bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual working memory recruits two functionally distinct alpha rhythms in posterior cortex
Authors: Rodriguez-Larios Julio , ElShafei Alma , Wiehe Melanie , Haegens Saskia 
Published: April 2022

AbstractOscillatory activity in the human brain is dominated by posterior alpha oscillations (8-14 Hz), which have been shown to be functionally relevant in a wide variety of cognitive tasks. Although posterior alpha oscillations are commonly considered a single oscillator anchored at an individual alpha frequency (IAF; ∼10 Hz), previous work suggests that IAF reflects a spatial mixture of different brain rhythms. In this study, we assess whether Independent Component Analysis (ICA) can disentangle functionally distinct posterior alpha rhythms in the context of visual short-term memory retention. Magnetoencephalography (MEG) was recorded in 33 subjects while performing a visual working memory task. Group analysis at sensor level suggested the existence of a single posterior alpha oscillator that increases in power and decreases in frequency during memory retention. Conversely, single-subject analysis of independent components revealed the existence of two dissociable alpha rhythms: one that increases in power during memory retention (Alpha1) and another one that decreases in power (Alpha2). Alpha1 and Alpha2 rhythms were differentially modulated by the presence of visual distractors (Alpha1 increased in power while Alpha2 decreased) and had an opposite relationship with accuracy (positive for Alpha1 and negative for Alpha2). In addition, Alpha1 rhythms showed a lower peak frequency, a narrower peak width, a greater relative peak amplitude and a more central source than Alpha2 rhythms. Together, our results demonstrate that modulations in posterior alpha oscillations during short-term memory retention reflect the dynamics of at least two distinct brain rhythms with different functions and spatiospectral characteristics.Significance statementAlpha oscillations are the most prominent feature of the human brain’s electrical activity, and consist of rhythmic neuronal activity in posterior parts of the cortex. Alpha is usually considered a single brain rhythm that changes in power and frequency to support cognitive operations. We here show that posterior alpha entails at least two dissociable rhythms with distinct functions and characteristics. These findings could solve previous inconsistencies in the literature regarding the direction of task-related alpha power/frequency modulations and their relation to cognitive performance. In addition, the existence of two distinct posterior alpha rhythms could have important consequences for the design of neurostimulation protocols aimed at modulating alpha oscillations and subsequently cognition.
Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation
Authors: Alavattam Kris G , Mitzelfelt Katie A , Bonora Giancarlo , Fields Paul A , Yang Xiulan , Chiu Han Sheng , Pabon Lil , Bertero Alessandro , Palpant Nathan J , Noble William S , Murry Charles E 
Published: April 2022

AbstractBackgroundVascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. However, the gene regulatory mechanisms that underpin endothelial specialization are largely unknown, as are the roles of 3D chromatin organization in regulating endothelial cell transcription.MethodsTo investigate the relationships between 3D chromatin organization and gene expression in endothelial cell differentiation, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-seq assays at specific timepoints in differentiation.ResultsOur analyses reveal that long-range intrachromosomal contacts increase over the course of endothelial cell differentiation, as do genomic compartment transitions between active and inactive states. These compartmental states are tightly associated with endothelial transcription. Dynamic topologically associating domain (TAD) boundaries strengthen and converge on an endothelial cell state, and nascent TAD boundaries are linked to the expression of genes that support endothelial cell specification. Relatedly, chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes with essential roles in vascular biology, includingMECOM, TFPI, andKDR. To identify forms of regulation specific to endothelial cell differentiation, we compared the functional chromatin dynamics of endothelial cells with those of developing cardiomyocytes. Cardiomyocytes exhibit greater long-rangecisinteractions than endothelial cells, whereas endothelial cells have increased local intra-TAD interactions and much more abundant pairwise point interactions.ConclusionsGenome topology changes dynamically during endothelial differentiation, including acquisition of long-rangecisinteractions and new TAD boundaries, interconversion of hetero- and euchromatin, and formation of DNA loops. These chromatin dynamics guide transcription in the development of endothelial cells and promote the divergence of endothelial cells from related cell types such as cardiomyocytes.
A Deep SE(3)-Equivariant Model for Learning Inverse Protein Folding
Authors: McPartlon Matt , Lai Ben , Xu Jinbo 
Published: April 2022

AbstractIn this work, we establish a framework to tackle the inverse protein design problem; the task of predicting a protein’s primary sequence given its backbone conformation. To this end, we develop a generative SE(3)-equivariant model which significantly improves upon existing autoregressive methods. Conditioned on backbone structure, and trained with our novel partial masking scheme and side-chain conformation loss, we achieve state-of-the-art native sequence recovery on structurally independent CASP13, CASP14, CATH4.2, and TS50 test sets. On top of accurately recovering native sequences, we demonstrate that our model captures functional aspects of the underlying protein by accurately predicting the effects of point mutations through testing on Deep Mutational Scanning datasets. We further verify the efficacy of our approach by comparing with recently proposed inverse protein folding methods and by rigorous ablation studies.
Theory of spontaneous persistent activity and inactivity in vivo reveals differential cortico-entorhinal functional connectivity
Authors: Choudhary Krishna , Berberich Sven , Hahn Thomas T. G. , Mehta Mayank R. 
Published: April 2022

AbstractPersistent activity is thought to mediate working memory. While such stimulus evoked persistence is well studied, mechanisms of internally generated or spontaneous persistence in vivo are unknown. Further, current theories based on attractor dynamics focus on elevated activity as a memory substrate, while little attention has focused on the role of inactivity attractors. Here, we present a mean field model of functional interaction between large cortical networks that predicts both spontaneous persistent activity (SPA) and inactivity (SPI); the latter has never been seen before in experiments or models. We confirm these predictions using simultaneously recorded neocortical local field potential (LFP) and the membrane potential (Vm) of identified excitatory neurons from several brain areas in vivo during slow oscillations, especially from layer 3 of the medial (MECIII) and lateral entorhinal cortex (LECIII), which show SPA and SPI. By matching model and experimental statistics, we predict the relative strength of internal and external excitation in the LECIII and MECIII networks. Our predictions match anatomical data. Further, the model predicts, and the experiments confirm, that SPA and SPI are quantized by cortical UDS and follow the statistics of a history dependent Bernoulli process. These convergent, theory-experiment results thus reveal the differential nature of cortico-entorhinal functional connectivity, resulting in a unique pattern of persistent activity and persistent inactivity, a novel and energetically efficient memory substrate.
Resilience to anxiety and anhedonia after predator scent stress is accompanied by increased nucleus accumbens mGlu5 in female rats
Authors: Blount H.L. , Dee J. , Wu L. , Schwendt M. , Knackstedt L.A. 
Published: April 2022

AbstractDespite the higher prevalence of post-traumatic stress disorder (PTSD) in women, the majority of preclinical neuroscience research has been conducted utilizing male subjects. We have found that male rats exposed to the predator scent 2,4,5-trimethyl-3-thiazoline (TMT) show heterogenous development of long-term anxiety-like behavior and conditioned fear to the TMT environment. Stress-Resilient males exhibit increased mGlu5 mRNA expression in the basolateral amygdala (BLA) and prefrontal cortex. Here we sought to determine whether the same behavioral and genetic responses would be observed in female rats exposed to TMT. Sprague-Dawley rats were exposed to TMT for ten minutes, while Controls were exposed to an unscented environment. Anxiety and anhedonia were assessed 7-14 days later with elevated plus maze (EPM), acoustic startle response (ASR), light/dark box, and sucrose preference test. TMT-exposed females spent less time in the EPM open arms and exhibited greater startle amplitude, and reduced sucrose intake compared to Controls. Median split analyses conducted on EPM and sucrose intake yielded phenotypes that displayed behavior in the light/dark box consistent with EPM and sucrose testing. Unlike male Susceptible rats, female Susceptible rats showed no freezing when re-exposed to the TMT context, nor did Resilient female rats present elevated BLA mGlu5 mRNA levels. Instead, Susceptible females had greater BLA mGlu5 than Resilient or Control rats. This work indicates that, as in humans, rats exhibit sex-dependent responses to stress. This translational animal model may provide insight into how females are uniquely affected by PTSD.
Genomic underpinnings of population persistence in Isle Royale moose
Authors: Kyriazis Christopher C. , Beichman Annabel C. , Brzeski Kristin E. , Hoy Sarah R. , Peterson Rolf O. , Vucetich John A. , Vucetich Leah M. , Lohmueller Kirk E. , Wayne Robert K. 
Published: April 2022

AbstractIsland ecosystems provide models to assess the impacts of isolation on population persistence. However, most studies of persistence have focused on a single species, without comparisons to other organisms they interact with in the ecosystem. The simple predator-prey system of moose and gray wolves on Isle Royale provides allows a direct contrast of genetic variation in a prey species with their natural predator. Wolves on Isle Royale exhibited signs of severe inbreeding depression, which nearly drove the population to extinction in 2019. In the relative absence of wolves, the moose population has thrived and exhibits no obvious signs of inbreeding depression despite being isolated for ∼120 years and having low genetic diversity. Here, we examine the genomic underpinnings of population persistence in the Isle Royale moose population. We document high levels of inbreeding in the population, roughly as high as the wolf population at the time of its decline. However, inbreeding in the moose population manifests in the form of intermediate-length runs of homozygosity indicative of gradual inbreeding, contrasting with the severe recent inbreeding observed in the wolf population. Using simulations, we demonstrate that this more gradual inbreeding in the moose population has resulted in an estimated 50% purging of the inbreeding load, helping to explain the continued persistence of the population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Finally, we document low diversity in mainland North American moose populations due to a severe founder event occurring near the end of the Holocene. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the importance of maintaining isolated populations at moderate size to avert extinction from genetic factors.Significance statementIsolated wildlife populations face a high risk of extinction due in part to the deleterious consequences of inbreeding. Whether purifying natural selection can overcome these negative impacts by “purging” harmful recessive mutations is a topic of active debate. We characterized the extent of purging in an isolated moose population. Our results demonstrate signatures of gradual inbreeding in the population, ideal circumstances to facilitate purging. Using simulations, we demonstrate substantial potential for purging in the population, though we also show that fitness is reduced by small population size and inbreeding. Our findings provide insight into the mechanisms enabling persistence in isolated populations, with implications for conserving the growing number of isolated populations worldwide.
Evaluation of Nav1.8 as a therapeutic target for Pitt Hopkins Syndrome
Authors: Martinowich Keri , Das Debamitra , Sripathy Srinidhi Rao , Maher Brady J. 
Published: April 2022

AbstractPitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Nav1.8 and is consistently shown to be upregulated in PTHS mouse models. In this perspective, we review prior literature and present novel data that suggests inhibiting Nav1.8 in PTHS mouse models is effective at normalizing neuron function, brain circuit activity and behavioral abnormalities and posit this therapeutic approach as a treatment for PTHS.
A general framework for species-abundance distributions: linking traits and dispersal to explain commonness and rarity
Authors: Koffel Thomas , Umemura Kaito , Litchman Elena , Klausmeier Christopher A. 
Published: April 2022

AbstractSpecies-abundance distributions (SADs) describe the spectrum of commonness and rarity in a community. Beyond the universal observation that most species are rare and only a few common, more-precise description of SAD shape is controversial. Furthermore, the mechanisms behind SADs and how they vary along environmental gradients remain unresolved. We lack a general non-neutral theory of SADs. Here we develop a trait-based framework, focusing on a local community coupled to the region by dispersal. The balance of immigration and exclusion determines abundances, which vary over orders-of-magnitude. Under stabilizing selection, the local trait-abundance distribution (TAD) reflects a transformation of the regional TAD. The left-tail of the SAD depends on scaling exponents of the exclusion function and the regional species pool. More-complex local dynamics can lead to multimodal TADs and SADs. Connecting SADs with trait-based ecological theory provides a way to generate more-testable hypotheses on the controls over commonness and rarity in communities.
USAT: a Bioinformatic Toolkit to Facilitate Interpretation and Comparative Visualization of Tandem Repeat Sequences
Authors: Wang Xuewen , Budowle Bruce , Ge Jianye 
Published: April 2022

AbstractTandem repeats (TR), which are highly variable genomic variants, are widely used in individual identification, disease diagnostics and evolutionary studies. The recent advances of sequencing technologies and bioinformatic tools facilitate calling TR haplotypes. Both length-based and sequence-based TR alleles are used in different applications. However, sequence-based TR alleles could provide the highest precision to characterize TR haplotypes. Analysis of the differences between or among TR haplotypes, especially at the single nucleotide level, is the focus of TR haplotype characterization. In this study, we developed a Universal STR Allele Toolkit (USAT) for TR haplotype analysis, which includes allele size conversion, sequence comparison of haplotypes, figure plotting and comparison for allele distribution, and interactive visualization. An example application of USAT for analysis of the CODIS core STR loci with benchmarking human individuals demonstrated the capabilities of USAT. USAT has a user-friendly graphic interface and runs in all major computing operating systems at a fast speed with parallel computing enabled. In summary, USAT is able to facilitate the interpretation, visualization, and comparisons of TRs.
RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release from Enteroendocrine Cells
Authors: Shepherd Amy , Feinstein Laurence , Sabel Svetlana , Rastelli Daniella , Mezhibovsky Esther , Matthews Lynley , Muppirala Anoohya , Robinson Ariel , Gershon Michael D. , Rao Meenakshi 
Published: April 2022

AbstractBackground & AimsRET receptor tyrosine kinase is necessary for enteric nervous system (ENS) development. Loss-of-functionRETmutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, HSCR patients often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility.MethodsRetCFP/+mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET signaling in these cells regulates adult gut motilityin vivo, genetic and pharmacologic approaches were used to disrupt RET in either all RET-expressing cells, a major subset of enteric neurons, or intestinal epithelial cells.ResultsDistinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the intestinal epithelium, rather than in enteric neurons, slowed GI motility selectively in adult male mice. This effect was phenocopied by RET kinase inhibition. Most RET+epithelial cells were either enterochromaffin cells that release serotonin (5-HT) or L-cells that release peptide YY (PYY), both of which can alter motility. RET kinase inhibition exaggerated PYY release in a nutrient-dependent manner without altering 5-HT secretion. PYY receptor blockade fully rescued dysmotility in mice lacking epithelial RET.ConclusionRET signaling normally limits nutrient-dependent PYY release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to post-operative dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.Abstract Figure
Reconstructing physical cell interaction networks from single-cell data using Neighbor-seq
Authors: Ghaddar Bassel , De Subhajyoti 
Published: April 2022

ABSTRACTCell-cell interactions are the fundamental building blocks of tissue organization and multicellular life. We developed Neighbor-seq, a method to identify and annotate the architecture of direct cell-cell interactions and relevant ligand-receptor signaling from the undissociated cell fractions in massively parallel single cell sequencing data. Neighbor-seq accurately identifies microanatomical features of diverse tissue types such as the small intestinal epithelium, terminal respiratory tract, and splenic white pulp. It also captures the differing topologies of cancer-immune-stromal cell communications in pancreatic and skin tumors, which are consistent with the patterns observed in spatial transcriptomic data. Neighbor-seq is fast and scalable. It draws inferences from routine single-cell data and does not require prior knowledge about sample cell-types or multiplets. Neighbor-seq provides a framework to study the organ-level cellular interactome in health and disease, bridging the gap between single-cell and spatial transcriptomics.
Reproducible data integration and visualization of biological networks in R
Authors: Auer Florian , Chereda Hryhorii , Perera-Bel Júlia , Kramer Frank 
Published: April 2022

AbstractMotivationCollaborative workflows in network biology not only require the documentation of the performed analysis steps but also of the network data on which the decisions were based. However, replication of the entire workflow or tracking of the intermediate networks used for a particular visualization remains an intricate task. Also, the amount and heterogeneity of the integrated data requires instruments to explore and thus comprehend the results.ResultsHere we demonstrate a collection of software tools and libraries for network data integration, exploration, and visualization to document the different stages of the workflow. The integrative steps are performed in R, and the entire process is accompanied by an interchangeable toolset for data exploration and network visualization.AvailabilityThe source code of the performed workflow is available as R markdown scripts at https://github.com/frankkramer-lab/reproducible-network-visualization. A compiled HTML version is also hosted on Github pages at https://frankkramer-lab.github.io/reproducible-network-visualization.Contactflorian.auer@informatik.uni-augsburg.de
C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Dehairs Jonas , Angelino Paolo , Mouche Sarah , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jérôme , Sarry Jean-Emmanuel 
Published: April 2022

ABSTRACTWhile transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application.SIGNIFICANCEThe transcription factor C/EBPα is as a master regulator of normal and leukemic myeloid differentiation. Here, we discovered that C/EBPα regulates fatty acid biosynthesis and metabolic adaptation to redox imbalance in leukemic cells. This confers a vulnerability to lipid oxidative stress to FLT3-mutant cells and supports novel therapeutic opportunities for patients.