bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical Stimulated GLUT4 Signaling Attenuates Critical Illness-Associated Muscle Wasting
Authors: Addinsall Alex B , Cacciani Nicola , Backéus Anders , Hedström Yvette , Shevchenko Ganna , Bergquist Jonas , Larsson Lars 
Published: November 2021

AbstractBackgroundCritical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a byproduct of critical care, attributed to impaired recovery, long‐term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood, however loss of mechanical stimuli contributes to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care.MethodsRats were subjected to 8 days critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and Western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM.ResultsFollowing 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, Myosin:Actin ratio and single muscle fiber maximum force normalized to cross-sectional area (specific force) were reduced by 40-50% (p< 0.0001). ES significantly reduced the loss of soleus muscle fiber cross-sectional area (CSA) and Myosin:Actin ratio by approximately 30% (p< 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signaling in the soleus muscle following critical care and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (p< 0.01). ES promoted phosphofructokinase and insulin signaling pathways to control levels (p< 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signaling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (p= 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately 2-fold (p= 0.06). Reduction of muscle protein degradation rather than protein synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (p= 0.006) and MuRF1 (p= 0.08) by approximately 50%, downstream of AMPK-FoxO3.ConclusionsES maintained GLUT4 translocation through increased AMPK-TBC1D4 signaling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signaling and reduced muscle protein degradation in CIM.
GEDI: an R package for integration of transcriptomic data from multiple high-throughput platforms
Authors: Stokholm Mathias N. , Rabaglino Maria B. , Kadarmideen Haja N. 
Published: November 2021

AbstractTranscriptomic data is often expensive and difficult to generate in large cohorts in comparison to genomic data and therefore is often important to integrate multiple transcriptomic datasets from both microarray and next generation sequencing (NGS) based transcriptomic data across similar experiments or clinical trials to improve analytical power and discovery of novel transcripts and genes. However, transcriptomic data integration presents a few challenges including re-annotation and batch effect removal. We developed the Gene Expression Data Integration (GEDI) R package to enable transcriptomic data integration by combining already existing R packages. With just four functions, the GEDI R package makes constructing a transcriptomic data integration pipeline straightforward. Together, the functions overcome the complications in transcriptomic data integration by automatically re-annotating the data and removing the batch effect. The removal of the batch effect is verified with Principal Component Analysis and the data integration is verified using a logistic regression model with forward stepwise feature selection. To demonstrate the functionalities of the GEDI package, we integrated five bovine endometrial transcriptomic datasets from the NCBI Gene Expression Omnibus. The datasets included Affymetrix, Agilent and RNA-sequencing data. Furthermore, we compared the GEDI package to already existing tools and found that GEDI is the only tool that provides a full transcriptomic data integration pipeline including verification of both batch effect removal and data integration.
MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses
Authors: Devine Jay , Vidal-García Marta , Liu Wei , Neves Amanda , Vercio Lucas D. Lo , Green Rebecca M. , Richbourg Heather A. , Marchini Marta , Unger Colton M. , Nickle Audrey C. , Radford Bethany , Young Nathan M. , Gonzalez Paula N. , Schuler Robert E. , Bugacov Alejandro , Rolian Campbell , Percival Christopher J. , Williams Trevor , Niswander Lee , Calof Anne L. , Lander Arthur D. , Visel Axel , Jirik Frank R. , Cheverud James M. , Klein Ophir , Birnbaum Ramon Y. , Merrill Amy E. , Ackermann Rebecca R. , Graf Daniel , Hemberger Myriam , Dean Wendy , Forkert Nils D. , Murray Stephen A. , Westerberg Henrik , Marcucio Ralph S. , Hallgrímsson Benedikt 
Published: November 2021

AbstractComplex morphological traits are the product of many genes with transient or lasting developmental effects that interact in anatomical context. Mouse models are a key resource for disentangling such effects, because they offer myriad tools for manipulating the genome in a controlled environment. Unfortunately, phenotypic data are often obtained using laboratory-specific protocols, resulting in self-contained datasets that are difficult to relate to one another for larger scale analyses. To enable meta-analyses of morphological variation, particularly in the craniofacial complex and brain, we created MusMorph, a database of standardized mouse morphology data spanning numerous genotypes and developmental stages, including E10.5, E11.5, E14.5, E15.5, E18.5, and adulthood. To standardize data collection, we implemented an atlas-based phenotyping pipeline that combines techniques from image registration, deep learning, and morphometrics. Alongside stage-specific atlases, we provide aligned micro-computed tomography images, dense anatomical landmarks, and segmentations (if available) for each specimen (N=10,056). Our workflow is open-source to encourage transparency and reproducible data collection. The MusMorph data and scripts are available on FaceBase (www.facebase.org, doi.org/10.25550/3-HXMC) and GitHub (https://github.com/jaydevine/MusMorph).
High-sensitivity pattern discovery in large, paired multi-omic datasets
Authors: Ghazi Andrew R. , Sucipto Kathleen , Rahnavard Gholamali , Franzosa Eric A. , McIver Lauren J. , Lloyd-Price Jason , Schwager Emma , Weingart George , Moon Yo Sup , Morgan Xochitl C. , Waldron Levi , Huttenhower Curtis 
Published: November 2021

AbstractModern biological screens yield enormous numbers of measurements, and identifying and interpreting statistically significant associations among features is essential. Here, we present a novel hierarchical framework, HAllA (Hierarchical All-against-All association testing), for structured association discovery between paired high-dimensional datasets. HAllA efficiently integrates hierarchical hypothesis testing with false discovery rate correction to reveal significant linear and non-linear block-wise relationships among continuous and/or categorical data. We optimized and evaluated HAllA using heterogeneous synthetic datasets of known association structure, where HAllA outperformed all-against-all and other block testing approaches across a range of common similarity measures. We then applied HAllA to a series of real-world multi-omics datasets, revealing new associations between gene expression and host immune activity, the microbiome and host transcriptome, metabolomic profiling, and human health phenotypes. An open-source implementation of HAllA is freely available at http://huttenhower.sph.harvard.edu/halla along with documentation, demo datasets, and a user group.Author SummaryModern scientific datasets increasingly include multiple measurements of many complementary data types. Here, we present HAllA, a method and implementation that overcomes the statistical challenges presented by data of this type by using feature similarity within each dataset to find statistically significant groups of features between them. We applied HAllA to simulated and real datasets, showing that HAllA outperformed existing procedures and identified compelling biological relationships. HAllA is widely applicable to diverse data structures and presents the user with grouped results that are easier to interpret than traditional methods.
Oxidative respiration through the bd-I and cbb3 oxidases is required for Vibrio cholerae pathogenicity and proliferation in vivo
Authors: Van Alst Andrew. J. , Demey Lucas M. , DiRita Victor J. 
Published: November 2021

AbstractVibrio cholerae respires both aerobically and anaerobically and, while oxygen may be available to it during infection, other terminal electron acceptors are proposed for population expansion during infection. Unlike gastrointestinal pathogens that stimulate significant inflammation leading to elevated levels of oxygen or alternative terminal electron acceptors, V. cholerae infections are not understood to induce a notable inflammatory response. To ascertain the respiration requirements of V. cholerae during infection, we used Multiplex Genome Editing by Natural Transformation (MuGENT) to create V. cholerae strains lacking aerobic or anaerobic respiration. V. cholerae strains lacking aerobic respiration were attenuated in infant mice 105-fold relative to wild type, while strains lacking anaerobic respiration had no colonization defect, contrary to earlier work suggesting a role for anaerobic respiration during infection. Using several approaches, including one we developed for this work termed Comparative Multiplex PCR Amplicon Sequencing (CoMPAS), we determined that the bd-I and cbb3 oxidases are essential for small intestinal colonization of V. cholerae in the infant mouse. The bd-I oxidase was also determined as the primary oxidase during growth outside the host, making V. cholerae the only example of a Gram-negative bacterial pathogen in which a bd-type oxidase is the primary oxidase for energy acquisition inside and outside of a host.Author SummaryThe bacterium that causes cholera, Vibrio cholerae, can grow with or without oxygen. When growing without oxygen it may use other molecules that serve the same purpose as oxygen, acting as a terminal electron acceptor in an energy-generating process known as respiration. Given the largely anaerobic nature of the gastrointestinal tract, and the lack of significant inflammation during cholera infection, a process that can stimulate elevated levels of oxygen and other terminal electron acceptors, we sought to understand the respiratory mechanisms of V. cholerae during infection. We used a powerful genome-editing method to construct mutant strains of V. cholerae lacking some or all of the complement of proteins required for aerobic or anaerobic respiration. By analyzing these mutants in the laboratory and in intestinal colonization of infant mice, we determined that the ability to respire without oxygen is completely dispensable for V. cholerae to thrive during infection. We determined that two of the four oxygen-dependent respiration mechanisms are essential for V. cholerae to grow during infection, with the other two dispensable for wild type levels of colonization.
A novel non-genetic murine model of hyperglycemia and hyperlipidemia-associated aggravated atherosclerosis
Authors: Gaul Susanne , Shahzad Khurrum , Medert Rebekka , Gadi Ihsan , Mäder Christina , Schumacher Dagmar , Wirth Angela , Ambreen Saira , Fatima Sameen , Boeckel Jes-Niels , Khawaja Hamzah , Haas Jan , Brune Maik , Nawroth Peter P , Isermann Berend , Laufs Ulrich , Freichel Marc 
Published: November 2021

AbstractObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s).Methods and ResultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks.ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.
Hydrodynamic model of fish orientation in a channel Flow
Authors: Porfiri Maurizio , Zhang Peng , Peterson Sean D. 
Published: November 2021

AbstractFor over a century, scientists have sought to understand how fish orient against an incoming flow, even without visual and flow cues. Here, we elucidate a potential hydrodynamic mechanism of rheotaxis through the study of the bidirectional coupling between fish and the surrounding fluid. By modeling a fish as a vortex dipole in an infinite channel with an imposed background flow, we establish a planar dynamical system for the cross-stream coordinate and orientation. The system dynamics captures the existence of a critical flow speed for fish to successfully orient while performing cross-stream, periodic sweeping movements. Model predictions are examined in the context of experimental observations in the literature on the rheotactic behavior of fish deprived of visual and lateral line cues. The crucial role of bidirectional hydrodynamic interactions unveiled by this model points at an overlooked limitation of existing experimental paradigms to study rheotaxis in the laboratory.
Mothers front-load their investment to the egg stage when helped in a wild cooperative bird
Authors: Capilla-Lasheras Pablo , Wilson Alastair J. , Young Andrew J. 
Published: November 2021

AbstractIn many cooperative societies, including our own, helpers assist with the post-natal care of breeders’ young, and may thereby benefit thepost-nataldevelopment of offspring. Here we present evidence of a novel mechanism by which such post-natal helping could also have hitherto unexplored beneficial effects onpre-nataldevelopment: by lightening post-natal maternal workloads, helpers may allow mothers to increase their pre-natal investment per offspring. We present the findings of a decade-long study of cooperatively breeding white-browed sparrow weaver,Plocepasser mahali, societies. Within each social group, reproduction is monopolized by a dominant breeding pair, and non-breeding helpers assist with nestling feeding. Using a within-mother reaction norm approach to formally identify maternal plasticity, we demonstrate that when mothers have more female helpers they decrease their ownpost-natalinvestment per offspring (feed their nestlings at lower rates) but increase theirpre-natalinvestment per offspring (lay larger eggs, which yield heavier hatchlings). That these plastic maternal responses are predicted by female helper number, and not male helper number, implicates the availability of post-natal helpingper seas the likely driver (rather than correlated effects of group size), because female helpers feed nestlings at substantially higher rates than males. We term this novel maternal strategy “maternal front-loading” and hypothesize that the expected availability ofpost-natalhelp allows helped mothers to focus maternal investment on thepre-natalphase, to which helpers cannot contribute directly. Such cryptic maternally mediated helper effects on pre-natal development may markedly complicate attempts to identify and quantify the fitness consequences of helping.
Subiculum – BNST Structural Connectivity in Humans and Macaques
Authors: Berry Samuel C. , Lawrence Andrew D. , Lancaster Thomas M. , Casella Chiara M. , Aggleton John P. , Postans Mark 
Published: November 2021

AbstractInvasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily mediated through the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts are moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. We did, however, find subiculum complex-BNST tract microstructure associations with BMI, age, and sex. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.
Gene drives and population persistence vs elimination: the impact of spatial structure and inbreeding at low density
Authors: Beaghton PJ , Burt Austin 
Published: November 2021

AbstractSynthetic gene drive constructs are being developed to control disease vectors, invasive species, and other pest species. In a well-mixed random mating population a sufficiently strong gene drive is expected to eliminate a target population, but it is not clear whether the same is true when spatial processes play a role. In species with an appropriate biology it is possible that drive-induced reductions in density might lead to increased inbreeding, reducing the efficacy of drive, eventually leading to suppression rather than elimination, regardless of how strong the drive is. To investigate this question we analyse a series of explicitly solvable stochastic models considering a range of scenarios for the relative timing of mating, reproduction, and dispersal and analyse the impact of two different types of gene drive, a Driving Y chromosome and a homing construct targeting an essential gene. We find in all cases a sufficiently strong Driving Y will go to fixation and the population will be eliminated, except in the one life history scenario (reproduction and mating in patches followed by dispersal) where low density leads to increased inbreeding, in which case the population persists indefinitely, tending to either a stable equilibrium or a limit cycle. These dynamics arise because Driving Y males have reduced mating success, particularly at low densities, due to having fewer sisters to mate with. Increased inbreeding at low densities can also prevent a homing construct from eliminating a population. For both types of drive, if there is strong inbreeding depression, then the population cannot be rescued by inbreeding and it is eliminated. These results highlight the potentially critical role that low-density-induced inbreeding and inbreeding depression (and, by extension, other sources of Allee effects) can have on the eventual impact of a gene drive on a target population.
The structural determinants of intra-protein compensatory substitutions
Authors: Chaurasia Shilpi , Dutheil Julien Y. 
Published: November 2021

AbstractCompensating substitutions happen when one mutation is advantageously selected because it restores the loss of fitness induced by a previous deleterious mutation. How frequent such mutations occur in evolution and what is the structural and functional context permitting their emergence remain open questions. We built an atlas of intra-protein compensatory substitutions using a phylogenetic approach and a dataset of 1,630 bacterial protein families for which high-quality sequence alignments and experimentally derived protein structures were available. We identified more than 51,000 positions coevolving by the mean of predicted compensatory mutations. Using the evolutionary and structural properties of the analyzed positions, we demonstrate that compensatory mutations are scarce (typically only a few in the protein history) but widespread (the majority of proteins experienced at least one). Typical coevolving residues are evolving slowly, are located in the protein core outside secondary structure motifs, and are more often in contact than expected by chance, even after accounting for their evolutionary rate and solvent exposure. An exception to this general scheme are residues coevolving for charge compensation, which are evolving faster than non-coevolving sites, in contradiction with predictions from simple coevolutionary models, but similar to stem pairs in RNA. While sites with a significant pattern of coevolution by compensatory mutations are rare, the comparative analysis of hundreds of structures ultimately permits a better understanding of the link between the three-dimensional structure of a protein and its fitness landscape.