bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase
Authors: Woolley Phillip R. , Wen Xuemei , Conway Olivia M. , Ender Nicolette A. , Lee Ji-Hoon , Paull Tanya T. 
Published: December 2023

SummaryThe ATM protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in Ataxia-telangiectasia patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with expression level and GC content of transcribed genes. In human neuron-like cells in culture we map locations of poly-ADP-ribose and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of ROS in promoting these lesions. Based on these results we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.
CD20 expression regulates CD37 levels in B-cell lymphoma – implications for immunotherapies
Authors: Bobrowicz Malgorzata , Kusowska Aleksandra , Krawczyk Marta , Slusarczyk Aleksander , Barankiewicz Joanna , Domagala Joanna , Kubacz Matylda , Šmída Michal , Dostalova Lenka , Marhelava Katsiaryna , Fidyt Klaudyna , Forcados Christopher , Pepek Monika , Baranowska Iwona , Szumera-Cieckiewicz Anna , Inderberg Else Marit , Wälchli Sébastien , Graczyk-Jarzynka Agnieszka , Gehlert Carina Lynn , Peipp Matthias , Firczuk Malgorzata , Prochorec-Sobieszek Monika , Winiarska Magdalena 
Published: December 2023

AbstractRituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized with a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate for the first time that CD20 and CD37 form a complex and the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates. Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
Histone Deacetylase Inhibitors Prevent Cytokine-Induced β Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry
Authors: Lee Chih-Chun , Kono Tatsuyoshi , Syed Farooq , Weaver Staci A. , Sohn Paul , Wu Wenting , Chang Garrick , Liu Jing , Rupnik Marjan Slak , Evans-Molina Carmella 
Published: December 2023

AbstractHistone deacetylase inhibitors (HDIs) modulate β cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been determined. In this study, we investigated the impact of the HDI sodium butyrate (NaB) on β cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 β cells. Consistently, NaB partially rescued glucose-stimulated Ca2+oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+in the β cell is governed by changes in endoplasmic reticulum (ER) Ca2+levels, next we explored the relationship between NaB and store-operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+levels through STIM1-mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+levels and restored SOCE in IL-1β-treated INS-1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine-treated INS-1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent β cell death in response to IL-1β treatment. Mechanistically, NaB counteracted cytokine-mediated reductions in phosphorylation levels of key signaling molecules, including AKT, ERK1/2, glycogen synthase kinase-3α (GSK-3α), and GSK-3β. Taken together, these data support a model whereby HDI treatment promotes β cell function and Ca2+homeostasis under proinflammatory conditions through STIM1-mediated control of SOCE and AKT-mediated inhibition of GSK-3.
Breast cancer cells promote osteoclast differentiation in an MRTF-dependent paracrine manner
Authors: Chawla Pooja , Sharma Ishani , Gau David , Eder Ian , Chen Fangyuan , Yu Virginia , Welling Niharika , Boone David , Taboas Juan , Lee Adrian V. , Larregina Adriana , Galson Deborah L. , Roy Partha 
Published: December 2023

ABSTRACTBone is a frequent site for breast cancer metastasis. The vast majority of breast cancer-associated metastasis is osteolytic in nature, and RANKL (receptor activator for nuclear factor κB)-induced differentiation of bone marrow-derived macrophages (BMDMs) to osteoclasts (OCLs) is a key requirement for osteolytic metastatic growth of cancer cells. In this study, we demonstrate that Myocardin-related transcription factor (MRTF) in breast cancer cells plays an important role in paracrine modulation of RANKL-induced osteoclast differentiation. This is partly attributed to MRTF’s critical role in maintaining the basal cellular expression of connective tissue growth factor (CTGF), findings that align with a strong positive correlation between CTGF expression and MRTF-A gene signature in the human disease context. Luminex analyses reveal that MRTF depletion in breast cancer cells has a broad impact on OCL-regulatory cell-secreted factors that extend beyond CTGF. Experimental metastasis studies demonstrate that MRTF depletion diminishes OCL abundance and bone colonization breast cancer cellsin vivo, suggesting that MRTF inhibition could be an effective strategy to diminish OCL formation and skeletal involvement in breast cancer. In summary, this study highlights a novel tumor-extrinsic function of MRTF relevant to breast cancer metastasis.SIGNIFICANCE STATEMENTMRTF, a transcriptional coactivator of SRF, is known to promote breast cancer progression through its tumor-cell-intrinsic function. Whether and how MRTF activity in tumor cells modulates other types of cells in the tumor microenvironment are not clearly understood.This study uncovers a novel tumor-cell-extrinsic function of MRTF in breast cancer cells in promoting osteoclast differentiation partly through CTGF regulation, and further demonstrates MRTF’s requirement for bone colonization of breast cancer cells in vivo.Our studies suggest that MRTF inhibition could be an effective strategy to diminish osteoclast formation and skeletal involvement in metastatic breast cancer.
Multi-Level Contrastive Learning for Protein-Ligand Binding Residue Prediction
Authors: Zhang Jiashuo , Wang Ruheng , Wei Leyi 
Published: December 2023

AbstractProtein-ligand interactions play a crucial role in various biological functions, with their accurate prediction being pivotal for drug discovery and design processes. Traditional methods for predicting protein-ligand interactions are limited. Some can only predict interactions with a specific molecule, restricting their applicability, while others aim for multiple types but fail to effectively utilize information across different interactions, leading to increased complexity and inefficiency. This study presents a novel deep learning model named MucLiPred and a dual contrastive learning mechanism aimed at improving the prediction of multiple ligand-protein interactions and the identification of potential ligand-binding residues. We proposed two novel contrastive learning paradigms at residue and type levels, training the discriminative representation of samples. The residue-level contrastive learning hones in on distinguishing binding from non-binding residues with precision, shedding light on nuanced local interactions. In contrast, the type-level contrastive learning delves into the overarching context of ligand types, ensuring that representations of identical ligand types gravitate closer in the representational space and bolstering the model’s proficiency in discerning interaction motifs, enhancing the model’s ability to recognize global interaction patterns. This approach culminates in nuanced multi-ligand predictions, unraveling relationships between various ligand types, and fortifying the potential for precise protein-ligand interaction predictions. Empirical findings underscore MucLiPred’s dominance over existing models, highlighting its robustness and unparalleled prediction accuracy. The integration of dual contrastive learning techniques amplifies its capability to detect potential ligand-binding residues with precision. By optimizing the model’s structure, we discovered that separating representation and classification tasks, leads to improved performance. Consequently, MucLiPred stands out as a groundbreaking tool in protein-ligand interaction prediction, laying the groundwork for future endeavors in this complex arena.
Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer
Authors: Boidot Romain , Blum Michael G.B. , Wissler Marie-Pierre , Gottin Céline , Ruzicka Jiri , Chevrier Sandy , Delhomme Tiffany M. , Audoux Jérome , Jeanniard Adrien , Just Pierre-Alexandre , Harter Philipp , Pignata Sandro , González-Martin Antonio , Marth Christian , Mäenpää Johanna , Colombo Nicoletta , Vergote Ignace , Fujiwara Keiichi , Duforet-Frebourg Nicolas , Bertrand Denis , Philippe Nicolas , Ray-Coquard Isabelle , Pujade-Lauraine Eric 
Published: December 2023

AbstractBackgroundThe PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, a decentralized HRD test based on low coverage shallow Whole Genome Sequencing (sWGS).MethodsThe study comprised 368 patients from the PAOLA-1 trial. The sWGS test was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS).ResultsWe found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI) 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 90%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). Only 1% (95% CI; 0-3%) of its results were inconclusive. In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with sWGS and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.98 (95% CI; 0.68-1.41) and 1.05 (95% CI; 0.70-1.57) with sWGS and Myriad tests. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with sWGS and Myriad test.ConclusionThe SeqOne sWGS assay offers a clinically validated approach to detect HRD.
Telemedicine Perspectives of Patients with Non-Dialysis Kidney Disease and Kidney Transplant – A Qualitative Meta-Analysis
Authors: Manko Christopher D. , Apple Benjamin J. , Chang Alexander R. , Johannes Bobbie L. 
Published: December 2023

AbstractRationale & ObjectiveWhile the use of telemedicine has increased dramatically across disciplines, patient perspectives on telemedicine related to chronic kidney disease are not well understood. We systematically reviewed qualitative studies on patients with chronic kidney disease to better understand these patients’ perspectives related to telemedicine.Study DesignQualitative Meta-AnalysisSetting & Study PopulationsPre-dialysis chronic kidney disease and kidney transplant patients that used telemedicine.Selection Criteria for StudiesEnglish language studies published in the year 2000 and beyond that investigated patient perspectives in a qualitative manner. Works that were not qualitative or did not focus on provider-patient interactive modes of telemedicine were excluded.Data Extraction375 papers were pulled from PubMed, Embase, and Academic Science Premier. After filtering, 8 final papers were selected. These papers were critically appraised for quality and were used in the final analysis.Analytical ApproachWe developed a codebook to systematically review each of the selected papers through qualitative meta-analysis.ResultsFour primary themes were identified (autonomy, logistics, privacy/confidentiality, and trust) with additional subthemes and further subdivisions to signify positive versus negative experiences. The majority of subthemes and subdivisions (n=9) identified were positively attributed by patients compared to negative attributes (n=6). The subtheme most commonly found was avoiding travel to the hospital, which was identified in all 8 papers. There was substantial variability in the number of papers demonstrating the other subthemes and subdivisions.LimitationsLack of provider perspectives, non-English studies, and studies published before the year 2000. Papers published after the start of data extraction were also not included.ConclusionsTelemedicine should continue to be offered to patients with kidney disease and kidney transplant patients to facilitate access. Additional research should focus on ways to decrease negative factors experienced by some patients such as difficulty with using the technology.
Perspectives on using a celebrity narrative to teach the psychiatric formulation to final year medical students
Authors: Hickey David , McFarland John 
Published: December 2023

AbstractObjectivesThe proficiency of an accomplished psychiatrist encompasses the development, adaptation, and refinement of a biopsychosocial formulation. A formulation aids clinical decision-making by organizing information and furnishes a documented rationale for decisions. Despite its significance, psychiatric trainees often perceive the formulation as arduous and time-intensive, leading to avoidance. Educational shortcomings are pervasive. Addressing this calls for low-cost, novel solutions. Undergraduate medical education possesses aspiring psychiatrists and provides a platform to develop a foundational understanding of formulation. This study aims to explore the viability of a novel, resource-efficient approach employing a celebrity case narrative to attain a fundamental understanding of the psychiatric formulation while concurrently elucidating activated pedagogical cognitions by using such methodology from the student’s perspective.MethodsA psychiatric formulation tutorial was conducted across five distinct final-year medical student cohorts during one academic year. A standardized tutorial structure was devised, incorporating interchangeable case studies. Following the tutorial, a post-tutorial survey was administered, followed by interviews that underwent qualitative analysis.ResultsSeventy-seven participants responded to the survey, expressing favourable views. Twenty students consented to interviews. They were distributed across five sessions with an average of four participants per group. Interviews yielded five key themes: Understanding of formulation, cognitive engagement, emotional salience and ethical considerations with twelve corresponding subthemes. The results suggested viability in using this methodology to teach formulation to foster a basic understanding and elicited a range of pedagogical phenomenon that may have contributed to this understanding.ConclusionThis study indicates that integrating a celebrity narrative into psychiatric formulation teaching intervention bears potential for enhancing engagement concurrently mitigating negative attitudes towards the formulation. The approach reveals latent learning outcomes suggesting a profound pedagogical impact. The range of pedagogical process elucidated lays a foundational research base for future instructional design and research.Declaration of interestNone
Improving the suppressive power of homing gene drive by co-targeting a distant-site female fertility gene
Authors: Faber Nicky R. , Xu Xuejiao , Chen Jingheng , Hou Shibo , Du Jie , Pannebakker Bart A. , Zwaan Bas J. , van den Heuvel Joost , Champer Jackson 
Published: December 2023

AbstractGene drive technology has the potential to address major biological challenges, including the management of disease vectors, invasive species, and agricultural pests. After releasing individuals carrying the gene drive in the target population, suppression gene drives are designed to spread at a rapid rate and carry a recessive fitness cost, thus bringing about a decline in population size or even complete suppression. Well-studied homing suppression drives have been shown to be highly efficient inAnophelesmosquitoes and were successful in eliminating large cage populations. However, for other organisms, includingAedesmosquitoes, homing gene drives are so far too inefficient to achieve complete population suppression, mainly due to lower rates of drive conversion, which is the rate at which wild type alleles are converted into drive alleles. Low drive conversion is also a major issue in vertebrates, as indicated by experiments in mice. To tackle this issue, we propose a novel gene drive design that has two targets: a homing site where the drive is located and drive conversion takes place (with rescue for an essential gene), and a distant site for providing the fitness cost for population suppression (preferably a female fertility gene, for which no rescue is provided). We modeled this design and found that the two-target system allows suppression to occur over a much wider range of drive conversion efficiency. Specifically, in the new design, the suppressive power depends mostly on total gRNA cutting efficiency instead of just drive conversion efficiency, which is advantageous because cut rates are often substantially higher than drive conversion rates. We constructed a proof of concept inDrosophila melanogasterand show that both components of the gene drive function successfully. However, embryo drive activity from maternally deposited Cas9 as well as fitness costs for female drive heterozygotes both remain significant challenges for two-target and standard suppression drives. Overall, our improved gene drive design eases the development of strong homing suppression gene drives for many species where drive conversion is less efficient.
Unified Multi-caller Ensemble (UME) generates an unbiased maize haplotype map for variable coverage whole genome data
Authors: Vallebueno-Estrada Miguel , Swarts Kelly 
Published: December 2023

AbstractWe present a novel diversity-focused haplotype map (HapMap) that characterizes over 64.5 million maize (Zea maysssp. mays) single nucleotide polymorphisms (SNPs) genotyped across 818 individuals from diverse backgrounds. This HapMap aims to balance the variation obtained from domesticated landraces and inbred lines, outgroupZea spp.and more distantTripsacum spp.in order to minimize ascertainment bias for diversity studies. Included individuals derive from public data from various experimental setups and coverages, which is challenging for standard SNP callers to accommodate. We provide evidence of coverage biases associated with standard callers that influence resulting variation and introduce a novel approach called Unified Multi-Caller Ensemble (UME), which enhances variant calling accuracy in low-coverage and mixed-coverage genomic datasets. UME corrects for coverage bias resulting from inter-sample coverage heterogeneity by leveraging evidence from variant callers with orthogonal strategies, re-calibrating the error probabilities across callers to minimize the impact of error biases inherent to a given caller. It outperforms individual strategies and excels inde novovariant calling, taking advantage of instances of higher depth reads, even in low coverage individuals, while preserving biologically informative variant relationships across coverage levels. An important feature of UME is the independence from population allele frequencies in the discovery panel, thus avoiding ascertainment bias resulting from unbalanced input genetic diversity. Discovered variants are unbiased because no population filtering is used, and the full diversity of SNPs is retained in the final variant call set to maximize the utility of the dataset for production calling newly sequenced samples. We present a strategy for filtering the recalibrated error profiles that relies on maximizing demographic signals to retain genetic relationships within the population while reducing sequencing error. After the variant discovery phase, we employ the UME production stage, which enriches genotype calling across all coverage levels, benefiting low-coverage samples. Error introduced in this process is removed through subsequent filtering. Using this approach, we generated a coverage bias-controlled maize HapMap database, providing a comprehensive representation of maize accessions and emphasizing landrace diversity. This diverse panel of domesticated maize and outgroups from across the Americas enables accurate genotyping in low-coverage samples while offering crucial context for interpreting diversity, particularly for natural diversity and paleogenomic analyses.