bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning to Predict in Networks with Heterogeneous and Dynamic Synapses
Authors: Burnham Daniel , Shea-Brown Eric , Mihalas Stefan
Published: May 2021

Abstract

A salient difference between artificial and biological neural networks is the complexity and diversity of individual units in the latter (Tasic et al., 2018). This remarkable diversity is present in the cellular and synaptic dynamics. In this study we focus on the role in learning of one such dynamical mechanism missing from most artificial neural network models, short-term synaptic plasticity (STSP). Biological synapses have dynamics over at least two time scales: a long time scale, which maps well to synaptic changes in artificial neural networks during learning, and the short time scale of STSP, which is typically ignored. Recent studies have shown the utility of such short-term dynamics in a variety of tasks (Masse et al., 2019; Perez-Nieves et al., 2021), and networks trained with such synapses have been shown to better match recorded neuronal activity and animal behavior (Hu et al., 2020). Here, we allow the timescale of STSP in individual neurons to be learned, simultaneously with standard learning of overall synaptic weights. We study learning performance on two predictive tasks, a simple dynamical system and a more complex MNIST pixel sequence. When the number of computational units is similar to the task dimensionality, RNNs with STSP outperform standard RNN and LSTM models. A potential explanation for this improvement is the encoding of activity history in the short-term synaptic dynamics, a biological form of long short-term memory. Beyond a role for synaptic dynamics themselves, we find a reason and a role for their diversity: learned synaptic time constants become heterogeneous across training and contribute to improved prediction performance in feedforward architectures. These results demonstrate how biologically motivated neural dynamics improve performance on the fundamental task of predicting future inputs with limited computational resources, and how learning such predictions drives neural dynamics towards the diversity found in biological brains.
Genomic reconstruction of the SARS-CoV-2 epidemic in England
Authors: Vöhringer Harald S. , Sanderson Theo , Sinnott Matthew , Maio Nicola De , Nguyen Thuy , Goater Richard , Schwach Frank , Harrison Ian , Hellewell Joel , Ariani Cristina , Gonçalves Sonia , Jackson David , Johnston Ian , Jung Alexander W. , Saint Callum , Sillitoe John , Suciu Maria , Goldman Nick , Panovska-Griffiths Jasmina ,   The Wellcome Sanger Institute Covid-19 Surveillance Team,   The COVID-19 Genomics UK (COG-UK) Consortium, Birney Ewan , Volz Erik , Funk Sebastian , Kwiatkowski Dominic , Chand Meera , Martincorena Inigo , Barrett Jeffrey C. , Gerstung Moritz
Published: May 2021

The evolution of the SARS-CoV-2 pandemic continuously produces new variants, which warrant timely epidemiological characterisation. Here we use the dense genomic surveillance generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of sub-epidemics that peaked in the early autumn of 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. Alpha grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed Alpha and eliminated nearly all other lineages in early 2021. However, a series of variants (mostly containing the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. Accounting for sustained introductions, however, indicates that their transmissibility is unlikely to have exceeded that of Alpha. Finally, B.1.617.2/Delta was repeatedly introduced to England and grew rapidly in the early summer of 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on June 26.
Single-cell analysis of the epigenomic and transcriptional landscape of innate immunity to seasonal and adjuvanted pandemic influenza vaccination in humans
Authors: Wimmers Florian , Donato Michele , Kuo Alex , Ashuach Tal , Gupta Shakti , Li Chunfeng , Dvorak Mai , Foecke Mariko Hinton , Chang Sarah E. , De Jong Sanne E. , Maecker Holden T. , van der Most Robbert , Cheung Peggie , Cortese Mario , Hagan Thomas , Bosinger Steven E. , Davis Mark , Rouphael Nadine , Subramaniam Shankar , Yosef Nir , Utz Paul J. , Khatri Purvesh , Pulendran Bali
Published: May 2021

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we used a systems biology approach to map the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza resulted in persistently reduced H3K27ac in monocytes and myeloid dendritic cells, which was associated with impaired cytokine responses to TLR stimulation. Single cell ATAC-seq analysis of 120,305 single cells revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were also observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at loci targeted by interferon response factors (IRFs). This was associated with elevated expression of antiviral genes and type 1 IFN production and heightened resistance to infection with the heterologous viruses Zika and Dengue. These results demonstrate that influenza vaccines stimulate persistent epigenomic remodeling of the innate immune system. Notably, AS03-adjuvanted vaccination remodeled the epigenome of myeloid cells to confer heightened resistance against heterologous viruses, revealing its potentially unappreciated role as an epigenetic adjuvant.
The LeVe CPAP System for oxygen-efficient CPAP respiratory support: Development and pilot evaluation
Authors: Culmer P. , Birch W. Davis , Waters I. , Keeling A. , Osnes C. , Jones D. , de Boer G. , Hetherington R. , Ashton S. , Latham M. , Beacon T. , Royston T. , Miller R. , Littlejohns A. , Parmar J. , Lawton T. , Murdoch S. , Brettle D. , Musasizi R. , Nampiina G. , Namulema E. , Kapur N.
Published: May 2021

Background

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a significant demand on healthcare providers (HCPs) to provide respiratory support for patients with moderate to severe symptoms. Continuous Positive Airway Pressure (CPAP) non-invasive ventilation can help patients with moderate symptoms to avoid the need for invasive ventilation in intensive care. However, existing CPAP systems can be complex (and thus expensive) or require high levels of oxygen, limiting their use in resource-stretched environments.

Technical Development + Testing

The LeVe (“Light”) CPAP system was developed using principles of frugal innovation to produce a solution of low complexity and high resource efficiency. The LeVe system exploits the air flow dynamics of electric fan blowers which are inherently suited to delivery of positive pressure at appropriate flow rates for CPAP. Laboratory evaluation demonstrated that performance of the LeVe system was equivalent to other commercially available systems used to deliver CPAP.

Pilot Evaluation

The LeVe CPAP system was tested to evaluate safety and acceptability in a group of ten healthy volunteers at Mengo Hospital in Kampala, Uganda. The study demonstrated that the system can be used safely without inducing hypoxia or hypercapnia and that its use was well tolerated by users, with no adverse events reported.

Conclusions

CPAP ventilation systems provide an important treatment option for COVID-19 patients. To deliver this for the high patient numbers associated with the COVID-19 pandemic, healthcare providers require resource efficient solutions. We have shown that this can be achieved through frugal engineering of a CPAP ventilation system, in a system which is safe for use and well tolerated in healthy volunteers. This approach may also benefit other respiratory conditions which often go unaddressed in LMICs for want of context-appropriate technology.
Modellinggambiensehuman African trypanosomiasis infection in villages of the Democratic Republic of Congo using Kolmogorov forward equations
Authors: Davis Christopher N. , Keeling Matt J. , Rock Kat S.
Published: May 2021

Stochastic methods for modelling disease dynamics enables the direct computation of the probability of elimination of transmission (EOT). For the low-prevalence disease of human African trypanosomiasis (gHAT), we develop a new mechanistic model for gHAT infection that determines the full probability distribution of the gHAT infection using Kolmogorov forward equations. The methodology allows the analytical investigation of the probabilities of gHAT elimination in the spatially-connected villages of the Kwamouth and Mosango health zones of the Democratic Republic of Congo, and captures the uncertainty using exact methods. We predict that, if current active and passive screening continue at current levels, local elimination of infection will occur in 2029 for Mosango and after 2040 in Kwamouth, respectively. Our method provides a more realistic approach to scaling the probability of elimination of infection between single villages and much larger regions, and provides results comparable to established models without the requirement of detailed infection structure. The novel flexibility allows the interventions in the model to be implemented specific to each village, and this introduces the framework to consider the possible future strategies of test-and-treat or direct treatment of individuals living in villages where cases have been found, using a new drug.
COVID-19 mass testing: harnessing the power of wastewater epidemiology
Authors: Fitzgerald Stephen F. , Rossi Gianluigi , Low Alison S. , McAteer Sean P. , O’Keefe Brian , Findlay David , Cameron Graeme J. , Pollard Peter , Singleton Peter T. R. , Ponton George , Singer Andrew C. , Farkas Kata , Jones Davey , Graham David W , Quintela-Baluja Marcos , Tait-Burkard Christine , Gally David L. , Kao Rowland , Corbishley Alexander
Published: May 2021

Background

COVID-19 patients shed SARS-CoV-2 RNA in their faeces. We hypothesised that detection of SARS-CoV-2 RNA in wastewater treatment plant (WWTP) influent could be a valuable tool to assist in public health decision making. We aimed to rapidly develop and validate a scalable methodology for the detection of SARS-CoV-2 RNA in wastewater that could be implemented at a national level and to determine the relationship between the wastewater signal and COVID-19 cases in the community.

Methods

We developed a filtration-based methodology for the concentration of SARS-CoV-2 from WWTP influent and subsequent detection and quantification by RT-qPCR. This methodology was used to monitor 28 WWTPs across Scotland, serving 50% of the population. For each WWTP catchment area, we collected data describing COVID-19 cases and deaths. We quantified spatial and temporal relationships between SARS-CoV-2 RNA in wastewater and COVID-19 cases.

Findings

Daily WWTP SARS-CoV-2 influent viral RNA load, calculated using daily influent flow rates, had the strongest correlation (ρ>0.9) with COVID-19 cases within a catchment. As the incidence of COVID-19 cases within a community increased, a linear relationship emerged between cases and influent viral RNA load. There were significant differences between WWTPs in their capacity to predict case numbers based on influent viral RNA load, with the limit of detection ranging from twenty-five cases for larger plants to a single case in smaller plants.

Interpretation

The levels of SARS-CoV-2 RNA in WWTP influent provide a cost-effective and unbiased measure of COVID-19 incidence within a community, indicating that national scale wastewater-based epidemiology can play a role in COVID-19 surveillance. In Scotland, wastewater testing has been expanded to cover 75% of the population, with sub-catchment sampling being used to focus surge testing. SARS-CoV-2 variant detection, assessment of vaccination on community transmission and surveillance for other infectious diseases represent promising future applications.

Funding

This study was funded by project grants from the Scottish Government via the Centre of Expertise for Waters (CD2019/06) and The Natural Environment Research Council’s COVID-19 Rapid Response grants (NE/V010441/1). The Roslin Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BB/P013740/1, BBS/E/D/20002173). Sample collection and supplementary analysis was funded and undertaken by Scottish Water and the majority of the sample analysis was funded and undertaken by the Scottish Environment Protection Agency.
Methylation-derived Inflammatory Measures and Lung Cancer Risk and Survival
Authors: Zhao Naisi , Ruan Mengyuan , Koestler Devin C. , Lu Jiayun , Kelsey Karl T. , Platz Elizabeth A. , Michaud Dominique S.
Published: May 2021

Background

Examining inflammation-related DNA methylation alterations in blood could help elucidate the role of inflammation in lung cancer etiology and aid discovery of factors that are key to lung cancer development and progression. In a nested case-control study, we estimated the neutrophil-to-lymphocyte ratio using a validated index, methylation-derived NLR (mdNLR), and quantified DNA methylation levels at loci previously linked with circulating concentrations of C-reactive protein (CRP). We examined associations between these measures and lung cancer risk, and among the cases, lung cancer survival, using pre-diagnostic blood samples of cases (median of 14 years before diagnosis) and controls in the CLUE I/II cohorts. Our analyses controlled for self-reported smoking and methylation-predicted cumulative smoking in order to better focus our examinations on the DNA methylation marks that are informative of the immune response profile.

Results

Using conditional logistic regression and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation increase in mdNLR (n = 150 pairs; OR: 1.47 [1.08, 2.02]) and found the estimated CRP Scores to be inversely associated with risk of NSCLC risk after additionally adjusting for methylation-predicted pack-years (n = 150 pairs; Score 1 OR: 0.57 [0.40, 0.81]; Score 2 OR: 0.62 [0.45, 0.84]; Score 3 OR: 0.65 [0.44, 0.95]). Using Cox proportional-hazards models and adjusting age, sex, smoking status, methylation-predicted pack-years, BMI, batch effect, and stage, we observed a 27% increased risk of dying from lung cancer for one standard deviation increase in mdNLR (n = 145 deaths in 205 cases; HR: 1.27 [1.08, 1.50]). A 50% increased risk of dying from lung cancer for one standard deviation increase in mdNLR was observed for NSCLC cases (n = 103 deaths in 149 cases; HR: 1.50 [1.19, 1.89]).

Conclusions

A better understanding of inflammation-associated methylation-based biomarkers in lung cancer development could provide insight into critical pathways that may help identify new markers of early disease and survival.
Neurotrophin signaling is modulated by specific transmembrane domain interactions
Authors: Franco María L. , Nadezhdin Kirill D. , Light Taylor P. , Goncharuk Sergey A. , Soler-Lopez Andrea , Ahmed Fozia , Mineev Konstantin S. , Hristova Kalina , Arseniev Alexander S. , Vilar Marçal
Published: May 2021

The neurotrophin receptors p75 and TrkA play an important role in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of NGF and TrkA promotes p75 shedding by α-secretases in a ligand-dependent manner. The current model is that p75 and TrkA are regulated by means of a physical direct interaction, however the nature of such interaction has been elusive so far. Here using NMR in micelles, multiscale molecular dynamics (MD), FRET and functional studies we identified and characterized the direct interaction between TrkA and p75 through the transmembrane domains (TMDs). MD of p75-TMD mutants suggests that although the interaction between TrkA and p75 TMDs is maintained, a specific protein interface is required to facilitate TrkA active homodimerization in the presence of NGF. The same mutations in the TMD protein interface of p75 reduced the activation of TrkA by NGF and cell differentiation. In summary we provide a structural model of the p75/TrkA receptor complex stabilized by transmembrane domain interactions.
Pollinator habitat plantings benefit wild, native bees, but do not necessarily favor rare species
Authors: Cariveau Daniel P. , Roswell Michael , Harrison Tina , Genung Mark , Gibbs Jason , Winfree Rachael
Published: May 2021

Installing pollinator habitat is a ubiquitous conservation tool, but little is known about which pollinator taxa require support, or which benefit from habitat installations.

We studied the response of rare and common bees to pollinator habitat enhancement. We used independent regional datasets to designate bee species as common or rare based on their rank according to one of three metrics: a) site occurrence frequency, b) local relative abundance, and c) geographic range size. We asked whether the abundance or richness of rare and common bees were greater in pollinator habitat, relative to old-field controls. Because we used an arbitrary, quantile-based cutoff to categorize species rarity, we conducted sensitivity analysis and controlled for rarity classification errors with a null model. With this null model, we determined whether rare and/or common species responded to pollinator habitat disproportionately, compared to the expectation for ‘typical’ bee species.

We found that the number of individuals and of species designated as rare based on local relative abundance was greater in pollinator habitat enhancements. The number of individuals from bee species designated as rare based on site occurrence was lower in pollinator habitat enhancements, but the number of species was not clearly different between habitat types. We did not find a clear positive nor negative effect of habitat enhancement for species designated rare based on geographic range size. For all three rarity metrics, common species increased in abundance and richness in pollinator habitat relative to controls. Null models indicated that in most cases, neither rare nor common species disproportionately benefited from pollinator habitat.

Synthesis and Applications:Our results suggest that pollinator habitat can lead to an increase in the abundance and richness of bees, including species that are rare and that are common. However, rare species appeared to respond differently than typical species, and depending on how species were classified as rare, could display muted or even negative responses to habitat enhancement. Targeting rare species with specific floral resources or unique habitat types may lead to better outcomes for rare and threatened species.
Fast raster-scan optoacoustic mesoscopy enables assessment of human melanoma microvasculature in vivo
Authors: He Hailong , Schönmann Christine , Schwarz Mathias , Hindelang Benedikt , Bereznhoi Andrei , Steimle-Grauer Annette , Darsow Ulf , Aguirre Juan , Ntziachristos Vasilis
Published: May 2021

The development and progression of melanoma tumors is associated with angiogenesis, manifesting as changes in vessel density, morphology, and architecture that may extend through the entire skin depth. Three-dimensional imaging of vascular characteristics in skin lesions could allow diagnostic insights not available to the conventional visual inspection. Raster-scan optoacoustic mesoscopy (RSOM) has emerged as a unique modality to image microvasculature through the entire skin depth with resolutions of tens of micrometers, offering new possibilities to assess angiogenetic processes. However, current RSOM implementations are slow, exacerbating motion artifacts and reducing image quality, particularly when imaging melanoma lesions that often appear on the upper torso where breathing motion is strongest. To visualize for the first time melanoma vasculature in humans, in high-resolution, we accelerated RSOM scanning using an illumination scheme that is co-axial with a high-sensitivity ultrasound detector path, yielding 15 second single-breath-hold scans that minimize motion artifacts. Applied to 10 melanomas and 10 benign nevi in humans, we demonstrate visualization of microvasculature with performance never before shown in vivo. We show marked differences between malignant and benign lesions, supporting the possibility to use vasculature as a biomarker for lesion characterization. The study points to promising clinical potential for Fast-RSOM (FRSOM) as a three dimensional visualization method that can enable the complete assessment of microvascular parameters of melanoma and improve diagnostics.
Behaviour of smokers and their influencers in the UK during COVID-19 pandemic
Authors: Patwardhan Sudhanshu , Trainer Claudia
Published: May 2021

Purpose

The COVID-19 pandemic has resulted in unprecedented circumstances and changes in behaviour. This research sought to better understand the impact of the COVID-19 pandemic, and lockdown, on smoking behaviour in the UK from the perspectives of consumers (current and former smokers) and some of their smoking-related behaviour-influencers.

Design/methodology/approach

This research project encompassed two surveys, one for current and former smokers (Consumers) and one for those individuals in professions with the potential to influence smoking behaviours (Influencers). Both surveys were conducted online and were infield for approximately two weeks during UK’s first COVID-19 lockdown. Because of the unprecedented times the society was experiencing, several questions relating directly to COVID-19 were added to the survey and this paper is based only on findings only from those questions and not the whole project. The results were analysed descriptively.

Findings

A total of 954 consumers and 1027 influencers participated in the surveys. Increased smoking was reported by 67% of the consumers mainly due to stress and boredom arising out of COVID-19 lockdown. Consumers under 45 years of age, those in professional and managerial occupations, and among dual users reported increased smoking in lockdown. The COVID-19 situation changed the plans to quit smoking in 36% of consumers, with only 6% deciding to quit. Only 40% of healthcare professionals (HCPs) documented patient smoking status in over half their interactions.

Originality/ value

This research among current and former smokers and their influencers highlights important changes in behaviour during the COVID-19 times and underscores urgent measures to be taken by HCPs and policymakers for staying on course of achieving smokefree goals despite challenges posed by COVID-19.
Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types
Authors: Sinha Neelam , Sinha Sanju , Valero Cristina , Schäffer Alejandro A. , Aldape Kenneth , Litchfield Kevin , Chan Timothy A , Morris Luc G T , Ruppin Eytan
Published: May 2021

The FDA has recently approved high tumor mutational burden (TMB), defined by ≥10 mutations/Mb, as a biomarker for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies testify that high TMB levels are only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power) in a cancer type, leading to this observation. To systematically study this hypothesis, we analyzed TCGA expression data to infer the levels of 31 immune-related factors characteristic of the TME of different cancer types. We integrated this information with TMB and response data of 2,277 patients treated with anti-PD1 or anti-PD-L1 ICI to identify the key immune factors that can determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterize cancer types with high TMB power. A model based on these two immune factors is strongly predictive of the TMB power in a given cancer type (Spearman Rho=0.76, P<3.6×10−04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. Our analysis indicates that TMB-High may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.
Dynamics of Functional Network Organization Through Graph Mixture Learning
Authors: Ricchi Ilaria , Tarun Anjali , Maretic Hermina Petric , Frossard Pascal , Van De Ville Dimitri
Published: May 2021

Understanding the organizational principles of human brain activity at the systems level remains a major challenge in network neuroscience. Here, we introduce a fully data-driven approach based on graph learning to extract meaningful repeating network patterns from regionally-averaged time-courses. We use the Graph Laplacian Mixture Model (GLMM), a generative model that treats functional data as a collection of signals expressed on multiple underlying graphs. By exploiting covariance between activity of brain regions, these graphs can be learned without resorting to structural information. To validate the proposed technique, we first apply it to task fMRI with a known experimental paradigm. The probability of each graph to occur at each time-point is found to be consistent with the task timing, while the spatial patterns associated to each epoch of the task are in line with previously established activation patterns using classical regression analysis. We further on apply the technique to resting state data, which leads to extracted graphs that correspond to well-known brain functional activation patterns. The GLMM allows to learn graphs entirely from the functional activity that, in practice, turn out to reveal high degrees of similarity to the structural connectome. We compared similarity of the default mode network estimated from different task data and comparing them to each other and to structure. Using different metrics, a similar distinction between high- and low-level cognitive tasks arises.

Overall, this method allows us to infer relevant functional brain networks without the need of structural connectome information. Moreover, we find that these networks correspond better to structure compared to traditional methods.
Feasibility of FreeSurfer processing for T1-weighted brain images of 5-year-olds: semiautomated protocol of FinnBrain Neuroimaging Lab
Authors: Pulli Elmo P. , Silver Eero , Kumpulainen Venla , Copeland Anni , Merisaari Harri , Saunavaara Jani , Parkkola Riitta , Lähdesmäki Tuire , Saukko Ekaterina , Nolvi Saara , Kataja Eeva-Leena , Korja Riikka , Karlsson Linnea , Karlsson Hasse , Tuulari Jetro J.
Published: May 2021

Pediatric neuroimaging is a quickly developing field that still faces important methodological challenges. One key challenge is the use of many different atlases, automated segmentation tools, manual edits in semiautomated protocols, and quality control protocols, which complicates comparisons between studies. In this article, we present our semiautomated segmentation protocol using FreeSurfer v6.0, ENIGMA consortium software, and the quality control protocol that was used in FinnBrain Birth Cohort Study. We used a dichotomous quality rating scale for inclusion and exclusion of images, and then explored the quality on a region of interest level to exclude all regions with major segmentation errors. The effects of manual edits on cortical thickness values were minor: less than 2% in all regions. Supplementary materials cover registration and additional edit options in FreeSurfer and comparison to the computational anatomy toolbox (CAT12). Overall, we conclude that despite minor imperfections FreeSurfer can be reliably used to segment cortical metrics from T1-weighted images of 5-year-old children with appropriate quality assessment in place. However, custom templates may be needed to optimize the results for the subcortical areas. Our semiautomated segmentation protocol provides high quality pediatric neuroimaging data and could help investigators working with similar data sets.
TRPA1 block protects against loss of white matter function during ischaemia in the mouse optic nerve
Authors: Lajoso Wendy , Flower Grace , Giacco Vincenzo , Kaul Anjuli , La Mache Circe , Brăban Andra , Roxas Angela , Hamilton Nicola
Published: May 2021

Oligodendrocytes produce myelin which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions myelin is damaged, resulting in mental and physical disabilities. Therefore, it is important to understand how the function of oligodendrocytes and myelin is affected by ischaemia. Recent evidence suggests that oligodendrocyte damage during ischaemia is mediated by TRPA1, whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is constitutively active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential. Conversely, TRPA1 agonists reduce the size of the optic nerve compound action potential, and this effect is significantly reduced by the TRPA1 antagonist. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of compound action potentials during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during or after OGD, indicating that the damage is occurring during ischaemia and during the recovery, but importantly, that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating oligodendrocyte loss and damage in many white matter diseases.
Alpha phase-amplitude tradeoffs predict visual perception
Authors: Fakche Camille , VanRullen Rufin , Marque Philippe , Dugué Laura
Published: May 2021

Spontaneous alpha oscillations (~10 Hz) have been associated with various cognitive functions, including perception. Their phase and amplitude independently predict cortical excitability and subsequent perceptual performance. Yet, the causal role of alpha phase-amplitude tradeoffs on visual perception remains ill-defined. We aimed to fill this gap and tested two clear predictions from the Pulsed Inhibition theory according to which alpha oscillations are associated with periodic functional inhibition. (1) High alpha amplitude induces cortical inhibition at specific phases, associated with low perceptual performance, while at opposite phases, inhibition decreases (potentially increasing excitation) and perceptual performance increases. (2) Low alpha amplitude is less susceptible to these phasic (periodic) pulses of inhibition, leading to overall higher perceptual performance. Here, cortical excitability was assessed in humans using phosphene (illusory) perception induced by single pulses of transcranial magnetic stimulation (TMS) applied over visual cortex at perceptual threshold, and its post-pulse evoked activity recorded with simultaneous electroencephalography (EEG). We observed that pre-pulse alpha phase modulates the probability to perceive a phosphene, predominantly for high alpha amplitude, with a non-optimal phase for phosphene perception between −π/2 and −π/4. The pre-pulse non-optimal phase further leads to an increase in post-pulse evoked activity (ERP), in phosphene-perceived trials specifically. Together, these results show that alpha oscillations create periodic inhibitory moments when alpha amplitude is high, leading to periodic decrease of perceptual performance. This study provides strong causal evidence in favor of the Pulsed Inhibition theory.

Visual Abstract

Significance Statement

The Pulsed Inhibition theory predicts that the functional inhibition induced by high alpha oscillations’ amplitude is periodic, with specific phases decreasing neural firing and perceptual performance. In turn, low alpha oscillations’ amplitude is less susceptible to phasic moments of pulsed inhibition leading to overall higher perceptual performance. Using TMS with simultaneous EEG recordings in humans, we found that specific phases of spontaneous alpha oscillations (~10 Hz) decrease cortical excitability and the subsequent perceptual outcomes predominantly when alpha amplitude is high. Our results provide strong causal evidence in favor of the Pulsed Inhibition theory.
High fidelity epigenetic inheritance: Information theoretic model predicts k-threshold filling of histone modifications post replication
Authors: Ramakrishnan Nithya , Pillai Sibi Raj B , Padinhateeri Ranjith
Published: May 2021

Beyond the genetic code, there is another layer of information encoded as chemical modifications on histone proteins positioned along the DNA. Maintaining these modifications is crucial for survival and identity of cells. How the information encoded in the histone marks gets inherited, given that only half the parental nucleosomes are transferred to each daughter chromatin, is a puzzle. Mapping DNA replication and reconstruction of modifications to equivalent problems in communication of information, we ask how well enzymes can recover the parental modifications, if they were ideal computing machines. Studying a parameter regime where realistic enzymes can function, our analysis predicts that, pragmatically, enzymes may implement a threshold − k filling algorithm which fills unmodified regions of length at most k. This algorithm, motivated from communication theory, is derived from the maximum à posteriori probability (MAP) decoding which identifies the most probable modification sequence based on available observations. Simulations using our method produce modification patterns similar to what has been observed in recent experiments. We also show that our results can be naturally extended to explain inheritance of spatially distinct antagonistic modifications.
PERK Activation by SB202190 Attenuates Amyloidogenesis via TFEB-induced Autophagy-Lysosomal Pathway
Authors: Do Mihyang , Park Jeongmin , Chen Yubing , Rah So-Young , Nghiem Thu-Hang Thi , Gong Jeong Heon , Kim Byung-Sam , Park Jeong Woo , Ryter Stefan W. , Surh Young-Joon , Kim Uh-Hyun , Joe Yeonsoo , Chung Hun Taeg
Published: May 2021

The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1α (IRE1α) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.
Parthenogenesis and the Evolution of Anisogamy
Authors: Constable George W.A. , Kokko Hanna
Published: May 2021

Recently, it was pointed out [1] that classic models for the evolution of anisogamy do not take into account the possibility of parthenogenetic reproduction, even though sex is facultative in many relevant taxa (e.g. algae) that harbour both anisogamous and isogamous species. Here we complement the analysis of [1] with an approach where we assume that the relationship between progeny size and its survival may differ between parthenogenetically and sexually produced progeny, favouring either the former or the latter. We show that the findings of [1], that parthenogenesis can stabilise isogamy relative to the obligate sex case, extend to our scenarios. We additionally investigate two different ways for one mating type to take over the entire population. First, parthenogenesis can lead to biased sex ratios that are sufficiently extreme that one type can displace the other, leading to de facto asexuality for the remaining type that now lacks partners to fuse with. This process involves positive feedback: microgametes, being numerous, lack opportunities for syngamy, and should they proliferate parthenogenetically, the next generation makes this asexual route even more prominent for microgametes. Second, we consider mutations to strict asexuality in producers of micro- or macrogametes, and show that the prospects of asexual invasion depend strongly on the mating type in which the mutation arises. Perhaps most interestingly, we also find scenarios in which parthenogens have an intrinsic survival advantage yet facultatively sexual isogamous populations are robust to the invasion of asexuals, despite us assuming no genetic benefits of recombination. Here equal contribution from both mating types to zygotes that are sufficiently well provisioned can outweigh the additional costs associated with syngamy.
Orthogonal translation initiation using the non-canonical initiator tRNA(AAC) alters protein sequence and stability in vivo
Authors: Hutvagner Andras , Scopelliti Dominic , Whelan Fiona , Jaschke Paul R.
Published: May 2021

Biological engineers seek to have better control and a more complete understanding of the process of translation initiation within cells so that they may produce proteins more efficiently, as well as to create orthogonal translation systems. Previously, initiator tRNA variants have been created that initiate translation from non-AUG start codons, but their orthogonality has never been measured and the detailed characteristics of proteins produced from them have not been well defined. In this study we created an initiator tRNA mutant with anticodon altered to AAC to be complementary to GUU start codons. We deploy this i-tRNA(AAC) into E. coli cells and measure translation initiation efficiency against all possible start codons. Using parallel reaction monitoring targeted mass spectrometry we identify the N-terminal amino acids of i-tRNA(AAC)-initiated reporter proteins and show these proteins have altered stability within cells. We also use structural modeling of the peptide deformylase enzyme interaction with position 1 valine peptides to interrogate a potential mechanism for accumulation of formylated-valine proteins observed by mass spectrometry. Our results demonstrate that mutant initiator tRNAs have potential to initiate translation more orthogonally than the native initiator tRNA but their interactions with cellular formyltransferases and peptide deformylases can be inefficient because of the amino acid they are charged with. Additionally, engineered initiator tRNAs may enable tuning of in vivo protein stability through initiation with non-methionine amino acids that alter their interaction with cellular proteases.
Internal and external features of wild birds after collisions without apparent trauma in Japan
Authors: Ushine Nana , Tanaka Aki , Sato Tatsuo , Nonagase Masaki , Hayama Shin-ichi
Published: May 2021

Wild birds often require rehabilitation after collisions, even with no apparent injury. Information about aftermath of collisions is still scares. Here, we investigated external characteristics and clinical features of the internal organs of wild birds that experienced collision and compared them with birds admitted to rehabilitation center for other reasons. Necropsy was performed on 55 bird carcasses from Passeriformes and Coraciiform. Five external characteristics were recorded before necropsy including; cause of admission, keel score, life stage, fat score, and number of days before death. The median survival time was calculated by Kaplan-Meier estimates. Data on external and internal features were compared using univariate and multivariate multinomial regressions. There was no significant difference in the median survival time among the causes of admission: 1 day for collision, 2 days for trauma, and 2 days for malnutrition. Kidney discoloration was more significantly associated with collision than with other trauma (p = 0.01). Although no apparent kidney abnormality (including enlargement) were observed, anterior lobe was significantly larger than posterior lobe with collision compared with malnutrition (p = 0.045). Birds that experienced collision exhibited a higher fat score than malnourished birds (p = 0.03). Our results suggested that wild birds with abundant fat were more likely to be admitted due to collision. The gross characteristics of collision included kidney discoloration and anterior lobe extension, which was possibly due to rupture of renal blood vessels by blunt external force. From these findings, it was considered that collision caused major axis of anterior lobe significantly larger than posterior lobe, even though no abnormal finding in renal size such as hypertrophy was recognized. This was the first study to evaluate the cause of admission, necropsy results, and external characteristics in wild birds admitted to rehabilitation centers. Absolute cage rest should be adhered to restore renal function for those birds admitted due to collision, and handling and treatment should be minimized to avoid excess movement of the birds.
CoRe: A robustly benchmarked R package for identifying core-fitness genes in genome-wide pooled CRISPR-Cas9 screens
Authors: Vinceti Alessandro , Karakoc Emre , Pacini Clare , Perron Umberto , De Lucia Riccardo Roberto , Garnett Mathew J. , Iorio Francesco
Published: May 2021

CRISPR-Cas9 genome-wide screens are being increasingly performed, allowing systematic explorations of cancer dependencies at unprecedented accuracy and scale. Identifying from these screens the genes that are essential for cell survival invariantly across tissues, conditions, and genomic-contexts (core-fitness genes), is of paramount importance to assess the safety profile of candidate therapeutic targets and for elucidating mechanisms involved in tissue-specific genetic diseases. We present CoRe: An R package implementing novel methods for identifying core-fitness genes from joint analyses of multiple CRISPR-Cas9 screens. We demonstrate that CoRe outperforms state-of-the-art tools, yielding more reliable sets of core-fitness genes than existing and widely used reference sets.
Computational Design Map for Heterogeneous Experimental Studies
Authors: Kulkarni Chhaya , Maisha Nuzhat , Schaub Leasha J , Glaser Jacob , Lavik Erin , Janeja Vandana P.
Published: May 2021

This paper focuses on the discovery of a computational design map of disparate heterogeneous outcomes from bioinformatics experiments in pig (porcine) studies to help identify key variables impacting the experiment outcomes. Specifically we aim to connect discoveries from disparate laboratory experimentation in the area of trauma, blood loss and blood clotting using data science methods in a collaborative ensemble setting. Trauma related grave injuries cause exsanguination and death, constituting up to 50% of deaths especially in the armed forces. Restricting blood loss in such scenarios usually requires the presence of first responders, which is not feasible in certain cases. Moreover, a traumatic event may lead to a cytokine storm, reflected in the cytokine variables. Hemostatic nanoparticles have been developed to tackle these kinds of situations of trauma and blood loss. This paper highlights a collaborative effort of using data science methods in evaluating the outcomes from a lab study to further understand the efficacy of the nanoparticles. An intravenous administration of hemostatic nanoparticles was executed in pigs that had to undergo hemorrhagic shock and blood loss and other immune response variables, cytokine response variables are measured. Thus, through various hemostatic nanoparticles used in the intervention, multiple data outcomes are produced and it becomes critical to understand which nanoparticles are critical and what variables are key to study further variations in the lab. We propose a collaborative data mining framework which combines the results from multiple data mining methods to discover impactful features. We used frequent patterns observed in the data from these experiments. We further validate the connections between these frequent rules by comparing the results with decision trees and feature ranking. Both the frequent patterns and the decision trees help us identify the critical variables that stand out in the lab studies and need further validation and follow up in future studies. The outcomes from the data mining methods help produce a computational design map of the experimental results. Our preliminary results from such a computational design map provided insights in determining which features can help in designing the most effective hemostatic nanoparticles.
Diversity of satellite glia in sympathetic and sensory ganglia
Authors: Mapps Aurelia A , Thomsen Michael B , Boehm Erica , Zhao Haiqing , Hattar Samer , Kuruvilla Rejji
Published: May 2021

Satellite glia are the major glial type found in ganglia of the peripheral nervous system and wrap around cell bodies of sympathetic and sensory neurons that are very diverse. Other than their close physical association with peripheral neurons, little is known about this glial population. Here, we performed single cell RNA sequencing analysis and identified five different populations of satellite glia from sympathetic and sensory ganglia. We identified three shared populations of satellite glia enriched in immune-response genes, immediate-early genes and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid synthesis and metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Further, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals remarkable heterogeneity of satellite glia in the peripheral nervous system.