bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of GCN5 decreases skeletal muscle fat metabolism during high fat diet feeding
Authors: Green Alexander E. , Perras Brayden L. , Zhang Hongbo , Katsyuba Elena , Haboush Alaa , Nyarko Kwadjo M. , Pandey Dheeraj K. , Nik-Akhtar Abolfazl , Ryu Dongryeol , Auwerx Johan , Menzies Keir J. 
Published: October 2022

AbstractIntroductionGCN5 (Kat2a) is a lysine acetyl transferase capable of acetylating and inhibiting PGC-1α activity. As such, it is described as a negative regulator of PGC-1α and subsequently restricts mitochondrial content. However, elimination of GCN5 in skeletal muscle does not increase mitochondrial content or alter lipid metabolism under normal metabolic conditions. GCN5 levels increase with high-fat diet (HFD) feeding in rodents. Additionally, the GCN5 homolog, PCAF, has previously been shown to also acetylate and inhibit PGC-1α and therefore may possibly compensate for loss of GCN5.ObjectiveThe objective of this study was to examine if with HFD feeding that elimination of GCN5 (Kat2agene) from skeletal muscle would elicit improvements in mitochondrial and metabolic markers.MethodsSkeletal muscle specific GCN5 knockouts (Gcn5 skm-/-) were fed an HFD. Body composition, cardio-metabolic and physical fitness outcomes were monitored. Additionally, cultured myotubes were treated with a pan-GCN5/PCAF inhibitor and examined for changes in mitochondrial markers.ResultsElimination of skeletal muscle GCN5 did not alter body composition, tissue masses, energy intake, or energy expenditure measurements of mice fed an HFD. Furthermore, whole body glucose homeostasis and cardiac measurements were not altered. There were few differences in lipid metabolism genes, relatively more glucose oxidation versusGcn5 skm+/+(wildtype) mice, and a reduction inPdk4expression. Exercise capacity and mitochondrial content levels were not altered inGcn5 skm-/-mice. Further, elimination of GCN5 in skeletal muscle increasedKat2b(PCAF) mRNA expression; however, inhibition of GCN5/PCAF bromodomains in cultured myotubes did not increase oxidative metabolism genes and decreased expression of some mitochondrial genes andPdk4mRNA.ConclusionsNeither elimination of GCN5, nor simultaneous inhibition of GCN5 and its homolog PCAF improved skeletal muscle mitochondrial content under normal or HFD-fed conditions. Despite this, GCN5 may play a role in regulating macronutrient preference by regulatingPdk4content. Thus, HFD/macronutrient excess revealed novel roles of GCN5 in skeletal muscle.Highlights– Skeletal muscle specific elimination ofGcn5/Kat2adecreases fat oxidation without 1) preventing high-fat diet induced weight gain, 2) improving whole body glucose handling, or 3) improving skeletal muscle mitochondrial content.– Inhibition of the GCN5 and PCAF bromodomains andGcn5ablation decreases expression ofPdk4.– Expression ofKat2bincreases withGcn5elimination in skeletal muscle.– Inhibition of the GCN5 and PCAF bromodomains do not result in increased skeletal muscle mitochondrial content.
Sex differences in pain: Spinal cord injury in female and male mice elicits behaviors related to neuropathic pain
Authors: Lee Sydney E. , Greenough Emily K. , Oancea Paul , Scheinfeld Ashley R. , Douglas Apsaline M. , Gaudet Andrew D. 
Published: October 2022

AbstractSpinal cord injury (SCI) in humans frequently causes intractable chronic pain. Females are susceptible to worsened pain compared to males, and females may show higher pain prevalence after SCI. Despite this difference in clinical prevalence of SCI pain, few preclinical studies have systematically studied in rodents sex differences in SCI-elicited pain-related behaviors. Here, we leverage data from a large cohort of mice to test whether contusion SCI consistently causes pain symptoms in mice, and to establish whether female (vs. male) mice display heightened hypersensitivity after SCI. Mechanical and heat sensory thresholds were assessed using the von Frey test and Hargreaves test, respectively. In an initial experiment, female mice receiving moderate 60 kDyn SCI or moderate-to-severe 75 kDyn SCI at T9 both exhibited mechanical and heat pain symptoms compared to sham controls. 75 kDyn SCI caused excess motor deficits that confounded defining pain sensitivity at acute times, so the moderate SCI force was used for subsequent experiments. Next, adult female and male C57BL6/J mice received sham surgery or T9 moderate contusion SCI. Comparing female to male mice after SCI, we reveal that mice of both sexes displayed mechanical and heat hypersensitivity compared to sham controls, from acute-to-chronic post-injury times. Females had amplified SCI-elicited hypersensitivity compared to males. Our data suggest that thoracic contusion SCI elicits consistent and persistent pain-associated symptoms, which are more intense in female vs. male mice. These results have important implications for uncovering sex-specific mechanisms and therapeutic targets to ameliorate neuropathic pain after SCI.
Comparative genome analysis ofEnterococcus cecorumreveals intercontinental spread of a lineage of clinical poultry isolates
Authors: Laurentie Jeanne , Loux Valentin , Hennequet-Antier Christelle , Chambellon Emilie , Deschamps Julien , Trotereau Angélina , Furlan Sylviane , Darrigo Claire , Kempf Florent , Lao Julie , Milhes Marine , Roques Céline , Quinquis Benoit , Vandecasteele Céline , Boyer Roxane , Bouchez Olivier , Repoila Francis , Le Guennec Jean , Chiapello Hélène , Briandet Romain , Helloin Emmanuelle , Schouler Catherine , Kempf Isabelle , Serror Pascale 
Published: October 2022

ABSTRACTEnterococcus cecorumis an emerging pathogen responsible for osteomyelitis, spondylitis, and femoral head necrosis causing animal suffering, mortality, and requiring antimicrobial use in poultry. Paradoxically,E. cecorumis a common inhabitant of the intestinal microbiota of adult chickens. Despite evidence suggesting the existence of clones with pathogenic potential, the genetic and phenotypic relatedness of disease-associated isolates remains little investigated. Here, we sequenced and analyzed the genomes and characterized the phenotypes of more than 100 isolates, the majority of which were collected over the last ten years in 16 French broiler farms. Comparative genomics, genome-wide association study, and measured susceptibility to serum, biofilm forming capacity, and adhesion to chicken type II collagen were used to identify features associated with clinical isolates. We found that none of the tested phenotypes could discriminate origin of the isolates or phylogenetic group. Instead, we found that most clinical isolates are grouped phylogenetically and our analyses selected six genes that discriminate 94% of isolates associated with disease from those that are not. Analysis of the resistome and the mobilome revealed that multidrug-resistant clones ofE. cecorumcluster in few clades and that integrative conjugative elements and genomic islands are the main carriers of antimicrobial resistance. This comprehensive genomic analysis shows that disease-associated clones ofE. cecorumbelong mainly to one phylogenetic clade.IMPORTANCEEnterococcus cecorumis an important pathogen in poultry worldwide. It causes a number of locomotor disorders and septicemia, particularly in fast-growing broilers. Animal suffering, antimicrobial use, and associated economic losses require a better understanding of disease-associatedE. cecorumisolates. To address this need, we performed whole genome sequencing and analysis of a large collection of isolates responsible for outbreaks in France. By providing the first dataset on the genetic diversity and resistome ofE. cecorumstrains circulating in France, we pinpoint an epidemic lineage probably also circulating elsewhere and which should be targeted preferentially by preventive strategies in order to reduce the burden ofE. cecorum-related diseases.
Correcting batch effects in large-scale multiomic studies using a reference-material-based ratio method
Authors: Yu Ying , Zhang Naixin , Mai Yuanbang , Chen Qiaochu , Cao Zehui , Chen Qingwang , Liu Yaqing , Ren Luyao , Hou Wanwan , Yang Jingcheng , Hong Huixiao , Xu Joshua , Tong Weida , Shi Leming , Zheng Yuanting 
Published: October 2022

AbstractBatch effects are notorious technical variations that are common in multiomic data and may result in misleading outcomes. With the era of big data, tackling batch effects in multiomic integration is urgently needed. As part of the Quartet Project for quality control and data integration of multiomic profiling, we comprehensively assess the performances of seven batch-effect correction algorithms (BECAs) for mitigating the negative impact of batch effects in multiomic datasets, including transcriptomics, proteomics, and metabolomics. Performances are evaluated based on accuracy of identifying differentially expressed features, robustness of predictive models, and the ability of accurately clustering cross-batch samples into their biological sample groups. Ratio-based method is more effective and widely applicable than others, especially in cases when batch effects are highly confounded with biological factors of interests. We further provide practical guidelines for the implementation of ratio-based method using universal reference materials profiled with study samples. Our findings show the promise for eliminating batch effects and enhancing data integration in increasingly large-scale, cross-batch multiomic studies.
Neural activity in human eyeblink conditioning: an optically pumped magnetometer-based MEG study
Authors: Lin Chin-Hsuan Sophie , Tierney Tim M , Mellor Stephanie , O’Neill George C , Bestmann Sven , Barnes Gareth R , Miall R Chris 
Published: October 2022

AbstractThere is a profound lack of electrophysiological data from the cerebellum in humans, as compared to animals, because the pervading perception is that it is difficult to record human cerebellar activity non-invasively using magnetoencephalography (MEG) or electroencephalography (EEG). We used on-scalp MEG based on optically pumped magnetometers (OP-MEG) to detect learning related cerebellar signals in a classical eyeblink conditioning paradigm. In four healthy human adults, we observed unconditioned stimulus-related evoked responses locating in the cerebellum. These evoked responses diminished during the acquisition of conditioned responses, which corresponds with previous observed changes of Purkinje cell activities in animals. We also observed evoked responses immediately before conditioned blinks in 3 out of 4 participants, which were also located in the cerebellum. We discuss the potential nature of these cerebellar evoked responses and future applications of OP-MEG to the studies of human cerebellar physiology.
Next-generation ABACUS biosensors reveal cellular ABA dynamics driving root growth at low aerial humidity
Authors: Rowe James , Grangé-Guermente Mathieu , Exposito-Rodriguez Marino , Wimalasekera Rinukshi , Lenz Martin , Shetty Kartika , Cutler Sean R. , Jones Alexander M. 
Published: October 2022

AbstractThe plant hormone abscisic acid (ABA) accumulates under abiotic stress to recast water relations and development. To overcome a lack of high-resolution, sensitive reporters, we developed ABACUS2s, next-generation FRET biosensors for ABA with high affinity, signal-to-noise ratio and orthogonality, that reveal endogenous ABA patterns in Arabidopsis thaliana. We mapped stress-induced ABA dynamics in high-resolution to reveal the cellular basis for local and systemic ABA functions. At reduced foliar humidity, roots cells accumulated ABA in the elongation zone, the site of phloem transported ABA unloading. Phloem ABA and root ABA signalling were both essential to maintain root growth at low humidity. ABA coordinates a robust system to maintain root growth in response to foliar stresses, enabling plants to maintain foraging of deeper soil for water uptake
DANCE: A Deep Learning Library and Benchmark Platform for Single-Cell Analysis
Authors: Ding Jiayuan , Wen Hongzhi , Tang Wenzhuo , Liu Renming , Li Zhaoheng , Venegas Julian , Su Runze , Molho Dylan , Jin Wei , Zuo Wangyang , Wang Yixin , Yang Robert , Xie Yuying , Tang Jiliang 
Published: October 2022

AbstractIn the realm of single-cell analysis, computational approaches have brought an increasing number of fantastic prospects for innovation and invention. Meanwhile, it also presents enormous hurdles to reproducing the results of these models due to their diversity and complexity. In addition, the lack of gold-standard benchmark datasets, metrics, and implementations prevents systematic evaluations and fair comparisons of available methods. Thus, we introduce the DANCE platform, the first standard, generic, and extensible benchmark platform for accessing and evaluating computational methods across the spectrum of benchmark datasets for numerous single-cell analysis tasks. Currently, DANCE supports 3 modules and 8 popular tasks with 32 state-of-art methods on 21 benchmark datasets. People can easily reproduce the results of supported algorithms across major benchmark datasets via minimal efforts (e.g., only one command line). In addition, DANCE provides an ecosystem of deep learning architectures and tools for researchers to develop their own models conveniently. The goal of DANCE is to accelerate the development of deep learning models with complete validation and facilitate the overall advancement of single-cell analysis research. DANCE is an open-source python package that welcomes all kinds of contributions. All resources are integrated and available athttps://omicsml.ai/.
Elevated oxidative phosphorylation is critical for immune cell activation by polyethylene wear particles
Authors: Maduka Chima V. , Kuhnert Maxwell M. , Habeeb Oluwatosin M. , Tundo Anthony , Makela Ashley V. , Goodman Stuart B. , Contag Christopher H. 
Published: October 2022

AbstractChronic inflammation is a major concern after total joint replacements (TJRs), as it is associated with bone loss, limited bone-implant integration (osseointegration), implant loosening and failure. Inflammation around implants could be directed away from adverse outcomes and toward enhanced osseointegration and improved surgical outcome. Activated macrophages exposed to polyethylene particles play a dominant inflammatory role, and exhibit elevated mitochondrial oxidative phosphorylation (OXPHOS) whose role is unclear. By probing the contribution of the electron transport chain (ETC), we show that increased oxygen consumption does not contribute to bioenergetic (ATP) levels in fibroblasts and primary bone marrow-derived macrophages activated by polyethylene particles. Rather, it generates reactive oxygen species (ROS) at complex I by increasing mitochondrial membrane potential in macrophages. Inhibition of OXPHOS in a dosedependent manner without affecting glycolysis was accomplished by targeting complex I of the ETC using either rotenone or metformin. Metformin decreased mitochondrial ROS and, subsequently, expression of proinflammatory cytokines, including IL-1β, IL-6 and MCP-1 but not TNF-a in macrophages. These results highlight the contribution of mitochondrial bioenergetics to activation of immune cells by polyethylene wear particles, offering new opportunities to modulate macrophage states toward desired clinical outcomes.
Matrix mechanics, not hypoxia, modulate quiescin sulfhydryl oxidase 1 (QSOX1) in pancreatic tumor cells
Authors: Millar-Haskell Catherine S. , Thorpe Colin , Gleghorn Jason P. 
Published: October 2022

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the U.S., despite only being the 11th most common cancer. The high mortality rates of PDAC can be partially attributed to the tumor microenvironment. Unlike most carcinomas, PDAC is characterized by a strong desmoplastic reaction, or a fibrotic stiffening of the extracellular matrix (ECM) in response to chronic inflammation. The desmoplastic reaction is mediated by cancer-associated fibroblasts that deposit ECM proteins (collagens, laminins, fibronectin, etc.) and secrete matrix-remodeling proteins in the tumor parenchyma. Within the past decade, the enzyme quiescin sulfhydryl oxidase 1 (QSOX1) has gained recognition as a significant contributor to solid tumor pathogenesis, but its biological role remains uncertain. QSOX1 is a disulfide bond-generating catalyst that participates in oxidative protein folding in the mammalian cell. Current studies show that inhibiting or knocking down QSOX1 reduces pancreatic cancer cell migration and invasion, alters ECM deposition and organization, and decreases overall tumor growth in mice. However, it is unclear which features of the tumor microenvironment modulate QSOX1 and cause its overexpression in cancer. In this study, we explored potential regulators of QSOX1 expression and secretion by testing two major features of PDAC: hypoxia and mechanical stiffness. To induce hypoxia, we exposed pancreatic cancer cells to atmospheric (low O2) and chemical (CoCl2) hypoxia for up to 48 hours. QSOX1 gene and protein expression did not change in response to hypoxia. Substratum stiffness was modulated using polyacrylamide gels to represent the dynamic pathological range of elastic moduli found in PDAC tissue. We discovered that QSOX1 levels were decreased on softer surfaces compared to conventional tissue culture plastic. This paper presents new results and challenges prior findings on QSOX1 regulation in pancreatic tumor cells.
Long-range DNA end resection supports homologous recombination by checkpoint activation rather than extensive homology generation
Authors: Kimble Michael T , Johnson Matthew J , Nester Mattie R , Symington Lorraine S 
Published: October 2022

AbstractHomologous recombination (HR), the error-free mechanism for double-strand break (DSB) repair, relies on DNA end resection by nucleolytic degradation of the 5′-terminated ends. However, the role of long-range resection mediated by Exo1 and/or Sgs1-Dna2 in HR is not fully understood. Here, we show that Exo1 and Sgs1 are dispensable for recombination between closely-linked repeats but are required for interchromosomal repeat recombination inSaccharomyces cerevisiae. This requirement for long-range resection is coupled to DNA damage checkpoint activation and the need for checkpoint proteins. Furthermore, artificial activation of the checkpoint partially restores interchromosomal recombination toexo1Δ sgs1Δcells. However, cell cycle delay is insufficient to rescue the interchromosomal recombination defect ofexo1Δ sgs1Δcells, suggesting an additional role for the checkpoint. Given that the checkpoint is necessary for DNA damage-induced chromosome mobility, we propose that the importance of the checkpoint, and therefore long-range resection, in interchromosomal recombination is due to a need to increase chromosome mobility to facilitate pairing of distant sites. The need for long-range resection is circumvented when the DSB and its repair template are in close proximity.
Accurate rare variant phasing of whole-genome and whole-exome sequencing data in the UK Biobank
Authors: Hofmeister Robin J. , Ribeiro Diogo M. , Rubinacci Simone , Delaneau Olivier 
Published: October 2022

AbstractThe UK Biobank performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) across hundreds of thousands of individuals, allowing researchers to study the effects of both common and rare variants. Haplotype phasing distinguishes the two inherited copies of each chromosome into haplotypes and unlocks novel analyses at the haplotype level. In this work, we describe a new phasing method, SHAPEIT5, that accurately and rapidly phases large sequencing datasets and illustrates its key features on the UK Biobank WGS and WES data. First, we show that it phases rare variants with high accuracy. For instance, variants found in 1 sample out of 100,000 in the WES data are phased with accuracy above 95%. Second, we show that it can phase singletons, although with moderate accuracy, thereby making their inclusion in downstream analyses possible. Third, we show that the use of UK Biobank as a reference panel increases the accuracy of genotype imputation, an increase that is more pronounced when phased with SHAPEIT5 compared to other methods. Finally, we screen the phased WES data for loss-of-function (LoF) compound heterozygous (CH) events and identify 549 genes in which both gene copies are found knocked out. This list of genes complements current knowledge of gene essentiality in the human genome. We provide SHAPEIT5 in an open-source format, providing researchers with the means to leverage haplotype information in genetic studies.
TF-Prioritizer: a java pipeline to prioritize condition-specific transcription factors
Authors: Hoffmann Markus , Trummer Nico , Schwartz Leon , Jankowski Jakub , Lee Hye Kyung , Willruth Lina-Liv , Lazareva Olga , Yuan Kevin , Baumgarten Nina , Schmidt Florian , Baumbach Jan , Schulz Marcel H. , Blumenthal David B. , Hennighausen Lothar , List Markus 
Published: October 2022

ABSTRACTBackgroundEukaryotic gene expression is controlled by cis-regulatory elements (CREs), including promoters and enhancers, which are bound by transcription factors (TFs). Differential expression of TFs and their binding affinity at putative CREs determine tissue- and developmental-specific transcriptional activity. Consolidating genomic data sets can offer further insights into the accessibility of CREs, TF activity, and, thus, gene regulation. However, the integration and analysis of multi-modal data sets are hampered by considerable technical challenges. While methods for highlighting differential TF activity from combined chromatin state data (e.g., ChIP-seq, ATAC-seq, or DNase-seq) and RNA-seq data exist, they do not offer convenient usability, have limited support for large-scale data processing, and provide only minimal functionality for visually interpreting results.ResultsWe developed TF-Prioritizer, an automated pipeline that prioritizes condition-specific TFs from multi-modal data and generates an interactive web report. We demonstrated its potential by identifying known TFs along with their target genes, as well as previously unreported TFs active in lactating mouse mammary glands. Additionally, we studied a variety of ENCODE data sets for cell lines K562 and MCF-7, including twelve histone modification ChIP-seq as well as ATAC-seq and DNase-seq datasets, where we observe and discuss assay-specific differences.ConclusionTF-Prioritizer accepts ATAC-seq, DNase-seq, or ChIP-seq and RNA-seq data as input and identifies TFs with differential activity, thus offering an understanding of genome-wide gene regulation, potential pathogenesis, and therapeutic targets in biomedical research.