bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic score associations with birthweight in preterm-born infants compared with term-born infants
Authors: Beaumont Robin N , Kotecha Sarah J , Simpson Shannon J , Kotecha Sailesh , Freathy Rachel M 
Published: January 2025

AbstractObjectiveIn preterm infants, lower birthweight correlates with a higher risk of neonatal complications. Understanding the factors influencing birthweight in these infants is important as it may guide future antenatal and perinatal care. Genetic variants account for at least one-quarter of variation in birthweight in term-born infants, but the genetic contribution to birthweight in preterm infants is not well understood. We aimed to compare genetic score associations with birthweight in a well-powered sample of preterm infants with those in term-born infants.Study designWe used linear regression to test the association between birth weight and fetal genetic scores for birthweight (BW-GS) in a total of 1,416 preterm, singleton and 15,253 term, singleton infants. Analyses, adjusted for ancestry principal components were performed within each of 4 datasets and meta-analysed.ResultsIn term-born infants: a 1 SD higher BW-GS was associated with a 1.20 (95% CI 1.10-1.29) SD higher birthweight. In preterm infants, there was also strong evidence of association, but with a smaller effect size (0.76SD (0.41-1.11) higher birthweight per 1-SD higher BW-GS). In preterms, when stratifying by gestational duration, we found that the associations strengthened with increasing gestational duration.ConclusionsGenetic scores composed of variants identified in term-born infants also influenced birthweight in preterm infants. However, the associations had smaller effects in preterms and were weaker at earlier gestations. This suggests that while many of the same genetic factors influence birthweight in preterm and term-born infants, other factors (environmental, placental, different genetic) may be more important in preterms. Future well-powered studies are required to investigate this.
Homologous recombination deficiency in ovarian high-grade serous carcinoma by self-reported race
Authors: Lawson-Michod Katherine A. , Johnson Courtney E. , Barnard Mollie E. , Davidson Natalie , Collin Lindsay J. , Nix David A. , Huff Chad , Berchuck Andy , Salas Lucas A. , Greene Casey , Marks Jeffrey R. , Peres Lauren C. , Doherty Jennifer A. , Schildkraut Joellen M. 
Published: January 2025

ABSTRACTBackgroundApproximately half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well-characterized in Black individuals.ObjectiveTo characterize HGSC HRD by self-reported race and evaluate whether differences in HRD are associated with ovarian cancer mortality.Study populationCohort study using data collected from two population-based case-control studies of ovarian cancer. Cases were selected based on self-reported race (178 Black, 123 White) and pathologically-confirmed HGSC.ExposuresHRD features identified using matched tumor-normal whole-exome DNA sequencing and categorized as germline or somatic variants in homologous recombination pathway genes, or the SBS3 HRD-associated signature.OutcomesMedian difference and 95% confidence intervals (CI) for age at diagnosis and tumor mutation burden, and age and stage-adjusted hazard ratios (HR) and 95%CIs for survival, comparing individuals with an HRD feature to those without, separately by self-reported race.ResultsMore of the germline and somatic variants detected among Black individuals compared with White individuals were unannotated or variants of uncertain significance (VUS; germline 65% versus 45%; somatic 62% versus 50%, respectively). While the prevalences of many HRD features were similar between Black individuals and White individuals, Black individuals had a higher prevalence of the HRD signature identified using de novo mutational signature analysis (40% versus 29%) and germlineBRCA2variants (8% versus 2%) compared with White individuals. We observed that among Black individuals,BRCA2variants were associated with better survival (somatic HR=0.23, 95%CI 0.07–0.76; germline HR=0.48, 95%CI 0.22–1.03), while germlineBRCA1variants were associated with worse survival (HR=2.11, 95%CI 1.14–3.88). When we restricted to VUS and unannotated variants, we observed similar associations with survival forBRCA2 among Black individuals (somatic HR=0.18, 95%CI 0.04-0.75; germline HR=0.40, 95%CI 0.15–1.09).Conclusions and RelevanceHRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care. Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.
Impact of Serum Sample Storage on the Stability of TRAIL, IP-10, and CRP: Implications for Biomarker Research Employing Biobanks
Authors: Kalfon Roy , Raz Ayelet , Halabi Salim , Navon Roy , Gottlieb Tanya M. , Eden Eran , Hainrichson Mary 
Published: January 2025

1.ABSTRACTSerum biobanks are a valuable resource for proteomic screening, clinical validation and tool comparison studies. Protein integrity can be impacted by sample handling from blood draw until serum separation, by serum processing and freezing, and by storage time in the freezer. Since proteins are destabilized with different dynamics, it is critical to consider each biomarker’s behavior under the conditions relevant to a given biobank, before employing the biobank to study a biomarker panel. MeMed BV®is a next generation host-based diagnostic test for discriminating between bacterial and viral infection that computationally integrates the circulating levels of three biomarkers: TNF-related apoptosis-inducing ligand (TRAIL), interferon γ-induced protein 10 (IP-10), and C-reactive protein (CRP). Here we report the impact of serum sample storage at −80°C on the stability of these three biomarkers. Notably, TRAIL levels decrease by approximately 30% after five years of storage at −80°C, while IP-10 levels decrease by only 17% and CRP levels do not decrease significantly. We conclude that long-term freezer storage differentially compromises the integrity of MeMed BV’s constituent biomarkers.
Restoring Cholesterol Efflux in Vascular Smooth Muscle Cells Transitioning into Foam Cells Through Liver X Receptor Activation
Authors: Borràs Carla , Rotllan Noemí , Griñán Raquel , Santos David , Mourín Marta , Soto Begoña , Camacho Mercedes , Tondo Mireia , Canyelles Marina , Blanco-Vaca Francisco , Escolà-Gil Joan Carles 
Published: January 2025

AbstractObjectiveMacrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30–70% of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LXR activation on the reverse cholesterol transport (RCT) rate from VSMCs to fecesin vivo.Approach and ResultsCholesterol efflux induced by serum and HDL was evaluated in human and mouse VSMCs treated with the LXR agonist T090137 before and after methyl-β-cyclodextrin (MBD)-cholesterol loading. Additional experiments included treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor. Cholesterol-radiolabeled VSMCs were injected into the peritoneal cavity of mice, and RCT was assessed by measuring radiolabeled cholesterol in serum, liver, and feces over 48 hours. Serum and HDL induced cholesterol efflux at similar levels in both human and mouse VSMCs. Cholesterol efflux was significantly reduced following MBD-cholesterol loading; however, treatment with the LXR agonist significantly enhanced efflux. Radiolabeled foam-like VSMCs injected into mice exhibited impaired cholesterol transfer to serum, HDL, and feces compared to non-lipid-laden VSMCs. Pre-treatment with the LXR agonist increased radiolabeled cholesterol levels in serum and HDL and doubled its fecal excretion. Additionally, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an ACAT inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT.ConclusionsHDL-mediated cholesterol efflux is significantly impaired in VSMCs during their transition into foam cells. Pharmacological activation of LXR enhances RCT from VSMCs to fecesin vivoand restores the impaired RCT from transitioning VSMCs. The combination of LXR agonists and ACAT inhibitors holds promise as a synergistic therapeutic approach to restoring cholesterol homeostasis in lipid-laden VSMCs, offering potential strategies to mitigate atherosclerosis.HighlightsLXR activation enhances cholesterol efflux in VSMCsin vitro, even after their transition into foam cells.VSMCs transitioning into foam cells exhibit reduced cholesterol transfer to HDL and feces in mice.LXR agonist treatment enhances reverse cholesterol transport (RCT) from VSMCs to fecesin vivo.Selective ACAT inhibition restores RCT in foam-like VSMCs, with further enhancement observed upon LXR activation.
Addressing SARS-CoV-2 Evolution: Neutralization of Emerging Variants of Concern by the AVX/COVID-12 ‘Patria’ Vaccine Based on HexaPro-S Ancestral Wuhan Spike or Its Updated BA.2.75.2 Version
Authors: Carballo-Uicab Gregorio , Mellado-Sánchez Gabriela , González-González Edith , Salinas-Trujano Juana , Mendoza-Salazar Ivette , López-Olvera Karina , Gómez-Castellano Keyla M. , Salazar Ma. Isabel , Torres-Flores Jesús M. , Chagoya-Cortés Héctor Elías , Paz-De la Rosa Georgina , Mena Ignacio , Rojas-Martínez Oscar , Lara Puente Jesús Horacio , Peralta-Sánchez Gustavo Javier , Sarfati-Mizrahi David , Torres-Flores Alejandro , Sun Weina , Krammer Florian , García-Sastre Adolfo , Palese Peter , López-Macías Constantino , Lozano-Dubernard Bernardo , Pérez-Tapia Sonia M. , Almagro Juan C. 
Published: January 2025

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global health challenge, causing severe morbidity and mortality, particularly in vulnerable groups such as the elderly, immunocompromised individuals, and those with comorbidities. In low- and middle-income countries (LMICs), vaccine access is hindered by high costs and inequitable distribution. To tackle these issues, Mexico developed the AVX/COVID-12 (V-Wu) vaccine, a recombinant Newcastle disease virus (NDV)-based platform expressing a stabilized ancestral Wuhan spike protein (HexaPro-S). Locally manufactured after rigorous testing and regulatory approval, V-Wu aims to enhance self-sufficiency and equity in immunization. This study evaluates an updated vaccine version, AVX/COVID-12 (V-BA), designed to combat Omicron subvariants by expressing the HexaPro-S protein of BA.2.75.2. Both vaccines were administered intramuscularly in K18-hACE2 transgenic and BALB/c mouse models using a prime-boost regimen. Immunogenicity was analyzed by measuring antibodies against Omicron S proteins BA.2.75.2 and XBB.1.5, as well as neutralizing antibodies against Wuhan, BA.1, XBB.1.16, and JN.1 variants. Both vaccines were safe, eliciting robust antibody responses against Omicron S proteins and neutralizing antibodies against multiple emerging SARS-CoV-2 variants of concern (VOCs). V-BA demonstrated superior protection against current Omicron variants, while V-Wu offered broader coverage, including the ancestral Wuhan strain and emerging variants like JN.1. These findings underscore the adaptability of NDV-based platforms in addressing the evolving SARS-CoV-2 landscape and reaffirm the ongoing utility of the ancestral Patria vaccine. Together, they demonstrate the potential of these platforms to drive the development of next-generation vaccines tailored to emerging viral threats, contributing to global health equity.
Identification of a novel papillary renal cell carcinoma molecular subtype characterized by HIF-pathway over-activation
Authors: de Nicolás-Hernández Javier , Arenas Alicia , Valdivia Carlos , Santos María , Lanillos Javier , Bechmann Nicole , Peitzsch Mirko , Gil-Vilariño Eduardo , Monteagudo María , Mellid Sara , Montero-Conde Cristina , Cascón Alberto , Leandro-García Luis Javier , de Velasco Guillermo , Durán Ignacio , Puente Javier , García-Donas Jesús , Caleiras Eduardo , Robledo Mercedes , Rodríguez-Antona Cristina 
Published: January 2025

ABSTRACTPurposePapillary renal cell carcinoma (pRCC), the second most common subtype of renal cancer, exhibits heterogeneity in molecular features and response to targeted therapies, including antiangiogenic drugs. Discovering molecular biomarkers able to stratify pRCC patients into clinically relevant subgroups and understanding the underlying mechanisms are urgently needed to advance precision medicine. Here, we molecularly dissect a large pRCC series through the expression of the targets of hypoxia inducible factors (HIF), master regulators of angiogenesis, metabolic reprogramming and immune microenvironment.Experimental DesignWe merged and analyzed multi-omic and clinical data of 346 patients derived from two pRCC series (TCGA-KIRP and a Spanish metastatic series). Altered pathways and differences in tumor microenvironment were identified through tumor transcriptomic analyses. Tumor metabolome analysis was performed in selected cases.ResultsMolecular revision of driver mutations classified 302 patients as pRCC, while uncovering misclassified cases. Analysis of HIF targets gene expression identified a subset of pRCC tumors with increased HIF activity (31%; “HIF-active”). These tumors were characterized by high hypoxia scores, increased angiogenesis, low expression of Krebs cycle genes and mitochondrial activity, high immune infiltration and increased epithelial-mesenchymal transition (P<0.0001; each feature) and they were associated with increased metastasis risk and worse overall survival (P<0.005). Metabolome analyses revealed that HIF-active tumors accumulated L-2-hydroxyglutarate (L-2-HG), an oncometabolite that leads to pseudohypoxia by inhibiting HIF prolyl hydroxylases and preventing HIFα degradation. L-2-HG-accumulation agreed with diminishedL2HGDHexpression, associated with losing one copy of the gene and low expression ofPPARGC1A, which regulates its transcription.ConclusionsHIF-pathway overactivation defines a pseudohypoxic pRCC molecular subgroup characterized by high angiogenesis, immune infiltration and aggressive features. These findings advance our understanding of pRCC diversity, revealing potential clues for the variable response of patients to targeted therapies and paving the way to more personalized pRCC treatments.
CellPhenoX: An eXplainable Cell-specific machine learning method to predict clinical Phenotypes using single-cell multi-omics
Authors: Young Jade , Inamo Jun , Caterer Zachary , Krishna Revanth , Zhang Fan 
Published: January 2025

SUMMARYSingle-cell technologies have enhanced our knowledge of molecular and cellular heterogeneity underlying disease. As the scale of single-cell datasets expands, linking cell-level phenotypic alterations with clinical outcomes becomes increasingly challenging. To address this, we introduce CellPhenoX, an eXplainable machine learning method to identify cell-specific phenotypes that influence clinical outcomes. CellPhenoX integrates classification models, explainable AI techniques, and a statistical framework to generate interpretable, cell-specific scores that uncover cell populations associated with relevant clinical phenotypes and interaction effects. We demonstrated the performance of CellPhenoX across diverse single-cell designs, including simulations, binary disease-control comparisons, and multi-class studies. Notably, CellPhenoX identified an activated monocyte phenotype in COVID-19, with expansion correlated with disease severity after adjusting for covariates and interactive effects. It also uncovered an inflammation-associated gradient in fibroblasts from ulcerative colitis. We anticipate that CellPhenoX holds the potential to detect clinically relevant phenotypic changes in single-cell data with multiple sources of variation, paving the way for translating single-cell findings into clinical impact.
Affinity-guided labeling reveals P2X7 nanoscale membrane redistribution during microglial activation
Authors: Arnould Benoit , Martz Adeline , Belzanne Pauline , Peralta Francisco Andrés , Cevoli Federico , Hovhannisyan Volodya , Goumon Yannick , Hosy Eric , Specht Alexandre , Grutter Thomas 
Published: January 2025

AbstractATP-gated purinergic P2X7 receptors are crucial ion channels involved in inflammation. They sense abnormal ATP release during stress or injury and are considered promising clinical targets for therapeutic intervention. However, despite their predominant expression in immune cells such as microglia, there is limited information on P2X7 membrane expression and regulation during inflammation at the single-molecule level, necessitating new labeling approaches to visualize P2X7 in native cells. Here, we presentX7-uP, an unbiased, affinity-guided P2X7 chemical labeling reagent that selectively biotinylates endogenous P2X7 in BV2 cells, a murine microglia model, allowing subsequent labeling with streptavidin-Alexa 647 tailored for super-resolution imaging. We uncovered a nanoscale microglial P2X7 redistribution mechanism where evenly spaced individual receptors in quiescent cells undergo upregulation and clustering in response to the pro-inflammatory agent lipopolysaccharide and ATP, leading to synergistic interleukin-1β release. Our method thus offers a new approach to revealing endogenous P2X7 expression at the single-molecule level.
Mutations adjacent to the nucleotide-binding cleft ofArabidopsis thalianaACTIN7 confer resistance to the actin-disrupting compound latrunculin B
Authors: Sparks J. Alan , Sun Liang , Chin Sabrina , Ramanjulu Nolan , Wen Jiangqi , Gilroy Simon , Blancaflor Elison B. , Khan Bibi Rafeiza 
Published: January 2025

AbstractA forward genetic screen identified a dominant-negativeArabidopsis thalianamutant resistant to growth inhibition caused by the actin-disrupting compound latrunculin B (LatB). Map-based cloning combined with whole-genome sequencing revealed that the mutant referred to here aslbr1forLatB resistant1had a point mutation in theAT5G09810gene, which encodes the vegetative actin (ACT) isoform ACT7. The cytosine to thymine mutation in the second exon ofACT7oflbr1led to substitution of proline to serine at position 34 (P34S) adjacent to the nucleotide-binding cleft of the ACT7 protein. Confirmation thatACT7is the causal gene for thelbr1phenotype was achieved through transgenic complementation withACT7 wild type(ACT7WT) andACT7 P34S(ACT7P34S) constructs.ACT7P34also rescued the seedling developmental defects and conferred partial resistance to LatB in the recessiveact7-5mutant. Furthermore, expressing a P34S mutation in ACT2 (ACT2P34S), another vegetative ACT isoform, conferred partial LatB resistance to wild type. Finally, site-directed mutagenesis of ACT7 amino acid residues forming putative hydrogen bonds with LatB, based on yeast and mammalian actin docking and structural analyses, reveals domains adjacent to the actin nucleotide-binding cleft crucial for LatB’s effects on the plant actin cytoskeleton.HighlightCharacterization of the dominant-negativelbr1mutant uncovers amino acid residues in the actin protein crucial for latrunculin’s mechanism of action in plants.
The dynamics of SNARE complex assembly and disassembly in response to Ca2+current activation in live chromaffin cells
Authors: Fang Qinghua , Zhao Ying , An Dong , Lindau Manfred 
Published: January 2025

AbstractA SNAP25 based FRET construct named SCORE (SNARE COmplex REporter) has revealed a transient FRET increase that specifically occurred at fusion sites preceding fusion events by tens of milliseconds and presumably reflects vesicle priming. The FRET increase lasts for a few seconds until it is reversed. In those experiments, the FRET increase was found to be localized to areas <0.5 µm2at sites of transmitter release as detected amperometrically using electrochemical detector arrays. Due to the localization to such small areas, it was unknown if the reversal of the FRET increase is due to local dispersion of high-FRET SCORE copies leaving the site after fusion and exchange with surrounding low-FRET copies, or if it reflects disassembly of the high-FRET complexes. To resolve this question, we performed whole-cell patch clamp pulse stimulation experiments, imaging the entire footprint of the cells in Total Internal Reflection Fluorescence (TIRF) excitation mode such that diffusional exchange between high-FRET and low-FRET copies does not produce a net FRET change. We show here that pulse stimulation of calcium currents results in FRET ratio transients with a time course very similar that related to fusion events. By comparing the kinetics of the FRET ratio decay with analytical and numerical diffusion simulation results, we show that the experimentally observed kinetics cannot be explained by diffusional exchange and conclude that the SCORE FRET ratio transients reflect incorporation of SCORE in SNARE complexes followed by SNARE complex disassembly. Experiments using Synaptobrevin 2/Cellubrevin double knock-out mouse embryonal chromaffin cells showed no pulse induced FRET change, indicating that the vSNARE is required for the incorporation of SCORE (or SNAP25 in wild type cells) in the SNARE complex during priming.Statement of SignificanceIn chromaffin cells, SNAP25-based FRET constructs (SCORE) revealed transient FRET increases within <0.5 µm2areas, preceding individual fusion events that reversed within seconds. It remained unknown whether this reversal stems from high-FRET complex disassembly or diffusion-mediated exchange with low-FRET complexes. Here, we performed whole-cell patch-clamp pulse stimulation with TIRF microscopy, imaging large ∼30 µm2areas of the cell footprint. Calcium currents induced FRET transients with the same decay time constant of ∼1.5 s, significantly shorter than the time scale of diffusion. The SCORE FRET ratio thus reports in real time the dynamics of SNRE complex assembly and disassembly in live cells. Using Synaptobrevin 2/Cellubrevin double knock-out mouse chromaffin cells we show that vSNAREs are required for SNAP25 incorporation into SNARE complexes during priming.