bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural crest cells give rise to non-myogenic mesenchymal tissue in the adult murid ear pinna
Authors: Allen Robyn S. , Biswas Shishir K. , Seifert Ashley W. 
Published: August 2023

ABSTRACTDespite being a major target of reconstructive surgery, development of the external ear pinna remains poorly studied. As a craniofacial organ highly accessible to manipulation and highly conserved among mammals, the ear pinna represents a valuable model for the study of appendage development and wound healing in the craniofacial complex. Here we provide a cellular characterization of late gestational and postnatal ear pinna development inMus musculusandAcomys cahirinusand demonstrate that ear pinna development is largely conserved between these species. UsingWnt1-cre;ROSAmT/mGmice we find that connective tissue fibroblasts, elastic cartilage, dermal papilla cells, dermal sheath cells, vasculature, and adipocytes in the adult pinna are derived from cranial crest. In contrast, we find that skeletal muscle and hair follicles are not derived from neural crest cells. Cellular analysis using the naturally occurringshort earmouse mutant shows that elastic cartilage does not develop properly in distal pinna due to impaired chondroprogenitor proliferation. Interestingly, while chondroprogenitors develop in a mostly continuous sheet, the boundaries of cartilage loss in theshort earmutant strongly correlate with locations of vasculature-conveying foramen. Concomitant with loss of elastic cartilage we report increased numbers of adipocytes, but this seems to be a state acquired in adulthood rather than a developmental abnormality. In addition, chondrogenesis remains impaired in the adult mid-distal ear pinna of these mutants. Together these data establish a developmental basis for the study of the ear pinna with intriguing insights into the development of elastic cartilage.
RNA-mediated ribonucleoprotein assembly controls TDP-43 nuclear retention
Authors: dos Passos Patricia M. , Hemamali Erandika H. , Mamede Lohany D. , Hayes Lindsey R. , Ayala Yuna M. 
Published: August 2023

ABSTRACTTDP-43 is an essential RNA-binding protein strongly implicated in the pathogenesis of neurodegenerative disorders characterized by cytoplasmic aggregates and loss of nuclear TDP-43. The protein shuttles between nucleus and cytoplasm, yet maintaining predominantly nuclear TDP-43 localization is important for TDP-43 function and for inhibiting cytoplasmic aggregation. We previously demonstrated that specific RNA binding mediates TDP-43 self-assembly and biomolecular condensation, requiring multivalent interactions via N- and C-terminal domains. Here, we show that these complexes play a key role in TDP-43 nuclear retention. TDP-43 forms macromolecular complexes with a wide range of size distribution in cells and we find that defects in RNA binding or inter-domain interactions, including phase separation, impair the assembly of the largest species. Our findings suggest that recruitment into these macromolecular complexes prevents cytoplasmic egress of TDP-43 in a size-dependent manner. Our observations uncover fundamental mechanisms controlling TDP-43 cellular homeostasis, whereby regulation of RNA-mediated self-assembly modulates TDP-43 nucleocytoplasmic distribution. Moreover, these findings highlight pathways that may be implicated in TDP-43 proteinopathies and identify potential therapeutic targets.
Dietaryindex: A User-Friendly and Versatile R Package for Standardizing Dietary Pattern Analysis in Epidemiological and Clinical Studies
Authors: Zhan Jiada James , Hodge Rebecca A , Dunlop Anne L , Lee Matthew M. , Bui Linh , Liang Donghai , Ferranti Erin P 
Published: August 2023

AbstractBackgroundFew standardized and open-source tools exist for calculating dietary pattern indexes from dietary intake data in epidemiological and clinical studies. Miscalculations of dietary indexes, with suspected erroneous findings, are occasionally noted in the literature.ObjectiveThe primary aim is to develop and validate dietaryindex, a user-friendly and versatile R package that standardizes the calculation of dietary indexes.MethodsDietaryindex utilizes a two-step process: an initial calculation of serving size for each food and nutrient category, followed by the calculation of individual dietary indexes. It includes generic functions that accept any preprocessed serving sizes of food groups and nutrients, with the standard serving sizes defined according to the methodologies used in well-known prospective cohort studies. For ease of use, dietaryindex also offers one-step functions that directly reference common datasets and tools, including the National Health and Nutrition Examination Survey (NHANES) and Block Food Frequency Questionnaire, eliminating the need for data preprocessing. At least two independent researchers validated the serving size definitions and scoring algorithms of dietaryindex.ResultsDietaryindex can calculate multiple dietary indexes of high interest in research, including Healthy Eating Index (HEI) - 2020, Alternative Healthy Eating Index 2010, Dietary Approaches to Stop Hypertension Index, Alternate Mediterranean Diet Score, Dietary Inflammatory Index, American Cancer Society 2020 dietary index, and Planetary Health Diet Index from the EAT-Lancet Commission. In our validation process, dietaryindex demonstrated full accuracy (100%) in all generic functions with two-decimal rounding precision in comparison to hand-calculated results. Similarly, using NHANES 2017-2018 data and ASA24 and DHQ3 example data, the HEI2015 outputs from dietaryindex aligned (99.95% - 100%) with results using the SAS codes from the National Cancer Institute.ConclusionsDietaryindex is a user-friendly, versatile, and validated informatics tool for standardized dietary index calculations. We have open-sourced all the validation files and codes with detailed tutorials on GitHub (https://github.com/jamesjiadazhan/dietaryindex).
Cell-free chromatin particles from dying cells promote the induction of an immune response in human lymphocytes
Authors: Shabrish Snehal , Raghuram Gorantla V. , Raphael Nimisha , Narayanan Ranjani , Lopes Relestina , Kondhalkar Dipali , Khare Naveen Kumar , Mittra Indraneel 
Published: August 2023

AbstractIt is long established that cell death and immune response are closely related, although the nature of this relationship has remained unclear. We earlier reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day to enter into the blood circulation, or those that are released locally from dying cells, can readily enter into healthy cells to induce DNA damage and activate inflammatory cytokines. In this study we investigated whether cfChPs from dying cells might be the missing link between cell death and immune response. We treated human lymphocytes with cfChPs isolated from sera of healthy individuals or with cfChPs released from hypoxia-induced dying lymphocytes. We observed that cfChPs from both sources readily entered into lymphocytes to accumulate in their nuclei within 2 h. This was associated with marked activation of CD69 and release of inflammatory cytokines, as well as of p-STING and cGAS expression. The addition of the STING protein inhibitor H151 to the cfChPs treated cells abolished the release of inflammatory cytokines. These findings lead us to suggest that cfChPs from dying cells are the critical triggers of immune response which act via cGAS-STING pathway.
Visualizing and quantifying structural diversity around mobile resistance genes
Authors: Shaw Liam P. , Neher Richard A. 
Published: August 2023

AbstractUnderstanding the evolution of mobile genes is important for understanding the spread of antimicrobial resistance (AMR). Many clinically important AMR genes have been mobilized by mobile genetic elements (MGEs) on the kilobase scale, such as integrons and transposons, which can integrate into both chromosomes and plasmids and lead to rapid spread of the gene through bacterial populations. Looking at the flanking regions of these mobile genes in diverse genomes can highlight common structures and reveal patterns of MGE spread. However, historically this has been a largely descriptive process, relying on gene annotation and expert knowledge. Here we describe a general method to visualize and quantify the structural diversity around genes usingpangraphto find blocks of homologous sequence. We apply this method to a set of twelve clinically important beta-lactamase genes and provide interactive visualizations of their flanking regions athttps://liampshaw.github.io/flanking-regions. We show that nucleotide-level variation in the mobile gene itself generally correlates with increased structural diversity in its flanking regions, demonstrating a relationship between rates of mutational evolution and rates of structural evolution, and find a bias for greater structural diversity upstream. Our framework is a starting point to investigate general rules that apply to the horizontal spread of new genes through bacterial populations.Impact statementUnderstanding the evolution and spread of mobile resistance genes is challenging because of the high variability in their genomic contexts. Here we outline a fast computational approach that identifies stretches of homologous sequence in the flanking regions of a gene, simultaneously producing interactive visualizations of these regions and quantifying the diversity within them. As an example, we apply the method to twelve clinically important beta-lactamase genes. We find that structural diversity around the resistance gene is correlated with mutations within it and that there is greater structural diversity upstream of many genes. There may be other general patterns about the evolution of mobile resistance genes that can be recovered with this kind of analysis.
Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression
Authors: Mobilia Maura , Karakashian Alexander , Whitus Callie , Neupane Khaga R. , Johnson Lance A. , Graf Gregory A. , Gordon Scott M. 
Published: August 2023

AbstractBackgroundInflammatory cells within atherosclerotic lesions secrete various proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. The relative contributions of specific proteases to atherogenesis is not well understood. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We have previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as an endogenous modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression.MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models.ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasmaex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after systemic administration toApoe-/-mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed usingLdlr-/-mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features.ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.
Inference of Selective Force on House Mouse Genomes during Secondary Contact in East Asia
Authors: Fujiwara Kazumichi , Kubo Shunpei , Endo Toshinori , Takada Toyoyuki , Shiroishi Toshihiko , Suzuki Hitoshi , Osada Naoki 
Published: August 2023

AbstractThe house mouse (Mus musculus), commensal to humans, has spread globally via human activities, leading to secondary contact between genetically divergent subspecies. This pattern of genetic admixture can provide insights into the selective forces at play in this well-studied model organism. Our analysis of 163 house mouse genomes, with a particular focus on East Asia, revealed substantial admixture between the subspeciescastaneusandmusculus, particularly in Japan and southern China. We revealed, despite the admixture, all Y chromosomes in the East Asian samples belonged to themusculus-type haplogroup, potentially explained by genomic conflict under sex ratio distortion due to varying copy numbers of ampliconic genes on sex chromosomes. We also investigated the influence of selection on the post-hybridization of the subspeciescastaneusandmusculusin Japan. Even though the genetic background of most Japanese samples closely resembles the subspeciesmusculus, certain genomic regions overrepresented thecastaneus-like genetic components, particularly in immune-related genes. Furthermore, a large genomic block containing a vomeronasal/olfactory receptor gene cluster predominantly harboredcastaneus-type haplotypes in the Japanese samples, highlighting the crucial role of olfaction-based recognition in shaping hybrid genomes.
Compartment specific responses to contractility in the small intestinal epithelium
Authors: Hinnant Taylor , Ning Wenxiu , Lechler Terry 
Published: August 2023

AbstractTissues are subject to multiple mechanical inputs at the cellular level that influence their overall shape and function. In the small intestine, actomyosin contractility can be induced by many physiological and pathological inputs. However, we have little understanding of how contractility impacts the intestinal epithelium on a cellular and tissue level. In this study, we probed the cell and tissue-level effects of contractility by using mouse models to genetically increase the level of myosin activity in the two distinct morphologic compartments of the intestinal epithelium, the crypts and villi. We found that increased contractility in the villar compartment caused shape changes in the cells that expressed the transgene and their immediate neighbors. While there were no discernable effects on villar architecture, even low levels of transgene induction in the villi caused non-cell autonomous hyperproliferation of the transit amplifying cells in the crypt, driving increased cell flux through the crypt-villar axis. In contrast, induction of increased contractility in the proliferating cells of the crypts resulted in nuclear deformations, DNA damage, and apoptosis. This study reveals the complex and diverse responses of different intestinal epithelial cells to contractility and provides important insight into mechanical regulation of intestinal physiology.Author SummaryThe small intestine epithelium is comprised of two main compartments: the villi which contain differentiated cells that function in nutrient absorption, and the crypts which are made up of undifferentiated cells which serve to replenish cells of the villi. Because of their physical location within the tissue, villi and crypts are subjected to different types of insults and mechanical forces. We sought to directly test how villi and crypts respond to mechanical changes in the epithelia by genetically inducing actomyosin contraction. Increasing contractility in villar cells resulted in cell shape changes without affecting their overall polarity or organization. However, it led to a non-autonomous increase in proliferation of the undifferentiated cells of the intestine. In contrast, increased contractility in the proliferative cells of the crypt resulted in nuclear shape changes, DNA damage and ultimately a rapid cell death. Thus, our work demonstrates that the crypt and villi epithelia respond differently to mechanical changes and highlights long-range regulation between villi and crypt compartments.
Variant annotation across homologous proteins (“Paralogue Annotation”) identifies disease-causing missense variants with high precision, and is widely applicable across protein families
Authors: Li Nicholas , Mazaika Erica , Theotokis Pantazis , Zhang Xiaolei , Jang Mikyung , Ahmad Mian , Powell George , Heyne Henrike O. , Lal Dennis , Barton Paul JR , Walsh Roddy , Whiffin Nicola , Ware James S 
Published: August 2023

AbstractBackgroundDistinguishing pathogenic variants from those that are rare but benign remains a key challenge in clinical genetics, especially for variants not previously observed and characterised in humans.In vitroandin vivofunctional characterisation are typically resource intensive, and model systems may not accurately predict influence on human disease. Manyin silicotools have been developed to predict which variants are disease-causing, but typically lack precision. Here we demonstrate the applicability of a framework, called Paralogue Annotation, that draws on information from previously-characterised variants in homologous proteins to predict whether variants in a gene of interest are likely disease causing.MethodsWe assessed the performance of Paralogue Annotation through three orthogonal approaches: (1) comparison to establishedin silicovariant prediction tools using 47,360 missense variants from ClinVar across 3,524 genes representing a broad range of diverse protein classes, by calculating precision and sensitivity; (2) evaluation against large-scale functional assays of variant effect inTP53andPPARG; and (3) comparing odd ratios calculated from case-control association tests for inherited cardiac arrhythmia syndromes, and neurodevelopmental disorders with epilepsy, stratifying variants by Paralogue Annotation.ResultsParalogue Annotation correctly annotates 4,328 ClinVar pathogenic variants, with 245 false positives, yielding a precision of 0.95. This increases to 0.99 with more stringent annotation parameters (requiring greater conservation of amino acids between annotated orthologues) at the expense of sensitivity. Compared to established tools, Paralogue Annotation has higher precision for identification of pathogenic variants, albeit with lower sensitivity across diverse test sets. Extending the technique by transferring annotations between homologous protein domains, rather than full-length protein paralogues, increases sensitivity. Rare variants predicted pathogenic by Paralogue Annotation were more strongly disease-associated (increased odds ratio) than unstratified rare variants for six out of eight genes tested with case-control cohort approaches.ConclusionsParalogue Annotation has high precision for detection of pathogenic missense variants, outperformingin silicomethods where data are available to make a prediction. As the number of characterised variants increases in reference datasets such as ClinVar, Paralogue Annotation will further increase in sensitivity and applicability.
Extracellular vesicles are the main contributor to the non-viral protected extracellular sequence space
Authors: Lücking Dominik , Mercier Coraline , Alarcón-Schumacher Tomas , Erdmann Susanne 
Published: August 2023

AbstractMarine environmental virus metagenomes, commonly referred to as ’viromes’, are typically generated by physically separating virus-like particles (VLPs) from the microbial fraction based on their size and mass. However, most methods used to purify VLPs, enrich extracellular vesicles (EVs) and gene transfer agents (GTAs) simultaneously. Consequently, the sequence space traditionally referred to as a ’virome’ contains host-associated sequences, transported via EVs or GTAs. We therefore propose to call the genetic material isolated from size-fractionated (0.22 µm) and DNase-treated samplesprotected environmental DNA (peDNA).This sequence space contains viral genomes, DNA transduced by viruses and DNA transported in EVs and GTAs. Since there is no genetic signature for peDNA transported in EVs, GTAs and virus particles, we rely on the successful removal of contaminating remaining cellular and free DNA when analyzing peDNA. Using marine samples collected from the North Sea, we generated a thoroughly purified peDNA dataset and developed a bioinformatic pipeline to determine the potential origin of the purified DNA. This pipeline was applied to our dataset as well as existing global marine ’viromes’. Through this pipeline, we identified known GTA and EV producers, as well as organisms with actively transducing proviruses as the source of the peDNA, thus confirming the reliability of our approach. Additionally, we identified novel and widespread EV producers, and found quantitative evidence suggesting that EV-mediated gene transfer plays a significant role in driving horizontal gene transfer (HGT) in the world’s oceans.
Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation
Authors: Cheng Kevin C.L. , Frost Jennifer M. , Sánchez-Luque Francisco J. , García-Canãdas Marta , Taylor Darren , Yang Wan R. , Irayanar Branavy , Sampath Swetha , Patani Hemalvi , Agger Karl , Helin Kristian , Ficz Gabriella , Burns Kathleen H. , Ewing Adam , García-Pérez José L. , Branco Miguel R. 
Published: August 2023

AbstractVitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells. Here we show that vitC increases the expression of evolutionarily young LINE-1 (L1) elements in mouse ESCs. We find that TET activity is dispensable for these effects, and that instead L1 upregulation occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, which could impact the genetic and epigenetic stability of human pluripotent stem cells.
CurveCurator: A recalibrated F-statistic to assess, classify, and explore significance of dose-response curves
Authors: Bayer Florian P. , Gander Manuel , Kuster Bernhard , The Matthew 
Published: August 2023

AbstractDose-response curves are key metrics in pharmacology and biology to assess phenotypic or molecular actions of bioactive compounds in a quantitative fashion. Yet, it is often unclear whether or not a response significantly differs from a curve without regulation, particularly in high-throughput applications or unstable assays. Treating potency and effect size estimates from random and true curves with the same level of confidence can lead to incorrect hypotheses and issues in training machine learning models. Here, we present CurveCurator, an open-source software and interactive dashboard that provides reliable dose-response characteristics by computing p-values and false discovery rates based on a recalibrated F-statistic and a novel thresholding procedure. Application of CurveCurator to large-scale data sets demonstrates its scalable utility across several application areas.