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Wu, Y.

Publications and source records attributed to Wu, Y..

At least 145 records · Page 8Linked to original sources

Generalizable Finger Movement Decoding from Intracranial Recordings Across Static and Dynamic Actions

Reliable decoding of finger movements requires brain-computer interfaces (BCIs) that generalize across the diverse static and dynamic actions performed in daily life. Static postures and dynamic movement sequences rely on partially distinct neural representations, and the balance between these components varies widely across tasks. Yet most BCI decoding pipelines are optimized for a narrow task domain, limiting their ability to transfer to new scenarios. Here we show that standard intracranial decoding approaches show notable performance drops when applied to previously unseen finger tasks with different static-dynamic compositions, and that generalization critically depends on multiple elements of the decoding pipeline. High gamma features and short temporal windows yield the most robust cross task transfer. Although nonlinear models perform best when examples of all tasks are represented during training, linear decoders generalize better to novel, particularly dynamic, actions. We identify a consistent static-dynamic structure across tasks that may provide a useful basis for improving generalization. Finally, we show that anatomical heterogeneity between tasks also constrains generalization. Together, these results establish design principles for BCIs that generalize reliably across the rich repertoire of human finger movements.

neuroscience↗

IDBSpred: An intrinsically disordered binding site predictor using machine learning and protein language model

Intrinsically disordered proteins (IDPs) mediate many cellular functions through interactions with structured protein partners, but predicting the corresponding binding sites on the structured partner remains challenging. Here, we present IDBSpred, a sequence-based method for residue-level prediction of IDP-binding sites on structured proteins. Training and test data were collected from the DIBS database, which contains more than 700 non-redundant IDP-protein complexes. Residue-level embeddings of structured partner sequences were generated using the ESM-2 protein language model and used as input to a multilayer perceptron classifier for binary prediction of binding versus non-binding residues. Analysis of amino acid composition showed that IDP-binding sites are enriched in aromatic residues, especially Trp, Tyr, and Phe, as well as several charged and polar residues, whereas Ala and several small or conformationally restrictive residues are depleted. The classifier achieved an ROC AUC of 0.87 and an average precision of 0.61. Structural case studies further showed that the predicted sites largely recapitulate the major experimentally defined binding interfaces. These results demonstrate that protein language model embeddings plus machine learning algorithms can effectively capture sequence features associated with IDP recognition on structured proteins. IDBSpred provides a practical framework for studying IDP-mediated interfaces and identifying potential therapeutic hotspots.

bioinformatics↗

Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase and RNF168

The molecular mechanisms driving SLFN11 chromatin recruitment remain partially elucidated. Using high-throughput imaging of 162 oncology-focused compounds in U2OS cells with inducible SLFN11 expression, we discovered that deubiquitinase (DUB) inhibitors drive massive SLFN11 recruitment to chromatin, preferentially at promoter regions while concurrently suppressing transcription. DUB inhibitors such as VLX-1570 promote ubiquitin-dependent enrichment of SLFN11 without detectable DNA damage, distinct from the camptothecin-induced RPA-associated SLFN11 foci formed at stressed replication forks. Yet, SLFN11 chromatin recruitment both by DUB inhibitors and DNA damage are suppressed by TAK243 demonstrating their ubiquitylation dependency. RNF168 is required for SLFN11 ubiquitylation and its subsequent chromatin association, and ubiquitylation within SLFN11s middle linker domain (lysines 390, 391, and 429) with K27-linked polyubiquitin chains is essential for the chromatin recruitment of SLFN11. These findings suggest the importance of SLFN11 ubiquitylation by RNF168 for SLFN11 chromatin recruitment and SLFN11 transcriptional regulatory role at promoter regions.

cell biology↗

OPTIMIS: Optimizing Personalized Therapies through Integrated Multiscale Intelligent Simulation

Controlling complex biological systems across multiple scales remains a major challenge in computational medicine, because whole-body disease behavior is closely shaped by noisy cellular events at much smaller scales. Standard deterministic models often miss this molecular variability, while fully stochastic simulations are too slow for the repeated, high-throughput interactions needed to train artificial intelligence. To address this problem, we developed a new AI-based framework that combines a discrete stochastic Gillespie algorithm for microscale receptor dynamics with continuous, nonlinear ordinary differential equations for systemic macroscale behavior. To reach the speed needed for deep reinforcement learning (RL), we compress this hybrid system into a differentiable Neural ODE surrogate that acts as a fast digital twin. As a proof of concept, we applied this framework to engineered cellular therapy and used RL agents to learn dynamic, closed-loop treatment policies inside the surrogate environment. By tracking microscopic, unpredictable cellular activity as an early-warning signal, the AI learned to continuously adjust the drug dose--anticipating and stopping dangerous immune reactions before they could spiral out of control. This computational advance improved successful control rates to more than 70% in highly unstable simulated phenotypes and provides a practical, general framework for adaptive intervention in multiscale biological systems.

bioinformatics↗

Starvation-induced autophagy occurs independently of the ATG1 complex in Chlamydomonas

The survival of eukaryotes during starvation depends on effective nutrient recycling via autophagy. Accordingly, loss of autophagy-related (ATG) proteins, including the nutrient-sensing ATG1 kinase complex, typically results in reduced fitness or lethality under nutrient limitation. The green alga Chlamydomonas reinhardtii provides a tractable model for autophagy studies, as its ATG repertoire is encoded by single-copy genes. Here, we generated a comprehensive library of ATG deletion mutants and examined their growth and autophagy during starvation. Surprisingly, starvation-induced autophagy occurred in the absence of ATG1 complex components (ATG1, ATG11, ATG13, and ATG101), revealing ATG1-independent autophagy and challenging the canonical model for autophagy initiation.

molecular biology↗

Dingent: An Easily Deployable Database Retrieval and Integration Agent framework

AI-driven data search and integration represent an emerging research direction. Although several LLM-based backend frameworks and agentic frameworks have emerged, significant gap remains in developing a one-stop, configurable agent framework that supports various data sources and provides a web interface for efficient data retrieval using natural language. To address this, we present Dingent, a novel and configurable agent framework that facilitates data access from various resources and enables the flexible constructions of agent applications. We demonstrate its capabilities across three distinct application scenarios, achieving promising results. The Dingent framework can be readily applied to other fields, such as earth sciences and ecology, to facilitate data discovery.

bioinformatics↗

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

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

immunology↗

Coordinated yet asymmetric striatal neuromodulatory dynamics encode associative learning

The striatum integrates dopamine and acetylcholine to support learning and behavioral flexibility, yet how these neuromodulators coordinate during associative learning remains unclear. Using longitudinal dual-color fiber photometry in mice, we simultaneously tracked both signals in the anterior dorsolateral striatum throughout Pavlovian conditioning. We find that learning recruits distinct forms of neuromodulatory plasticity: dopamine maintains rapid, contingency-dependent cue responses, whereas acetylcholine undergoes broader reorganization across training. Despite these differences, trial-by-trial covariance between the two signals converges onto a compact low-dimensional structure that reliably captures learned behavioral state and distinguishes associative learning from sensory exposure alone. Granger causality analyses further reveal a directional asymmetry, present in both paired and unpaired mice, whereby dopamine reliably predicts subsequent acetylcholine fluctuations, with only weak reciprocal prediction. Together, our results identify a low-dimensional organizational principle for dopamine-acetylcholine interactions, and suggest that dopamine acts as a leading temporal signal that shapes cholinergic dynamics during striatal learning.

neuroscience↗

Mitotically Driven Cytoskeletal Reorganization Governs Zebrafish Left-Right Organizer Detachment from EVL and Lumen Morphogenesis

Left-right asymmetry in vertebrate embryos is established by the left-right organizer (LRO), with the zebrafish Kupffers vesicle (KV) providing a tractable model for studying de novo epithelial morphogenesis. During KV formation, dorsal forerunner cells (DFCs) initially form polarized attachments to the enveloping layer (EVL) before reorganizing into multicellular rosettes that precede lumen formation. Here, we show that while DFC-EVL junctions form independently of mitosis, early cytokinetic events play an instructive role in remodeling these contacts. Live imaging and targeted laser ablation reveal that cytokinetic bridges and their associated microtubule bundles recruit actin, seed rosette centers, and promote the transition from external to internal epithelial organization. Disruption of early, but not later, DFC divisions impairs actin accumulation, rosette coalescence, KV detachment from the EVL, and lumenogenesis. These findings identify a temporally restricted role for cytokinesis in organizing cytoskeletal architecture and reveal how division history directs epithelial tissue assembly during LRO development.

cell biology↗

A Multiscale Computational Architecture to Study Signaling Dynamics at Cell-Cell Interfaces

Intercellular communication is governed by the spatiotemporal dynamics of protein complexes at the cell-cell interface. However, conventional static interaction models fail to incorporate key physical constraints, such as steric hindrance, spatial compartmentalization, and dimensionality reduction that regulate complex assembly in vivo. To bridge the gap between static network topology and dynamic systems biology, we developed a multi-scale computational framework. We first identified a highly conserved, Fibroblast Growth Factor Receptor 1 (FGFR1)-centered cell adhesion and signaling motif by analyzing a diverse set of human cell-cell interfaces. We then constructed a multi-layer spatial stochastic simulator to recapitulate and interrogate the dynamic behavior of this network motif at cell-cell interfaces. Atomic-resolution structural models of the protein complexes within the motif were further generated using AlphaFold to define interaction rules for the stochastic simulations by categorizing binding interfaces. Our results show that the structural arrangement of cell-cell adhesion complexes controls how FGFR1 receptors cluster at the cell-cell interface, effectively dividing the membrane into distinct functional microdomains. Competition from decoy receptors further regulates this process by capturing receptors before they can participate in signaling. Even small changes in binding affinity can therefore alter receptor organization and disrupt normal signal transduction, which may contribute to human disease. By integrating macro-scale interactomics, atomic-level structural bioinformatics, and mesoscale stochastic modeling, this study reveals how structural interaction rules, combined with spatial constraints, shape the formation and function of intercellular signaling networks.

systems biology↗

Tempo and mode of gene evolution revealed by the Lenski long-term evolution experiment

The process of evolutionary change remains poorly understood. By analyzing genomic data from 12 populations in Lenskis long-term evolution experiment (LTEE) over 60,000 generations, we identified a clear sequence in gene adaptation: growth-related genes evolved early, while survival-related genes evolved later. Early-evolving genes exhibited higher rates of both nonsynonymous and synonymous substitutions. We also observed a general decline in gene evolutionary rates across LTEE populations, with additional data highlighting the role of fitness gains in determining evolutionary rates. These findings suggest that, in a relatively stable environment, the fitness gains from beneficial mutations decrease as adaptation progresses. This diminishing return on fitness gains may represent a key evolutionary rule, potentially contributing to evolutionary stasis and the prevalence of neutral evolution.

evolutionary biology↗

Multiscale conformational sampling of multidomain fusion proteins by a physics informed diffusion model

Multidomain fusion proteins, such as bispecific antibodies, rely on highly flexible linker regions for their therapeutic efficacy. Characterizing these vast conformational ensembles is crucial for rational drug design; however, while all-atom molecular dynamics (MD) is the traditional gold standard, its immense computational cost makes simulating large-scale domain motions prohibitive. Recently, deep generative diffusion models have emerged as a rapid alternative for sampling protein dynamics. Yet, being trained primarily on massive databases of structured, static domains, these generic models often lack the biophysical constraints required to thoroughly sample the large-scale dynamics of highly flexible multidomain architectures. To overcome this, we leverage microsecond MD trajectories of a multidomain protein construct with various linkers to train a multiscale diffusion framework utilizing an Equivariant Graph Neural Network (EGNN). To efficiently model the dynamics of the large molecular complexes, we employ a coarse-grained spatial graph that condenses rigid domains into center-of-mass anchors while preserving explicit backbone resolution for the flexible linker. By further integrating foundational rules in biophysics directly into both the training objective and the inference process, our model generates high-fidelity conformational ensembles that reproduce the thermodynamic distributions of long-timescale MD. This physics-informed approach provides a mathematically stable, highly scalable platform for the rapid multiscale characterization of flexible biologics, significantly accelerating the rational design of fusion protein therapeutics.

bioinformatics↗

Antibody recycling via FcRn drives atherosclerotic plaque vulnerability

Atherosclerotic plaques accumulate low-density lipoprotein (LDL) together with antibodies targeting LDL and its apolipoprotein B (apoB) component. Given the association between IgG and plaque vulnerability, we hypothesized that apoB-specific immune complexes actively promote plaque destabilization. Using immunohistochemistry in carotid endarterectomy specimens, we quantified antibody deposition across morphologically defined plaque regions, and measured apoB reactivity and immune complex levels in matched plaque and plasma samples. IgG deposition was strongly associated with thin fibrous caps, reduced collagen content, and higher overall plaque vulnerability. Symptomatic patients exhibited increased apoB-specific IgG and reduced apoB-IgG immune complexes within plaques, indicating enhanced IgG recycling and heightened inflammatory activity. The neonatal Fc receptor (FcRn) was predominantly expressed by CD163+ macrophages, and mediated antibody recycling, LDL uptake, and production of tumor necrosis factor (TNF) and matrix metalloproteinase-9 (MMP-9) in vitro. Plaque FcRn expression increased with age and correlated with mediators of vulnerability, including collagen-degrading enzymes and pro-inflammatory cytokines. Ex vivo treatment of human plaques with a clinically used FcRn-blocking monoclonal antibody reduced IgG recycling and suppressed TNF and MMP-9 production. These findings identify FcRn-dependent antibody recycling as a contributor to inflammatory plaque vulnerability and highlight FcRn as a potential therapeutic target in atherosclerosis.

immunology↗

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

Constructing a single-objective oblique plane microscope (OPM) for fast, multi-colour, high-resolution volumetric fluorescence imaging

Oblique plane microscopy (OPM) is a light sheet microscopy technique that uses a single high numerical aperture (NA) objective for both illuminating the sample and collecting emission fluorescence from a tilted plane within the specimen. OPM has become indispensable in biological and biomedical research, providing rapid, high-resolution volumetric fluorescence imaging of live cells and tissues while minimising phototoxicity and photobleaching. It also overcomes the sample mounting challenges associated with conventional light sheet microscopes that require two orthogonally placed objectives. However, the application of OPM has been limited by the complex design and the intricate optical alignment and characterisation needed, particularly with the remote-refocusing system (RFS) in the emission path. This protocol offers a detailed, step-by-step guide for constructing an OPM setup using commercially available components and for characterising its performance to ensure optimal imaging quality. We aim to deliver the unique merits of OPM to researchers in life science and medicine, enabling them to visualise the spatiotemporal organisation of key biomolecules, structures, and cells in 3D at high resolutions.

biophysics↗

Myofibroblast lineage mapping and inhibiting subretinal fibrosis by targeting SMAD3 and MRTF pathways via microRNA-24 functional study

Subretinal fibrosis underlies the end-stage pathogenesis of retinal diseases including age-related macular degeneration (AMD). It can disrupt retinal structure and eventually lead to legal blindness by generating contractile force, fibrotic scarring, subretinal hemorrhage, and retinal detachment. Myofibroblasts are the predominant cells critically involved in subretinal fibrosis, however, the cellular contribution to myofibroblasts remains unclear. Here we demonstrate that multiple cell lineages, including macrophages, endothelial cells (EC), retinal pigment epithelial (RPE) cells and pericytes, significantly contribute to myofibroblasts in a laser-induced subretinal fibrosis model. We found microRNA miR-24 is significantly downregulated in the plasma of wet AMD patients. Overexpression of miR-24 represses epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), and the resulting fibrosis by regulating TGF-{beta}/SMAD3 and PAK4/LIMK2/MRTF pathways. Consistently, a combination of SMAD3 and MRTF inhibitors show superior efficacy to individual inhibitors in repressing fibrosis in vitro and laser-induced subretinal fibrosis in vivo. Together, these suggest the contribution of multiple cell-types in myofibroblast transformation in subretinal fibrosis, and repression of miR-24-regulated TGF-{beta}/SMAD3 and PAK4/LIMK2/MRTF pathways in multiple cell types holds therapeutic potential for treating subretinal fibrosis in AMD and other fibrotic disorders.

molecular biology↗

Development of hybrid alphavirus-influenza A, B, and D pseudovirions for rapid quantification of neutralization antibodies and antiviral drugs

The emergence and spread of highly pathogenic avian influenza H5N1 subtypes have raised global concerns due to their ability to cross species barriers and occasional spillover to humans. The viruses primarily infect wild birds and poultry, which have caused significant, sporadic outbreaks in mammals including dairy cattle. Influenza D virus is a recently identified influenza virus that mainly affects cattle with frequent spillover to other species such as swine. Despite the availability of poultry vaccines, there are no H5N1 and Influenza D vaccines for cattle or other potentially affected livestock. Given a history of frequent influenza pandemics originating from avian and mammalian hosts, there is an urgent need for enhanced surveillance, biosecurity, and the development of antivirals and vaccines. Here we describe the development of a novel hybrid alphavirus-influenza pseudovirion (Ha-IV), which is a non-replicating influenza virus-like particle composed of viral structural proteins and an RNA genome derived from a fast-expressing alphaviral vector. As a proof-of-concept, we assembled Ha-IV pseudoviruses based on influenza D and influenza A and B subtypes, and demonstrated their infectivity. In addition, we validated an influenza A pseudovirus based on the H5N1 clade 2.3.4.4b strain, A/Texas/37/2024, for rapid quantification of neutralization antibodies within 4 to 18 hours. Furthermore, we used the pseudovirus to quantify infected cow sera and performed a correlation study with the classic hemagglutinin inhibition assay (HIA). We demonstrate that the Ha-IAV pseudovirus-based assay is consistent with HIA in identifying protective antibody responses. Our results demonstrate that this new Ha-IV pseudovirus provides a rapid tool for quantifying the infectivity of emerging HA mutants and for assessing neutralizing antibody responses.

microbiology↗

Evolutionary Divergence of Structure-Function Coupling between Human and Macaque: Spatial Patterns and Transcriptomic Basis

Structural-functional coupling (SFC) provides critical insights into how the brains structural architecture constrains functional organization for supporting higher-order cognition. Investigating evolutionary differences in SFC between humans and macaques may provide new insights into the neural basis of unique human cognitive abilities. In this study, we analyzed multimodal magnetic resonance imaging data from anesthetized and awake adult rhesus macaques and adult humans to examine cross-species divergences in SFC. Moreover, we integrated transcriptomic data to elucidate the molecular mechanisms underlying evolutionary differences in SFC patterns. We find that humans and macaques exhibit distinct SFC patterns: the human brain shows high SFC in the lateral and medial prefrontal cortex, whereas macaques show high SFC in the sensorimotor cortex. Notably, language-related regions in the human lateral temporal cortex exhibit relatively low SFC. Furthermore, the human whole-brain SFC pattern and the evolutionary differences in SFC between humans and macaques are negatively correlated with cortical evolutionary expansion. By integrating human and macaque transcriptomes, we reveal that the macaque SFC specifically associated genes are primarily involved in basic physiological functions, whereas the human SFC specifically associated genes exhibit evolutionary adaptations in synaptic function, neurotransmitter secretion, and other molecular processes. Moreover, the human-specific genes showing significant overlap with Human Accelerated Regions genes were mainly enriched in cell types of astrocyte and oligodendrocyte and in diseases of schizophrenia and Alzheimers diseases. Overall, these findings advance our understanding of the intricate relationships of SFC in human and macaque brains and provide novel insights in understanding evolutionary conservation and species specificity in cognitive function and gene regulation.

evolutionary biology↗