bluuebunny/crossref_metadata_2025_split huggingface dataset:
CLUSTERING OF RARE VARIANTS FOR CAUSAL VARIANTS IDENTIFICATION AND EFFECT
DIRECTION CLASSIFICATION
Authors: Sun Xianbang , Liu Xue , Liu Chunyu 
Published: December 2024

ABSTRACT
Several gene-based tests, e.g., sequence kernel association test, have been
developed for association testing of rare single nucleotide variants (SNVs) in
genomic regions with disease traits. A common limitation of these aggregate
methods is their inability to discriminate potentially causal variants from null
variants within the tested regions. We propose a novel clustering method to
classify rare variants into null and signal variant groups using summary
statistics from the gene-based tests based on a Gaussian mixture model (GMM). We
classify the signal variants into potentially risk and protective subgroups of
different effect sizes. We evaluate the performance of the proposed method by a
simulation study, considering several statistics such as the adjusted rand index
(ARI), mean square error (MSE), and accuracy in specifying the number of
clusters. We apply the proposed clustering method to identify possibly risk and
protective rare variants in six genes that are significantly associated with
blood pressure (BP) traits in the most recent large genomewide association study
(GWAS) and meta-analysis. This proposed method may facilitate the identification
of potentially causal rare variant clusters in genomic regions and ultimately
help understand the genetic architecture underlying human complex traits for the
discovery of drug target and the design of gene therapy.
Bilateral aldosterone production is most common in primary aldosteronism found by screening within primary care
Authors: Makhnov Nikita , Skov Jakob , Axling Fredrik , Andernord Daniel , Bergenheim Mikael , Waldén Mauritz , Hellman Per 
Published: December 2024

AbstractOBJECTIVEPrimary aldosteronism (PA) is the most common cause of secondary hypertension, and implies high risk of cardiovascular complications. Previously, our group had screened 1181 unselected Swedish primary care hypertensive patients, to find PA prevalence of 4,5%. The current study describes results of further diagnostics and specific treatment of these PA patients.DESIGNProspective evaluation of lateralization and treatment of patients with PA.PATIENTSFifty-three individuals with PA diagnosed by screening carried out in strict accordance with the current guidelines.MEASUREMENTSAll patients accepting possible surgery underwent adrenal venous sampling, complemented, if unsuccessful, by adrenal cortex-specific positron emission tomography. Lateralizing cases were advised laparoscopic adrenalectomy. Bilateral ones were treated by mineralocorticoid receptor antagonists. Treatment results were assessed by at least 6 - 12 months of follow-up.RESULTSLocalizing studies were accepted by 45 patients, 8 patients declined. Lateralized disease was found in 14 cases. Of 11 operated cases 3 had adenoma (prevalence 7-13%). Remaining operated cases comprised micro- and macronodular pathology. Thirty-one patients had bilateral PA. Screening and specific PA treatment led to better blood pressure and raising renin signifying risk amelioration. Both surgical and conservative treatment were tolerated well even when mainly conducted at regional healthcare level.CONCLUSIONSBilateral production of aldosterone is common in a patient cohort derived from screening within primary care. Lateralization may be due to either adenoma, which is very rare, or due to nodular forms of PA, and both are successfully treated with adrenalectomy.
A Population-Based Cross-Sectional Investigation of COVID-19 Hospitalizations and Mortality Among Autistic People
Authors: Nijhof Dewy , Sosenko Filip , Mackay Daniel , Fleming Michael , Jani Bhautesh D , Pell Jill , Hatton Chris , Cairns Deborah , Henderson Angela , Ward Laura , Rydzewska Ewelina , Gardani Maria , Millington Elliot , Melville Craig 
Published: December 2024

Abstract

Background
Current evidence suggests the possibility that autistic people may be at more risk of COVID-19 infection, hospitalisation, and mortality than the general population. Previous studies, however, are either limited in scale or do not investigate potential risk factors. Whilst many risk factors have been speculated to be responsible for severe COVID-19, this research has focused on general population samples.

Methods
Using data-linkage and a whole-country population, this study modelled associations between autism and COVID-19 hospitalisation and mortality risk in adults, investigating a multitude of clinical and demographic risk factors.

Results
Autistic adults had higher rates of hospitalisation, Standardised Incident Ratio 1.6 in 2020 and 1.3 in 2021, and mortality, Standardised Mortality Ratio 1.52 in 2020 and 1.34 in 2021, due to COVID-19 than the general population. In both populations, age, complex multimorbidity and vaccination status were the most significant predictors of COVID-19 hospitalisation and mortality. Effects of psychotropic medication varied by class.

Conclusions
Although similar factors exhibited a positive association with heightened risk of severe COVID-19 in both the autistic and general populations, with comparable effect sizes, mortality rates were elevated among the autistic population as compared to the general population. Specifically, the presence of complex multimorbidity and classification of prescribed medications may emerge as particularly significant predictors of severe COVID-19 among individuals within the autistic population due to higher prevalence of complex multimorbidity in the autistic population and variability in the association between medication classes and severe COVID-19 between both populations, though further research is needed.
Multi-ancestry Genome Wide Association Study Meta-analysis of Non-syndromic Orofacial Clefts
Authors: Jia Zhonglin , Mukhopadhyay Nandita , Yang Zhenglin , Butali Azeez , Sun Jialin , You Yue , Yao Meilin , Zhen Qi , Ma Jian , He Miao , Pan Yongchu , Alade Azeez , Wang Yirui , Olujitan Mojisola , Qi Mengchun , Adeyemo Wasiu Lanre , Buxó Carmen J. , Gowans Lord J.J , Eshete Mekonen , Huang Yongqing , Li Chenghao , Leslie Elizabeth J. , Wang Lin , Bian Zhuan , Carlson Jenna C. , Shi Bing , Weinberg Seth M. , Murray Jeffrey C. , Sun Liangdan , Marazita Mary L. , Freathy Rachel M. , Beaumont Robin N. 
Published: December 2024

ABSTRACTNon-syndromic orofacial clefts (NSOC) are common craniofacial birth defects, and result from both genetic and environmental factors. NSOC include three major sub-phenotypes: non-syndromic cleft lip with palate (NSCLP), non-syndromic cleft lip only (NSCLO) and non-syndromic cleft palate only (NSCPO), NSCLP and NSCLO are also sometimes grouped as non-syndromic cleft lip with or without cleft palate (NSCL/P) based on epidemiology. Currently known loci only explain a limited proportion of the heritability of NSOC. Further, differences in genetic susceptibility among the sub-phenotypes are poorly characterized. We performed a multi-ancestry GWAS meta-analysis on 44,094 individuals (9,381 cases, 28,510 controls, 2042 case-parent trios and 18 multiplex pedigrees) of East Asian, European, Latin and South American, and African ancestry for both NSOC and subtypes. We identified 50 loci, including 11 novel loci: four loci (CALD1,SHH,NRG1andLINC00320) associated with both NSOC and NSCL/P, two loci (NTRK1andRUNX1) only associated with NSOC, four loci (HMGCR,PRICKLE1,SOX9andMYH9) only associated with NSCL/P and one locus (ALX1) specifically associated with NSCLO. Five of the novel loci are located in regions containing genes associated with syndromic orofacial clefts (SHH,NTRK1, CALD1, ALX1andSOX9); seven of the novel loci are located in regions containing genes-implicated in craniofacial development (HMGCR, SHH, PRICKLE1, ALX1, SOX9, RUNX1, MYH9). Genetic correlation and colocalization analyses revealed an overlap between signals associated with NSCLO, NSCPO and NSCLP, but there were also notable differences, emphasizing the complexity of common and distinct genetic processes affecting lip and palate development.
Modulation of all-transretinoic acid by light and dopamine in the murine eye
Authors: Talwar Sarah , Mazade Reece , Bentley-Ford Melissa , Yu Jianshi , Pilli Nageswara , Kane Maureen A , Ethier C Ross , Pardue Machelle T 
Published: December 2024

AbstractPurposeAmbient light exposure is linked to myopia development in children and affects myopia susceptibility in animal models. Currently, it is unclear which signals mediate the effects of light on myopia. All-transretinoic acid (atRA) and dopamine (DA) oppositely influence experimental myopia and may be involved in the retino-scleral signaling cascade underlying myopic eye growth. However, how ocular atRA responds to different lighting and whether atRA and DA interact remains unknown.MethodsDark-adapted C57BL/6J mice (29-31 days old) were exposed to Dim (1 lux), Mid (59 lux), or Bright (12,000 lux) ambient lighting for 5-60 minutes. Some mice were also systemically administered the DA precursor, LDOPA, or atRA prior to light exposure. After exposure, the retina and the back-of-the-eye (BOE) were collected and analyzed for levels of atRA, DA, and the DA metabolite, DOPAC.ResultsDA turnover (DOPAC/DA ratio) in the retina increased in magnitude after only five minutes of exposure to higher ambient luminance but was minimal in the BOE. In contrast, atRA levels in the retina and BOE significantly decreased with higher ambient luminance and longer duration exposure. Intriguingly, LDOPA-treated mice had a transient reduction in retinal atRA compared to saline-treated mice, whereas atRA treatment had no effect on ocular DA.ConclusionsOcular atRA was affected by the duration of exposure to different ambient lighting and retinal atRA levels decreased with increased DA. Overall, these data suggest specific interactions between ambient lighting, atRA, and DA that could have implications for the retino-scleral signaling cascade underlying myopic eye growth.
Seed dispersal disruption limits tropical forest regrowth
Authors: Fricke Evan C. , Cook-Patton Susan C. , Harvey Charles F. , Terrer César 
Published: December 2024

AbstractMany trees depend on animals for seed dispersal, and human activities that disrupt seed dispersal by animals may impact forest regeneration and carbon storage. Yet whether expected negative impacts are observable across regrowing forests remains untested. We modeled seed dispersal disruption and its relationship to aboveground carbon accumulation observed across 3026 sites in the tropics, where most trees are animal dispersed. We found that seed dispersal disruption explains wide variation in local carbon accumulation rates. Across areas identified for restoration, we estimate that seed dispersal disruption reduces carbon accumulation rates by 57% on average. These results advance understanding of animal biodiversity’s impact on forest carbon and emphasize the need to address biodiversity loss and climate change together.
Alteration of skin fibroblast steady state contributes to healing outcomes
Authors: Huang Yaqing , Wang Nuoya , Xing Hao , Tian Jingru , Zhang Dingyao , Gao Daqian , Hsia Henry C. , Lu Jun , Raredon Micha Sam Brickman , Kyriakides Themis R. 
Published: December 2024

AbstractFibroblasts display complex functions associated with distinct gene expression profiles that influence matrix production and cell communications and the autonomy of tissue development and repair. Thrombospondin-2 (TSP-2), produced by fibroblasts, is a potent angiogenesis inhibitor and negatively associated with tissue repair. Single-cell (sc) sequencing analysis on WT and TSP2KO skin fibroblasts demonstrate distinct cell heterogeneity. Specifically, we found an enrichment of Sox10+ multipotent progenitor cells, identified as Schwann precursor cells, in TSP2KO fibroblasts, while fibrosis-related subpopulations decreased. Immunostaining of tissue and cells validated the increase of this Sox10+ population in KO fibroblasts. Furthermore, in silico analysis suggested enhanced pro-survival signaling, including WNT, TGF-β, and PDGF-β, alongside a reduced BMP4 response. Additionally, the creation of two TSP2KO NIH3T3 cell lines using the CRISPR/Cas9 technique allowed functional and signaling validation in a less complex system. Moreover, KO 3T3 cells exhibited enhanced migration and proliferation, with elevated levels of pro-regenerative molecules including TGF-β3 and Wnt4, and enrichment of nuclear β-catenin. These functional and molecular alterations likely contribute to improved healing and increased neurogenesis in TSP2-deficient wounds. Overall, our findings describe the heterogeneity of dermal fibroblasts and identify pro-regenerative features of TSP2KO fibroblasts.
Spatiotemporal dynamics of non-ecological speciation in rubyspot damselflies (Hetaerinaspp.)
Authors: Patterson C. , Brennan A. , Cowling H. , González-Rodríguez A. , Grether G.F. , Mendoza Cuenca L. , Springer M. , Vega-Sanchez Y. M. , Drury J. 
Published: December 2024

AbstractNon-ecological speciation is a common mode of speciation which occurs when allopatric lineages diverge in the absence of pronounced ecological differences. Yet, relative to other speciation mechanisms, non-ecological speciation remains understudied. Numerous damselfly clades are characterized as non-adaptive radiations (the result of several rounds of non-ecological speciation), but there are few damselfly lineages for which we have a detailed understanding of the spatiotemporal dynamics of divergence. Recent phylogeographic analyses demonstrate that American rubyspot damselflies (Hetaerina americanasensu lato) actually comprise at least two cryptic lineages that coexist sympatrically across most of Mexico. To broaden our understanding of the dynamics of diversification to other rubyspot lineages, we investigated the phylogeographic history of smoky rubyspot damselflies (Hetaerina titia) using genomic data collected across Central and North America. Unexpectedly, we found evidence of reproductive isolation between the highly genetically differentiated Pacific and Atlantic lineages ofH. titiain a narrow secondary contact zone on the Isthmus of Tehuantepec, Mexico. We then fit models of historical demography to bothH. americanasensu lato andH. titiato place these comparisons in a temporal context. Our findings indicate that Pacific and Atlantic lineages ofH. titiasplit more recently than the broadly sympatric lineages withinH. americanasensu lato, supporting key assumptions of the non-ecological speciation model and demonstrating that these two pairs of sister lineages are at different stages of the speciation cycle.
Museum insights for conservation: Unraveling the Extinction Factors in the Jambato Harlequin Frog,Atelopus ignescens
Authors: Guerra Mónica A. , Gao Chengchen , Crickenberger Samuel , Vélez Michelle , Coloma Luis A. , Wang Silu 
Published: December 2024

AbstractNatural history museums harbor invaluable resources for conserving endangered species by providing insights into the mechanism of historical population declines. Here we conducted data synthesis to better understand the extinction factors of the iconic Jambato Harlequin frog,Atelopus ignescens, which was widespread in the Ecuadorian Andes before 1985 but vanished in 1988. The mechanism of extinction remains elusive, as it was uncertain whetherBatrachochytrium dendrobatidis (Bd)fungus infection, climate change, or the interaction of the two factors primarily contributed to the rapid population decline. Here we synthesize historical data from natural history museums, the Global Biodiversity Information Facility (GBIF), and mitochondrial DNA sequences to uncover the factors that have potentially contributed to the extinction of the Jambato Harlequin frog. We found excessive rare alleles reflected in the negative Tajima’s D estimated from the mitochondrial DNA samples collected in 1984, which indicates a selective sweep or bottleneck in the population shortly before the historical extinction. There was a marginal effect of the time before versus duringBdepizootics on the body sizes of the adult males, which was relatively weaker than the sex effect and geographic effect. The body size of adult males, but not the females form a geographic cline where the individuals in the northeast were larger than the males in the southwest. Species distribution modeling based on temperature and precipitation accurately predicted the occupancy ofA. ignescensin 1960-69 (R2= 0.72, accuracy = 0.9). This model further predicted the rapid decline in species distribution over decades of climate change between 1970-2020, which could have contributed to the rapid population decline in the 1980s. Collectively, our data synthesis revealed a strong climate effect and a weak epizootics effect onA. ignescensextinction, which unravels the mysterious rapid population decline and informs ongoing conservation efforts. This investigation inspires future museum genomic studies to dissect the potential climatic maladaptation behind one of the most dramatic extinction events in modern history.
Generative AI-assisted Virtual Screening Pipeline for Generalizable and Efficient Drug Repurposing
Authors: Pham Phuc , Duy Nguyen Viet Thanh , Cho Kyu Hong , Hy Truong Son 
Published: December 2024

AbstractDrug repurposing presents a valuable strategy to expedite drug discovery by identifying new therapeutic uses for existing compounds, especially for diseases with limited treatment options. We propose a Generative AI-assisted Virtual Screening Pipeline that combines generative modeling, binding pocket prediction, and similarity-based searches within drug databases to achieve a generalizable and efficient approach to drug repurposing. Our pipeline enables blind screening of any protein target without requiring prior structural or functional knowledge, allowing it to adapt to a wide range of diseases, including emerging health threats and novel targets where information is scarce. By rapidly generating potential ligands and efficiently identifying and ranking drug candidates, our approach accelerates the drug discovery process, broadening the scope and impact of repurposing efforts and offering new possibilities for therapeutic development. Detailed results and implementation can be accessed athttps://github.com/HySonLab/DrugPipe.
STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity
Authors: Girard Melanie , Yu Tianning , Batista Nathalia V , Yeung Karen K. M. , Lamorte Sara , Gao Wenting , Liu Miaoxi , McGaha Tracy L. , Watts Tania H. 
Published: December 2024

AbstractThe cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of pro-inflammatory cytokines, chemokines, and type I interferons (IFN-I), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage (MCs) cells in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/flmice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the interferon alpha/beta receptor 1 (IFNAR1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory cDC and a reduction in macrophages with a pro-tumor TGFβ/angiogenesis transcriptome. IL-18 - IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+T cells or NK cells. Blocking IL-18 reduced the therapeutic efficacy of STING agonist treatment in CCR2+/+but not CCR2-/-mice, implicating IL-18 production by the monocytes in STING agonist therapy of melanoma. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in tumor control following STING agonist treatment.
Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression between patients
Authors: Smith Alastair L. , Denny Nicholas , Chahrour Catherine , Sharp Kim , Elliott Natalina , Harman Joe , Jackson Thomas , Geng Huimin , Smith Owen , Bond Jonathan , Roberts Irene , Stam Ronald W. , Crump Nicholas T , Davies James O.J. , Roy Anindita , Milne Thomas A. 
Published: December 2024

AbstractGenetic alterations alone cannot account for the diverse phenotypes of cancer cells. Even cancers with the same driver mutation show significant transcriptional heterogeneity and varied responses to therapy. However, the mechanisms underpinning this heterogeneity remain under-explored. Here, we find that novel enhancer usage is a common feature in acute lymphoblastic leukemia (ALL). In particular,KMT2A::AFF1ALL, an aggressive leukemia with a poor prognosis and a low mutational burden, exhibits substantial transcriptional heterogeneity between individuals. Using single cell multiome analysis and extensive chromatin profiling, we reveal that much transcriptional heterogeneity inKMT2A::AFF1ALL is driven by novel enhancer usage. Using high resolution Micro-Capture-C in primary patient samples, we also identify patient-specific enhancer activity at key oncogenes such asMEIS1andRUNX2, driving high levels of expression of both oncogenes in a patient-specific manner. Overall, our data show that enhancer heterogeneity is highly prevalent inKMT2A::AFF1ALL and may also be a mechanism that drives transcriptional heterogeneity in cancer more generally.Key PointsLeukemia patients with the same driver mutations often display gene expression differencesUsing chromatin profiling and high resolution 3C methods we show that enhancer heterogeneity drives gene expression differences
“Photosynthetic and Genetic Adaptations Underpinning the Resilience ofCistanthe longiscapain the Atacama Desert”
Authors: Sandoval-Ibáñez Omar , Tapia-Reyes Patricio , Riveros Aníbal , Yusta Ricardo , Chang Shengxin , Ossa Paulina , Nilo-Poyanco Ricardo , Moreno Adrián A. , Miquel Alvaro , Almeida Andrea Miyasaka , Zurita-Silva Andrés , Orellana Daniela , Baeza Carlos , Blanco-Herrera Francisca , Genova Alex Di , Allende Miguel L. , González Mauricio , Maass Alejandro , Montecino Martin , Gutiérrez Rodrigo A. , Bock Ralph , Meneses Claudio , Orellana Ariel 
Published: December 2024

SummaryThe Atacama Desert is one of the most hostile environments for life. However, the plant speciesCistanthe longiscapa(C. longiscapa) completes its life cycle in the Atacama Desert after sporadic rainfall.Physiological analyses under controlled environmental conditions revealed superior photosynthetic performance, better light acclimation mechanisms, and larger accumulation of photosystem II inC. longiscapacompared to its mesophilic sister species.C. longiscapashows evolutionary expansions in gene families related to DNA repair, photosynthesis, and protein homeostasis. In addition, we observed substantial gene duplication and polymorphic variations between coastal and inland populations in the Atacama Desert. Finally, our assembled mitochondrial genome provides genetic information for all DNA-containing compartments ofC. longiscapa.Diurnal oscillations of malic acid and time-resolved transcriptome analyses of plants harvested in the Atacama Desert indicate thatC. longiscapaengages in CAM metabolism. We observed significant differences in transcripts encoding plastid-localized proteins, including those involved in carbon metabolism, light harvesting, and photoprotection, highlighting the critical role of chloroplasts in the adaptation ofC. longiscapato the Atacama Desert.Our study provides physiological and genetic evidence for the adaptations ofC. longiscapaand advances our understanding of how plants can cope with extreme environmental conditions.