bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reading the canid skeletal story: Coxofemoral joint pathology, and suggested implications for the phylogenetic and natural history of taxa
Authors: Lawler Dennis , Tangredi Basil , Widga Christopher , Etnier Michael , Martin Terrance , Kohn Luci 
Published: September 2022

ABSTRACTWe evaluated subtle-to-incipient pathology traits in coxofemoral joints from dry bone museum specimens of: Vulpes lagopus; Vulpes; Nyctereutes procyonoides; Urocyon cinereoargenteus; Canis lupus familiaris; and Canis latrans. Multiple intra-articular structures were evaluated on acetabula and proximal femora. Primary observations included multifocal, variable osteophytelike formations; osteophyte-like rimming of articular margins and femoral head (ligamentum teres attachment); and rough or worn bone. Within limitations on valid statistical applications, we observed little difference among the high trait frequencies across taxa, aligning with previous morphological observations.Additionally, for this study, we evaluated the known history of the taxa, from deep time to the present, to consider our data in a phylogenetic context. Potential introgression over the evolution of Canidae, along with early history of the canid genome, likely supported broad and deep conservation of pathophysiological processes associated with observable pathology at the same intra-articular foci, across taxa. We also evaluated the “modern” natural histories of the taxa, noting that coxofemoral joint impacts of their respective life habits did not appear to influence pathology trait outcomes differentially.We conclude that conservation of the physiology underlying subtle and incipient coxofemoral joint pathology that did not segregate among taxa. We hypothesize that the intersecting basic biology of growth-development and insult response, over long geological time, may owe in part to the evidently long histories of hybridization and generally high historical gene flow, with high levels of heterogeneity.These data argue for new research to advance an interdisciplinary, integrated understanding of relationships among canid growth-development, incipient-to-subtle joint pathology, influences of natural histories across related taxa, and implications for genomic interrelationships.
A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion
Authors: Mann JP , Duan X , Alvarez-Guaita A , Haider A , Luijten I , Page M , Patel S , Scurria F , Protasoni M , Tábara LC , Virtue S , O’Rahilly S , Armstrong M , Prudent J , Semple RK , Savage DB 
Published: September 2022

AbstractMitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin-2. How this selective perturbation of mitochondrial function leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation by isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation perturbs mitochondrial morphology and activates the integrated stress response selectively in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.
Is phase-dependent stability related to phase-dependent gait robustness?
Authors: Jin Jian , Kistemaker Dinant , van Dieën Jaap H. , Daffertshofer Andreas , Bruijn Sjoerd M. 
Published: September 2022

I.ABSTRACTPredicting gait robustness is useful for targeting interventions to prevent falls. A first step towards this is to properly quantify gait robustness. However, this step already comes with challenges, as humans can withstand different magnitudes of perturbations at different phases in a gait cycle. Earlier, we showed using a simple model that phase-dependent stability measures are limited to predict gait robustness. However, phase-dependent stability measures might relate to phase-dependent gait robustness. To study this, we simulated a ‘simple’ walker model that walks stably and periodically. We applied push and pull perturbations to the stance or swing leg at each phase of the single stance phase and evaluated how phase-dependent stability measures correlate with phase-dependent gait robustness. The latter was quantified via the maximum energy deviation induced by a perturbation that the walker could withstand without falling within 50 steps. Phase-dependent stability measures were obtained, after linearizing the system in a rotating hypersurface perpendicular to the periodic trajectory, via the maximum and the sum of the eigenvalues of the reduced Jacobian matrix, i.e., the trajectory-normal divergence rate. We did not find any strong association between phase-dependent stability measures and phase-dependent robustness. Combining this with our previous assessment of gait robustness, we conclude that phase-dependent stability does not allow for predicting gait robustness, let alone predicting fall risk.
Myosin II regulatory light chain phosphorylation and formin availability modulate cytokinesis upon changes in carbohydrate metabolism
Authors: Prieto-Ruiz Francisco , Gómez-Gil Elisa , Martín-García Rebeca , Pérez-Díaz Armando Jesús , Vicente-Soler Jero , Franco Alejandro , Soto Teresa , Pérez Pilar , Madrid Marisa , Cansado José 
Published: September 2022

AbstractCytokinesis, which achieves the separation of daughter cells after mitosis completion, relies in animal cells on a contractile actomyosin ring (CAR), made of actin and class II myosins, whose activity is heavily influenced by regulatory light chain (RLC) phosphorylation. However, in simple eukaryotes such as fission yeast Schizosaccharomyces pombe, regulation of CAR dynamics by RLC phosphorylation seems dispensable. We found that redundant phosphorylation at Ser35 of the S. pombe RLC homolog Rlc1 by the p21-activated kinases Pak1 and Pak2, modulates Myosin II Myo2 activity and becomes essential for cytokinesis and cell growth during respiration. Previously, we showed that the Stress Activated Protein Kinase Pathway (SAPK) MAPK Sty1 controls fission yeast CAR integrity by downregulating formin For3 levels (Gomez-Gil et al.,2020). Here we report that reduced availability of formin For3-nucleated actin filaments for the CAR is the main reason for the required control of myosin II contractile activity by RLC phosphorylation during respiration-induced oxidative stress. Hence, recovery of For3 levels with antioxidants bypasses the control of Myosin II function regulated by RLC phosphorylation to allow cytokinesis and cell proliferation during respiration. Therefore, a fine-tuned interplay between Myosin II function by Rlc1 phosphorylation and environmentally controlled actin filament availability is critical for a successful cytokinesis in response to a switch to a respiratory carbohydrate metabolism.
Predicting Peptide HLA-II Presentation Using Immunopeptidomics, Transcriptomics and Deep Multimodal Learning
Authors: ElAbd Hesham , Wendorff Mareike , Koudelka Tomas , Hentschker Christian , Kamps Ann-Kristin , Prieß Christoph , Wienbrandt Lars , Degenhardt Frauke , Steiert Tim A. , Bacher Petra , Mathur Piyush , Ellinghaus David , Völker Uwe , Tholey Andreas , Lenz Tobias L. , Franke Andre 
Published: September 2022

ABSTRACTThe human leukocyte antigen (HLA) class II proteins present peptides to CD4+T cells through an interaction with T cell receptors (TCRs). Thus, HLA proteins are key players in shaping immunogenicity and immunodominance. Nevertheless, factors governing peptide presentation by HLA-II proteins are still poorly understood. To address this problem, we profiled the blood transcriptome and immunopeptidome of 20 healthy individuals and integrated the profiles with publicly available immunopeptidomics datasets. In depth multi-omics analysis identified expression levels and subcellular locations as import sequence-independent features governing presentation. Levering this knowledge, we developed the Peptide Immune Annotator Multimodal (PIA-M) tool, as a novel pan multimodal transformer-based framework that utilises sequence-dependent along with sequence-independent features to model presentation by HLA-II proteins.PIA-Millustrated a consistently superior performance relative to existing tools across two independent test datasets (area under the curve: 0.93 vs. 0.84 and 0.95 vs. 0.86), respectively. Besides achieving a higher predictive accuracy,PIA-Mwith its Rust-based pre-processing engine, had significantly shorter runtimes.PIA-Mis freely available with a permissive licence as a standalone pipeline and as a webserver (https://hybridcomputing.ikmb.uni-kiel.de/pia). In conclusion,PIA-Menables a new state-of-the-art accuracy in predicting peptide presentation by HLA-II proteinsin vivo.
Microstructural and mechanical insight into atherosclerotic plaques– an ex vivo DTI study to better assess plaque vulnerability
Authors: Tornifoglio B , Johnston R. D. , Stone A. J. , Kerskens C. , Lally C. 
Published: September 2022

AbstractNon-invasive microstructural characterisation has the potential to determine the stability, or lack thereof, of atherosclerotic plaques and ultimately aid in better assessing plaques’ risk to rupture. If linked with mechanical characterisation using a clinically relevant imaging technique, mechanically sensitive rupture risk indicators could be possible. This study aims to provide this link – between a clinically relevant imaging technique and mechanical characterisation within human atherosclerotic plaques. Ex vivo diffusion tensor imaging, mechanical testing, and histological analysis were carried out on human carotid atherosclerotic plaques. DTI-derived tractography was found to yield significant mechanical insight into the mechanical properties of more stable and more vulnerable microstructures. Coupled with insights from digital image correlation and histology, specific failure characteristics of different microstructural arrangements furthered this finding. More circumferentially uniform microstructures failed at higher stresses and strains when compared to samples which had multiple microstructures, like those seen in a plaque cap. The novel findings in this study motivate diagnostic measures which use non-invasive characterisation of the underlying microstructure of plaques to determine their vulnerability to rupture.Statements and DeclarationsThe authors have no competing interests or declarations to declare.Graphical abstract
Biologically informed variational autoencoders allow predictive modeling of genetic and drug induced perturbations
Authors: Doncevic Daria , Herrmann Carl 
Published: September 2022

AbstractVariational Autoencoders (VAE) have rapidly increased in popularity in biological applications and have already successfully been used on many omic datasets. Their latent space provides a low dimensional representation of input data, and VAEs have been applied for example for clustering of single-cell transcriptomic data. However, due to their non-linear nature, the patterns that VAEs learn in the latent space remain obscure. To shed light on the inner workings of VAE and enable direct interpretability of the model through its structure, we designed a novel VAE, OntoVAE (Ontology guided VAE) that can incorporate any ontology in its latent space and decoder part and, thus, provide pathway or phenotype activities for the ontology terms. In this work, we demonstrate that OntoVAE can be applied in the context of predictive modeling, and show its ability to predict the effects of genetic or drug induced perturbations using different ontologies and both, bulk and single-cell transcriptomic datasets. Finally, we provide a flexible framework which can be easily adapted to any ontology and dataset.
Host infection dynamics and disease induced mortality modify species contributions to the environmental reservoir
Authors: Laggan Nichole A. , Parise Katy L. , White J. Paul , Kaarakka Heather M. , Redell Jennifer A. , DePue John E. , Scullon William H. , Kath Joseph , Foster Jeffrey T. , Kilpatrick A. Marm , Langwig Kate E. , Hoyt Joseph R. 
Published: September 2022

AbstractEnvironmental pathogen reservoirs exist for many globally important diseases and can fuel epidemics, influence pathogen evolution, and increase the threat of host extinction. Species composition can be an important factor that shapes reservoir dynamics and ultimately determines the outcome of a disease outbreak. However, disease induced mortality can change species communities, indicating that species responsible for environmental reservoir maintenance may change over time. Here we examine reservoir dynamics ofPseudogymnoascus destructans,the fungal pathogen that causes white-nose syndrome in bats. We quantified changes in pathogen shedding, infection prevalence and intensity, host abundance, and the subsequent propagule pressure imposed by each species over time. We find that highly shedding species are important during pathogen invasion, but contribute less over time to environmental contamination as they also suffer the greatest declines. Less infected species remain more abundant, resulting in equivalent or higher propagule pressure. More broadly, we demonstrate that high infection intensity and subsequent mortality during disease progression can reduce the contributions of high shedding species to long-term pathogen maintenance.
Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours
Authors: Nabbi Arash , Beck Pengbo , Delaidelli Alberto , Oldridge Derek A. , Sudhaman Sumedha , Zhu Kelsey , Cindy Yang S.Y. , Mulder David T. , Bruce Jeffrey P. , Paulson Joseph N. , Raman Pichai , Zhu Yuankun , Resnick Adam C. , Sorensen Poul H. , Sill Martin , Brabetz Sebastian , Lambo Sander , Malkin David , Johann Pascal D. , Kool Marcel , Jones David T.W. , Pfister Stefan M. , Jäger Natalie , Pugh Trevor J. 
Published: September 2022

SummaryTo inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Excluded (17%). We validated these clusters using immunohistochemistry, methylation immune inference, and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune-cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.
SRSF2 is required for mRNA splicing and spermatogenesis
Authors: Lei Wen-Long , Du Zongchang , Meng Tie-Gang , Su Ruibao , Li Yuan-Yuan , Liu Wenbo , Sun Si-Min , Liu Meng-Yu , Hou Yi , Zhang Chun-Hui , Gui Yaoting , Schatten Heide , Han Zhiming , Liu Chenli , Wang Zhen-Bo , Qian Wei-Ping , Sun Qing-Yuan 
Published: September 2022

AbstractRNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.
Cis-regulatory variation in relation to sex and sexual dimorphism inDrosophila melanogaster
Authors: Mishra Prashastha , Barrera Tania S. , Grieshop Karl , Agrawal Aneil F. 
Published: September 2022

AbstractMuch of sexual dimorphism is likely due to sex-biased gene expression, which results from differential regulation of a genome that is largely shared between males and females. Here we use allele-specific expression to explorecis-regulatory variation inDrosophila melanogasterin relation to sex. We develop a Bayesian framework to infer the transcriptome-wide joint distribution ofcis-regulatory effects across the sexes. We use this approach to quantify transcriptome-wide sex differences incis-regulatory effects as well as examine patterns ofcis-regulatory variation with respect to two other levels of variation in sexual dimorphism: (i) across genes varying in their degree of sex-biased expression, and (ii) among tissues that vary in their degree of dimorphism (e.g., relatively low dimorphism in heads vs high dimorphism in gonads). We uncover evidence of widespreadcis-regulatory variation in all tissues examined, with female-biased genes being especially enriched for this variation. A sizeable proportion ofcis-regulatory variation is inferred to have sex-specific effects, with sex-dependentciseffects being much more frequent in gonads than in heads. Finally, we detect some genes with reversed allelic imbalance between the sexes. Such variants could provide a mechanism for sex-specific dominance reversals, a phenomenon important for sexually antagonistic balancing selection.
T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation
Authors: Cho Nam Woo , Guldberg Sophia M. , Nabet Barzin Y. , Yu Jie Zeng , Kim Eun Ji , Hiam-Galvez Kamir J. , Yee Jacqueline L. , DeBarge Rachel , Tenvooren Iliana , Ashitey Naa Asheley , Lynce Filipa , Dillon Deborah A. , Rosenbluth Jennifer M. , Spitzer Matthew H. 
Published: September 2022

AbstractResistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells increased in ICI-resistant tumors following treatment as did neutrophils, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting neutrophils. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα bothin vitroandin vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a novel mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNFα, with important therapeutic implications.Statement of SignificanceAlthough T cell-infiltrated cancers are frequently resistant to immune checkpoint inhibitor therapies, mechanisms of resistance beyond T cell exhaustion remain unclear. Here, we reveal the functional significance of tumor- infiltrating T cells in resistant tumors, which surprisingly instruct immunosuppressive inflammation in mouse and human cancers responsive to IL-1 and TNFα.
Conserved coexpression at single cell resolution across primate brains
Authors: Suresh Hamsini , Crow Megan , Jorstad Nikolas , Hodge Rebecca , Lein Ed , Dobin Alexander , Bakken Trygve , Gillis Jesse 
Published: September 2022

AbstractEnhanced cognitive function in humans is hypothesized to result from cortical expansion and increased cellular diversity. However, the mechanisms that drive these phenotypic differences remain poorly understood, in part due to the lack of high-quality cellular resolution data in human and non-human primates. Here, we take advantage of single cell expression data from the middle temporal gyrus of five primates (human, chimp, gorilla, macaque and marmoset) to identify 57 homologous cell types and generate cell-type specific gene coexpression networks for comparative analysis. While ortholog expression patterns are generally well conserved, we find 24% of genes with extensive differences between human and non-human primates (3383/14,131), which are also associated with multiple brain disorders. To validate these observations, we perform a meta-analysis of coexpression networks across 19 animals, and find that a subset of these genes have deeply conserved coexpression across all non-human animals, and strongly divergent coexpression relationships in humans (139/3383, <1% of primate orthologs). Genes with human-specific cellular expression and coexpression networks (like NHEJ1, GTF2H2, C2 and BBS5) typically evolve under relaxed selective constraints and may drive rapid evolutionary change in brain function.One Sentence SummaryCross-primate middle temporal gyrus single cell expression data reveals patterns of conservation and divergence that can be validated with population coexpression networks.
Onecut1partially contributes to the liver progenitor cell transition and acquisition of metastatic potential in hepatocellular carcinoma
Authors: Liu Yu , Higashitsuji Hiroaki , Itoh Katsuhiko , Yamaguchi Kanji , Umemura Atsushi , Itoh Yoshito , Fujita Jun 
Published: September 2022

AbstractMetastasis-initiating cells are considered to originate from stem cell-like cancer cells. In hepatocellular carcinoma, liver progenitor-like cells are reported to be derived from hepatocytes, indicating the possible acquisition of metastatic potential during hepatocyte-to-cholangiocyte transdifferentiation. Consistent with the expression pattern observed during ductal plate formation, we revealed an LPC transition withOnecut1accumulation both during hepatocyte-to-cholangiocyte transdifferentiation and in a cell model. This event may be associated with transient acquisition of metastatic potential.