bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pipeline for constructing reference genomes for large cohort-specific metagenome compression
Authors: Wang Linqi , Ding Renpeng , He Shixu , Wang Qinyu , Zhou Yan 
Published: September 2023

AbstractMetagenomic data compression is very important as metagenomic projects are facing the challenges of larger data volumes per sample and more samples nowadays. The reference-based compression is a promising method to obtain a high compression ratio. However, existing microbial reference genome databases are not suitable to be directly used as references for compression due to their large size and redundancy, and different metagenomic cohorts often have various microbial compositions. We presented a novel pipeline that generated simplified and tailored reference genomes for large metagenomic cohorts, enabling reference-based compression for metagenomic data. We constructed customized reference genomes, ranging from 2.4 to 3.9GB, for 29 real metagenomic datasets, and evaluated their compression performance. Reference-based compression achieved an impressive compression ratio of over 20 for human whole-genome data and up to 33.8 for all samples, demonstrating a remarkably 4.5 times improvement than the standard Gzip compression. Our method provides new insights into reference-based metagenomic data compression and has a broad application potential for faster and cheaper data transfer, storage, and analysis.
Toolkits for detailed and high-throughput interrogation of synapses inC. elegans
Authors: Majeed Maryam , Han Haejun , Zhang Keren , Cao Wen Xi , Liao Chien-Po , Hobert Oliver , Lu Hang 
Published: September 2023

ABSTRACTVisualizing synaptic connectivity has traditionally relied on time-consuming electron microscopy-based imaging approaches. To scale the analysis of synaptic connectivity, fluorescent protein-based techniques have been established, ranging from the labeling of specific pre- or postsynaptic components of chemical or electrical synapses to transsynaptic proximity labeling technology such as GRASP and iBLINC. In this paper, we describe WormPsyQi, a generalizable image analysis pipeline that automatically quantifies synaptically localized fluorescent signals in a high-throughput and robust manner, with reduced human bias. We also present a resource of 30 transgenic strains that label chemical or electrical synapses throughout the nervous system of the nematodeC. elegans, using CLA-1, RAB-3, GRASP (chemical synapses), or innexin (electrical synapse) reporters. We show that WormPsyQi captures synaptic structures in spite of substantial heterogeneity in neurite morphology, fluorescence signal, and imaging parameters. We use these toolkits to quantify multiple obvious and subtle features of synapses - such as number, size, intensity, and spatial distribution of synapses - in datasets spanning various regions of the nervous system, developmental stages, and sexes. Although the pipeline is described in the context of synapses, it may be utilized for other ‘punctate’ signals, such as fluorescently-tagged neurotransmitter receptors and cell adhesion molecules, as well as proteins in other subcellular contexts. By overcoming constraints on time, sample size, cell morphology, and phenotypic space, this work represents a powerful resource for further analysis of synapse biology inC. elegans.
Inference of multiple mergers while dating a pathogen phylogeny
Authors: Helekal David , Koskela Jere , Didelot Xavier 
Published: September 2023

ABSTRACTThe vast majority of pathogen phylogenetic studies do not consider the possibility of multiple merger events being present, where a single node of the tree leads to more than two descendent branches. These events are however likely to occur when studying a relatively small population or if there is high variability in the reproductive chances. Here we consider the problem of detecting the presence of multiple mergers in the context of dating a phylogeny, that is determining the date of each of the nodes. We use the Lambda-coalescent theory as a modelling framework and show how Bayesian inference can be efficiently performed using a Billera-Holmes-Vogtmann space embedding and a customised Markov Chain Monte Carlo sampling scheme. We applied this new analysis methodology to a large number of simulated datasets to show that it is possible to infer if and when multiple merger events occurred, and that the phylogenetic dating is improved as a result of taking this information into account. We also analysed real datasets ofVibrio choleraeandMycobacterium tuberculosisto demonstrate the relevance of our approach to real pathogen evolutionary epidemiology. We have implemented our new methodology in a R package which is freely available athttps://github.com/dhelekal/MMCTime.
Inferring viral transmission time from phylogenies for known transmission pairs
Authors: Goldberg Emma E. , Lundgren Erik J. , Romero-Severson Ethan O. , Leitner Thomas 
Published: September 2023

AbstractWhen the time of an HIV transmission event is unknown, methods to identify it from virus genetic data can reveal the circumstances that enable transmission. We developed a single-parameter Markov model to infer transmission time from an HIV phylogeny constructed of multiple virus sequences from people in a transmission pair. Our method finds the statistical support for transmission occurring in different possible time slices. We compared our time-slice model results to previously-described methods: a tree-based logical transmission interval, a simple parsimony-like rules-based method, and a more complex coalescent model. Across simulations with multiple transmitted lineages, different transmission times relative to the source’s infection, and different sampling times relative to transmission, we found that overall our time-slice model provided accurate and narrower estimates of the time of transmission. We also identified situations when transmission time or direction was difficult to estimate by any method, particularly when transmission occurred long after the source was infected and when sampling occurred long after transmission. Applying our model to real HIV transmission pairs showed some agreement with facts known from the case investigations. We also found, however, that uncertainty on the inferred transmission time was driven more by uncertainty from time-calibration of the phylogeny than from the model inference itself. Encouragingly, comparable performance of the Markov time-slice model and the coalescent model—which make use of different information within a tree—suggests that a new method remains to be described that will make full use of the topology and node times for improved transmission time inference.
A Meta-Atlas of the Developing Human Cortex Identifies Modules Driving Cell Subtype Specification
Authors: Nano Patricia R. , Fazzari Elisa , Azizad Daria , Nguyen Claudia V. , Wang Sean , Kan Ryan L. , Wick Brittney , Haeussler Maximilian , Bhaduri Aparna 
Published: September 2023

AbstractHuman brain development requires the generation of hundreds of diverse cell types, a process targeted by recent single-cell transcriptomic profiling efforts. Through a meta-analysis of seven of these published datasets, we have generated 225 meta-modules – gene co-expression networks that can describe mechanisms underlying cortical development. Several meta-modules have potential roles in both establishing and refining cortical cell type identities, and we validated their spatiotemporal expression in primary human cortical tissues. These include meta-module 20, associated with FEZF2+ deep layer neurons. Half of meta-module 20 genes are putative FEZF2 targets, including TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical organoid experiments validated that both factors are necessary for deep layer neuron specification. Importantly, subtle manipulations of these factors drive slight changes in meta-module activity that cascade into strong differences in cell fate – demonstrating how of our meta-atlas can engender further mechanistic analyses of cortical fate specification.
SKIN REINNERVATION BY COLLATERAL SPROUTING FOLLOWING SPARED NERVE INJURY IN MICE
Authors: Jeon S.M. , Pradeep A. , Chang D. , McDonough L. , Chen Y. , Latremoliere A. , Crawford L.K. , Caterina M.J. 
Published: September 2023

AbstractFollowing peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured afferents into the denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received relatively less attention. In this study, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hind paw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following an initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated the denervated epidermis, Interestingly, GFRα2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by trend towards regression. Presumptive sympathetic nerve fibers also sprouted into the denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so less efficiently. Conversely, rapidly adapting Aβ fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing collateral sprouting up to 8 weeks after nerve injury. Optogenetics and behavioral assays further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury.Significance StatementFollowing nerve injury, whereas one mechanism for tissue reinnervation is regeneration of injured neurons, another, less well studied mechanism is collateral sprouting of nearby uninjured neurons. In this study, we examined collateral sprouting in denervated mouse skin and showed that it involves some, but not all neuronal subtypes. Despite such heterogeneity, a significant degree of restoration of punctate mechanical sensitivity is achieved. These findings highlight the diversity of collateral sprouting among peripheral neuron subtypes and reveal important differences between pre- and post-denervation skin that might be appealing targets for therapeutic correction to enhance functional recovery from denervation and prevent unwanted sensory phenomena such as pain or numbness.
ATLAS: A rationally designed anterograde transsynaptic tracer
Authors: Rivera Jacqueline F. , Weng Weiguang , Huang Haoyang , Rao Sadhna , Herring Bruce E. , Arnold Don B. 
Published: September 2023

ABSTRACTNeural circuits, which constitute the substrate for brain processing, can be traced in the retrograde direction, from postsynaptic to presynaptic cells, using methods based on introducing modified rabies virus into genetically marked cell types. These methods have revolutionized the field of neuroscience. However, similarly reliable, transsynaptic, and non-toxic methods to trace circuits in the anterograde direction are not available. Here, we describe such a method based on an antibody-like protein selected against the extracellular N-terminus of the AMPA receptor subunit GluA1 (AMPA.FingR). ATLAS (AnterogradeTranssynapticLabel based onAntibody-likeSensors) is engineered to release the AMPA.FingR and its payload, which can include Cre recombinase, from presynaptic sites into the synaptic cleft, after which it binds to GluA1, enters postsynaptic cells through endocytosis and subsequently carries its payload to the nucleus. Testing in vivo and in dissociated cultures shows that ATLAS mediates monosynaptic tracing from genetically determined cells that is strictly anterograde, synaptic, and non-toxic. Moreover, ATLAS shows activity dependence, which may make tracing active circuits that underlie specific behaviors possible.
Reduced cerebellar Gq-protein signaling elicits early onset spatial navigation deficits in a SCA6 mouse model
Authors: Grömmke Michelle , Schulte Hannah , Theis Candy D. C. , Nonnweiler Lena , Mark Melanie D. 
Published: September 2023

AbstractSpinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease that manifests in a late onset and progressive impairment of motor coordination, balance and speech as well as cerebellar and brainstem atrophy. It is caused by a polyglutamine expansion in theCACNA1Agene which bicistronically encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor α1ACT. To date, no effective treatment exists and the exact pathobiology is controversially discussed; especially the impact on cognition is poorly understood. Here, we demonstrate that SCA6 84Q mice exhibit cognitive deficits in their spatial navigation abilities. Surprisingly, spatial memory impairments develop prior to motor impairments at 5 months of age. By expressing and stimulating a Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD) in the cerebellum, we were able to counteract these spatial navigation deficits indicating that a reduced Gq-protein signaling is part of the SCA6 phenotype. Electrophysiological recordings in anaesthetized mice further revealed that Purkinje cells (PCs) of SCA6 84Q mice exhibit a disrupted spontaneous simple spike activity that precedes the development of both cognitive and motor deficits. Concurrently, PC dysfunction was further confirmed by elevated numbers of torpedoes found in the proximal axon of PCs throughout the cerebellum. Overall, our study raises awareness to survey cognitive abnormalities more carefully during clinical examination to detect the disease earlier and potentially optimize the individual treatment by enhancing PC signaling.Significance statementSCA6 is a hereditary neurological disease that is mainly characterized by the late-onset development of progressive motor deficits. Here we show, using a SCA6 mouse model, that cognitive impairments in spatial navigation are also a non-negligible feature of the disease which manifests earlier than the motor deficits. Moreover, we demonstrate that these spatial navigation deficits are caused by a reduced Gq-protein signaling in the cerebellum. Electrophysiological and histological analysis further confirmed dysfunctional PC signaling even before the onset of first symptoms. Since no effective treatment is available for SCA6 patients, early onset stimulation of PC signaling may be a new therapeutic approach.
Unraveling Neural Complexity: Exploring Brain Entropy to Yield Mechanistic Insight in Neuromodulation Therapies for Tobacco Use Disorder
Authors: Jordan Timothy , Apostol Michael R. , Nomi Jason , Petersen Nicole 
Published: September 2023

AbstractNeuromodulation therapies, such as repetitive transcranial magnetic stimulation (rTMS), have shown promise as treatments for tobacco use disorder (TUD). However, the underlying mechanisms of these therapies remain unclear, which may hamper optimization and personalization efforts. In this study, we investigated alteration of brain entropy as a potential mechanism underlying the neural effects of noninvasive brain stimulation by rTMS in people with TUD. We employed sample entropy (SampEn) to quantify the complexity and predictability of brain activity measured using resting-state fMRI data. Our study design included a randomized single-blind study with 42 participants who underwent 2 data collection sessions. During each session, participants received high-frequency (10Hz) stimulation to the dorsolateral prefrontal cortex (dlPFC) or a control region (visual cortex), and resting-state fMRI scans were acquired before and after rTMS. Our findings revealed that individuals who smoke exhibited higher baseline SampEn throughout the brain as compared to previously-published SampEn measurements in control participants. Furthermore, high-frequency rTMS to the dlPFC but not the control region reduced SampEn in the insula and dlPFC, regions implicated in TUD, and also reduced self-reported cigarette craving. These results suggest that brain entropy may serve as a potential biomarker for effects of rTMS, and provide insight into the neural mechanisms underlying rTMS effects on smoking cessation. Our study contributes to the growing understanding of brain-based interventions for TUD by highlighting the relevance of brain entropy in characterizing neural activity patterns associated with smoking. The observed reductions in entropy following dlPFC-targeted rTMS suggest a potential mechanism for the therapeutic effects of this intervention. These findings support the use of neuroimaging techniques to investigate the use of neuromodulation therapies for TUD.
Smooth Pursuit Inhibition Reveals Audiovisual Enhancement of Fast Movement Control
Authors: Kreyenmeier Philipp , Bhuiyan Ishmam , Gian Mathew , Chow Hiu Mei , Spering Miriam 
Published: September 2023

AbstractThe sudden onset of a visual object or event elicits an inhibition of eye movements at latencies approaching the minimum delay of visuomotor conductance in the brain. Typically, information presented via multiple sensory modalities, such as sound and vision, evokes stronger and more robust responses than unisensory information. Whether and how multisensory information affects ultra-short latency oculomotor inhibition is unknown. In two experiments, we investigate smooth pursuit and saccadic inhibition in response to multisensory distractors. Observers tracked a horizontally moving dot and were interrupted by an unpredictable visual, auditory, or audiovisual distractor. Distractors elicited a transient inhibition of pursuit eye velocity and catch-up saccade rate within ∼100 ms of their onset. Audiovisual distractors evoked stronger oculomotor inhibition than visual-or auditory-only distractors, indicating multisensory response enhancement. Multisensory response enhancement magnitudes were equal to the linear sum of responses to component stimuli. These results demonstrate that multisensory information affects eye movements even at ultra-short latencies, establishing a lower time boundary for multisensory-guided behaviour. We conclude that oculomotor circuits must have privileged access to sensory information from multiple modalities, presumably via a fast, subcortical pathway.
Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency
Authors: Papandreou Apostolos , Singh Nivedita , Gianfrancesco Lorita , Budinger Dimitri , Barwick Katy , Agrotis Alexander , Luft Christin , Shao Ying , Lenaerts An-Sofie , Gregory Allison , Jeong Suh Young , Hogarth Penelope , Hayflick Susan , Barral Serena , Kriston-Vizi Janos , Gissen Paul , Kurian Manju A , Ketteler Robin 
Published: September 2023

AbstractBeta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45. The mechanisms linking autophagy, iron overload and neurodegeneration in BPAN are poorly understood and, as a result, there are currently no disease-modifying treatments for this progressive disorder. We have developed a patient-derived, induced pluripotent stem cell (iPSC)-based midbrain dopaminergic neuronal cell model of BPAN (3 patient, 2 age-matched controls and 2 isogenic control lines) which shows defective autophagy and aberrant gene expression in key neurodegenerative, neurodevelopmental and collagen pathways. A high content imaging-based medium-throughput blinded drug screen using the FDA-approved Prestwick library identified 5 cardiac glycosides that both corrected disease-related defective autophagosome formation and restored BPAN-specific gene expression profiles. Our findings have clear translational potential and emphasise the utility of iPSC-based modelling in elucidating disease pathophysiology and identifying targeted therapeutics for early-onset monogenic disorders.
The functional background of the compensation committee chair: the choice and weight of performance measures in CEO compensation
Authors: Kalelkar Rachana , Nwaeze Emeka 
Published: September 2023

PurposeThe authors analyze the association between the functional background of the compensation committee chair and CEO compensation. The analysis is motivated by the continuing debate about the reasonableness of executive pay patterns and the growing emphasis on the role of compensation committees.Design/methodology/approachThe authors define three expert categories—accounting, finance, and generalist—and collect data on the compensation committee (CC) chairs of the S&P 500 firms from 2008 to 2018. The authors run an ordinary least square model and regress CEO total and cash compensation on the three expert categories.FindingsThe authors find that firms in which the CC chair has expertise in accounting, finance, and general business favor performance measures that are more aligned with accounting, finance, and general business, respectively. There is little evidence that CC chairs who are CEOs of other firms endorse more generous pay for the host CEO; the authors find some evidence that CC chairs tenure relative to the host CEO's is negatively associated with the level of the CEO's pay.Research limitations/implicationsThis study suggests that firms and regulators should consider the background of the compensation committee chair to understand the variations in top executive.Practical implicationsCompanies desiring to link executive compensation to particular areas of strategy must also consider matching the functional background of the compensation committee chair with the target strategy areas. From regulatory standpoint, requiring compensation committees to operate independent of inside directors can reduce attempts by inside directors to skim the process, but a failure to also consider the impact of compensation committees' discretion over the pay-setting process can distort the executives' pay-performance relation.Originality/valueThis is the first study to examine the effects of the functional background of the compensation committee chair on CEO compensation.