Biology subjects

Cheng, Y.

Publications and source records attributed to Cheng, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Port of Protein-Protein Interactomes: An experiment-based protein-protein interactome database for rice

Protein-protein interactions (PPIs) play a crucial role in enabling proteins to carry out their functions within various biological processes (Hui et al., 2003). Since the introduction of the yeast two-hybrid (Y2H) method for PPI detection in 1989 (Fields and Song, 1989), the identification of PPIs has become a significant focus in modern biological research. PPI goes beyond examining individual proteins, allowing researchers to establish a comprehensive network that regulates biological processes. Rice, as a key model organism in plant biological studies, has been at the forefront of PPI research. In 2008, prominent rice scientists in China called for concerted efforts to define a comprehensive protein-protein interaction network experimentally, which aimed to facilitate the prediction of the functional mechanisms operating throughout a plants lifecycle (Zhang et al., 2008). With efforts for 2 decades, the experimentally identified rice PPIs have reached over ten thousand. Several public databases have been established to systematically collate and store PPIs, including STRING (Szklarczyk et al., 2019), BioGRID (Oughtred et al., 2020), IntAct (del Toro et al., 2022), PRIN (Gu et al., 2011), RicePPINet (Liu et al., 2017) and RiceNet v2 (Lee et al., 2015). However, most PPI datasets in rice stem from computational predictions, while experiment-based rice PPI datasets are fragmented due to the lack of systematic profiling at the rice PPIome level, which largely hinders information sharing in the rice research community. To bridge this gap, we constructed the Port of Protein-Protein Interactomes (POPPIN; https://riceome.hzau.edu.cn/poppin/), an integrated database dedicated to sharing experimentally verified PPIs and functional clues in rice. Empowered by high-throughput PPIome profiling technologies and text mining assisted by a large language model (Huang et al., 2025; Liu et al., 2025), POPPIN currently has deposited over 150,451 pieces of rice PPI-related information. Additionally, POPPIN provides detailed protein information, including GO annotations, subcellular localizations, domains, trait ontology (TO) information, and hyperlinks to external biological databases. Through offering a user-friendly web interface for search and dynamic network visualization, POPPIN serves as the first large-scale, experiment-based database for searchable PPIs in rice, and has the potential to be extended to other species under this structural framework.

systems biology↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

A retinal adrenergic module tunes mammalian visual evolution

How conserved neural circuits are modified during mammalian evolution remains poorly understood. Here we combine cross-species single-cell transcriptomics, in situ validation, retinal physiology, and conditional genetics to identify a superorder-associated adrenergic module in the mammalian retina. We find that ADRB1, which encodes the {beta}1-adrenergic receptor, is uniquely expressed in rod bipolar cells of sampled Euarchontoglires, but is absent from homologous cells in sampled Laurasiatheria and Marsupialia. In mice, {beta}1-adrenergic receptor localizes to rod bipolar cell terminals and boosts transmission to AII amacrine cells through Gs-adenylyl cyclase-cAMP-PKA signaling pathway. This modulation enhances synchronous release, accelerates downstream ganglion cell output, and increases scotopic electroretinographic responses, while rod-bipolar-cell-specific Adrb1 deletion abolishes norepinephrine-induced enhancement without disrupting baseline vision. In the diurnal tree shrew, a Euarchontoglires species with a cone-dominated retina, ADRB1 is instead redeployed from rod bipolar cells to cone photoreceptors. These findings reveal an evolutionarily mobile neuromodulatory module that tunes retinal computation according to visual ecology.

evolutionary biology↗

bioRxiv2026

ATP-dependent reorientation on a nucleosome primes INO80 for DNA translocation

ATP-dependent chromatin remodeling enzymes play central roles in genome regulation by mobilizing nucleosomes. All remodelers except for one, position their core ATPase at an internal nucleosome location, superhelical location (SHL) 2, and translocate DNA from this site to alter nucleosome conformation. The exception, the remodeler INO80, positions its core ATPase, Ino80, near the DNA exit/entry site, SHL -6. This major architectural difference has raised the question of whether INO80 acts by a fundamentally different mechanism from other remodelers. Here, using cryogenic electron microscopy we capture a new conformation of INO80 that is substantially enriched upon ATP hydrolysis and has Ino80 positioned at an internal nucleosomal location. Comprehensive conformational landscape analysis further uncovers an ATP hydrolysis dependent continuum of additional INO80 conformational states on a nucleosome that were not previously detected. Our studies provide compelling evidence to support a model where INO80 initially engages nucleosomes near SHL -6, followed by a dramatic ATP hydrolysis dependent ~180{degrees} reorientation around the nucleosome to place its Ino80 near SHL -2 from where DNA is translocated. INO80s unique reorientation has broad implications for understanding how ATP-dependent steps that precede nucleosome mobilization can increase the fidelity of remodeling by being responsive to nucleosomal cues.

biophysics↗

bioRxiv2026

CryoROLE: describing large inter-domain rotation in single particle cryo-EM

In single particle cryo-EM, analysis of continuous conformational heterogeneity has always been challenging. Both linear and deep learning-based methods treat conformational heterogeneity as perturbations to the consensus average conformation, limiting their capability in analyzing large protein motions. While classic conformational classifications are capable of handling large domain motion, they bin continuous protein dynamics into discrete static substates. Here, we present cryoROLE, a computational tool that extracts the continuous conformational dynamics embedded in the static composite map constructed from multi-body refinement into a landscape of relative orientation between the moving domains. Depicted in real space, the landscape allows intuitive interpretations of domain motion and the population of poses in the conformational space. Applying it to various biological systems reveals hidden conformational dynamics that are relevant to protein functions.

biophysics↗

bioRxiv2026

Chromatin topology control by a muscle-specific ribosomal protein

Three-dimensional genome organization stabilizes cell-type-specific gene expression, yet the tissue-restricted factors that maintain chromatin insulation remain poorly understood. Here, we identify the muscle-specific ribosomal protein Rpl3l as an unexpected nuclear regulator of genome architecture in atrial cardiomyocytes. Rpl3l is enriched in the nucleus and nucleolus, where it binds its own genomic locus and stabilizes a CTCF-anchored chromatin boundary that represses the T-type calcium channel gene Cacna1h. Loss of Rpl3l weakens local chromatin insulation, increases long-range contacts across the Rpl3l-Cacna1h locus, derepresses Cacna1h, and increases susceptibility to atrial fibrillation (AF), which is suppressed by pharmacological inhibition of T-type calcium channels. Furthermore, AF-associated RPL3L variants exhibit impaired nucleolar localization, reduced rRNA binding, and defective repression of CACNA1H in human iPSC-derived atrial cardiomyocytes. Together, these findings reveal a ribosomal protein-chromatin axis linking genome insulation to ion-channel dosage control and cardiac rhythm stability, expanding the repertoire of cell-type-specific genome architecture regulators. HighlightsThe muscle-specific ribosomal protein Rpl3l exhibits unexpected nuclear and nucleolar enrichment. Rpl3l stabilizes a CTCF-anchored chromatin boundary to maintain atrial-specific local genome insulation. Loss of Rpl3l derepresses Cacna1h which encodes a T-type Ca2+ channel and increases atrial fibrillation susceptibility. Atrial fibrillation-associated RPL3L variants impair nucleolar targeting and CACNA1H repression

physiology↗

bioRxiv2026

Persistent Post-Inflammatory Matrix Stiffening Defines a Premalignant Mechanical Niche in Ulcerative Colitis-Associated Neoplasia

Patients with long-standing ulcerative colitis (UC) remain at risk for colorectal neoplasia even after overt inflammatory activity improves, suggesting that repaired mucosa may retain residual tissue-level abnormalities. Whether extracellular matrix remodeling leaves a persistent mechanical cue that contributes to early neoplastic remodeling is unknown. Here we identify post-inflammatory matrix stiffening as a premalignant mechanical niche in UC-associated neoplasia. In human colonic biopsies, collagen remodeling and atomic-force-microscopy-based mucosal stiffness increased from non-UC controls to UC and UC-associated dysplasia. A stiffness-associated transcriptional program was also enriched in histologically non-dysplastic mucosa from patients with UC-associated neoplasia. In mouse models, colonic stiffness increased along the colitis-to-tumorigenesis axis and remained elevated during apparent recovery, when epithelial permeability, junctional protein loss, crypt proliferation and nuclear {beta}-catenin accumulation persisted despite reduced disease activity. Stiffness-controlled intestinal epithelial cultures showed that stiff substrates were sufficient to disrupt ZO-1 organization and enhance {beta}-catenin redistribution, particularly under TNF- stimulation. Pharmacological matrix normalization with {beta}-aminopropionitrile partially restored barrier organization and attenuated early epithelial remodeling in vivo. Single-cell profiling identified a stiffness-associated MMP7-positive/YAP-active epithelial state that was enriched in collagen-rich regions and reduced after matrix softening. Inhibition of YAP or MMP7 attenuated stiffness-associated junctional disruption and {beta}-catenin redistribution. These findings suggest that inflammatory recovery and mechanical recovery can be uncoupled, and that persistent mucosal stiffening provides a tissue-level mechanism by which chronically injured UC mucosa may remain biologically vulnerable to premalignant epithelial remodeling.

Cancer Biology↗

bioRxiv2026

CryoDiff: An uncertainty-aware diffusion model for Cryo-EM map enhancement

Cryogenic electron microscopy (cryo-EM) enables high-resolution structural determination of large macromolecular complexes. However, the interpretability of cryo-EM maps is often hindered by substantial background noise and signal attenuation, which obscure structural details. Although existing post-processing methods can partially mitigate these artifacts, they typically suffer from over-smoothing and lack reliable confidence estimation. Here, we present CryoDiff, an uncertainty-aware diffusion model for cryo-EM map enhancement. CryoDiff employs a multi-step diffusion process to progressively denoise and restore high-resolution structural features. Importantly, CryoDiff incorporates a voxel-wise confidence metric derived from Monte Carlo sampling. It unifies map enhancement and voxel-level uncertainty estimation within a diffusion-based generative framework, representing the first approach to achieve such joint modeling for cryo-EM map enhancement. In comprehensive experiments, CryoDiff markedly out-performs existing methods in both map-model correlation and map interpretability, improving the average FSC0.5 metric by 0.356 [A] over state-of-the-art approaches. When applied to de novo model building with ModelAngelo, CryoDiff further increases model completeness by 5.5%, exceeding the gains achieved by competing method.

bioinformatics↗

bioRxiv2026

(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both {micro}- and {delta}-opioid receptors in astrocytes. Chronic stress reduces {micro}-{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased {micro}-{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the {micro}-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic {micro}-{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.

neuroscience↗

bioRxiv2026

IL-1-activated cancer-associated fibroblasts promote STAT1-driven transcriptional reprogramming of pancreatic tumour cells

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited treatment options and poor survival rates. It is characterised by strong driver mutations, epigenetic reprogramming, and a dense tumour microenvironment (TME). A defining feature of the PDAC TME is its fibrotic stroma, which is largely composed of cancer-associated fibroblasts (CAFs). Distinct CAF populations have been implicated in PDAC progression, but the mechanisms that govern their crosstalk with the cancer cells are poorly understood. We generated genetically engineered pancreatic stellate cells (PSCs) modelling interleukin-1 (IL-1)-dependent inflammatory CAFs (iCAFs) and transforming growth factor-{beta} (TGF-{beta})-dependent myofibroblastic CAFs (myCAFs) to investigate how distinct stromal populations shape the epigenetic landscape of pancreatic ductal adenocarcinoma (PDAC). We found that iCAFs, but not myCAFs, promoted gemcitabine resistance in epithelial tumour cells and identified STAT1 as a critical mediator of iCAF-tumour cell crosstalk. Mechanistically, STAT1 drove the induction of interferon (IFN)-responsive genes, while blockade of IFN-{beta} attenuated iCAF-mediated transcriptional reprogramming. Genetic ablation of STAT1 in tumour cells abolished iCAF-induced chemoresistance and associated transcriptional changes. In an orthotopic in vivo model, STAT1 knockout significantly prolonged survival following gemcitabine treatment, supporting a central role for STAT1 signalling in stromal-driven therapy resistance. We provide a comprehensive analysis on how IL-1-dependent iCAFs contribute to epigenetic reprogramming in PDAC and uncover a previously undescribed role for STAT1 in stromal-epithelial interactions. These findings reveal distinct, non-overlapping mechanisms by which CAF subtypes modulate tumour behaviour and identify STAT1 as a therapeutic vulnerability that can be exploited to sensitise PDAC to standard chemotherapy. Significance statementThis study establishes that the epigenetic landscape of PDAC is differentially shaped by iCAF- and myCAF-like PSCs and defines STAT1 as a mediator of iCAF-induced chemoresistance and transcriptional reprogramming. We demonstrate that genetic ablation of STAT1 sensitises tumours to gemcitabine in vivo, extending survival and positioning STAT1 as an actionable target to overcome stromal-mediated therapy resistance in PDAC.

cancer biology↗

bioRxiv2026

WTAP-mediated epitranscriptomic program in alveolar macrophages confers prolonged protection against postinfluenza bacterial pneumonia

Secondary bacterial infections remain an intractable problem of seasonal influenza, primarily due to the depletion and defunctionalization of alveolar macrophages (AMs). Here, we described that N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, critically orchestrates trained immunity (TRIM) establishment in AMs. Influenza A virus (IAV)-trained AMs maintained low Wilms tumor 1-associated protein (WTAP) expression and reduced global m6A deposition for over two months. Mechanistically, this IAV-induced m6A decrease promotes TRIM by enhancing the RNA stability of phagocytic and metabolic genes, thereby boosting antibacterial function. Mimicking this m6A reduction pharmacologically or genetically recapitulates the IAV-trained TRIM phenotype, which improves phagocytosis and protects mice from secondary infection. Clinically, elevated WTAP in AMs correlates with impaired phagocytosis and disease severity in COVID-19 and COPD. These findings for the first time unveil how respiratory virus infection shapes AM TRIM via epitranscriptomic reprogramming, and offer prospective strategies for the prevention and treatment of post-viral bacterial complications.

immunology↗

bioRxiv2026

Retinal scRNAseq reveals cell-type-specific responses to bacterial infection

PurposeEndophthalmitis is a serious complication of intraocular surgery due to the risk of irreversible retinal damage. Because retinal cell populations are highly heterogenous, single-cell resolution is required to uncover the detailed mechanisms of infection response. Using a mouse model of bacterial endophthalmitis, we investigated transcriptional changes across resident and infiltrating cell types in the retina. MethodsA methicillin-sensitive strain of Staphylococcus aureus was isolated from a patient with endophthalmitis. Adult C57Bl/6J mice received an intravitreal injection of phosphate-buffer solution (PBS) with or without 5000 CFU S. aureus (n=3 per group). 24 hours later, retinas were isolated and single-cell suspensions were sent to the Penn Genomic Core for sequencing with an Illumina NovaSeq 6000. After standard pre-processing of the data, differential genes and pathways were identified for each cell type (adjusted p < 0.01, log2FC > 1 or < -1). ResultsOur analysis identified all expected retinal cell types, including a population of infiltrating neutrophils in the infected retinas. We surveyed genes known to be upregulated at the bulk-retina level in this model (e.g. Tlr2, Nlrp3, Il1b), and found that infiltrating cells mainly drove this expression. Several genes were altered across nearly all retinal cell types, including upregulation of Hsph1 and Stat3. Muller glia downregulated Gpx4 while upregulating Acsl4 and iron importers Tfrc, Zip14, and Dmt1. Top pathways for macrophages/microglia included chemotaxis, cell-cell adhesion, and wound healing. Vascular cells upregulated angiogenesis-related genes. Cellular respiration was a commonly affected pathway across several neuronal populations, with most genes decreasing. ConclusionsThis study advances our understanding of the pathobiology of bacterial endophthalmitis. Muller glia appear to be undergoing ferroptosis, potentially while activating a program to sequester iron away from bacteria. Decreased cellular respiration may indicate hypoxia among neurons. Our results reveal several trends in the retinal response to infection, including iron dysregulation and hypoxia. Understanding these cell-type-specific responses to endophthalmitis may help design therapies to combine with antibiotics.

microbiology↗

bioRxiv2026

Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2

Following intracerebral haemorrhage (ICH), secondary injury contributes to negative outcomes. Here, we describe inter-dependent injurious and adaptive-protective pathways that form a therapeutically modifiable ICH response. In perihaematomal tissue from post-mortem ICH patients, transcriptomic analysis pointed to concurrent perihaematomal activation of the cytoprotective stress-induced transcription factor NRF2 and activation of interferon responses, with mononuclear myeloid cells (microglia and monocyte-derived cells, MMCs) and astrocytes contributing to this signature. In vitro, microglia-astrocyte-neuron co-culture studies revealed that microglial NRF2 activation was induced by clot-conditioned medium and could influence the interferon pathway in both microglia themselves as well as astrocytes. In vivo, MMC-specific deletion of NRF2 inhibited NRF2 target-gene induction, exacerbated interferon pathway activation following ICH, and impaired functional recovery. Pharmacological NRF2 activation suppressed interferon pathway induction post-ICH, and direct interferon pathway antagonism rescued neurological recovery deficits caused by MMC-specific NRF2 deficiency. Thus, augmenting NRF2- or inhibiting interferon-signalling may improve outcomes after ICH.

neuroscience↗

bioRxiv2026

ProteinFlux: accurate, rapid and scalable generative prediction of protein dynamics driven by post-translational modifications

The function of proteins, the building blocks of life, in health and disease depends not only on their 3D-conformational states but most importantly on the dynamic transition between states controlled by a wide array of post-translational modifications (PTMs). Recent major advances have been made in our ability to predict static 3D structures; however, understanding and predicting the impact of PTMs on protein conformational dynamics remains a major question and challenge in the field. Molecular dynamics (MD) simulation remains the major computational approach for studying protein dynamics. However, the high computational cost, lack of integration of PTMs as conditioning inputs and inefficient generation of continuous protein dynamics largely precludes PTM-regulated conformational dynamics and the study of slow conformational processes. To address this critical bottleneck, we developed ProteinFlux, a flow-matching generative framework that links PTM-conditioned conformational dynamics to evolutionary constraints encoded by PTM sites. Evolutionary information plays a critical role in capturing conformational dynamics beyond sequence identity, and PTM sites inherently encode evolutionary constraints critical to protein functional regulation. We therefore built FluxSite, a dual-modal PTM site predictor that integrates sequence evolutionary information and 3D structural features to generate a continuous conditional signal encoding conservation and functional importance for each predicted site. FluxSite achieves robust generalization across 18 PTM types and 30 disease-associated proteomes. ProteinFlux generates phosphorylation-conditioned, all-atom conformational trajectories across diverse protein fold classes, faithfully reproducing both thermodynamic properties such as free energy landscapes and kinetic features such as conformational transition pathways. It outperforms state-of-the-art predictors while achieving inference speeds several orders of magnitude faster than traditional MD. In addition, we introduce DynaMo-phos, a benchmark dataset of phosphorylated protein MD simulations. Together, ProteinFlux, FluxSite and DynaMo-phos provide a scalable, high-throughput platform for elucidating PTM-driven conformational mechanisms, with potential applications across allosteric drug design, functional annotation of disease-associated modifications and mechanism-guided therapeutic development.

bioinformatics↗

bioRxiv2026

A shared neural code for gender across faces, bodies, and objects in the human brain

Humans can readily infer gender from diverse visual categories, including faces, bodies, and objects, yet it remains unclear whether the brain constructs a shared, category-general representation of gender. To fill the gap, we measured neural responses using fMRI while participants viewed female and male stimuli across these three categories. Multivoxel pattern analyses revealed that gender information was encoded throughout distributed occipitotemporal regions for all categories. Critically, cross-category decoding and regression-based representational similarity analyses converged on a region of the right middle temporal gyrus (rMTG) that encoded gender independently of stimulus category. This region also carried category information, indicating mixed selectivity. Comparisons between neural representational dissimilarity matrices and those from a fine-tuned convolutional neural network (CNN) showed that rMTG activity most closely resembled intermediate CNN layers, suggesting that shared gender representations rely on mid-level visual features. Finally, functional connectivity analyses revealed that gender-related interactions among occipitotemporal regions were similar for faces and bodies but not for objects. Together, these findings identify a category-general neural hub for gender perception and illuminate how mid-level visual features and distributed networks support the abstraction of gender across heterogeneous visual inputs.

neuroscience↗

bioRxiv2026

Structure-guided reinterpretation of a disease-associated CWH43 residue-533 truncation identifies internal disruption of a conserved C-terminal module in idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurological disorder characterized by ventricular enlargement together with gait impairment, cognitive decline, and urinary dysfunction. Disease-associated CWH43 variants have emerged as genetic clues in iNPH, but the molecular consequences of truncating variants remain poorly defined. Here, we used structure-guided analysis to reinterpret the disease-associated human CWH43 variant c.1596del, annotated as p.Leu533Ter and referred to here as the residue-533 truncation. AlphaFold-based modeling of the full-length 699-amino-acid protein supported a conserved C-terminal D3 module spanning residues 407-699. Within this framework, the residue-533 truncation is best interpreted as an internal interruption of D3 rather than deletion of a poorly constrained terminal tail. Pocket analysis identified a dominant candidate surface site within D3 containing 18 pocket-lining residues, 55.6% of which (10/18) are removed by truncation. Independent cavity mapping further showed that the affected region is better understood as a broader cavity-bearing architecture rather than a single local pocket. Cross-boundary contact analysis, multi-model reproducibility, and representative local geometry supported structural coupling between retained and deleted D3 segments, indicating that truncation is predicted to cause retained-side decoupling in addition to direct residue loss. Together, these findings support a model in which the disease-associated residue-533 truncation disrupts a structurally integrated C-terminal module and its associated cavity-bearing architecture. This framework refines interpretation of CWH43-associated iNPH variants and provides a mechanistic bridge between human genetic association and architecture-level loss of function.

genetics↗

bioRxiv2026

Colocalization and discordance between plasma and brain protein quantitative trait loci

Studies of protein quantitative trait loci (pQTLs) provide opportunities to interpret complex trait genetics and identify potential biomarkers and therapeutic targets. Circulating proteins are commonly used in pQTL studies due to the accessibility of blood-based measurements, but their levels may not always reflect regulation in disease-relevant tissues. We assessed colocalization and discordance between plasma and dorsal prefrontal cortex cis-pQTLs using data from four large-scale studies and investigated their implications for downstream analyses. Across the proteins examined, at most 80% of the cis-pQTLs showed evidence of colocalization. Among the colocalized loci, approximately 20% exhibited opposite directions of genetic effects. We characterized tissue-specific gene expression profiles based on data from the Genotype-Tissue Expression project. Proteins with colocalized cis-pQTLs were more likely to have high gene expression levels in systemic tissues and immune cells, whereas the remaining proteins were more likely to have high expression in brain tissues. We conducted Mendelian randomization (MR) analyses using neuroticism as an illustrative outcome to compare effect estimates derived using instruments from different pQTL studies. MR analyses identified 13 proteins significantly associated with neuroticism, including six with opposite effect directions between plasma and dorsal prefrontal cortex, highlighting the importance of tissue context. Overall, circulating pQTLs remain informative for proteins from systemic and immune pathways, while incorporating tissue-specific data may provide additional insight for proteins with more localized expression. Considering multiple tissue contexts may refine the interpretation of protein-trait associations and may improve the prioritization of candidate targets.

genetics↗

bioRxiv2026

A sequence-based proactive intelligence for influenza antigenic profiling improves vaccine strain selection

Seasonal influenza viruses accumulate antigenic changes, eroding population immunity and necessitating recurrent vaccine updates. Hemagglutination inhibition (HI) assays are the standard for measuring antigenic relationships between circulating and vaccine strains; however, their limited throughput constrains the scale and timeliness of surveillance. Here, we present fluProfiler, a foundation-model-based framework that learns a stable mapping from viral sequences to antigenic space and uses this representation to support influenza antigenic prediction, vaccine strain evaluation, and diversity-driven sampling. fluAgPredictor aligns hemagglutinin (HA) and neuraminidase (NA) sequence representations with HI-derived antigenicity, enabling accurate and consistent inference of pairwise antigenic distances across surveillance-aligned evaluation settings. Without prior annotation of antigenic sites, it identifies key residues in immunodominant epitopes and reveals the cooperative contributions of HA and NA to antigenic variation. Building on this antigenic-space representation, fluVacSelector provides antigenic coverage scores that are concordant with World Health Organization (WHO) vaccine recommendations while also flagging potential candidates that may offer broader coverage ahead of formal consultations. fluAgEnhancer further leverages the same representation to prioritize antigenically informative and diverse strains for experimental characterization, achieving comparable predictive accuracy with approximately 25% fewer HI measurements than random sampling. Together, these modules provide a high-throughput and interpretable complement to HI testing, converting routine genomic surveillance into a more proactive, data-driven support system for antigenic monitoring and vaccine strain selection.

bioinformatics↗