bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of mutations on gene expression and alternative splicing: a case study of EMS-induced heritable mutations in the microcrustaceanDaphnia
Authors: Snyman Marelize , Xu Sen 
Published: March 2023

AbstractUnderstanding the relationship between mutations and their genomic and phenotypic consequences has been a longstanding goal of evolutionary biology. However, few studies have investigated the impact of mutations on gene expression and alternative splicing on the genome- wide scale. In this study, we aim to bridge this knowledge gap by utilizing whole-genome sequencing data and RNA sequencing data from 16 OPDaphniamutant lines to investigate the effects of EMS-induced mutations on gene expression and alternative splicing. Using rigorous analyses of mutations, expression changes, and alternative splicing, we show that trans-effects are the major contributor to the variance in gene expression and alternative splicing between the wildtype and mutant lines, whereas cis mutations only affected a limited number of genes and do not always alter gene expression. Moreover, we show that there is a significant association between DE genes and exonic mutations, indicating that exonic mutations are an important driver of altered gene expression.
Histology-based Prediction of Therapy Response to Neoadjuvant Chemotherapy for Esophageal and Esophagogastric Junction Adenocarcinomas Using Deep Learning
Authors: Hörst Fabian , Ting Saskia , Liffers Sven-Thorsten , Pomykala Kelsey L. , Steiger Katja , Albertsmeier Markus , Angele Martin K. , Lorenzen Sylvie , Quante Michael , Weichert Wilko , Egger Jan , Siveke Jens T. , Kleesiek Jens 
Published: March 2023

AbstractBackgroundQuantifying treatment response to gastroesophageal junction (GEJ) adenocarcinomas is crucial to provide optimal therapeutic strategy. Routinely taken tissue samples provide an opportunity to enhance existing PET/CT-based therapy response evaluation. Our objective was to investigate if deep learning algorithms are capable to predict the therapy response of GEJ patients to neoadjuvant chemotherapy based on histological tissue samples.MethodsThis diagnostic study recruited 67 patients with GEJ I-III from the multicentric non-randomized MEMORI trial including 3 German university hospitals TUM (Munich), LMU (Munich), and UME (Essen). All patients underwent baseline PET/CT scans and esophageal biopsy before and 14-21 days after treatment initiation. Treatment response was defined as a ≥ 35% decrease in SUVmax from baseline. Several deep learning algorithms were developed to predict PET/CT-based responders and non-responders to neoadjuvant chemotherapy using digitized histopathological whole slide images.ResultsThe resulting models were trained on TUM (n=25 pre-therapy, n=47 on-therapy) patients and evaluated on our internal validation cohort from LMU and UME (n=17 pre-therapy, n=15 on-therapy). Compared with multiple architectures, the best pre-therapy network achieves an area under the precision-recall curve (AUPRC) of 0.81 (95% confidence interval (CI), 0.61-1.00), area under the precision-recall curve (AUPRC) of 0.82 (95% CI, 0.61-1.00), balanced accuracy of 0.78 (95% CI, 0.60-0.94), and a Matthews correlation coefficient (MCC) of 0.55 (95% CI, 0.18-0.88). The best on-therapy network achieves an AUROC of 0.84 (95% CI, 0.64-1.00), AUPRC of 0.82 (95% CI, 0.56-1.00), balanced accuracy of 0.80 (95% CI, 0.63-1.00), and MCC of 0.71 (95% CI, 0.38-1.00), solving a task beyond the pathologists’ capabilities.ConclusionsThe findings suggest that the networks can predict treatment response using WSI with high accuracy even pre-therapy, suggesting morphological tissue biomarkers. Subject to further validation, this could lead to earlier therapy intensification compared to current PET/CT diagnostic system for non-responder.
Causal evidence for an ApoB-independent metabolomic risk profile associated with coronary artery disease
Authors: Ao Linjun , van Heemst Diana , Jukema J. Wouter , Rensen Patrick C.N. , van Dijk Ko Willems , Noordam Raymond 
Published: March 2023

AbstractBackground and aims1-H nuclear magnetic resonance (1H-NMR) metabolomic measures in plasma have yielded significant insight into the pathophysiology of cardiometabolic disease, but their interrelated nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated1H-NMR metabolomic profiles with coronary artery disease (CAD), type 2 diabetes (T2D) and ischemic stroke (ISTR).MethodsPrincipal component (PC) analysis was performed on 1681H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve unrelated PCs, which were used in multivariable-adjusted cox-proportional hazard models and genome-wide association analyses for Mendelian Randomization (MR). Two-sample MR analyses were conducted in three non-overlapping databases which were subsequently meta-analysed, resulting in combined sample sizes of 755,481 (128,728 cases), 1,017,097 (121,977 cases), and 1,002,264 (56,067 cases) for CAD, T2D, and ISTR, respectively.ResultsWe identified six PCs which collectively explained 88% of the total variance. For CAD in particular, results from both multivariable-adjusted and MR analyses were generally directionally consistent. The pooled odds ratios (ORs) [95% CI] of per one-SD increase in genetically-influenced PC1 and PC3 (both characterized by distinct ApoB-associated lipoprotein profiles) were 1.04 [1.03, 1.05] and 0.94 [0.93, 0.96], respectively. In addition, the pooled OR for CAD of PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 [1.03, 1.07]. For the other outcomes, PC5 (characterized by increased amino acids) was associated with a higher risk of T2D and ISTR.ConclusionsThis study highlights the existence of an ApoB-independent lipoprotein profile driving CAD. Interestingly, this profile is characterized by a distinctive HDL sub-particle distribution, providing evidence for a role of HDL in the development of CAD.
Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease
Authors: Whittaker Hannah , Kallis Constantinos , Bolton Thomas , Wood Angela , Walker Samantha , Sheikh Aziz , Brownrigg Alex , Akbari Ashley , Sterniczuk Kamil , Quint Jennifer 
Published: March 2023

AbstractBackgroundCOVID-19 is associated with a higher risk of cardiovascular outcomes in the general population, but it is unknown whether people with pre-existing chronic respiratory disease (CRD) have a higher risk of cardiovascular events post-COVID-19 compared with the general population and, if so, what respiratory-related risk factors may modify this risk in these people.MethodsPrimary and secondary care data from the National Health Service and COVID-19-specific linked data were used to define a population of adults in England with COVID-19 (index date) between 01/01/2020-30/11/2021. Adjusted Cox Proportional Hazard regression was used to quantify the association between CRD, asthma-related factors, COPD-related factors, and risk of cardiovascular events. CRD included asthma, COPD, bronchiectasis, cystic fibrosis, or pulmonary fibrosis prior to COVID-19 diagnosis. Asthma-specific factors included baseline asthma control, exacerbations, and inhaled corticosteroid (ICS) dose. COPD-specific risk factors included baseline ICS prescriptions and exacerbations. Secondary objectives quantified the impact of COVID-19 hospitalisation and vaccine dose on cardiovascular outcomes.ResultsOf 3,670,455 people, those with CRD had a modest higher risk of cardiovascular events (HRadj1.11, 95%CI 1.07-1.14), heart failure (HRadj1.15, 1.09-1.21), and pulmonary emboli (HRadj1.20, 1.11-1.30) compared with people without CRD. In people with asthma, baseline exacerbations and high-dose ICS were associated with a higher risk of cardiovascular outcomes (HRadj1.24, 1.15-1.34 and 1.12, 1.01-1.24, respectively). In people with COPD, exacerbations were associated with a higher risk of cardiovascular outcomes (HRadj1.40, 1.28-1.52). Regardless of CRD, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose.ConclusionsHigher risk of cardiovascular events following COVID-19 might be explained at least in part by the underlying CRD and severity of that condition. In addition, COVID-19 vaccines were beneficial to both people with and without CRD with regards to CV events.Key MessagesPre-existing chronic respiratory disease, asthma and COPD severity were associated with a higher risk of various types of cardiovascular outcomes following COVID-19. Regardless of having pre-existing chronic respiratory disease, COVID-19 vaccination reduced the risk of cardiovascular events following COVID-19.
Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of Long-Term Care Facilities in the VIVALDI study
Authors: Stirrup Oliver , Shrotri Madhumita , Adams Natalie L. , Krutikov Maria , Azmi Borscha , Monakhov Igor , Tut Gokhan , Moss Paul , Hayward Andrew , Copas Andrew , Shallcross Laura 
Published: March 2023

AbstractWe evaluated the effectiveness of 1-3 booster vaccinations against SARS-CoV-2 related mortality among a cohort of 13407 older residents of long-term care facilities (LTCFs) participating in the VIVALDI study in England in 2022. Cox regression was used to estimate relative hazards of SARS-CoV-2 related death following booster vaccination relative to 2 doses (after 84+ days), stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF capacity. Each booster provided additional short-term protection relative to primary vaccination, with consistent pattern of waning to 45-75% reduction in risk beyond 112 days.
Geospatial assessment of the convergence of communicable and non-communicable diseases in South Africa
Authors: Cuadros Diego F. , Moreno Claudia M. , Tomita Andrew , Singh Urisha , Olivier Stephen , Castle Alison , Moosa Yumna , Edwards Johnathan A , Kim Hae-Young , Siedner Mark J , Wong Emily B , Tanser Frank 
Published: March 2023

ABSTRACTBackgroundSeveral low- and middle-income countries are undergoing a rapid epidemiological transition with a rising burden of non-communicable diseases (NCDs). South Africa (SA) is a country with one of the largest HIV epidemics worldwide and a growing burden of NCDs where the collision of these epidemics poses a major public health challenge.MethodsUsing data from a large nationally representative survey, the South Africa Demographic and Health Survey (SADHS 2016), we conducted a geospatial analysis of several diseases including HIV, tuberculosis (TB), cardiovascular, respiratory, and metabolic diseases to identify areas with a high burden of co-morbidity within the country. We explored the spatial structure of each disease and the associations between diseases using different spatial and visual data methodologies. We also assessed the individual-level co-occurrence of HIV and the other diseases included in the analysis.ResultsThe spatial distribution for HIV prevalence showed that this epidemic is most intense in the eastern region of the country, mostly within the Gauteng, Mpumalanga, and Kwazulu-Natal provinces. In contrast, chronic diseases had their highest prevalence rates in the southern region of the country, particularly in the Eastern and Western Cape provinces. Individual-level analyses were consistent with the spatial correlations and found no statistically significant associations between HIV infection and the presence of any NCDs.ConclusionsWe found no evidence of geospatial overlap between the HIV epidemic and NCDs in SA. These results evidence the complex epidemiological landscape of the country, characterized by geographically distinct areas exhibiting different health burdens. The detailed description of the heterogenous prevalence of HIV and NCDs in SA reported in this study could be a useful tool to inform and direct policies to enhance targeted health service delivery according to the local health needs of each community.
Esm-1 mediates transcriptional polarization associated with diabetic kidney disease
Authors: Gaudet Alexandre , Zheng Xiaoyi , Kambham Neeraja , Bhalla Vivek 
Published: March 2023

AbstractBackgroundEsm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria.Esm1has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes.MethodsWe utilized publicly available single-cell RNA sequencing data to explore the characteristics ofEsm1expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1.ResultsIn both mice and humans,Esm1is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients,Esm1(+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such asIgfbp5for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts.Esm1significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude ofEsm1deficiency. In diabetic mice, these gene clusters linkEsm1expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes.ConclusionsA comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lowerEsm1expression and with changes in the functional characterization ofEsm1(+) cells.Esm1is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.
Plasticity in parental behavior and vasopressin: Responses to co-parenting, pup age, and an acute stressor are experience-dependent
Authors: Hiura Lisa C. , Lazaro Vanessa A. , Ophir Alexander G. 
Published: March 2023

AbstractThe impact of variation in parental caregiving has lasting implications for the development of offspring. However, the ways in which parents impact each other in the context of caregiving is comparatively less understood, but can account for much of the variation observed in the postnatal environment. Prairie voles (Microtus ochrogaster) demonstrate a range of postnatal social groups, including biparental pairs and pups raised by their mothers alone. In addition to the challenges of providing parental care, prairie vole parents often experience acute natural stressors (e.g., predation, foraging demands, thermoregulation) that could alter the way co-parents interact. We investigated how variation in the experience of raising offspring impacts parental behavior and neurobiology by administering an acute handling stressor on prairie vole families of single mothers and biparental parents over the course of offspring postnatal development. Mothers and fathers exhibited robust behavioral plasticity in response to the age of their pups, but in sex-dependent ways. Pup-directed care from mothers did not vary as a function of their partner’s presence, but did covary with the number of hypothalamic vasopressin neurons in experience-dependent ways. The relationship between vasopressin neuron numbers and fathers’ behaviors was also contingent upon the stress handling manipulation, suggesting that brain-behavior associations exhibit stress-induced plasticity. These results demonstrate that the behavioral and neuroendocrine profiles of adults are sensitive to distinct and interacting experiences as a parent, and extend our knowledge of the neural mechanisms that may facilitate parental behavioral plasticity.
The eccDNA mediated spread and rapid evolution of herbicide resistance in pigweed interspecific hybrids
Authors: Koo Dal-Hoe , Sathishraj Rajendran , Nakka Sridevi , Ju Yoonha , Nandula Vijay K. , Jugulam Mithila , Friebe Bernd , Gill Bikram S. 
Published: March 2023

AbstractExtrachromosomal circular DNAs (eccDNAs) are found in many eukaryotic organisms. The eccDNA-powered copy number variation plays diverse roles from oncogenesis in humans to herbicide resistance in crop weeds. Here we report interspecific eccDNA flow and its dynamic behavior in soma cells of natural populations and F1hybrids ofAmaranthussp. The glyphosate resistance (GR) trait is controlled by eccDNA-based amplification harboring the5-enolpyruvylshikimate-3-phosphate synthase(EPSPS) gene (EPSPS-eccDNA), the molecular target of glyphosate. We documented pollen-mediated transfer of eccDNA in experimental hybrids between GSA. tuberculatusx GRA. palmeri. Experimental hybridization and fluorescencein situhybridization (FISH) analysis revealed that theEPSPS-eccDNA present inA. spinosuswas derived from GRA. palmeriby natural hybridization. FISH analysis also revealed random chromosome anchoring and massiveEPSPS-eccDNA copy number variation in soma cells of weedy hybrids. The results suggest that eccDNAs are inheritable across compatible species contributing to genome plasticity and rapid adaptive evolution.
SnapHiC-G: identifying long-range enhancer-promoter interactions from single-cell Hi-C data via a global background model
Authors: Liu Weifang , Zhong Wujuan , Giusti-Rodríguez Paola , Wang Geoffery W. , Hu Ming , Li Yun 
Published: March 2023

AbstractHarnessing the power of single-cell genomics technologies, single-cell Hi-C (scHi-C) and its derived technologies provide powerful tools to measure spatial proximity between regulatory elements and their target genes in individual cells. Using a global background model, we propose SnapHiC-G, a computational method to identify long-range enhancer-promoter interactions from scHi-C data. We applied SnapHiC-G to scHi-C datasets generated from mouse embryonic stem cells and human brain cortical cells and demonstrated that SnapHiC-G achieved high sensitivity in identifying long-range enhancer-promoter interactions. Moreover, SnapHiC-G can identify putative target genes for non-coding GWAS variants, and the genetic heritability of neuropsychiatric diseases is enriched for single nucleotide polymorphisms (SNPs) within SnapHiC-G-identified interactions in a cell-type-specific manner. In sum, SnapHiC-G is a powerful tool for characterizing cell-type-specific enhancer-promoter interactions from complex tissues and can facilitate the discovery of chromatin interactions important for gene regulation in biologically relevant cell types.
Inhibitory control of speech production in the human premotor frontal cortex
Authors: Zhao Lingyun , Silva Alexander B. , Kurteff Garret L. , Chang Edward F. 
Published: March 2023

AbstractNatural speech is full of starts and stops. Here, we studied the neural mechanisms that underlie the inhibitory control of speech, specifically the ability to stop speaking on demand. We recorded direct cortical activity while participants made continuous speech production and were given a visual cue to stop speaking. Neural recordings revealed activity in the premotor frontal cortex associated with speech stopping. Cortical sites showing stop activity were largely distinct from sites involved in active speech production or, more specifically, encoding articulatory movements. Electrocortical stimulation mapping at many premotor sites with stop activity caused involuntary speech arrest, an immediate inability to speak or vocalize. Furthermore, many speech arrest sites did not co-localize with neural activity correlating with speech motor planning or execution, contrary to this long-assumed function in clinical brain mapping. Together, these results suggest a previously unknown premotor cortical network that underlies the inhibitory control of speech, which has significant implications for understanding the dynamics of normal and altered speech production, as well as clinical brain mapping.
Assessment of neutralization susceptibility of Omicron subvariants XBB.1.5 and BQ.1.1 against broad-spectrum neutralizing antibodies through epitopes mapping
Authors: Shah Masaud , Woo Hyun Goo 
Published: March 2023

AbstractThe emergence of new variants of the SARS-CoV-2 virus has posed a significant challenge in developing broadly neutralizing antibodies (nAbs) with guaranteed therapeutic potential. Some nAbs, such as Sotrovimab, have exhibited varying levels of efficacy against different variants, while others, such as Bebtelovimab and Bamlanivimab-etesevimab are ineffective against specific variants, including BQ.1.1 and XBB. This highlights the urgent need for developing broadly active mAbs providing prophylactic and therapeutic benefits to high-risk patients, especially in the face of the risk of reinfection from new variants. Here, we aimed to investigate the feasibility of redirecting existing mAbs against new variants of SARS-CoV-2, as well as to understand how BQ.1.1 and XBB.1.5 can evade broadly neutralizing mAbs. By mapping epitopes and escape sites, we discovered that the new variants evade multiple mAbs, including FDA-approved Bebtelovimab, which showed resilience against other Omicron variants. Our approach, which included simulations, free energy perturbations, and shape complementarity analysis, revealed the possibility of identifying mAbs that are effective against both BQ.1.1 and XBB.1.5. We identified two broad-spectrum mAbs, R200-1F9 and R207-2F11, as potential candidates with increased binding affinity to XBB.1.5 and BQ.1.1 compared to the wild-type virus. Additionally, we propose that these mAbs do not interfere with ACE2 and bind to conserved epitopes on the RBD that are not-overlapping, potentially providing a solution to neutralize these new variants either independently or as part of a combination (cocktail) treatment.