Biology subjects

Xu, H.

Publications and source records attributed to Xu, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation MTA-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated mechanisms of acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was not fully explained by alterations in PRMT5 activity or reduced MTA levels. Instead, resistance was associated with collateral sensitivity to MEK inhibition and enrichment of MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as an actionable collateral vulnerability in MTAP-null NSCLC cells that acquire resistance to PRMT5 inhibition.

cancer biology↗

bioRxiv2026

Targeting ALA3 with propiconazole regulates plant growth and enables discovery of promising inhibitor leads

Propiconazole (PCZ) is widely misused growth regulator in leafy Brassica vegetables. Developing green strategies for managing plant architecture has become an urgent agricultural priority. Here, we identified from a membrane-protein-defective yeast library a P4-ATP phospholipid flippase, aminophospholipid ATPase 3 (ALA3), as a target sensitive to PCZ. ALA3 exhibits high binding affinity for PCZ, which inhibits its ATPase activity. Knockdown of ALA3 rendered yeast, Arabidopsis, and Brassica rapa less sensitive to PCZ and conferred a growth-inhibited phenotype. This dwarfing phenotype is mediated through the interaction between ALA3 and CYP51G1 that jointly acts within the brassinosteroid regulatory pathway. Furthermore, we identified lead compounds A01 and A15 as ALA3-targeting agents, and compared to PCZ, they display superior binding affinity and reduced toxicity. Our work establishes ALA3 as a key mediator of PCZ-induced dwarfism and provides dual strategies--creating promising varieties through gene editing and developing targeted green pesticides--to reduce PCZ use. TeaserTargeting ALA3 reduces PCZ use through gene-edited varieties and green pesticides.

plant biology↗

bioRxiv2026

Therapeutic knockdown of MLKL reduces diet-induced obesity and improves insulin signalling in mature adipocytes

Obesity affects one in three adults and is complicated by adipose inflammation, lipotoxicity and cell death. We previously identified RIPK1 as a genetic determinant of human obesity risk and adipose inflammation. Because RIPK1 is the apical kinase in the necroptosis pathway upstream of RIPK3 and the executioner protein MLKL, and emerging evidence links MLKL to lipid metabolism, MLKL has surfaced as a potential metabolic regulator. However, conflicting findings in Mlkl knockout mice fed a high fat diet have left its therapeutic relevance unresolved. MLKL has not been previously targeted through therapeutic knockdown in vivo in the context of diet-induced obesity. Here, we evaluated two independent MLKL antisense oligonucleotides (ASOs) in high fat diet (HFD)-fed C57BL/6J mice. In a 24-week progression model, MLKL ASO markedly reduced body weight, fat mass and hepatic steatosis compared with controls, while preserving lean mass. MLKL knockdown also lowered the respiratory exchange ratio, indicating a shift toward increased fat oxidation. In the intervention model, once obesity was established after 12 weeks of HFD feeding, both MLKL ASOs, and similarly, two independent RIPK1 ASOs, reversed weight gain and improved systemic glucose control. In vitro, MLKL-CRISPR/Cas9 knockout blocked 3T3-L1 adipogenesis, indicating a requirement for MLKL during adipocyte differentiation. However, in mature adipocytes, MLKL siRNA reduced palmitic acid-induced lipid accumulation, increased isoprenaline-stimulated lipolysis, and prevented TNF-mediated suppression of insulin-mediated AKT signalling and glucose uptake. Collectively, these findings demonstrate that partial MLKL suppression reprograms whole-body energy metabolism, enhances insulin sensitivity and limits diet-induced adiposity. MLKL, therefore, represents a promising and mechanistically novel therapeutic target for obesity and insulin resistance.

physiology↗

bioRxiv2026

The BraALA3 Homologs Mediate Propiconazole-Modulated Plant Growth in flowering Chinese cabbage

In agriculture, propiconazole (PCZ) controls excessive growth in flowering Chinese cabbage but poses dietary safety risks due to residue accumulation. Therefore, identifying novel PCZ targets and breeding PCZ-free cultivars is critical for the safe production of flowering Chinese cabbage. Here, we identified three P4-ATPase flippase homologs aminophospholipid ATPase 3 (BraALA3a/b/c) in flowering Chinese cabbage that function as sensitive targets for PCZ. These proteins exhibit high binding affinity for PCZ, which directly inhibits their ATPase activity. Overexpression of the BraALA3 homologs enhanced plant growth and increased sensitivity to PCZ, whereas knockdown led to dwarfism and reduced sensitivity. Based on these findings, we identified editable active sites via protoplast-based screening. Genetic transformation of one such site yielded BraALA3a/braala3aK200T mutant lines, which displayed a dwarf and compact architecture. These findings provide a precise molecular target for developing PCZ-free germplasm in flowering Chinese cabbage through gene editing.

plant biology↗

bioRxiv2026

Vascularized Human Cardiac Organoids Reveal Endothelial-Cardiomyocyte Crosstalk and Mechanisms of Carfilzomib-Induced Cardiotoxicity

Human cardiac organoids (hCOs) provide a powerful platform for modeling heart development and disease, yet their lack of vasculature limits physiological relevance. Here, we generate vascularized human cardiac organoids (vhCOs) by assembling hCOs with blood vessel organoids, enabling the self-organized formation of unified tissues with extensive vascular networks and substantially enhanced cardiomyocyte (CM) maturation. Single-nucleus multiomic profiling reveals CM state resembling the 17-week human fetal heart, while endothelial cells (ECs) acquire cardiac-specific and arterial-like identities. Integrative cell-cell communication analyses and experimental validation identify CM-derived Laminin-2 as a driver of arterial EC specification, while reciprocal EFNB2 signaling from arterial ECs promotes CM maturation, uncovering bidirectional cardiac-vascular crosstalk. Modeling carfilzomib-induced cardiotoxicity in vhCOs reveals ATF4-dependent endoplasmic reticulum (ER) stress and IL8-mediated inflammatory responses that are blunted in non-vascularized hCOs. Pharmacological attenuation of ER stress alleviates carfilzomib-induced cardiotoxicity. Altogether, vhCOs provide a developmentally advanced and physiologically faithful human cardiac model.

cell biology↗

bioRxiv2026

Expectation triggers a change-like EEG response without acoustic change

Predictive processing theories posit that the auditory system continuously generates expectations and updates internal models when incoming evidence violates those expectations. Whether such updating can be expressed as a temporally precise, change-like neural response at a context-defined moment during continuous stimulation--without any physical change--has remained unclear. Using a transitional click-train paradigm in human EEG, we show that listeners reliably detect subtle midpoint transitions when click timing is fixed, whereas temporal uncertainty markedly weakens this sensory-driven detection. Strikingly, even in a physically unchanged stimulus, variable click timing elicits a robust response time-locked to the nominal midpoint. This endogenous change-like signal is stimulus-statistics dependent--absent in the fixed-timing no-change control--temporally confined to the early post-change window, and strongly state dependent, being amplified during active change detection relative to passive listening. Moreover, within identical no-change trials, the response tracks subjective change reports. Together, these findings show that temporal uncertainty and task engagement jointly gate predictive updating in continuous auditory streams, providing a compact assay to dissociate sensory-driven change responses from context- and state-dependent predictive signals.

neuroscience↗

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

Mosaic terrestrial diversity dynamics through the Permo-Triassic interval

The end-Permian mass extinction (EPME) represents the most severe biotic crisis of the Phanerozoic Eon on Earth and has been well documented in marine taxa. However, its impact on terrestrial organisms and ecosystems remains incompletely understood. Here we present a high-resolution reconstruction of terrestrial diversification dynamics and spatial reorganization across the Permo-Triassic boundary (PTB) using comprehensive occurrence data of macroplants, sporomorphs and vertebrates. Terrestrial responses to the EPME show highly temporal, regional and taxonomic heterogeneities. Plants experienced a genus-level diversity loss of [~] 6.7%, across the PTB, whilst vertebrates, a lagged decline from the late Permian, peaking at a diversity loss of [~] 66.7%. Global distributions of plant and vertebrate show converging on similar latitudinal gradients post the PTB. Plant diversity loss is disproportionately high in low-latitude and tropical regions and progressively lower toward mid- and high-latitudes. Our study facilitates a fine-grained understanding to terrestrial macroevolution in geologic history through multi-analysis of a large volume of fossil data. Our findings challenge the long-held notion of global terrestrial collapse and mass extinction in plants during the PTB and offer a deep-time analogue for uneven response of extant terrestrial biodiversity to ongoing climate change.

paleontology↗

bioRxiv2026

A nucleolar stress gene signature for quantitative scoring across multi-omics contexts

The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, which has been implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological alterations or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) that is applicable across bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signalling, whereas these responses are attenuated in oxaliplatin-resistant cells. In combination with a ribosome biogenesis activity score (RiboSis), NuS captures related yet distinct dimensions of nucleolar function and stratifies tumors into functional states associated with distinct clinical outcomes. Furthermore, NuS-based analysis of perturbational transcriptomes enables prioritization of compounds with putative nucleolar stress-inducing activity. Collectively, this study establishes a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.

cell biology↗

bioRxiv2026

An oxytocin-gated circuit from the hypothalamus silences olfactory tubercle neurons to drive prosocial grooming

Spontaneous helping behaviors such as allogrooming are vital for survival in social species, yet their underlying neural mechanisms remain largely unknown. Although oxytocin (OXT) is known to modulate allogrooming, the precise neural circuits, molecular pathways, and sensory drivers remain unclear. Here, using a social emergency paradigm in mice, we show that observer mice selectively allogroom distressed, anesthetized conspecifics, a behavior that is guided by main olfactory system cues and mitigates the demonstrators anxiety. We identify an oxytocinergic circuit from the paraventricular hypothalamus to the medial olfactory tubercle (PVNOXT[->]mOT) that is necessary and sufficient for this helping behavior. In vivo fiber photometry reveals that PVNOXT[->]mOT activity and OXT release are temporally locked to allogrooming initiation. This behavioral effect requires oxytocin receptor (OXTR) signaling specifically on mOT dopamine D1 receptor-expressing neurons, where OXTRs suppress neuronal excitability via G protein-gated inwardly rectifying K+ (GIRK) channels. Disruption of this inhibitory mechanism induces neuronal hyperexcitability and impairs allogrooming, a deficit rescued by restoring GIRK function. These findings define a PVNOXT-mOT circuit for prosocial helping, revealing an oxytocinergic pathway with potential therapeutic relevance for neuropsychiatric disorders characterized by social deficits.

neuroscience↗

bioRxiv2026

Beyond Acoustic Cues: Olfactory-Mediated Avoidance of Bats by Crickets

The evolutionary arms race between insectivorous bats and their insect prey is a classic paradigm of acoustic predation and evasion, with insects having evolved sophisticated auditory countermeasures. Both bats and insects also rely heavily on olfaction for key behaviors, such as social communication. Moreover, predator-derived odors are well-established as risk cues in many other predator-prey systems. However, whether olfaction plays a role in the bat-insect arms race remains unknown. Here, we unveil a previously unknown olfactory dimension to this interaction. We demonstrated that the body odor of the insectivorous bat Scotophilus kuhlii triggered robust avoidance and electrophysiological antennal responses in a common cricket prey, Loxoblemmus equestris. We identified limonene as a behaviorally active volatile in bat odor that elicited electrophysiological responses in cricket antennae and was sufficient to elicit avoidance in crickets. Field experiments confirmed that limonene exposure reduced cricket calling activity, demonstrating the ecological relevance of this cue. Our findings establish that insects can detect and initiate avoidance of phylogenetically distant vertebrate predators via olfaction, a process that could be mediated by the elemental perception of individual odor compounds. This work broadens the sensory framework of a classic predator-prey system, and highlights olfactory eavesdropping as a functional strategy in phylogenetically distant predator-prey systems.

ecology↗

bioRxiv2026

Hydrogel Fiber Endomicroscopy

Multimode fibers enable minimally invasive, high-resolution imaging through ultrathin probes, thereby enhancing diagnostic precision and facilitating real-time monitoring in delicate anatomical regions. In this work, we introduce HYFEN, a hydrogel-based endomicroscopic imaging platform for flexible, biocompatible, and subcellular-scale fluorescence microscopy. HYFEN leverages the unique properties of hydrogel materials, adaptive optics, and pixel-wise image enhancement to address challenges associated with silica-based fibers, including mode scrambling, limited field of view, and mechanical rigidity. The technique achieves precise mode threading, rapid diffraction-limited focusing at kilohertz speeds, and high-fidelity fluorescence signal acquisition with subcellular resolution. Notably, the approach extends fluorescence imaging under enhanced fiber dimensions and bending conditions that are unachievable with conventional modalities. Together, these advances establish HYFEN as a versatile platform for next-generation biointerfacing and minimally invasive imaging across biomedical and clinical settings.

bioengineering↗

bioRxiv2026

EvoRMD: Integrating Biological Context and Evolutionary RNA Language Models for Interpretable Prediction of RNA Modifications

RNA modifications are essential regulators of post-transcriptional gene expression, influencing RNA stability, localization, translation, and degradation. Determining the specific modification at a given nucleotide is therefore critical for understanding its regulatory role. Most computational approaches treat each modification type as an independent binary task. This strategy provides a macro-level statistical perspective, but it does not reflect that, under a defined biochemical or cellular condition, only one modification type can occur at a specific site. Current mapping assays also report a single observed modification per site, leaving all other types unlabeled rather than truly negative. These properties motivate a framework that can reason over competing modification types. We introduce EvoRMD, a unified model for biologically contextualized and interpretable prediction of RNA modification types. EvoRMD integrates contextual sequence embeddings from a large-scale RNA language model with structured biological metadata--including species, organ, cell type, and subcellular localization. A lightweight attention mechanism highlights informative sequence positions. A shared multi-class classifier then generates a context-conditioned plausibility distribution over eleven modification types (Am, Cm, Um, Gm, D, pseudouridine, m1A, m5C, m5U, m6A, m7G), consistent with the single-positive, multiple-unlabeled nature of existing datasets. Although trained in a multi-class setting, EvoRMD also produces calibrated multi-label predictions through sigmoid-transformed logits, enabling direct comparison with existing single-modification and multi-label methods. EvoRMD achieves strong predictive performance and offers interpretable insights through attention profiles and motif analyses. Together, these components establish a biologically grounded framework for identifying and prioritizing RNA modification types from sequence and context.

bioinformatics↗

bioRxiv2026

Clarified an rDNA Gene Unit Pattern with (CTTT)n and (CT)n Microsatellites Aggregation Ahead of and Behind the Gene in Human Genome

BackgroundConventional models of human ribosomal DNA (rDNA) array organization have historically depended on transcription-centric boundaries, partitioning the unit into a [~]13 kb rDNA transcription region and a monolithic [~]31 kb intergenic spacer (IGS). While our previous identification of Duplication Segment Units (DSUs) mapped these arrays based on an intuitive analysis of the microsatellite density landscape of the complete reference human genome, our present deep mining of this landscape has revealed a more accurate rDNA Gene Unit Pattern. Methods & ResultsIn this study, we conducted a deep mining analysis of our previously established microsatellite density landscape of the T2T-CHM13 assembly, focusing specifically on nucleolar organizing regions (NORs). We suggest a more accurate rDNA Gene Unit Pattern containing a (CTTT)n microsatellite aggregation ahead of the rDNA gene and a (CT)n microsatellite aggregation behind the gene, rather than a pattern featuring an IGS region inserted between two rDNA genes. ConclusionsA correct rDNA gene pattern of the human genome probably includes a (CTTT)n microsatellite aggregation ahead of the gene and a (CT)n microsatellite aggregation behind it, which possibly constitute cis- and trans-regulating regions; the (CTTT)n and (CT)n microsatellite aggregations may provide two different local stable DNA structures for regulatory protein binding.

genetics↗

bioRxiv2026

Gq-pathway activation in hippocampal CA1 astrocytes rescues ischemia-induced memory deficits and synaptic plasticity

More than 30% of stroke survivors develop post-stroke cognitive impairment (PSCI), for which current neuron-centric therapies not only lack cellular specificity but also carry risks of adverse effects such as epilepsy. Here, we explore the therapeutic potential of astrocytes by chemogenetically activating Gq signaling in hippocampal astrocytes, which rescues memory deficits and synaptic plasticity impairments in a mouse model of ischemic stroke. Gq activation restores dendritic complexity, spine density, and long-term potentiation in hippocampal CA1 neurons. Fiber photometry further reveals that astrocytic Ca{superscript 2} signals precede neuronal activity by 600 ms during novel environment exploration, indicating that astrocytes prime memory encoding. In contrast, Gi pathway activation induces pathological neuronal hyperactivity without cognitive improvement. These findings establish that astrocytes regulate post-stroke recovery through pathway-specific calcium signaling and uncover a previously unknown temporal hierarchy in astrocyte-neuron communication during memory processing, offering a new glia-targeted strategy to overcome the limitations of current neuromodulation approaches for PSCI.

neuroscience↗

bioRxiv2026

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

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

immunology↗

bioRxiv2026

Nucleotide-dependent Structural Selection Governs c-Src Phosphorylation of Oncogenic KRas4B-G12D

c-Src, the first identified oncogene, and KRas, one of the most frequently mutated proteins in human cancers, can activate each other to promote tumorigenesis. Although normal KRas proteins cycle between the inactive GDP bound and the active GTP bound forms, oncogenic mutants are predominantly GTP bound. Importantly, c-Src preferentially recognizes and phosphorylates the GTP-bound form of KRas but the molecular mechanism underlying this specific recognition remains unknown. Here, we employ molecular simulation tools to identify the mechanism underlying the c-Src recognition of the GTP-loaded state of the G12D mutant of KRas4B (the most prevalent in humans). Combining extensive all-atom Molecular Dynamics simulations and Markov State Models analysis, we found that the most populated states of GTP-bound KRas maintain more open and dynamic switch regions, facilitating easier access of c-Src to the phosphorylation sites of KRas (Tyr32 and Tyr64). These states are sparsely populated for GDP loaded KRas. Docking calculations refined by molecular dynamics identify two c-Src specific regions (residues 340-359 and 453-473) able to stabilize phosphorylation-competent KRas conformations. Therefore, c-Src engages highly populated macrostates of GTP-loaded KRas, while interactions with the GDP form are limited to rare conformations. These KRas conformations selectively recognized by c-Src constitute privileged targets for the rational design of peptide-based or small-molecule inhibitors that specifically target active KRas4B-G12D while sparing the inactive GDP-bound form.

biophysics↗

bioRxiv2026

Indazolone-Based Molecular Glue Degraders as a Tunable Platform for Reprogramming Cereblon Substrate Specificity

Molecular glue degraders (MGDs) represent a transformative modality in drug discovery, with the cereblon (CRBN)-MGD axis offering a strategic gateway to systematically address the historically undruggable proteome. However, the limited chemical diversity of existing CRBN-mediated MGDs has constrained the full exploration of the degradable landscape. Here, we introduce an innovative indazolone-based platform that extends beyond canonical isoindolinone-glutarimide scaffolds, significantly expanding the accessible chemical space for CRBN modulation. Guided by mechanistic insights into CRBN-MGD complex conformational plasticity, we rationally designed indazolone architectures as novel CRBN ligands, developing diverse MGDs with potent ligase binding and exceptional substrate programmability. This platform enables fine-tuned control over neo-substrate recognition, supporting diverse degradation profiles ranging from the broad targeting of critical proteins (IKZF1/3, ZFP91, and LIMD1) to the exquisitely selective degradation of CK1 and IKZF2. Beyond expanding the chemical landscape for intractable targets, our indazolone-based MGDs exhibit favorable pharmacokinetic properties, offering robust promise for therapeutic development. Collectively, the remarkable tunability and exceptional neo-substrate programmability of the indazolone-based platform provide a highly transformative blueprint for next-generation MGD discovery, enabling systematic exploration of the vast CRBN-accessible proteome. Furthermore, as superior CRBN ligands, this platform holds immense potential for PROTAC discovery to systematically address previously intractable targets.

biochemistry↗