Biology subjects

Hsu, D.

Publications and source records attributed to Hsu, D..

11 recordsLinked to original sources

bioRxiv2026

Systematic exploration of predicted quaternary structures within pandemic-relevant viral proteomes

Mechanistic understanding of viral protein-protein interactions enables global health security and pandemic preparedness, yet experimental characterisation remains difficult, costly, and often restricted to specialised laboratories. Here, we describe an in silico campaign using AlphaFold2 and AlphaFold-Multimer to predict monomers and dimer structures within 2,812 viral proteomes from 23 viral families relevant to human health. We report high-confidence predicted structures of 5,279 hetero-, and 2,749 homo-dimers. Structural clustering of interfaces reduces the set fivefold to 1,598 consolidated by form and function, of which 471 (29.5%) lacked detectable similarity to experimentally determined interfaces in the PDB. These clusters yielded two notable findings: new data on vaccinology-relevant glycoproteins, and accurate prediction of the specificity and cleavage-site recognition of viral proteases, which are targets for anti-viral development. Viral monomers and high-confidence dimers are available for interactive browsing in the Pandemic Preparedness Portal of the AlphaFold Database (https://alphafold.ebi.ac.uk/), and the full dataset is available for bulk download.

bioinformatics↗

bioRxiv2026

AlphaFold Database expands to proteome-scale quaternary structures

Protein function is governed by molecular interactions, yet structural coverage of these interactions remains sparse. The AlphaFold Protein Structure Database (AFDB) transformed access to accurate monomeric protein structures at scale. Here, we expand the AFDB to quaternary structures by predicting 31M candidate homo- and heterodimeric protein complexes, compiled from 4,777 proteomes, including model- and global health organisms. We established confidence criteria via analysis of experimentally determined structures, resulting in 1.81M high-confidence predictions. These models enabled the discovery of emergent structures and topologies not present in monomeric predictions. Additionally, the top 1% of structural clusters accounted for [~]44% of all complexes, and [~]8.3% of clusters were conserved across multiple domains of life, pointing to a substantial fraction of ancient, universally retained assemblies. Structural search highlighted that high-confidence predictions are anchored in experimental multimer space, yet 31.3% extend beyond detectable PDB coverage. These freely accessible proteome-scale predictions facilitate functional and mechanistic hypothesis generation across biology.

synthetic biology↗

bioRxiv2025

Blind Virtual Screening at Scale: A Scalable End-to-End Pipeline for Blind Docking and Affinity Prediction

Accurate and scalable prediction of protein-ligand interactions remains a central challenge in computational drug discovery, especially when the binding site is unknown (i.e., blind docking). We present a high-throughput, end-to-end algorithm for virtual screening that combines DiffDock, a diffusion-based generative model for blind docking, with UniDock Vina, an algorithm for rapid scoring. We benchmarked this approach on the CASF-2016 and DUD-E datasets, analyzing pose quality, scoring accuracy, and screening performance. We find that competitive screening power can be achieved when generating and scoring as few as three poses and without pose refinement, which facilitates scalability. Notably, our method achieves 86.78% and 82.00% for the percent of actives among the top 1% and 10% of ranked ligands, respectively, when generating as few as three poses per protein-ligand pair. The workflow is scalable, supporting blind docking and affinity prediction at a mean throughput of 0.76 seconds per protein-ligand pair when generating 40 ligand poses in batched mode parallelized to 8 NVIDIA A100 80G GPUs. These results demonstrate that accurate, large-scale blind virtual screening is feasible and offers a practical solution for screening against novel or less characterized protein targets. Code is available at: https://github.com/xinyu-dev/blind-screening-benchmark

bioinformatics↗

bioRxiv2023

Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting

The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the underlying mechanisms remain unclear. The difficulty in capturing the earliest moment of coreceptor switch in vivo limits our understanding of this phenomenon. Here, by tracking the evolution of the transmitted/founder (T/F) HIV-1 in a prospective cohort of individuals at risk for HIV-1 infection identified very early in acute infection, we investigated this process with high resolution. The earliest X4 variants evolved from the R5 tropic T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive X4 variants to replicate mainly in the central memory and naive CD4+ T cells. We propose a novel concept to explain the co-evolution of virus antigenicity and entry tropism termed "escape by shifting". This concept posits that for viruses with receptor or coreceptor flexibility, entry tropism alteration represents a mechanism of immune evasion in vivo.

microbiology↗

bioRxiv2023

Arginine limitation causes a directed DNA sequence evolution response in colorectal cancer cells

Utilization of specific codons varies significantly across organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine restriction--a feature of tumor microenvironments--is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced a proteomic shift towards low arginine codon containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons--reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

cancer biology↗

bioRxiv2022

Productive and latent HIV infections originate in resting CD4+ T cells

Productively and latently HIV-infected cells are the source of virus that respectively establishes and sustains systemic infections and the reservoir in which HIV persists and rebounds when anti-retroviral therapy (ART) is interrupted. While infected activated CD4+ T cells are thought to be the principal source of HIV production, and reversion of activated infected cells to a resting state as the major pathway to establishment of the latently infected cell reservoir, we now show that in the earliest stages of detectable HIV infection in the lymphoid tissue reservoir, infection of resting CD4+ T cells establishes the first populations of both productively and latently infected cells. We further show that the early infection of resting T cells reflects their predominance in lymphoid tissues and the expression of pTEFb in vivo in resting T cells to support their infection. The immediate establishment of productively and latently infected cell populations enable HIV to propagate and persist, and generates reservoirs from which infection can rebound despite instituting ART at the earliest stage of detectable infection.

immunology↗

bioRxiv2022

Chromatin Remodeling in Patient-Derived Colorectal Cancer Models

Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, we compared the transcriptomic and chromatin accessibility landscapes of six matched sets of colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) and discovered two major remodeling axes. The first axis delineates PDX and PDO from PT, and the second axis distinguishes PDX and PDO. PDOX were more similar to PDX than they were to PDO, indicating that the growth environment is a driving force for chromatin adaptation. Using bivariate genomic footprinting analysis, we identified transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX. Among them, KLF14 and EGR2 footprints were enriched in all six PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.

cancer biology↗

bioRxiv2022

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

Upon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We analyzed productively and latently infected cells in blood and lymphoid tissue from individuals in acute infection. The phenotype of productively infected cells rapidly evolved with time and differed between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded/disseminated cells, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells in blood and lymph nodes and latently infected cells are generated simultaneously. One-Sentence SummaryHIV initially infects phenotypically and clonotypically distinct T cells and establishes a latent reservoir concomitantly.

microbiology↗

bioRxiv2021

Two Isoleucyl tRNAs that Decode 'Synonymous' Codons Divergently Regulate Breast Cancer Progression

The human genome contains 61 codons that encode for the 20 amino acids. The synonymous codons of a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons are modulated in opposing directions during breast cancer progression. Specifically, tRNAIleUAU is upregulated, whereas tRNAIleGAU is repressed as breast cancer cells attained enhanced metastatic capacity. Functional studies revealed that tRNAIleUAU promoted and tRNAIleGAU suppressed metastatic colonization. The expression of these tRNAs mediated opposing effects on codon-dependent translation of growth promoting genes. Consistent with this, multiple mitotic gene sets in the human genome are significantly enriched in the codon cognate to the growth-promoting tRNAIleUAU and significantly depleted of the codon cognate to the growth-suppressive tRNAIleGAU. Our findings uncover a specific isoacceptor tRNA pair that act in opposition--divergently regulating genes that contribute to growth and a disease phenotype. The degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that facilitate the transition towards a growth-promoting state.

cancer biology↗

bioRxiv2020

A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

PurposeOsteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Experimental designTo overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. ResultsCoupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. ConclusionsThese collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.

cancer biology↗

bioRxiv2019

Dietary methionine restriction targets one carbon metabolism in humans and produces broad therapeutic responses in cancer

Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component, the principles that define whether nutrition may be used to influence tumour outcome are unclear. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has aging and obesogenic properties, influences cancer outcome through controlled and reproducible changes to one carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts and autochthonous KRASG12D+/-;TP53-/- -driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumor cell autonomous effects on the flux through one carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide evidence that a targeted dietary manipulation can affect specific tumor cell metabolism to mediate broad aspects of cancer outcome.

cancer biology↗