multivariate logistic regression model. Next, we further investigated the role of circRNA polymorphism in predicting stroke recurrence by using Cox proportional hazard regression model. Five circRNA polymorphisms were genotyped by using polymerase chain reaction and ligation detection reaction method. We identified circ-STAT3 (signal transducer and activator of transcription) rs2293152 GG genotype to be associated with poorer recovery 90 days after stroke (OR = 1.452, 95% CI: 1.165–4.362, p = 0.016). After adjusting for confound factors, the association for rs2293152 with 3 months outcome after IS was stronger, suggesting a mechanism that rs2293152 is an independent risk factor for stroke recovery (OR = 2.255, 95% CI: 1.034–2.038, p = 0.031). However, no other circRNA polymorphisms (circ-DLGAP4 rs41274714, circ-TRAF2 rs10870141, circ-ITCH rs10485505, rs4911154) were associated with functional outcome 3 months after stroke in any genetic models. Subgroup analysis revealed that the negative effect of rs2293152 GG genotype was greater in female and older patients, subjects with history of hypertension. Additionally, all the circRNA polymorphisms were not correlated with recurrent risk of ischemic stroke. Our results indicated that circ-STAT3 might be a novel biomarker for predicting functional outcome after stroke and an important contributor to the ischemic stroke recovery.

in Journal of Molecular Neuroscience on July 17, 2021 12:00 AM.

### Abstract

How does your brain decide what you will do next? Over the past few decades compelling evidence has emerged that the basal ganglia, a collection of nuclei in the fore- and mid-brain of all vertebrates, are vital to action selection. Gurney, Prescott, and Redgrave published an influential computational account of this idea in Biological Cybernetics in 2001. Here we take a look back at this pair of papers, outlining the “GPR” model contained therein, the context of that model’s development, and the influence it has had over the past twenty years. Tracing its lineage into models and theories still emerging now, we are encouraged that the GPR model is that rare thing, a computational model of a brain circuit whose advances were directly built on by others.

in Biological Cybernetics on July 17, 2021 12:00 AM.

• #### An association between prediction errors and risk-seeking: Theory and behavioral evidence

by Moritz Moeller, Jan Grohn, Sanjay Manohar, Rafal Bogacz

Reward prediction errors (RPEs) and risk preferences have two things in common: both can shape decision making behavior, and both are commonly associated with dopamine. RPEs drive value learning and are thought to be represented in the phasic release of striatal dopamine. Risk preferences bias choices towards or away from uncertainty; they can be manipulated with drugs that target the dopaminergic system. Based on the common neural substrate, we hypothesize that RPEs and risk preferences are linked on the level of behavior as well. Here, we develop this hypothesis theoretically and test it empirically. First, we apply a recent theory of learning in the basal ganglia to predict how RPEs influence risk preferences. We find that positive RPEs should cause increased risk-seeking, while negative RPEs should cause risk-aversion. We then test our behavioral predictions using a novel bandit task in which value and risk vary independently across options. Critically, conditions are included where options vary in risk but are matched for value. We find that our prediction was correct: participants become more risk-seeking if choices are preceded by positive RPEs, and more risk-averse if choices are preceded by negative RPEs. These findings cannot be explained by other known effects, such as nonlinear utility curves or dynamic learning rates.

in PLoS Computational Biology on July 16, 2021 02:00 PM.

• #### Prioritizing and characterizing functionally relevant genes across human tissues

by Gowthami Somepalli, Sarthak Sahoo, Arashdeep Singh, Sridhar Hannenhalli

Knowledge of genes that are critical to a tissue’s function remains difficult to ascertain and presents a major bottleneck toward a mechanistic understanding of genotype-phenotype links. Here, we present the first machine learning model–FUGUE–combining transcriptional and network features, to predict tissue-relevant genes across 30 human tissues. FUGUE achieves an average cross-validation auROC of 0.86 and auPRC of 0.50 (expected 0.09). In independent datasets, FUGUE accurately distinguishes tissue or cell type-specific genes, significantly outperforming the conventional metric based on tissue-specific expression alone. Comparison of tissue-relevant transcription factors across tissue recapitulate their developmental relationships. Interestingly, the tissue-relevant genes cluster on the genome within topologically associated domains and furthermore, are highly enriched for differentially expressed genes in the corresponding cancer type. We provide the prioritized gene lists in 30 human tissues and an open-source software to prioritize genes in a novel context given multi-sample transcriptomic data.

in PLoS Computational Biology on July 16, 2021 02:00 PM.

• #### An electrodiffusive neuron-extracellular-glia model for exploring the genesis of slow potentials in the brain

by Marte J. Sætra, Gaute T. Einevoll, Geir Halnes

Within the computational neuroscience community, there has been a focus on simulating the electrical activity of neurons, while other components of brain tissue, such as glia cells and the extracellular space, are often neglected. Standard models of extracellular potentials are based on a combination of multicompartmental models describing neural electrodynamics and volume conductor theory. Such models cannot be used to simulate the slow components of extracellular potentials, which depend on ion concentration dynamics, and the effect that this has on extracellular diffusion potentials and glial buffering currents. We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine compartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for action potentials and dendritic calcium spikes in neurons, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. The edNEG model accounts for the concentration-dependent effects on ECS potentials that the standard models neglect. Using the edNEG model, we analyze these effects by splitting the extracellular potential into three components: one due to neural sink/source configurations, one due to glial sink/source configurations, and one due to extracellular diffusive currents. Through a series of simulations, we analyze the roles played by the various components and how they interact in generating the total slow potential. We conclude that the three components are of comparable magnitude and that the stimulus conditions determine which of the components that dominate.

in PLoS Computational Biology on July 16, 2021 02:00 PM.

• #### Determinants of cognition in autoimmune limbic encephalitis—A retrospective cohort study

Abstract Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood‐cerebrospinal fluid (CSF)‐barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer‐ and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2‐/fluid attenuated inversion recovery (FLAIR)‐signal‐weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.

in Hippocampus on July 16, 2021 12:55 PM.

• #### Altered static and dynamic functional network connectivity in temporal lobe epilepsy with different disease duration and their relationships with attention

Compared with healthy controls, patients with temporal lobe epilepsy patients with a shorter duration of disease showed differences in static and dynamic functional network connectivity (sFNC and dFNC). Compared with sFNC, dFNC analysis showed more and inconsistent inter‐network functional connectivity abnormalities. At the same time, the variability of inter‐network dFNC is correlated with orienting function. Abstract The brain network alterations associated with temporal lobe epilepsy (TLE) progression are still unclear. The purpose of this study was to investigate altered patterns of static and dynamic functional network connectivity (sFNC and dFNC) in TLE with different durations of disease. In this study, 19 TLE patients with a disease duration of ≤5 years (TLE‐SD), 24 TLE patients with a disease duration of >5 years (TLE‐LD), and 21 healthy controls (HCs) underwent resting‐state functional magnetic resonance imaging and attention network test. We used group independent component analysis to determine the target resting‐state networks. Sliding window correlation and k‐means clustering analysis methods were used to obtain different dFNC states, temporal properties, and temporal variability. We then compared sFNC and dFNC between groups and found that compared with HCs, TLE‐SD patients had increased sFNC between the dorsal attention network and sensorimotor network/visual network (VN), but decreased sFNC between the inferior–posterior default mode network and VN. In the strongly connected dFNC state, TLE‐SD patients spent more time, had greater mean dwell time, and showed greater inconsistent abnormal network connectivity. There was a significant negative correlation between the temporal variability of auditory network‐ left fronto‐parietal network connectivity and orienting effect. No significant differences in sFNC and dFNC were detected between TLE‐LD and HC groups. These findings suggest that the damage and functional brain network abnormalities gradually occur in TLE patients after the onset of epilepsy, which might lead to functional network reorganization and compensatory remodeling as the disease progresses.

in Journal of Neuroscience Research on July 16, 2021 12:04 PM.

• #### The distribution of Cdh20 mRNA demarcates somatotopic subregions and subpopulations of spiny projection neurons in the rat dorsolateral striatum

The dorsolateral striatum (DLS) is functionally subdivided into somatotopic subregions that represent each body part and play crucial roles in sensorimotor functions. Here, we show that the cell adhesion molecule gene Cdh20, which encodes a Type II cadherin, is expressed in discrete subregions covering the inner orofacial area and a part of the forelimb area in the ventral domain of the DLS in rats. Abstract The dorsolateral striatum (DLS) of rodents is functionally subdivided into somatotopic subregions that represent each body part along both the dorsoventral and anteroposterior (A‐P) axes and play crucial roles in sensorimotor functions via corticostriatal pathways. However, little is known about the spatial gene expression patterns and heterogeneity of spiny projection neurons (SPNs) within somatotopic subregions. Here, we show that the cell adhesion molecule gene Cdh20, which encodes a Type II cadherin, is expressed in discrete subregions covering the inner orofacial area and part of the forelimb area in the ventral domain of the DLS (v‐DLS) in rats. Cdh20‐expressing cells were localized in the v‐DLS at the intermediate level of the striatum along the A‐P axis and could be classified as direct‐pathway SPNs or indirect‐pathway SPNs. Unexpectedly, comprehensive analysis revealed that Cdh20 is expressed in SPNs in the rat DLS but not in the mouse DLS or the ferret putamen (Pu). Our observations reveal that Cdh20 expression demarcates somatotopic subregions and subpopulations of SPNs specifically in the rat DLS and suggest divergent regulation of genes differentially expressed in the v‐DLS and Pu among mammals.

in Journal of Comparative Neurology on July 16, 2021 12:00 PM.

• #### Ephrin‐A3 is required for tonotopic map precision and auditory functions in the mouse auditory brainstem

We investigated the molecular basis of tonotopic map formation in the mouse auditory brainstem. We found that the axon guidance cue ephrin‐A3 is differentially expressed along the tonotopic map in the mouse auditory brainstem. Ephrin‐A3 is sufficient to repel growing auditory nerve fibers in vitro. In mice lacking ephrin‐A3, the tonotopic map is degraded in the anteroventral cochlear nucleus, and auditory activation patterns and the ability to discriminate sound frequency changes are also impaired. Abstract Tonotopy is a prominent feature of the vertebrate auditory system and forms the basis for sound discrimination, but the molecular mechanism that underlies its formation remains largely elusive. Ephrin/Eph signaling is known to play important roles in axon guidance during topographic mapping in other sensory systems, so we investigated its possible role in the establishment of tonotopy in the mouse cochlear nucleus. We found that ephrin‐A3 molecules are differentially expressed along the tonotopic axis in the cochlear nucleus during innervation. Ephrin‐A3 forward signaling is sufficient to repel auditory nerve fibers in a developmental stage‐dependent manner. In mice lacking ephrin‐A3, the tonotopic map is degraded and isofrequency bands of neuronal activation upon pure tone exposure become imprecise in the anteroventral cochlear nucleus. Ephrin‐A3 mutant mice also exhibit a delayed second wave in auditory brainstem responses upon sound stimuli and impaired detection of sound frequency changes. Our findings establish an essential role for ephrin‐A3 in forming precise tonotopy in the auditory brainstem to ensure accurate sound discrimination.

in Journal of Comparative Neurology on July 16, 2021 11:53 AM.

• #### Characterization of Tbr2‐expressing retinal ganglion cells

Using genetic sparse labeling and recording on a newly engineered T‐brain 2 (Tbr2)CreERT2 mouse line paired with various reporter lines, we identified seven types of Tbr2‐expressing retina ganglion cells, including M1–M6 types of intrinsically photosensitive retinal ganglion cells (RGCs) and a Pou4f1+ RGC with bushy and small dendritic arbors stratifying into the OFF sublaminae (in red). Additionally, we identified three types of Tbr2‐expressing amacrine cells, including two widefield and a mediumfield displaced amacrine cell (AC) types, all with dendritic arbors stratifying into the ON sublaminae (in black). Furthermore, we have demonstrated that Tbr2 is essential for the survival of these RGCs and displaced ACs, as well as maintaining the expression of Opn4. Abstract The mammalian retina contains more than 40 retinal ganglion cell (RGC) subtypes based on their unique morphologies, functions, and molecular profiles. Among them, intrinsically photosensitive RGCs (ipRGCs) are the first specified RGC type emerging from a common retinal progenitor pool during development. Previous work has shown that T‐box transcription factor T‐brain 2 (Tbr2) is essential for the formation and maintenance of ipRGCs, and that Tbr2‐expressing RGCs activate Opn4 expression upon native ipRGC ablation, suggesting that Tbr2+ RGCs contain a reservoir for ipRGCs. However, the identity of Tbr2+ RGCs has not been fully vetted. Here, using genetic sparse labeling and single cell recording, we showed that Tbr2‐expressing retinal neurons include RGCs and a subset of GABAergic displaced amacrine cells (dACs). Most Tbr2+ RGCs are intrinsically photosensitive and morphologically resemble native ipRGCs with identical retinofugal projections. Tbr2+ RGCs also include a unique and rare Pou4f1‐expressing OFF RGC subtype. Using a loss‐of‐function strategy, we have further demonstrated that Tbr2 is essential for the survival of these RGCs and dACs, as well as maintaining the expression of Opn4. These data set a strong foundation to study how Tbr2 regulates ipRGC development and survival, as well as the expression of molecular machinery regulating intrinsic photosensitivity.

in Journal of Comparative Neurology on July 16, 2021 11:28 AM.

• #### Axonal injury alters the extracellular glial environment of the axon initial segment and allows substantial mitochondrial influx into axon initial segment

Our present focused ion beam/scanning electron microscopy analysis demonstrates marked mitochondrial influx into the axon initial segment (AIS) in response to axonal injury. In the healthy (control) AIS, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. On the other hand, after injury, numerous mitochondria were observed throughout the AIS (scale bar 5 μm). Abstract The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra‐AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three‐dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non‐injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury.

in Journal of Comparative Neurology on July 16, 2021 11:28 AM.

• #### Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease

Objective Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. Methods Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α‐/β‐diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. Results Among risk and prodromal markers, physical inactivity, occupational solvent exposure, and constipation showed associations with α‐diversity. Physical inactivity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β‐diversity. Subthreshold parkinsonism and physical inactivity showed an interaction effect. Among other factors, age and urate‐lowering medication were associated with α‐ and β‐diversity. Constipation was highest in individuals with the Firmicutes‐enriched enterotype, and physical inactivity was most frequent in the Bacteroides‐enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella‐enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. Interpretation Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome‐dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2021

in Annals of Neurology on July 16, 2021 11:24 AM.

• #### Functional Neurological Disorders and COVID‐19 Vaccination

Annals of Neurology, EarlyView.

in Annals of Neurology on July 16, 2021 11:24 AM.

• #### Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Objective Low‐level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation‐carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood. Methods To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole‐cell patch‐clamp and array‐based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network‐level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non–cell‐autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons. Results We generated mice with a low‐level somatic mutation in MTOR presenting spontaneous seizures. The seizure‐triggering hyperexcitability originated from nonmutated neurons near mutation‐carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons. Interpretation This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non–cell‐autonomous hyperexcitability of nearby nonmutated neurons. ANN NEUROL 2021

in Annals of Neurology on July 16, 2021 11:24 AM.

• #### Organization and neural connections of the lateral complex in the brain of the desert locust

Single cell tracer injections suggest that the lateral complex in the brain of the desert locust integrates sensory signals with internal compass information to drive descending and premotor neurons that are likely involved in steering of the animal during locomotion. Overlap of inputs and outputs of the central complex in the gall and ovoid body of the lateral complex suggest feedback loops in the sky compass system. Abstract The lateral complexes (LXs) are bilaterally paired neuropils in the insect brain that mediate communication between the central complex (CX), a brain center controlling spatial orientation, various sensory processing areas, and thoracic motor centers that execute locomotion. The LX of the desert locust consists of the lateral accessory lobe (LAL), and the medial and lateral bulb. We have analyzed the anatomical organization and the neuronal connections of the LX in the locust, to provide a basis for future functional studies. Reanalyzing the morphology of neurons connecting the CX and the LX revealed likely feedback loops in the sky compass network of the CX via connections in the gall of the LAL and a newly identified neuropil termed ovoid body. In addition, we characterized 16 different types of neuron that connect the LAL with other areas in the brain. Eight types of neuron provide information flow between both LALs, five types are LAL input neurons, and three types are LAL output neurons. Among these are neurons providing input from sensory brain areas such as the lobula and antennal neuropils. Brain regions most often targeted by LAL neurons are the posterior slope, the wedge, and the crepine. Two descending neurons with dendrites in the LAL were identified. Our data support and complement existing knowledge about how the LAL is embedded in the neuronal network involved in processing of sensory information and generation of appropriate behavioral output for goal‐directed locomotion.

in Journal of Comparative Neurology on July 16, 2021 11:23 AM.

• #### Exploring the diverse, intimate lives of plants

Nature Methods, Published online: 16 July 2021; doi:10.1038/s41592-021-01228-x

New ways to assess plant–microbe interactions can yield unexpected paths to biodiversity.

in Nature Methods on July 16, 2021 12:00 AM.

• #### Triangulating spatial relationships from single-cell interaction maps

Nature Methods, Published online: 16 July 2021; doi:10.1038/s41592-021-01221-4

A combined experimental and computational approach to transcriptomic profiling of cell ‘multiplets’ enables the reconstruction of cell–cell interactions and higher-order structural features of biological tissues.

in Nature Methods on July 16, 2021 12:00 AM.

• #### Reduced replay and distorted maps

Nature Reviews Neuroscience, Published online: 16 July 2021; doi:10.1038/s41583-021-00498-w

In individuals with schizophrenia, a reduced capacity to infer relationships between visual stimuli is associated with impaired spontaneous neural replay.

in Nature Reviews on July 16, 2021 12:00 AM.

• #### Daily briefing: Maths proof hints at the true nature of infinity

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01980-2

An extra size of infinity might sit between the first and second infinitely large numbers. Plus, severe COVID-19 seems to be even rarer in children than we thought, and AlphaFold is going open source.

in Nature on July 16, 2021 12:00 AM.

• #### Coronapod: does England's COVID strategy risk breeding deadly variants?

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01977-x

Researchers are alarmed at England's plan to lift COVID restrictions on 'freedom day' amidst soaring infections

in Nature on July 16, 2021 12:00 AM.

• #### Cooperation’s pros and cons, construction decarbonized, and into the wild: Books in brief

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01973-1

Andrew Robinson reviews five of the week’s best science picks.

in Nature on July 16, 2021 12:00 AM.

• #### Influential US climate report moves ahead — under new leadership

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01969-x

With Allison Crimmins completing the new federal climate team, scientists say the fifth National Climate Assessment is back on solid ground.

in Nature on July 16, 2021 12:00 AM.

• #### The vanishing neutrinos that could upend fundamental physics

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01955-3

The search for exotic ‘Majorana’ particles that could solve a big antimatter mystery is ramping up around the world.

in Nature on July 16, 2021 12:00 AM.

• #### Astronomers push for global debate on giant satellite swarms

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01954-4

Working with the United Nations, scientists hope to establish standards for satellite ‘megaconstellations’ and reduce disruption of astronomical observations.

in Nature on July 16, 2021 12:00 AM.

• #### Massive DNA ‘Borg’ structures perplex scientists

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01947-3

Researchers say they have discovered unique and exciting DNA strands in the mud — others aren’t sure of their novelty.

in Nature on July 16, 2021 12:00 AM.

• #### Tied in knots: Zika virus tangles are the most stable RNA known

Nature, Published online: 16 July 2021; doi:10.1038/d41586-021-01911-1

A dangerous virus uses a ring-shaped structure to make its RNA resistant to attack.

in Nature on July 16, 2021 12:00 AM.

• #### Investigating Post-translational Modifications in Neuropsychiatric Disease: The Next Frontier in Human Post-mortem Brain Research

Gene expression and translation have been extensively studied in human post-mortem brain tissue from subjects with psychiatric disease. Post-translational modifications (PTMs) have received less attention despite their implication by unbiased genetic studies and importance in regulating neuronal and circuit function. Here we review the rationale for studying PTMs in psychiatric disease, recent findings in human post-mortem tissue, the required controls for these types of studies, and highlight the emerging mass spectrometry approaches transforming this research direction.

in Frontiers in Molecular Neuroscience on July 16, 2021 12:00 AM.

• #### Super-Selective Reconstruction of Causal and Direct Connectivity With Application to in vitro iPSC Neuronal Networks

Despite advancements in the development of cell-based in-vitro neuronal network models, the lack of appropriate computational tools limits their analyses. Methods aimed at deciphering the effective connections between neurons from extracellular spike recordings would increase utility of in vitro local neural circuits, especially for studies of human neural development and disease based on induced pluripotent stem cells (hiPSC). Current techniques allow statistical inference of functional couplings in the network but are fundamentally unable to correctly identify indirect and apparent connections between neurons, generating redundant maps with limited ability to model the causal dynamics of the network. In this paper, we describe a novel mathematically rigorous, model-free method to map effective—direct and causal—connectivity of neuronal networks from multi-electrode array data. The inference algorithm uses a combination of statistical and deterministic indicators which, first, enables identification of all existing functional links in the network and then reconstructs the directed and causal connection diagram via a super-selective rule enabling highly accurate classification of direct, indirect, and apparent links. Our method can be generally applied to the functional characterization of any in vitro neuronal networks. Here, we show that, given its accuracy, it can offer important insights into the functional development of in vitro hiPSC-derived neuronal cultures.

in Frontiers in Neuroscience: Neural Technology on July 16, 2021 12:00 AM.

• #### Decreased Functional Connectivity of Vermis-Ventral Prefrontal Cortex in Bipolar Disorder

Objectives: To investigate changes in functional connectivity between the vermis and cerebral regions in the resting state among subjects with bipolar disorder (BD).

Methods: Thirty participants with BD and 28 healthy controls (HC) underwent the resting state functional magnetic resonance imaging (fMRI). Resting-state functional connectivity (rsFC) of the anterior and posterior vermis was examined. For each participant, rsFC maps of the anterior and posterior vermis were computed and compared across the two groups.

Results: rsFC between the whole vermis and ventral prefrontal cortex (VPFC) was significantly lower in the BD groups compared to the HC group, and rsFC between the anterior vermis and the middle cingulate cortex was likewise significantly decreased in the BD group.

Limitations: 83.3% of the BD participants were taking medication at the time of the study. Our findings may in part be attributed to treatment differences because we did not examine the effects of medication on rsFC. Further, the mixed BD subtypes in our current study may have confounding effects influencing the results.

Conclusions: These rsFC differences of vermis-VPFC between groups may contribute to the BD mood regulation.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Early Blindness Limits the Head-Trunk Coordination Development for Horizontal Reorientation

During locomotion, goal-directed orientation movements in the horizontal plane require a high degree of head-trunk coordination. This coordination is acquired during childhood. Since early visual loss is linked to motor control deficits, we hypothesize that it may also affect the development of head-trunk coordination for horizontal rotations. However, no direct evidence exists about such a deficit. To assess this hypothesis, we tested early blind and sighted individuals on dynamic sound alignment through a head-pointing task with sounds delivered in acoustic virtual reality. Participants could perform the head-pointing with no constraints, or they were asked to immobilize their trunk voluntarily. Kinematics of head and trunk were assessed individually and with respect to each other, together with spatial task performance. Results indicated a head-trunk coordination deficit in the early blind group; yet, they could dampen their trunk movements so as not to let their coordination deficit affect spatial performance. This result highlights the role of vision in the development of head-trunk coordination for goal-directed horizontal rotations. It also calls for clarification on the impact of the blindness-related head-trunk coordination deficit on the performance of more complex tasks akin to daily life activities such as steering during locomotion or reaching to targets placed sideways.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Brain Functional Changes in Stroke Following Rehabilitation Using Brain-Computer Interface-Assisted Motor Imagery With and Without tDCS: A Pilot Study

Brain-computer interface-assisted motor imagery (MI-BCI) or transcranial direct current stimulation (tDCS) has been proven effective in post-stroke motor function enhancement, yet whether the combination of MI-BCI and tDCS may further benefit the rehabilitation of motor functions remains unknown. This study investigated brain functional activity and connectivity changes after a 2 week MI-BCI and tDCS combined intervention in 19 chronic subcortical stroke patients. Patients were randomized into MI-BCI with tDCS group and MI-BCI only group who underwent 10 sessions of 20 min real or sham tDCS followed by 1 h MI-BCI training with robotic feedback. We derived amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) from resting-state functional magnetic resonance imaging (fMRI) data pre- and post-intervention. At baseline, stroke patients had lower ALFF in the ipsilesional somatomotor network (SMN), lower ReHo in the contralesional insula, and higher ALFF/Reho in the bilateral posterior default mode network (DMN) compared to age-matched healthy controls. After the intervention, the MI-BCI only group showed increased ALFF in contralesional SMN and decreased ALFF/Reho in the posterior DMN. In contrast, no post-intervention changes were detected in the MI-BCI + tDCS group. Furthermore, higher increases in ALFF/ReHo/FC measures were related to better motor function recovery (measured by the Fugl-Meyer Assessment scores) in the MI-BCI group while the opposite association was detected in the MI-BCI + tDCS group. Taken together, our findings suggest that brain functional re-normalization and network-specific compensation were found in the MI-BCI only group but not in the MI-BCI + tDCS group although both groups gained significant motor function improvement post-intervention with no group difference. MI-BCI and tDCS may exert differential or even opposing impact on brain functional reorganization during post-stroke motor rehabilitation; therefore, the integration of the two strategies requires further refinement to improve efficacy and effectiveness.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Prediction of Second Language Proficiency Based on Electroencephalographic Signals Measured While Listening to Natural Speech

This study had two goals: to clarify the relationship between electroencephalographic (EEG) features estimated while non-native speakers listened to a second language (L2) and their proficiency in L2 determined by a conventional paper test and to provide a predictive model for L2 proficiency based on EEG features. We measured EEG signals from 205 native Japanese speakers, who varied widely in English proficiency while they listened to natural speech in English. Following the EEG measurement, they completed a conventional English listening test for Japanese speakers. We estimated multivariate temporal response functions separately for word class, speech rate, word position, and parts of speech. We found significant negative correlations between listening score and 17 EEG features, which included peak latency of early components (corresponding to N1 and P2) for both open and closed class words and peak latency and amplitude of a late component (corresponding to N400) for open class words. On the basis of the EEG features, we generated a predictive model for Japanese speakers’ English listening proficiency. The correlation coefficient between the true and predicted listening scores was 0.51. Our results suggest that L2 or foreign language ability can be assessed using neural signatures measured while listening to natural speech, without the need of a conventional paper test.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Determination of Dynamic Brain Connectivity via Spectral Analysis

Spectral analysis based on neural field theory is used to analyze dynamic connectivity via methods based on the physical eigenmodes that are the building blocks of brain dynamics. These approaches integrate over space instead of averaging over time and thereby greatly reduce or remove the temporal averaging effects, windowing artifacts, and noise at fine spatial scales that have bedeviled the analysis of dynamical functional connectivity (FC). The dependences of FC on dynamics at various timescales, and on windowing, are clarified and the results are demonstrated on simple test cases, demonstrating how modes provide directly interpretable insights that can be related to brain structure and function. It is shown that FC is dynamic even when the brain structure and effective connectivity are fixed, and that the observed patterns of FC are dominated by relatively few eigenmodes. Common artifacts introduced by statistical analyses that do not incorporate the physical nature of the brain are discussed and it is shown that these are avoided by spectral analysis using eigenmodes. Unlike most published artificially discretized “resting state networks” and other statistically-derived patterns, eigenmodes overlap, with every mode extending across the whole brain and every region participating in every mode—just like the vibrations that give rise to notes of a musical instrument. Despite this, modes are independent and do not interact in the linear limit. It is argued that for many purposes the intrinsic limitations of covariance-based FC instead favor the alternative of tracking eigenmode coefficients vs. time, which provide a compact representation that is directly related to biophysical brain dynamics.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Neurobehavioral, Neuromotor, and Neurocognitive Effects in Agricultural Workers and Their Children Exposed to Pyrethroid Pesticides: A Review

In recent years, pyrethroids have emerged as a less toxic alternative to eliminate insect pests. However, some animal studies and studies with children show that these pesticides are toxic and lead to neurobehavioral effects similar to other pesticides, such as organophosphates. The purpose of this review was to systematize the epidemiological scientific evidence about the neurobehavioral, neuromotor, and neurocognitive effects in agricultural workers and their children exposed to pyrethroid pesticides. We conducted two searches (with different terms) in PubMed and Scopus databases, including articles in Spanish and English language on the effects of occupational exposure to pyrethroid pesticides associated with neurobehavioral, neuromotor, and neurocognitive functioning of agricultural workers and their children. There were no filters by year, and the search included studies till march 2021. To develop the search, we followed the recommendations contained in the PRISMA guidelines and the PICO strategy. The results show that in 66.6% of the studies reviewed (8 of 12 studies), agricultural workers or their children occupationally exposed to pyrethroid pesticides have a higher risk of presenting difficulties in their neurocognitive, neuromotor, or neurobehavioral performance, mainly associated with attention, processing speed (linked to hand-eye coordination), and motor coordination. There are still few studies that address this issue. However, the quality of most of the research conducted (83% intermediate or high quality) confirms the risk for neurobehavioral health in agricultural workers due to occupational exposure to pyrethroids. More research is required evaluating the exposure to pyrethroids, including biomarkers and validated neurobehavioral and neuromotor tests, in addition to evaluating the effect of simultaneous exposure to other hazardous pesticides. Assuming that the use of pyrethroids is increasing considerably and faster than the scientific evidence, it is suggested as a precautionary principle to regulate, more strictly, the sale of pyrethroids and other pesticides.

in Frontiers in Human Neuroscience on July 16, 2021 12:00 AM.

• #### Commentary: Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons

in Frontiers in Cellular Neuroscience on July 16, 2021 12:00 AM.

• #### Effects of 1p/19q Codeletion on Immune Phenotype in Low Grade Glioma

Background: Chromosome 1p/19q codeletion is one of the most important genetic alterations for low grade gliomas (LGGs), and patients with 1p/19q codeletion have significantly prolonged survival compared to those without the codeletion. And the tumor immune microenvironment also plays a vital role in the tumor progression and prognosis. However, the effect of 1p/19q codeletion on the tumor immune microenvironment in LGGs is unclear.

Methods: Immune cell infiltration of 281 LGGs from The Cancer Genome Atlas (TCGA) and 543 LGGs from the Chinese Glioma Genome Atlas (CGGA) were analyzed for immune cell infiltration through three bioinformatics tools: ESTIMATE algorithm, TIMER, and xCell. The infiltrating level of immune cells and expression of immune checkpoint genes were compared between different groups classified by 1p/19q codeletion and IDH (isocitrate dehydrogenase) mutation status. The differential biological processes and signaling pathways were evaluated through Gene Set Enrichment Analysis (GSEA). Correlations were analyzed using Spearman correlation.

Results: 1p/19q codeletion was associated with immune-related biological processes in LGGs. The infiltrating level of multiple kinds of immune cells and expression of immune checkpoint genes were significantly lower in 1p/19q codeletion LGGs compared to 1p/19q non-codeletion cohorts. There are 127 immune-related genes on chromosome 1p or 19q, such as TGFB1, JAK1, and CSF1. The mRNA expression of these genes was positively correlated with their DNA copy number. These genes are distributed in multiple immune categories, such as chemokines/cytokines, TGF-β family members, and TNF family members, regulating immune cell infiltration and expression of the immune checkpoint genes in tumors.

Conclusion: Our results indicated that 1p/19q codeletion status is closely associated with the immunosuppressive microenvironment in LGGs. LGGs with 1p/19q codeletion display less immune cell infiltration and lower expression of immune checkpoint genes than 1p/19q non-codeletion cases. Mechanistically, this may be, at least in part, due to the deletion of copy number of immune-related genes in LGGs with 1p/19q codeletion. Our findings may be relevant to investigate immune evasion in LGGs and contribute to the design of immunotherapeutic strategies for patients with LGGs.

in Frontiers in Cellular Neuroscience on July 16, 2021 12:00 AM.

• #### A Large-Scale Open Motion Dataset (KFall) and Benchmark Algorithms for Detecting Pre-impact Fall of the Elderly Using Wearable Inertial Sensors

Research on pre-impact fall detection with wearable inertial sensors (detecting fall accidents prior to body-ground impacts) has grown rapidly in the past decade due to its great potential for developing an on-demand fall-related injury prevention system. However, most researchers use their own datasets to develop fall detection algorithms and rarely make these datasets publicly available, which poses a challenge to fairly evaluate the performance of different algorithms on a common basis. Even though some open datasets have been established recently, most of them are impractical for pre-impact fall detection due to the lack of temporal labels for fall time and limited types of motions. In order to overcome these limitations, in this study, we proposed and publicly provided a large-scale motion dataset called “KFall,” which was developed from 32 Korean participants while wearing an inertial sensor on the low back and performing 21 types of activities of daily living and 15 types of simulated falls. In addition, ready-to-use temporal labels of the fall time based on synchronized motion videos were published along with the dataset. Those enhancements make KFall the first public dataset suitable for pre-impact fall detection, not just for post-fall detection. Importantly, we have also developed three different types of latest algorithms (threshold based, support-vector machine, and deep learning), using the KFall dataset for pre-impact fall detection so that researchers and practitioners can flexibly choose the corresponding algorithm. Deep learning algorithm achieved both high overall accuracy and balanced sensitivity (99.32%) and specificity (99.01%) for pre-impact fall detection. Support vector machine also demonstrated a good performance with a sensitivity of 99.77% and specificity of 94.87%. However, the threshold-based algorithm showed relatively poor results, especially the specificity (83.43%) was much lower than the sensitivity (95.50%). The performance of these algorithms could be regarded as a benchmark for further development of better algorithms with this new dataset. This large-scale motion dataset and benchmark algorithms could provide researchers and practitioners with valuable data and references to develop new technologies and strategies for pre-impact fall detection and proactive injury prevention for the elderly.

in Frontiers in Ageing Neuroscience on July 16, 2021 12:00 AM.

• #### Adaptation of Melodic Intonation Therapy to Greek: A Clinical Study in Broca’s Aphasia With Brain Perfusion SPECT Validation

Melodic intonation therapy (MIT) is one of the most well-known treatment methods which is based on pitch and rhythm and was developed to increase verbal output in adults with non-fluent aphasia. Although MIT has been adapted to several languages, in Greece it is almost unknown. The aim of the proposed study is twofold: (1) to translate and adapt the MIT to the Greek language, and (2) to conduct an experimental study in order to examine the effect of MIT on Greek patients with Broca’s aphasia. To this aim, a 64-year-old, right-handed male who had a 6-year primary school education level, no musical abilities and poor performance on the recognition of prosody attended the MIT intervention program almost two and a half years after the event of suffering an ischemic stroke. The MIT intervention was administered three times per week for a 12-week period, in which each session lasted from 30 to 40 min. The patient underwent three assessments all using both the Boston Diagnostic Aphasia Examination–Short Form (BDAE-SF) and brain perfusion single-photon emission computed tomography (SPECT); (1) before the MIT, (2) immediately after, and (3) 3 months after the completion of MIT. The results from the BDAE-SF revealed an impressive improvement on both trained and prepositional speech production, immediately after the completion of the MIT, and a stable improved performance 3 months after MIT. The SPECT scan revealed reactivation of the perilesional areas of the left hemisphere, and considerably improved perfusion of the frontal lobe, the anterior temporal lobe, and the upper part of the parietal lobe of the right hemisphere. The improvement persisted and even expanded 3 months after MIT. Therefore, MIT is a promising intervention program and its positive effects last for at least 3 months after the completion of the intervention.

in Frontiers in Ageing Neuroscience on July 16, 2021 12:00 AM.

• #### Reconciling functional differences in populations of neurons recorded with two-photon imaging and electrophysiology

Extracellular electrophysiology and two-photon calcium imaging are widely used methods for measuring physiological activity with single-cell resolution across large populations of cortical neurons. While each of these two modalities has distinct advantages and disadvantages, neither provides complete, unbiased information about the underlying neural population. Here, we compare evoked responses in visual cortex recorded in awake mice under highly standardized conditions using either imaging of genetically expressed GCaMP6f or electrophysiology with silicon probes. Across all stimulus conditions tested, we observe a larger fraction of responsive neurons in electrophysiology and higher stimulus selectivity in calcium imaging, which was partially reconciled by applying a spikes-to-calcium forward model to the electrophysiology data. However, the forward model could only reconcile differences in responsiveness when restricted to neurons with low contamination and an event rate above a minimum threshold. This work established how the biases of these two modalities impact functional metrics that are fundamental for characterizing sensory-evoked responses.

in eLife on July 16, 2021 12:00 AM.

• #### Distinct Synaptic Transfer Functions in Same-Type Photoreceptors

Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous “dual-colour” 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.

in eLife on July 16, 2021 12:00 AM.

• #### Homo-oligomerization of the human adenosine A2a receptor is driven by the intrinsically disordered C-terminus

G protein-coupled receptors (GPCRs) have long been shown to exist as oligomers with functional properties distinct from those of the monomeric counterparts, but the driving factors of oligomerization remain relatively unexplored. Herein, we focus on the human adenosine A2A receptor (A2AR), a model GPCR that forms oligomers both in vitro and in vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A2AR drives receptor homo-oligomerization. The formation of A2AR oligomers declines progressively with the shortening of the C-terminus. Multiple interaction types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions, giving rise to a tunable network of bonds that allow A2AR oligomers to adopt multiple interfaces. This study uncovers the disordered C-terminus as a prominent driving factor for the oligomerization of a GPCR, offering important insight into the effect of C-terminus modification on receptor oligomerization of A2AR and other GPCRs reconstituted in vitro for biophysical studies.

in eLife on July 16, 2021 12:00 AM.

• #### Localization, proteomics, and metabolite profiling reveal a putative vesicular transporter for UDP-glucose

Vesicular neurotransmitter transporters (VNTs) mediate the selective uptake and enrichment of small molecule neurotransmitters into synaptic vesicles (SVs) and are therefore a major determinant of the synaptic output of specific neurons. To identify novel VNTs expressed on SVs (thus identifying new neurotransmitters and/or neuromodulators), we conducted localization profiling of 361 solute carrier (SLC) transporters tagging with a fluorescent protein in neurons, which revealed 40 possible candidates through comparison with a known SV marker. We parallelly performed proteomics analysis of immunoisolated SVs and identified 7 transporters in overlap. Ultrastructural analysis confirmed one of the transporters, SLC35D3, localized to SVs. Finally, by combining metabolite profiling with a radiolabeled substrate transport assay, we identified UDP-glucose as the principal substrate for SLC35D3. These results provide new insights into the functional role of SLC transporters in neurotransmission and improve our understanding of the molecular diversity of chemical transmitters.

in eLife on July 16, 2021 12:00 AM.

• #### Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.

in eLife on July 16, 2021 12:00 AM.

• #### Calponin-homology domain mediated bending of membrane associated actin filaments

Actin filaments are central to numerous biological processes in all domains of life. Driven by the interplay with molecular motors, actin binding and actin modulating proteins, the actin cytoskeleton exhibits a variety of geometries. This includes structures with a curved geometry such as axon-stabilizing actin rings, actin cages around mitochondria and the cytokinetic actomyosin ring, which are generally assumed to be formed by short linear filaments held together by actin cross-linkers. However, whether individual actin filaments in these structures could be curved and how they may assume a curved geometry remains unknown. Here, we show that 'curly', a region from the IQGAP family of proteins from three different organisms, comprising the actin-binding calponin-homology domain and a C-terminal unstructured domain, stabilizes individual actin filaments in a curved geometry when anchored to lipid membranes. Whereas F-actin is semi-flexible with a persistence length of ~10 mm, binding of mobile curly within lipid membranes generates actin filament arcs and full rings of high curvature with radii below 1 mm. Higher rates of fully formed actin rings are observed in the presence of the actin-binding coiled-coil protein tropomyosin and when actin is directly polymerized on lipid membranes decorated with curly. Strikingly, curly induced actin filament rings contract upon the addition of muscle myosin II filaments and expression of curly in mammalian cells leads to highly curved actin structures in the cytoskeleton. Taken together, our work identifies a new mechanism to generate highly curved actin filaments, which opens a range of possibilities to control actin filament geometries, that can be used, for example, in designing synthetic cytoskeletal structures.

in eLife on July 16, 2021 12:00 AM.

• #### Risk sensitivity and theory of mind in human coordination

by Pedro L. Ferreira, Francisco C. Santos, Sérgio Pequito

What humans do when exposed to uncertainty, incomplete information, and a dynamic environment influenced by other agents remains an open scientific challenge with important implications in both science and engineering applications. In these contexts, humans handle social situations by employing elaborate cognitive mechanisms such as theory of mind and risk sensitivity. Here we resort to a novel theoretical model, showing that both mechanisms leverage coordinated behaviors among self-regarding individuals. Particularly, we resort to cumulative prospect theory and level-k recursions to show how biases towards optimism and the capacity of planning ahead significantly increase coordinated, cooperative action. These results suggest that the reason why humans are good at coordination may stem from the fact that we are cognitively biased to do so.

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Data integration uncovers the metabolic bases of phenotypic variation in yeast

by Marianyela Sabina Petrizzelli, Dominique de Vienne, Thibault Nidelet, Camille Noûs, Christine Dillmann

The relationship between different levels of integration is a key feature for understanding the genotype-phenotype map. Here, we describe a novel method of integrated data analysis that incorporates protein abundance data into constraint-based modeling to elucidate the biological mechanisms underlying phenotypic variation. Specifically, we studied yeast genetic diversity at three levels of phenotypic complexity in a population of yeast obtained by pairwise crosses of eleven strains belonging to two species, Saccharomyces cerevisiae and S. uvarum. The data included protein abundances, integrated traits (life-history/fermentation) and computational estimates of metabolic fluxes. Results highlighted that the negative correlation between production traits such as population carrying capacity (K) and traits associated with growth and fermentation rates (Jmax) is explained by a differential usage of energy production pathways: a high K was associated with high TCA fluxes, while a high Jmax was associated with high glycolytic fluxes. Enrichment analysis of protein sets confirmed our results. This powerful approach allowed us to identify the molecular and metabolic bases of integrated trait variation, and therefore has a broad applicability domain.

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Responses to 10 common criticisms of anti-racism action in STEMM

by Maya L. Gosztyla, Lydia Kwong, Naomi A. Murray, Claire E. Williams, Nicholas Behnke, Porsia Curry, Kevin D. Corbett, Karen N. DSouza, Julia Gala de Pablo, Joanina Gicobi, Monica Javidnia, Navina Lotay, Sidney Madison Prescott, James P. Quinn, Zeena M. G. Rivera, Markia A. Smith, Karen T. Y. Tang, Aarya Venkat, Megan A. Yamoah

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Ten simple rules for attending your first conference

by Elizabeth Leininger, Kelly Shaw, Niema Moshiri, Kelly Neiles, Getiria Onsongo, Anna Ritz

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Ten simple rules to improve academic work–life balance

by Michael John Bartlett, Feyza Nur Arslan, Adriana Bankston, Sarvenaz Sarabipour

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Sperm migration in the genital tract—<i>In silico</i> experiments identify key factors for reproductive success

by Jorin Diemer, Jens Hahn, Björn Goldenbogen, Karin Müller, Edda Klipp

Sperm migration in the female genital tract controls sperm selection and, therefore, reproductive success as male gametes are conditioned for fertilization while their number is dramatically reduced. Mechanisms underlying sperm migration are mostly unknown, since in vivo investigations are mostly unfeasible for ethical or practical reasons. By presenting a spatio-temporal model of the mammalian female genital tract combined with agent-based description of sperm motion and interaction as well as parameterizing it with bovine data, we offer an alternative possibility for studying sperm migration in silico. The model incorporates genital tract geometry as well as biophysical principles of sperm motion observed in vitro such as positive rheotaxis and thigmotaxis. This model for sperm migration from vagina to oviducts was successfully tested against in vivo data from literature. We found that physical sperm characteristics such as velocity and directional stability as well as sperm-fluid interactions and wall alignment are critical for success, i.e. sperms reaching the oviducts. Therefore, we propose that these identified sperm parameters should be considered in detail for conditioning sperm in artificial selection procedures since the natural processes are normally bypassed in reproductive in vitro technologies. The tremendous impact of mucus flow to support sperm accumulation in the oviduct highlights the importance of a species-specific optimum time window for artificial insemination regarding ovulation. Predictions from our extendable in silico experimental system will improve assisted reproduction in humans, endangered species, and livestock.

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Accumulation of continuously time-varying sensory evidence constrains neural and behavioral responses in human collision threat detection

by Gustav Markkula, Zeynep Uludağ, Richard McGilchrist Wilkie, Jac Billington

Evidence accumulation models provide a dominant account of human decision-making, and have been particularly successful at explaining behavioral and neural data in laboratory paradigms using abstract, stationary stimuli. It has been proposed, but with limited in-depth investigation so far, that similar decision-making mechanisms are involved in tasks of a more embodied nature, such as movement and locomotion, by directly accumulating externally measurable sensory quantities of which the precise, typically continuously time-varying, magnitudes are important for successful behavior. Here, we leverage collision threat detection as a task which is ecologically relevant in this sense, but which can also be rigorously observed and modelled in a laboratory setting. Conventionally, it is assumed that humans are limited in this task by a perceptual threshold on the optical expansion rate–the visual looming–of the obstacle. Using concurrent recordings of EEG and behavioral responses, we disprove this conventional assumption, and instead provide strong evidence that humans detect collision threats by accumulating the continuously time-varying visual looming signal. Generalizing existing accumulator model assumptions from stationary to time-varying sensory evidence, we show that our model accounts for previously unexplained empirical observations and full distributions of detection response. We replicate a pre-response centroparietal positivity (CPP) in scalp potentials, which has previously been found to correlate with accumulated decision evidence. In contrast with these existing findings, we show that our model is capable of predicting the onset of the CPP signature rather than its buildup, suggesting that neural evidence accumulation is implemented differently, possibly in distinct brain regions, in collision detection compared to previously studied paradigms.

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement

by Samuel A. Ramirez, Michael Pablo, Sean Burk, Daniel J. Lew, Timothy C. Elston

Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering within the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations of cluster behavior, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.

in PLoS Computational Biology on July 15, 2021 02:00 PM.

• #### Don’t let the perfect be the enemy of the good

by Marcus Munafò

There is a growing interest in the factors that influence research quality and into research culture more generally. Reform must be evidence based, but experimental studies in real-world settings can be challenging. Observational evidence, even if imperfect, can be a valuable and efficient starting point to help identify the most fruitful avenues for meta-research investment. There is growing interest in the factors that influence research quality, and into research culture more generally. Reform must be evidence-based, but experimental studies in real-world settings can be challenging. This Perspective article argues that observational evidence, even if imperfect, can be a valuable and efficient starting point to help identify the most fruitful avenues for meta-research investment.

in PLoS Biology on July 15, 2021 02:00 PM.

• #### Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex

by Qingguang Zhang, Kyle W. Gheres, Patrick J. Drew

The concentration of oxygen in the brain spontaneously fluctuates, and the distribution of power in these fluctuations has a 1/f-like spectra, where the power present at low frequencies of the power spectrum is orders of magnitude higher than at higher frequencies. Though these oscillations have been interpreted as being driven by neural activity, the origin of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations and mathematical modeling show that stochastic fluctuations in erythrocyte flow could underlie 1/f-like dynamics in oxygenation. These results suggest that the discrete nature of erythrocytes and their irregular flow, rather than fluctuations in neural activity, could drive 1/f-like fluctuations in tissue oxygenation.

in PLoS Biology on July 15, 2021 02:00 PM.

• #### Perception of biological motion by jumping spiders

by Massimo De Agrò, Daniela C. Rößler, Kris Kim, Paul S. Shamble

The body of most creatures is composed of interconnected joints. During motion, the spatial location of these joints changes, but they must maintain their distances to one another, effectively moving semirigidly. This pattern, termed “biological motion” in the literature, can be used as a visual cue, enabling many animals (including humans) to distinguish animate from inanimate objects. Crucially, even artificially created scrambled stimuli, with no recognizable structure but that maintains semirigid movement patterns, are perceived as animated. However, to date, biological motion perception has only been reported in vertebrates. Due to their highly developed visual system and complex visual behaviors, we investigated the capability of jumping spiders to discriminate biological from nonbiological motion using point-light display stimuli. These kinds of stimuli maintain motion information while being devoid of structure. By constraining spiders on a spherical treadmill, we simultaneously presented 2 point-light displays with specific dynamic traits and registered their preference by observing which pattern they turned toward. Spiders clearly demonstrated the ability to discriminate between biological motion and random stimuli, but curiously turned preferentially toward the latter. However, they showed no preference between biological and scrambled displays, results that match responses produced by vertebrates. Crucially, spiders turned toward the stimuli when these were only visible by the lateral eyes, evidence that this task may be eye specific. This represents the first demonstration of biological motion recognition in an invertebrate, posing crucial questions about the evolutionary history of this ability and complex visual processing in nonvertebrate systems.

in PLoS Biology on July 15, 2021 02:00 PM.

• #### A cross-institutional analysis of the effects of broadening trainee professional development on research productivity

by Patrick D. Brandt, Susi Sturzenegger Varvayanis, Tracey Baas, Amanda F. Bolgioni, Janet Alder, Kimberly A. Petrie, Isabel Dominguez, Abigail M. Brown, C. Abigail Stayart, Harinder Singh, Audra Van Wart, Christine S. Chow, Ambika Mathur, Barbara M. Schreiber, David A. Fruman, Brent Bowden, Christopher A. Wiesen, Yvonne M. Golightly, Chris E. Holmquist, Daniel Arneman, Joshua D. Hall, Linda E. Hyman, Kathleen L. Gould, Roger Chalkley, Patrick J. Brennwald, Rebekah L. Layton

PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce.

in PLoS Biology on July 15, 2021 02:00 PM.

• #### Orexin (hypocretin) mediates light‐dependent fluctuation of hippocampal function in a diurnal rodent

Abstract Environmental lighting conditions play a central role in cognitive function, but the underlying mechanisms remain unclear. Utilizing a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), we previously found that daytime light intensity affects hippocampal function in this species in a manner similar to its effects in humans. Compared to animals housed in a 12:12 h bright light–dark (brLD) cycle, grass rats kept in a 12:12 h dim light–dark (dimLD) cycle showed impaired spatial memory in the Morris water maze (MWM) and reduced CA1 apical dendritic spine density. The present study explored the neural substrates mediating the effects of daylight intensity on hippocampal function focusing on the hypothalamic orexin (hypocretin) system. First, animals housed in dimLD were treated with daily intranasal administration of orexin A peptide over five training days of the MWM task. Compared to vehicle controls, this treatment led to superior spatial memory accompanied by increased phosphorylation of Ca2+/calmodulin‐dependent protein kinase II α and glutamate receptor 1 within the CA1. To assess the role of hippocampal orexinergic signaling, an adeno‐associated viral vector (AAV) expressing an orexin receptor 1 (OX1R) shRNA was injected into the dorsal hippocampus targeting the CA1 of animals housed in brLD. AAV‐mediated knockdown of OX1R within the hippocampus resulted in deficits in MWM performance and reduced CA1 apical dendritic spine density. These results are consistent with the view that the hypothalamic orexinergic system underlies the modulatory role of daytime illumination on hippocampal function in diurnal mammals.

in Hippocampus on July 15, 2021 12:12 PM.

• #### Diffusive wave dynamics beyond the continuum limit

Author(s): Paul B. Dieterle and Ariel Amir

A new model shows that the properties of waves produced in a cell-signaling process strongly depend on whether the cells are considered to be discrete entities or a collective mass.

[Phys. Rev. E 104, 014406] Published Thu Jul 15, 2021

in Physical Review E: Biological physics on July 15, 2021 10:00 AM.

• #### The basal ganglia control the detailed kinematics of learned motor skills

Nature Neuroscience, Published online: 15 July 2021; doi:10.1038/s41593-021-00889-3

By recording and manipulating neural activity in rats performing a skilled behavior, the authors show that the basal ganglia control the detailed kinematics of learned skills and can do so independently of the motor cortex.

in Nature Neuroscience on July 15, 2021 12:00 AM.

• #### Highly accurate protein structure prediction with AlphaFold

Nature, Published online: 15 July 2021; doi:10.1038/s41586-021-03819-2

Highly accurate protein structure prediction with AlphaFold

in Nature on July 15, 2021 12:00 AM.

• #### Have tail, will travel

Nature Physics, Published online: 15 July 2021; doi:10.1038/s41567-021-01301-4

The flagella of microorganisms have provided inspiration for many synthetic devices, but they’re typically not easy to produce. A new class of swimmer makes it look simple by spontaneously growing a tail that it can whip to self-propel.

in Nature Physics on July 15, 2021 12:00 AM.

• #### Rechargeable self-assembled droplet microswimmers driven by surface phase transitions

Nature Physics, Published online: 15 July 2021; doi:10.1038/s41567-021-01291-3

A class of synthetic microswimmers self-assembled from alkane oil drops in a surfactant solution offers a rechargeable platform for studying how microorganisms exploit flagellar elasticity to move around.

in Nature Physics on July 15, 2021 12:00 AM.

• #### Detecting photoelectrons from spontaneously formed excitons

Nature Physics, Published online: 15 July 2021; doi:10.1038/s41567-021-01289-x

Excitons have been predicted to form spontaneously—without external excitation—in some materials. Low-temperature ARPES measurements on Ta2NiSe5 now provide evidence for such an excitonic insulator and for so-called preformed excitons.

in Nature Physics on July 15, 2021 12:00 AM.

• #### Exceptional behaviour without exceptional effort

Nature Photonics, Published online: 15 July 2021; doi:10.1038/s41566-021-00849-0

The adiabatic encirclement of exceptional points in non-Hermitian systems is known to produce surprising non-adiabatic effects. A new study finds a cheat code to exactly emulate this behaviour without ever having to produce an exceptional point.

in Nature Photomics on July 15, 2021 12:00 AM.

• #### Thalamo-Nucleus Accumbens Projections in Motivated Behaviors and Addiction

The ventral striatum, also called nucleus accumbens (NAc), has long been known to integrate information from cortical, thalamic, midbrain and limbic nuclei to mediate goal-directed behaviors. Until recently thalamic afferents have been overlooked when studying the functions and connectivity of the NAc. However, findings from recent studies have shed light on the importance and roles of precise Thalamus to NAc connections in motivated behaviors and in addiction. In this review, we summarize studies using techniques such as chemo- and optogenetics, electrophysiology and in vivo calcium imaging to elucidate the complex functioning of the thalamo-NAc afferents, with a particular highlight on the projections from the Paraventricular Thalamus (PVT) to the NAc. We will focus on the recent advances in the understanding of the roles of these neuronal connections in motivated behaviors, with a special emphasis on their implications in addiction, from cue-reward association to the mechanisms driving relapse.

in Frontiers in Systems Neuroscience on July 15, 2021 12:00 AM.

• #### Plasticity of GluN1 at Ventral Hippocampal Synapses in the Infralimbic Cortex

Although the infralimbic cortex (IL) is not thought to play a role in fear acquisition, recent experiments found evidence that synaptic plasticity is occurring at ventral hippocampal (vHPC) synapses in IL during auditory fear acquisition as measured by changes in the N-methyl-D-aspartate (NMDA) receptor-mediated currents in male rats. These electrophysiological data suggest that fear conditioning changes the expression of NMDA receptors on vHPC-to-IL synapses. To further evaluate the plasticity of NMDA receptors at this specific synapse, we injected AAV particles expressing channelrhodopsin-EYFP into the vHPC of male and female rats to label vHPC projections with EYFP. To test for NMDA receptor changes in vHPC-to-IL synapses after fear learning, we used fluorescence-activated cell sorting (FACS) to quantify synaptosomes isolated from IL tissue punches that were positive for EYFP and the obligatory GluN1 subunit. More EYFP+/GluN1+ synaptosomes with greater average expression of GluN1 were isolated from male rats exposed to auditory fear conditioning (AFC) than those exposed to context and tones only or to contextual fear conditioning (CFC), suggesting that AFC increased NMDA receptor expression in males. In a second experiment, we found that pairing the tones and shocks was required to induce the molecular changes and that fear extinction did not reverse the changes. In contrast, females showed similar levels of EYFP+/GluN1+ synaptosomes in all behavioral groups. These findings suggest that AFC induces synaptic plasticity of NMDA receptors in the vHPC-to-IL projection in males, while female rats rely on different synaptic mechanisms.

in Frontiers in Synaptic Neuroscience on July 15, 2021 12:00 AM.

• #### Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits

Animals adapt their behaviors to their ever-changing needs. Internal states, such as hunger, fear, stress, and arousal are important behavioral modulators controlling the way an organism perceives sensory stimuli and reacts to them. The translucent zebrafish larva is an ideal model organism for studying neuronal circuits regulating brain states, owning to the possibility of easy imaging and manipulating activity of genetically identified neurons while the animal performs stereotyped and well-characterized behaviors. The main neuromodulatory circuits present in mammals can also be found in the larval zebrafish brain, with the advantage that they contain small numbers of neurons. Importantly, imaging and behavioral techniques can be combined with methods for generating targeted genetic modifications to reveal the molecular underpinnings mediating the functions of such circuits. In this review we discuss how studying the larval zebrafish brain has contributed to advance our understanding of circuits and molecular mechanisms regulating neuromodulation and behavioral flexibility.

in Frontiers in Molecular Neuroscience on July 15, 2021 12:00 AM.

• #### Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids

Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity of three-dimensional (3D) human organ-like cell culture systems (“organoids”) can generate potentially more relevant models of human physiology and disease, including toxicity predictions. However, so far, the inherent biological heterogeneity and cumbersome generation and analysis of organoids has rendered efficient, unbiased, high throughput evaluation of toxic effects in these systems challenging. Recent advances in both standardization and quantitative fluorescent imaging enabled us to dissect the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level in a framework that is compatible with high throughput approaches. Screening a library of 84 compounds in standardized human automated midbrain organoids (AMOs) generated from two independent cell lines correctly recognized known nigrostriatal toxicants. This approach further identified the flame retardant 3,3′,5,5′-tetrabromobisphenol A (TBBPA) as a selective toxicant for dopaminergic neurons in the context of human midbrain-like tissues for the first time. Results were verified with high reproducibility in more detailed dose-response experiments. Further, we demonstrate higher sensitivity in 3D AMOs than in 2D cultures to the known neurotoxic effects of the pesticide lindane. Overall, the automated nature of our workflow is freely scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro.

in Frontiers in Molecular Neuroscience on July 15, 2021 12:00 AM.

• #### How to Arrange Follow-Up Time-Intervals for Longitudinal Brain MRI Studies in Neurodegenerative Diseases

Background

Longitudinal brain MRI monitoring in neurodegeneration potentially provides substantial insights into the temporal dynamics of the underlying biological process, but is time- and cost-intensive and may be a burden to patients with disabling neurological diseases. Thus, the conceptualization of follow-up time-intervals in longitudinal MRI studies is an essential challenge and substantial for the results. The objective of this work is to discuss the association of time-intervals and the results of longitudinal trends in the frequently used design of one baseline and two follow-up scans.

Methods

Different analytical approaches for calculating the linear trend of longitudinal parameters were studied in simulations including their performance of dealing with outliers; these simulations were based on the longitudinal striatum atrophy in MRI data of Huntington’s disease patients, detected by atlas-based volumetry (ABV).

Results

For the design of one baseline and two follow-up visits, the simulations with outliers revealed optimum results for identical time-intervals between baseline and follow-up scans. However, identical time-intervals between the three acquisitions lead to the paradox that, depending on the fit method, the first follow-up scan results do not influence the final results of a linear trend analysis.

Conclusions

This theoretical study analyses how the design of longitudinal imaging studies with one baseline and two follow-up visits influences the results. Suggestions for the analysis of longitudinal trends are provided.

in Frontiers in Neuroscience: Brain Imaging Methods on July 15, 2021 12:00 AM.

• #### Evaluation of Multilevel Surgeries in Children With Spastic Cerebral Palsy Based on Surface Electromyography

The root mean square (RMS) of the surface electromyography (sEMG) signal can respond to neuromuscular function, which displays a positive correlation with muscle force and muscle tension under positive and passive conditions, respectively. The purpose of this study was to investigate the changes in muscle force and tension after multilevel surgical treatments, functional selective posterior rhizotomy (FSPR) and tibial anterior muscle transfer surgery, and evaluate their clinical effect in children with spastic cerebral palsy (SCP) during walking. Children with diplegia (n = 13) and hemiplegia (n = 3) with ages from 4 to 18 years participated in this study. They were requested to walk barefoot at a self-selected speed on a 15-m-long lane. The patient's joints' range of motion (ROM) and sEMG signal of six major muscles were assessed before and after the multilevel surgeries. The gait cycle was divided into seven phases, and muscle activation state can be divided into positive and passive conditions during gait cycle. For each phase, the RMS of the sEMG signal amplitude was calculated and also normalized by a linear envelope (10-ms running RMS window). The muscle tension of the gastrocnemius decreased significantly during the loading response, initial swing, and terminal swing (p < 0.05), which helped the knee joint to get the maximum extension when the heel is on the ground and made the heel land smoothly. The muscle force of the gastrocnemius increased significantly (p < 0.05) during the mid-stance, terminal stance, and pre-swing, which could generate the driving force for the human body to move forward. The muscle tension of the biceps femoris and semitendinosus decreased significantly (p < 0.05) during the terminal stance, pre-swing, and initial swing. The decreased muscle tension could relieve the burden of the knee flexion when the knee joint was passively flexed. At the terminal swing, the muscle force of the tibial anterior increased significantly (p < 0.05), which could improve the ankle dorsiflexion ability and prevent foot drop and push forward. Thus, the neuromuscular function of cerebral palsy during walking can be evaluated by the muscle activation state and the RMS of the sEMG signal, which showed that multilevel surgical treatments are feasible and effective to treat SCP.

in Frontiers in Neuroscience: Neural Technology on July 15, 2021 12:00 AM.

• #### Commentary: The Historical Roots of Visual Analog Scale in Psychology as Revealed by Reference Publication Year Spectroscopy

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Computerized Dual-Task Testing of Gait Visuomotor and Cognitive Functions in Parkinson’s Disease: Test-Retest Reliability and Validity

Background

Mobility and cognitive impairments in Parkinson’s disease (PD) often coexist and are prognostic of adverse health events. Consequently, assessment and training that simultaneously address both gait function and cognition are important to consider in rehabilitation and promotion of healthy aging. For this purpose, a computer game-based rehabilitation treadmill platform (GRP) was developed for dual-task (DT) assessment and training.

Objective

The first objective was to establish the test-retest reliability of the GRP assessment protocol for DT gait, visuomotor and executive cognitive function in PD patients. The second objective was to examine the effect of task condition [single task (ST) vs. DT] and disease severity (stage 2 vs. stage 3) on gait, visuomotor and cognitive function.

Methods

Thirty individuals aged 55 to 70 years, diagnosed with PD; 15 each at Hoehn and Yahr scale stage 2 (PD-2) and 3 (PD-3) performed a series of computerized visuomotor and cognitive game tasks while sitting (ST) and during treadmill walking (DT). A treadmill instrumented with a pressure mat was used to record center of foot pressure and compute the average and coefficient of variation (COV) of step time, step length, and drift during 1-min, speed-controlled intervals. Visuomotor and cognitive game performance measures were quantified using custom software. Testing was conducted on two occasions, 1 week apart.

Results

With few exceptions, the assessment protocol showed moderate to high intraclass correlation coefficient (ICC) values under both ST and DT conditions for the spatio-temporal gait measures (average and COV), as well as the visuomotor tracking and cognitive game performance measures. A significant decline in gait, visuomotor, and cognitive game performance measures was observed during DT compared to ST conditions, and in the PD-3 compared to PD-2 groups.

Conclusion

The high to moderate ICC values along with the lack of systematic errors in the measures indicate that this tool has the ability to repeatedly record reliable DT interference (DTI) effects over time. The use of interactive digital media provides a flexible method to produce and evaluate DTI for a wide range of executive cognitive activities. This also proves to be a sensitive tool for tracking disease progression.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier NCT03232996.

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Interbrain Synchrony of Team Collaborative Decision-Making: An fNIRS Hyperscanning Study

In many situations, decision-making behaviors are mostly composed of team patterns (i.e., more than two persons). However, brain-based models that inform how team interactions contribute and impact team collaborative decision-making (TCDM) behavior, is lacking. To examine the neural substrates activated during TCDM in realistic, interpersonal interaction contexts, dyads were asked to model TCDM toward their opponent, in a multi-person prisoner’s dilemma game, while neural activity was measured using functional near infrared spectroscopy. These experiments resulted in two main findings. First, there are different neural substrates between TCDM and ISDM, which were modulated by social environmental cues. i.e., the low incentive reward yielded higher activation within the left inferior frontal gyrus (IFG), in individual separately decision-making (ISDM) stage while the dorsolateral prefrontal cortex (DLPFC) and the middle frontopolar area was activated in TCDM stage. The high incentive reward evoked a higher interbrain synchrony (IBS) value in the right IFG in TCDM stage. Second, males showed higher activation in the DLPFC and the middle frontopolar area during ISDM, while females evoked higher IBS in the right IFG during TCDM. These sex effects suggest that in individual social dilemma situations, males and females may separately depend on non-social and social cognitive ability to make decisions, while in the social interaction situations of TCDM, females may depend on both social and non-social cognitive abilities. This study provide a compelling basis and interesting perspective for future neuroscience work of TCDM behaviors.

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Adaptation of the Compensatory Stepping Response Following Predictable and Unpredictable Perturbation Training

Background

Effective training of the backward step response could be beneficial to improve postural stability and prevent falls. Unpredicted perturbation-based balance training (PBT), widely known as compensatory-step training, may enhance the fear of falling and the patterns of postural muscle co-contraction. Contrastingly, PBT with predictable direction or both direction and timing would suppress the fear and the co-contraction patterns during training, but the efficacy of predictable PBT for unpredictable perturbations is still unknown.

Objective

To compare the adaptation effects of compensatory-step training with and without predictable perturbations on backward stepping against unpredictable perturbations.

Methods

Thirty-three healthy young adults were randomly assigned to one of the following step training groups: Unpredicted, Predicted, and Self-initiated. In training sessions, participants were perturbed to induce a compensatory step with (Predicted group) or without (Unpredicted group) knowledge of the perturbation’s direction or while knowing both the direction and timing of the perturbation (Self-initiated group). In test sessions (pre- and post-training), participants were instructed to recover their postural stability in response to an unpredicted perturbation. The margin of stability (MOS), center of mass (COM) shift, and step characteristics were measured during a backward step in both test and training sessions.

Results

All three groups showed a significant increase in the step length and velocity in the post-training sessions compared to those in the pre-training sessions. Moreover, in the Unpredicted and Predicted groups, but not in the Self-initiated group, the MOS at step contact was significantly increased following the training session. In addition, the Self-initiated group showed a significant increase in COM shift at 50 ms after slip onset during training compared to the Unpredicted and Predicted groups.

Conclusion

Unpredicted and predicted PBT improve step characteristics during backward stepping against unpredictable perturbations. Moreover, the unpredictable PBT and PBT with direction-predictable perturbations enhance the feedback postural control reflected as the postural stability at step contact.

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Functional Cortical Connectivity Related to Postural Control in Patients Six Weeks After Anterior Cruciate Ligament Reconstruction

Whereas initial findings have already identified cortical patterns accompanying proprioceptive deficiencies in patients after anterior cruciate ligament reconstruction (ACLR), little is known about compensatory sensorimotor mechanisms for re-establishing postural control. Therefore, the aim of the present study was to explore leg dependent patterns of cortical contributions to postural control in patients 6 weeks following ACLR. A total of 12 patients after ACLR (25.1 ± 3.2 years, 178.1 ± 9.7 cm, 77.5 ± 14.4 kg) and another 12 gender, age, and activity matched healthy controls participated in this study. All subjects performed 10 × 30 s. single leg stances on each leg, equipped with 64-channel mobile electroencephalography (EEG). Postural stability was quantified by area of sway and sway velocity. Estimations of the weighted phase lag index were conducted as a cortical measure of functional connectivity. The findings showed significant group × leg interactions for increased functional connectivity in the anterior cruciate ligament (ACL) injured leg, predominantly including fronto−parietal [F(1, 22) = 8.41, p ≤ 0.008, η2 = 0.28], fronto−occipital [F(1, 22) = 4.43, p ≤ 0.047, η2 = 0.17], parieto−motor [F(1, 22) = 10.30, p ≤ 0.004, η2 = 0.32], occipito−motor [F(1, 22) = 5.21, p ≤ 0.032, η2 = 0.19], and occipito−parietal [F(1, 22) = 4.60, p ≤ 0.043, η2 = 0.17] intra−hemispherical connections in the contralateral hemisphere and occipito−motor [F(1, 22) = 7.33, p ≤ 0.013, η2 = 0.25] on the ipsilateral hemisphere to the injured leg. Higher functional connectivity in patients after ACLR, attained by increased emphasis of functional connections incorporating the somatosensory and visual areas, may serve as a compensatory mechanism to control postural stability of the injured leg in the early phase of rehabilitation. These preliminary results may help to develop new neurophysiological assessments for detecting functional deficiencies after ACLR in the future.

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Intrinsic Network Brain Dysfunction Correlates With Temporal Complexity in Generalized Anxiety Disorder and Panic Disorder

Background: Generalized anxiety disorder (GAD) and panic disorder (PD) are the two severe subtypes of anxiety disorders (ADs), which are similar in clinical manifestation, pathogenesis, and treatment. Earlier studies have taken a whole-brain perspective on GAD and PD in the assumption that intrinsic fluctuations are static throughout the entire scan. However, it has recently been suggested that the dynamic alternations in functional connectivity (FC) may reflect the changes in macroscopic neural activity patterns underlying the critical aspects of cognition and behavior, and thus may act as biomarkers of disease.

Methods: In this study, the resting-state functional MRI (fMRI) data were collected from 26 patients with GAD, 22 patients with PD, and 26 healthy controls (HCs). We investigated dynamic functional connectivity (DFC) by using the group spatial independent component analysis, a sliding window approach, and the k-means clustering methods. For group comparisons, the temporal properties of DFC states were analyzed statistically.

Results: The dynamic analysis demonstrated two discrete connectivity “States” across the entire group, namely, a more segregated State I and a strongly integrated State II. Compared with HCs, patients with both GAD and PD spent more time in the weakly within-network State I, while performing fewer transitions and dwelling shorter in the integrated State II. Additionally, the analysis of DFC strength showed that connections associated with ADs were identified including the regions that belonged to default mode (DM), executive control (EC), and salience (SA) networks, especially the connections between SA and DM networks. However, no significant difference was found between the GAD and PD groups in temporal features and connection strength.

Conclusions: More common but less specific alterations were detected in the GAD and PD groups, which implied that they might have similar state-dependent neurophysiological mechanisms and, in addition, could hopefully help us better understand their abnormal affective and cognitive performances in the clinic.

in Frontiers in Human Neuroscience on July 15, 2021 12:00 AM.

• #### Multiple Sources of Cholinergic Input to the Superior Olivary Complex

The superior olivary complex (SOC) is a major computation center in the brainstem auditory system. Despite previous reports of high expression levels of cholinergic receptors in the SOC, few studies have addressed the functional role of acetylcholine in the region. The source of the cholinergic innervation is unknown for all but one of the nuclei of the SOC, limiting our understanding of cholinergic modulation. The medial nucleus of the trapezoid body, a key inhibitory link in monaural and binaural circuits, receives cholinergic input from other SOC nuclei and also from the pontomesencephalic tegmentum. Here, we investigate whether these same regions are sources of cholinergic input to other SOC nuclei. We also investigate whether individual cholinergic cells can send collateral projections bilaterally (i.e., into both SOCs), as has been shown at other levels of the subcortical auditory system. We injected retrograde tract tracers into the SOC in gerbils, then identified retrogradely-labeled cells that were also immunolabeled for choline acetyltransferase, a marker for cholinergic cells. We found that both the SOC and the pontomesencephalic tegmentum (PMT) send cholinergic projections into the SOC, and these projections appear to innervate all major SOC nuclei. We also observed a small cholinergic projection into the SOC from the lateral paragigantocellular nucleus of the reticular formation. These various sources likely serve different functions; e.g., the PMT has been associated with things such as arousal and sensory gating whereas the SOC may provide feedback more closely tuned to specific auditory stimuli. Further, individual cholinergic neurons in each of these regions can send branching projections into both SOCs. Such projections present an opportunity for cholinergic modulation to be coordinated across the auditory brainstem.

in Frontiers in Neural Circuits on July 15, 2021 12:00 AM.

• #### Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions

Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a critically understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### A Temporal Activity of CA1 Neurons Underlying Short-Term Memory for Social Recognition Altered in PTEN Mouse Models of Autism Spectrum Disorder

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research

Over the past decades, microbiome research has evolved rapidly and became a hot topic in basic, preclinical and clinical research, for the pharmaceutical industry and for the general public. With the help of new high-throughput sequencing technologies tremendous progress has been made in the characterization of host-microbiota interactions identifying the microbiome as a major factor shaping mammalian physiology. This development also led to the discovery of the gut-brain axis as the crucial connection between gut microbiota and the nervous system. Consequently, a rapidly growing body of evidence emerged suggesting that the commensal gut microbiota plays a vital role in brain physiology. Moreover, it became evident that the communication along this microbiota-gut-brain axis is bidirectional and primarily mediated by biologically active microbial molecules and metabolites. Further, intestinal dysbiosis leading to changes in the bidirectional relationship between gut microbiota and the nervous system was linked to the pathogenesis of several psychiatric and neurological disorders. Here, we discuss the impact of the gut microbiota on the brain in health and disease, specifically as regards to neuronal homeostasis, development and normal aging as well as their role in neurological diseases of the highest socioeconomic burden such as Alzheimer’s disease and stroke. Subsequently, we utilize Alzheimer’s disease and stroke to examine the translational research value of current mouse models in the spotlight of microbiome research. Finally, we propose future strategies on how we could conduct translational microbiome research in the field of neuroscience that may lead to the identification of novel treatments for human diseases.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### Ferroptosis and Its Role in Epilepsy

Epilepsy is one of the most common symptoms of many neurological disorders. The typical excessive, synchronous and aberrant firing of neurons originating from different cerebral areas cause spontaneous recurrent epileptic seizures. Prolonged epilepsy can lead to neuronal damage and cell death. The mechanisms underlying epileptic pathogenesis and neuronal death remain unclear. Ferroptosis is a newly defined form of regulated cell death that is characterized by the overload of intracellular iron ions, leading to the accumulation of lethal lipid-based reactive oxygen species (ROS). To date, studies have mainly focused on its role in tumors and various neurological disorders, including epilepsy. Current research shows that inhibition of ferroptosis is likely to be an effective therapeutic approach for epilepsy. In this review, we outline the pathogenesis of ferroptosis, regulatory mechanisms of ferroptosis, related regulatory molecules, and their effects on epilepsy, providing a new direction for discovering new therapeutic targets in epilepsy.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### Astrocytic Ca2+ Signaling in Epilepsy

Epilepsy is one of the most common neurological disorders – estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### A Novel Small Molecule Neurotrophin-3 Analogue Promotes Inner Ear Neurite Outgrowth and Synaptogenesis In vitro

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.

in Frontiers in Cellular Neuroscience on July 15, 2021 12:00 AM.

• #### Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model.

Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls.

Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced.

Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency.

in Frontiers in Ageing Neuroscience on July 15, 2021 12:00 AM.

• #### Management Based on Multimodal Brain Monitoring May Improve Functional Connectivity and Post-operative Neurocognition in Elderly Patients Undergoing Spinal Surgery

Perioperative neurocognitive disorder (PND) is a common condition in elderly patients undergoing surgery. Sedation, analgesia, regional cerebral oxygen saturation (rSO2), and body temperature are known to be associated with PND, but few studies have examined the contribution of these factors combined in detail. This prospective, randomized, controlled, double-blinded study investigated whether anesthesia management based on multimodal brain monitoring—an anesthesia management algorithm designed by our group—could improve the post-operative cognitive function and brain functional connectivity (FC) in elderly patients undergoing elective spinal surgery with general anesthesia. The patients (aged ≥65 years) were randomized into two groups [control (Group C), n = 12 and intervention (Group I), n = 14]. Patients in Group I were managed with multimodal brain monitoring (patient state index, spectral edge frequency, analgesia nociception index, rSO2, and temperature), and those in Group C were managed with routine anesthesia management. All patients were pre- and post-operatively evaluated (7 days after surgery) with the Montreal Cognitive Assessment (MoCA). Amplitude of low-frequency fluctuation (ALFF) and FC were analyzed after resting-state functional MRI. Serum C-reactive protein (CRP) and lipopolysaccharide levels were measured, and the correlation between FC and changes in inflammatory marker levels was analyzed. Mean post-operative MoCA score was higher in Group I (24.80 ± 2.09) than in Group C (22.56 ± 2.24) (p = 0.04), with no difference in PND incidence between groups (28.57 vs. 16.67%; p = 0.47). Group I also showed significantly increased ALFF values in several brain regions after surgery (p < 0.05), and FC between the left hippocampus and left orbital inferior frontal gyrus (FG), left middle FG, left superior temporal gyrus, and left precentral gyrus was enhanced (p < 0.05), which was negatively correlated with the change in serum CRP (pre vs. post-intervention) (R = −0.58, p = 0.01). These results suggest that management of elderly patients undergoing surgery by multimodal brain monitoring may improve post-operative neurocognition and FC by reducing systemic inflammation.

Clinical Trial Registration:http://www.chictr.org.cn/index.aspx, identifier: ChiCTR1900028024.

in Frontiers in Ageing Neuroscience on July 15, 2021 12:00 AM.

• #### Research Progress on the Mechanism of Mitochondrial Autophagy in Cerebral Stroke

Mitochondrial autophagy is an early defense and protection process that selectively clears dysfunctional or excessive mitochondria through a distinctive mechanism to maintain intracellular homeostasis. Mitochondrial dysfunction during cerebral stroke involves metabolic disbalance, oxidative stress, apoptosis, endoplasmic reticulum stress, and abnormal mitochondrial autophagy. This article reviews the research progress on the mechanism of mitochondrial autophagy in ischemic stroke to provide a theoretical basis for further research on mitochondrial autophagy and the treatment of ischemic stroke.

in Frontiers in Ageing Neuroscience on July 15, 2021 12:00 AM.

• #### RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease

Introduction

Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease.

Patients and Methods

The present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded.

Results

Four hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant.

Conclusion

Our findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.

in Frontiers in Ageing Neuroscience on July 15, 2021 12:00 AM.

• #### Cryo-EM structures of the caspase activated protein XKR9 involved in apoptotic lipid scrambling

The exposure of the negatively charged lipid phosphatidylserine on the cell-surface, catalyzed by lipid scramblases, is an important signal for the clearance of apoptotic cells by macrophages. The protein XKR9 is a member of a conserved family that has been associated with apoptotic lipid scrambling. Here, we describe structures of full-length and caspase-treated XKR9 from Rattus norvegicus in complex with a synthetic nanobody determined by cryo-electron microscopy. The 43 kDa monomeric membrane protein can be divided into two structurally related repeats, each containing four membrane-spanning segments and a helix that is partly inserted into the lipid bilayer. In the full-length protein, the C-terminus interacts with a hydrophobic pocket located at the intracellular side acting as an inhibitor of protein function. Cleavage by caspase-3 at a specific site releases 16 residues of the C-terminus thus making the pocket accessible to the cytoplasm. Collectively, the work has revealed the unknown architecture of the XKR family and has provided initial insight into its activation by caspases.

in eLife on July 15, 2021 12:00 AM.

• #### A plant-like mechanism coupling m6A reading to polyadenylation safeguards transcriptome integrity and developmental gene partitioning in Toxoplasma

Correct 3'end processing of mRNAs is one of the regulatory cornerstones of gene expression. In a parasite that must adapt to the regulatory requirements of its multi-host life style, there is a need to adopt additional means to partition the distinct transcriptional signatures of the closely and tandemly-arranged stage specific genes. In this study, we report our findings in T. gondii of an m6A-dependent 3'end polyadenylation serving as a transcriptional barrier at these loci. We identify the core polyadenylation complex within T. gondii and establish CPSF4 as a reader for m6A-modified mRNAs, via a YTH domain within its C-terminus, a feature which is shared with plants. We bring evidence of the specificity of this interaction both biochemically, and by determining the crystal structure at high resolution of the T. gondii CPSF4-YTH in complex with an m6A modified RNA. We show that the loss of m6A, both at the level of its deposition or its recognition was associated with an increase in aberrantly elongated chimeric mRNAs emanating from impaired transcriptional termination, a phenotype previously noticed in the plant model Arabidopsis thaliana. Nanopore direct RNA sequencing shows the occurrence of transcriptional read-through breaching into downstream repressed stage-specific genes, in the absence of either CPSF4 or the m6A RNA methylase components in both T. gondii and A. thaliana. Taken together, our results shed light on an essential regulatory mechanism coupling the pathways of m6A metabolism directly to the cleavage and polyadenylation processes, one that interestingly seem to serve, in both T. gondii and A. thaliana, as a guardian against aberrant transcriptional read-throughs.

in eLife on July 15, 2021 12:00 AM.

• #### Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

in eLife on July 15, 2021 12:00 AM.

• #### Functional interdependence of the actin nucleator Cobl and Cobl-like in dendritic arbor development

Local actin filament formation is indispensable for development of the dendritic arbor of neurons. We show that, surprisingly, the action of single actin filament-promoting factors was insufficient for powering dendritogenesis. Instead, this required the actin nucleator Cobl and its only evolutionary distant ancestor Cobl-like acting interdependently. This coordination between Cobl-like and Cobl was achieved by physical linkage by syndapins. Syndapin I formed nanodomains at convex plasma membrane areas at the base of protrusive structures and interacted with three motifs in Cobl-like, one of which was Ca2+/calmodulin-regulated. Consistently, syndapin I, Cobl-like’s newly identified N terminal calmodulin-binding site and the single Ca2+/calmodulin-responsive syndapin-binding motif all were critical for Cobl-like’s functions. In dendritic arbor development, local Ca2+/CaM-controlled actin dynamics thus relies on regulated and physically coordinated interactions of different F-actin formation-promoting factors and only together they have the power to bring about the sophisticated neuronal morphologies required for neuronal network formation in mammals.

in eLife on July 15, 2021 12:00 AM.

• #### Rare occurrence of severe blindness and deafness in Friedreich ataxia: a case report

Friedreich ataxia is the most frequent hereditary ataxia worldwide. Subclinical visual and auditory involvement has been recognized in these patients, with co-occurrence of severe blindness and deafness being ...

in Cerebellum and Ataxias on July 15, 2021 12:00 AM.

• #### Toll‐like receptor 10 controls TLR2‐induced cytokine production in monocytes from patients with Parkinson's disease

Parkinson's disease (PD) patients present higher frequency of intermediate monocytes expressing TLR10. The expression of TLR10 on monocytes can protect against PD by controlling TLR2‐induced cytokine production. Abstract Peripheral inflammation, particularly mediated by monocytes, can cause neuroinflammation in Parkinson's disease (PD). We investigated the mechanism of TLR2‐induced cytokine impairment in peripheral monocytes from PD patients and the association between the presence of CD14+TLR10+ monocytes and PD severity. Peripheral blood mononuclear cells from PD patients and healthy individuals were evaluated for TLR expression on monocyte subsets (CD14 and CD16 expression) using flow cytometry. Moreover, cytokines were evaluated using flow cytometry after stimulation with Pam3Cys (TLR2/TLR1 agonist) in the absence or presence of neutralizing antibodies to TLR10. The severity of PD was assessed using the unified PD rating scale (UPDRS) and motor activity, anxiety (BAI), depression (BDI), and fatigue (PD Fatigue Scale‐16) scales. The frequency of CD14+TLR10+ monocytes and expression intensity of TLR2 and TLR10 were higher in patients with PD than healthy individuals. The frequency of intermediate monocytes (CD14++CD16+) was not significantly increased in patients with PD, but was the main monocyte subset expressing TLR10. The TLR2/TLR1‐impaired cytokine production (IL‐6, TNFα, IL‐8, and IL‐10) in PD patients was reversed by neutralizing TLR10. The high frequency of total CD14+TLR10+ monocytes was associated with a reduction in the severity of PD according to the evaluation of motor and nonmotor symptoms. Peripheral monocytes from patients with PD showed phenotypic and functional alterations. The expression of TLR10 on monocytes can protect against PD by controlling TLR2‐induced cytokine production. Furthermore, data suggested that a low frequency of CD14+TLR10+ monocytes indicates the severity of PD. The results identified new opportunities for the development of novel PD neuroprotective therapies.

in Journal of Neuroscience Research on July 14, 2021 06:27 PM.

• #### Genome‐Wide Association Study Identifies Risk Loci for Cluster Headache

Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome‐wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene‐set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10−17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10−17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10−8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10−8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome‐wide significant associations supporting a genetic predisposition in cluster headache in a genome‐wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021

in Annals of Neurology on July 14, 2021 04:41 PM.

• #### RETRACTION

Annals of Neurology, EarlyView.

in Annals of Neurology on July 14, 2021 03:05 PM.

• #### COVIDomic: A multi-modal cloud-based platform for identification of risk factors associated with COVID-19 severity

by Vladimir Naumov, Evgeny Putin, Stefan Pushkov, Ekaterina Kozlova, Konstantin Romantsov, Alexander Kalashnikov, Fedor Galkin, Nina Tihonova, Anastasia Shneyderman, Egor Galkin, Arsenii Zinkevich, Stephanie M. Cope, Ramanathan Sethuraman, Tudor I. Oprea, Alexander T. Pearson, Savas Tay, Nishant Agrawal, Alexey Dubovenko, Quentin Vanhaelen, Ivan Ozerov, Alex Aliper, Evgeny Izumchenko, Alex Zhavoronkov

Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in December 2019 in Wuhan, China. It was quickly established that both the symptoms and the disease severity may vary from one case to another and several strains of SARS-CoV-2 have been identified. To gain a better understanding of the wide variety of SARS-CoV-2 strains and their associated symptoms, thousands of SARS-CoV-2 genomes have been sequenced in dozens of countries. In this article, we introduce COVIDomic, a multi-omics online platform designed to facilitate the analysis and interpretation of the large amount of health data collected from patients with COVID-19. The COVIDomic platform provides a comprehensive set of bioinformatic tools for the multi-modal metatranscriptomic data analysis of COVID-19 patients to determine the origin of the coronavirus strain and the expected severity of the disease. An integrative analytical workflow, which includes microbial pathogens community analysis, COVID-19 genetic epidemiology and patient stratification, allows to analyze the presence of the most common microbial organisms, their antibiotic resistance, the severity of the infection and the set of the most probable geographical locations from which the studied strain could have originated. The online platform integrates a user friendly interface which allows easy visualization of the results. We envision this tool will not only have immediate implications for management of the ongoing COVID-19 pandemic, but will also improve our readiness to respond to other infectious outbreaks.

in PLoS Computational Biology on July 14, 2021 02:00 PM.

• #### On the influence of prior information evaluated by fully Bayesian criteria in a personalized whole-brain model of epilepsy spread

by Meysam Hashemi, Anirudh N. Vattikonda, Viktor Sip, Sandra Diaz-Pier, Alexander Peyser, Huifang Wang, Maxime Guye, Fabrice Bartolomei, Marmaduke M. Woodman, Viktor K. Jirsa

Individualized anatomical information has been used as prior knowledge in Bayesian inference paradigms of whole-brain network models. However, the actual sensitivity to such personalized information in priors is still unknown. In this study, we introduce the use of fully Bayesian information criteria and leave-one-out cross-validation technique on the subject-specific information to assess different epileptogenicity hypotheses regarding the location of pathological brain areas based on a priori knowledge from dynamical system properties. The Bayesian Virtual Epileptic Patient (BVEP) model, which relies on the fusion of structural data of individuals, a generative model of epileptiform discharges, and a self-tuning Monte Carlo sampling algorithm, is used to infer the spatial map of epileptogenicity across different brain areas. Our results indicate that measuring the out-of-sample prediction accuracy of the BVEP model with informative priors enables reliable and efficient evaluation of potential hypotheses regarding the degree of epileptogenicity across different brain regions. In contrast, while using uninformative priors, the information criteria are unable to provide strong evidence about the epileptogenicity of brain areas. We also show that the fully Bayesian criteria correctly assess different hypotheses about both structural and functional components of whole-brain models that differ across individuals. The fully Bayesian information-theory based approach used in this study suggests a patient-specific strategy for epileptogenicity hypothesis testing in generative brain network models of epilepsy to improve surgical outcomes.

in PLoS Computational Biology on July 14, 2021 02:00 PM.

• #### Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

by Debojyoti Biswas, Peter N. Devreotes, Pablo A. Iglesias

During the last decade, a consensus has emerged that the stochastic triggering of an excitable system drives pseudopod formation and subsequent migration of amoeboid cells. The presence of chemoattractant stimuli alters the threshold for triggering this activity and can bias the direction of migration. Though noise plays an important role in these behaviors, mathematical models have typically ignored its origin and merely introduced it as an external signal into a series of reaction-diffusion equations. Here we consider a more realistic description based on a reaction-diffusion master equation formalism to implement these networks. In this scheme, noise arises naturally from a stochastic description of the various reaction and diffusion terms. Working on a three-dimensional geometry in which separate compartments are divided into a tetrahedral mesh, we implement a modular description of the system, consisting of G-protein coupled receptor signaling (GPCR), a local excitation-global inhibition mechanism (LEGI), and signal transduction excitable network (STEN). Our models implement detailed biochemical descriptions whenever this information is available, such as in the GPCR and G-protein interactions. In contrast, where the biochemical entities are less certain, such as the LEGI mechanism, we consider various possible schemes and highlight the differences between them. Our stimulations show that even when the LEGI mechanism displays perfect adaptation in terms of the mean level of proteins, the variance shows a dose-dependence. This differs between the various models considered, suggesting a possible means for determining experimentally among the various potential networks. Overall, our simulations recreate temporal and spatial patterns observed experimentally in both wild-type and perturbed cells, providing further evidence for the excitable system paradigm. Moreover, because of the overall importance and ubiquity of the modules we consider, including GPCR signaling and adaptation, our results will be of interest beyond the field of directed migration.

in PLoS Computational Biology on July 14, 2021 02:00 PM.

• #### MycoRed: Betalain pigments enable in vivo real-time visualisation of arbuscular mycorrhizal colonisation

by Alfonso Timoneda, Temur Yunusov, Clement Quan, Aleksandr Gavrin, Samuel F. Brockington, Sebastian Schornack

Arbuscular mycorrhiza (AM) are mutualistic interactions formed between soil fungi and plant roots. AM symbiosis is a fundamental and widespread trait in plants with the potential to sustainably enhance future crop yields. However, improving AM fungal association in crop species requires a fundamental understanding of host colonisation dynamics across varying agronomic and ecological contexts. To this end, we demonstrate the use of betalain pigments as in vivo visual markers for the occurrence and distribution of AM fungal colonisation by Rhizophagus irregularis in Medicago truncatula and Nicotiana benthamiana roots. Using established and novel AM-responsive promoters, we assembled multigene reporter constructs that enable the AM-controlled expression of the core betalain synthesis genes. We show that betalain colouration is specifically induced in root tissues and cells where fungal colonisation has occurred. In a rhizotron setup, we also demonstrate that betalain staining allows for the noninvasive tracing of fungal colonisation along the root system over time. We present MycoRed, a useful innovative method that will expand and complement currently used fungal visualisation techniques to advance knowledge in the field of AM symbiosis.

in PLoS Biology on July 14, 2021 02:00 PM.

• #### Diversity in neuroscience education: A perspective from a Historically Black institution

Abstract The events of 2020, including the pandemic which highlighted the extent of health disparities in the United States, combined with the Black Lives Matter protests, have focused public attention on the systemic inequities that continue to afflict our nation. Publicly available data from the National Center for Education Statistics show that our discipline of neuroscience shows the same types of disparities, particularly for African‐American students. I have drawn on data from the Integrated Postsecondary Education Data Survey of U.S. colleges and universities to show that while the number of graduates from neuroscience undergraduate and graduate degree programs has grown dramatically in this century, only a small percentage of those graduates are African American, and the numbers are growing very slowly. I also present data on the neuroscience PhD program at my institution, Delaware State University, the only Historically Black University in the United States to offer a PhD in neuroscience. Because a high percentage of our students and graduates are African American, our small, young program has the potential for great impact in diversifying our discipline of neuroscience. While elite colleges and research‐intensive universities have been engaged for decades in efforts to increase diversity in their academic programs, change is slow, and large inequities remain. With Delaware State University's neuroscience PhD program as an example, I hope to convince readers that it is time for our nation to recognize the institutions that are best positioned to serve students from communities of color, and direct resources to support their growth and success.

in Journal of Neuroscience Research on July 14, 2021 12:31 PM.

• #### Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair

Abstract Astrocytes play essential roles in development, homeostasis, injury, and repair of the central nervous system (CNS). Their development is tightly regulated by distinct spatial and temporal cues during embryogenesis and into adulthood throughout the CNS. Astrocytes have several important responsibilities such as regulating blood flow and permeability of the blood‐CNS barrier, glucose metabolism and storage, synapse formation and function, and axon myelination. In CNS pathologies, astrocytes also play critical parts in both injury and repair mechanisms. Upon injury, they undergo a robust phenotypic shift known as “reactive astrogliosis,” which results in both constructive and deleterious outcomes. Astrocyte activation and migration at the site of injury provides an early defense mechanism to minimize the extent of injury by enveloping the lesion area. However, astrogliosis also contributes to the inhibitory microenvironment of CNS injury and potentiate secondary injury mechanisms, such as inflammation, oxidative stress, and glutamate excitotoxicity, which facilitate neurodegeneration in CNS pathologies. Intriguingly, reactive astrocytes are increasingly a focus in current therapeutic strategies as their activation can be modulated toward a neuroprotective and reparative phenotype. This review will discuss recent advancements in knowledge regarding the development and role of astrocytes in the healthy and pathological CNS. We will also review how astrocytes have been genetically modified to optimize their reparative potential after injury, and how they may be transdifferentiated into neurons and oligodendrocytes to promote repair after CNS injury and neurodegeneration.

in Journal of Neuroscience Research on July 14, 2021 12:10 PM.

• #### The distribution, number and certain neurochemical identities of infracortical white matter neurons in the brains of a southern lesser galago, a black‐capped squirrel monkey and a crested macaque

Immunohistochemical staining for neuronal nuclear marker (NeuN) reveals the subcortical white matter neurons, or white matter interstitial cells (WMICs), deep to the grey matter of the parietal neocortex in the brain of a squirrel monkey. GM – grey matter, WM – white matter, dashed line indicates the approximate GM/WM border. Abstract In the current study we examined the number, distribution, and aspects of the neurochemical identities of infracortical white matter neurons, also termed white matter interstitial cells (WMICs), in the brains of a southern lesser galago (Galago moholi), a black‐capped squirrel monkey (Saimiri boliviensis boliviensis) and a crested macaque (Macaca nigra). Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most dense close to inner cortical border, decreasing in density with depth in the white matter. Stereological analysis of NeuN‐immunopositive cells revealed estimates of approximately 1.1 million, 10.8 million, and 37.7 million WMICs within the infracortical white matter of the galago, squirrel monkey and crested macaque, respectively. The total numbers of WMICs form a distinct negative allometric relationship with brain mass and white matter volume when examined in a larger sample of primates where similar measures have been obtained. In all three primates studied, the highest densities of WMICs were in the white matter of the frontal lobe, with the occipital lobe having the lowest. Immunostaining revealed significant subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS) and calretinin, with very few WMICs containing parvalbumin, and none containing calbindin. The nNOS and calretinin immunopositive WMICs, represent approximately 21% of the total WMIC population; however, variances in the proportions of these neurochemical phenotypes were noted. Our results indicate that both the squirrel monkey and crested macaque might be informative animal models for the study of WMICs in neurodegenerative and psychiatric disorders in humans. This article is protected by copyright. All rights reserved.

in Journal of Comparative Neurology on July 14, 2021 10:07 AM.

• #### Anatomy and function of retinorecipient arborization fields in zebrafish

Abstract In 1994, Burrill and Easter described the retinal projections in embryonic and larval zebrafish, introducing the term “arborization fields” (AFs) for the retinorecipient areas. AFs were numbered from 1 to 10 according to their positions along the optic tract. With the exception of AF10 (neuropil of the optic tectum), annotations of AFs remained tentative. Here we offer an update on the likely identities and functions of zebrafish AFs after successfully matching classical neuroanatomy to the digital Max Planck Zebrafish Brain Atlas. In our system, individual AFs are neuropil areas associated with the following nuclei: AF1 with the suprachiasmatic nucleus; AF2 with the posterior parvocellular preoptic nucleus; AF3 and AF4 with the ventrolateral thalamic nucleus; AF4 with the anterior and intermediate thalamic nuclei; AF5 with the dorsal accessory optic nucleus; AF7 with the parvocellular superficial pretectal nucleus; AF8 with the central pretectal nucleus; and AF9d and AF9v with the dorsal and ventral periventricular pretectal nuclei. AF6 is probably part of the accessory optic system. Imaging, ablation, and activation experiments showed contributions of AF5 and potentially AF6 to optokinetic and optomotor reflexes, AF4 to phototaxis, and AF7 to prey detection. AF6, AF8 and AF9v respond to dimming, and AF4 and AF9d to brightening. While few annotations remain tentative, it is apparent that the larval zebrafish visual system is anatomically and functionally continuous with its adult successor and fits the general cyprinid pattern. This study illustrates the synergy created by merging classical neuroanatomy with a cellular‐resolution digital brain atlas resource and functional imaging in larval zebrafish.

in Journal of Comparative Neurology on July 14, 2021 07:00 AM.

• #### Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headaches

Objective Identifying common genetic variants that confer genetic risk for cluster headache. Methods We conducted a case–control study in the Dutch Leiden University Cluster headache neuro‐Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord‐Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell‐derived RNA‐sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10−8), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33–1.72 near RP11‐815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene‐based mapping yielded ASZ1 as possible fifth locus. RNA‐sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headaches with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021

in Annals of Neurology on July 14, 2021 07:00 AM.

• #### Sex Differences in the Ventral Tegmental Area and Nucleus Accumbens Proteome at Baseline and Following Nicotine Exposure

Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging, and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. In C3H/HeJ mice, similar numbers of proteins were differentially regulated between sexes at baseline compared with within each sex after sub-chronic nicotine administration. In C57BL/6J mice, there were significantly greater numbers of proteins differentially regulated between sexes at baseline compared with within each sex after chronic nicotine administration and withdrawal. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.

in Frontiers in Molecular Neuroscience on July 14, 2021 12:00 AM.

• #### The Effects of Repetitive Transcranial Magnetic Stimulation on Cognitive Impairment and the Brain Lipidome in a Cuprizone-Induced Mouse Model of Demyelination

The protective effects of repetitive transcranial magnetic stimulation (rTMS) on myelin integrity have been extensively studied, and growing evidence suggests that rTMS is beneficial in improving cognitive functions and promoting myelin repair. However, the association between cognitive improvement due to rTMS and changes in brain lipids remains elusive. In this study, we used the Y-maze and 3-chamber tests, as well as a mass spectrometry-based lipidomic approach in a CPZ-induced demyelination model in mice to assess the protective effects of rTMS on cuprizone (CPZ)-induced cognitive impairment and evaluate changes in lipid composition in the hippocampus, prefrontal cortex, and striatum. We found that CPZ induced cognitive impairment and remarkable changes in brain lipids, specifically in glycerophospholipids. Moreover, the changes in lipids within the prefrontal cortex were more extensive, compared to those observed in the hippocampus and striatum. Notably, rTMS ameliorated CPZ-induced cognitive impairment and partially normalized CPZ-induced lipid changes. Taken together, our data suggest that rTMS may reverse cognitive behavioral changes caused by CPZ-induced demyelination by modulating the brain lipidome, providing new insights into the therapeutic mechanism of rTMS.

in Frontiers in Neuroscience: Neurogenesis on July 14, 2021 12:00 AM.

• #### Mapping Knowledge Structure and Research Frontiers of Ultrasound-Induced Blood-Brain Barrier Opening: A Scientometric Study

Background: Among the effective approaches developed for blood-brain barrier (BBB) opening, ultrasound is recognized as a non-invasive technique that can induce localized BBB opening transiently and repeatedly. This technique has aroused broad attention from researchers worldwide, and numerous articles have been published recently. However, no existing study has systematically examined this field from a scientometric perspective. The aim of this study was to summarize the knowledge structure and identify emerging trends and potential hotspots in this field.

Methods: Publications related to ultrasound-induced BBB opening published from 1998 to 2020 were retrieved from Web of Science Core Collection. The search strategies were as follows: topic: (“blood brain barrier” OR “BBB”) AND topic: (ultrasound OR ultrason* OR acoustic* OR sonopora*). The document type was set to articles or reviews with language restriction to English. Three different analysis tools including one online platform, VOS viewer1.6.16, and CiteSpace V5.7.R2 software were used to conduct this scientometric study.

Results: A total of 1,201 valid records were included in the final analysis. The majority of scientific publication was produced by authors from North America, Eastern Asia, and Western Europe. Ultrasound in Medicine and Biology was the most prominent journal. The USA, China, and Canada were the most productive countries. Hynynen K, and Mcdannold N were key researchers with considerable academic influence. According to analysis of keywords, four main research directions were identified: cluster 1 (microbubbles study), cluster 2 (management of intracranial tumors), cluster 3 (ultrasound parameters and mechanisms study), and cluster 4 (treatment of neurodegenerative diseases). The current research hotspot has shifted from the basic research of ultrasound and microbubbles to management of intracranial tumors and neurodegenerative diseases. Burst detection analysis showed that Parkinson's disease, doxorubicin, gold nanoparticle, glioblastoma, gene therapy, and Alzheimer's disease may continue to be the research frontiers.

Conclusion: Ultrasound-induced BBB opening research is in a period of robust development. This study is a starting point, providing a comprehensive overview, development landscape, and future opportunities of this technology, which standout as a useful reference for researchers and decision makers interested in this area.

in Frontiers in Neuroscience: Neurodegeneration on July 14, 2021 12:00 AM.

• #### Changes in Resting-State Spontaneous Brain Activity in Patients With Allergic Rhinitis: A Pilot Neuroimaging Study

Background

Allergic rhinitis (AR) is an inflammatory disorder of the nose caused by immunoglobulin E (IgE)-mediated immune response to allergens. Apart from the typical symptoms of sneezing, itching, rhinorrhea, and nasal congestion, behavioral complications were also reported to be associated with the progression of AR, such as cognitive deficits, mood changes, memory decline, attention deficiency, poor school performance, anxiety, and depression. Recent human studies have suggested that alterations in brain function caused by allergen exposure may precipitate high levels of anxiety and emotional reactivity in asthma patients. But until now, there is no direct evidence of the relationship between brain activity and allergic rhinitis.

Methods

Resting-state functional magnetic resonance imaging (rs-fMRI) was used to excavate whether there remain functional changes of brain activity in AR patients. We measured the amplitude of low-frequency fluctuation (ALFF) and the z conversion of ALFF (zALFF) in 20 patients with AR and 20 age- and sex-matched healthy controls (HCs) using the rs-fMRI data.

Results

Compared with healthy controls, AR patients exhibited lower ALFF values in the precuneus (PCUN) and higher ALFF values in the anterior cingulate cortex (ACC). The ALFF values of these features were significantly correlated with the visual analog scale (VAS) scores, the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, the subscales of RQLQ, and specific IgE, partly.

Conclusion

We found changes in resting-state spontaneous brain activity in AR patients with hypoactivity in the PCUN and hyperactivity of the ACC. The brain-related symptoms of AR might be another potential clinical intervention target for improving the life quality of AR patients. Further attention to brain activity is essential for a deeper understanding of AR.

in Frontiers in Neuroscience: Brain Imaging Methods on July 14, 2021 12:00 AM.

• #### Altered Topological Properties of Static/Dynamic Functional Networks and Cognitive Function After Radiotherapy for Nasopharyngeal Carcinoma Using Resting-State fMRI

Objectives

The purpose of this study was to (1) explore the changes in topological properties of static and dynamic brain functional networks after nasopharyngeal carcinoma (NPC) radiotherapy (RT) using rs-fMRI and graph theoretical analysis, (2) explore the correlation between cognitive function and changes in brain function, and (3) add to the understanding of the pathogenesis of radiation brain injury (RBI).

Methods

Fifty-four patients were divided into 3 groups according to time after RT: PT1 (0–6 months); PT2 (>6 to ≤12 months); and PT3 (>12 months). 29 normal controls (NCs) were included. The subjects’ topological properties were evaluated by graph-theoretic network analysis, the functional connectivity of static functional networks was calculated using network-based statistics, and the dynamic functional network matrix was subjected to cluster analysis. Finally, correlation analyses were conducted to explore the relationship between the altered network parameters and cognitive function.

Results

Assortativity, hierarchy, and network efficiency were significantly abnormal in the PT1 group compared with the NC or PT3 group. The small-world variance in the PT3 group was smaller than that in NCs. The Nodal ClustCoeff of Postcentral_R in the PT2 group was significantly smaller than that in PT3 and NC groups. Functional connectivities were significantly reduced in the patient groups. Most of the functional connectivities of the middle temporal gyrus (MTG) were shown to be significantly reduced in all three patient groups. Most of the functional connectivities of the insula showed significantly reduced in the PT1 and PT3 groups, and most of the functional connectivities in brain regions such as frontal and parietal lobes showed significantly reduced in the PT2 and PT3 groups. These abnormal functional connectivities were correlated with scores on multiple scales that primarily assessed memory, executive ability, and overall cognitive function. The frequency F of occurrence of various states in each subject differed significantly, and the interaction effect of group and state was significant.

Conclusion

The disruption of static and dynamic functional network stability, reduced network efficiency and reduced functional connectivity may be potential biomarkers of RBI. Our findings may provide new insights into the pathogenesis of RBI from the perspective of functional networks.

in Frontiers in Neuroscience: Brain Imaging Methods on July 14, 2021 12:00 AM.

• #### Study of Human Tacit Knowledge Based on Electroencephalogram Signal Characteristics

Tacit knowledge is the kind of knowledge that is difficult to transfer to another person by means of writing it down or verbalizing it. In the mineral grinding process, the proficiency of the operators depends on the tacit knowledge gained from their experience and training rather than on knowledge learned from a handbook. This article proposed a method combining the electroencephalogram (EEG) signals and the industrial process to detect the proficiency of the operators in the mineral grinding process to reveal the effect of tacit knowledge on the functional cortical connection. The functional brain networks of operators were established based on partial direct coherence and directed transfer function of EEG, and the multi-classifiers were used with the graph-theoretic indexes of the FBNs as input to distinguish the trained operators (Hps) from the non-trained operators (Lps). The results showed that the brain networks of Hps had a better connectivity than those of Lps (p < 0.01), and the accuracy of classification was up to 94.2%. Our studies confirm that based on the performance of EEG features and the combination of industrial operational operation and cognitive processes, the proficiency of the operators can be detected.

in Frontiers in Neuroscience: Neural Technology on July 14, 2021 12:00 AM.

• #### Dual-Threshold-Based Microstate Analysis on Characterizing Temporal Dynamics of Affective Process and Emotion Recognition From EEG Signals

Recently, emotion classification from electroencephalogram (EEG) data has attracted much attention. As EEG is an unsteady and rapidly changing voltage signal, the features extracted from EEG usually change dramatically, whereas emotion states change gradually. Most existing feature extraction approaches do not consider these differences between EEG and emotion. Microstate analysis could capture important spatio-temporal properties of EEG signals. At the same time, it could reduce the fast-changing EEG signals to a sequence of prototypical topographical maps. While microstate analysis has been widely used to study brain function, few studies have used this method to analyze how brain responds to emotional auditory stimuli. In this study, the authors proposed a novel feature extraction method based on EEG microstates for emotion recognition. Determining the optimal number of microstates automatically is a challenge for applying microstate analysis to emotion. This research proposed dual-threshold-based atomize and agglomerate hierarchical clustering (DTAAHC) to determine the optimal number of microstate classes automatically. By using the proposed method to model the temporal dynamics of auditory emotion process, we extracted microstate characteristics as novel temporospatial features to improve the performance of emotion recognition from EEG signals. We evaluated the proposed method on two datasets. For public music-evoked EEG Dataset for Emotion Analysis using Physiological signals, the microstate analysis identified 10 microstates which together explained around 86% of the data in global field power peaks. The accuracy of emotion recognition achieved 75.8% in valence and 77.1% in arousal using microstate sequence characteristics as features. Compared to previous studies, the proposed method outperformed the current feature sets. For the speech-evoked EEG dataset, the microstate analysis identified nine microstates which together explained around 85% of the data. The accuracy of emotion recognition achieved 74.2% in valence and 72.3% in arousal using microstate sequence characteristics as features. The experimental results indicated that microstate characteristics can effectively improve the performance of emotion recognition from EEG signals.

in Frontiers in Neuroscience: Neural Technology on July 14, 2021 12:00 AM.

• #### Synaptic Plasticity in Memristive Artificial Synapses and Their Robustness Against Noisy Inputs

Emerging brain-inspired neuromorphic computing paradigms require devices that can emulate the complete functionality of biological synapses upon different neuronal activities in order to process big data flows in an efficient and cognitive manner while being robust against any noisy input. The memristive device has been proposed as a promising candidate for emulating artificial synapses due to their complex multilevel and dynamical plastic behaviors. In this work, we exploit ultrastable analog BiFeO3 (BFO)-based memristive devices for experimentally demonstrating that BFO artificial synapses support various long-term plastic functions, i.e., spike timing-dependent plasticity (STDP), cycle number-dependent plasticity (CNDP), and spiking rate-dependent plasticity (SRDP). The study on the impact of electrical stimuli in terms of pulse width and amplitude on STDP behaviors shows that their learning windows possess a wide range of timescale configurability, which can be a function of applied waveform. Moreover, beyond SRDP, the systematical and comparative study on generalized frequency-dependent plasticity (FDP) is carried out, which reveals for the first time that the ratio modulation between pulse width and pulse interval time within one spike cycle can result in both synaptic potentiation and depression effect within the same firing frequency. The impact of intrinsic neuronal noise on the STDP function of a single BFO artificial synapse can be neglected because thermal noise is two orders of magnitude smaller than the writing voltage and because the cycle-to-cycle variation of the current–voltage characteristics of a single BFO artificial synapses is small. However, extrinsic voltage fluctuations, e.g., in neural networks, cause a noisy input into the artificial synapses of the neural network. Here, the impact of extrinsic neuronal noise on the STDP function of a single BFO artificial synapse is analyzed in order to understand the robustness of plastic behavior in memristive artificial synapses against extrinsic noisy input.

in Frontiers in Neuroscience: Neural Technology on July 14, 2021 12:00 AM.

• #### NIRS-ICA: A MATLAB Toolbox for Independent Component Analysis Applied in fNIRS Studies

Independent component analysis (ICA) is a multivariate approach that has been widely used in analyzing brain imaging data. In the field of functional near-infrared spectroscopy (fNIRS), its promising effectiveness has been shown in both removing noise and extracting neuronal activity-related sources. The application of ICA remains challenging due to its complexity in usage, and an easy-to-use toolbox dedicated to ICA processing is still lacking in the fNIRS community. In this study, we propose NIRS-ICA, an open-source MATLAB toolbox to ease the difficulty of ICA application for fNIRS studies. NIRS-ICA incorporates commonly used ICA algorithms for source separation, user-friendly GUI, and quantitative evaluation metrics assisting source selection, which facilitate both removing noise and extracting neuronal activity-related sources. The options used in the processing can also be reported easily, which promotes using ICA in a more reproducible way. The proposed toolbox is validated and demonstrated based on both simulative and real fNIRS datasets. We expect the release of the toolbox will extent the application for ICA in the fNIRS community.

in Frontiers in Neuroinformatics on July 14, 2021 12:00 AM.

• #### Brain-Computer Interfaces for Children With Complex Communication Needs and Limited Mobility: A Systematic Review

Brain-computer interfaces (BCIs) represent a new frontier in the effort to maximize the ability of individuals with profound motor impairments to interact and communicate. While much literature points to BCIs' promise as an alternative access pathway, there have historically been few applications involving children and young adults with severe physical disabilities. As research is emerging in this sphere, this article aims to evaluate the current state of translating BCIs to the pediatric population. A systematic review was conducted using the Scopus, PubMed, and Ovid Medline databases. Studies of children and adolescents that reported BCI performance published in English in peer-reviewed journals between 2008 and May 2020 were included. Twelve publications were identified, providing strong evidence for continued research in pediatric BCIs. Research evidence was generally at multiple case study or exploratory study level, with modest sample sizes. Seven studies focused on BCIs for communication and five on mobility. Articles were categorized and grouped based on type of measurement (i.e., non-invasive and invasive), and the type of brain signal (i.e., sensory evoked potentials or movement-related potentials). Strengths and limitations of studies were identified and used to provide requirements for clinical translation of pediatric BCIs. This systematic review presents the state-of-the-art of pediatric BCIs focused on developing advanced technology to support children and youth with communication disabilities or limited manual ability. Despite a few research studies addressing the application of BCIs for communication and mobility in children, results are encouraging and future works should focus on customizable pediatric access technologies based on brain activity.

in Frontiers in Human Neuroscience on July 14, 2021 12:00 AM.

• #### Neural Kinesthetic Contribution to Motor Imagery of Body Parts: Tongue, Hands, and Feet

Motor imagery (MI) is assimilated to a perception-action process, which is mentally represented. Although several models suggest that MI, and its equivalent motor execution, engage very similar brain areas, the mechanisms underlying MI and their associated components are still under investigation today. Using 22 Ag/AgCl EEG electrodes, 19 healthy participants (nine males and 10 females) with an average age of 25.8 years old (sd = 3.5 years) were required to imagine moving several parts of their body (i.e., first-person perspective) one by one: left and right hand, tongue, and feet. Network connectivity analysis based on graph theory, together with a correlational analysis, were performed on the data. The findings suggest evidence for motor and somesthetic neural synchronization and underline the role of the parietofrontal network for the tongue imagery task only. At both unilateral and bilateral cortical levels, only the tongue imagery task appears to be associated with motor and somatosensory representations, that is, kinesthetic representations, which might contribute to verbal actions. As such, the present findings suggest the idea that imagined tongue movements, involving segmentary kinesthetic actions, could be the prerequisite of language.

in Frontiers in Human Neuroscience on July 14, 2021 12:00 AM.

• #### Structural Features of the Human Connectome That Facilitate the Switching of Brain Dynamics via Noradrenergic Neuromodulation

The structural connectivity of human brain allows the coexistence of segregated and integrated states of activity. Neuromodulatory systems facilitate the transition between these functional states and recent computational studies have shown how an interplay between the noradrenergic and cholinergic systems define these transitions. However, there is still much to be known about the interaction between the structural connectivity and the effect of neuromodulation, and to what extent the connectome facilitates dynamic transitions. In this work, we use a whole brain model, based on the Jasen and Rit equations plus a human structural connectivity matrix, to find out which structural features of the human connectome network define the optimal neuromodulatory effects. We simulated the effect of the noradrenergic system as changes in filter gain, and studied its effects related to the global-, local-, and meso-scale features of the connectome. At the global-scale, we found that the ability of the network of transiting through a variety of dynamical states is disrupted by randomization of the connection weights. By simulating neuromodulation of partial subsets of nodes, we found that transitions between integrated and segregated states are more easily achieved when targeting nodes with greater connection strengths—local feature—or belonging to the rich club—meso-scale feature. Overall, our findings clarify how the network spatial features, at different levels, interact with neuromodulation to facilitate the switching between segregated and integrated brain states and to sustain a richer brain dynamics.

in Frontiers in Computational Neuroscience on July 14, 2021 12:00 AM.

• #### Quantitative Assessment of Stress Through EEG During a Virtual Reality Stress-Relax Session

Recent studies have addressed stress level classification via electroencephalography (EEG) and machine learning. These works typically use EEG-based features, like power spectral density (PSD), to develop stress classifiers. Nonetheless, these classifiers are usually limited to the discrimination of two (stress and no stress) or three (low, medium, and high) stress levels. In this study we propose an alternative for quantitative stress assessment based on EEG and regression algorithms. To this aim, we conducted a group of 23 participants (mean age 22.65 ± 5.48) over a stress-relax experience while monitoring their EEG. First, we stressed the participants via the Montreal imaging stress task (MIST), and then we led them through a 360-degree virtual reality (VR) relaxation experience. Throughout the session, the participants reported their self-perceived stress level (SPSL) via surveys. Subsequently, we extracted spectral features from the EEG of the participants and we developed individual models based on regression algorithms to predict their SPSL. We evaluated stress regression performance in terms of the mean squared percentage error (MSPE) and the correlation coefficient (R2). The results yielded from this evaluation (MSPE = 10.62 ± 2.12, R2 = 0.92 ± 0.02) suggest that our approach predicted the stress level of the participants with remarkable performance. These results may have a positive impact in diverse areas that could benefit from stress level quantitative prediction. These areas include research fields like neuromarketing, and training of professionals such as surgeons, industrial workers, or firefighters, that often face stressful situations.

in Frontiers in Computational Neuroscience on July 14, 2021 12:00 AM.

• #### Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.

in Frontiers in Cellular Neuroscience on July 14, 2021 12:00 AM.

• #### The Role of Platelets in the Stimulation of Neuronal Synaptic Plasticity, Electric Activity, and Oxidative Phosphorylation: Possibilities for New Therapy of Neurodegenerative Diseases

The central nervous system (CNS) is highly vascularized where neuronal cells are located in proximity to endothelial cells, astroglial limitans, and neuronal processes constituting integrated neurovascular units. In contrast to many other organs, the CNS has a blood-brain barrier (BBB), which becomes compromised due to infection, neuroinflammation, neurodegeneration, traumatic brain injury, and other reasons. BBB disruption is presumably involved in neuronal injury during epilepsy and psychiatric disorders. Therefore, many types of neuropsychological disorders are accompanied by an increase in BBB permeability leading to direct contact of circulating blood cells in the capillaries with neuronal cells in the CNS. The second most abundant type of blood cells are platelets, which come after erythrocytes and outnumber ~100-fold circulating leukocytes. When BBB becomes compromised, platelets swiftly respond to the vascular injury and become engaged in thrombosis and hemostasis. However, more recent studies demonstrated that platelets could also enter CNS parenchyma and directly interact with neuronal cells. Within CNS, platelets become activated by recognizing major brain gangliosides on the surface of astrocytes and neurons and releasing a milieu of pro-inflammatory mediators, neurotrophic factors, and neurotransmitters. Platelet-derived factors directly stimulate neuronal electric and synaptic activity and promote the formation of new synapses and axonal regrowth near the site of damage. Despite such active involvement in response to CNS damage, the role of platelets in neurological disorders was not extensively studied, which will be the focus of this review.

in Frontiers in Cellular Neuroscience on July 14, 2021 12:00 AM.

• #### Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Deficiency of otoferlin causes profound prelingual deafness in humans and animal models. Here, we closely analyzed developmental deficits and degenerative mechanisms in Otof knock-out (Otof–/–) mice over the course of 48 weeks. We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age. At postnatal day 14 (P14), we found on average ∼15 synapses per inner hair cell (IHC) in Otof–/– cochleae as well as in wild-type controls. Further on, the number of synapses in Otof–/– IHCs was reduced to ∼7 at 8 weeks of age and to ∼6 at 48 weeks of age. In the same period, the number of spiral ganglion neurons (SGNs) declined in Otof–/– animals. Importantly, we found an age-progressive loss of IHCs to an overall number of 75% of wildtype IHCs. The IHC loss more prominently but not exclusively affected the basal aspects of the cochlea. For outer hair cells (OHCs), we observed slightly accelerated age-dependent degeneration from base to apex. This was associated with a progressive decay in DPOAE amplitudes for high frequency stimuli, which could first be observed at the age of 24 weeks in Otof–/– mice. Our data will help to plan and predict the outcome of a gene therapy applied at various ages of DFNB9 patients.

in Frontiers in Cellular Neuroscience on July 14, 2021 12:00 AM.

• #### Focused Ultrasound Thalamotomy for the Treatment of Essential Tremor: A 2-Year Outcome Study of Chinese People

Background: Essential tremor (ET) is a common movement disorder among elderly individuals worldwide and is occasionally associated with a high risk for mild cognitive impairment and dementia. This retrospective study aimed to determine the clinical outcome of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET.

Methods: In total, 31 male and 17 female patients with drug-refractory ET were enrolled in this research study from January 2017 to September 2019. The severity of tremor and disability were assessed using the Clinical Rating Scale for Tremor (CRST) within a 2-year follow-up period.

Results: The mean age of the participants was 59.14 ± 13.5 years. The mean skull density ratio (SDR) was 0.5 ± 0.1. The mean highest temperature was 57.0 ± 2.4°C. The mean number of sonications was 10.0 ± 2.6. The average maximum energy was 19,710.5 ± 8,624.9 J. The total CRST scores and sub-scores after MRgFUS thalamotomy significantly reduced during each follow-up (p < 0.001). All but four (8.3%) of the patients had reversible adverse events (AEs) after the procedure.

Conclusions: MRgFUS had sustained clinical efficacy 2 years after treatment for intractable ET. Only few patients presented with thalamotomy-related AEs including numbness, weakness, and ataxia for an extended period. Most Chinese patients were treated safely and effectively despite their low SDR.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Cortical Engagement Metrics During Reactive Balance Are Associated With Distinct Aspects of Balance Behavior in Older Adults

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical mechanisms for balance control, particularly in relation to balance function, remain unclear. Here we aimed to investigate motor cortical activity in relation to the level of balance challenge presented during reactive balance recovery and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions in relation to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater motor cortical beta power evoked following standing balance perturbations demonstrated lower general clinical balance function. Individual older adults demonstrated a wide range of cortical responses during balance reactions at the same perturbation magnitude, showing no group-level change in prefrontal- or somatosensory-motor coherence in response to perturbations. However, older adults with the highest prefrontal-motor coherence during the post-perturbation, but not pre-perturbation, period showed greater cognitive dual-task interference (DTI) and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-motor cortical networks in distinct aspects of balance control involving response inhibition of reactive stepping in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall prevention with aging.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Neurological Mechanisms of Animal-Assisted Intervention in Alzheimer’s Disease: A Hypothetical Review

Alzheimer’s disease (AD) is an irreversible neurodegenerative brain disorder with aggregation of amyloid-beta (Aβ) and tau as the pathological hallmarks. AD is the most common form of dementia and is characterized by a progressive decline of cognition. The failure of pharmacological approaches to treat AD has resulted in an increased focus on non-pharmacological interventions that can mitigate cognitive decline and delay disease progression in patients with AD. Animal-assisted intervention (AAI), a non-pharmacological intervention, improves emotional, social, and cognitive dysfunction in patients with neurodegenerative diseases. In particular, AAI is reported to mitigate the effects of cognitive impairment in patients with AD. Despite the positive effects of AAI on cognitive dysfunction in patients with AD, there have been no studies on how AAI affects AD-related pathologies. This review postulates potential neurological mechanisms of emotional or social interaction through AAI in countering AD-related pathologies, such as Aβ deposition, tau hyperphosphorylation, neuroinflammation, and impaired adult hippocampal neurogenesis (AHN), and proposes insights for future research by organizing accumulated previous evidence.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Screening Tools and Assessment Methods of Cognitive Decline Associated With Age-Related Hearing Loss: A Review

Strong links between hearing and cognitive function have been confirmed by a growing number of cross-sectional and longitudinal studies. Seniors with age-related hearing loss (ARHL) have a significantly higher cognitive impairment incidence than those with normal hearing. The correlation mechanism between ARHL and cognitive decline is not fully elucidated to date. However, auditory intervention for patients with ARHL may reduce the risk of cognitive decline, as early cognitive screening may improve related treatment strategies. Currently, clinical audiology examinations rarely include cognitive screening tests, partly due to the lack of objective quantitative indicators with high sensitivity and specificity. Questionnaires are currently widely used as a cognitive screening tool, but the subject’s performance may be negatively affected by hearing loss. Numerous electroencephalogram (EEG) and magnetic resonance imaging (MRI) studies analyzed brain structure and function changes in patients with ARHL. These objective electrophysiological tools can be employed to reveal the association mechanism between auditory and cognitive functions, which may also find biological markers to be more extensively applied in assessing the progression towards cognitive decline and observing the effects of rehabilitation training for patients with ARHL. In this study, we reviewed clinical manifestations, pathological changes, and causes of ARHL and discussed their cognitive function effects. Specifically, we focused on current cognitive screening tools and assessment methods and analyzed their limitations and potential integration.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Association of Tau Pathology With Clinical Symptoms in the Subfields of Hippocampal Formation

Objective: To delineate the relationship between clinical symptoms and tauopathy of the hippocampal subfields under different amyloid statuses.

Methods: One hundred and forty-three subjects were obtained from the ADNI project, including 87 individuals with normal cognition, 46 with mild cognitive impairment, and 10 with Alzheimer’s disease (AD). All subjects underwent the tau PET, amyloid PET, T1W, and high-resolution T2W scans. Clinical symptoms were assessed by the Neuropsychiatric Inventory (NPI) total score and Alzheimer’s Disease Assessment Scale cognition 13 (ADAS-cog-13) total score, comprising memory and executive function scores. The hippocampal subfields including Cornu Ammonis (CA1–3), subiculum (Sub), and dentate gyrus (DG), as well as the adjacent para-hippocampus (PHC) and entorhinal cortex (ERC), were segmented automatically using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. The relationship between tauopathy/volume of the hippocampal subfields and assessment scores was calculated using partial correlation analysis under different amyloid status, by controlling age, gender, education, apolipoprotein E (APOE) allele ɛ4 carrier status, and, time interval between the acquisition time of tau PET and amyloid PET scans.

Results: Compared with amyloid negative (A−) group, individuals from amyloid positive (A+) group are more impaired based on the Mini-mental State Examination (MMSE; p = 3.82e-05), memory (p = 6.30e-04), executive function (p = 0.0016), and ADAS-cog-13 scores (p = 5.11e-04). Significant decrease of volume (CA1, DG, and Sub) and increase of tau deposition (CA1, Sub, ERC, and PHC) of the hippocampal subfields of both hemispheres were observed for the A+ group compared to the A- group. Tauopathy of ERC is significantly associated with memory score for the A- group, and the associated regions spread into Sub and PHC for the A+ group. The relationship between the impairment of behavior or executive function and tauopathy of the hippocampal subfield was discovered within the A+ group. Leftward asymmetry was observed with the association between assessment scores and tauopathy of the hippocampal subfield, which is more prominent for the NPI score for the A+ group.

Conclusion: The associations of tauopathy/volume of the hippocampal subfields with clinical symptoms provide additional insight into the understanding of local changes of the human HF during the AD continuum and can be used as a reference for future studies.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Brain Frequency-Specific Changes in the Spontaneous Neural Activity Are Associated With Cognitive Impairment in Patients With Presbycusis

Presbycusis (PC) is characterized by preferential hearing loss at high frequencies and difficulty in speech recognition in noisy environments. Previous studies have linked PC to cognitive impairment, accelerated cognitive decline and incident Alzheimer’s disease. However, the neural mechanisms of cognitive impairment in patients with PC remain unclear. Although resting-state functional magnetic resonance imaging (rs-fMRI) studies have explored low-frequency oscillation (LFO) connectivity or amplitude of PC-related neural activity, it remains unclear whether the abnormalities occur within all frequency bands or within specific frequency bands. Fifty-one PC patients and fifty-one well-matched normal hearing controls participated in this study. The LFO amplitudes were investigated using the amplitude of low-frequency fluctuation (ALFF) at different frequency bands (slow-4 and slow-5). PC patients showed abnormal LFO amplitudes in the Heschl’s gyrus, dorsolateral prefrontal cortex (dlPFC), frontal eye field and key nodes of the speech network exclusively in slow-4, which suggested that abnormal spontaneous neural activity in PC was frequency dependent. Our findings also revealed that stronger functional connectivity between the dlPFC and the posterodorsal stream of auditory processing, as well as lower functional coupling between the PCC and key nodes of the DMN, which were associated with cognitive impairments in PC patients. Our study might underlie the cross-modal plasticity and higher-order cognitive participation of the auditory cortex after partial hearing deprivation. Our findings indicate that frequency-specific analysis of ALFF could provide valuable insights into functional alterations in the auditory cortex and non-auditory regions involved in cognitive impairment associated with PC.

in Frontiers in Ageing Neuroscience on July 14, 2021 12:00 AM.

• #### Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy

Abstract Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in‐depth study of these unconventional animals are threefold. First, to increase knowledge of the often‐understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans.

in Journal of Neuroscience Research on July 13, 2021 05:29 PM.

• #### Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

Objective The MAST family of microtubule‐associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP‐16 in HEK293T cells. Results We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug‐resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient‐specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP‐16, compared to wild‐type. These findings suggest the patient‐specific variants may confer MAST3 gain‐of‐function. Moreover, single‐nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. Interpretation In summary, we describe MAST3 as a novel epilepsy‐associated gene with a potential gain‐of‐function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021

in Annals of Neurology on July 13, 2021 01:30 PM.

• #### On-chip ultra-compact solution

Nature Photonics, Published online: 13 July 2021; doi:10.1038/s41566-021-00850-7

Reducing the footprint of optical spectrometers is a critical requirement for many in-field applications. Now, a single black phosphorus photodetector with a wavelength-scale size enables mid-infrared computational spectrometry.

in Nature Photomics on July 13, 2021 12:00 AM.

• #### A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons

Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease.

in Frontiers in Neuroscience: Neurodegeneration on July 13, 2021 12:00 AM.

• #### Recording Strategies for High Channel Count, Densely Spaced Microelectrode Arrays

Neuroscience research into how complex brain functions are implemented at an extra-cellular level requires in vivo neural recording interfaces, including microelectrodes and read-out circuitry, with increased observability and spatial resolution. The trend in neural recording interfaces toward employing high-channel-count probes or 2D microelectrodes arrays with densely spaced recording sites for recording large neuronal populations makes it harder to save on resources. The low-noise, low-power requirement specifications of the analog front-end usually requires large silicon occupation, making the problem even more challenging. One common approach to alleviating this consumption area burden relies on time-division multiplexing techniques in which read-out electronics are shared, either partially or totally, between channels while preserving the spatial and temporal resolution of the recordings. In this approach, shared elements have to operate over a shorter time slot per channel and active area is thus traded off against larger operating frequencies and signal bandwidths. As a result, power consumption is only mildly affected, although other performance metrics such as in-band noise or crosstalk may be degraded, particularly if the whole read-out circuit is multiplexed at the analog front-end input. In this article, we review the different implementation alternatives reported for time-division multiplexing neural recording systems, analyze their advantages and drawbacks, and suggest strategies for improving performance.

in Frontiers in Neuroscience: Neural Technology on July 13, 2021 12:00 AM.

• #### Decoding EEG Brain Activity for Multi-Modal Natural Language Processing

Until recently, human behavioral data from reading has mainly been of interest to researchers to understand human cognition. However, these human language processing signals can also be beneficial in machine learning-based natural language processing tasks. Using EEG brain activity for this purpose is largely unexplored as of yet. In this paper, we present the first large-scale study of systematically analyzing the potential of EEG brain activity data for improving natural language processing tasks, with a special focus on which features of the signal are most beneficial. We present a multi-modal machine learning architecture that learns jointly from textual input as well as from EEG features. We find that filtering the EEG signals into frequency bands is more beneficial than using the broadband signal. Moreover, for a range of word embedding types, EEG data improves binary and ternary sentiment classification and outperforms multiple baselines. For more complex tasks such as relation detection, only the contextualized BERT embeddings outperform the baselines in our experiments, which raises the need for further research. Finally, EEG data shows to be particularly promising when limited training data is available.

in Frontiers in Human Neuroscience on July 13, 2021 12:00 AM.

• #### Spatiotemporal Dynamics of Affective and Semantic Valence Among Women

As an important dimension of emotional assessment, valence can refer to affective valence reflecting an emotional response, or semantic valence reflecting knowledge about the nature of a stimulus. A previous study has used repeated exposure to separate these two similar cognitive processes. Here, for the first time, we compared the spatiotemporal dynamics of the affective and semantic modes of valence by combining event-related potentials with repeated exposure. Forty-seven female participants were assigned to the feeling-focused and semantic-focused groups and thereafter repeatedly viewed the pictures selected for the study. Self-report behavioral results showed that post-test scores were significantly lower than pre-test scores in the feeling-focused group, while the differences between the two tests were not significant in the semantic-focused group. At the neural level, N2 amplitudes decreased and early late positive potential amplitudes increased in both groups, suggesting that the participants perceived the repeated pictures more fluently and retrieved the traces of the stimulus spontaneously regardless of the valence they judged. However, the late positive potential amplitudes in anterior areas and the activity of the middle frontal gyrus were attenuated in the feeling-focused group; however, this component in posterior areas and the activity of the precentral gyrus were increased in the semantic-focused group. Therefore, the processes of affective and semantic valence are similar in the early stages of image perception and retrieval, while in the later stage of valence judgment, these processes show different brain activation patterns. The results provide electrophysiological evidence for the differences in psychological processes when judging the two modes of valence.

in Frontiers in Human Neuroscience on July 13, 2021 12:00 AM.

• #### Negative Feedback Role of Astrocytes in Shaping Excitation in Brain Cell Co-cultures

Glial cells play an important role in maintaining neuronal homeostasis and may thus influence excitability in epileptogenesis. These cells in the brain have glutamate (Glu) transporters, which remove this neurotransmitter from the extracellular space. Lack of negative (−) feedback makes local neuronal circuits more excitable and potentially contributing to epileptogenic phenomena. In this study, the role of glial cells in providing (−) feedback is shown through different models of brain cells in culture imaged for intracellular calcium concentration [(Ca2+)i]. Moreover, here we study the individual cells by putting them in categories. Neuronal networks with high and low (−) feedback were established by using anti-mitotics to deplete glial cells. Separate stimuli with very low subthreshold concentrations of Glu (250–750 nM) were added to cultures to test if the order of stimulations matter in regard to calcium dynamics outcomes. Additionally, KCl and ATP were used to stimulate glial cells. We found that for cultures high in (−) feedback, order of the stimulus was not important in predicting cellular responses and because of the complexity of networks in low (−) feedback cultures the order of stimulus matters. As an additional method for analysis, comparison of high (−) feedback cultures, and pure astrocytes was also considered. Glial cells in pure astrocyte cultures tend to be larger in size than glial cells in high (−) feedback cultures. The potential effect of (−) feedback at the blood brain barrier (BBB) was also considered for the inflammatory responses of nitric oxide (NO) production and [Ca2+]i regulation using brain microvascular endothelial cells (BMVECs). The inflammatory and calcium signaling pathways both indicate the negative feedback role of astrocytes, poised between the BBB and structures deeper within the brain, where neuronal synapses are homeostatically maintained by glial uptake of neurotransmitters.

in Frontiers in Cellular Neuroscience on July 13, 2021 12:00 AM.

• #### Neuroimaging Markers of Cerebral Small Vessel Disease on Hemorrhagic Transformation and Functional Outcome After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Objective: The aim of this study was to perform a systematic review and meta-analysis to assess whether cerebral small vessel disease (CSVD) on neuroimaging of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) is associated with an increased risk of hemorrhagic transformation (HT), symptomatic intracranial hemorrhage (sICH), and poor functional outcome (PFO).

Methods: A thorough search of several databases was carried out to identify relevant studies up to December 2020. We included studies of patients with AIS and neuroimaging markers of CSVD treated with IVT. The primary outcome was HT, and the secondary outcomes were sICH and 3-month PFO. The quality of the studies involved was evaluated using the Newcastle–Ottawa Scale (NOS). The meta-analysis with the fixed effects model was performed.

Results: Twenty-four eligible studies (n = 9,419) were pooled in the meta-analysis. All included studies were regarded as high quality with the NOS scores of at least 6 points. The meta-analysis revealed associations between the presence of CSVD and HT, sICH, and the 3-month PFO after IVT. Compared with no CSVD, the presence of CSVD was associated with an increased risk of HT (OR: 1.81, 95% CI: 1.52–2.16), sICH (OR: 2.42, 95% CI: 1.76–3.33), and 3-month PFO (OR: 2.15, 95% CI: 1.89–2.44). For patients with AIS complicated with CSVD, compared with a CSVD score of 0–1, a CSVD score of 2–4 was associated with an increased risk of HT (OR: 3.10, 95% CI: 1.67–5.77), sICH (OR: 2.86, 95% CI: 1.26–6.49), and 3-month PFO (OR: 4.58, 95% CI: 2.97–7.06).

Conclusion: Patients with AIS complicated with neuroimaging markers of CSVD are at increased risk of HT and 3-month PFO after IVT. However, it is still necessary to clarify the exact role of CSVD in the occurrence, development, and prognosis of AIS.

Systematic Review Registration:www.ClinicalTrials.gov, identifier CRD4202123 3900.

in Frontiers in Ageing Neuroscience on July 13, 2021 12:00 AM.

• #### Acute TBK1/IKK-ε Inhibition Enhances the Generation of Disease-Associated Microglia-Like Phenotype Upon Cortical Stab-Wound Injury

Traumatic brain injury has a poorer prognosis in elderly patients, possibly because of the enhanced inflammatory response characteristic of advanced age, known as “inflammaging.” Recently, reduced activation of the TANK-Binding-Kinase 1 (Tbk1) pathway has been linked to age-associated neurodegeneration and neuroinflammation. Here we investigated how the blockade of Tbk1 and of the closely related IKK-ε by the small molecule Amlexanox could modify the microglial and immune response to cortical stab-wound injury in mice. We demonstrated that Tbk1/IKK-ε inhibition resulted in a massive expansion of microglial cells characterized by the TMEM119+/CD11c+ phenotype, expressing high levels of CD68 and CD317, and with the upregulation of Cst7a, Prgn and Ccl4 and the decrease in the expression levels of Tmem119 itself and P2yr12, thus a profile close to Disease-Associated Microglia (DAM, a subset of reactive microglia abundant in Alzheimer’s Disease and other neurodegenerative conditions). Furthermore, Tbk1/IKK-ε inhibition increased the infiltration of CD3+ lymphocytes, CD169+ macrophages and CD11c+/CD169+ cells. The enhanced immune response was associated with increased expression of Il-33, Ifn-g, Il-17, and Il-19. This upsurge in the response to the stab wound was associated with the expanded astroglial scars and increased deposition of chondroitin-sulfate proteoglycans at 7 days post injury. Thus, Tbk1/IKK-ε blockade results in a massive expansion of microglial cells with a phenotype resembling DAM and with the substantial enhancement of neuroinflammatory responses. In this context, the induction of DAM is associated with a detrimental outcome such as larger injury-related glial scars. Thus, the Tbk1/IKK-ε pathway is critical to repress neuroinflammation upon stab-wound injury and Tbk1/IKK-ε inhibitors may provide an innovative approach to investigate the consequences of DAM induction.

in Frontiers in Ageing Neuroscience on July 13, 2021 12:00 AM.

• #### The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

in Frontiers in Ageing Neuroscience on July 13, 2021 12:00 AM.

• #### Bayesian back-calculation and nowcasting for line list data during the COVID-19 pandemic

by Tenglong Li, Laura F. White

Surveillance is critical to mounting an appropriate and effective response to pandemics. However, aggregated case report data suffers from reporting delays and can lead to misleading inferences. Different from aggregated case report data, line list data is a table contains individual features such as dates of symptom onset and reporting for each reported case and a good source for modeling delays. Current methods for modeling reporting delays are not particularly appropriate for line list data, which typically has missing symptom onset dates that are non-ignorable for modeling reporting delays. In this paper, we develop a Bayesian approach that dynamically integrates imputation and estimation for line list data. Specifically, this Bayesian approach can accurately estimate the epidemic curve and instantaneous reproduction numbers, even with most symptom onset dates missing. The Bayesian approach is also robust to deviations from model assumptions, such as changes in the reporting delay distribution or incorrect specification of the maximum reporting delay. We apply the Bayesian approach to COVID-19 line list data in Massachusetts and find the reproduction number estimates correspond more closely to the control measures than the estimates based on the reported curve.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### Partial information decomposition reveals that synergistic neural integration is greater downstream of recurrent information flow in organotypic cortical cultures

by Samantha P. Sherrill, Nicholas M. Timme, John M. Beggs, Ehren L. Newman

The directionality of network information flow dictates how networks process information. A central component of information processing in both biological and artificial neural networks is their ability to perform synergistic integration–a type of computation. We established previously that synergistic integration varies directly with the strength of feedforward information flow. However, the relationships between both recurrent and feedback information flow and synergistic integration remain unknown. To address this, we analyzed the spiking activity of hundreds of neurons in organotypic cultures of mouse cortex. We asked how empirically observed synergistic integration–determined from partial information decomposition–varied with local functional network structure that was categorized into motifs with varying recurrent and feedback information flow. We found that synergistic integration was elevated in motifs with greater recurrent information flow beyond that expected from the local feedforward information flow. Feedback information flow was interrelated with feedforward information flow and was associated with decreased synergistic integration. Our results indicate that synergistic integration is distinctly influenced by the directionality of local information flow.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### SCMFMDA: Predicting microRNA-disease associations based on similarity constrained matrix factorization

by Lei Li, Zhen Gao, Yu-Tian Wang, Ming-Wen Zhang, Jian-Cheng Ni, Chun-Hou Zheng

miRNAs belong to small non-coding RNAs that are related to a number of complicated biological processes. Considerable studies have suggested that miRNAs are closely associated with many human diseases. In this study, we proposed a computational model based on Similarity Constrained Matrix Factorization for miRNA-Disease Association Prediction (SCMFMDA). In order to effectively combine different disease and miRNA similarity data, we applied similarity network fusion algorithm to obtain integrated disease similarity (composed of disease functional similarity, disease semantic similarity and disease Gaussian interaction profile kernel similarity) and integrated miRNA similarity (composed of miRNA functional similarity, miRNA sequence similarity and miRNA Gaussian interaction profile kernel similarity). In addition, the L2 regularization terms and similarity constraint terms were added to traditional Nonnegative Matrix Factorization algorithm to predict disease-related miRNAs. SCMFMDA achieved AUCs of 0.9675 and 0.9447 based on global Leave-one-out cross validation and five-fold cross validation, respectively. Furthermore, the case studies on two common human diseases were also implemented to demonstrate the prediction accuracy of SCMFMDA. The out of top 50 predicted miRNAs confirmed by experimental reports that indicated SCMFMDA was effective for prediction of relationship between miRNAs and diseases.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### Detecting behavioural changes in human movement to inform the spatial scale of interventions against COVID-19

by Hamish Gibbs, Emily Nightingale, Yang Liu, James Cheshire, Leon Danon, Liam Smeeth, Carl A. B. Pearson, Chris Grundy, LSHTM CMMID COVID-19 working group , Adam J. Kucharski, Rosalind M. Eggo

On March 23 2020, the UK enacted an intensive, nationwide lockdown to mitigate transmission of COVID-19. As restrictions began to ease, more localized interventions were used to target resurgences in transmission. Understanding the spatial scale of networks of human interaction, and how these networks change over time, is critical to targeting interventions at the most at-risk areas without unnecessarily restricting areas at low risk of resurgence. We use detailed human mobility data aggregated from Facebook users to determine how the spatially-explicit network of movements changed before and during the lockdown period, in response to the easing of restrictions, and to the introduction of locally-targeted interventions. We also apply community detection techniques to the weighted, directed network of movements to identify geographically-explicit movement communities and measure the evolution of these community structures through time. We found that the mobility network became more sparse and the number of mobility communities decreased under the national lockdown, a change that disproportionately affected long distance connections central to the mobility network. We also found that the community structure of areas in which locally-targeted interventions were implemented following epidemic resurgence did not show reorganization of community structure but did show small decreases in indicators of travel outside of local areas. We propose that communities detected using Facebook or other mobility data be used to assess the impact of spatially-targeted restrictions and may inform policymakers about the spatial extent of human movement patterns in the UK. These data are available in near real-time, allowing quantification of changes in the distribution of the population across the UK, as well as changes in travel patterns to inform our understanding of the impact of geographically-targeted interventions.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### OpenABM-Covid19—An agent-based model for non-pharmaceutical interventions against COVID-19 including contact tracing

by Robert Hinch, William J. M. Probert, Anel Nurtay, Michelle Kendall, Chris Wymant, Matthew Hall, Katrina Lythgoe, Ana Bulas Cruz, Lele Zhao, Andrea Stewart, Luca Ferretti, Daniel Montero, James Warren, Nicole Mather, Matthew Abueg, Neo Wu, Olivier Legat, Katie Bentley, Thomas Mead, Kelvin Van-Vuuren, Dylan Feldner-Busztin, Tommaso Ristori, Anthony Finkelstein, David G. Bonsall, Lucie Abeler-Dörner, Christophe Fraser

SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an agent-based simulation of the epidemic including detailed age-stratification and realistic social networks. By default the model is parameterised to UK demographics and calibrated to the UK epidemic, however, it can easily be re-parameterised for other countries. OpenABM-Covid19 can evaluate non-pharmaceutical interventions, including both manual and digital contact tracing, and vaccination programmes. It can simulate a population of 1 million people in seconds per day, allowing parameter sweeps and formal statistical model-based inference. The code is open-source and has been developed by teams both inside and outside academia, with an emphasis on formal testing, documentation, modularity and transparency. A key feature of OpenABM-Covid19 are its Python and R interfaces, which has allowed scientists and policymakers to simulate dynamic packages of interventions and help compare options to suppress the COVID-19 epidemic.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### Integration of sleep homeostasis and navigation in <i>Drosophila</i>

by Andres Flores-Valle, Pedro J. Gonçalves, Johannes D. Seelig

During sleep, the brain undergoes dynamic and structural changes. In Drosophila, such changes have been observed in the central complex, a brain area important for sleep control and navigation. The connectivity of the central complex raises the question about how navigation, and specifically the head direction system, can operate in the face of sleep related plasticity. To address this question, we develop a model that integrates sleep homeostasis and head direction. We show that by introducing plasticity, the head direction system can function in a stable way by balancing plasticity in connected circuits that encode sleep pressure. With increasing sleep pressure, the head direction system nevertheless becomes unstable and a sleep phase with a different plasticity mechanism is introduced to reset network connectivity. The proposed integration of sleep homeostasis and head direction circuits captures features of their neural dynamics observed in flies and mice.

in PLoS Computational Biology on July 12, 2021 02:00 PM.

• #### gen3sis: A general engine for eco-evolutionary simulations of the processes that shape Earth’s biodiversity

by Oskar Hagen, Benjamin Flück, Fabian Fopp, Juliano S. Cabral, Florian Hartig, Mikael Pontarp, Thiago F. Rangel, Loïc Pellissier

Understanding the origins of biodiversity has been an aspiration since the days of early naturalists. The immense complexity of ecological, evolutionary, and spatial processes, however, has made this goal elusive to this day. Computer models serve progress in many scientific fields, but in the fields of macroecology and macroevolution, eco-evolutionary models are comparatively less developed. We present a general, spatially explicit, eco-evolutionary engine with a modular implementation that enables the modeling of multiple macroecological and macroevolutionary processes and feedbacks across representative spatiotemporally dynamic landscapes. Modeled processes can include species’ abiotic tolerances, biotic interactions, dispersal, speciation, and evolution of ecological traits. Commonly observed biodiversity patterns, such as α, β, and γ diversity, species ranges, ecological traits, and phylogenies, emerge as simulations proceed. As an illustration, we examine alternative hypotheses expected to have shaped the latitudinal diversity gradient (LDG) during the Earth’s Cenozoic era. Our exploratory simulations simultaneously produce multiple realistic biodiversity patterns, such as the LDG, current species richness, and range size frequencies, as well as phylogenetic metrics. The model engine is open source and available as an R package, enabling future exploration of various landscapes and biological processes, while outputs can be linked with a variety of empirical biodiversity patterns. This work represents a key toward a numeric, interdisciplinary, and mechanistic understanding of the physical and biological processes that shape Earth’s biodiversity.

in PLoS Biology on July 12, 2021 02:00 PM.

• #### Viral dynamics of acute SARS-CoV-2 infection and applications to diagnostic and public health strategies

by Stephen M. Kissler, Joseph R. Fauver, Christina Mack, Scott W. Olesen, Caroline Tai, Kristin Y. Shiue, Chaney C. Kalinich, Sarah Jednak, Isabel M. Ott, Chantal B. F. Vogels, Jay Wohlgemuth, James Weisberger, John DiFiori, Deverick J. Anderson, Jimmie Mancell, David D. Ho, Nathan D. Grubaugh, Yonatan H. Grad

SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019–2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval [CI] 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days [95% CI 7.9, 14.4]) than for asymptomatic individuals (7.8 days [95% CI 6.1, 9.7]). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient’s infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient’s progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious.

in PLoS Biology on July 12, 2021 02:00 PM.

• #### Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in <i>Caenorhabditis elegans</i>

by Maria Sladowska, Michał Turek, Min-Ji Kim, Krzysztof Drabikowski, Ben Hur Marins Mussulini, Karthik Mohanraj, Remigiusz A. Serwa, Ulrike Topf, Agnieszka Chacinska

Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the “mitochondrial unfolded protein response” [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the “unfolded protein response activated by mistargeting of proteins” [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.

in PLoS Biology on July 12, 2021 02:00 PM.

• #### ANXA1 with Anti‐Inflammatory Properties Might Contribute to Parkinsonism

We here describe the identification of a novel variant in the anti‐inflammatory Annexin A1 protein likely to be the cause of disease in two siblings with autosomal recessive parkinsonism. The disease‐segregating variant was ascertained through a combination of homozygosity mapping and whole genome sequencing and was shown to impair phagocytosis in zebrafish mutant embryos. The highly conserved variant, absent in healthy individuals and public SNP databases, affected a functional domain of the protein with neuroprotective properties. This study supports the hypothesis that damaged microglia might lead to impairments in the clearance of accumulated and aggregated proteins resulting in parkinsonism. ANN NEUROL 2021

in Annals of Neurology on July 12, 2021 11:59 AM.

• #### Contact inhibition of locomotion generates collective cell migration without chemoattractants in an open domain

Author(s): Hamid Khataee, Andras Czirok, and Zoltan Neufeld

Neural crest cells are embryonic stem cells that migrate throughout embryos and, at different target locations, give rise to the formation of a variety of tissues and organs. The directional migration of the neural crest cells is experimentally described using a process referred to as contact inhibi...

[Phys. Rev. E 104, 014405] Published Mon Jul 12, 2021

in Physical Review E: Biological physics on July 12, 2021 10:00 AM.

• #### A quiet innovator: Peter Lakatos (1972–2021)

Nature Neuroscience, Published online: 12 July 2021; doi:10.1038/s41593-021-00897-3

Peter Lakatos passed away on Sunday, 30 May 2021. He was 49 years old. Peter was a Research Scientist at the Nathan S. Kline Institute for Psychiatric Research in New York State and a Research Assistant Professor in the Department of Psychiatry at NYU Grossman School of Medicine. With Peter’s sudden death, neuroscience has lost a gentle giant.

in Nature Neuroscience on July 12, 2021 12:00 AM.

• #### Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time

Nature Neuroscience, Published online: 12 July 2021; doi:10.1038/s41593-021-00888-4

Lee et al. show that in male Shank3-mutant mice, mPFC neurons are impaired in encoding of social agency. Shank3 reexpression in mPFC restored this ability in real time, and this was accompanied by rescue of normal social behavior.

in Nature Neuroscience on July 12, 2021 12:00 AM.

• #### Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges

Nature Neuroscience, Published online: 12 July 2021; doi:10.1038/s41593-021-00880-y

The skull dura contains B cells and B lineage precursors under homeostatic conditions. These cells are long-term tissue resident and mature upon neuroinflammation. This identifies the dura as a site of B cell residence and potentially development.

in Nature Neuroscience on July 12, 2021 12:00 AM.

• #### CloudReg: automatic terabyte-scale cross-modal brain volume registration

Nature Methods, Published online: 12 July 2021; doi:10.1038/s41592-021-01218-z

CloudReg: automatic terabyte-scale cross-modal brain volume registration

in Nature Methods on July 12, 2021 12:00 AM.

• #### An unsupervised method for physical cell interaction profiling of complex tissues

Nature Methods, Published online: 12 July 2021; doi:10.1038/s41592-021-01196-2

CIM-seq offers an unsupervised deconvolution method to profile cell–cell interactions by sequencing cell multiplets of a given tissue, and was employed to analyze diverse tissues such as the intestinal epithelium, lung and spleen.

in Nature Methods on July 12, 2021 12:00 AM.