bluuebunny/crossref_metadata_2025_split huggingface dataset:
The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming
Authors: Oger Frédérik , Moreno Maeva , Derhourhi Mehdi , Thiroux Bryan , Berberian Lionel , Bourouh Cyril , Durand Emmanuelle , Amanzougarene Souhila , Badreddine Alaa , Blanc Etienne , Molendi-Coste Olivier , Pineau Laurent , Pasquetti Gianni , Rolland Laure , Carney Charlène , Bornaque Florine , Courty Emilie , Gheeraert Céline , Eeckhoute Jérôme , Dombrowicz David , Kerr-Conte Julie , Pattou François , Staels Bart , Froguel Philippe , Bonnefond Amélie , Annicotte Jean-Sébastien 
Published: December 2022

AbstractObjectiveThe pancreatic islets of Langerhans contain distinct cell subtypes including insulin-producing β cells. Although their cell-specific gene expression pattern defines their identity, the underlying molecular network driving this transcriptional specificity is not fully understood. Among the numerous transcriptional regulators, histone deacetylases (HDAC) enzymes are potent chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone proteins. The precise molecular mechanisms underlying HDAC effects on cellular plasticity and β-cell identity are currently unknown.MethodsThe pharmacological inhibition of HDAC activity by trichostatin A (TSA) was studied in the mouse Min6 and human EndocBH1 cell lines, as well as primary mouse sorted β cells and human pancreatic islets. The molecular and functional effects of treating these complementary β-cell models with TSA was explored at the epigenomic and transcriptomic level through next-generation sequencing of chromatin immunoprecipitation (ChIP) assays (ChIP-seq) and RNA sequencing (RNA-seq) experiments, respectively.ResultsWe showed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers.ConclusionsTaken together, our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
A Cancer-Associated Fibroblast Classification Framework for Single-Cell Data
Authors: Cords Lena , Tietscher Sandra , Anzeneder Tobias , Langwieder Claus , Rees Martin , de Souza Natalie , Bodenmiller Bernd 
Published: December 2022

AbstractCancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on tumour evolution and patient prognosis. To define CAF phenotypes, we analysed a single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours of 14 breast cancer patients, based on which we defined and functionally annotated nine CAF phenotypes and one class of pericytes. We validated this classification system in four additional cancer types and used highly multiplexed imaging mass cytometry on matched breast cancer samples to confirm our defined CAF phenotypes at the protein level and to analyse their spatial distribution within tumours. This general CAF classification scheme will allow comparison of CAF phenotypes across studies, facilitate analysis of their functional roles, and potentially guide development of new treatment strategies in the future.
CAAStools: a toolbox to identify and test Convergent Amino Acid Substitutions
Authors: Barteri Fabio , Valenzuela Alejandro , Farré Xavier , de Juan David , Muntané Gerard , Esteve-Altava Borja , Navarro Arcadi 
Published: December 2022

AbstractBackgroundCoincidence of Convergent Amino Acid Substitutions (CAAS) with phenotypic convergences allow pinpointing genes and even individual mutations that are likely to be associated with trait variation within their phylogenetic context. Such findings can provide useful insights into the genetic architecture of complex phenotypes. Here we introduce CAAStools, a set of bioinformatics tools to identify and validate CAAS in orthologous protein alignments for pre-defined groups of species representing the phenotypic values targeted by the user.Implementation and availabilityCAAStools source code is available athttp://github.com/linudz/caastools, along with documentation and examples.Supplementary informationSupplementary data are available.
MSL2 targets histone genes inDrosophila virilis
Authors: Xie Mellisa , Hodkinson Lauren J. , Comstra H. Skye , Diaz-Saldana Pamela P. , Gilbonio Hannah E. , Gross Julia L. , Chavez Robert M. , Puckett Gwyn L. , Aoki Tsutomu , Schedl Paul , Rieder Leila E. 
Published: December 2022

AbstractHistone genes are amongst the most evolutionary conserved in eukaryotic genomes, yetcis-regulatory mechanisms of histone gene regulation differ considerably amongst species. InDrosophila melanogaster, an interaction between GA-richciselements in theH3/H4promoter and the GA-binding transcription factor CLAMP is important for promoting histone gene regulation and factor recruitment to the locus. CLAMP also participates in male dosage compensation by recruiting the Male Specific Lethal Complex (MSLc) to the X-chromosome. We discovered that the male-specific protein of MSLc, MSL2, is recruited to the autosomal major histone locus inD. virilisbut not to the minor locus or to the single histone locus in other species. While the histone coding sequences are well conserved between species, the critical GA-richciselements in theH3/H4promoter are poorly conserved betweenD. melanogasterandD. virilis. We show that CLAMP still targets the twoD. virilishistone lociin vivo. Further, CLAMP interacts with theD. virilis H3/H4promoterin vitro, even when the poorly-conserved GA-richciselements are deleted, indicating that the protein interacts differently with theD. virilispromoter than it does with theD. melanogasterpromoter. Since CLAMP and MSL2 directly interact inD. melanogaster, we propose thatD. virilisCLAMP recruits MSL2 to an ectopic autosomal site through interaction with X-likeciselements. Further, localization of MSL2 to one of theD. virilishistone loci suggests that the loci are regulated differently and that males and females have different requirements for histone gene regulation.
3D-printed polymeric scaffolds with optimized architecture to repair a sheep metatarsal critical-size bone defect
Authors: Garot Charlotte , Schoffit Sarah , Monfoulet Cécile , Machillot Paul , Deroy Claire , Roques Samantha , Vial Julie , Vollaire Julien , Renard Martine , Ghanem Hasan , El-Hafci Hanane , Decambron Adeline , Josserand Véronique , Bordenave Laurence , Bettega Georges , Durand Marlène , Manassero Mathieu , Viateau Véronique , Logeart-Avramoglou Delphine , Picart Catherine 
Published: December 2022

AbstractThe reconstruction of critical-size bone defects in long bones remains a challenge for clinicians. We developed a new bioactive medical device for long bone repair by combining a 3D-printed architectured cylindrical scaffold made of clinical-grade polylactic acid (PLA) with a polyelectrolyte film coating delivering the osteogenic bone morphogenetic protein 2 (BMP-2). This film-coated scaffold was used to repair a sheep metatarsal 25-mm long critical-size bone defect.In vitroandin vivobiocompatibility of the film-coated PLA material were proved according to ISO standards. Scaffold geometry was found to influence BMP-2 incorporation. Bone regeneration was followed using X-ray scans, µCT scans, and histology. We showed that scaffold internal geometry, notably pore shape, influenced bone regeneration, which was homogenous longitudinally. Scaffolds with cubic pores of ∼870 µm and a low BMP-2 dose of ∼120 µg/cm3induced the best bone regeneration without any adverse effects. The visual score given by clinicians during animal follow-up was found to be an easy way to predict bone regeneration. This work opens perspectives for a clinical application in personalized bone regeneration.
Monitoring RNA restructuring in a human cell-free extract reveals eIF4A-dependent and eIF4A-independent unwinding activity
Authors: O’Sullivan Mattie H. , Fraser Christopher S. 
Published: December 2022

ABSTRACTThe canonical DEAD-box helicase, eIF4A, unwinds 5’ UTR secondary structures to promote mRNA translation initiation. Growing evidence has indicated that other helicases, such as DHX29 and DDX3/ded1p, also function to promote the scanning of the 40S subunit on highly structured mRNAs. It is unknown how the relative contributions of eIF4A and other helicases regulate duplex unwinding on an mRNA to promote initiation. Here, we have adapted a real-time fluorescent duplex unwinding assay to precisely monitor helicase activity in the 5’ UTR of a reporter mRNA that can be translated in a cell-free extract in parallel. We monitored the rate of 5’ UTR-dependent duplex unwinding in the absence or presence of Hippuristanol, a dominant negative eIF4A (eIF4A-R362Q), or a mutant eIF4E (eIF4E-W73L) that can bind the m7G cap but not eIF4G. Our experiments reveal that roughly 50% of the duplex unwinding activity in the cell-free extract can be attributed to an eIF4A-dependent mechanism, while the remaining 50% of duplex unwinding activity is attributed to an eIF4A-independent mechanism. Importantly, we show that the robust eIF4A-independent duplex unwinding is not sufficient for translation. We also show that the m7G cap structure, and not the poly(A) tail, is the primary mRNA modification responsible for promoting duplex unwinding in our cell-free extract system. Overall, the fluorescent duplex unwinding assay provides a precise method to investigate how eIF4A-dependent and eIF4A-independent helicase activity regulates translation initiation in cell-free extracts. We anticipate that potential small molecule inhibitors could be tested for helicase inhibition using this duplex unwinding assay.
Probing the Biology of Zinc Alpha2-Glycoprotein and the role it plays in cachexia
Authors: Pandit Parth , Panigrahi Subrat 
Published: December 2022

AbstractCachexia is a metabolic disease that results in drastic weight loss and muscle wasting. 20% of total cancer patients will die due to cachexia related complications. ZAG contributes to the regulation of weight and body fat through lipid and glucose metabolism. In healthy individuals, ZAG exerts a homeostasis effect by inducing lipolysis of adipose tissue to help reduce fat storage and overall weight. ZAG is upregulated in various carcinomas and cancer patients with upregulated ZAG are observed to lose weight rapidly. The mutants of ZAG which are the 4 amino acids Tryptophan 148, Arginine 73, Phenylalanine 101, Isoleucine 76 have all been mutated to Alanine. The effect of mutants and the wild type ZAG can also be found out by conducting experiments. ZAG has a potential lipid binding site that could be imperative to the function of ZAG. A lipolysis colorimetric kit allows us to measure the ZAG variants effects on 3T3 adipose cells to determine what β-adrenoreceptor signaling pathways are being utilized in its lipolytic effect. The Tryptophan-Alanine mutant showed increased lipolysis after 1h treatment than other variants. The time period is also a rate limiting step which can play major factor in lipolysis. The ultimate goal is to identify the ligand(s) and the interactions between them and ZAG. The design of a therapeutic would give patients options of treatments brought about by attenuating the weight loss. With this, it would offer a better prognosis for patients and provide them with a greater quality of life.
Genomic loci involved in sensing environmental cues and metabolism affect seasonal coat shedding inBos taurusandBos indicuscattle
Authors: Durbin Harly J. , Yampara Helen , Rowan Troy N. , Schnabel Robert D. , Koltes James E. , Powell Jeremy G. , Decker Jared E. 
Published: December 2022

AbstractSeasonal shedding of winter hair at the start of summer is well studied in wild and domesticated populations. However, the genetic influences on this trait and their interactions are poorly understood. We use data from 13,364 cattle with 36,899 repeated phenotypes to investigate the relationship between hair shedding and environmental variables, single nucleotide polymorphisms, and their interactions to understand quantitative differences in seasonal shedding. Using deregressed estimated breeding values from a repeated records model in a genome-wide association analysis (GWAA) and meta-analysis of year-specific GWAA gave remarkably similar results.These GWAA identified hundreds of variants associated with seasonal hair shedding. There were especially strong associations on chromosomes 5 and 23. Genotype-by- environment interaction GWAA identified 1,040 day length-by-genotype interaction associations and 17 apparent temperature-by-genotype interaction associations with hair shedding, highlighting the importance of day length on hair shedding. Accurate genomic predictions of hair shedding were created for the entire dataset, Angus, Hereford, Brangus, and multi-breed datasets. Loci related to metabolism and light- sensing have a large influence on seasonal hair shedding. This is one of the largest genetic analyses of a phenological trait and provides insight for both agriculture production and basic science.
Astroglial gap junctions strengthen hippocampal network activity by sustaining afterhyperpolarization via KCNQ channels
Authors: Dossi Elena , Zonca Lou , Pivonkova Helena , Vargova Lydia , Chever Oana , Holcman David , Rouach Nathalie 
Published: December 2022

AbstractThroughout the brain, astrocytes form networks mediated by gap-junction channels that promote the activity of neuronal ensembles. Although their inputs on neuronal information processing are well established, how molecularly gap junction channels shape neuronal network patterns remains unclear. Here using astroglial connexin-deficient mice, in which astrocytes are disconnected and neuronal bursting patterns are abnormal, we found that astrocyte networks strengthen bursting activity via dynamic regulation of extracellular potassium levels, independently of glutamate homeostasis or metabolic support. Using a novel facilitation-depression model, we identified neuronal afterhyperpolarization as the key parameter underlying bursting patterns regulation by extracellular potassium in mice with disconnected astrocytes. We confirmed experimentally this prediction, and revealed that astroglial network-control of extracellular potassium sustains neuronal afterhyperpolarization via activation of KCNQ voltage-gated K+channels. Altogether, these data delineate how astroglial gap-junctions mechanistically strengthen neuronal population bursts, and points to approaches for controlling aberrant activity in neurological diseases.
The Challenge Dataset – simple evaluation for safe, transparent healthcare AI deployment
Authors: Sanayei James K. , Abdalla Mohamed , Ahluwalia Monish , Seyyed-Kalantari Laleh , Minotti Simona , Fine Benjamin A. 
Published: December 2022

AbstractIn this paper, we demonstrate the use of a “Challenge Dataset”: a small, site-specific, manually curated dataset – enriched with uncommon, risk-exposing, and clinically important edge cases – that can facilitate pre-deployment evaluation and identification of clinically relevant AI performance deficits. The five major steps of the Challenge Dataset process are described in detail, including defining use cases, edge case selection, dataset size determination, dataset compilation, and model evaluation. Evaluating performance of four chest X-ray classifiers (one third-party developer model and three models trained on open-source datasets) on a small, manually curated dataset (410 images), we observe a generalization gap of 20.7% (13.5% - 29.1%) for sensitivity and 10.5% (4.3% - 18.3%) for specificity compared to developer-reported values. Performance decreases further when evaluated against edge cases (critical findings: 43.4% [27.4% - 59.8%]; unusual findings: 45.9% [23.1% - 68.7%]; solitary findings 45.9% [23.1% - 68.7%]). Expert manual audit revealed examples of critical model failure (e.g., missed pneumomediastinum) with potential for patient harm. As a measure of effort, we find that the minimum required number of Challenge Dataset cases is about 1% of the annual total for our site (approximately 400 of 40,000). Overall, we find that the Challenge Dataset process provides a method for local pre-deployment evaluation of medical imaging AI models, allowing imaging providers to identify both deficits in model generalizability and specific points of failure prior to clinical deployment.
Appropriateness of video call consultations in a Dutch primary care setting
Authors: Lindh Daniel , Luiten Eric 
Published: December 2022

AbstractThe pressure on healthcare is increasing worldwide. The trend toward digitalization in recent decades and the emergence of modern technologies have enabled remote treatment and offered patients new ways to interact with physicians. Despite numerous studies showing promising results in the use of video calls for primary care consultations, some survey studies report lingering doubts about the effectiveness of this method among general practitioners (GPs) and patients. Because the organization of health care varies widely across countries, we set out to investigate the appropriateness of video calling in a Dutch health care setting. Unlike many survey studies, we collected real-life data where GPs evaluated the video call directly after the consultation, allowing a more realistic assessment of perceived quality. We find that video calls are appropriate 84.2% (95% CI 80.3%-87.8%) of the time for consultations with patients of moderate to low urgency. Importantly, the appropriateness of video calls decreased with increasing urgency. These results build on previous studies and confirm the positive use cases of video calls focused on primary care in the Netherlands.
Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study
Authors: Katsimpris Andreas , Baumeister Sebastian-Edgar , Baurecht Hansjörg , Tatham Andrew , Nolde Michael 
Published: December 2022

AbstractBackgroundSeveral observational studies have investigated the association between cannabis use and intraocular pressure, but its association with primary open-angle glaucoma (POAG) remains unclear. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) whether cannabis use affects POAG.MethodsWe used five single-nucleotide polymorphisms (SNPs) associated with lifetime cannabis use (P-value < 5×10−8) from a genome-wide association study (GWAS) (N = 184,765) by the International Cannabis Consortium, 23andMe, and UK Biobank and eleven SNPs associated with cannabis use disorder (P-value < 5×10−7) from a GWAS meta-analysis of (17,068 cases and 357,219 controls of European descent) from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and deCode. We associated these SNPs with the largest to date GWAS meta-analysis of POAG (16,677 cases and 199,580 controls).ResultsMR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio (OR) of outcome per doubling of the odds of the exposure (95% confidence interval): 1.04 (0.88; 1.23) for lifetime cannabis use and 0.97 (0.92; 1.03) for cannabis use disorder). Sensitivity analyses to address pleiotropy and weak instrument bias yielded similar estimates to the primary analysis.ConclusionsOur results do not support a causal association between cannabis use and POAG.
Reduced Middle Cerebral Artery Blood Velocity Response during Low-Volume High-Intensity Interval Exercise in Chronic Stroke
Authors: Whitaker Alicen A. , Waghmare Saniya , Montgomery Robert N. , Aaron Stacey E. , Eickmeyer Sarah M. , Vidoni Eric D. , Billinger Sandra A. 
Published: December 2022

AbstractBackgroundHigh-intensity interval exercise (HIIT) is currently being implemented in stroke rehabilitation to improve walking function. HIIT alternates between high-intensity and recovery bouts, which causes rapid increases and decreases in blood pressure, which may impact cerebrovascular function in people post-stroke. To date, there is no information on the acute cerebrovascular response in people post-stroke. To address this gap in knowledge, we tested whether the cerebrovascular response was reduced when compared to sedentary age- and sex-matched adults (CON) at the following timepoints: 1) baseline (BL), 2) during a single 10-minute bout of low-volume HIIT, 3) immediately following HIIT, and 4) 30 minutes after HIIT.MethodsMiddle cerebral artery blood velocity (MCAv), mean arterial pressure (MAP), heart rate (HR), and end tidal carbon dioxide (PETCO2) were recorded at all timepoints. A submaximal exercise test was used to determine the estimated maximal workload. The low-volume HIIT bout was performed on a recumbent stepper and consisted of 1-minute high-intensity bouts (70% estimated maximal watts) separated by 1-minute active recovery (10% estimated maximal watts). Statistical analysis used linear mixed models and ANCOVA.ResultsIndividuals post-stroke demonstrated a reduced MCAv response during HIIT compared to CON (p = 0.03) and MCAv remained lower immediately following HIIT and 30-minutes after HIIT. MCAv decreased below BL immediately following HIIT in both groups (p ≤ 0.04) and returned to BL at 30-minutes after HIIT. No between differences were found for MAP, HR, and PETCO2.ConclusionsThe key finding from this study suggests a reduced MCAv response during low-volume HIIT in individuals post-stroke compared to age and sex-matched sedentary adults and these differences remained up to 30 minutes following HIIT. Future work is needed to better understand the reduced MCAv response during HIIT despite increased metabolic demand.Clinicaltrials.gov#NCT04673994.
Protein biomarkers for response to XPO1 inhibition in hematologic malignancies
Authors: Totiger Tulasigeri M. , Chaudhry Sana , Musi Elgilda , Afaghani Jumana , Montoya Skye , Owusu-Ansah Frank , Lee Stanley , Schwartz Gary , Klimek Virginia , Taylor Justin 
Published: December 2022

AbstractXPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumor and hematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using hematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision making in the personalized treatment of cancer patients undergoing treatment with selinexor.