bluuebunny/crossref_metadata_2025_split huggingface dataset:
TransHLA: A Hybrid Transformer Model for HLA-Presented Epitope Detection
Authors: Lu Tianchi , Wang Xueying , Nie Wan , Huo Miaozhe , Li Shuaicheng 
Published: January 2025

AbstractBackgroundPrecise prediction of epitope presentation on human leukocyte antigen (HLA) molecules is crucial for advancing vaccine development and immunotherapy. Conventional HLA-peptide binding affinity prediction tools often focus on specific alleles and lack a universal approach for comprehensive HLA site analysis. This limitation hinders efficient filtering of invalid peptide segments.ResultsWe introduce TransHLA, a pioneering tool designed for epitope prediction across all HLA alleles, integrating Transformer and Residue CNN architectures. TransHLA utilizes the ESM2 large language model for sequence and structure embeddings, achieving high predictive accuracy. For HLA class I, it reaches an accuracy of 84.72% and an AUC of 91.95% on IEDB test data. For HLA class II, it achieves 79.94% accuracy and an AUC of 88.14%. Our case studies using datasets like CEDAR and VDJdb demonstrate that TransHLA surpasses existing models in specificity and sensitivity for identifying immunogenic epitopes and neoepitopes.ConclusionsTransHLA significantly enhances vaccine design and immunotherapy by efficiently identifying broadly reactive peptides. Our resources, including data and code, are publicly accessible athttps://github.com/SkywalkerLuke/TransHLAKey PointsWe developed TransHLA, a deep learning tool for predicting epitopes across all HLA alleles using Transformer and Residue CNN architectures.The model uses ESM2 embeddings to improve predictive accuracy and efficiency.TransHLA shows superior specificity and sensitivity in identifying immunogenic epitopes and neoepitopes compared to existing models.Our approach offers potential advancements in vaccine design and immunotherapy through enhanced peptide analysis.
Estimation of Respiratory Syncytial Virus-attributable Hospitalizations among Older Adults in Japan between 2015 and 2018: an Administrative Health Claims Database Analysis
Authors: Seki Masafumi , Kobayashi Yasuhiro , Méroc Estelle , Kitano Takahiro , Polkowska-Kramek Aleksandra , Yoshida Asuka , Ito Shuhei , Liang Caihua , Bruyndonckx Robin , Moges Solomon Molalign , Conde-Sousa Eduardo , Nuttens Charles , Gessner Bradford D. , Begier Elizabeth 
Published: January 2025

ABSTRACTObjectiveWe estimated the incidence rates (IRs) of respiratory syncytial virus (RSV)-related hospitalizations among adults aged ≥60 years in Japan from 2015 to 2018, using a model-based approach to better understand the disease burden.MethodsWe obtained hospitalization data from the Medical Data Vision (MDV) database, restricted to Diagnosis Procedure Combination (DPC) hospitals. We estimated the annual age-specific RSV-attributable IR of hospitalizations for five cardiorespiratory outcomes based on selected ICD-10 codes employing a quasi-Poisson regression model. We projected our results to all DPC hospitals in Japan and also to all Japanese hospitals.ResultsIn adults aged ≥60 years, the annual IR of RSV-attributable cardiorespiratory hospitalizations at DPC hospitals was estimated at between 100 and 124 per 100,000 person-years, projecting to 134 to 229 cardiorespiratory hospitalizations per 100,000 person-years at all hospitals. For respiratory hospitalizations at DPC hospitals, the annual IR was from 69 to 85 per 100,000 person-years (projecting to 96 to 157 hospitalizations per 100,000 person-years at all hospitals). IRs for all outcomes were consistently higher among adults aged ≥80 years than those 60-79 years.ConclusionOur results indicate a high burden of RSV-attributable hospitalizations in older adults in Japan, highlighting the need to implement effective RSV prevention strategies.HighlightsRSV-attributable hospitalizations were estimated among older adults in JapanWe used data from national hospitals and a comprehensive list of ICD-10 codesWe performed a time series analysis utilizing a quasi-Poisson regression modelRSV causes significant cardiorespiratory hospitalizations in older adultsFuture RSV burden studies should consider respiratory and cardiovascular outcomes
From Background to Signal: Simultaneously derived Copy Numbers from Methylation-Dependent Sequencing cell-free DNA
Authors: Hazelaar Daan M , Boers Ruben G , Boers Joachim B , de Weerd Vanja , Jansen Maurice PHM , Verheul Henk MW , Verhoef Cornelis , Gribnau Joost , Martens John WM , Makrodimtris Stavros , Wilting Saskia M 
Published: January 2025

AbstractCell-free DNA (cfDNA) analysis offers a powerful, non-invasive approach to cancer diagnostics and monitoring by revealing tumor-specific genomic and epigenetic alterations. Here, we demonstrate the versatility of MeD-seq, a methylation-dependent sequencing assay, for comprehensive cfDNA analysis, including methylation profiling, chromosomal copy number (CN) alterations, and tumor fraction (TF) estimation. MeD-seq-derived CN profiles and TF estimates from 38 colorectal cancer with liver metastases (CRLM) and 5 ovarian cancer patients were highly comparable to shallow whole-genome sequencing (sWGS) validating our approach. These findings establish MeD-seq as a robust and cost-effective platform for detecting cancer-specific signals directly from plasma without prior tissue-based information. Future work should expand its application to other cancer types, solidifying MeD-seq as a versatile tool for minimally-invasive cfDNA profiling.
Unveiling Hidden Microbial Diversity in Mars 2020 Mission Assembly Cleanrooms with Molecular Insights into the Persistent and Perseverance of Novel Species Defying Metagenome Sequencing
Authors: Sivabalan Shobhan Karthick Muthamilselvi , Vijayakumar Varsha , Sengupta Pratyay , Palmal Siddhakam , Krishnamurthi Srinivasan , Singh Nitin Kumar , Kyrpides Nikos C. , Raman Karthik , Venkateswaran Kasthuri 
Published: January 2025

AbstractNASA cleanrooms, where space mission components are assembled, maintain stringent cleaning protocols and nutrient-poor environments, resulting in low yet persistent microbial loads. Although these oligotrophic extremophiles are reported in small numbers, their resistance to environmental stresses, sparse presence, and difficulty in extracting biomolecules often lead to their omission, even with advanced sequencing technologies. Traditional metagenomic approaches fail to detect these rare species due to challenges in lysing robust microbial cells and isolating minute amounts of DNA from dominant microorganisms. Additionally, the absence of database references for novel extremophiles limits their identification. Over a six month period of monitoring Mars 2020 mission cleanrooms, 182 bacterial strains from 19 families were identified using advanced molecular techniques. This included 14 novel Gram-positive species, eight of which were spore-formers. Despite being present at only about 0.001% abundance in metagenomic sequencing data, they were successfully cultured. Functional studies revealed their capabilities in nitrogen cycling, carbohydrate metabolism, and radiation resistance. Furthermore, 12 biosynthetic gene clusters, including those linked to ectoine andɛ-poly-L-lysine production, underscore their biotechnological potential. These findings emphasize the hidden microbial diversity in spacecraft assembly cleanrooms and highlight the need for advanced detection methods to uncover extremophiles with potential applications in biotechnology and space exploration.SynopsisUnderstanding extremophiles in NASA spacecraft assembly cleanrooms aids contaminant management in confined habitats, ensuring sustainability and safety in future space missions.TOC Graphic
The Lipidome Landscape of Amiodarone Toxicity: Anin vivoLipid-centric Multi-Omics Study
Authors: Thu Nguyen Quang , Oh Jung-Hwa , Nam Tien Nguyen Tran , Park Se-Myo , Hai Yen Nguyen Thi , Phat Nguyen Ky , Hung Tran Minh , Nguyen Huy Truong , Nguyen Duc Ninh , Yoon Seokjoo , Kim Dong Hyun , Long Nguyen Phuoc 
Published: January 2025

ABSTRACTAmiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.
Human milk bacteria assembled into functionally distinct synthetic communities in infant formula differently affect intestinal physiology and microbiota in neonatal mini-piglets
Authors: Bras Charles Le , Randuineau Gwenaelle , Cahu Armelle , Dahirel Patrice , Guérin Sylvie , Janvier Regis , Romé Véronique , Rault Lucie , Maillard Marie-Bernadette , Bellanger Amandine , Loir Yves Le , Blat Sophie , Even Sergine , Huërou-Luron Isabelle Le 
Published: January 2025

AbstractThe contribution of Human milk (HM) microbiota to infant gut health was addressed by evaluating the effects of HM bacteria combined in two synthetic communities (SynComs, with anin vitrocharacterized anti-inflammatory (AI) or high immunomodulatory (HI) profile) on systemic and ileal immune cell functions, gut epithelial barrier and microbiota. Neonatal mini-piglets were fed either a formula without supplementation (CTRL) or supplemented with AI or HI SynComs and compared to sow milk-fed (SM) piglets. The two HM-derived SynComs differently modulated microbiota and intestinal functions (mainly immunity). Notably, the abundance of more than half of the intestinal taxa that differed between the three formula groups differed between AI and HI piglets. In addition, fewer differently abundant genera were observed between HI and SM piglets than between CTRL and SM piglets, suggesting that SynCom HI supplementation brought the microbiota of HI piglets closer to that of SM piglets. SynCom supplementation affected immune functions at both systemic and mucosal levels. Fecal sIgA level in HI piglets, which was slightly lower than in SM piglets, was markedly higher than in CTRL and AI piglets. Finally, SynCom bacteria were correlated with several genera in ileum and colon microbiota and both were highly correlated with physiological variables, supporting the HM bacteria-driven influence on gut microbiota and on multiple gut functions. Overall, our data show that SynComs with contrasting immunomodulatory properties but similar taxonomic composition can differently modulate the developmental profile of intestinal functions and microbiota in mini-piglets used as a human infant model.ImportanceEarly life environmental factors, such as neonatal diet, modulate gut microbiota that is a driving force for the functional development of the gut. However, the role of the human milk (HM) microbiota is not well understood, particularly the importance of the immunomodulatory properties of HM bacteria. This study provides insight into the differential effects of two synthetic communities, with similar taxonomic composition representative of the taxonomic diversity of the HM cultivable microbiota, but with contrasting immunomodulatory properties (previously characterizedin vitroon an intestinal quadricellular model). Daily supplementation with these two SynComs differently modulated gut microbiota composition and gut physiology, particularly intestinal immune signatures. In conclusion, the functional profile of bacteria within the HM microbiota may induce a different developmental profile of gut physiology in infants.
Blockade of mTOR ameliorates IgA nephropathy by correcting CD89 and CD71 dysfunctions in humanized mice
Authors: Cambier Alexandra , Da Silva Jennifer , Bex Julie , Canesi Fanny , Lachize Lison , Sannier Aurélie , Patey Natacha , Boedec Erwan , Badie Amandine , Monteiro Renato C. 
Published: January 2025

AbstractBackground and hypothesisIgA nephropathy (IgAN) is the most common glomerulonephritis and major cause of renal failure worldwide. Pathogenesis involves galactose deficient IgA1-immune complexes containing soluble IgA Fc receptor (sCD89). Both IgA1 and sCD89 bind independently to transferrin receptor (TfR1, CD71), a mesangial IgA1 receptor. Here, we hypothesize that sCD89 plays a pathogenic role in IgAN by driving a tri-partite IgA1-sCD89-CD71 complex inducing activationin situof the mTOR (mammalian target of rapamycin) signaling pathway in mesangial cells and contributing to disease progression. mTOR inhibition may disrupt this pathogenic axis, reducing IgA1 and sCD89 deposits, modulating CD71 expression, and alleviating disease manifestations. Here, we investigated the role of sCD89 and a mTOR inhibitor using humanized mouse models of IgAN expressing CD89 and/or IgA1.MethodsSingle cell and RNAseq were obtained from IgAN public dataset and immunostaining from childhood IgAN (cIgAN) biopsies. Human mesangial cell (HMC) stimulation by recombinant sCD89 (rsCD89) was followed by western blot analysis. Pre-clinical assays with mTOR inhibitor (Everolimus) by oral gavage were performed using young α1KImice injected with rsCD89 for 25 days (preventive protocol) and adult α1KICD89Tgmice (treated protocol) for 75 days. Proteinuria, renal function, and circulating immune-complexes (CIC) were analysed and kidneys harvested for histology. Results: RNAseq revealed increased TfR1 and mTOR mesangial cell expression in IgAN patients. TfR1 upregulation was confirmed in cIgAN biopsies. sCD89 stimulation induced HMC TfR1 expression and phosphorylation of mTOR, Akt and p70S6K1. Everolimus treatment prevented or reverted mesangial IgA1 and C3 deposits but also decreased mesangial TfR1 and cell proliferation. Everolimus impaired levels of sCD89- and IgA-CIC, proteinuria, as well as renal function.ConclusionThese findings highlight the critical role of the sCD89-TfR1-mTOR axis in IgAN pathogenesis and support the use of mTOR inhibitors as a novel therapeutic approach. This approach could significantly improve outcomes by slowing disease progression and minimizing the systemic toxic effects of current immunosuppressive therapies. This is particularly crucial for pediatric patients, where the only approved treatment – steroids – has severe side effects, including detrimental impacts on bone health and growth.
Proof-of-principle of NF1 Gene Therapy in plexiform neurofibroma mice models
Authors: Bostanthirige Dhanushka Hewa , Plante Camille , Vatasescu Jean-Paul Sabo , Lévesque Maude , Poirier Colin , Deschenes Mathieu , Chabot Benoit , Laurent Benoit , Geha Sameh , Brosseau Jean-Philippe 
Published: January 2025

ABSTRACTNeurofibromatosis type I is a rare neurocutaneous syndrome characterized by the development of disfiguring neurofibroma tumors with unmet clinical needs. As Neurofibromatosis Type I is a monogenic disease, the development of gene therapy is highly attractive, but it is currently unknown if rescuing theNF1gene in established neurofibroma is sufficient for tumor regression. Here, we test this hypothesis by building two novel NF1 mouse models with reversibleNF1expression. In the first model, the humanNF1−/-Schwann cells named ipNF95.11b were genetically modified with a doxycycline-inducible full-length mouseNf1gene. One month after cells implantation in the sciatic nerve, mice were split into 2 groups. Strikingly, all sciatic nerves from mice allowed to drink doxycycline water for one month display complete normalization of the sciatic nerve histologically (n=6 sciatic nerves) whereas 83% (5 out of 6 sciatic nerves) develop or maintain a neurofibroma when drinking regular water. In the second model, the humanNF1+/-Schwann cells named ipNF95.11c were genetically modified with a doxycycline-inducible potent shRNA against theNF1mRNA transcript. Strikingly, doxycycline withdrawal after neurofibroma establishment allowed complete normalization (n=4 sciatic nerves), whereas all sciatic nerves showed evidence of neurofibroma when kept on doxycycline (n=4 sciatic nerves). Thus, we proof-of-principle NF1 Gene Therapy in plexiform neurofibroma mice models.
Guard cell photorespiration has a major impact on photosynthesis, growth and stomatal behavior in Arabidopsis
Authors: Sun Hu , Schmidt Nils , Lawson Tracy , Hagemann Martin , Timm Stefan 
Published: January 2025

SummaryPhotorespiration is a mandatory metabolic repair shunt of carbon fixation by the Calvin-Benson (CB) cycle in oxygenic phototrophs. Its extent depends mainly on the CO2/O2ratio in chloroplasts, which is regulated via stomatal movements. However, despite comprehensive understanding on the role of photorespiration in mesophyll cells (MC), its role in guard cells (GC) is yet unknown. To analyze this issue, the key enzyme of photorespiration, glycine decarboxylase (GDC), was manipulated through overexpression and antisense suppression of theGDCH-protein gene.A positive correlation ofGDC-Hexpression with growth, photosynthesis and carbohydrate biosynthesis was observed in the transgenic lines, demonstrating active photorespiration is involved in stomatal regulation. This view is supported by gas exchange measurements showing that optimized GC photorespiration improves plant acclimation towards conditions requiring a high photorespiratory capacity, including high light. Microscopic analysis revealed that altered photorespiratory flux also affected starch accumulation patterns in GC, eventually serving as the underlying mechanistic for altered stomatal behavior.Collectively, our data suggest that photorespiration is a key component of the regulatory circuit that coordinates stomatal movements with external and internal CO2availability. Thus, manipulation of photorespiration in GC has the potential to engineer crops maintaining growth and photosynthesis under future climates.One-sentence summaryGuard-cell-specific manipulation of photorespiratory glycine decarboxylase reveals photorespiration is active in guard cells and makes a major contribution to stomatal metabolism and movements.
Appendometer: A system for simultaneous, high-throughput morphometry ofDrosophilalegs and wings
Authors: Rossoni Daniela M. , Murray Connor , Porto Arthur , Houle David 
Published: January 2025

ABSTRACTThe inheritance of many different organismal features is correlated, as is their evolution, sug-gesting that we need to understand the pattern and causes of those correlations to understand evolution. Unfortunately, we generally lack the ability to rapidly and accurately measure large numbers of traits, making it difficult to describe the patterns of trait relationships or for-mulate hypothesis about the causes of their entanglement. We have previously developed a system to make high-dimensional measurements of Drosophilid fly wings in live specimens. Here, we report the extension of this approach to rapidly assess the dimensions of the distal leg segments, femur, tibia, and tarsi. Using the system, we describe the covariance of the wing and leg morphology and evaluate the relative rates of evolution of legs and wings.We use two simple suction devices to immobilize and position legs and wings of an anaes-thetized fly for imaging, then take a single image incorporating both appendages. We em-ployed a machine learning method to measure leg segment lengths, which should be broadly applicable across diverse taxa. Experienced users can image the legs and wings of a fly every two minutes, with outlier detection and correction taking approximately 40 seconds. To demonstrate the usefulness of these methods, we measured the legs and wings of over 4,000 specimens from 43 different Drosophilid taxa. We estimated the rate of wing and leg evolu-tion using a phylogenetic mixed model.Repeatabilities of leg segments lengths averaged over 80%. The rate of evolution of wing and leg sizes are similar, but the rate of wing proportion evolution is 1.6 times as high as that of leg proportions due to strong allometric changes in wing shape. Within-species variation in leg proportions is highly correlated with the rate of leg proportion evolution, as is true for wings. Relative lengths of leg segments showed a strong pattern of negative correlations be-tween the lengths of the tarsal segments and of the femurs and tibias, while all other segment correlations were positive. This pattern was repeated in the rate estimates, suggesting that se-lection favors tradeoffs between tarsi and the remainder of the leg.Our simple system for imaging and measuring legs and wings simultaneously has high throughput and repeatability. It is readily applicable to a wide variety of winged insects and other traits, including wings, that could be imaged. Applied toDrosophila, our morphometric system enlarges the ability to study inheritance, pleiotropy, and evolution in this important model taxon.
A GPVI-platelet-neutrophil-NET axis drives systemic sclerosis
Authors: Darbousset Roxane , Senkpeil Leetah , Kuehn Julia , Balu Spoorthi , Miglani Dhruv , Dillon Eilish , Fromson Caroline , Elahee Mehreen , Jarrot Pierre-Andre , Montesi Sydney B. , Rao Deepak A. , Ware Jerry , Wagner Denisa D. , Bujor Andreea M. , Gutierrez-Arcelus Maria , Nigrovic Peter A. 
Published: January 2025

ABSTRACTSystemic sclerosis (SSc) is characterized by progressive fibrosis of skin, lung, and other organs and retains among the highest rates of mortality among autoimmune diseases. We identified activation of circulating neutrophils from patients with diffuse SSc, together with concordant transcriptomic evidence of neutrophil activation in blood, skin, and lungs, and in mice with experimental SSc of skin and lung induced by hypochlorous acid or bleomycin. Neutrophil depletion abrogated experimental SSc, while adoptive transfer of SSc neutrophils induced skin and lung fibrosis in healthy mice, identifying neutrophils as both necessary and sufficient for disease. In patients, platelet activation accompanied diffuse SSc, and in mice platelet activation preceded neutrophil activation, suggesting an upstream role. Platelet depletion abrogated both neutrophil activation and tissue fibrosis. SSc platelets conferred upon neutrophils the capacity to induce SSc. This capacity corresponded to enhanced production of neutrophil extracellular traps (NETs); experimental SSc was abrogated in NET-deficient PAD4−/−mice, a resistance bypassed by adoptive transfer of PAD4-suficient SSc neutrophils, confirming NETs as a key effector mechanism of SSc. In turn, platelet activation was mediated via the platelet collagen receptor GPVI, while GPVI deficiency resulted in attenuated platelet and neutrophil activation, fewer circulating NETs, and protection from fibrosis in both murine models of SSc. Together, these findings define a GPVI-platelet-neutrophil-NET axis in SSc and identify a new set of therapeutic targets in this often-refractory condition.