bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cocaine extended access gates compulsive-like seeking in rats
Authors: Tapia-Pacheco Mónica , de Peretti Jeanne-Laure , Vignal Lucie , Williams Maya , Baunez Christelle , Goaillard Jean-Marc , Degoulet Mickael 
Published: February 2025

AbstractWhen does compulsive-like drug seeking emerge? Despite decades of research, and critical advances in our understanding of brain processes leading to addiction, this question remains widely unanswered. So far, behavioral models assessing compulsive-like cocaine seeking following an extended access to cocaine failed to capture the development of its compulsive seeking. In fact, compulsive-like animals immediately displayed pathological seeking when facing its negative consequences of drug seeking, usually materialized by an unescapable mild electric shock on the paws. Here, we designed a new task, ‘Punished Seeking during Extended access’ (PSE), by inserting punished seeking trials within the sessions of extended access to cocaine. We show that compulsive-like cocaine seeking progressively emerges after several PSE sessions, once cocaine intake has been escalated. We thus provide the addiction community a pertinent model to explore brain mechanisms sustaining the emergence of compulsive-like cocaine seeking.
Coralysis enables sensitive identification of imbalanced cell types and states in single-cell data via multi-level integration
Authors: Sousa António G.G. , Smolander Johannes , Junttila Sini , Elo Laura L. 
Published: February 2025

AbstractCurrent state-of-the-art integration methods for single-cell transcriptomics often struggle with imbalanced cell types across heterogeneous datasets, particularly when the datasets include similar but unshared cell types. Here, we introduce Coralysis, an R package featuring a multi-level integration algorithm to overcome these challenges. Coralysis enables sensitive integration, reference-mapping, and cell state identification across single-cell datasets, demonstrating consistent performance across diverse single-cell RNA-seq integration tasks and outperforming state-of-the-art methods when similar cell types are unevenly distributed across batches or completely absent from some datasets. Beyond single-cell transcriptomics, Coralysis enables the integration of rare cell populations from single-cell proteomic assays, such as basophils (0.5%) from whole blood. It also accurately predicts cell type identities across various query-reference scenarios. For instance, it successfully reclassifies CD16+ monocytes and natural killer cells that were previously misclassified as CD14+ monocytes and cytotoxic T cells in peripheral blood mononuclear cells. Finally, a key feature of Coralysis is its ability to provide probability scores that enable identifying both transient and steady cell states along with their differential expression programs. Overall, Coralysis facilitates the study of subtle biological variation and its dynamics by improving the integration of imbalanced cell types and states, enabling a more faithful representation of the cellular landscape in complex single-cell experiments.
High-throughput behavioural phenotyping of 25C. elegansdisease models including patient-specific mutations
Authors: O’Brien Thomas J. , Navarro Eneko P. , Barroso Consuelo , Menzies Lara , Martinez-Perez Enrique , Carling David , Brown André E. X. 
Published: February 2025

AbstractGenetic diagnosis is fast and cheap, challenging our capacity to evaluate the functional impact of novel disease-causing variants or identify potential therapeutics. Model organisms includingC. eleganspresent the possibility of systematically modelling genetic diseases, yet robust, high-throughput methods have been lacking. Here we show that automated multi-dimensional behaviour tracking can detect phenotypes in 25 newC. elegansdisease models spanning homozygous loss-of-function alleles and patient-specific single-amino-acid substitutions. We find that homozygous loss-of-function (LoF) mutants across diverse genetic pathways (including BORC, FLCN, and FNIP-2) exhibit strong, readily detectable abnormalities in posture, locomotion, and stimulus responses compared to wild-type animals. Ansmc-3mutant strain—modelled by introducing a patient-identified missense change—causes developmental anomalies and distinct behavioural profiles even though complete loss of SMC-3 is lethal. In contrast, patient-derived missense mutations in another essential gene,tnpo-2, did not show a strong phenotype initially but it could be “sensitized” chemically (e.g., with aldicarb), potentially facilitating future drug screens. Our findings show that scalable behavioural phenotyping can capture a wide range of mutant effects—from strong to subtle—in patient-avatar worm lines. We anticipate that this standardized approach will enable systematic drug repurposing for rare genetic disorders as new disease variants are discovered.
Defining the limits of differential transpiration
Authors: Sinha Ranjita , Peláez-Vico María Ángeles , Fritschi Felix B. , Mittler Ron 
Published: February 2025

ABSTRACTDifferential transpiration is a newly discovered acclimation strategy of annual plants to a combination of water deficit (WD) and heat stress (HS). Under these conditions (i.e.,WD+HS), transpiration of vegetative tissues is suppressed in plants such as soybean and tomato, while transpiration of reproductive tissues is not (termed ‘Differential Transpiration’; DT). This newly discovered acclimation process enables the cooling of reproductive organs under conditions of WD+HS, limiting HS-induced damage to plant reproduction. However, at what temperature and WD extremes will this process be active and functional at reducing the internal temperature of reproductive tissues, and at what developmental stages of the plant is it activated, remain unknown. Here, we report that DT occurs at most nodes (leaf developmental stages) of soybean plants subjected to WD+HS, and that it can function under extreme conditions of WD+HS (i.e.,18% of field water capacity and 42°C combined). Our findings reveal that DT is an effective acclimation strategy that protects reproductive processes from extreme conditions of WD+HS, at almost all developmental stages. In addition, our findings suggest that under field conditions DT could also be active in plants subjected to low or mild levels of WD during a heat wave.
The fluid genomic organisation of jingmenviruses
Authors: Valle Coralie , Parry Rhys H. , Coutard Bruno , Colmant Agathe M.G. 
Published: February 2025

AbstractJingmenviruses are a distinct group of flavi-like viruses characterized by a genome consisting of four to five segments. Here, we report the discovery of three novel putative jingmenviruses, identified by mining publicly available metagenomics data from mosquito and arachnid samples. Strikingly, these novel jingmenvirus sequences contain up to six genomic segments, with pairs of homologous segments coding for putative structural proteins. Following this discovery, we found an additional homologous segment for two other jingmenvirus genomes, which had gone unnoticed in the initial publications. The presence of a single version of the segments coding for non-structural proteins suggests we have indeed identified jingmenviruses with infectious units that contain up to six segments. We compared these novel jingmenvirus sequences to published sequences, in particular the segments with multiple open reading frames, and we propose that the putative translation initiation mechanisms involved for these segments are ribosomal frameshift resulting in the fusion of open reading frames and leaky scanning for overlapping ORFs. These putative mechanisms, conserved for all jingmenvirus sequences analysed, including in homologous segments, require biological confirmation. We also generated structural models of two putative structural proteins in the duplicated segments, and the corresponding alignments enabled us to confirm or identify the homologous relationship between sequences that shared limited nucleotide or amino acid identity. Altogether, these results highlight the fluid nature of jingmenviruses, which is a hallmark of multipartite viruses. Different combinations of segments packaged in different virus particles could facilitate the acquisition or loss of genomic segments and a segment duplication following genomic drift. Our data therefore contribute to the evidence of the multipartite nature of jingmenviruses and the evolutionary role this organisation may play.
VirMake: a flexible and user-friendly pipeline for viral taxonomic and functional characterisation from shotgun metagenomic sequencing data
Authors: Birkeland Einar , Istvan Paula , Avershina Ekaterina , Rognes Torbjørn , Rounge Trine B 
Published: February 2025

ABSTRACTBackgroundBacteriophages (phages) are recognized as key regulators of microbial communities, and it is pivotal to understand viral ecology, diversity, and evolution. However, identification and characterization of phages from shotgun metagenome sequencing pose unique bioinformatic challenges owing to the inherent complexity and scale of the data.ResultsHere, we introduce VirMake, a comprehensive, flexible, and scalable pipeline developed for viral taxonomic and functional analysis of shotgun metagenome data. It enables high-throughput end-to-end processing, assembly, and annotation of metagenomic data, including viral sequence identification, taxonomic and functional annotation, and using a modular framework, allows users to integrate viral analysis at different stages of metagenome data analysis. VirMake can be installed on Linux operating systems that support Conda and is freely available athttps://github.com/Rounge-lab/VirMake. Here, we showcase VirMake capabilities using three metagenome datasets of varying sizes (up to 2.9 Tbp), generated from various environments (human gut and water) and using different sample preparation protocols (VLP enrichment and bulk DNA extraction).ConclusionsVirMake enabled robust processing of all datasets, showing viral genome richness, taxonomy and integration status to vary according to sampling environments and laboratory protocols.
Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma
Authors: Anichini Andrea , Caruso Francesca P. , Lagano Vincenzo , Noviello Teresa M.R. , Tufano Rossella , Nicolini Gabriella , Molla Alessandra , Bersani Ilaria , Sgambelluri Francesco , Covre Alessia , Lofiego Maria F. , Coral Sandra , Di Giacomo Anna Maria , Simonetti Elena , Valeri Barbara , Cossa Mara , Ugolini Filippo , Simi Sara , Massi Daniela , Milione Massimo , Maurichi Andrea , Patuzzo Roberto , Santinami Mario , Maio Michele , Ceccarelli Michele , Mortarini Roberta 
Published: February 2025

AbstractThe biological and clinical relevance of the DNA methylation landscape in metastatic melanoma (MM) remains underexplored. In a retrospective cohort of 191 MM lesions from 165 AJCC Stage III and IV patients (EPICA cohort) we identified four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation. These findings were validated in the TCGA MM. In EPICA, patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. Furthermore, in an independent adjuvant immune checkpoint blockade MM cohort, patients with DEM/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for pre-exhausted and exhausted T cells and more frequent retention of HLA Class I antigens. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response. These findings underscore the role of DNA methylation in driving MM biological and clinical heterogeneity and support exploration of methylome targeting strategies for precision immunotherapy in melanoma.
Computing pathogenicity of mutations in human cytochrome P450 superfamily
Authors: Mondal Somnath , Shrivastava Pranchal , Mehra Rukmankesh 
Published: February 2025

ABSTRACTCytochrome P450 (CYP) are heme-containing enzymes involved in the metabolism of drugs and endogenous compounds. Humans have 57 known CYPs, with >200 mutations linked to severe disorders, highlighting their role in disease etiology. To investigate their pathogenicity, we performed an in-depth computational study, comparing pathogenic mutations with non-pathogenic ones. First, we evaluated the effects of all possible mutations across 26 known CYP’s structures using five structure-and five sequence-based methods, aiming to reproduce pathogenesis. We computed 23,46,410 mutations, categorized into: all possible, non-pathogenic, and pathogenic. Comparisons consistently revealed a meaningful stability pattern: non-pathogenic > all > pathogenic. Second, we found that a significantly higher number of pathogenic mutations were buried in CYP structures, relating to their higher pathogenesis potential. Third, we analyzed mutation allele frequency relative to solvent accessibility. Fourth, we computed change in 48 amino acid properties upon mutation and identified three distinguishing features: Gibbs free energy, isoelectric point and volume. Fifth, the positive residue content was reduced significantly in diseased mutations, with arginine mutations being the main culprit, directly linked to isoelectric point change. Sixth, we found a higher propensity for pathogenic mutations in conserved sites, suggesting disruption of CYP function. Finally, analysis of heme versus substrate sites showed a higher frequency of pathogenic mutations in heme site, with arginine being the main mutating residue, possibly disrupting arginine-heme interactions. We provide the first comprehensive analysis of mutation effects across multiple CYPs. We model the chemical basis of CYP-related pathogenicity, paving way for a semi-quantitative model to predict diseases.
Computation-through-Dynamics Benchmark: Simulated datasets and quality metrics for dynamical models of neural activity
Authors: Versteeg Christopher , McCart Jonathan D. , Ostrow Mitchell , Zoltowski David M. , Washington Clayton B. , Driscoll Laura , Codol Olivier , Michaels Jonathan A. , Linderman Scott W. , Sussillo David , Pandarinath Chethan 
Published: February 2025

AbstractA primary goal of systems neuroscience is to discover how ensembles of neurons transform inputs into goal-directed behavior, a process known as neural computation. A powerful framework for understanding neural computation uses neural dynamics – the rules that describe the temporal evolution of neural activity – to explain how goal-directed input-output transformations occur. As dynamical rules are not directly observable, we need computational models that can infer neural dynamics from recorded neural activity. We typically validate such models using synthetic datasets with known ground-truth dynamics, but unfortunately existing synthetic datasets don’t reflect fundamental features of neural computation and are thus poor proxies for neural systems. Further, the field lacks validated metrics for quantifying the accuracy of the dynamics inferred by models. The Computation-through-Dynamics Benchmark (CtDB) fills these critical gaps by providing: 1) synthetic datasets that reflect computational properties of biological neural circuits, 2) interpretable metrics for quantifying model performance, and 3) a standardized pipeline for training and evaluating models with or without known external inputs. In this manuscript, we demonstrate how CtDB can help guide the development, tuning, and troubleshooting of neural dynamics models. In summary, CtDB provides a critical platform for model developers to better understand and characterize neural computation through the lens of dynamics.
Pannagram: unbiased pangenome alignment and the Mobilome calling
Authors: Igolkina Anna A. , Bezlepsky Alexander D. , Nordborg Magnus 
Published: February 2025

AbstractPannagram is a toolkit for unbiased pangenome alignment and Mobilome detection based on full-genome assemblies. It consists of two components: a command-line interface for performing the multiple genome alignment in different modes, extracting features such as structural variants (SVs), and searching sequences between datasets; and an R library that provides tools for analyzing alignments and SVs, as well as visualizing every step of the Mobilome analysis pipeline. As a proof of concept, we applied Pannagram to 12Cucumis sativusgenomes, identified SVs, and constructed the graph of nestedness for these variants. Within this graph, we identified families of actually mobile elements belonging to known transposable element families (LINEs, LTRs, and TIRs) and uncovered candidates for a novel type of mobile elements. Our results highlight the power of Pannagram in Mobilome discovery while ensuring an unbiased approach to pangenome analysis.
Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
Authors: Toro C , Real S , Laurito S , Branham MT 
Published: February 2025

ABSTRACTBasal-like breast cancer (BLBC) is characterized by an aggressive clinical course, high genomic instability, and limited therapeutic options. The Inhibitor of Differentiation 4 (ID4) protein has been identified as a critical regulator of BLBC, where its overexpression correlates with poor prognosis. However, the mechanistic contributions of ID4 to BLBC tumorigenesis remain incompletely understood. In this study, we employed an integrative approach combining CRISPR-Cas9-mediated ID4 knockout, small-molecule inhibition, in vivo tumor modeling, and in silico transcriptional analyses to investigate the functional role of ID4 in BLBC.CRISPR-Cas9-mediated knockout of ID4 in MDA-MB-231 cells resulted in significant reductions in proliferation, colony formation, and Ki67 expression, indicating a loss of aggressive phenotypic traits. In vivo xenograft studies further revealed that ID4-silenced cells exhibited markedly delayed tumor formation and a significant reduction in metastatic potential compared to controls. Kaplan-Meier survival analysis of basal-like tumors from The Cancer Genome Atlas (TCGA) dataset demonstrated that patients with low ID4 expression had improved relapse-free survival.Gene set enrichment analysis (GSEA) of BLBC tumors stratified by ID4 expression revealed a shift toward luminal-like transcriptional programs in the ID4-low subgroup, including increased estrogen response and inflammatory signaling pathways. Furthermore, transcription factor activity analysis identified the activation of MYC, JUN, and STAT in ID4-low tumors, suggesting a transition toward a more differentiated phenotype. Finally, pharmacological inhibition of ID4 using the small-molecule degrader AGX51 effectively reduced proliferation in TNBC cells, highlighting ID4 as a potential therapeutic target.Together, these findings establish ID4 as a key driver of BLBC aggressiveness and suggest that its inhibition may represent a viable therapeutic strategy. This study provides compelling evidence supporting the development of ID4-targeted therapies for TNBC patients, with the potential to improve clinical outcomes in this challenging disease subset.
Opposing Functions of Distinct Regulatory T Cell Subsets in Colorectal Cancer
Authors: Huang Xiao , Feng Dan , Mitra Sneha , Andretta Emma S. , Hooshdaran Nima B. , Ghelani Aazam P. , Wang Eric Y. , Frost Joe N. , Lawless Victoria , Vancheswaran Aparna , Jiang Qingwen , Leslie Christina S. , Rudensky Alexander Y. 
Published: February 2025

SUMMARYRegulatory T (Treg) cells contribute to solid organ cancer progression, except in colorectal cancer (CRC) despite being abundantly present. Here, we demonstrate that two distinct tumoral IL-10⁺ and IL-10⁻ Treg cell subsets exert opposing functions by counteracting and promoting CRC tumor growth, respectively. The tumor restraining activity of IL-10⁺ Treg cells was mediated by their suppression of effector CD4 T cell production of IL-17, which directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁻ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal tissues, whereas IL-10+Treg cells exhibited the opposite distribution. Furthermore, relative abundance of IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg cell subsets provides a rationale for therapeutic strategies to selectively target pro-tumoral Treg cells while preserving their anti-tumoral counterparts across barrier tissue cancers that harbor both subsets.
Genomic insights reveal community structure and phylogenetic associations of endohyphal bacteria and viruses in fungal endophytes
Authors: Escudero-Leyva E. , Belle M. , Dadkhahtehrani A. , Culver J.N. , Araya-Salas M. , Kutza J.P. , Goldson N. , Chavarría M. , Chaverri P. 
Published: February 2025

ABSTRACTBackgroundEndohyphal microbiomes, comprising bacteria and viruses, significantly influence fungal phenotypes, host fitness, and ecological interactions. Endohyphal bacterial symbionts are known to affect fungal pathogenicity, secondary metabolite production, and adaptability, yet many aspects of their diversity and interactions remain uncertain. In contrast, endohyphal viruses, despite their widespread presence, are poorly understood in terms of their diversity, ecological roles, and evolutionary relationships with fungal hosts. These gaps highlight the need for integrative studies to explore the composition, diversity, host associations, and functional roles of both bacterial and viral communities in fungi. This study aimed to (1) characterize the diversity of endohyphal bacterial and viral communities within selected fungal endophytes using genomic and transcriptomic approaches, and (2) test for host specialization through phylogenetic signals and core microbial taxa.ResultsEndohyphal microbial communities from 19 fungal isolates from eight fungal orders (Amphisphaeriales, Botryosphaeriales, Diaporthales, Glomerellales, Mucorales, Pleosporales, Sordariales, andXylariales) obtained fromFagus grandifolialeaves were characterized. Bacterial communities exhibited high diversity and significant phylogenetic signals, with core taxa such asBacillales, Burkholderiales, Enterobacterales, Hyphomicrobiales, andPseudomonadales, shared across all fungal samples. Specific bacterial taxa displayed potential host specialization, includingMoraxellales, Sphingomonadales, andStreptosporangiaceaeforAmphisphaerialesfungal samples;Enterobacterales(e.g.,Enterobacteraceae),Hyphomicrobiales(e.g.,Rhizobiaceae), andMicrococcalesforGlomerellales; andCytophagalesforDiaporthales. Viral communities were less diverse, withBamfordviraeandHeunggongvirae(double-stranded DNA viruses) identified as core taxa in metagenomic data, while metatranscriptomic data revealed no core taxa. Surprisingly, only a few reads of double-stranded RNA mycoviruses were detected.ConclusionsThe findings suggest a level of host specialization in bacterial communities and a more complex, limited association for viral communities, with dsDNA dominating the endohyphal virome. This study enhances our understanding of fungal-microbe interactions and highlights the ecological and evolutionary dynamics of endohyphal microbiota. Future efforts to expand reference databases and investigate the functional roles of these microbial taxa will further elucidate their contributions to fungal biology, impacts on their plant hosts, and ecosystem processes.