Biology subjects

Zhu, J.

Publications and source records attributed to Zhu, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

cGAS-mediated IFN-I signaling contributes to disease progression in drug-refractory epilepsy

Epilepsy is a prevalent neurological disease with a third of patients becoming non-responsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we report that DRE disease progression is contributed by overactive cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN-I) signaling. In human DRE microglia, we observe a robust IFN-I signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we observe the activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS reduces epileptic phenotypes, glial inflammatory signatures, and neuronal transcriptomic changes, underscoring the therapeutic potential of targeting cGAS for DRE treatment.

neuroscience↗

bioRxiv2026

MolSpecFlow: Mass-Constrained Hybrid Flow Matching for Joint Molecular-Spectral Analysis

Identifying the "dark matter" of the chemical universe requires bridging the fundamental gap between molecules and mass spectra. Existing approaches struggle to accurately map between these distinct data formats, often yielding results that are either chemically implausible or inconsistent with the physical evidence. We introduce MolSpecFlow, a unified foundation model pretrained on 100 million molecules and 42 million spectra, which leverages a hybrid flow matching framework to orchestrate optimal transport paths for spectral peaks and discrete probability flows for molecular tokens. Furthermore, to guarantee the physicochemical validity of the generated structures, we incorporate explicit rule-based constraints into the generative process, utilizing a token-level mass control mechanism that strictly enforces alignment with the precursor molecular weight. MolSpecFlow establishes a new state-of-the-art on the MassSpecGym benchmark, surpassing diffusion and retrieval baselines in de novo generation (Top-1 accuracy +35%), spectral simulation, and molecular retrieval, demonstrating the power of physics-grounded unified modeling.

bioinformatics↗

bioRxiv2026

FluNexus: a versatile web platform for antigenic prediction and visualization of influenza A viruses

Influenza A viruses continuously undergo antigenic evolution to escape host immunity induced by previous infections or vaccinations, consequently causing seasonal epidemics and occasional pandemics. Antigenic prediction and visualization of influenza A viruses are crucial for precise vaccine strain selection and robust pandemic preparedness. However, a user-friendly online platform for these capabilities remains notably absent, despite widespread demand. Here, we present FluNexus (https://flunexus.com), the first-of-its-kind, one-stop-shop web platform designed to facilitate the prediction and visualization of the antigenic change in emerging variants. FluNexus features a data preprocessing module for hemagglutinin subunit 1 (HA1) and hemagglutination inhibition (HI) data across three major public health threat subtypes (H1, H3 and H5). Meanwhile, FluNexus provides an interactive interface for online antigenic prediction and offers practical guidance for researchers. Most notably, FluNexus offers the visualization of influenza A virus antigenic evolution, providing intuitive insights into its antigenic dynamics. Specially, FluNexus proposes a novel manifold-based method for positioning antigens and antisera, generating accurate antigenic cartographies even with sparse HI data. By alleviating the programming burden on biologists, FluNexus supports more informed decision-making in vaccine strain selection and strengthens surveillance and pandemic preparedness. HighlightsO_LIFluNexus features a data preprocessing module for HA1 and HI data spanning the H1, H3, and H5 subtypes. C_LIO_LIFluNexus facilitates online antigenic prediction utilizing ten state-of-the-art antigenic prediction tools, and offers practical guidance based on a comparative evaluation of their performance. C_LIO_LIFluNexus provides a visualization module for mapping antigenic evolution of influenza A viruses, incorporating a novel manifold-based method for antigenic cartography. C_LI

bioinformatics↗

bioRxiv2026

Calcium directs actin assembly via allosteric activation of formin INF2

Calcium signals spatiotemporally orchestrate cytoskeletal dynamics, typically through Rho GTPase-mediated signaling cascades, yet the direct molecular transducers that convert local calcium transients into spatially controlled actin assembly have remained elusive. Here, we uncover a structure-based mechanism by which calcium-bound calmodulin (Ca2+-CaM) directly activates formin INF2 to drive actin assembly. We demonstrate that Ca2+-CaM binds to the diaphanous inhibitory domain (DID) of INF2 with nanomolar affinity, inducing allosteric conformational changes that sterically disrupt INF2 autoinhibition. The unexpected bipartite Ca2+-CaM binding interface on INF2 enables ultrasensitive decoding of local calcium microdomains, such as ER-mitochondrial contacts, where activated INF2 promotes actin polymerization to facilitate mitochondrial fission. We further show that the Charcot-Marie-Tooth disease-associated INF2 R91G mutation enhances Ca2+-CaM binding via optimized interfacial dynamics, suggesting a gain-of-function disease mechanism. Our work establishes the Ca2+-CaM-INF2 axis as a direct molecular transducer linking spatial calcium signals to actin-dependent organelle dynamics, defining a Rho-GTPase-independent paradigm for calcium-cytoskeleton communication, with broad implications for INF2-linked pathologies.

biochemistry↗

bioRxiv2026

Targeted Delivery of Nucleic Acid and Protein Cargos into Primary Human Hematopoietic Stem Cells Using Bacteriophage T4

Here, we report, for the first time, delivery of mRNA and/or protein payloads into primary adult human hematopoietic stem cells (HSCs) using a bacteriophage-derived nanoparticle vector. We have been developing a new category of bacteriophage T4-engineered nanoparticles, termed "artificial viral vectors" (AVVs), for delivering therapeutic nucleic acid and protein complexes into human cells. Using a defined in vitro assembly-line platform, we decorated the capsid surface with mRNA and protein complexes through two outer capsid proteins, Hoc (highly antigenic outer capsid protein) and Soc (small outer capsid protein). First, we displayed a Hoc-protein G fusion protein to which HSC-targeted monoclonal antibodies (mAbs) are attached. Then we decorated the nanoparticle with the Soc-fused HIV-TAT molecule to create a positively charged capsid surface with cell penetrating function. Reporter mRNA molecules are then displayed on the capsid surface and the nanoparticle is coated with lipids. Such T4-AVVs transduced HSCs and delivered GFP and Luciferase reporter mRNAs at levels as high as 20% efficiency and exhibited targeted Ab-dependent phenotypes. Furthermore, we demonstrate simultaneous delivery of both protein and mRNA payloads, by decorating the capsid with mRNA and [~]507 kDa tetrameric {beta}-galactosidase. The AVV-transduced HSCs maintain viability, and once optimized, the T4-AVV platform will provide enormous versatility to target various types of human cells and deliver next generation therapies for cancer and genetic diseases.

bioengineering↗

bioRxiv2026

Inhibition of KDM5A/B promotes antitumor innate immune responses in HHV-8/KSHV2 positive B-cell lymphomas

Summary/AbstractHistone methylation is a dynamic and reversible epigenetic modification that critically controls the progression of human diseases, including infections and cancers. Here we reported that histone lysine demethylases (KDMs) in the KDM5 family KDM5A/B play profound roles in suppressing lytic reactivation of oncogenic human herpesvirus 8 (HHV-8), i.e., Kaposis sarcoma-associated herpesvirus (KSHV), as well as antiviral/antitumor innate immune responses in KSHV-infected B-cell lymphomas. We showed that KSHV lytic replication decreases KDM5A/B protein stability by enhancing their K-48 linked polyubiquitination while KDM5A/B depletion facilitates KSHV lytic reactivation. Mechanistic studies illustrated that KDM5A/B associate with KSHV LANA protein and dampen its chromatin association at both KSHV viral lytic promoter and promoters of antitumor immune-responsive genes (IRGs). In comparisons to normal B cells, KDM5A/B expression significantly increased in B-cell lymphoma cells, including KSHV-positive primary effusion lymphoma (PEL). We demonstrated that KDM5A/B inhibition remarkably induces both KSHV lytic reactivation and innate immune responses in PEL cells, resulting in a strong viral oncolytic effect, both in vitro in cell cultures and in vivo using a PEL xenograft mouse model. Overall, our studies identified the novel functions of KDM5A/B to silence KSHV lytic replication and antiviral/antitumor innate immune responses, which can be blocked to benefit the treatment of KSHV-associated B-cell lymphomas that are usually aggressive and difficult to treat.

microbiology↗

bioRxiv2026

Coordinated chromosome motion emerges from mechanical coupling mediated by the physical spindle environment

During metaphase, chromosomes undergo oscillatory motion and exhibit distance-dependent coordinated movement with neighboring chromosomes within the spindle. However, the physical mechanism that gives rise to coordinated chromosome motion remains unclear. Here, we combine quantitative live-cell imaging in PTK1 cells, targeted perturbations of spindle microtubules and chromatin, and minimal mechanical modeling to uncover the mechanical basis of chromosome coordination during metaphase. We show that chromosome oscillations are dampened by stabilizing microtubules or by decondensing chromatin, yet inter-chromosomal coordination is preserved. The dissociation between chromosome oscillations and chromosome coordination suggests that coordination can arise from forces transmitted through the spindle environment. To test this idea, we developed a minimal mechanical model in which oscillating chromosome pairs are coupled through transient inter-chromosomal springs, while oscillations of each chromosome pair are generated by feedback between kinetochore-microtubule dynamics and centromere elasticity. The model demonstrates that stochastic mechanical connections are sufficient to generate correlated chromosome motion. To quantify chromosome coordination in a manner that reflects the mechanical properties of the surrounding spindle environment, we employed a microrheology-inspired analysis of time-lagged chromosome displacements. This framework reveals that microtubules and chromatin play distinct mechanical roles: microtubules primarily determine the spatial range and temporal build-up of coordination, while chromatin tunes its strength. Together, our results establish coordinated chromosome motion as an emergent mechanical property of the mitotic spindle, mediated by its viscoelastic properties and collective force transmission.

cell biology↗

bioRxiv2026

Proteomic Profiling of Human Omental and Subcutaneous Adipose Tissue in Individuals with a Broad Range of BMI.

Obesity is a major public health challenge affecting an ever-increasing proportion of the global population. It is associated with numerous comorbidities. Progressive expansion and remodeling of adipose tissue may lead to depot specific changes in adipose tissue biology and energy partitioning. Such changes likely precede the development of obesity-related complications. To facilitate a deeper understanding of adipose tissue biology, a comprehensive and quantitative proteomic dataset at the peptide and protein level is presented. Data-independent acquisition LC-MS/MS data were acquired from matched subcutaneous and omental adipose tissues from metabolically healthy individuals with no comorbidities and covering a wide range of body mass indexes. Adipose tissue samples were collected during elective surgeries and immediately processed for histology or frozen until proteomic analysis. Internal and external quality control systems ensured high quality data. All data presented are available via ProteomeXchange. This dataset will allow new insights into biological changes that evolve with increasing adiposity captured before the onset of comorbidities. Matched sampling across fat depots provides an opportunity to uncover depot-specific physiological signatures.

systems biology↗

bioRxiv2026

Extending Conformational Ensemble Prediction to Multidomain Proteins and Protein Complex

Proteins execute cellular functions through a structural continuum ranging from stable, folded domains to highly dynamic intrinsically disordered regions (IDRs). Conformational ensembles represent the set of three-dimensional structures a protein adopts under a specific set of conditions, and underlie essential processes from catalysis to complex signaling networks. While deep learning has revolutionized structure prediction, capturing the distinct conformational diversity of folded and disordered regions--especially within multidomain proteins and large assemblies--remains a fundamental challenge. Here we introduce IDPFold2, a generative framework that models the heterogenous protein thermodynamics by integrating a Mixture-of-Experts architecture into the flow matching framework. By routing residues from different regions to specialized expert networks, IDPFold2 accurately predicts conformational ensembles for folded domains, IDRs and multidomain proteins. IDPFold2 outperforms state-of-the-art methods in capturing key functional states and fitting the experimental observations across local and global scales. Furthermore, we describe an extension of IDPFold2 to protein assemblies, deciphering the complex binding modes of IDRs within large macromolecular complexes, providing a generalizable tool for exploring the dynamic proteome.

bioinformatics↗

bioRxiv2026

Soluble DLK1 secreted by telomere-shortening-induced senescent microglia impairs oligodendrocyte functions and alters neuronal activity

Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. Because telomere erosion is a hallmark of aging, we examined its impact on glial and neuronal physiology. Telomere shortened mice showed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single nuclei RNA-seq revealed accelerated glial aging, elevated microglial senescence pathways, and impaired oligodendrocyte functions. Inducing senescence in human iPSC derived microglia with shortened telomeres identified soluble DLK1 as a novel senescence associated ligand. sDLK1 was increased in the cerebrospinal fluid of telomere shortened and naturally aged mice, and this increase was eliminated by microglial depletion. AAV delivery of sDLK1 in vivo caused hypomyelination and blocked oligodendrocyte lineage progression, demonstrating the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

neuroscience↗

bioRxiv2026

Ultra-fast genetic recovery of dead fish through cross-family germline stem cell transplantation

AbstactThe conservation of genetic resources from aquaculture species and endangered fish is increasingly challenged by large body size, long reproductive cycles, and limited opportunities for timely intervention after death. Here, we establish and validate an ultra-fast genetic platform based on germline stem cell transplantation to enable postmortem genetic recovery in fish. Using grass carp (Ctenopharyngodon idella) as a representative warm-water species, we systematically quantified the relationships among postmortem tissue freshness, germline stem cell viability, and transplantation efficiency, and demonstrated that low-temperature preservation plays a decisive role in maintaining germline activity after death. Germline stem cells isolated from deceased grass carp were transplanted into germ-cell-depleted zebrafish recipients, where they rapidly colonized recipient gonads, underwent proliferation and differentiation, and generated functional donor-derived gametes within three months. These gametes supported successful fertilization and normal embryonic development, ultimately yielding viable grass carp offspring. Our results reveal an intrinsic postmortem resilience of germline stem cells and demonstrate that cross-species transplantation into small, fast-maturing hosts can dramatically accelerate genetic recovery. This strategy overcomes key biological and logistical constraints associated with conventional breeding-based rescue approaches and provides a rapid, scalable, and broadly applicable framework for postmortem genetic resource conservation in aquaculture and endangered fish species.

zoology↗

bioRxiv2026

DNA sequence quantitatively encodes CTCF-binding affinity at genome scale

CTCF is a central architectural protein that shapes 3D genome organization through sequence-specific DNA binding, but how DNA sequence quantitatively determines CTCF-binding strength remains poorly understood. Progress has been hampered by the lack of large, high-quality measurements of binding affinity. Here, we experimentally determine in vitro CTCF-binding affinity for 276,765 DNA sequences derived from the human genome, generating a comprehensive quantitative landscape of CTCF-DNA interactions. Leveraging these data, we develop DeepCTCF, a deep learning model that predicts CTCF-binding strength directly from DNA sequence and enables quantitative interpretation of CTCF motif grammar. Using this framework, we systematically dissect how specific sequence features modulate CTCF-binding affinity and generate quantitative predictions for disease-associated variants that alter CTCF binding. Together, this study defines general principles by which DNA sequence encodes CTCF-binding affinity and provides a quantitative framework for interpreting regulatory sequence variation. TeaserMapping how DNA encodes CTCF binding reveals quantitative rules across over 1{per thousand} of the human genome.

genomics↗

bioRxiv2026

PRADA-DTI: A Prototype-Retrieval Augmented Domain-Adaptation Framework for Drug-Target Interaction Prediction

Drug target interaction (DTl) prediction is a fundamental task in computational drug discovery. However, most existing DTI models assume a static learning environment, whereas real-world biomedical data are dynamic, characterized by the continuous emergence of new protein families and interaction patterns. This poses major challenges for model generalization and continual adaptation, especially under privacy and data-access constraints. To address these issues, we introduce PRADA-DTI, a retrieval-augmented, parameter-efficient framework for domain-incremental DTI learning. Built on a shared physicochemical backbone, PRADA-DTI learns domain-specialized prompts for representation-level modulation, coupled with Low-Rank Adaptation (LoRA) modules for parameter-space adaptation. At inference, protein embeddings query a compact prototype memory without storing raw molecular data, retrieving similar domains to dynamically compose the relevant prompts and LoRA parameters without requiring domain labels. This retrieval-guided composition enables continual learning from new protein domains while mitigating catastrophic forgetting on previous ones. On BindingDB and BIOSNAP benchmarks, PRADA-DTI substantially outperforms state-of-the-art continual learning and parameter-efficient baselines in both predictive accuracy and forgetting mitigation with minimal parameter updates. Interpretability analysis through residue-level attribution visualization demonstrates that the model correctly attends to binding pocket regions across different protein domains, confirming that the retrieval-guided adaptation mechanism captures biologically relevant structural patterns. These results demonstrate the effectiveness of retrievalaugmented parameter adaptation for continual drug discovery.

bioinformatics↗

bioRxiv2026

Gliomas preferentially develop within the action-mode network

Gliomas tend to arise in specific brain regions and may integrate into functional circuits, suggesting they could be regulated by brain activity. However, it remains unclear whether glioma growth is related to system-level brain networks. Analyzing neuroimaging data from three datasets including 1,310 patients with cerebral gliomas, we identified and replicated a functionally connected glioma network, which overlaps with the action-mode network (AMN), somatomotor network (SMN), and action-related subcortical regions. Resting-state functional connectivity (RSFC) of the AMN successfully predicted the location of glioma occurrence in two independent datasets with complex tumor distributions. Remarkably, no patient had a glioma entirely outside the AMN, and over 89% of patients exhibited gliomas with at least 50% overlap with the network. Moreover, the spatial overlap between glioma location and the AMN demonstrated significant prognostic value in survival analyses, with higher AMN-tumor overlap associated with poorer overall survival. Notably, the acetylcholine transporter, a key player in glioma pathogenesis that drives transcriptional reprogramming, showed an expression pattern overlapping with the AMN. Meta-analytic annotations further linked the glioma network to processes of action initiation, execution, and feedback. These findings indicate that gliomas preferentially arise in circuits involved in action and highlight the central role of the AMN in glioma pathophysiology and growth.

neuroscience↗

bioRxiv2026

Regional analysis of spatiotemporal trends in Colorado potato beetle abundance

Crop pests can significantly damage crops, cause economic loss, and reduce the sustainability of agroecosystems. New ecoinformatic approaches are needed to understand the drivers of pest population dynamics and improve pest management practices. Here we analyze spatiotemporal drivers of Colorado potato beetle (CPB, Leptinotarsa decemlineata) abundance across Wisconsin potato fields using multi-year scouting data (2014-2024) linked with climate and cropping histories. We develop statistical models that account for spatial and temporal correlations, and find these approaches substantially improve fit and prediction. After accounting for spatiotemporal random effects, we find that three predictors increased CPB abundance: cumulative growing degree days (GDD), recent potato intensity in the surrounding landscape, and winter coldest-day temperature. Cumulative GDD and potato intensity are positively associated with abundance, and warmer winter minima (higher coldest-day temperatures) are likewise associated with higher abundance, consistent with improved overwintering survival. Using the best-performing model, we generate a preliminary, statewide risk surface for Wisconsin in order to support regional decision-making. Our results highlight the value of integrating field-level history with landscape context and explicit spatial structure when forecasting pest pressures in agroecosystems.

ecology↗

bioRxiv2025

A Foundational Generative Model for Cross-platform Unified Enhancement of Spatial Transcriptomics

Spatial transcriptomics (ST) platforms are limited by spatial resolution, sensitivity to low expression levels, alignment with tissue structures, and the balance across tissue complexity. Computational enhancement typically targets a single challenge, e.g., super-resolution using hematoxylin and eosin (H&E) images or sensitivity enhancement with single-cell RNA sequencing (scRNA-seq). However, most ignore the interdependence across challenges, yielding biologically inconsistent enhancement. Here we introduce FOCUS, a foundational generative model for unified ST enhancement, conditioned on H&E images, scRNA-seq references, and spatial co-expression priors. With large-scale pretrained encoders, FOCUS uses a modular design for multimodal integration and a cross-challenge coordination strategy to target co-occurring challenges, enabling joint optimization. FOCUS was trained and comprehensively benchmarked on >1.7 million H&E-ST pairs and >5.8 million single-cell profiles, demonstrating state-of-the-art performance across ten ST platforms, on both individual and coupled challenges. The real-world utility and generalizability were validated on a rare suprasellar tumor, papillary craniopharyngioma, and an unseen ST platform (Open-ST) for primary and metastatic head and neck squamous cell carcinoma.

bioengineering↗

bioRxiv2025

New potential antimicrobial peptides with amazing symmetrical structure in fungi and insects

We have discovered a new family of genes encoding potential antimicrobial peptides with unique compact and elegant structure in the genomes of several Fungi and some arthropod species. Their expression products are constituted of about 85 amino acids, including a signal peptide, and are folded into two -helical segments connected by a short unstructured coil. Three conserved disulphide bridges between cysteines located in symmetrically mirrored positions connect the two helical domains. The two ends of the chain are thus brought together and the elongated and compact shape suggests that of a nail, potentially able to penetrate the cell membrane. A high abundance of hydrophobic residues supports such hypothesis. These peptides, that we name Hairpin Loop Peptides (HLPs), have been found in the genomes of many Fungi species but only in selected clades. Orthologues have also been discovered in the genomes of some insects, notably Hemiptera, a few other arthropods and other organisms, but are absent in plants. They appear to have originated in Fungi and then migrated to insects through horizontal gene transfer. The antimicrobial activity of HLPs is predicted by several software programmes, although this still needs to be confirmed by experimental evidence. The occurrence of HLPs in several edible mushrooms supports potential uses of these peptides in food preservation and possibly also in medical applications. Their simple and nearly rigid structure can be easily modified to improve specificity, stability and solubility, thus making these molecular weapons suitable for a variety of different applications. Significance statementThe increasing emergence of bacteria resistant to current antibiotics has stimulated a rapid search for alternative treatments. In recent years, antimicrobial peptides have attracted considerable interest for their potential applications in medicine and as food preservatives. We have identified a new class of peptides primarily expressed in fungi, including edible mushrooms, and also detected in some insects and other arthropods, likely as a result of horizontal gene-transfer events. These peptides are particularly noteworthy because of their compact, elongated, and highly symmetrical structures, which give them a nail-like shape capable of penetrating cellular membranes. Such structural features suggest potential antimicrobial activity, a prediction supported by computational analyses. Their widespread presence in edible mushrooms further indicates the potential safety of these peptides for human use.

microbiology↗

bioRxiv2025

Two Small Proteins Enable N2O Reduction in Acidic Environments

Denitrifying bacteria are major contributors to nitrous oxide (N2O) emissions, which rise with global soil acidification, likely because low pH impairs maturation of the periplasmic enzyme N2O reductase (NosZ) in most bacteria. While some bacteria can reduce N2O under acidic conditions, the underlying mechanism remain unclear. Here, we isolated bacteria from acidic soils and identified strains that efficiently reduce N2O at low pH. They carry two novel proteins, NosP and NosQ, along with NosZ clade I. Functional analyses of deletion mutants demonstrated that NosP and NosQ are essential for the maturation of NosZ at low pH, but are not required at circumneutral pH. Cryo-EM analysis indicates that NosPQ forms a protective complex with NosZ, safeguarding its maturation under acidic conditions. Metagenomic analysis shows that nosPQ genes are widely distributed across diverse bacterial taxa and soil types. Our findings reveal a key molecular adaptation mechanism for N2O reduction in acidic environments and provide valuable insights for developing efficient N2O mitigation strategies.

biochemistry↗