Biology subjects

Zhou, H.

Publications and source records attributed to Zhou, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Somatic-to-germline transmission of horizontally acquired extrachromosomal circular DNA in Brassica graft chimeras

Whether somatically acquired traits can contribute to heritable variation has remained an open question in plant biology for over a century. Here, using graft-induced periclinal chimeras between Brassica juncea and Brassica oleracea, we identified extrachromosomal circular DNA (eccDNA) as mobile genetic elements capable of crossing histological boundaries and entering the germline. We demonstrated that grafting could promote the horizontal transfer of eccDNA between somatic cell layers, enabling its stable maintenance in recipient tissues and permitting transmission through sexual reproduction across multiple generations. We found that transmitted eccDNA is non-randomly distributed across the genome, preferentially originating from gene-dense regions, and enriched for features associated with molecular persistence, such as inverted repeats, hairpin-forming sequences, and autonomously replicating sequence (ARS) consensus motifs. These genetic regions conferred replication competence, as evidenced by autonomous propagation in an ARS-less heterologous yeast system. Sexual progeny carrying graft-acquired eccDNA exhibited reproducible and lineage-dependent alterations in leaf morphology and drought tolerance, accompanied by coordinated transcriptional reprogramming. Notably, a subset of inherited eccDNA remained transcriptionally active in progeny, producing transcripts absent from self-grafted controls. Our findings establish eccDNA as heritable extrachromosomal elements that link graft-mediated somatic genetic transfer with stable germline transmission, thereby expanding the molecular scope of heritable variation in plants and providing a conceptual framework for graft-based trait transmission.

plant biology↗

bioRxiv2026

Understanding Substance Dependence: What Differentiates Addictive from Non-Addictive Drugs?

Addiction is a global health challenge, yet the molecular features that distinguish addictive from non-addictive drugs remain incompletely understood at the pathway and circuit levels. Here, we present a systematic computational framework that integrates drug-target binding predictions (provided by FINDSITEcomb2.0) with brain-region-specific protein expression to compare addictive and non-addictive compounds. We analyzed 457 addictive and 1,774 non-addictive blood-brain barrier permeable drugs and mapped their predicted targets and associated pathways onto proteins expressed across 120 addiction-relevant brain regions. This analysis reveals widespread convergence between the two classes (addictive and non-addictive drugs) on shared molecular pathways, accompanied by distinct patterns of target and pathway engagement. Functional annotation of differentially engaged targets highlights biases toward plasticity-associated components for addictive drugs. In contrast, non-addictive drugs interact with both plasticity-associated proteins and proteins within the same molecular complex that have addiction suppression, regulatory, and homeostatic functions. Notably, both target classes co-localize within the same addiction-relevant circuits and form an integrated protein-protein interaction network. Together, these results define a differential engagement landscape that links chemical interactions to pathway-level utilization in the brain, revealing molecular features associated with differences in addiction propensity. Significance StatementAddiction is a global health crisis, yet the molecular features that distinguish addictive from non-addictive drugs remain poorly defined. By systematically comparing drug-target and pathway engagement across shared addiction-relevant brain circuits, this study identifies distinct signatures in which addictive compounds preferentially engage plasticity- and stress-associated targets, while non-addictive compounds engage these as well as addiction suppression, regulatory, transport, and metabolic pathways. These results provide a circuit- and pathway-level framework for interpreting addiction liability and guiding the design of safer therapeutics.

biophysics↗

bioRxiv2026

AM-DMF-SCP-pro: An Ultrafast and Streamlined Nanolitre-Scale Lab-on-a-Chip Platform for Single-Cell Proteomics and Tumor Microenvironment Profiling

Single-cell proteomics (SCP) remains constrained by slow sample preparation and background interference in low-input, multistep workflows, limiting its broader practical use in complex biological samples. Here we report AM-DMF-SCP-pro, a streamlined active-matrix digital microfluidic workflow that enables rapid on-chip lysis and digestion in 6 nL droplets within a closed nanolitre-confined microenvironment. AM-DMF-SCP-pro reduces total sample-preparation time to as little as 30 min, including a 15 min digestion step, while maintaining quantitative reproducibility and digestion performance. Systematic optimization of mass spectrometry acquisition and nanolitre-scale digestion conditions enables deeper, more sensitive and lower-background proteome profiling from ultra-low peptide inputs. In murine tumor samples, AM-DMF-SCP-pro reliably resolves immune and tumor compartments, identifies treatment-associated tumor cell states and enables quantitative analysis of neutrophil-associated proteomic signatures. These results establish AM-DMF-SCP-pro as a practical workflow for rapid, low-background single-cell proteome profiling in complex biological samples.

systems biology↗

bioRxiv2026

Diagnosing protein sequence search in the era of language models

Protein language model (PLM) based search is rapidly emerging as a successor to classical sequence alignment, with recent high-profile studies reporting substantial improvements in speed and remote homology detection. However, success on standard benchmarks does not guarantee that similarity derived from PLM embeddings constitutes reliable biological evidence. Here, we introduce PLM-GUARD, a diagnostic framework designed to interrogate the underlying meaning of protein search scores and assess their biological trustworthiness. PLM-GUARD comprises six sanity checks spanning biological fidelity, semantic validity, and manipulation safety. Across eight representative search methods, classical alignment-based systems demonstrate remarkable robustness, whereas current PLM-based methods fail broadly across all three dimensions. Notably, hybrid methods show intermediate results, indicating that alignment is still critical for ensuring biologically grounded correspondence. Our findings provide a timely clarification for the field and underscore the necessity of diagnostic evaluation as protein search enters the era of language models.

bioinformatics↗

bioRxiv2026

Global Acetylome Profiling Reveals Extensive Lysine Acetylation in Acinetobacter baumannii Bacteriophage Proteins

Post-translational modifications (PTMs) are increasingly recognized as potential regulators of bacteriophage-host interactions, yet their functions remain largely undefined. Here, we present the first proteome-wide characterization of lysine acetylation in a bacteriophage, using Acinetobacter baumannii myovirus vB_AbaM_DLP3 as a model to investigate host-imposed modification during infection. An optimized proteomic workflow that eliminates chemical artifacts and improves peptide identification accuracy enabled detection of 86 acetylated proteins, representing nearly one-third of the DLP3 proteome. Comparative analysis of purified virions and infected host cells revealed distinct acetylation profiles, consistent with host-driven, transient modifications that are removed or lost after lysis. Functional annotation showed that acetylation predominantly targets proteins involved in DNA replication, genome packaging, and structural assembly. Structural modeling of the major capsid and replication-associated proteins demonstrated that acetylation neutralizes positive surface charges, potentially weakening DNA binding and intercapsomer interactions critical for replication and capsid cohesion. Together, these findings establish lysine acetylation as a widespread and dynamic feature of phage infection and identify host-imposed acetylation as a potential regulatory mechanism that modulates phage replication, assembly, and infectivity. This work expands the molecular framework of phage-host interactions, providing a foundation for future studies aimed at understanding how bacterial PTMs influence phage function and for engineering phages resistant to host-mediated inhibition. ImportanceBacteriophages are being developed as alternatives to antibiotics, yet little is known about how bacterial hosts chemically modify phage proteins during infection. This study reveals that A. baumannii imposes extensive lysine acetylation on its infecting phage DLP3, affecting proteins involved in DNA replication and structural assembly. By demonstrating that acetylation neutralizes positive surface charges and is largely absent after phage release, this work identifies host-driven acetylation as a previously unrecognized, reversible mechanism that may influence phage infectivity. Understanding how bacteria use post-translational modifications to interfere with phage function provides new insight into phage-host molecular interactions and informs strategies for engineering therapeutic phages resistant to host-imposed inhibition.

microbiology↗

bioRxiv2026

Prpf8N1531S homozygous mutant mouse embryos have multiple defects in cardiac development and show aberrant splicing of the cardiac transcription factor Tead1

Mutations in the spliceosomal gene PRPF8 are associated with a range of human diseases. Studies in mouse and zebrafish suggest that Prpf8 also has a developmental function. Here, using a Prpf8 mutant mouse line isolated from a chemical induced mutagenesis screen, we uncover a previously unrecognised and essential role for Prpf8 in heart development, consistent with the embryonic lethality observed in Prpf8N1531S homozygous mutants. Prpf8N1531S mutant embryos display severe defects in ventricular trabeculation and compact zone formation, accompanied by increased cardiomyocyte proliferation specifically in the compact zone. Mutant embryonic hearts also exhibit disrupted cellular organisation, altered cytoskeletal architecture and changes in extracellular matrix protein expression. Notably, these cardiac abnormalities were exacerbated in embryos exhibiting cardiac looping defects. Transcriptomic analysis identified multiple aberrantly spliced transcripts in Prpf8N1531S mutant embryos, among which the cardiac transcription factor Tead1 was selected as a key functional candidate due to it known role in cardiac ventricle wall developemnt. Tead1 mis-splicing generated an in-frame, lower molecular weight protein isoform, associated with reduced overall TEAD1 expression. The Tead1 mis-spliced isoform showed altered nuclear localisation and dysregulation of TEAD1-dependent gene network important for heart development, including known cardiac sarcomeric genes. In addition, we observed reduced levels of the intracellular domain of the NOTCH1 receptor (NICD1), indicating impaired Notch signalling.. These findings suggest that impaired TEAD1-dependent transcription and Notch signalling contribute to abnormal cardiac trabeculation and compact zone development, highlighting a critical role for Prpf8 in maintaining proper heart development through the regulation of cardiac transcription factor expression and associated signalling networks. This study offers new mechanistic insights into congenital heart diseases linked to spliceosomal gene mutations.

developmental biology↗

bioRxiv2026

Enforced ZFP281 expression delays breast cancer initiation and can provide lifelong protection against breast cancer metastasis

Breast cancer metastatic reactivation and its links to mammary development are largely unknown. Here, using conditional knockout and overexpression in normal and HER2+ mammary glands, we show that the dormancy regulator ZFP281 promotes branching and dissemination while suppressing growth, and its overexpression can even override HER2-driven cancer initiation. Notably, while ZFP281 does not limit HER2-driven early dissemination, it constrains DCC plasticity, confining cells to a dormant mesenchymal/hybrid-like state and effectively suppressing metastasis throughout the mouse lifespan. ZFP281 is induced by estrogen, progesterone, and glucocorticoid signaling, and RNA sequencing of early lesions revealed that it regulates glutathione metabolism and ferroptosis, potentially supporting fitness during dormancy, while repressing angiogenesis, Th17-like inflammation, innate immune genes, and pro-inflammatory programs that might otherwise trigger awakening. Integrating these findings with human data, we show that DCIS and IBC (invasive breast cancer) lesions that later relapse are selectively enriched for ZFP281-regulated M-like and dormancy signatures and, after pregnancy, depleted for a ZFP281-induced stress-autophagy module, indicating that erosion or imbalance of these programs marks lesions that seed DCCs with higher reactivation potential. We propose that ZFP281 acts as a hormone-regulated dormancy gatekeeper that uncouples dissemination from growth, enforcing a metabolically fit, angiogenesis-low, immune-evasive dormant state in breast DCCs, thereby shaping the timing of metastatic relapse and potentially exploitable for durable prevention of metastasis. STATEMENT OF SIGNIFICANCEZFP281, a hormone-regulated dormancy gatekeeper, uncouples dissemination from growth and constrains DCCs into long-term arrest, defining human gene signatures that distinguish dormancy-prone from awakening-prone lesions and predict breast cancer relapse dynamics.

cancer biology↗

bioRxiv2026

MTB-KB: A Curated Knowledgebase of Mycobacterium tuberculosis Related Studies

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), has regained its position as the worlds leading killer among infectious diseases. Despite extensive research progress across epidemiology, diagnosis, drug development, treatment regimens, vaccines, drug resistance, virulence factors, and immune mechanisms, MTB-related knowledge remains fragmented across thousands of publications, limiting its effective use. To address this gap, we present MTB-KB, a literature-curated knowledgebase that systematically integrates high-impact findings from eight major sections of TB research. The current release contains 75,170 associations from 1,246 publications, covering 18,439 entities standardized using authoritative databases and WHO-endorsed classifications. A central feature is the interactive knowledge graph, which links cross-section associations to reveal and infer MTB-host interactions, treatment strategies, and vaccine development opportunities. MTB-KB also provides a user-friendly interface with browsing, advanced search, and statistical visualization. Overall, by consolidating dispersed MTB knowledge into a structured and accessible platform, MTB-KB provides a valuable resource for researchers, clinicians, and policymakers, supporting both basic and clinical TB research, enabling evidence-based TB prevention, diagnosis, and treatment, and contributing to global elimination efforts. MTB-KB is accessible at https://ngdc.cncb.ac.cn/mtbkb/.

bioinformatics↗

bioRxiv2026

A multi-omic atlas in the African turquoise killifish reveals increased glucocorticoid signaling as a hallmark of brain aging

Aging is the leading risk factor for cognitive impairment and neurodegeneration, yet molecular changes that unfold in the brain over time, and how they drive this vulnerability, remain unclear. The naturally short-lived African turquoise killifish (Nothobranchius furzeri) offers a powerful model to understand brain aging on an accelerated timescale and test the impact of potential interventions. Here, we present a multi-omic atlas of brain aging of female and male African turquoise killifish from 2 independent genetic strains of different captive lifespans, encompassing single-nuclei RNA-seq, single nuclei ATAC-seq, and bulk ATAC-seq to capture transcriptional and regulatory changes. Interestingly, our atlas indicates that aging leads to a significant expansion of microglia numbers, regardless of sex or strain, which we independently validate using in-situ hybridization. In addition, we identify robust and conserved gene regulation changes, that are consistent with activation of glucocorticoid signalling as a hallmark (and potential driver) of vertebrate brain aging. Furthermore, pharmacological inhibition of glucocorticoid receptor activity starting at middle-age led to significant rescue of key molecular and cellular aging phenotypes. Thus, our study provides a powerful resource and framework to leverage the African turquoise killifish and rapidly uncover actionable pathways driving brain aging.

neuroscience↗

bioRxiv2026

Density-dependent facilitation of livestock by small mammal ecosystem engineers

Small mammals and large herbivores have co-evolved in grasslands for millions of years, yet how they interplay remains unclear. Although large herbivores can significantly affect the smaller ones, the reversal effect is largely unknown. On the Qinghai-Tibetan Plateau, plateau pikas (Ochotona curzoniae) are often considered pests that compete with livestock at high densities. Using field experiments, we show that the presence of pikas facilitates weight gains of yaks (Bos grunniens) by improving vegetation composition at a moderate density level. Compared to the pika-present treatment, pika removal dramatically increased cover of the poisonous Stellera forbs by two-fold, reducing the abundance and protein content of palatable grasses and sedges, yak foraging efficiency, and yak weight gain by up to 42%. Notably, we found a humped relationship between yak weight gains and pika burrow densities in the pika-present plots; the facilitative effect of pikas on yaks was highest at about 200 burrows/ha, but shifted to a competitive effect at pika densities exceeding 400 burrows/ha. These results provide the first empirical evidence that maintaining a moderate density of small mammalian herbivores can benefit growth performance of livestock by improving vegetation composition. Our study highlights the significance of moderate populations of ecosystem-engineering small mammals in sustaining pastoral productivity in rangelands.

ecology↗

bioRxiv2026

PROTAC internalization and target degradation require clathrin-mediatedendocytosis

Proteolysis-targeting chimeras (PROTACs) are emerging as potent tools for targeted protein degradation that overcome many of the limitations of traditional small molecule inhibitors. Yet how these hetero-bifunctional therapeutics enter cells remains a mystery. While passive diffusion is conventionally assumed, the bulky structure of PROTACs suggests that active transport may be required. Recently, the fatty acid transporter CD36 was identified as a key receptor for PROTACs. However, because the uptake mechanism of CD36 is itself unknown, how PROTACs enter cells remains a mystery. Here we show that PROTAC uptake and function require clathrin-mediated endocytosis. We uncover previously unrecognized clathrin adaptor-binding motifs in the CD36 C-terminus and use live-cell imaging to visualize the recruitment of both CD36 and PROTACs to sites of clathrin-mediated endocytosis on the cellular plasma membrane. Strikingly, disruption of clathrin assembly through either genetic or pharmacological means abolishes all detectable PROTAC-induced protein degradation, demonstrating that the clathrin pathway is required for the function of PROTACs that utilize diverse E3 enzymes against multiple targets. These results elucidate the molecular mechanism of PROTAC entry into cells, providing critical information for optimizing cellular uptake and response to targeted degraders.

pharmacology and toxicology↗

bioRxiv2026

A lateral linker histone binding mode scaffolds dinucleosome stacking in chromatin fibers

Linker histones are essential for chromatin compaction, yet how they contribute to higher-order fiber assembly remains poorly understood. Here, we determined cryo-electron microscopy structures of Arabidopsis dodeca-nucleosome fibers containing distinct H2A/H3 variants and linker histone H1.3, revealing a noncanonical binding mode that a laterally positioned H1.3 connects the acidic patch of one nucleosome and the DNA of the neighboring nucleosome, thereby scaffolding dinucleosomes into two-start chromatin fibers. This noncanonical binding mode is structurally conserved when H1.3 is replaced by Gallus gallus H5. Furthermore, incorporation of H2A.W and H3.3 further induces back-to-back fiber dimerization. Cryo-electron tomography and in vivo cross-linking mass spectrometry analyses support the physiological relevance of H1 lateral engagement. Our findings establish that linker histones act as active architectural scaffolds in higher-order chromatin organization.

molecular biology↗

bioRxiv2026

PHENOCAUZ: Linking Human Symptoms, Drug Side Effects and Efficacy to Their Molecular Causes Using Mendelian Disease Biology

Human diseases and adverse drug reactions are ultimately recognized through clinical symptoms, yet the molecular determinants of most symptoms remain unknown. To address this key issue, we present PHENOCAUZ, a computational framework that links symptoms to their causative proteins by integrating Mendelian phenotype-gene relationships with molecular features of proteins. Starting from symptom annotations derived from Mendelian phenotypes and their causal genes, PHENOCAUZ identifies biological pathways and processes associated with individual symptoms and trains a machine learning model to predict symptom-causing proteins beyond those currently implicated in Mendelian diseases. The approach is motivated by the hypothesis that if dysfunction of a protein produces a symptom in a Mendelian disorder, the same protein may contribute to the same symptom in a complex disease or cause drug toxicity. Benchmarking across 2,344 symptoms and 4,828 Mendelian proteins using leave-one-out cross-validation yielded an estimated precision of approximately 0.70 among the top predictions. Predicted symptom-protein relationships show strong pathway-level agreement with literature-curated symptom-protein associations, efficacious drug targets and disease mode-of-action proteins. PHENOCAUZ also enables practical applications including prediction of severe drug side effects and identification of candidate therapeutics for ovarian, prostate, and breast cancers as well as noncancer diseases such as dementia and Crohns disease. These results demonstrate that Mendelian disease biology provides a powerful route to connect clinical symptoms with their molecular determinants and translate those insights into drug discovery and safety prediction. Significance StatementClinical symptoms define how diseases and drug side effects are recognized, yet the molecular determinants of most symptoms remain unknown. We introduce PHENOCAUZ, a framework that uses Mendelian disease gene-phenotype relationships to infer the proteins and pathways responsible for human symptoms, by linking symptoms to molecular mechanisms and enabling the prediction of adverse drug reactions and discovery of potential therapeutic targets for both Mendelian and complex diseases.

bioinformatics↗

bioRxiv2026

Probiotic Lactiplantibacillus plantarum VB165 improves metabolic disorders in Insulin-Resistant Mice

This study investigated the effects of Lactiplantibacillus plantarum VB165, a probiotic strain with intrinsic -glucosidase inhibitor (AGI) activity, on metabolic disorders in high-fat diet (HFD)-induced insulin-resistant (IR) mice. Male C57BL/6 mice were divided into four groups: normal control diet (NCD), NCD supplemented with VB165, HFD, and HFD supplemented with VB165. After 16 weeks, VB165 supplementation significantly attenuated HFD-induced weight gain and reduced epididymal and inguinal white adipose tissue indices. VB165 also improved glucose intolerance and insulin resistance (IR), as demonstrated by oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT), and lowered fasting blood glucose, fasting insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels. Additionally, it ameliorated dyslipidemia by reducing serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), while alleviating hepatic steatosis and adipocyte hypertrophy. Mechanistically, VB165 enhanced intestinal barrier function by upregulating tight junction proteins (ZO-1 and Occludin), reduced systemic inflammation by lowering LPS, IL-6, and IL-1{beta}. Gut microbiota analysis revealed that VB165 modulated community composition, suppressing HFD-enriched genera (e.g., Ileibacterium and Coriobacteriaceae_UCG_002) and promoting beneficial taxa (e.g., Faecalibaculum and Oscillibacter). These findings demonstrate that L. plantarum VB165 improves HFD-induced metabolic disorders via multi-target mechanisms, highlighting its potential as a probiotic intervention for IR and related metabolic diseases.

microbiology↗

bioRxiv2026

Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System

Somatic mutations rewire the ubiquitin-proteasome system (UPS) to support tumor growth, but the proteome-wide consequences of cancer-driver alterations on UPS composition remain incompletely understood. Using harmonized proteogenomic data from up to 11 CPTAC cohorts, we performed an integrated pan-cancer analysis of UPS protein dysregulation, prognostic associations, and mutation-driven remodeling. We show that mRNA poorly predicts UPS protein abundance, that a defined set of E3 ligases is recurrently dysregulated across cancers, and that somatic mutations (most strikingly TP53 loss) produce coherent UPS protein-quantitative trait locus (pQTL) signatures. Two case studies (UBR5 and TRIM28) illustrate orthogonal modes of UPS rewiring: a mutation-driven axis in which TP53-mutant tumors elevate UBR5 to support replication stress tolerance, and a lineage-driven axis in which TRIM28 engages tissue-restricted regulatory networks with opposing prognostic effects in glioblastoma versus head and neck cancer. Each axis exposes context-specific therapeutic vulnerabilities, including sensitivity to DNA damage response inhibitors (UBR5-high) and lineage-specific drug responses (TRIM28-high). Together, these analyses define a mechanistic framework for how cancer-driver mutations reshape proteostasis through the UPS and nominate mutation- and lineage-defined dependencies for precision degrader therapy. The harmonized pan-tissue atlas and the UbiDash interactive resource that underpin parts of this analysis are reported in our companion paper1. HighlightsO_LIProteome-centric profiling reveals UPS dysregulation invisible at the transcript level across human cancers C_LIO_LIPan-cancer differential expression identifies recurrently dysregulated E3 ligases with prognostic value C_LIO_LIGenome-wide pQTL analysis uncovers mutation-driven UPS remodeling, with TP53 loss as a dominant driver C_LIO_LIUBR5 and TRIM28 define orthogonal mutation- and lineage-driven axes of UPS rewiring with distinct therapeutic vulnerabilities C_LI

systems biology↗

bioRxiv2026

Complete Genomes of Cultivated Gut Bacteria Reveal Mobile Genetic Element-Driven Functional Diversity with Therapeutic Implications

Cultivated bacterial isolates are essential for elucidating gut microbiota functions, yet reliance on fragmented draft genomes and limited mobile genetic element (MGE) annotation has constrained high-resolution analyses. Here, we present the Cultivated Complete Genome Reference (CCGR), a comprehensive compendium of 1,150 fully circularized human gut bacterial genomes. Overcoming draft limitations, CCGR achieves chromosome-scale resolution and reveals distinct evolutionary strategies shaping gene topological organization in response to bacterial growth. Furthermore, we decode the dynamic landscape of MGEs, demonstrating that broad-host-range phages follow strict positional patterns by integrating at conserved chromosomal hotspots flanked by nutrient transporter loci. Importantly, we provide mechanistic in vivo evidence that accessory genomic elements drive strain-level functional heterogeneity. Specifically, the plasmid-encoded scrK gene in Levilactobacillus brevis involved in fructose catabolism is required to mitigate fructose-diet-exacerbated colitis. Collectively, CCGR establishes a framework linking chromosomal architecture and MGEs to bacterial evolution and host health, enabling precise, strain-resolved functional investigations.

microbiology↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

A feed-forward loop between niche adenosine and Gzmk⁺ CD8 T cells propagates systemic inflammaging

The causal link between the aging microenvironment and T cell aging remains elusive. Here, we demonstrate that adenosine within aging tissues actively reprograms CD8+ T cells into a pro-aging Granzyme K+ (Gzmk+) population. Mechanistically, senescent cells create an adenosine-rich niche via p16-dependent CD39 upregulation, triggering A2aR signaling to induce Gzmk+ T cell differentiation. Once released, Gzmk promotes systemic inflammaging through PAR1 and complement activation. Crucially, targeting this axis--either via genetic Gzmk ablation or pharmacological A2aR blockade--reverses multi-organ aging phenotypes and significantly extends healthy lifespan in mice. Human analysis reveals age-dependent Gzmk+ T cell accumulation in multi organs, while coffee intake (an A2aR antagonist) inversely correlates with plasma Gzmk levels. Our findings uncover how metabolic niche changes drive T cell aging and establish the adenosine-Gzmk axis as a pivotal therapeutic target for combating age-related diseases.

immunology↗