Biology subjects

Zhang, G.

Publications and source records attributed to Zhang, G..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Intestinal Dysbiosis in Necrotic Enteritis: Dissecting the Roles of Eimeria and Clostridium perfringens

Necrotic enteritis (NE), caused by Clostridium perfringens, is a major enteric disease in poultry with substantial economic impact. NE is frequently triggered by co-infection with Eimeria spp., yet the relative contributions of Eimeria and C. perfringens to NE-induced dysbiosis and disease progression remain poorly defined. To address this, Cobb broiler chickens were challenged with Eimeria maxima, C. perfringens, or both, and ileal and cecal microbiota were analyzed using 16S rRNA gene sequencing and shotgun metagenomics. Temporal dynamics of intestinal microbiota shifts were further assessed at multiple time points post-infection. Our findings demonstrate that NE-associated dysbiosis is characterized by enrichment of pathobionts including C. perfringens, Escherichia, and Enterococcus cecorum, along with differential abundance of certain lactic acid-and short chain fatty acid-producing bacteria. Dysbiosis and disease progression were driven by synergistic interactions between E. maxima and C. perfringens, with E. maxima exerting a dominant influence. Notably, E. maxima alone promoted expansion of commensal C. perfringens or closely-related bacteria, even without prior exposure. Metagenomic analysis of the cecal microbiota further revealed a functional shift favoring utilization of host-derived glycans and simple carbohydrates over dietary fibers, in response to E. maxima and NE challenges. This transition coincided with E. maxima-induced epithelial damage, increased mucogenesis, and nutrient malabsorption. NE-associated dysbiosis emerged four days post-E. maxima infection and peaked 2-3 days following C. perfringens challenge. These findings suggest that Eimeria infection creates a permissive intestinal environment for C. perfringens colonization and proliferation, underscoring its pivotal role in NE pathogenesis. IMPORTANCENE is a major health and economic burden in poultry production, primarily driven by C. perfringens and potentiated by Eimeria infection. This study provides critical mechanistic insights into the distinct and synergistic roles of E. maxima and C. perfringens in NE disease progression. We show that Eimeria plays a dominant role in driving NE-associated dysbiosis and disease progression by inducing epithelial damage, inflammation, and nutrient malabsorption, which facilitate C. perfringens colonization, proliferation, and toxin production. Comprehensive characterizations of both structural and functional microbiome shifts revealed that NE-associated dysbiosis is marked by enrichment of facultative pathobionts that favors utilization of host-derived mucins and simple dietary carbohydrates, alongside depletion of strictly anaerobic, fiber-fermenting, SCFA-producing bacteria. These microbial shifts reflect disease progression and offer potential biomarkers for early diagnosis and therapeutic intervention. Our findings lay a foundation for microbiota-based diagnostics and interventions to mitigate NE and other enteric diseases.

systems biology↗

bioRxiv2026

Lipogenesis-driven EGFR palmitoylation enables metastatic immune evasion in triple-negative breast cancer.

Metastasis is the leading cause of death in triple-negative breast cancer (TNBC), yet how tumor cells evade immune recognition during dissemination remain unclear. Here, we show that de novo lipogenesis drives metastatic immune evasion through FASN-mediated palmitoylation of EGFR. This modification establishes a lipid-dependent membrane signaling scaffold that sustains PI3K-AKT-mTOR signaling independently of MAPK compensation, thereby suppressing MHC-I antigen presentation through post-translational regulation. As a result, metastatic-competent cells escape CD8+ T cell surveillance and colonize distant organs. Genetic or pharmacologic inhibition of fatty acid synthase (FASN), or expression of palmitoylation-deficient EGFR mutants restores MHC-I surface expression, unleashes robust CD8 T cell activation, and markedly impairs lung metastasis without affecting primary tumor growth. This lipid-dependent EGFR-PI3K-mTOR axis operates independently of MAPK signaling and is not rescued by exogenous lipids, revealing a non-redundant metabolic dependency. Our results identify FASN-driven EGFR palmitoylation as a tumor-intrinsic immunometabolic checkpoint that couples lipid metabolism to antigen-presentation and metastatic competence. Targeting this pathway with clinically advancing FASN inhibitors offers a promising strategy to suppress metastasis by restoring anti-tumor immunity in TNBC.

cancer biology↗

bioRxiv2026

dbGIST: An LLM-Assisted Multi-Omics Resource for Target Exploration and Cross-Dataset Validation in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, yet GIST-specific omics evidence remains scattered across small cohorts and is not represented as a dedicated disease project in major cancer genomics resources, limiting reproducible target exploration. Here, we present dbGIST (https://www.dbgist.com), a dedicated GIST-focused multi-omics resource built to make dispersed GIST evidence searchable, analyzable, and reusable. dbGIST harmonizes data from 37 centers and 1,991 samples, including pathologically verified in-house cohorts, across genomics, bulk transcriptomics, proteomics, phosphoproteomics, and single-cell transcriptomics, and couples these data with curated clinical annotations covering survival, mutation status, risk stratification, metastasis or recurrence, mitotic index, tumor site and size, and imatinib response. The platform supports cohort-level molecular-clinical association, survival, enrichment, immune-infiltration, drug-sensitivity, and single-cell analyses through interactive visualizations, downloadable source data, and public APIs for programmatic access to reusable analysis outputs and visualization-ready data. An optional LLM-assisted interface helps users navigate analyses and interpret outputs. Using MCM7 as a case study, dbGIST linked a resource-derived candidate to survival, risk features, metastatic or recurrent disease, imatinib-response phenotypes, proliferative cell states, and in vitro GIST-cell behavior. dbGIST therefore provides a traceable and interoperable resource for target exploration and precision oncology research in GIST.

cancer biology↗

bioRxiv2026

Evolutionary analysis of vertebrate KCNH voltage-gated potassium channels and their expression in zebrafish embryos

Voltage-gated potassium channels (Kv) are a large family of potassium channels composed of 40 members across 12 subtypes. The KCNH genes encode 3 subfamilies of voltage-gated potassium channels: Kv10 (EAG, ether a go go), Kv11 (ERG, EAG-related gene), and Kv12 (ELK, EAG-like K). Kv channels play prominent roles in the neuronal and cardiovascular systems. Mutations in Kv channels have been linked to many human diseases, such as epilepsy, heart arrhythmias, and cancers. Significant progress has been made in understanding protein structures, physiological functions, and the pharmacological modifiers. However, the evolutionary history and gene expression of vertebrate KCNH genes during embryonic development remain largely unknown. We systematically identified and cloned 14 kcnh genes in zebrafish. Then, we examined vertebrate KCNH channel evolution by phylogenetic and syntenic analyses. Our data revealed that the three subtypes of the KCNH gene family have already evolved in invertebrates, long before the emergence of vertebrates. The number of vertebrate KCNH genes increased, most likely due to whole-genome duplications (WGDs). In addition, we examined zebrafish kcnh gene expression during early embryogenesis by in situ hybridization. Each subgroups genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues. Notably, kcnh6a showed robust expression in the developing heart, consistent with its conserved role in cardiac repolarization. Additionally, a few kcnh genes were transiently expressed in nonneural tissues, such as somites and the notochord, suggesting they may have a unique role in embryonic development. Our phylogenetic and developmental analyses of KCNH channels shed light on their evolutionary history and potential roles during embryogenesis, in line with their physiological functions and human channelopathies.

developmental biology↗

bioRxiv2026

Modeling Complex Effects and Individual Variability in Multi-Paradigm fMRI with Nonlinear Mixed Models

Functional magnetic resonance imaging (fMRI) data are inherently complex, characterized by high dimensionality, intricate inter-regional dependencies, and substantial individual variability across experimental paradigms. Traditional linear mixed models (LMMs) provide a principled framework that models population-level fixed effects while estimating variance components arising from subject-level random effects; however, they often fail to adequately capture nonlinear relationships inherent in neuroimaging data. To address these limitations, we introduce the nonlinear mixed model (NMM) approach, an innovative extension of the LMM framework that integrates neural networks to flexibly model complex fixed-effect relationships while preserving the random-effects structure to account for individual differences. NMM advances fMRI analysis by: (1) identifying robust functional connectivity (FC) patterns consistently observed across multiple paradigms; (2) leveraging SHapley Additive exPlanations (SHAP) analysis to provide post-hoc interpretability of the nonlinear fixed effects, quantifying how age, sex, and paradigm contribute to predicted FC and how these effects are distributed across large-scale brain networks; and (3) using subject-specific random effects as neural fingerprints that not only show systematic variability across attention and default mode systems but also predict standardized cognitive scores, demonstrating biological relevance. Applied to the Philadelphia Neurodevelopmental Cohort (PNC) across emotion, n-back, and resting-state paradigms, NMM achieved superior model fit relative to classical LMMs, as evidenced by lower mean squared error (MSE) in predicting FC. This framework offers a statistically rigorous and practically explainable approach for modeling large-scale FC from modest covariates while explicitly separating population-level effects from stable individual variability in functional brain organization.

bioengineering↗

bioRxiv2026

Piezo3 is a novel mechanosensitive Piezo ion channel in vertebrates

Mechanosensing and mechanotransduction are essential for all living cells. In mammals, Piezo1 and Piezo2 are two mechanically activated cation channels that serve as mechanosensors for a variety of physiological and pathological processes, ranging from touch sensing to sickle cell disease. These two channels are well evolutionarily conserved, and orthologous genes can be traced back to the origin of vertebrates, which underwent whole-genome duplications (WGDs). The number of paralogous genes originating from the vertebrate WGD varies across gene families. Thus, whether there are more PIEZO paralogous genes in vertebrates remains understudied. Here, we identified piezo3, a new paralog of the piezo gene family, and analyzed its evolutionary history using phylogenetic and synteny analyses. The piezo3 gene is present in most vertebrate lineages but absent in birds and most mammals, likely due to nonfunctionalization after WGDs. In addition, we demonstrated that this channel could mediate calcium flux in response to mechanical stimuli in HEK293T cells, suggesting that Piezo3 exhibits PIEZO1/2-like activation and conduction channel functions. Our CRISPR mutation analysis revealed that the zebrafish piezo3 gene is not developmentally essential, possibly because its expression overlaps with other PIEZO channels. Mutant zebrafish showed elevated sensitivity to mechanical force and increased locomotor activity under (photopic) light illumination. Our results suggest that this new mechanical-sensing Piezo channel is widespread in vertebrates and may be critical for vertebrate adaptation by modulating mechanical sensing and light responses during evolution. SIGNIFICANCEAll living cells must sense mechanical forces, whether endogenous or exogenous, and respond to them by transforming these forces into biological signals, which is essential to a wide range of cellular processes, including cell division, growth, and differentiation. PIEZO channels are well-characterized, critical, versatile mechanotransducers for touch and pain physiology and for human diseases. Currently, PIEZO1 and PIEZO2 are the only two known PIEZO channels in most vertebrates. In zebrafish, there are two Piezo2 channels (Piezo2a and Piezo2b) due to extra genome duplication in the ray-finned fishes. Here, we report Piezo3 channel, a long-missing paralog of Piezo1 and Piezo2, in most vertebrates. This channel is present in the majority of vertebrate lineages, except for most birds and mammals. The zebrafish piezo3 gene is expressed during early embryogenesis, and mutation of this gene leads to zebrafish larvae responding to tapping mechanical force and light with active movement. The widespread distribution of this Piezo3 channel across most vertebrate species, but its absence in birds and most mammals, suggests it may play important roles in vertebrate physiology and evolution.

evolutionary biology↗

bioRxiv2026

CAD rewires nucleotide metabolism to drive oxidative stress in myocardial ischemia/reperfusion injury

Myocardial ischemia/reperfusion (I/R) injury is a major determinant of infarct size and clinical outcome, yet effective therapies remain limited. Although metabolic remodeling is central to I/R pathology, the contribution of nucleotide biosynthesis remains unclear. Here, we identify CAD, the multifunctional rate-limiting enzyme of de novo pyrimidine biosynthesis, as a previously unrecognized regulator of myocardial reperfusion injury. CAD activation exacerbated cardiomyocyte death during simulated I/R, whereas CAD knockdown or pharmacological inhibition was protective in vitro. Mechanistically, CAD enhanced dihydroorotate dehydrogenase (DHODH)-dependent electron transfer, increased the CoQH2/CoQ ratio, and promoted complex I reverse electron transport (RET), thereby amplifying mitochondrial ROS. In parallel, CAD suppressed de novo purine synthesis, causing purine insufficiency, DIS3L-dependent RNA decay, and cytosolic ROS. Importantly, cardiomyocyte-specific CAD deletion protected against cardiac I/R injury in vivo. Together, these findings establish CAD as a metabolic hub linking nucleotide flux to dual-compartment ROS signaling and identify nucleotide metabolism as a therapeutic vulnerability in myocardial I/R injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/725578v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@14c4fedorg.highwire.dtl.DTLVardef@1138ed2org.highwire.dtl.DTLVardef@1057d8borg.highwire.dtl.DTLVardef@17546bd_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Multi-Stage Singular Value Decomposition for Ultrafast Ultrasound Imaging of Microbubbles

Microbubble contrast-enhanced ultrasound (CEUS) relies on discriminating nonlinear bubble signals from linear tissue backscattering. While Singular Value Decomposition (SVD) filtering improves this discrimination, existing techniques often fail to retain the slowly-moving microbubble signals from static clutter. Here, we present a novel multi-stage singular value decomposition (MS-SVD) framework for ultrafast CEUS imaging. Our method employs plane-wave transmissions at multiple angles and acoustic pressure levels (implemented via duty-cycle modulation) and alternating transmit polarity. The beamformed data are then processed by three sequential SVD filters: (1) spatial-angular SVD to extract coherent signals across all transmit angles, (2) spatial-pressure SVD to separate linear fundamental and nonlinear harmonic components, and (3) spatiotemporal SVD to isolate moving microbubble echoes from tissue clutter. In in vitro flow phantoms and in vivo rat brain through a cranial window, MS-SVD dramatically improves microbubble detection compared to conventional SVD filtering, MS-SVD yields much stronger vascular contrast and suppresses tissue clutter to a greater extent. The resulting power-Doppler and super-resolution maps are notably cleaner and more complete: MS-SVD detects substantially more microbubble events in ULM, revealing finer vessel details and more accurate flow speeds. By capturing the full acoustic signature of microbubbles (both fundamental and harmonic), MS-SVD achieves higher contrast-to-noise and sensitivity in CEUS. These gains make it a powerful front-end for super-resolution ultrasound localization microscopy and other high-sensitivity microvascular imaging applications.

bioengineering↗

bioRxiv2026

Salvianolic acids are natural senolytics and increase lifespan in old age

Cellular senescence plays a critical role in chronological aging and is implicated in the onset and progression of multiple age-related disorders. Targeting senescent cells represents a promising strategy to reduce disease burden and improve healthspan. Here we report the senotherapeutic properties of salvianolic acid (SA) family members, specifically A (SAA), B (SAB) and E (SAE). From a natural medicinal agent library, we identified selective cytotoxicity of these SA compounds against senescent cells across diverse senescence types and cell lineages. Mechanistically, SAA, SAB and SAE enhance ROS production and target glutathione S-transferase Pi1 (GSTP1), a redox homeostasis modulator, inducing both apoptosis and ferroptosis in senescent cells. Incorporation of SAs into chemotherapeutic regimens enhanced anticancer efficacy and prolonged post-treatment survival. Intermittent SA administration improved physical function and increased healthspan and lifespan in aged mice. Collectively, our study establishes SAs as an emerging class of natural senolytics (phenolic acids) with the capacity to delay aging and alleviate age-related pathologies in advanced life.

cell biology↗

bioRxiv2026

Repeated mutation of a GT92 glycosyltransferase gene confers antiviral resistance in two Caenorhabditis species

Host-pathogen interactions evolve rapidly within species, providing natural genetic resources for the identification of specific ecological interaction factors. We previously identified RNA viruses that infect the nematodes C. elegans and C. briggsae in a species-specific manner. Wild strains of both host species demonstrate ample variation in viral sensitivity. Specifically, the wild C. elegans strain MY10, despite carrying a deletion in a key immunity factor, was among the most resistant strains. Here we use recombinant inbred lines and pool-sequencing approaches to genetically map the major MY10 resistance locus, narrowing down its position by CRISPR/Cas9 mediated recombination and testing candidates by genome editing. A rare non-synonymous polymorphism in the gtnt-1 gene, encoding a putative glycosyltransferase of the GT92 family, causes resistance to viral infection in MY10. We find that viral resistance through gtnt-1 mutation occurred repeatedly in C. elegans, with diverse resistance alleles each remaining at low frequency (<1%). Furthermore, leveraging closely related C. briggsae strains differing in viral susceptibility, we demonstrate that repeated reduction-of-function alleles of the Cbr-gtnt-1 ortholog similarly impair viral infection and enhance host fitness upon infection. In conclusion, we found recurrent evolution in two host species of reduction-of-function alleles of the gtnt-1 orthologs, which repeatedly lead to viral resistance yet remain at low frequency. These repeated events provide a case of transient ecological adaptation to a pathogen through recurrent mutation of the same gene in two species. The low population frequencies of the resistant alleles point to a changing eco-evolutionary context that prevents their spread in populations, resulting in high allelic heterogeneity.

evolutionary biology↗

bioRxiv2026

Highly Accurate Estimation of the Fold Accuracy of Protein Structural Models

BackgroundThe function of a protein is intrinsically linked to its three-dimensional fold, and deep learning has revolutionized the field by enabling high-accuracy structure prediction at an unprecedented scale. Nevertheless, the growing deployment of these predictive pipelines in drug discovery and structural biology reveals a critical bottleneck that lies in the lack of independent and rigorous estimation of model accuracy (EMA) methodologies. ResultsHere we present DeepUMQA-Global, a single-model deep learning framework for estimating accuracy of protein structure models. Our method employs a structure-sequence cross-consistency mechanism to evaluate the bidirectional compatibility between the predicted structure and the input sequence, enabling comprehensive characterization of fold accuracy. DeepUMQA-Global outperforms the self-assessment confidence scores of AlphaFold3, achieving improvements of 57.8% in Pearson correlation and 49.0% in Spearman correlation. With respect to the CASP16 retrospective benchmark, DeepUMQA-Global outperforms all single-model accuracy estimation methods that participated in CASP16 and achieves performance comparable to that of the top consensusObased methods. A lightweight consensus strategy built upon DeepUMQA-Global ranks first among all CASP16 participants, surpassing all other methods, including consensus approaches, and highlighting the strength of our method. Remarkably, DeepUMQA-Global demonstrates a strong ability to discriminate between alternative conformational states of proteins, as evidenced in the CASP unique alternative conformation protein complex target and the CoDNaS benchmark. ConclusionsOur results indicate that DeepUMQA-Global can be extended to broader protein modeling tasks, moving beyond static evaluation to offer a foundation for dynamic conformation EMA, where it accurately discriminates alternative conformational states and demonstrates reliable predictive fidelity in model accuracy estimation.

bioinformatics↗

bioRxiv2026

Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation

Propionic acidemia (PA) is an inborn error of metabolism caused by propionyl-CoA carboxylase (PCC) deficiency due to mutations in either PCCA or PCCB. Without proper management, the disease is associated with high mortality. Even with dietary restriction, patients often develop complications later in life, and the underlying pathological mechanisms remain poorly understood. The liver is the primary organ responsible for propionyl-CoA metabolism, yet the metabolic alterations induced by PCC deficiency in the liver have not been systematically investigated. In this study, we used a hepatocyte model of PA-- PCCAnull-HepG2 cells--to comprehensively examine metabolic alterations using stable isotope-based metabolic flux analysis. The PCCA knockout recapitulated key metabolic features of PA in HepG2 cells. Furthermore, PCCA deficiency reduced mitochondrial fatty acid oxidation while increasing glucose oxidation through pyruvate dehydrogenase. In contrast, pyruvate anaplerosis via pyruvate carboxylase was markedly reduced in PCCA knockout cells. This reduction in anaplerotic flux impaired the capacity for gluconeogenesis and lipid synthesis, consistent with observations from in vivo studies in Pcca-/- (A138T) mice. Additionally, branched-chain keto acid catabolism was reduced in PCCA knockout HepG2 cells. Threonine showed minimal metabolic contribution in this model, further supporting the role of propionate as a major source of propionyl-CoA production. Collectively, these findings highlight the metabolic vulnerabilities associated with PCC deficiency and underscore the increased risk of prolonged fasting in patients with PA, particularly those with severe disease.

genetics↗

bioRxiv2026

The compartmentalized activity of a legume subtilase SBT12a allows symbiosome stabilization

The stabilization of rhizobia in specialized organelles, called symbiosomes, is an evolutionary hallmark for maintaining high rates of nitrogen fixation in legumes. This is achieved by releasing thousands of bacteria from nodular infection threads within in a single plant cell, which poses a great challenge for the host to keep control over these differentiated bacteria. Considering the importance of proteolytic degradation of antimicrobial proteins or generation of symbiosis-promoting peptides, proteolytic activity may represent a key regulatory system. Indeed, we identified the Medicago truncatula subtilisin-like protease (subtilase, SBT) 12a acting as a novel regulator of symbiosome functionality and maintenance. Loss-of-function mutations in SBT12a led to severe symbiotic defects with nodules of sbt12a being characterized by high level induction of defense/senescence-related genes. Using untargeted proteomic High-efficiency Undecanal-based N-Termini EnRichment (HUNTER) we identified and individually confirmed specific SBT12a target proteins that are involved in plant defense responses and symbiosome maintenance. This positions SBT12a as a central host factor controlling symbiosome performance.

plant biology↗

bioRxiv2026

Curvature-mediated prewetting organize mitochondrial nucleoid

The emergence of spatiotemporal order in diffusive cellular environments requires physical mechanisms to overcome the entropic drive toward disorder. While the organizing role of chemical signaling is well characterized, how complex membrane curvature regulate soluble molecular organization remains a fundamental open question. Here, we establish membrane curvature as a thermodynamic control parameter for the condensation of soluble proteins through prewetting. Using the mitochondrial transcription factor TFAM, we demonstrate that intrinsic membrane curvature locally drives a prewetting transitiona surface-mediated phase separation distinct from bulk condensation. By combining in vitro reconstitution, live-cell super-resolution imaging, cryo-electron tomography, and thermodynamic theory, we show that negatively high-curvature regions lower the nucleation energy barrier of Tfam, driving localized protein condensation at physiological concentrations. These results reveal that membrane curvature does not merely scaffold cellular machinery but manipulates the local free energy landscape, establishing a geometric principle for the spatial control of biological processes.

biophysics↗

bioRxiv2026

Global genomic diversity of the selfing nematode Caenorhabditis tropicalis correlates with geography

Self-fertilization reduces genetic diversity compared to outcrossing and hypothetically decreases the ability to adapt to diverse environments. Among Caenorhabditis nematodes, self-fertilization evolved three times independently in Caenorhabditis elegans, Caenorhabditis briggsae, and the more recently discovered Caenorhabditis tropicalis. To survey C. tropicalis genetic relatedness, the influence of geography and niche on species-wide variation, and the signatures of selection, we collected 785 wild strains, sequenced their genomes, and identified 622 distinct genotypes (isotypes). In contrast to C. elegans and C. briggsae, C. tropicalis relatedness shows substantial association with geography and no transcontinental selective sweeps or broadly sampled isotypes. Populations from the Hawaiian Islands or Taiwan harbor more genetic variation than populations from the Caribbean or Americas, suggesting a Pacific species origin similar to other members of the Elegans subclade. Punctuated genomic regions of extreme genetic variation pervade the genome. These hyper-divergent regions (HDRs) comprise less than 6% of the reference genome in any given strain despite harboring 73% of all variant sites and are enriched for genes likely involved in environmental adaptation. HDRs represent a shared genomic feature of self-fertilizing Caenorhabditis nematodes despite their independent evolutionary origins and suggest a mechanism to explain worldwide distributions despite low species-wide levels of genetic variation.

genomics↗

bioRxiv2026

A genome-wide atlas of meiotic recombination intermediates reveals distinct modes of DNA repair that direct crossovers away from transcriptionally marked genes

Crossovers are essential for accurate chromosome segregation in meiosis. Yet the programmed DNA double-strand breaks that initiate them frequently occur in genes and pose a risk to transcription required for gametogenesis. How meiotic cells reconcile these competing demands has remained unclear. Here, we generate a genome-wide in vivo atlas of meiotic recombination intermediates across [~]42,000 hotspots by mapping repair proteins BLM, HFM1, and RPA in wild-type and genome-engineered mutant mouse testes. These maps reveal two distinct modes of break repair: a fast-resolving class with short-lived intermediates that are repaired predominantly as non-crossovers, and a slower class with persistent intermediates that give rise to nearly all crossovers. Fast-resolving hotspots occur almost exclusively within a deeply conserved set of [~]4,500 genes marked by structural and chromatin features established during an early stage of meiotic transcription. This transcriptional memory predicts repair fate with high accuracy across mouse subspecies and sexes. Across widely diverged mammals, including humans and cattle, orthologous genes show similar crossover suppression. Our findings reveal an early bifurcation between crossover and non-crossover repair that is governed by the transcriptional context of meiotic breaks. Together, they establish an evolutionarily conserved principle in which crossovers are directed away from transcriptionally important genes, thereby safeguarding gene function and shaping their evolution.

genomics↗

bioRxiv2026

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain -hydroxy acid, D--hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8+ T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

immunology↗

bioRxiv2026

Reconstructing their genomes confirms the historically attested genealogy of the two medieval emperors Otto I (the Great) and Heinrich II (Saint Henry)

The Medieval Ottonian dynasty had a lasting impact on European history. We obtained ancient genomic DNA from the purported remains of Otto I (912-973) and Heinrich (Henry) II (973-1024), the first and last emperors of this dynasty, preserved in the cathedrals of Magdeburg and Bamberg, respectively. Historical records attest that they were related as a great-uncle and a grandnephew via the paternal line. Whole-genome sequencing confirms such a relationship between the two individuals, as we identify a third-degree genetic relationship based on shared DNA segments and infer matching Y haplogroups. This genetic relatedness effectively identifies the remains of the two emperors. The authentication yields a valuable resource for refining and calibrating bio-archaeological methods. Because historical records provide the precise lifespans and dates of death of these individuals, their remains can serve as a "ground-truth" for methods such as radiocarbon dating and age-at-death estimates. They can provide calibration data to improve our understanding of the radiocarbon reservoir effects of Medieval elites. As the Ottonian lineage was closely linked to the mating networks of elites across Europe, the genomes of the two emperors are valuable resources for identifying other potential elite burials.

genetics↗