Biology subjects

Thomas, A.

Publications and source records attributed to Thomas, A..

At least 19 recordsLinked to original sources

bioRxiv2026

High-resolution HLA and MICA/MICB typing of the 1000 Genomes panel: a resource for precision medicine

High-resolution characterization of human leukocyte antigen (HLA) and MICA/MICB variation is important for transplantation, immunogenetics, and the interpretation of disease associations within the major histocompatibility complex (MHC). However, publicly available population reference datasets remain limited in their resolution and coverage of these loci. We performed high-resolution typing of the 1000 Genomes Phase 3 panel across 13 HLA and MIC loci, generating HLA genotypes for 2,486 individuals, extended HLA-A, -B, and -C allele assignments, and MICA/MICB genotypes for 2,393 individuals representing 25 populations and five continental super-populations. Concordance with previously reported HLA genotypes was 96.2-97.4% at two-field resolution, and independent retyping confirmed the present assignments for samples exhibiting reciprocal genotype discrepancies with an earlier dataset. Analysis of extended class I variation within defined assay boundaries revealed that most of the 78 common three-field HLA lineages were dominated by a single extended sequence group. However, eleven lineages exhibited substantial heterogeneity, with the predominant group accounting for less than 80% of observed copies. The distinguishing sequence differences were noncoding, involving intronic and 3' untranslated regions, and their distributions varied among ancestral populations. These findings identify recurrent, population-relevant variants for which functional consequences remain to be established. Population analyses demonstrated extensive allelic diversity at classical class I loci and DRB1, whereas the greatest between-population differentiation occurred at selected class II and DRB-linked loci. Most common alleles were shared among populations but differed substantially in frequency. Multilocus haplotypes revealed characteristic population-associated combinations of HLA and MIC alleles and provided the basis for predicting MIC genotypes from existing HLA typing. Using two-field HLA-B and HLA-C genotypes, five-fold cross-validation achieved exact genotype prediction accuracies of 77.3% for MICA and 53.6% for MICB, compared with 4.6% and 21.6%, respectively, without HLA information. Together, these results provide an extended-resolution HLA and MIC reference resource, demonstrate the limited routine utility of universal fourth-field typing while identifying specific variants for functional investigation, and establish the potential for recovering MIC variation from existing HLA-typed cohorts. The resource also supports future investigations of MHC variation underlying disease associations and transplantation outcomes.

genetics↗

bioRxiv2026

Technology solutions for immune loci: integrated high-resolution KIR genotyping reveals allelic, structural, and KIR-HLA diversity across 24 human populations

High-resolution genotyping of killer cell immunoglobulin-like receptor (KIR) genes remains challenging because of extensive sequence homology, copy-number variation, and complex haplotype structures. Although KIR allelic variation influences receptor expression and function, routine typing has largely been limited to gene presence or absence. Here, we evaluated an integrated short-read sequencing system combining a four-reaction, two-stage multiplex PCR assay (ScisGo-KIR-v3), centralized cloud-based copy-aware allele analysis, and interactive genotype review. The system was applied to 2,298 individuals representing 24 populations from the 1000 Genomes Project, with matched high-resolution HLA class I genotypes. Independent validation against complete, phased PacBio KIR sequences from 48 samples demonstrated 98.6% automated copy-number concordance and 92.8% combined copy-number and allele concordance across 768 gene-sample comparisons. Following desktop review, all evaluated assignments were concordant with the reference sequences. In a separate comparison of four computational genotyping methods involving 311 shared samples, the automated Scisco pipeline showed the lowest overall mismatch with the four-method consensus (1.62%). Population analyses identified substantial allele diversity and distinct centromeric and telomeric haplotype-motif distributions. Although exact haplotype pairs were frequently ambiguous, structural assignments became increasingly resolvable at the motif level, and motif backgrounds exhibited characteristic allele compositions. Paired KIR and HLA analysis revealed inherited receptor-ligand configurations concealed by gene-content typing. Among 1,401 KIR3DL1/HLA-B Bw4 co-carriers, 57 lacked an allele annotated for ordinary surface expression, while 457 of 1,175 KIR2DS4 co-carriers of six specified HLA-C allotypes carried only truncated receptor forms. Allele-specific KIR2DL1 and KIR2DS5 classifications further distinguished receptor properties and published ligand-binding annotations that varied among populations. Although potential receptor-ligand repertoire composition differed across populations, analyses did not establish preferential KIR-HLA genetic association after accounting for population structure and multiple testing. Together, these findings demonstrate that integrated short-read KIR genotyping can provide scalable, high-resolution allele and copy-number information while explicitly retaining uncertainty in inferred haplotype structures. Compatibility with established HLA laboratory workflows provides a practical foundation for incorporating allele-resolved KIR analysis into immunogenetic research and future clinical investigations.

genetics↗

bioRxiv2026

Metabolomics identifies endocannabinoid system remodeling during obesity associated inflammation in adipose tissue

Visceral white adipose tissue (vAT) is more susceptible than subcutaneous white adipose tissue (scAT) to obesity-associated metaflammation, but the metabolic pathways accompanying this depot specific transition remain incompletely defined. We profiled vAT and scAT from mice fed a control diet or a 60% kcal high-fat diet (HFD) for 1 or 8 weeks. Untargeted metabolomics was integrated with targeted endocannabinoid quantification, gene expression and promoter associated chromatin analyses, adipocyte and stromal vascular fraction (SVF) measurements, cross-omics correlation analysis, and cell-culture perturbations. After 1 week, HFD induced relatively few metabolic changes, although vAT showed early alterations associated with sphingomyelin metabolism. By week 8, both depots exhibited extensive but distinct metabolic remodeling. The KEGG retrograde endocannabinoid-signaling pathway was the highest-ranked enriched pathway in vAT, with arachidonoylglycerol (2AG) among the most strongly altered metabolites. Targeted analysis confirmed selective 2AG accumulation in vAT, accompanied by coordinated changes in genes and promoter-associated chromatin marks related to endocannabinoid synthesis, degradation and receptor expression. Cellular fractionation localized excess 2AG predominantly to vAT adipocytes, whereas Cnr2 was enriched in the SVF and induced by HFD specifically in vAT. Cross omics integration further revealed a denser and predominantly inverse transcript metabolite association network in vAT than in scAT. Using macrophage adipocyte co-culture and secretome profiling, we demonstrated that cannabinoid stimulation shifts activated macrophage outputs away from pro-inflammatory cytokines (Il1b, Ccl2) toward extracellular matrix (ECM) proteoglycan remodeling and intercellular signaling.

molecular biology↗

bioRxiv2026

Topotecan Syndergizes with SP141 in the Management of Uveal Melanoma

Purpose: Uveal melanoma (UM) is a rare but aggressive intraocular malignancy originating in the uvea (choroid, iris, and ciliary body). Despite primary treatment, 50% of UM patients develop metastases to the liver, lungs, bones, and skin. Topotecan, a topoisomerase I inhibitor, and SP141, an MDM2 inhibitor, have been studied in cancers, including retinoblastoma. This study explores a combined approach with these drugs in the 92-1 UM cell line. Methods: Primary choroidal melanoma-derived 92-1 cells were treated with topotecan and SP141 individually to determine IC50 values. Cell viability and proliferation were assessed using the MTT assay and the xCELLigence real-time monitoring system. The synergistic effects were analyzed quantitatively using the Loewe Additivity and Highest Single-Agent (HSA) models. Flow cytometry was employed to analyze cell cycle distribution, while cell death and apoptosis were monitored via high-throughput, real-time quantitative analysis using the IncuCyte live-cell kinetic imaging system. Results: Both Topotecan and SP141 induced significant cell death in 92-1 cells. xCELLigence showed dose- and time-dependent inhibition of proliferation. Combining sub-IC50 concentrations of topotecan and SP141 exhibited significant synergistic effects, markedly reducing growth. Cell cycle analysis revealed that topotecan causes a dose-dependent biphasic arrest in G2 and S phases, while SP141 causes G2/M arrest, leading to cell death. Cytotoxicity assays corroborated increased cell death following combination therapy, and the Caspase 3/7 assay indicated that apoptosis is the mechanism underlying cell death. Conclusions: The multi-targeted approach combining topotecan and SP141 drugs demonstrated synergistic therapeutic effects in 92-1 cells, suggesting a potential treatment strategy for managing UM.

cancer biology↗

bioRxiv2026

Resolving context-specific protein-protein interactomes forbiological discovery and therapeutic target prioritisation

Protein function is shaped by cellular context, yet most protein representations and interaction maps remain context-agnostic. Here we present ProtScape, a multiscale graph-learning framework integrating global protein interactions, cell-type gene expression and protein language models to learn context-specific representations and infer interactomes across more than 200 cell types. ProtScape substantially outperforms existing approaches in interaction reconstruction, increasing the area under the precision-recall curve by 40 percentage points. Its predicted interactions were supported by held-out continuous STRING global evidence, while its representations recovered higher-order protein organisation. In patient-derived amyotrophic lateral sclerosis motor neurons, ProtScape revealed stage-specific network changes implicating RAB-dependent trafficking as a candidate early disease mechanism. In Parkinson's disease, it recovered clinically supported therapeutic targets from a proteome-wide search space 16-fold smaller than that required by competing representations. Together, ProtScape provides a scalable framework for translating context-specific interactome organisation into experimentally testable disease mechanisms and therapeutic hypotheses.

bioinformatics↗

bioRxiv2026

Single-cell metabolomics reveals infection-specific metabolic reprogramming of human macrophages

During intracellular infection, host cells adopt different metabolic states that traditional bulk analyses cannot distinguish. Using single-cell spatial metabolomics of human macrophages infected with Legionella pneumophila, we show that bacterial uptake activates host metabolism, whereas the bacterial effectors secreted through the type IV secretion system counteract this response and promote a glycolytic shift. The activity of effectors also generates distinct metabolic states within the infected macrophage population.

microbiology↗

bioRxiv2026

The QxxR Motif of RNA Helicase Me31B Is Essential for Drosophila Female Fertility and Germline Development

The QxxR motif is evolutionarily conserved within DEAD-box RNA helicases, including Drosophila Me31B and human DDX6, which post-transcriptionally regulate gene expression during animal development. A pathogenic H372R substitution (QxHR to QxRR) in the QxxR motif of human DDX6 has been associated with various developmental defects, but how this motif contributes to DDX6-family protein function remains unclear. Here, we used Drosophila Me31B as an in vivo model to investigate the QxxR motifs developmental role. We generated a Drosophila strain carrying the corresponding H333R missense mutation in Me31B and characterized its effects on female fertility, embryonic viability, germline development, and Me31B-associated molecular pathways. The me31BH333R mutation reduced female fertility in a gene dose-dependent manner, with homozygous mutant females being sterile. Embryos from the mutant females also exhibited primordial germ cell defects. Despite these developmental phenotypes, the me31BH333R mutation did not significantly alter Me31B protein abundance, global ovarian transcriptome or proteome profiles, or representative germ plasm mRNA and protein localization. In contrast, bait-normalized IP-MS analysis revealed altered enrichment of selected Me31B-associated proteins, including increased association of known Me31B interactors Trailer hitch (Tral) and Ypsilon Schachtel (Yps). These findings establish Me31BH333R as an in vivo model for investigating the conserved QxxR motif and suggest that disruption of this motif compromises development not through broad changes in gene expression, but potentially through altered composition or regulation of Me31B-containing ribonucleoprotein complexes.

genetics↗

bioRxiv2026

A genetically encoded RhoG FRET biosensor reveals spatially compartmentalized RhoG-Rac1 signaling during cell protrusion

RhoG is a member of the Rho-family of small GTPases, and is closely related to the canonical Rac1 GTPase, implicated in membrane trafficking, dorsal ruffling, macropinocytosis, and cell protrusion, but its activity has been difficult to visualize directly in living cells with high spatial and temporal resolution. Here, we developed and validated a genetically encoded, single-chain Forster resonance energy transfer (FRET) biosensor for RhoG based on a C-terminal full-length RhoG and an intramolecular RhoG-binding domain derived from ELMO1. The biosensor showed a robust dynamic range when comparing constitutively active and inactive RhoG mutants, responded appropriately to regulation by RhoGDI, GAPs, and GEFs, and detected growth factor-stimulated RhoG activation in live cells. Imaging in mouse embryonic fibroblasts revealed dynamic RhoG activation at leading-edge protrusions, dorsal ruffles, and forming pinocytic and macropinocytic structures. To define the signaling relationship between RhoG and its closely related family member Rac1, we combined the RhoG biosensor with a near-infrared Rac1 FRET biosensor for simultaneous live-cell imaging. Morphodynamic mapping showed that both RhoG and Rac1 activities were positively coupled to edge protrusion, with strongest correlations near the leading-edge, but their direct coupling varied with distance from the edge, indicating partial spatial decoupling within protrusive regions. Inhibition of Src-family kinases altered RhoG dynamics, strongly suppressed Rac1 coupling to protrusion, and inverted the normal positive correlation between RhoG and Rac1 activities. Signaling microdomain analysis further showed that Src inhibition selectively prolonged Rac1 microdomain lifetimes without significantly affecting RhoG domains. Together, these results establish a new biosensor for direct visualization of RhoG activity and reveal that RhoG and Rac1 are coordinated but spatially and temporally distinct components of protrusion-associated signaling networks, with Src-family kinases playing a central role in maintaining their normal coupling.

cell biology↗

bioRxiv2026

Spatially Organized Tertiary Lymphoid Structures Emerge in Small Cell Lung Cancer and Associate with Improved Survival

Tertiary lymphoid structures (TLS) are ectopic immune aggregates associated with improved prognosis and response to immunotherapy in multiple solid tumors. However, their presence, spatial organization, and functional relevance in small cell lung cancer (SCLC), a malignancy characterized by profound immune evasion, remain poorly understood. Using imaging mass cytometry (IMC) across 320 regions of interest spanning primary lung tumor, tumor-adjacent lung, liver and lymph node metastasis, complemented by Visium HD spatial transcriptomics, we characterized the cellular architecture and molecular programs of TLS-like niches in SCLC. TLS-like niches were identified in a subset of SCLC samples, predominantly primary lung tumor tissues and adjacent lung, spanning a continuum from loose lymphoid aggregates to compact follicle-like immune structures. Organized TLS-like niches contained CD20+ B-cell cores, closely associated with CD4+ and CD8A+ T cells, proliferating lymphocytes, HLA-DR+ antigen-presenting compartments, and SMA+ stromal scaffolds, and were enriched for canonical TLS organizer signals (CXCL13, LTB, FDCSP). Patients with TLS-positive tumors demonstrated improved overall survival, and core TLS-associated transcriptional programs were associated with favorable survival in an independent bulk RNA-seq cohort. To our knowledge, this represents one of the first spatially resolved analyses of TLS-like immune architecture in SCLC, demonstrating that organized lymphoid immunity can emerge in this classically immune-evasive disease and is associated with improved survival.

cancer biology↗

bioRxiv2026

Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer

BackgroundSmall-cell lung cancer (SCLC) is characterized by pervasive chromosomal instability (CIN) and remains largely refractory to targeted therapies. KIF18A, a motor protein that regulates chromosome alignment during mitosis, has emerged as a selective dependency in CIN-high tumors. Whether this dependency extends to SCLC, a prototypical CIN-high cancer, has not been established, and biomarkers predicting response to KIF18A inhibition, currently in clinical trials, are lacking. MethodsWe integrated analyses of patient tumor datasets, neuroendocrine (NE) and non- NE SCLC cell lines, and functional perturbation models to define the determinants of response to KIF18A inhibition. Chromosomal instability metrics, transcriptional programs, mitotic dynamics, and spindle assembly checkpoint (SAC) function were assessed using genomic profiling, live-cell imaging, genetic perturbation, and pharmacologic inhibition. ResultsKIF18A expression was elevated in SCLC tumors and correlated with CIN-associated transcriptional programs, proliferative markers, and NE status; however, these features did not predict sensitivity to KIF18A inhibition. Instead, response was determined by the functional integrity of the SAC. SAC-proficient SCLC cells underwent sustained mitotic arrest followed by apoptotic cell death upon KIF18A inhibition, whereas SAC-defective cells failed to maintain checkpoint activation and survived. Mechanistically, resistant cells exhibited impaired kinetochore recruitment of core SAC components, including MAD1 and BUBR1. Importantly, transient induction of acute CIN through MPS1 inhibition partially restored sensitivity to KIF18A inhibition in resistant models. ConclusionsThis study provides the first mechanistic characterization of KIF18A dependency in SCLC, identifying SAC competency as the primary determinant of response. These findings establish a biologically informed framework for patient stratification and rational combination strategies. Translational RelevanceSmall-cell lung cancer (SCLC) is an aggressive malignancy with few effective targeted therapies and marked chromosomal instability. KIF18A has emerged as a potential therapeutic target in genomically unstable cancers, but biomarkers predicting response to KIF18A inhibition are lacking. We demonstrate that sensitivity to KIF18A inhibition in SCLC is determined not by KIF18A expression, neuroendocrine subtype, or baseline chromosomal instability, but by the functional integrity of the spindle assembly checkpoint (SAC). SCLC cells with intact SAC signaling undergo sustained mitotic arrest and apoptosis upon KIF18A inhibition, whereas SAC-defective cells bypass checkpoint activation and survive aberrant mitosis. Notably, transient induction of acute chromosomal instability through MPS1 inhibition partially restores sensitivity in resistant models. Together, these findings identify mitotic checkpoint competency as a mechanistic determinant and candidate predictive biomarker for KIF18A-targeted therapies, providing a biologically informed framework for patient stratification and rational combination strategies relevant to ongoing KIF18A inhibitor clinical trials.

cancer biology↗

bioRxiv2026

Tumor-hepatocyte crosstalk drives a hepatic lactate-TGF-β axis of CD8⁺ T cell exhaustion and immunotherapy resistance in small-cell lung cancer liver metastases

PurposeLiver metastases confer poor outcomes and attenuate the benefit of immunotherapy across solid tumors. This study investigated how the hepatic metastatic niche promotes CD8 T cell dysfunction and immunotherapy resistance in small-cell lung cancer (SCLC). Experimental DesignClinical outcomes and tumor gene expression were integrated with multi-region single-cell RNA sequencing of T cells from rapid-autopsy SCLC metastases, together with spatial transcriptomics. SCLC-hepatocyte conditioned-media models were combined with stable-isotope tracing, mass spectrometry, functional and metabolic assays, and ChIP-qPCR to define mechanisms of CD8 T cell suppression. ResultsLiver metastases were associated with inferior survival and reduced benefit from immune checkpoint blockade. Multi-region single-cell analysis showed that CD8 T cells from liver metastases exhibited an exhaustion-associated state enriched for hypoxia, lactate, and TGF-{beta} programs. SCLC-hepatocyte crosstalk generated a lactate- and TGF-{beta}-rich microenvironment that reduced CD8 T cell effector function, proximal T cell receptor signaling, glycolytic fitness, viability, and proliferation. Stable-isotope tracing demonstrated transfer and accumulation of co-culture-derived lactate in recipient CD8 T cells, with limited entry into downstream pyruvate-linked pathways. Lactate accumulation was accompanied by increased H3K18 lactylation at the PDCD1, LAG3, and TGFB1 regulatory loci. In parallel, SCLC-hepatocyte crosstalk increased paracrine TGF-{beta} and activated canonical SMAD2 signaling in CD8 T cells. TGF-{beta} receptor inhibition restored CD8 T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-{beta} transcriptional program was associated with inferior survival, most strongly in patients with liver metastases. ConclusionsTumor-hepatocyte crosstalk generates convergent lactate and TGF-{beta} signals that drive CD8 T cell dysfunction in liver metastases. This hepatic immune-metabolic circuit provides a potential mechanism for immunotherapy resistance and supports therapeutic strategies targeting TGF-{beta} signaling in liver-metastatic SCLC. Translational RelevancePatients with SCLC liver metastases have poor outcomes and derive limited benefit from immune checkpoint blockade, but actionable mechanisms of hepatic immune resistance remain undefined. We identify an immune-metabolic circuit in which SCLC-hepatocyte crosstalk generate lactate and TGF-{beta} signals that converge on CD8 T cells. Stable-isotope tracing demonstrates the transfer and accumulation of tumor-hepatocyte-derived lactate in recipient T cells, which causes H3K18 lactylation at exhaustion- and TGFB1-associated loci. In parallel, paracrine TGF-{beta} activates canonical SMAD signaling and reinforces proliferative dysfunction. TGF-{beta} receptor inhibition restores CD8 T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-{beta} program is associated with inferior survival, particularly among patients with liver metastases. These findings provide a mechanistic and biomarker framework for testing TGF-{beta}-directed strategies in liver-metastatic SCLC, a population with substantial unmet clinical need.

cancer biology↗

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

Safety profiling of CAR-T cells using an organotypic human tissue platform

CAR-T-cell-associated on-target off-tumor (OTOT) toxicity represents a major safety concern, as recognition of target antigens on healthy tissues can trigger severe and potentially life-threatening complications. Predicting OTOT toxicity remains a challenge because current preclinical models fail to capture the complexity of native human tissues. Here, we developed a human organotypic tissue platform that enables functional assessment of CAR-T-cell activity in intact human tissues across organ-specific and inflammatory contexts. Using a panel of clinically relevant CAR-T-cell products with known OTOT toxicities, we demonstrate that the platform faithfully recapitulates clinically observed tissue-specific toxicity profiles. CAR-T cells targeting EGFR, HER2, and mesothelin induced inflammatory and cytotoxic responses in healthy human lung tissue, whereas CD19 CAR-T cells remained inactive. We further show that OTOT toxicity cannot be reliably predicted from antigen abundance alone but instead results from the integration of multiple target-dependent determinants, including CAR affinity, inflammatory context, antigen accessibility, and effector-cell dose. The platform also enables quantitative assessment of inflammatory and cytotoxic responses and supports evaluation of pharmacological and CAR design-based strategies to mitigate toxicity. Together, this work establishes the first human organotypic platform for functional modeling of CAR-T-cell-associated OTOT toxicity, providing a clinically relevant framework for preclinical safety evaluation and the rational development of safer engineered cell therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/740527v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@12c8addorg.highwire.dtl.DTLVardef@150d392org.highwire.dtl.DTLVardef@17218f7org.highwire.dtl.DTLVardef@1c54078_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Who Funds Open Data Sharing? Analysis of data availability statements in biomedical publications

Open data sharing is increasingly mandated by research funders, journals, and institutions, yet large-scale compliance measurement remains challenging. We analyzed 951,949 open access biomedical research articles published between January 2024 and June 2025 using a dual-source pipeline: PDF-based text extraction (MinerU) where PDFs were available and PMC XML otherwise, followed by algorithmic detection of data sharing statements (oddpub v7.2.3), enriched with funder, journal, and institutional metadata from OpenAlex. The corpus included 294,172 PDF-covered articles (30.9%) and 657,777 XML-only articles (69.1%). We found an over-all open data rate of 8.7%, rising to 11.7% among funder-linked articles (those with at least one funder identified in the metadata). Rates varied more than tenfold across the research ecosystem: leading major funders reached observed open data rates of 20-24%, while top journals reached observed rates of 70-86%, with corrected estimates as high as 92.9% (Nature Genetics) after adjusting for XML-only coverage limitations. PDF-based detection identified approximately 52% more data sharing statements than XML-based methods on the same articles. These observed rates differ markedly across funders and journals, and current overall sharing remains far below universal compliance. These patterns provide an empirical baseline against which future policy changes can be measured. An interactive dashboard at https://www.opensciencemetrics.org enables stakeholders to explore and benchmark these results.

scientific communication and education↗

bioRxiv2026

Ebola virus exploits host lncRNA LINC01740 to enhance ATF3 and suppress antiviral immune responses

Ebola virus (EBOV) infection causes severe hemorrhagic fever marked by dysregulated cytokine production, impaired antiviral defenses, and multi-organ failure. Macrophages are primary targets of EBOV, and viral replication profoundly alters macrophage transcriptional programs, driving hyperinflammation. Although long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of immunity and viral pathogenesis, their roles in EBOV infection remain poorly understood. We performed comprehensive transcriptomic profiling of primary human monocyte-derived macrophages infected with the highly pathogenic EBOV Mayinga variant. Infection triggered extensive remodeling of both coding and non-coding transcriptomes, including hundreds of differentially expressed lncRNAs. Functional analysis of neighboring protein-coding genes of EBOV-induced lncRNAs (EVILs) revealed enrichment of pathways linked to cytokine signaling, transcriptional regulation, and cell signaling, all of which are central to Ebola virus disease (EVD) pathogenesis. Among the most strongly induced EVILs, LINC01740 and its neighboring protein-coding gene, Activating Transcription Factor 3 (ATF3), were significantly upregulated. Antisense oligonucleotide-mediated inhibition of LINC01740 reduced ATF3 mRNA and protein levels. CRISPR/Cas13d-mediated knockdown of ATF3 restored type I interferon (IFN-I) signaling and antiviral gene expression in EBOV-infected macrophages. Mechanistically, ATF3 functions as a negative regulator of IFN-I and type I interferon-stimulated gene expression, thereby suppressing antiviral immune responses in EBOV-infected macrophages. Together, these findings identify a previously unrecognized LINC01740-ATF3-IFN-I regulatory axis that EBOV exploits to promote immune suppression and viral replication.

immunology↗

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2026

Passive Acoustic Monitoring within the Northwest Forest Plan Area: 2025 Annual Report

The Northwest Forest Plan (NWFP) Passive Acoustic Monitoring (PAM) program is a large-scale interagency biodiversity monitoring framework designed to assess the status and trends of northern spotted owls (Strix occidentalis caurina), barred owls (Strix varia), marbled murrelets (Brachyramphus marmoratus), and broader forest biodiversity across federally administered lands in the Pacific Northwest. In 2025, we deployed autonomous recording units at 2,095 sampling stations within 532 5-km2 hexagons randomly selected across approximately 24 million acres of federal forest lands in Washington, Oregon, and California. These deployments generated 1.37 million hours of acoustic recordings that we processed using the convolutional neural network PNW-Cnet v5 for automated species identification and subsequent human validation of focal species detections. Northern spotted owls were detected in 28% of sampled hexagons range-wide, including 16% in Washington, 25% in Oregon, and 60% in California. Occupancy patterns remained consistent compared to previous years, with higher occupancy concentrated in southern portions of the geographic range and continued low occupancy across much of the Washington Cascades and Oregon Coast Range. Barred owls were detected in 86% of sampled hexagons and remained broadly distributed throughout most of the NWFP area. Marbled murrelets were detected in 50% of reviewed hexagons within NWFP marbled murrelet management zones, with highest occupancy occurring in coastal forests of Oregon and Washington. The 2025 field season occurred under substantial operational constraints that reduced sampling effort by approximately half relative to 2023 and 2024 because of staffing limitations affecting participating federal agencies. Despite these reductions, the NWFP-PAM framework continued to provide broad-scale, spatially representative ecological information across the NWFP area. Results highlight the growing importance of passive acoustic monitoring and machine learning approaches for long-term biodiversity monitoring under changing environmental and operational conditions.

ecology↗

bioRxiv2026

Age Dependent Immunopathology Drives Pneumonia-Associated Cardiac Dysfunction During Streptococcus pneumoniae Infection

Aging is a major risk factor for severe Streptococcus pneumoniae (Spn) infection and pneumonia-associated - major adverse cardiac events (PA-MACE), yet underlying mechanisms remain unclear. Using young and aged murine models, we show that aging exacerbates bacterial burden, mortality, and cardiac dysfunction following Spn infection, associated with impaired macrophage bacterial killing. Single-cell RNA sequencing infected hearts revealed extensive age-dependent remodeling across immune and stromal compartments. Aged mice exhibited heightened pro-inflammatory myeloid responses, with increased neutrophil infiltration characterized by elevated S100A8/9 and LCN2 and reduced antimicrobial programs. Macrophages displayed defective efferocytosis, including disruption of the GAS6-AXL axis. Aging also drove expansion of an infection-responsive fibroblast population with inflammatory signatures and reduced extracellular matrix gene expression. These changes were linked to oxidative stress and impaired glucose oxidation. Notably, anti-inflammatory treatment rescued cardiac dysfunction, implicating excessive inflammation as a central driver of PA-MACE. Together, these findings define mechanisms linking aging to pneumococcal cardiac complications and identify potential therapeutic targets.

immunology↗