Biology subjects

Yu, Z.

Publications and source records attributed to Yu, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Time-resolved cryo-EM reveals conformational trajectory of allosteric activation in isocitrate lyase

Isocitrate lyase 2 (ICL2) from Mycobacterium tuberculosis undergoes dramatic conformational rearrangements upon binding to the allosteric effector acetyl-CoA. Time-resolved cryo-EM captured conformational states along the ICL2 activation trajectory, revealing how acetyl-CoA binding at the allosteric sites leads to asymmetric, half-of-site activity at the catalytic centres. These findings support a conformational selection model of allostery, whereby acetyl-CoA binding shifts the pre-existing equilibrium towards an active state of the enzyme.

biochemistry↗

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

Identity, ontogeny, and age-related changes in splenic white pulp macrophages in mouse and human spleen

The spleen contains diverse macrophage subsets that remove aged erythrocytes, prevent the dissemination of circulating pathogens, and shape the adaptive immune response1-3. The mouse spleen hosts red pulp macrophages (RPM), marginal zone macrophages (MZM), marginal zone metallophilic macrophages (MMM), and tingible body macrophages (TBM). However, their transcriptomic identity, ontogeny, and dynamics during aging are unknown. Furthermore, it is not known whether homologous populations of macrophages exist in the human spleen. We find that in mice, MZM and MMM are tissue-resident macrophages that maintain their population via local proliferation, while TBM are slowly replaced by circulating monocytes. Lineage tracing shows that MMM maintain the MZM pool, and that after MMM depletion, circulating monocytes restore MMM. We show that a decrease in MMM abundance in aging precedes changes in other cellular populations and splenic niches. In human spleen, we identify TBM and perifollicular zone macrophages (PFZM) as a single macrophage population homologous to MMM and MZM in mice. We show that in both mouse and human TBM become more abundant during aging. Our results suggest age-related changes in the splenic microenvironment drive changes in tissue-resident splenic macrophage populations with potential importance for the loss of immunologic function in older individuals.

immunology↗

bioRxiv2026

Nucleoid-associated proteins sense phage-induced genome damage to elicit abortive infection

Bacteria have evolved diverse immune strategies to detect and neutralize bacteriophage infection. Here, we describe an unprecedented paradigm in which a chromosome-architecting nucleoid-associated protein (NAP) is repurposed as a viral infection sensor. When phage attack leads to genome degradation, the NAP sensor is released from the nucleoid to the cytoplasm, where it binds and activates diverse immune effectors. One such effector is a nucleotide-modifying toxin normally existing as an inactive homotetramer. NAP binding converts it into a catalytically active heterotrimer that halts both transcription and translation. Phylogenetic analyses unveiled the high modularity, polyphyletic origin, and wide distribution of NAP-mediated defenses. Collectively, we define a distinct class of defense systems in which bacteria sense phage-induced genome damage through NAP relocation, highlighting an unexpected but essential role for these proteins as sentinels of genome integrity.

microbiology↗

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

IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-{kappa}B-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.

immunology↗

bioRxiv2026

Programming Biomolecular Interactions with All-Atom Generative Model

Biomolecular interactions lie at the core of cellular life, spanning diverse molecular modalities from small molecules to nucleic acids and proteins. Nevertheless, design strategies remain separated despite shared physicochemical principles of molecular recognition. Here we present AnewOmni, a unified generative framework trained on more than 5 million biomolecular complexes, that enables transferable molecular design across molecular scales by assembling chemically meaningful building blocks at atomic resolution. We further introduce programmable graph prompts to support user-defined chemical, topological, and geometric steering during generation, exploring hybrid and unconventional chemistries beyond canonical structures. We demonstrate that transferable learning of interaction patterns and physical constraints across molecular modalities is possible, via an atom-to-block latent space capturing both atomic details and structural priors. The framework successfully designed small molecules, peptides, and nanobodies targeting the challenging KRAS G12D switch II pocket, as well as orthosteric peptides and allosteric small-molecule inhibitors for PCSK9 in the absence of known binding site, achieving 23%-75% success with only low-throughput validation, bypassing modality-specific high-throughput screening. AnewOmni is the first to succeed in functional molecular design across all scales, from small chemical entities to large biologics, and represents a stepstone towards general molecular reasoning engines, advocating a generative foundation model for biomolecular interactions to enter regimes where data and human intuition remain limited.

bioengineering↗

bioRxiv2026

Structural Basis for C8 methylation of 23S ribosomal RNA by Cfr

Cfr methylates C8 of adenosine 2503 (A2503) in 23S ribosomal RNA (rRNA) and will also methylate C2 of A2503 after methylating C8. C8 methylation confers resistance to more than five classes of clinically used antibiotics, highlighting it as a worrisome mechanism of antibiotic resistance. Here, we report the structure of Cfr, determined by cryogenic electron microscopy (Cryo-EM). Despite its small size ([~]36 kDa), we exploit a transient protein-RNA crosslink that forms during catalysis, which requires Cys105 to resolve. Using a Cfr Cys105Ala variant and an 87-nucleotide strand of rRNA, we isolate the crosslinked species and determine its structure to 3.0 [A] resolution. Notably, the 87-mer rRNA adopts an L-shaped conformation characteristic of tRNAs, rather than the conformation it assumes in the ribosome. One Sentence SummaryCryo-EM structure of Cfr, a radical S-adenosylmethionine methylase that confers antibiotic resistance

biochemistry↗

bioRxiv2026

Kindlin-2-Moesin interaction orchestrates sprouting angiogenesis via modulating endothelial membrane mechanics and VEGF signaling

Membrane mechanics play a crucial role in cellular signaling and fate determination, yet their impact on angiogenesis remains poorly understood. Here, we identify Kindlin-2 as a key regulator of sprouting angiogenesis via regulating endothelial membrane tension through its interaction with Moesin, a crucial linker protein between the cell membrane and the actin cortex. Mechanistically, Kindlin-2 binds to the N62 residue of Moesin, limiting its overactivation and maintaining proper membrane tension to facilitate VEGFR2 endocytosis and downstream signaling. Using both developmental and pathological models, we demonstrate that the interaction of Kindlin-2 and Moesin is enhanced in high angiogenic conditions, and endothelial Kindlin-2 deletion reduces angiogenesis. Furthermore, mutation of Moesin at N62 phenocopies the effects of Kindlin-2 loss. Together, these findings uncover a previously unrecognized mechanism linking membrane tension regulation to angiogenesis and provide new insights into targeting the Kindlin-2-Moesin axis for therapeutic intervention in neovascular diseases.

developmental biology↗

bioRxiv2026

A biofidelic Goat Model of Traumatic Optic Neuropathy with Optic Canal Fracture via Transnasal Endoscopy

Traumatic optic neuropathy (TON) is a major cause of irreversible vision loss following blunt cranial trauma, yet the absence of clinically relevant large animal models that faithfully recapitulate human TON has significantly impeded translational research. Current rodent models do not reproduce optic canal fracture, a key injury mechanism in many patients with TON. Here, we combined high-fidelity finite element analysis (FEA) with iterative engineering to establish a reproducible goat model of TON. We first built a high-resolution human-head finite element model to characterize force transmission to the optic nerve. Across clinically relevant periorbital impacts, stress preferentially concentrated in the intracanalicular segment, reaching a peak force density of approximately 500 N/m2 at 50.6 ms, about fivefold higher than in the intraorbital segment. Simulations further showed that direct optic canal impact reproduced comparable intracanalicular stress with a markedly lower input force: 195 N, compared with 3900 N for periorbital impact. Guided by these insights, we developed transnasal endoscopic impact systems capable of inducing optic canal fractures in goats. TON was confirmed within 24 hours by a characteristic relative afferent pupillary defect (RAPD), and at 1 month post-injury goats (n = 14) exhibited a 10%-20% reduction in ganglion cell complex (GCC) thickness and 40%-65% reductions in flash visual evoked potential (FVEP) and pattern electroretinogram (PERG) amplitude ratios (all P [≤] 0.001), with structural and functional preservation of the fellow eye. This study presents a robust, standardized, and clinically relevant large-animal platform for investigating TON pathophysiology.

neuroscience↗

bioRxiv2026

Learning reweights the decision dynamics of cortico-basal ganglia-thalamic pathways from deliberation to commitment

Mammals flexibly adjust their decision strategies in dynamic environments based on prior experience. The cortico-basal ganglia-thalamic (CBGT) circuit is recognized as a critical driver of this adaptability, yet how plasticity-induced modifications to CBGT dynamics translate into modifications of decision policies remains poorly understood. Here we simulate learning in a biologically-grounded spiking CBGT model that learns to select a rewarded action via dopamine-dependent plasticity at corticostriatal synapses. Relying on three previously identified control ensembles (responsiveness, pliancy, and choice) within CBGT circuits, we disentangle the distinct roles these subnetworks have in reshaping decision trajectories across learning. Control ensemble dynamics were mapped onto the evolution of evidence accumulation, revealing within-trial parameter adjustments that shape decision dynamics and outcomes. Our results emphasize that learning optimizes not only what choice is favored, but also how the phases within the decision unfold. Early in the decision, learning accelerates evidence accumulation by driving the activity of corticothalamic and direct pathways. During later deliberation, this drive is temporarily restrained, and the indirect and pallidostriatal pathways become more critical for maintaining decision thresholds, preventing premature commitment despite the increased choice bias. As the system approaches the decision point, the direct pathway regains dominance, triggering boundary collapse to facilitate action selection. This mechanism effectively shifts decisions from deliberative to committed reward-directed choices, improving both speed and accuracy while preserving system stability and control throughout the process. Author summaryWe investigate how specific subnetworks within cortico-basal ganglia-thalamic (CBGT) circuits reshape decision-making through dopamine-dependent plasticity at corticostriatal synapses. Using simulations of a simple two-choice task with a single rewarded target, we identify phase-specific reconfigurations of subnetwork activity that emerge over the course of learning. We then link these circuit-level changes to an algorithmic description of behavior by mapping them onto decision policies within a dynamic evidence accumulation framework. This analysis reveals a learning-driven shift from deliberative to more committed decision strategies, achieved through flexible coordination of decision boundaries and evidence accumulation rates. Together, these adjustments optimize decision speed and accuracy while preserving caution during ongoing choices. Our findings provide mechanistic insight into how plasticity within CBGT circuits supports adaptive decision-making across different levels of uncertainty and task demands.

neuroscience↗

bioRxiv2026

Multi-agent reasoning enables predictive design of living materials

Artificial intelligence is increasingly used to accelerate scientific discovery, but most successful frameworks operate within well-defined molecular, protein or materials spaces. Living materials present a more formidable computational problem because functions emerge from context dependent coupling among cells, matrices, fabrication processes and evaluation conditions. Here we introduce LiveMat, a multi-agent reasoning framework that transforms unstructured literature into a computable design space for living materials. LiveMat standardizes 34,215 living material records, integrating 16,769 microorganism and 17,446 polymer entries into a knowledge graph linking living components, abiotic matrices, functional outputs, evaluation contexts and performance metrics. Benchmarking across five large language models shows that living material reasoning is limited mainly by cross-domain feature integration rather than coarse classification. LiveMat overcomes this limitation through constraint decomposition, provenance-aware extraction, consistency checking and expert-anchored ranking. In a prospective wound-healing task, it prioritizes a four-component design with state-of-the-art in vivo performance, establishing a scalable infrastructure for interpretable, evidence-grounded living material discovery.

biochemistry↗

bioRxiv2026

Antibiotic Persistence Emerges from Cell-State-Driven Transcriptional Reprogramming

Antibiotic persistence allows a subpopulation of bacterial cells to survive antibiotic treatment without acquiring resistance mutations, often contributing to treatment failure. Although many genes have been linked to persistence, their deletion rarely abolishes the phenotype, highlighting redundancy in persistence mechanisms. Moreover, the transient and heterogeneous nature of persister formation has made it difficult to resolve its molecular basis using bulk analyses. Here, we use bacterial single-cell RNA sequencing and functional assays in Klebsiella pneumoniae to demonstrate how transcriptional heterogeneity and redundancy in stress responses shape persistence outcomes. Using growth phase as a biologically meaningful axis of transcriptional variation, we reveal that even within an isogenic population, distinct transcriptional responses can be induced and co-contribute to survival. These responses are shaped by the cells pre-treatment transcriptional state and the mechanism of antibiotic action. Genetic and environmental perturbations, such as rpoS deletion and nutrient supplementation, shift pre-treatment cell states and alter persistence frequencies. Our findings establish the biological significance of transcriptional heterogeneity shaped by pre-treatment cell states, providing a systems-level framework for understanding persistence and suggesting strategies to enhance antibiotic efficacy by modulating cell states.

microbiology↗

bioRxiv2026

A novel uN2CpolyG Transgenic Mouse Model Recapitulates Multisystemic polyG Proteinopathy Pathology of Neuronal Intranuclear Inclusion Disease

Neuronal intranuclear inclusion disease (NIID) is a polyglycine disease that primarily affects the neuronal and neuromuscular systems. Here, we developed a novel transgenic mouse model that faithfully recapitulates the multisystemic impairments associated with polyG intranuclear inclusions. Our findings demonstrate that polyG expression induces neurodegeneration, behavioral deficits, and age-dependent accumulation of uN2CpolyG aggregates across multiple tissues.

animal behavior and cognition↗

bioRxiv2026

Intracellular TDP-43 amyloid nucleates from arrested nascent condensates

TDP-43 is a model protein for pathophysiological phase transitions, forming a multitude of intracellular assemblies with different physical properties. Physiological condensation is widely presumed to precede pathological aggregation, but the causal relationships between different modes of assembly in vivo are still unclear. Here we use Distributed Amphifluoric FRET (DAmFRET) and complementary approaches to map the phase space of TDP-43 self-assembly in yeast cells. We discovered that the low-complexity C-terminal domain (CTD) on its own partitions into soluble clusters that dynamically arrest en route to liquid-liquid phase separation. These clusters uniquely supported amyloid formation, and only when templated by pre-existing amyloids of other proteins. Self-interacting modules outside the CTD, whether in the full-length TDP-43, pathological C-terminal fragments, or fusion partners, all suppressed amyloid nucleation. They did this by promoting CTD condensation beyond the arrested state. Stress and cotranslational self-association had the same effect. We leveraged this property of condensation to stop CTD amyloid formation by co-expressing an oligomeric binder in cells. Our findings reveal that TDP-43 amyloid formation occurs only under very specific physical and biological circumstances that present new opportunities for therapeutic control.

biophysics↗

bioRxiv2026

Innovative Methods for Prenatal Cannabis Exposure: Vapor Inhalation Chamber and Metabolite Quantification in Prairie Voles and Rats

The increasing prevalence of cannabis use, including among pregnant women, highlights the critical need for a deeper understanding of prenatal cannabis exposure. This study aimed to develop a standardized cross-species inhalation exposure protocol to administer the principal psychoactive component of cannabis, {Delta}9-tetrahydrocannabinol (THC), to prairie voles (Microtus ochrogaster) and laboratory rats (Rattus norvegicus), and to investigate the distribution of THC in maternal and fetal tissues following prenatal exposure. Using an established e-cigarette system for delivering vaporized THC, we administered THC to pregnant prairie voles and rats. THC concentrations were measured in maternal plasma and fetal brain tissue using LC-MS/MS (Liquid Chromatography coupled with Tandem Mass Spectrometry). In both species, THC levels were compared across groups to evaluate the impact of fetal position on THC uptake. We found that THC readily crossed the placental barrier in both species, resulting in significantly higher concentrations of THC in the fetal brain within the THC-exposed groups compared to the vehicle controls. Interspecies comparison revealed higher THC concentrations in rat fetal brain tissue compared to prairie voles. No significant effects of fetal position on THC levels were found for either species. The findings confirm placental transfer of THC and reveal species-specific patterns of THC distribution. Additional studies were then carried out in voles to compare plasma and brain THC levels in maternal and virgin adult prairie voles. Maternal brain THC concentrations were significantly higher than fetal brain concentrations in prairie voles. Strong positive correlations were observed between plasma and brain THC concentrations in both maternal and virgin adult prairie voles. This study establishes a translational model for investigating prenatal cannabis exposure using an aerosolized administration method in voles compared to established methods in rats. The standardized protocol and results provide a foundation for future research into the developmental consequences of prenatal cannabis exposure and offer crucial insights for informing public health policies and clinical practices in response to the global increase in cannabis use.

neuroscience↗

bioRxiv2026

ChromBERT-tools: A versatile toolkit for context-specific embedding of transcription regulators across different cell types

MotivationRepresentations that capture the genome-wide context of transcription regulators are critical for establishing a shared backbone for flexible transcription modeling and in silico regulatory analysis. Yet, current embeddings predominantly rely on limited modalities, such as gene co-expression or static protein features, offering an incomplete perspective that ignores context-dependent transcription regulator activities across the genome. The lack of transcription regulation-informed embeddings, paired with the absence of a user-friendly and lightweight toolkit for their generation, adaption to different cell types and interpretation, impedes the capture of the regulatory logic that underpin cellular states and functions. ResultsTo address this need, we present ChromBERT-tools, a lightweight toolkit designed to operationalize regulation-informed embeddings derived from a foundation model pre-trained on the comprehensive landscapes of human and mouse transcription regulators. ChromBERT-tools provides user-friendly command-line interfaces (CLIs) and Python APIs to achieve two primary goals: (i) generating cell-type-agnostic embeddings that capture the semantic representations of individual regulators and their combinatorial interactions, serving as biological priors of transcription regulator modality to enhance transcription regulation modeling and rule interpretation; and (ii) generating cell-type-specific embeddings via fine-tuned model variants, which support in silico inference of regulatory roles of transcription regulators in cell types with scarce experimental data. The toolkit streamlines end-to-end workflows for embedding generation, adaption to different cell types and interpretation towards biological inferences such as regulator-regulator interaction across the genome and key regulators determining cell identity or cell state transition. Availability and implementationChromBERT-tools is freely available at https://github.com/TongjiZhanglab/ChromBERT-tools, with documentation at https://chrombert-tools.readthedocs.io/en/latest/.

bioinformatics↗

bioRxiv2026

Monoaminergic variation, cortical structure, and disaster trauma interact to shape emotional vulnerability

Emotional vulnerability arises from the interplay of genetic variation, cortical network capacity, and subjective processing of adverse experiences, yet these components are rarely examined together in population-scale datasets. Monoaminergic signaling offers an opportunity for understanding such interactions because variation in related genes shapes sensitivity to environmental inputs. Among them, the vesicular monoamine transporter 1 (VMAT1) Thr136Ile variant is notable for its functional effects and its long-term maintenance at intermediate frequencies, a pattern consistent with context-dependent selection. These properties make it an informative marker for investigating how genetic sensitivity interacts with neurobiological and experiential factors to shape affective functioning. Using data from up to 9,625 participants in the Tohoku Medical Megabank Project, a cohort established after the 2011 Great East Japan Earthquake, we investigated how monoaminergic variation, cortical morphology, and traumatic memory shape affective functioning. We found associations between the Thr136Ile variant and negative affectivity and depressive symptoms, consistent with prior reports of heightened emotional reactivity associated with the 136Thr allele. However, magnitude of these effects was substantially amplified in specific experiential and neurobiological contexts. Subjective trauma sensitivity, capturing the discrepancy between earthquake disruption and current traumatic memory, displayed a genotype-dependent association with depressive symptoms, and this relationship was strongest when parietal or insular cortical surface area was smaller. Together, these results identify a multilevel pathway through which monoaminergic variation contributes to emotional vulnerability by interacting with both cortical network capacity and trauma processing. The context-dependent influence of monoaminergic variation may further contribute to maintenance of affective diversity in human populations.

neuroscience↗