bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circadian metabolic adaptations to infections
Authors: Costantini Claudio , Brancorsini Stefano , Grignani Francesco , Romani Luigina , Bellet Marina Maria 
Published: January 2025

Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host–microbiota–pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.
This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Endocrine and molecular regulation of seasonal avian immune function
Authors: Sur Sayantan , Tiwari Jyoti , Malik Shalie , Stevenson Tyler 
Published: January 2025

Birds have evolved seasonal adaptations in multiple aspects of the innate and adaptive immune systems. Seasonal immunological adaptations are crucial for survival in harsh environmental conditions and in response to increased prevalence of acute and chronic diseases. Similar to other vertebrates, birds exhibit remarkable plasticity in cytokine production, chemotaxis, phagocytosis and inflammation across the year. In this review, we provide a comparative perspective on seasonal rhythms in bird immune function. We describe advances in our understanding of annual changes in immune cells and responses to innate and adaptive immune challenges. Then, the role of glucocorticoids, sex steroids, thyroid hormones (THs) and melatonin to act as immunomodulators is described. We then discuss the impact of a major and emerging disease, the high pathogenicity avian influenza, as one of the most critical seasonal diseases with significant implications for poultry and wild bird populations. The review identifies the need to enhance our knowledge of annual rhythms in immune cells and tissues in birds, at molecular, cellular and hormonal levels across the year. Moreover, there is a significant absence of information on sex-specific seasonal variation in immune function. Understanding seasonal immune system dynamics will aid in addressing the negative impacts of pathogenic diseases, minimize global economic losses and aid conservation efforts.
This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
A novel NLP-based method and algorithm to discover RNA-binding protein (RBP) motifs, contexts, binding preferences, and interactions
Authors: Elhajjajy Shaimae I. , Weng Zhiping 
Published: January 2025

ABSTRACTRNA-binding proteins (RBPs) are essential modulators in the regulation of mRNA processing. The binding patterns, interactions, and functions of most RBPs are not well-characterized. Previous studies have shown that motif context is an important contributor to RBP binding specificity, but its precise role remains unclear. Despite recent computational advances to predict RBP binding, existing methods are challenging to interpret and largely lack a categorical focus on RBP motif contexts and RBP-RBP interactions. There remains a need for interpretable predictive models to disambiguate the contextual determinants of RBP binding specificityin vivo. Here, we present a novel and comprehensive pipeline to address these knowledge gaps. We devise a Natural Language Processing-based decomposition method to deconstruct sequences into entities consisting of a central targetk-mer and its flanking regions, then use this representation to formulate the RBP binding prediction task as a weakly supervised Multiple Instance Learning problem. To interpret our predictions, we introduce a deterministic motif discovery algorithm designed to handle our data structure, recapitulating the established motifs of numerous RBPs as validation. Importantly, we characterize the binding motifs and binding contexts for 71 RBPs, with many of them being novel. Finally, through feature integration, transitive inference, and a new cross-prediction approach, we propose novel cooperative and competitive RBP-RBP interaction partners and hypothesize their potential regulatory functions. In summary, we present a complete computational strategy for investigating the contextual determinants of specific RBP binding, and we demonstrate the significance of our findings in delineating RBP binding patterns, interactions, and functions.
Discovery of single-stranded DNA in meteorite-derived cultures: evidence of novel genetic elements
Authors: López Ramón y Cajal Carlos 
Published: January 2025

AbstractThis study presents the first evidence of single-stranded DNA (ssDNA) sequences identified through shotgun metagenomic analysis of meteorite-derived cultures. These ssDNA sequences, predominantly isolated from the "no-hits" zone with no significant matches in existing genomic databases, exhibit conserved motifs, distinct secondary structural features, and a unique AT-rich composition. These characteristics suggest potential roles in autoreplication, molecular stabilization, and resilience under extreme conditions, consistent with extremophilic adaptations. Notably, this discovery aligns with observations of a provisionally termed New Biological Structure (NBS) detected in diverse contexts, including meteorites and biogenic materials, though its characterization lies beyond the scope of this study.The sequences were detected using a rigorous methodology that included stringent contamination controls, advanced metagenomic assembly techniques, and exhaustive taxonomic filtering to ensure robustness and minimize false positives. Their consistent detection across meteorites of varying types and geographic origins further underscores the reliability of the findings. Repeat analyses revealed specific motifs associated with potential regulatory or structural roles, while secondary structure predictions suggested configurations that could support autoreplication and stability under extreme conditions.This groundbreaking discovery highlights the potential of meteorites to harbor previously uncharacterized genomic elements, offering profound insights into molecular diversity, prebiotic chemistry, and molecular evolution. By situating these findings within the broader context of extremophilic biology and astrobiological exploration, this study establishes a foundation for investigating the structural, functional, and evolutionary implications of these sequences. Future research will also explore their relevance as biosignatures in the search for life under extreme and extraterrestrial conditions.
Bioinformatic analysis reveals the molecular mechanisms of Trefoil factor 3 involved in asthma pathogenesis
Authors: He Fang , Wang Shu , Huang Pengfei , Fan Xiaoyun 
Published: January 2025

AbstractObjectiveInvestigate the expression, regulatory network and function of TFF3 in asthma from a multi-omics perspective through bioinformatics and cellular experiments to provide clues for understanding its molecular mechanisms in asthma.MethodsDownloaded two asthma-related datasets (GSE67472 and GSE147878) from GEO. Conducted differential expression analysis and WGCNA to find common genes related to asthma phenotype and TFF3 expression. Constructed a PPI network to identify key genes interacting with TFF3. Performed GO and pathway enrichment analysis using DAVID. Analyzed the relationship between TFF3 and immune cell infiltration with CIBERSORTx. Used molecular docking to validate interactions. In vitro, induced 16HBE cells with HDM to establish asthma model and detected inflammatory indicators and TFF3 by RT-qPCR and western blotting.ResultsTFF3 expression was significantly increased in asthma patients in both datasets. ROC analysis showed good diagnostic specificity and sensitivity. 57 co-expressed genes related to asthma and TFF3 were screened, with 11 genes directly interacting with TFF3 and upregulated. Functional enrichment analysis indicated involvement in asthma-related processes. Immune infiltration analysis showed increased M2 macrophages and mast cells, decreased M1 macrophages, and positive correlation with TFF3. Molecular docking confirmed stable binding. In vitro experiments showed increased inflammation index and TFF3 expression after HDM intervention.ConclusionThe study used bioinformatics and cellular experiments to show TFF3’s key roles in asthma pathogenesis in aspects like gene expression, protein interaction, and immune microenvironment. TFF3 may regulate genes like AGR2 and AKT1, affect immune cells, and be involved in processes like cell migration and immune response. It provides clues for exploring molecular mechanisms and may offer new directions for asthma diagnosis and treatment.
Glycoprotein 130 Antagonism Counteracts Metabolic and Inflammatory Alterations to Enhance Right Ventricle Function in Pulmonary Artery Banded Pigs
Authors: Mendelson Jenna B. , Sternbach Jacob D. , Moon Ryan A. , Hartweck Lynn M. , Clark Sophia R. , Tollison Walt , Lahti Matthew T. , Carney John P. , Markowski Todd , Higgins LeeAnn , Kazmirczak Felipe , Prins Kurt W. 
Published: January 2025

AbstractBackgroundRight ventricular dysfunction (RVD) is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of glycoprotein-130 (GP130) signaling with the small molecule SC144 improves RV function in rodent RVD via anti-inflammatory and metabolic mechanisms. However, SC144’s efficacy and molecular effects in a translational large animal model of RVD are unknown.Methods4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144,n=5] or vehicle [PAB-Veh,n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac MRI quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue. Quantitative proteomics examined RV mitochondrial protein regulation.ResultsSC144 significantly improved RV ejection fraction (Control: 60±4%, PAB-Veh: 22±10%, PAB-SC144: 37±6%) despite similar RV afterload. Single-nucleus RNA sequencing demonstrated PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared to control, and many of these changes were blunted by SC144. SC144 combatted the downregulation of cardiomyocyte metabolic genes induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 activation. Correspondingly, SC144 rebalanced RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed SC144 restored fatty acid metabolism. Finally, CellChat analysis revealed SC144 restored pericyte-endothelial cell cross-talk.ConclusionGP130 antagonism blunts elevated immune cell abundance, reduces pro-inflammatory gene transcription in macrophages and lymphocytes, rebalances autophagy and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte communication to improve RV function.
Mathematical modelling of the immune response during endometriosis lesion onset
Authors: Miller Claire M. , Germano Domenic P.J. , Chenoweth Alicia M. , Holdsworth-Carson Sarah 
Published: January 2025

AbstractThe immune system is hypothesised to contribute to the onset of endometriosis lesions. However, the precise mechanisms underlying its role are not yet known. This paper introduces a novel compartmental mathematical model that describes the predicted interactions between the innate immune system (specifically macrophages and natural killer cells) and endometrial cells occurring within the peritoneal fluid during the early stages of endometriosis lesion onset. Our model suggests that an increased retrograde influx of endometrial cells into peritoneal fluid correlates with heightened M1-type macrophage activation, but does not lead to an increase in disease. We compare the system’s response to changes in immune cytotoxicity and ability to detect ectopic endometrial cells. The model indicates that a reduction in cytotoxicity is a key driver of disease. These findings align with the increased immune activation observed clinically. Lastly, our model predicts that an individual can transition to a diseased state following a reduction in immune system cytotoxicity and/or reduced ability to detect ectopic cells. Due to hysteresis, a significant improvement is then required to restore an individual to the disease-free state. This work provides a valuable framework to explore hypotheses of endometriosis lesion onset and assist in understanding of the disease.
Standardised TruAI automated quantification of intracellular neuromelanin granules in human brain tissue sections
Authors: Filimontseva Anastasia , Cuadros Thais , Chatterton Zac , Compte Joan , Fu YuHong , Vila Miquel , Halliday Glenda M 
Published: January 2025

AbstractAimsTo standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age.Methods5-6µm thick fixed and paraffin-embedded transverse midbrain tissue sections were supplied from 47 cases from three brain banks following ethics approvals. Sections were prepared and automated digital images acquired. Standardisation and automation of the quantification of neuromelanin granules was performed using the TruAI feature of the Olympus VS200 desktop platform. Comparisons between stained and unstained sections as well as correlations with age were performed.ResultsThe automated platform reliably identified both stained and unstained intracellular and extracellular neuromelanin granules, showing high reproducibility in measurements across laboratories using different tissue processing methods. Extracellular neuromelanin granules were significantly smaller than intracellular neuromelanin granules. Sections processed for hematoxylin and eosin staining impacted on size and colour of both neuromelanin and the neurons containing neuromelanin. Hematoxylin made neuromelanin bluer and the increased tissue processing made the intracellular area occupied by neuromelanin smaller in younger people. There was an increase in neuromelanin optical density and colour change (more brown) with age.ConclusionsThe TruAI automated platform reliably quantifies individual neuromelanin granules in catecholamine neurons. Extracellular neuromelanin is considerably smaller in size than intracellular neuromelanin, and intracellular neuromelanin changes its properties with age. The darkening and colour change of intracellular neuromelanin suggests an increase in eumelanin over time in healthy individuals. These changes can be reliably identified using the automated platform.Key pointsStandardised, reliable TruAI automated quantitation of intracellular neuromelanin granules in human brain sections gives novel insights into their structure and functionextracellular neuromelanin granules, released from dying pigmented neurons, are significantly smaller than intracellular neuromelanin granulesintracellular neuromelanin granules change their properties with healthy ageing becoming darker, consistent with more antioxidant eumelanin
Diagnosis of Blood Diseases and Disorders with Topological Deep Learning
Authors: Koung Philmore F. , Fatema Saba , Pakasticali Nagehan , Luu Hung S. , Coskunuzer Baris 
Published: January 2025

AbstractBlood diseases and disorders, including leukemia and infectious diseases of red blood cells, pose significant diagnostic challenges due to their complex presentations and reliance on time-consuming cytomorphological analysis to detect subtle morphologic features. While microscopic examination remains the gold standard in their diagnosis, its dependence on expert interpretation high-lights the need for advanced methods to enhance the diagnostic workflow. Recently, deep learning (DL) methods have shown promise in medical imaging by automating and improving accuracy. However, these approaches often require large, annotated datasets, which are scarce for rare diseases, and they often face interpretability issues, limiting their integration into clinical practice.In this study, we present a novel framework that integrates topological features with state-of-the-art DL techniques to enhance the analysis of cytomorphological images for diagnosing blood disorders. By combining global topological information with the localized patterns captured by DL models, our approach improves diagnostic accuracy while ensuring robustness, interpretability, and reproducibility. Experimental results demonstrate that the inclusion of topological features not only enhances model performance but also proves particularly effective in limited data settings. This methodology addresses critical limitations of existing techniques, advancing the classification and diagnosis of blood disorders while improving efficiency and reliability in medical imaging workflows.
Derivation and Validation of a Point-based Forecasting Tool for SARS-CoV-2 Critical Care Occupancy
Authors: Grima Alicia A. , Lee Clara Eunyoung , Tuite Ashleigh R. , Wilson Natalie J. , Simmons Alison , Fisman David N. 
Published: January 2025

BackgroundThe requirement for critical care in even a modest fraction of SARS-CoV-2 infected individuals made ICU resources an important societal chokepoint during the recent pandemic. We developed a simple regression-based point score in 2020 based on an objective of forecasting critical care occupancy in the Canadian province of Ontario based on mean age of cases, case numbers, and testing volume. Evolution of the pandemic (variants of concern, vaccination) led us to re-assess and re-calibrate our earlier work, with inclusion of information vaccination which became widespread in 2021.MethodsWe obtained complete provincial SARS-CoV-2 case, testing, and vaccination data for the period from March 2020 to September 2022, with data subdivided into 6 major “waves”, following the approach applied by other Canadian investigators. Our initial model was fit only using the first two “wild type” SARS-CoV-2 waves; an updated model included wave 3 (N501Y+ variants). Our model was validated by comparing model projections to waves not used for model fitting; validation model fits were evaluated with Spearman’s rho; counterfactuals without vaccination were modeled to impute fraction of critical care admissions prevented with vaccination. Costing was based on published economic estimates.ResultsOur initial model (fit to waves 1 and 2) was well calibrated (rho 0.85) but predictive validity was modest (rho 0.46). Predictive validity improved in models fit to the first 3 pandemic waves without vaccination (rho 0.60) or with vaccination (rho 0.68) (P for inclusion of vaccination 0.013 by Likelihood Ratio Test). Prevented fraction of ICU admissions attributable to vaccination was 144% (22017 admissions expected vs. 9020 observed); based on published estimates of ICU admission cost for SARS-CoV-2 the 12977 admissions averted $2.9 (CDN) billion in economic costs, in contrast to the $3 billion total cost of the vaccination program.ConclusionsSimple time series regression incorporating case and testing characteristics continues to be useful as a tool for forecasting critical care occupancy due to SARS-CoV-2 but early pandemic models need to be updated to capture the preventive effects of widespread vaccination. The economic benefit of vaccination for prevention of critical care resource consumption during the pandemic is substantial, achieving near cost neutrality with the province’s entire vaccination program.
Effect of JYNNEOS vaccination on mpox clinical progression among cisgender male cases with confirmed infection
Authors: Granskog Lauren , Saadeh Kayla , Lorenz Kieran , Quint Joshua , Vance Joshua , Salih Tarek , Lo Timothy , Jacobson Kathleen , Ramos Marisa , Peters Philip , Chapman Eric , Snyder Robert E. , Lewnard Joseph A. 
Published: January 2025

ABSTRACTBackgroundThe JYNNEOS modified vaccinia virus Ankara vaccine has proven effective in preventing clade IIb mpox disease during the ongoing global outbreak associated with sexual transmission. However, understanding of the effect of vaccination on mpox clinical presentation remains limited.MethodsWe interviewed cisgender males with confirmed mpox (cases) reported to the California Department of Public Health from May 2022 through December 2023. We ascertained cases’ vaccination statuses via the California Immunization Registry. We estimated JYNNEOS vaccine effectiveness against progression (VEP) to disease involving disseminated lesions via the adjusted odds ratio of vaccination, comparing cases who reported lesions disseminated across multiple anatomical regions to cases who reported lesions contained to a single anatomical region. We used the same approach to estimate VEP for prodromal symptoms.FindingsAnalyses included 4,613 cases, among whom 3,045 (66.0%) reported disseminated lesions and 1,956 (42.4%) had HIV infection. Among cases who reported disseminated lesions, 114 (3.7%) received pre-exposure vaccination and 43 (1.4%) received post-exposure vaccination only. In contrast, among cases who reported lesions contained to a single anatomical region, 286 (18.2%) received pre-exposure vaccination and 146 (9.3%) received post-exposure vaccination only. For any pre-exposure vaccination, VEPwas 58.9% (95% confidence interval: 50.4-65.9%), while VEPfor two pre-exposure doses was 61.0% (47.3-71.1%). For post-exposure vaccination, VEPwas 15.9% (3.3-26.8%). Among cases without HIV and cases with HIV, pre-exposure VEPwas 66.4% (56.6-74.0%) and 45.3% (28.0-58.5%), respectively. Pre-exposure vaccination was also associated with reduced odds for illness involving fever, chills, and lymphadenopathy.InterpretationAmong cisgender males with mpox, pre-exposure vaccination with JYNNEOS is associated with less severe illness. Awareness of an attenuated disease phenotype involving localized lesions without accompanying prodromal symptoms is needed among providers to ensure accurate diagnosis of mpox in previously-vaccinated individuals.