bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous binding of single-stranded RNAs to RRM proteins visualised by unbiased atomistic simulations with rescaled RNA force field
Authors: Krepl Miroslav , Pokorna Pavlina , Mlynsky Vojtech , Stadlbauer Petr , Sponer Jiri 
Published: July 2022

AbstractRecognition of single-stranded RNA (ssRNA) by RNA recognition motif (RRM) domains is an important class of protein-RNA interactions. Many such complexes were characterized using NMR and/or X-ray crystallography techniques, revealing ensemble-averaged pictures of the bound states. However, it is becoming widely accepted that better understanding of protein-RNA interactions would be obtained from ensemble descriptions. Indeed, earlier molecular dynamics (MD) simulations of bound states indicated visible dynamics at the RNA-RRM interfaces. Here, we report the first atomistic simulation study of spontaneous binding of short RNA sequences to RRM domains of HuR and SRSF1 proteins. Using millisecond-scale aggregate ensemble of unbiased simulations we were able to observe a few dozens of binding events. The HuR RRM3 utilizes a pre-binding state to navigate the RNA sequence to its partially disordered bound state and then to dynamically scan its different binding registers. The SRFS1 RRM2 binding is more straightforward but still multiple-pathway. The present study necessitated development of a goal-specific force-field modification scaling down the intramolecular vdW interactions of the RNA which also improves description of the RNA-RRM bound state. Our study opens a new avenue for large-scale atomistic investigations of binding landscapes of protein-RNA complexes and future perspectives of such research are discussed.
THINGS-data: A multimodal collection of large-scale datasets for investigating object representations in human brain and behavior
Authors: Hebart M.N. , Contier O. , Teichmann L. , Rockter A.H. , Zheng C.Y. , Kidder A. , Corriveau A. , Vaziri-Pashkam M. , Baker C.I. 
Published: July 2022

AbstractUnderstanding object representations requires a broad, comprehensive sampling of the objects in our visual world with dense measurements of brain activity and behavior. Here we present THINGS-data, a multimodal collection of large-scale neuroimaging and behavioral datasets in humans, comprising densely-sampled functional MRI and magnetoencephalographic recordings, as well as 4.70 million similarity judgments in response to thousands of photographic images for up to 1,854 object concepts. THINGS-data is unique in its breadth of richly-annotated objects, allowing for testing countless hypotheses at scale while assessing the reproducibility of previous findings. Beyond the unique insights promised by each individual dataset, the multimodality of THINGS-data allows combining datasets for a much broader view into object processing than previously possible. Our analyses demonstrate the high quality of the datasets and provide five examples of hypothesis-driven and data-driven applications. THINGS-data constitutes the core public release of the THINGS initiative (https://things-initiative.org) for bridging the gap between disciplines and the advancement of cognitive neuroscience.
MS2Query: Reliable and Scalable MS2 Mass Spectral-based Analogue Search
Authors: de Jonge Niek F. , Louwen Joris R. , Chekmeneva Elena , Camuzeaux Stephane , Vermeir Femke J. , Jansen Robert S. , Huber Florian , van der Hooft Justin J.J. 
Published: July 2022

AbstractMetabolomics-driven discoveries of biological samples remain hampered by the grand challenge of metabolite annotation and identification. Only few metabolites have an annotated spectrum in spectral libraries; hence, searching only for exact library matches generally returns a few hits. An attractive alternative is searching for so-called analogues as a starting point for structural annotations; analogues are library molecules which are not exact matches, but display a high chemical similarity. However, current analogue search implementations are not yet very reliable and relatively slow. Here, we present MS2Query, a machine learning-based tool that integrates mass spectral embedding-based chemical similarity predictors (Spec2Vec and MS2Deepscore) as well as detected precursor masses to rank potential analogues and exact matches. Benchmarking MS2Query on reference mass spectra and experimental case studies demonstrates an improved reliability and scalability. Thereby, MS2Query offers exciting opportunities for further increasing the annotation rate of complex metabolite mixtures and for discovering new biology.
Paralog Explorer: a resource for mining information about paralogs in common research organisms
Authors: Hu Yanhui , Ewen-Campen Ben , Comjean Aram , Rodiger Jonathan , Mohr Stephanie E. , Perrimon Norbert 
Published: July 2022

AbstractParalogs are genes which arose via gene duplication, and when such paralogs retain overlapping or redundant function, this poses a challenge to functional genetics research. Recent technological advancements have made it possible to systematically probe gene function for redundant genes using dual or multiplex gene perturbation, and there is a need for a simple bioinformatic tool to identify putative paralogs of a gene(s) of interest. We have developed Paralog Explorer (https://www.flyrnai.org/tools/paralogs/), an online resource that allows researchers to quickly and accurately identify candidate paralogous genes in the genomes of the model organisms D. melanogaster, C. elegans, D. rerio, M. musculus, and H. sapiens. Paralog Explorer deploys an effective between-species ortholog prediction software, DIOPT, to analyze within-species paralogs. Paralog Explorer allows users to identify candidate paralogs, and to navigate relevant databases regarding gene co-expression, protein-protein and genetic interaction, as well as gene ontology and phenotype annotations. Altogether, this tool extends the value of current ortholog prediction resources by providing sophisticated features useful for identification and study of paralogous genes.
Adiponectin Reverses β-Cell Damage and Impaired Insulin Secretion Induced by Obesity
Authors: Munhoz Ana Cláudia , Serna Julian D. C. , Vilas-Boas Eloisa Aparecida , da Silva Camille C. Caldeira , dos Santos Tiago Goss , Mosele Francielle C. , Felisbino Sergio L. , Martins Vilma Regina , Kowaltowski Alicia J. 
Published: July 2022

AbstractObesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including β-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs β-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fedad libitum, when compared to sera from lean, calorically-restricted, animals. The damaging effects of obese circulating factors on β-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving β-cell function; indeed, sera from adiponectin knockout mice limits β-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored β-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for β-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related β-cell dysfunction.Abstract FigureGraphical Abstract:Incubation of β-cells with sera or plasma from obese rats and humans hampers mitochondrial oxidative phosphorylation and glucose-stimulated insulin secretion (GSIS) relative to sera and plasma from lean rats and humans. Adiponectin, found at elevated levels in lean subjects, supports β-cell function on its own, in the absence of sera, and also reverses the effects of obese plasma. Prepared using Biorender.com.
GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc
Authors: Johnston Shira N. , Silagi Elizabeth S. , Madhu Vedavathi , Nguyen Duc H. , Shapiro Irving M. , Risbud Makarand V. 
Published: July 2022

ABSTRACTGlycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose importer, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and post-natal maintenance of the disc. Surprisingly, primary NP cells treated with two well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We show in vitro that NP cells mitigate GLUT1 loss by rewiring glucose import through GLUT3. Noteworthy, we demonstrate that substrates, such as glutamine and palmitate, do not compensate for glucose restriction resulting from dual inhibition of GLUT1/3 and inhibition compromises long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated two NP-specific knockout mice: Krt19CreERT; Glut1f/fand Foxa2Cre; Glut1f/f. Noteworthy, there were no apparent defects in post-natal disc health or development and maturation in mutant mice. Microarray analysis confirmed that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells.
Systematic integration of protein affecting mutations, gene fusions, and copy number alterations into a comprehensive somatic mutational profile
Authors: Striker Shawn S , Wilferd Sierra F , Lewis Erika M , O’Connor Samantha A , Plaisier Christopher L 
Published: July 2022

SummarySomatic mutations occur as random genetic changes in genes through protein-affecting mutations (PAMs), gene fusions, or copy number alterations (CNAs). Mutations of different types can have a similar phenotypic effect (i.e., allelic heterogeneity) and should be integrated into a unified gene mutation profile. We developed OncoMerge to fill this niche of integrating somatic mutations to capture allelic heterogeneity, assign a function to mutations, and overcome known obstacles in cancer genetics. Application of OncoMerge to the TCGA Pan-Cancer Atlas increased the number and frequency of somatically mutated genes and improved the prediction of the somatic mutation role as either activating or loss of function. Using integrated somatic mutation matrices increased the power to infer gene regulatory networks and uncovered the enrichment of switch-like feedback motifs and delay-inducing feed-forward loops. These studies demonstrate that OncoMerge efficiently integrates PAMs, fusions, and CNAs and strengthens downstream analyses linking somatic mutations to cancer phenotypes.MotivationGenes are mutated in tumors through either PAMs, CNAs, or gene fusions, thereby splitting the signal of the somatic mutation effect across these three mutation types. We developed OncoMerge to systematically integrate the three mutation types into a single mutation profile that better captures the impact of somatic mutations on cancer phenotypes. As a tool OncoMerge fills the gap between the sophisticated variant calling pipelines and downstream analyses.
Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons
Authors: Eguchi Kohgaku , Shigemoto Ryuichi 
Published: July 2022

AbstractPhosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2 and the co-clustering with these proteins on the neuronal cell membranes remain elusive at the electron microscopic level. In this study, we quantitatively investigated the nanoscale distribution of PI(4,5)P2 on the neuronal cell membranes by SDS-digested freeze-fracture replica labeling with cryo-fixed mouse cerebellum. We demonstrate that PI(4,5)P2 makes clusters with a mean size of ∼ 1,000 nm2 and these clusters show preferential accumulation in specific membrane compartments depending on cell types. Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones are particularly rich in the PI(4,5)P2 clusters. Furthermore, these clusters are extensively associated with clusters of CaV2.1 and GIRK3 throughout different membrane compartments of PCs, GCs, and molecular layer interneurons. In contrast, these clusters showed compartment-specific association with mGluR1α in PC spines. These results suggest that visualization of the nanoscale PI(4,5)P2 distribution may provide insight into the physiological functions of PI(4,5)P2 in neurons.
Breakdown of clonal cooperative architecture in multispecies biofilms and the spatial ecology of predation
Authors: Wucher Benjamin R. , Winans James B. , Elsayed Mennat , Kadouri Daniel E. , Nadell Carey D. 
Published: July 2022

AbstractAdherence to surfaces and secretion of extracellular matrix, or biofilm formation, is common in the microbial world, but we often do not know how interaction at the cellular spatial scale translates to higher-order biofilm community ecology. Here we explore an especially understudied element of biofilm ecology, namely predation by the bacteriumBdellovibrio bacteriovorus. This predator can kill and consume many different Gram-negative bacteria, includingVibrio choleraeandEscherichia coli.V. choleraecan protect itself from predation within highly packed biofilm structures that it creates, whereasE. colibiofilms are highly susceptible toB. bacteriovorus. Here we explore how predator-prey dynamics change whenV. choleraeandE. coliare growing in biofilms together. We find that in dual species prey biofilms,E. colisurvival underB. bacteriovoruspredation increases, whereasV. choleraesurvival decreases.E. colibenefits from predator protection when it becomes embedded within expanding groups of highly packedV. cholerae. But we also find that the ordered, highly packed, and clonal biofilm structure ofV. choleraecan be disrupted ifV. choleraecells are directly adjacent toE. colicells at the start of biofilm growth. When this occurs, the two species become entangled, and the resulting disordered cell groups do not block predator entry. Because biofilm cell group structure depends on initial cell distributions at the start of prey biofilm growth, the colonization dynamics have a dramatic impact on the eventual multispecies biofilm architecture, which in turn determines to what extent both species survive exposure toB. bacteriovorus.Significance StatementBacteria live in multispecies, spatially structured communities ubiquitously in the natural world. These communities, or biofilms, have a strong impact on microbial ecology, but we often do not know how cellular scale interactions determine overall biofilm structure and community dynamics. Here we explore this problem in the context of predator-prey interaction, with two prey species –Vibrio choleraeandEscherichia coli– being attacked by the bacterial predatorBdellovibrio bacteriovorus. We find that whenV. choleraeandE. coligrow together in biofilms, the architectures that they both produce change in ways that cannot be predicted from looking at each prey species alone, and that these changes in cell group structure impact the community dynamics of predator-prey interaction in biofilms.
Compartmentalization of specialized metabolites across vegetative and reproductive tissues in two sympatricPsychotria(Rubiaceae)
Authors: Schneider Gerald F. , Carlson Cole A. , Jos Elsa M. , Beckman Noelle G. 
Published: July 2022

Premise of the studyThe specialized metabolites of plants are recognized as key chemical traits in mediating the ecology and evolution of sundry plant-biotic interactions, from pollination to seed predation. Intra- and interspecific patterns of specialized metabolite diversity have been studied extensively in leaves, but the diverse biotic interactions which contribute to specialized metabolite diversity encompass all plant organs. Focusing on two species ofPsychotriashrubs, we investigate and compare patterns of specialized metabolite diversity in leaves and fruit with respect to each organ’s diversity of biotic interactions.MethodsTo evaluate associations between biotic interaction diversity and specialized metabolite diversity, we combine UPLC-MS metabolomic analysis of foliar and fruit specialized metabolites with existing surveys of leaf- and fruit-centered biotic interactions. We compare patterns of specialized metabolite richness and variance among vegetative and reproductive tissues, among plants, and between species.Key resultsIn our study system, leaves are involved in a greater number of host-specific biotic interactions than fruit, while fruit-centric interactions are more ecologically diverse. This was reflected in specialized metabolite richness – leaves contained more than fruit, while each contained over 200 organ-specific specialized metabolites. Within each species, leaf- and fruit specialized metabolite composition varied independently of one another across plants. Specialized metabolite composition exhibited stronger contrasts between organs than between species.ConclusionsAs ecologically disparate plant organs with organ-specific specialized metabolite traits, leaves and fruit can each contribute to the tremendous overall diversity of plant specialized metabolites.
Posttranslational modifications of the DUX4 protein impact toxic function
Authors: Knox Renatta N. , Eidahl Jocelyn O. , Wallace Lindsay , Choudury Sarah , Rashnonejad Afrooz , Saad Nizar Y. , Hoover Michael E. , Zhang Liwen , Branson Owen E. , Freitas Michael A. , Harper Scott Q. 
Published: July 2022

ABSTRACTObjectiveFacioscapulohumeral muscular dystrophy (FSHD) is caused by abnormal de-repression of the transcription factor DUX4, which is toxic to muscle in vitro and in vivo. While the transcriptional targets of DUX4 are known, the regulation of DUX4 protein and the molecular consequences of this regulation are unclear. Here, we used in vitro models of FSHD to identify and characterize DUX4 posttranslational modifications (PTMs) and their impact on the toxic function of DUX4.MethodsDUX4 protein was immunoprecipitated and mass spectrometry performed to identify PTMs. We then extensively characterized DUX4 PTMs and potential enzyme modifiers using mutagenesis, proteomics and biochemical assays in human cell lines and human myoblast cell lines.ResultsOur in vitro screen of DUX4 PTM mutants identified arginine methyl-null and serine/threonine phosphomimetic mutants that protected cells against DUX4-mediated toxicity and reduced the ability of DUX4 to transactivate downstream gene targets, including FSHD biomarkers. Using additional proteomics and biochemical approaches, we identified protein kinase A (PKA) and a protein arginine methyltransferase (PRMT1) as components of the DUX4 complex. Importantly, over-expression of PRKACA, a catalytic subunit of the PKA holoenzyme, mitigated DUX4 toxicity, while pharmacologic inhibition of PRMT1 protected human myoblasts from DUX4-mediated apoptosis.InterpretationThese results demonstrate that DUX4 is regulated by PTMs and that DUX4 PTMs, or associated modifying enzymes, may be druggable targets for FSHD therapy.
EpiCompare: R package for the comparison and quality control of epigenomic peak files
Authors: Choi Sera , Schilder Brian M. , Abbasova Leyla , Murphy Alan E. , Skene Nathan G. 
Published: July 2022

AbstractSummaryEpiCompare combines a variety of downstream analysis tools to compare, quality control and benchmark different epigenomic datasets. The package requires minimal input from users, can be run with just one line of code and provides all results of the analysis in a single interactive HTML report. EpiCompare thus enables downstream analysis of multiple epigenomic datasets in a simple, effective and user-friendly manner.Availability and ImplementationEpiCompare is available on Bioconductor (≥ v3.15):https://bioconductor.org/packages/release/bioc/html/EpiCompare.htmlAll source code is publically available via GitHub:https://github.com/neurogenomics/EpiCompareDocumentation websitehttps://neurogenomics.github.io/EpiCompareEpiCompare DockerHub repository:https://hub.docker.com/repository/docker/neurogenomicslab/epicompare
Resurrection genomics provides molecular and phenotypic evidence of rapid adaptation to salinization in a keystone aquatic species
Authors: Wersebe Matthew J. , Weider Lawrence J. 
Published: July 2022

AbstractEcologists and evolutionary biologists are increasingly cognizant of rapid adaptation in wild populations. Rapid adaptation to anthropogenic environmental change is critical for maintaining biodiversity and ecosystems services into the future. Anthropogenic salinization of freshwater ecosystems is quickly emerging as a primary threat, which is well documented in the northern temperate ecoregion. Specifically, many northern temperate lakes have undergone extensive salinization because of urbanization and the associated increase in impervious surfaces causing runoff, and the extensive use of road deicing salts (e.g., NaCl). It remains unclear if increasing salinization will lead to extirpation of species from these systems. Using a “resurrection genomics” approach, we investigated whether the keystone aquatic herbivore,Daphnia pulicaria, has evolved increased salinity tolerance in a severely salinized lake located in Minnesota, USA. Whole genome resequencing of 54Daphniaclones from the lake and hatched from resting eggs that represent a 25-year temporal contrast demonstrates that many regions of the genome containing genes related to osmoregulation are under selection in the study population. Tolerance assays of clones revealed that the most recent clones are more tolerant to salinity than older clones; this pattern is concomitant with the temporal pattern of stabilizing salinity in this lake. Together, our results demonstrate that keystone species such asDaphniacan rapidly adapt to increasing freshwater salinization. Further, our results indicate that rapid adaptation to salinity may allow lakeDaphniapopulations to persist in the face of anthropogenic salinization maintaining the food webs and ecosystem services they support despite global environmental change.Significance StatementRapid adaptation to human-induced environmental change is critical for preserving biodiversity and ecosystem services into the future. A key question is whether populations of keystone species can rapidly adapt to maintain the ecosystems they support. We investigated rapid adaptation to anthropogenic salinization inDaphnia pulicaria, a keystone aquatic herbivore in lake ecosystems. By resuscitating decades-old resting eggs, we investigate genomic changes across an approximately 25-year temporal contrast from a severely salinized lake. We report that the genes showing signatures of natural selection throughout the genome are related to osmoregulation and ion regulation. Phenotyping clones for salinity tolerance revealed evidence that genetic changes may underlie rapid evolution. We provide molecular genomic and phenotypic evidence for rapid adaptation to salinity inD. pulicaria.