Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 307 records · Page 17Linked to original sources

bioRxiv2026

Cell-type specific allelic dampening of sex-linked genes in sex chromosome aneuploidy

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions. HighlightsO_LISex chromosome aneuploidy induces cell-type specific changes in gene expression C_LIO_LIDampening of the inactive X chromosome in XXY alleviate X overexpression C_LIO_LIHigh Y-linked gene expression in XXY neuronal precursor cells but not cardiomyocytes C_LIO_LISex chromosome aneuploidy disrupts sex biases in autosomal gene expression C_LI

molecular biology↗

bioRxiv2026

Phosphoinositide Variant Fuels 53BP1 Oligomerization and Higher-Order Assembly in the DNA Damage Response

53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. Here, we show that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphate (PI(3)P) in vitro through a highly specific interaction with its C-terminal tandem BRCT domain (tBRCT). Consequently, mutational inactivation of the 53BP1 tBRCT domain compromised PI(3)P binding and suppressed 53BP1 optodroplet formation in vivo. We further show that rapid 53BP1 clustering following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its tBRCT, and is suppressed by sequestration of nuclear PI(3)P. Taken together, our findings identify PI(3)P binding as a mechanism that promotes the formation and maturation of 53BP1 condensate-like assemblies on damaged chromatin.

cell biology↗

bioRxiv2026

Evaluation of deep and dynamic proteomic screening strategies at sub-50Hz scan rate and without automation.

Advances in ultra-fast mass analyzer technology and procedural automation have enabled proteomics screening at the throughput of hundreds of proteomes per day. However, these approaches often require expensive instrumentation upgrades and robotic automation that remain inaccessible to many research laboratories and core facilities. In this study we address the feasibility of scaling up proteomic screening capabilities with minimal upgrade cost by focusing on (a) strategies for non-automated high-throughput sample preparation from 96-well cell culture, (b) data acquisition on sub-50Hz scan speed hybrid and tribrid Orbitrap instruments and (c) data analysis strategies for label-free and labeled proteomic screening. We find that the 96-well format STrap, in combination with C18 plates, provides the most robust throughput for a non-automated sample preparation workflow. Furthermore, we show that for static proteomes, an isobaric tandem mass tag-based (TMT) multiplexing approach provides deeper and more precise proteome coverage whereas label-free data-independent acquisition (DIA) is more accurate, albeit with a reduced dynamic range and more missing values. Finally, we extend the optimized workflow to proteome turnover studies using pulsed stable isotope labeling by amino acids in cell culture (pSILAC), highlighting the key advantages and trade-offs of DIA and TMT data-dependent acquisition strategies for capturing protein translation. Together, these results provide a practical framework for designing high-throughput proteomics experiments that balance throughput, depth, and quantitative accuracy using existing instrumentation, without requiring major hardware upgrades or automation.

molecular biology↗

bioRxiv2026

LagCI Enables Inference of Temporal Causal Relationships from Dense Multi-Omic Time Series

Inferring causal relationships from time-series data is critical for uncovering the dynamics of biological regulation. However, in multi-omics studies, this task is often hampered by sparse temporal sampling and the limitations of existing methods. To address this, we developed Lagged-Correlation Based Causal Inference (lagCI), a computational framework designed to identify time-lagged associations by combining comprehensive lag-correlation profiling with a robust statistical filtering scheme. Rather than relying on simple cross-correlation, lagCI analyzes the entire correlation profile and applies a quality-scoring system to filter out spurious associations that often plague high-dimensional datasets. We first tested lagCI on wearable physiological data, where it successfully captured the well-known causal link between physical activity and heart rate, even accounting for variations in lag times between individuals. Moving to high-frequency human multi-omics, we used lagCI to build a directed network of 1,624 molecules connected by over 157,000 predicted interactions. This network didnt just mirror established biology (such as cytokine-hormone crosstalk); it also pointed to specific molecular hubs that seem to orchestrate the timing of metabolic and immune responses. Overall, lagCI provides a data-driven way to extract temporal insights from dense longitudinal omics. Weve made the tool available as an R package with multiple interfaces to ensure its accessible for both bioinformaticians and clinicians.

bioinformatics↗

bioRxiv2026

Bacteria-mimetic bioadhesives with multivalent mucoadhesion and drug-compatible delivery

The ability to adhere to mucus-lined tissues underpins a range of biomedical devices and therapies. However, many existing strategies rely on covalent bonding chemistries and can be unstable, cytotoxic, or incompatible with therapeutics. Here, we present a bacteria-mimetic bioadhesion strategy inspired by Vibrio cholerae. A short Bap1-derived adhesion peptide is grafted onto chitosan to strengthen mucus interactions through multivalent, cooperative secondary bonding, while preserving pH-triggered interfacial bridging behavior. Bacterial peptide grafting significantly increases adhesion energy on porcine intestine, and when paired with a tough hydrogel matrix achieves adhesion energies >400 J/m2 without forming covalent bonds to tissue. Confocal imaging reveals deep tissue penetration ([~]80 m) with markedly enhanced mucin binding and no loss of cytocompatibility. Ex vivo intestinal delivery and in vitro drug release tests demonstrate improved drug transport and tissue exposure compared to carbodiimide-mediated covalent bonding strategy. These findings establish a bacteria-mimetic bioadhesion strategy for tissue repair and drug delivery. Novelty StatementBioadhesive designs have drawn inspiration from nature such as mussel-inspired catechol chemistry and gecko-inspired dry adhesion. In contrast, bacterial adhesion mechanisms, despite enabling robust colonization of mucus-lined tissues under demanding conditions, remain largely overlooked. This work introduces a bacteria-mimetic bioadhesion strategy that selectively repurposes a short, non-pathogenic peptide derived from a Vibrio cholerae adhesin to enhance bioadhesion through multivalent, cooperative physical interactions rather than covalent bonding. This strategy significantly toughens adhesion even on chitosan, a polymer already rich in adhesive functional groups. By decoupling bacterial adhesion function from pathogenic risk, this study establishes bacterial adhesion peptides as a safe, modular, and mechanistically distinct foundation for next generation bioadhesives with improved drug compatibility.

bioengineering↗

bioRxiv2026

N-3 Polyunsaturated Fatty Acids Ameliorate Post-infarction Cardiac Dysfunction Through Modulation Of Adiponectin-Ceramide Metabolism

BackgroundIt has been shown that n-3 polyunsaturated fatty acids (n-3 PUFA) of marine origin exert significant beneficial effects on myocardial infarction (MI); however, the underlying mechanisms remained unclear. Ceramides play a vital role in the regulation of energy metabolism, mitochondrial function, and apoptosis. Through the integration of clincial studies and animal experiments, this study aimed to determine whether n-3 PUFA improved myocardial function by modulating ceramide metabolism. MethodsIn a case-control study, 100 patients with AMI and 100 healthy pariticipants were enrolled to measure serum ceramide concentrations. Meanwhile, mice were randomly allocated into 4 groups and administrated to a 3-week intervention with n-3 PUFA in triglyceride and phospholipid forms. A mouse model of MI was then established, followed by an additional 4 weeks of continuous intervention. Subsequent comprehensive assessments of cardiac function were performed in the mice. Finally, the mice were euthanized to conduct targeted ceramide lipidomic analysis and other relevant assays. ResultsThe levels of serum C16:0-, C18:0-, C20:0-, C24:1-ceramides and total ceramides in patients with acute myocardial infarction (AMI) were significantly higher compared with the healthy controls. In the murine model of myocardial infarction, pathological analysis via TTC staining demonstrated that interventions with fish oil (triglyceride form) and krill oil (phospholipid form) both significantly reduced myocardial infarct size. Concomitant echocardiographic assessment confirmed that both treatments markedly elevated left ventricular ejection fraction (LVEF), with the magnitude of improvement being significantly superior to that of the model control group. Concurrently, compared with the model group, the concentrations of ceramides in cardiac tissue and serum were significantly lower in the groups with fish oil and krill oil intervention. Western blot analysis further confirmed that n-3 PUFA intervention upregulated adiponectin expression, reduced ceramide accumulation in myocardial tissue, and inhibited mitochondria-mediated cardiomyocyte apoptosis, thereby improving cardiac function and prognosis following myocardial infarction. ConclusionsThis work demonstrates that n-3 PUFA exert cardioprotective effects following MI mediated by adiponectin-ceramide axis. However, there is no significant difference regarding therapeutic efficacy of n-3 PUFA in triglyceride or phospholipid forms.

pharmacology and toxicology↗

bioRxiv2026

Nutrient availability shapes the diversity and structure ofmicrobial communities

Nutrients are key drivers of microbial community structure, yet we lack a data-driven quantitative framework linking nutrient environments to community assembly. Here, using controlled microcosm experiments, we systematically probe the effects of nutrient number, concentration, and type on community diversity and structure. To explain these effects, we construct a minimal consumer-resource model incorporating resource competition and cross-feeding. We find that cross-feeding network structure is critical: only shallow, wide networks -- where several byproducts are produced from a few supplied nutrients in a few trophic layers -- reproduce a linear increase in diversity with the number of supplied nutrients. We also perform new experiments varying nutrient concentration and reveal that diversity slowly decreases with increasing concentration. We explain this finding by incorporating consumption-dependent toxicity into the model, consistent with spent-media measurements. This extended model not only recapitulates virtually all observed patterns but makes an independent prediction: at high nutrient concentrations, communities should be enriched in bistable species pairs, which we confirm experimentally. Our work demonstrates that minimal data-driven consumer-resource frameworks -- systematically constrained by experiments -- can unify and predict a broad range of nutrient-community relationships.

ecology↗

bioRxiv2026

π-MSNet: A billion-scale, AI-ready living proteomics data portal

Artificial intelligence (AI) is reshaping proteomics workflows, delivering remarkable gains in both peptide identification sensitivity and quantitative performance. However, the potential of deep learning models in proteomics has not been fully exploited due to the scarcity of large-scale, high-quality and consistently labeled datasets. Here, we present {pi}-MSNet, a billion-scale, AI-ready living mass spectrometry (MS) data portal. Using a uniform identification and quality control workflow, it comprises over 1.66 billion MS/MS spectra, 501 million peptide-spectrum matches (PSMs), and 9 million precursors from 36,356 LC-MS/MS runs across ten instrument types and 55 diverse species. Through community collaboration, the data are shared via international, interactive, and living web resources. Enabled by the built-in MSNetLoader Python API for seamless and scalable data access--with native support for PyTorch and TensorFlow--{pi}-MSNet provides an AI-ready data framework for efficient training and systematic benchmarking of multiple models across three representative tasks (e.g., MS/MS spectrum prediction, retention time prediction, and de novo peptide sequencing). In particular, by retraining multiple models on {pi}-MSNet, we achieved consistent performance improvements over their original versions. These improved models were subsequently integrated into the {pi}-MSNet agent to enable interactive, deployment-free use. Through SDRF (Sample and Data Relationship Format) metadata, an open-source cloud analysis workflow, and a community-driven interactive data portal that supports continuous data submission, {pi}-MSNet serves as a living, AI-ready resource for reproducible benchmarking, robust model training, and accelerated AI innovation in proteomics.

bioinformatics↗

bioRxiv2026

Discovery of Scrophularia nodosa harpagoside synthase, a novel BAHD cinnamoyltransferase, bridges a key gap in the iridoid biosynthetic pathway

Harpagoside, a high-value anti-inflammatory iridoid compound, is traditionally extracted from the roots of Harpagophytum procumbens (Pedaliaceae, Lamiales), a Southern African desert plant widely used in traditional medicine but currently threatened by overexploitation. Scrophularia nodosa (Scrophulariaceae, Lamiales) is a perennial annual plant widely distributed in Western Europe and accumulates several iridoid compounds with known biological activities, such as catalpol, aucubin, harpagide and particularly harpagoside. We gathered extensive genomic and transcriptomics resources for this species and aimed at deciphering the biosynthetic pathway leading to the most abundant iridoid in S. nodosa, harpagoside. We found that the early iridoid pathway is well conserved with other iridoid-producing plants and validated the enzyme activities by transient co-expression in N. benthamiana. Investigation into the large BAHD family showed subclade 6i expanding in Scrophulariaceae, with an atypical VYPWG motif instead of the canonical DFGWG. In this branch, we discovered and characterized harpagoside synthase, a BAHD-type cinnamoyl transferase enzyme showing unique high specificity to the uncommon cinnamoyl-CoA acyl donor and catalyzing the final step of harpagoside biosynthesis. These results establish S. nodosa as a new model to investigate unexplored branches of the iridoids metabolism, and are a first step towards sustainable harpagoside and high-value cinnamoyl-containing conjugates production.

plant biology↗

bioRxiv2026

Long-lived yeast-derived lipids promote longevity via regional and systemic metabolic remodeling

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drives systemic decline in physiology and reduces lifespan. Here, we found that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila and further uncovered the mechanisms using deuterium oxide-probed stimulated Raman scattering microscopy to image metabolic dynamics and single nucleus RNA sequencing (scRNA-seq) to unveil the underlying pathways. These yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids as revealed by Raman spectroscopy and lipidomics, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. We show that these lipids reverse age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structural integrity and barrier function. snRNA-seq identifies transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. In the brain, dietary lipids orchestrate a dual metabolic strategy--promoting energy conservation and enhanced signaling across most neuronal and glial populations, while selectively boosting mitochondrial function in memory-critical Kenyon cells. All these leads to the enhancement of gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, analysis of our data with the Fly Metabolic Analysis Pipeline (FLY-MAP) reveals that yeast lipids restructure gut metabolic modules to coordinate energy production, redox balance, and nutrient flexibility. Our study uncovers a cross-kingdom mechanism of metabolic longevity regulation, paving the way for leveraging yeast-derived nutritional components to support tissue homeostasis and promote healthy aging.

molecular biology↗

bioRxiv2026

Levosimendan inhibits HIV-1 infection in myeloid cells in the RIOK1-dependent manner

Despite of the highly potent antiretroviral therapies, HIV-1 establishes persistent infection and causes chronic inflammation in AIDS patients. Beyond CD4+ T cells, HIV-1 infects myeloid cells, including circulating monocytes and tissue-resident macrophages, and integrates with host genomes to form stable viral reservoirs. To achieve a functional HIV cure, latency-promoting agents (LPAs) have been developed for the "block-and-lock" strategy to reinforce deep HIV-1 latency and permanently silence proviruses. However, most LPAs have been tested mainly in CD4+ T cells, and their efficacy in myeloid cells remains unclear. In this study, we reported that levosimendan (LSM), a drug approved for clinic use to treat heart failures, is able to inhibit HIV lytic infection and reactivation in myeloid cells. LSM blocked viral lytic reactivation in HIV-1 latently infected monocytic cells (TH89GFP, U1) and microglial cells (HC69). LSM also inhibited HIV infection in human induced pluripotent stem cell (iPSC) derived microglia (iMG), primary human resident liver macrophages (Kupffer cells) as well as human monocyte-derived macrophages (MDMs). Furthermore, we demonstrated that overexpression of a predicted drug target of LSM, the conserved serine/threonine kinase RIOK1 (RIO kinase 1), overcomes LSMs anti-HIV effect. Overall, our studies concluded that LSM is a promising LPA to inhibit HIV-1 infection in myeloid cells in the RIOK1-dependent manner.

microbiology↗

bioRxiv2026

Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/717004v2_ufig1.gif" ALT="Figure 1"> View larger version (82K): org.highwire.dtl.DTLVardef@ba3865org.highwire.dtl.DTLVardef@1cc9a58org.highwire.dtl.DTLVardef@1a90e7borg.highwire.dtl.DTLVardef@1f5e88f_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical AbstractMechanism of anti-aging action of red light: Red light can reduce SIRT4 signalling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn remodels the expression of age-related inflammatory factors and genes.

cell biology↗

bioRxiv2026

HeteroRC: Decoding latent information from dynamic neural responses with interpretable heterogeneous reservoir computing

Time-resolved neural decoding is widely used to track information represented in neural activity, but conventional linear decoders primarily capture phase-locked evoked responses and often fail to recover representations embedded in nonlinear or non-phase-locked dynamics, potentially limiting the interpretation of neural coding. Here, we introduce HeteroRC, a biologically inspired and interpretable decoding framework based on heterogeneous reservoir computing. HeteroRC projects neural signals into a high-dimensional recurrent state space with heterogeneous time constants, enabling nonlinear feature expansion and multiscale temporal integration directly from raw neural time series. Simulations demonstrate that HeteroRC significantly outperforms linear decoders and a suite of artificial neural networks (including RNNs, LSTMs, Transformers and EEGNet) on evoked responses while robustly capturing induced oscillatory power, phase synchrony, and aperiodic modulations--dynamics that are largely latent to conventional linear methods. We further validate HeteroRC on two empirical EEG datasets. In a motor imagery task, it substantially improves decoding accuracy and exhibits superior cross-temporal generalisation, revealing dynamic representational transformations. In an attentional priority task, HeteroRC uncovers statistically learned spatial priority information that remains hidden from conventional methods, successfully decoding these latent states previously thought to be activity-silent. Furthermore, we develop a dual-level interpretability framework linking reservoir dynamics to virtual sources and sensor space, revealing the temporal, spectral, and spatial signatures underlying decoding performance at both the individual and group levels. Together, HeteroRC offers an interpretable approach to decode information from dynamic neural responses, broadening the analytical scope of neural decoding while remaining computationally efficient and free from manual feature engineering, making it particularly suitable for small-sample electrophysiological studies.

neuroscience↗

bioRxiv2026

Longitudinal Single-Cell RNA-seq Profiling of Lung Cell Phenotypes, Signaling, and Cross-talk During Fibrosis Resolution

Resolution of fibrosis following lung injury is distinguished from persistent/progressive parenchymal scarring through the timely clearance of aberrant cell types, removal of excess collagens, and regeneration of alveolar structure. The requisite signaling pathways, cellular cross-talk, and phenotypic shifts associated with, and required for, resolution of established lung fibrosis have not been well characterized. To address this critical knowledge gap, we performed longitudinal single-cell RNA sequencing of whole mouse lung digests obtained during spontaneously resolving fibrosis. We observed a putatively pro-fibrotic macrophage population emerge during peak fibrosis and undergo partial clearance during resolution. Our study also revealed conspicuous shifts in well-established pathways associated with tissue repair and fibrosis among immune, mesenchymal, and epithelial cells during spontaneous resolution. In addition to a decline in pro-fibrotic driver pathways, the putative anti-fibrotic pathways cAMP, HGF/MET, and TWEAK were enriched in several cell types during spontaneous resolution. CellChat analysis was used to predict the cellular senders and recipients of each pathway and characterize their longitudinal changes. Our characterization of the cellular and molecular dynamics in whole lungs during spontaneous fibrosis resolution provides a foundation for the identification of endogenous pathways that might be leveraged to treat pulmonary fibrosis.

cell biology↗

bioRxiv2026

Integrative Multi-cohort Transcriptomics and Network Pharmacology Analysis Reveals Key Network Nodes and Potential Drug Clues in PCOS Granulosa Cells

BackgroundPolycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with complex pathophysiology and limited therapeutic options. Identifying key molecular drivers and potential drug candidates is critical for improving clinical outcomes. MethodsWe integrated multi-cohort transcriptomics (GSE155489, GSE138518, GSE226146) with weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and drug repurposing. Differential expression analysis identified 1,039 DEGs, and WGCNA identified 10 PCOS-associated modules. Intersection of DEGs with module genes yielded 498 core candidate genes, which were subjected to functional enrichment, PPI network analysis, and connectivity map-based drug repurposing (CLUE/LINCS). Candidate drugs were further evaluated by molecular docking and ADMET prediction using a triple intersection strategy (hub genes, high differential expression, drug-target evidence). ResultsFunctional enrichment revealed significant enrichment in cell adhesion and TGF-beta signaling. PPI network analysis identified CD44 as the top hub gene (degree=42). Drug repurposing identified 106 candidate drugs, including troglitazone and enzalutamide. Using the triple intersection strategy, five genes (ID2, NR4A1, GJA5, ID1, MYH11) were prioritized for molecular docking. GJA5 showed strong predicted binding affinity with flufenamic acid (-7.88 kcal/mol), and cytosporone B exhibited favorable druglikeness (0 Lipinski violations). ConclusionThis study systematically characterizes PCOS-associated gene networks and provides a prioritized set of candidate targets and drugs through a purely computational framework. CD44 emerges as a key network node with potential relevance in PCOS pathophysiology. These findings offer testable hypotheses for future mechanistic studies and drug discovery efforts in PCOS.

systems biology↗

bioRxiv2026

Bovine H5N1 influenza viruses have adapted to more efficiently use receptors abundant in cattle

Sustained mammal-to-mammal transmission of high pathogenicity H5N1 avian influenza viruses is reshaping the host range of these pathogens. One of the longest-running mammalian transmission chains involves the B3.13 genotype circulating in U.S. dairy cattle which was detected in early 2024. Genomic analyses revealed selection and rapid fixation of haemagglutinin mutations D104G and V147M. We demonstate, via glycomic profiling, that bovine tissues, including the mammary gland, are enriched in N- and O-linked glycans capped with N-glycolylneuraminic acid (NeuGc), a sialic acid absent in humans and birds, which instead express only N-acetylneuraminic acid (NeuAc). Early cattle H5 viruses poorly recognized NeuGc, but D104G and V147M enabled efficient engagement of both NeuAc- and NeuGc-containing receptors. These mutations enhanced replication in bovine mammary tissue without major attenuation of replication in human lung and primary nasal epithelial cells. NeuGc-driven receptor adaptation therefore promotes viral fitness in cattle while potentially limiting immediate zoonotic risk. Deep mutational scanning further identified alternative haemagglutinin substitutions that confer NeuGc usage and represent surveillance markers for emerging cattle H5 lineages.

microbiology↗

bioRxiv2026

Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.

physiology↗

bioRxiv2026

A confined gene drive for population modification in the malaria vector Anopheles stephensi

Gene drives are genetic elements that bias their own inheritance to spread desired traits in target populations, enabling population modification or suppression. Although homing-based drives can propagate efficiently, their potential for uncontrolled spread may present a challenge for field deployment. Thus, confined drive systems are needed. Here, we developed a confined modification drive, called Toxin-Antidote Recessive Embryo (TARE) drive, in the globally important malaria vector Anopheles stephensi. This drive works by cleaving and disrupting wild-type alleles in the germline or early embryo from maternally deposited Cas9. Disrupted alleles are recessive lethal, thus increasing the drive in a frequency-dependent manner. Inheritance bias was moderate in crosses between drive heterozygote mosquitoes, possibly due to low gRNA activity and thus moderate germline cleavage rates. Single-release cage trials confirmed the TARE drives ability to spread, although the drive ultimately declined due to fitness costs and resistance alleles associated with repetitive elements. Nonetheless our modelling analysis indicate that this TARE system could achieve population spread if the resistance issue is addressed. These findings demonstrate a functional prototype TARE drive in Anopheles stephensi and highlight key parameters governing its performance. Minor design optimizations could substantially improve efficiency and integrity, enabling rapid but confined population modification.

genetics↗