Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

LARP4 is a B cell-specific metabolic checkpoint for plasma cell differentiation and a therapeutic target in systemic lupus erythematosus

RNA-binding protein LARP4 plays an important role in T cell activation and differentiation, but its role in B cell biology and the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study found that LARP4 was specifically highly expressed in B cells of SLE patients and was positively correlated with disease activity. By constructing T cell-specific and B cell-specific conditional knockout mice, we found that deletion of LARP4 in B cells, but not in T cells, significantly alleviated pristane-induced and Bm12-induced lupus nephritis. Further analysis showed that LARP4 deletion selectively inhibited B cell differentiation into plasma cells, but did not affect germinal center B cell formation. Integrated transcriptomic and metabolomics analyses revealed that this effect is due to reduced phosphatidic acid synthesis and decreased mTORC1 activity caused by mitochondrial oxidative phosphorylation dysfunction. Furthermore, we used LIPEP, a LARP4 inhibitory peptide that effectively mimicked the therapeutic effects of LARP4 gene knockout in the MRL/lpr spontaneous lupus model and outperformed cyclophosphamide in reducing glomerular immune complex deposition and improving extrarenal dermatitis. These results indicates that LARP4 is a key metabolic checkpoint regulating B cell differentiation into Plasma cells and suggest that it may be a potential therapeutic target for SLE.

immunology↗

bioRxiv2026

FUNCTIONAL FRAGMENTATION AND STRUCTURAL DRIVERS OF THALAMO-CORTICAL CIRCUITS IN TEMPORAL LOBE EPILEPSY

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSObjectiveC_ST_ABSIn temporal lobe epilepsy (TLE), the thalamus acts as a nexus in a pathophysiological network that implicates mesiotemporal, subcortical, and neocortical regions. Studying a large multimodal and multicentre dataset, we profiled thalamic, hippocampal, and neocortical functional connectivity (FC), assessed structural mediators, and examined clinical associations. MethodsWe studied resting-state FC alongside structural and diffusion MRI data in 250 unilateral TLE patients and 259 healthy controls, with measures aggregated across four independent datasets. Data were processed using open-access neuroinformatics workflows and analyzed at a subregional level to maximize anatomical precision. Statistical analysis and mediation models assessed between-group FC changes, structural contributors, and clinical correlations. ResultsCompared to controls, TLE patients presented with reduced thalamo-cortical FC, which was most marked in mesiotemporal, fronto-central, and occipital regions. Thalamo-hippocampal FC was also reduced, with effects seen in all CA subfields. In the thalamus, FC reductions peaked in the ventral posterior nucleus when considering neocortical target regions and in the mediodorsal nucleus when considering hippocampal target regions. While ipsilateral hippocampal volume and diffusion changes mediated thalamo-hippocampal FC, thalamo-cortical FC appeared decoupled from structural alterations. Findings were consistent in left and right TLE patients, in patients with short and long disease duration, and across imaging sites, suggesting that thalamo-cortical FC imbalances are a consistent signature of TLE. Conversely, thalamo-hippocampal FC was elevated in patients with focal-to-bilateral-tonic-clonic seizures and FC alterations were more marked in the subgroup of operated patients that became seizure-free after surgery. ConclusionOur multi-site findings demonstrate marked thalamic circuit fragmentation in TLE. Ipsilateral findings robustly showed subdivision-specific effects, which point to both mesiotemporal co-lateralization as well as broader system-level involvement. Mediation analyses furthermore confirmed a key role of hippocampal pathology in disrupted thalamo-hippocampal connectivity in TLE, while broader thalamo-cortical fragmentation becomes increasingly independent of mesiotemporal compromise. Critically, thalamic FC represents a network substrate for seizure generalization and can serve as a prognostic indicator for surgical outcome. These results underscore the contribution of the thalamus as a hub in macroscale dysfunction in TLE.

neuroscience↗

bioRxiv2026

Mechanism of fatty acid uptake and inhibition in human FATP2

Fatty Acid Transport Protein 2 (FATP2) couples fatty acid uptake to intracellular activation and is associated with pathological lipid accumulation in cancer and nonalcoholic fatty liver disease. Here, we present cryo-electron microscopy structures of human FATP2 across its reaction cycle. Our structures suggest that FATP2 recruits fatty acids directly from the membrane interface through a hydrophobic tunnel. Catalysis involves a [~]130{degrees} rotation of the C-terminal domain, a transition trapped by the antihypertensive drugs isradipine and benidipine. Both drugs lock the enzyme in a thioester-forming state, but benidipine exhibits superior efficacy by extending a bulky moiety into the primary catalytic tunnel to sterically block substrate entry. Furthermore, we identify a product inhibition mechanism where excess acyl-CoA traps the enzyme, potentially limiting metabolic overload. These findings provide a structural framework for understanding vectorial fatty acid channeling and a scaffold for developing modulators of metabolic flux. HighlightsO_LICryo-EM structures of human FATP2 reveal a membrane-anchored lollipop topology C_LIO_LIEndogenous fatty acids within a hydrophobic tunnel delineate the fatty acid uptake pathway C_LIO_LIIsradipine and benidipine displace fatty acids to trap a non-productive conformation C_LIO_LIAcyl-CoA product inhibition may provide negative feedback via steric occlusion C_LI

biophysics↗

bioRxiv2026

Selenium-enriched rapeseed extract synergizes with chemotherapy drug cisplatin in inhibiting proliferation and promoting apoptosis of colorectal cancer cells

Chemotherapy treatment of colorectal cancers (CRC) using cisplatin (CDDP) encounters problems of drug resistance by the cancer cells and cytotoxicity to normal cells, highlighting the urgent need for joint therapeutical strategies. Selenium-enriched rapeseed extracts exhibit anti-cancer effects but the bioactive components and mechanisms remain unclear. Here, we applied different solvents to fractionate the extracts from Selenium-enriched rapeseed and found that the water extract (WE) fraction significantly enhanced the cytotoxic effect of CDDP on cancer cells but no damage on normal cells. HPLC-ICP-MS analysis revealed that methylselenocysteine (MSC) and selenocystine (SeCys2) were the main selenium speciation in WE. Through cell biology and integrative multi-omics analysis, we found a synergistic anti-CRC cell effect when combining CDDP with MSC, sulforaphane (SFN), celastrol (Cel), Indole-3-carbinol (I3C), -linolenic acid (ALA) or linoleic acid (LA). We propose that the CDDP-WE combination treatment holds the promise for improving curative efficacy for chemo-refractory CRC patients in the future.

cancer biology↗

bioRxiv2026

Inhibition of integrin αvβ8-mediated TGFβ activation and active-TGFβ blockade promote anti-tumor immunity through distinct biological mechanisms

Transforming Growth Factor {beta} (TGF{beta}) is a potent immunosuppressor and a primary driver of resistance to cancer immunotherapy. While preclinical models have long suggested that TGF{beta} inhibition could synergize with immune checkpoint inhibitors, these effects have proven difficult to replicate in clinical settings. The highly regulated TGF{beta} pathway can be inhibited through various mechanisms, including neutralizing activated ligands or inhibiting upstream activators, such as integrins. Recent structural data demonstrated that integrin v{beta}8 can enable TGF{beta}1/3 signaling without releasing the active cytokines from their Latency-Associated Peptides, suggesting that ligand-blocking antibodies may have limited access to their epitopes. Here, we show that integrin v{beta}8 blockade, while achieving anti-tumor responses similar to those of anti-TGF{beta} antibodies, does so through a distinct mechanism of action. Anti-v{beta}8 is 3 orders of magnitude more potent at inhibiting v{beta}8-mediated TGF{beta} activity than a commonly used antibody against the mature form of the cytokine. Whereas TGF{beta} ligand inhibition has little effect on TGF{beta} signaling in tumor-draining lymph nodes (tdLN) and requires IFN{gamma} for its anti-tumor effects, v{beta}8 blockade strongly inhibits TGF{beta} signaling in tdLN and, in combination with PD-L1 blockade, drives tumor control through an IFN{gamma} -independent mechanism that strictly requires T cell egress from tdLN. Combined v{beta}8 and anti-PD-L1 blockade enhances antigen presentation in dendritic cells (DCs) and, unlike TGF{beta} ligand blockade, improves the efficiency of DC-induced T cell activation in response to cross-presented antigen. These findings suggest that v{beta}8 blockade can disable an immunologically critical source of TGF{beta} signaling that is not addressed by antibodies targeting TGF{beta} ligands, suggesting a promising new approach to TGF{beta} pathway modulation. One Sentence SummaryUnlike ligand-neutralizing antibodies, v{beta}8 blockade suppresses TGF{beta} in tdLN and boosts DC-T cell activation, a differentiated immunotherapy strategy.

immunology↗

bioRxiv2026

An allosteric pocket in KV1.3 defines a distinct chemical space for immunomodulator design

KV1.3 is a validated autoimmune drug target, yet all disclosed inhibitors converge on a narrow set of conserved binding sites, suffering from poor selectivity or clinical failure. Whether KV1.3 harbors a distinctive, druggable pocket amenable to selective targeting has remained unknown. Here we report MPiN, a highly selective, state-dependent KV1.3 inhibitor with in vivo efficacy in a mouse psoriasis model, which engages a previously uncharacterized extracellular allosteric pocket framed by the PP1-PP2 turret loops, the pore helix and the outer S5/S6 helices, acting through a bidirectional pore-to-sensor coupling that simultaneously constricts the selectivity filter and facilitates the voltage sensor toward activation. Unexpectedly, despite the extensive structural conservation of this pocket across KV1 paralogs, subtype selectivity is dictated by the peripheral residues G427 and H451, which define pocket geometry without directly contacting the ligand, thereby establishing a geometry-driven "non-contact selectivity" mechanism. By opening an unrecognized, structurally distinct chemical space on KV1.3 and redefining how selectivity is achieved within a conserved channel family, this work lays the structural and conceptual foundation for rational, structure-guided design of next-generation KV1.3 immunomodulators.

biochemistry↗

bioRxiv2026

Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles

The cysteine to serine mutation at residue 481 of Brutons tyrosine kinase (BTK) is the most common mechanism of clinical resistance against ibrutinib for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. We report small molecule ligands containing chiral {beta}-lactone electrophiles to address this challenge. The asymmetric warhead enabled stereoselective covalent modification of wild-type and ibrutinib-resistant mutant BTK(C481S) through distinct sites of reactivity. Building on these findings, we developed kinase-directed {beta}-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish {beta}-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/736436v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1b407c6org.highwire.dtl.DTLVardef@6a79ddorg.highwire.dtl.DTLVardef@66a59dorg.highwire.dtl.DTLVardef@102ecc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Direct probabilistic quantification of mosaic loss of chromosome Y from sequencing data

Loss of chromosome Y (LOY) is the most common aneuploidy in aging men and is increasingly recognized as a marker of aging and genomic instability. Because LOY occurs in mosaic form, its degree reflects the fraction of cells lacking the Y chromosome. Existing SNP-array- and sequencing-based methods rely largely on single genomic features and indirect transformations to estimate this fraction. We developed BaySeq-Y, a Bayesian method that directly estimates LOY mosaicism from sequencing data using VCF files with read depth (DP) and allelic depth (AD). Within a rigorous Bayesian framework, BaySeq-Y integrates complementary LOY-associated genomic features, including decreased read depth and allelic imbalance, and can additionally leverage haplotype phasing to improve precision. In simulations and fluorescence in situ hybridization validation (FISH), BaySeq-Y provided accurate estimates and outperformed existing methods. Applications to ROSMAP and GTEx supported its biological relevance through transcriptomic validation, demonstrating its utility for quantifying LOY across diverse sequencing datasets.

bioinformatics↗

bioRxiv2026

Structural assemblies for an RNA world

Protein homo-oligomerization widely generates symmetric assemblies for encapsulation and scaffolding. Conversely, natural RNA quaternary structures appear limited, with known RNA-only multimers predominantly forming dimers or dihedral assemblies from long transcripts. Whether short RNAs can access broader higher-order assembly space has remained unclear. Here, using cryo-EM, we show that RNAs under 200 nucleotides form three distinct structural classes: a 60-subunit viral-capsid-like icosahedron, non-caged oligomers including a trimer and a strand-exchanged dimer, and a continuous filament assembled from a 57-nucleotide RNA. These structures demonstrate that assembly complexity does not simply scale with RNA length; compact RNAs can specify architectures traditionally associated with proteins. Our findings broaden the known RNA quaternary repertoire, strengthen the structural plausibility of higher-order organization in an RNA world, and establish foundational reference architectures to guide future RNA-based self-assembling nanoparticle design. HighlightsO_LIShort RNAs reveal protein-like assembly principles for an RNA world C_LIO_LIThe first natural RNA-only T=1 icosahedral cage is a viral-capsid-like 60-mer C_LIO_LICompact RNA-RNA interfaces encode global curvature, valency and propagation C_LIO_LIRNA motifs assemble into closed cages, finite oligomers and extended filaments C_LI

evolutionary biology↗

bioRxiv2026

Synapse-based bispecific immune cell engager model predicts invariance in synapse behavior across different effector-to-tumor cell ratios

Immune cell engagers (ICE) such as bispecific antibodies (bsAbs), within an immunological synapse, bind and link CD3 on a T cell to a target antigen (TAA) on a cancer cell, forming a trimer (CD3:bsAb:TAA complex). With sufficient trimer numbers within the synapse, the T cell can become activated and promote cancer cell killing. Elranatamab, a CD3-bispecific antibody for multiple myeloma, has received FDA and EMA filing acceptance (August 2023 and December 2023, respectively) adding to a growing list of bsAbs that are treating patients. In the drug development stages of ICE bsAbs, mechanistic modeling approaches are often used to attain a greater quantitative understanding of the modality, preclinically, and provide human pharmacokinetic and efficacious dose predictions to aide in Phase 1 trial design. To date, the majority of ordinary differential equation (ODE) trimer models treat the tumor compartment as well-mixed and trimer formation is governed by a bulk population reaction not accounting for individual synapses. This lack of discrimination can lead to imprecise analysis when analyzing results across E:T ratios using metrics like trimers per T cell or trimers per target cell. To this end we developed an ODE trimer model based on single-synapse complexes (one target cell/one immune cell) with 2D cross-linking trimer formation. We show computationally that the number of trimers per synapse is invariant to the value of the E:T ratio for a given free bsAb concentration, a property that cannot be captured by non-synapse models. A simple demonstration of this discrepancy using the well-known Betts trimer model is presented. We then apply the Betts trimer model coupled to a tumor growth inhibition (TGI) module to show that our synapse-based trimer model is easy to substitute in to model TGI, including the addition of a trimer-per-synapse activation threshold function for cell killing. Overall, our model attempts to balance mechanistic fidelity while limiting the complexity of the model.

pharmacology and toxicology↗

bioRxiv2026

The Two-Component System CrdRS Mediates Sub-inhibitory Antibiotic-Induced Biofilm Formation in Helicobacter pylori via Bidirectional Regulation of Transporters PlpA and GlnP

Biofilm formation by Helicobacter pylori is a major driver of antibiotic tolerance and treatment failure, yet the signaling pathways that trigger biofilm development under sub-inhibitory antibiotic pressure remain poorly understood. Here, we show that sub-MIC levels of metronidazole, amoxicillin, and ciprofloxacin potently induce dense H. pylori biofilms. Through transcriptomic and genetic analyses, we identify the two-component system CrdRS as a central signaling hub that orchestrates this response via the bidirectional regulation of two ATP-binding cassette (ABC) transporters. Phosphorylated CrdR binds to AC-rich promoter motifs to directly activate plpA, which encodes a substrate-binding protein that drives exopolysaccharide secretion and matrix assembly. Concomitantly, CrdR represses glnP, which encodes an inner-membrane permease, thereby relieving transcriptional inhibition of the L-asparaginase gene ansB. This derepression triggers aberrant reactive oxygen species (ROS) accumulation, which promotes oxidative stress-dependent biofilm maturation. Through phenotypic analysis of crdRS deletion mutants, phosphorylation-defective point mutants (CrdRD53A and CrdSH173A), and exogenous hydrogen peroxide (H2O2) induction, we demonstrate that CrdRS specifically responds to antibiotic-induced stress signals in a manner genetically separable from ROS sensing. Collectively, our findings establish a dual-mechanism model in which CrdRS orchestrates antibiotic-induced biofilm formation by simultaneously controlling matrix production and intracellular ROS generation. Notably, glnP expression was significantly lower in clinical multidrug-resistant isolates than in drug-sensitive ones, whereas plpA showed the opposite trend. These findings provide a mechanistic foundation for developing CrdRS-targeted strategies to combat biofilm-associated H. pylori infections.

microbiology↗

bioRxiv2026

Fault-tolerant 3D reconstruction from 2D spatial proteomics sections

Reconstructing 3D molecular volumes from sparsely sampled 2D tissue sections is limited by per-section marker dropout and tissue loss. We present 3D-Omics-Flow, a generative pipeline that jointly repairs damaged sections and interpolates between them at single-cell resolution. Across datasets spanning health and disease, 3D-Omics-Flow expands 3D spatial proteomics to practical sampling regimes, enabling atlas construction and downstream analysis from imperfect 2D section stacks.

bioinformatics↗

bioRxiv2026

Dawn of segmented bilaterians unveiled by soft-bodied fossils in microbial pseudomorphs from the Basal Cambrian

It is estimated that the evolution of segmented bilaterians occurred during the Ediacaran, whereas most of their unambiguous body fossils did not appear until Cambrian Stage 3. This fossil gap hampers our understanding of the early history of body segmentation, which is a crucial evolutionary innovation for bilaterians. Trace fossils from the late Ediacaran and basal Cambrian suggest this gap is likely to represent a taphonomic bias, implying that the progenitors of segmented bilaterians that existed within this temporal span were hardly preserved. Here, we report a variety of segmented bilaterians from the lowermost Cambrian of South China. These fossils are preserved as microbial pseudomorphs, rather than as ordinary phosphatization. These findings demonstrate that microbial pseudomorphs represent a major pathway for the preservation of segmented bilaterians during this period, as well as an effective mechanism for overcoming the taphonomic bias that affects micro-animals with delicate, non-biomineralized bodies. Moreover, the newly described animals, among the earliest segmented bilaterians, reveal a high diversity of segmented bilaterians during Ediacaran-Cambrian transition, shedding new light on the evolution of body segmentation.

paleontology↗

bioRxiv2026

Single-nucleus multiomic analysis reveals modulation of the gene regulatory circuit landscape in pituitary cell types during mouse estrous cycle.

Summary/AbstractThe estrous cycle transcriptional and chromatin dynamics in pituitary cell types have not been investigated. We report single-nucleus multiomics assays in 18 adult mouse pituitaries (102,069 post quality-control nuclei) across 6 cycle time points. Differential analysis revealed cycle stage-dependent epigenetic and transcriptional remodeling across the major pituitary cell populations. In gonadotropes and lactotropes, we identified temporal patterns of differential gene expression linked to various biological processes, notably neuronal and synaptic-related ontologies. Pseudotime trajectory analysis was consistent with a rapid transition of individual gonadotropes through different cellular states. In gonadotropes and lactotropes, we uncovered gene regulatory circuits whose activity varies between consecutive cycle time points. We experimentally validated a gonadotrope ETS2-driven circuit that differentially regulates Fshb gene expression between 2 and 9 am on estrus. Our data and analyses, available at https://rstudio-connect.hpc.mssm.edu/snpit_estrous_browser/, provide a window into gene regulatory mechanisms underlying estrous cycle stage transitions. HighlightsO_LIPituitary cells show chromatin and transcriptome plasticity across the estrous cycle C_LIO_LIWe identify stage-modulated gene regulatory circuits across pituitary cell types C_LIO_LIGonadotrope DEGs form distinct pathway-annotated temporal trajectory clusters C_LIO_LIWe validate a gonadotrope ETS2-driven circuit regulating the Fshb gene C_LI eTOC blurbZhang et al. conduct a single-nucleus multiomics analysis of mouse pituitaries in vivo across the estrous cycle. They reveal an epigenetic and transcriptomic plasticity in pituitary cell populations. In gonadotropes and lactotropes, they demonstrate that DEGs clustered by temporal trajectories are enriched for distinct biological processes and identify stage-modulated gene regulatory circuits. They experimentally validate a gonadotrope ETS2-driven circuit regulating Fshb expression. Their dynamic molecular atlas of the cycling pituitary captures key cis-regulatory mechanisms underlying estrous cycle stage transitions.

genomics↗

bioRxiv2026

ARID4 Modulates Stomatal ABA Signaling and Stress-Responsive Gene Expression to Confer Drought Tolerance in Arabidopsis

To identify novel regulators of plant drought tolerance, we performed a forward genetic screen using thermal infrared imaging to detect alterations in leaf temperature, a proxy for transpiration. This screen identified AT-rich Interacting Domain Protein 4 (ARID4), a protein involved in chromatin remodeling, as a modulator of transpiration. arid4 loss-of-function mutants exhibited cooler leaves, increased water loss from detached leaves, and heightened susceptibility to drought relative to wild-type plants. Stomata of arid4 mutants were hyposensitive to abscisic acid (ABA), displaying reduced ABA-induced reactive oxygen species (ROS) production and impaired stomatal closure. Transcriptome profiling under drought revealed extensive misregulation of genes involved in stress-responses, redox homeostasis, iron acquisition, and photosynthesis. These findings indicate that ARID4 modulates the expression of key regulatory genes to maintain redox homeostasis and photosynthetic efficiency, thereby conferring drought stress tolerance.

Plant Biology↗

bioRxiv2026

Kaposi Sarcoma herpesvirus reactivation and replication are dispensable for cell-lineage specific tumorigenesis in whole genome transgenic mice

Herpesvirus reactivation and replication depend on an ordered cascade of gene expression. The viral immediate-early replication and transcription activator protein (Rta) is necessary and sufficient to initiate this process. For Kaposi sarcoma herpesvirus (KSHV), Rta-interacting and Rta-regulated proteins are thought to contribute to cellular transformation. Using a novel, whole-genome transgenic mouse model, we show that KSHV tumorigenesis is independent of Rta in vivo. Rta-deleted, KSHV bacmid transgenic (tgKSHV{Delta}Rta) mice developed latency-associated nuclear antigen (LANA)-positive vascular sarcomas with the same endothelial cell-lineage composition and transcriptional profile as human Kaposi sarcoma (KS). The viral miRNAs were expressed in the tumors, as were all canonical latency and the K1 and K15 oncogenes. Importantly, this system is the first to model both KS and lymphoma, reflecting the development of both malignancies observed in KSHV-infected individuals. These results separate virus replication from KS tumorigenesis, which can proceed independently so long as the virus genome is maintained in a susceptible cell. SignificanceKaposi sarcoma (KS) is the most common cancer in people living with HIV worldwide. Like all herpesviruses, KS-associated herpesvirus (KSHV) has a latent and lytic phase. Hitherto, viral lytic genes are thought to play a role in KS. The KSHV replication and transcription activator (Rta) is both necessary and sufficient for reactivation and lytic viral replication, but Rta was not required for vascular tumor development in a whole virus genome mouse model. This new tgKSHV{Delta}RTA mouse model separates virus replication from viral tumorigenesis and defines a minimal set of viral oncogenes. This model enables mechanistic studies in vivo, and treatment modalities to be evaluated within a complete immune and stromal microenvironment.

Cancer Biology↗

bioRxiv2026

Virus-human protein-protein interactions predict viral phenotypes

Viral phenotypes such as host and tissue tropism are critical determinants of viral infection and transmission. Inferring viral phenotypes presents unique challenges compared to cellular organisms, as viruses rely entirely on host machinery for replication and survival. Current methods for predicting viral phenotypes mainly rely on viral genomic data, often overlooking host-related information. Here, we evaluated the utility of predicted virus-human protein-protein interactions (PPIs) in inferring diverse viral phenotypes using machine-learning algorithms. For predicting human infectivity, a PPI-based machine learning model outperformed both virus genomic and protein sequence-based models that used large language model embeddings. It also surpassed previous methods that incorporated both viral and host genomic data. The human proteins identified by the model were significantly enriched in functions related to viral infection and immune response. In predicting various phenotypes of human RNA viruses, PPI-based models performed better than virus sequence-based models in forecasting virulence, human transmissibility and transmission routes, while showing comparable performance to genomic sequence-based models in predicting tissue tropism. Finally, we demonstrated that a PPI-based model could distinguish high-risk HPV genotypes from low-risk ones. Proteins associated with high-risk HPV were involved in apoptosis and immune regulation, whereas those linked to low-risk HPV were enriched in telomere maintenance and DNA repair. Collectively, this study is the first to demonstrate the value of predicted virus-human PPIs in inferring viral phenotypes, thereby enhancing our understanding of the molecular mechanisms underlying these phenotypes. It also provides effective tools for risk assessment of emerging viruses, contributing to improved pandemic preparedness.

bioinformatics↗

bioRxiv2026

Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery

Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.

bioinformatics↗