Biology subjects

Leung, H.

Publications and source records attributed to Leung, H..

9 recordsLinked to original sources

bioRxiv2026

MINA: linear probes reveal coding-sequence family signal in frozen DNA encoders

Frozen DNA encoders are widely used as feature extractors, but fine-tuning hides what their fixed embeddings already make linearly accessible. We introduce MINA (Model Interrogation of Nucleotide Architectures), a lightweight benchmark testing whether frozen DNA embeddings can recover (i) a 5-way protein-family label and (ii) the 1,536-d GenePT natural-language embedding for each gene, comparing coding-sequence (CDS) and transcription-start-site (TSS) contexts under a homology-aware split, against translated-composition and protein-language-model baselines. Across 3,244 human genes from five families, the best DNA encoder recovers CDS family labels above 4-mer composition (NT-v2 macro-F1 0.727 vs. 0.633) but only reaches translated amino-acid composition (AA 2-mer 0.735), far below ESM-2 on translated proteins (0.960). GenePT recovery is weak (best DNA R2 = 0.077), and TSS family recovery collapses under homology control (NT-v2 0.447 [->] 0.313). Pooling and encoder choice matter as much, so encoders are not interchangeable: frozen DNA encoders expose coding-sequence protein-compositional signal from raw nucleotides, not robust gene-function signal from arbitrary genomic context.

bioinformatics↗

bioRxiv2025

Advancing Target Discovery Through Disease-Specific Integration of Multi-Modal Target Identification Models and Comprehensive Target Benchmarking System

Target identification is crucial for drug development. AI-driven approaches leveraging multi-omics and computational modeling can accelerate this process. However, integrating multi-modal data for disease-specific target identification and predicting translational potential remains challenging. Moreover, the absence of a systematic evaluation framework for model performance limits confidence in target reliability. We present a unified platform combining machine learning-based target identification with comprehensive benchmarking. As a testbed, we developed Target Identification Pro (TargetPro), a disease-specific model spanning 38 diseases across oncology, metabolic, immune, fibrotic, and neurological categories. TargetPro shows strong predictive performance for clinical-stage targets and reveals disease-specific patterns, underscoring the need for tailored target detection models. We next created Target Identification Benchmark (TargetBench 1.0) to rigorously assess target identification systems, including large language models, based on their ability to recover established targets and find high-quality novel candidates. This integrated approach offers a streamlined strategy to evaluate target discovery models, ultimately improving drug development efficiency.

bioinformatics↗

bioRxiv2024

Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

Prostate cancer (PC) is the most common male visceral cancer, and second leading cause of cancer mortality in men in the Western world. Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre) Pten-deficient mouse model of PC, we identified Arid1a loss as a driver in the development of metastatic disease. The insertion of transposon in the Arid1a gene resulted in a 60% reduction of Arid1a expression, and reduced tumour free survival (SB:Ptenfl/fl Arid1aINT median 226 days vs SB:Ptenfl/fl Arid1aWT293 days, p=0.02),with elevated rates of metastasis (SB:Ptenfl/fl Arid1aINT 75% lung metastasis rate vs 17% SB:Ptenfl/fl Arid1aWT, p<0.001 ). We further generated a Pb-Cre Pten- and Arid1a-deficient mouse model, in which loss of Arid1a demonstrated a profound acceleration in tumorigenesis in Ptenfl/fl mice compared to Pten loss alone (Pb-Cre Ptenfl/flArid1a+/+median survival of 267 days vs Pb-Cre Ptenfl/fl Arid1afl/fl103 days, p<0.0001). Our data revealed homozygous Arid1a loss is required to dramatically accelerate prostate tumourigenesis, resulting in tumours with a less differentiated phenotype and a disorganised stroma. Furthermore, Arid1a loss mediated tumour formation in the mouse involved both the anterior and dorsolateral lobes, a unique feature from Pten-loss and other reported PC GEMM where tumour formation tends to be limited to the anterior lobes. Analysis of RNA and ChIP -Sequencing data suggests Arid1a loss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.

cancer biology↗

bioRxiv2024

Antithrombotic Efficacy and Bleeding Risks of Vaccine-Induced Immune Thrombotic Thrombocytopenia Treatments

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend non-heparin anticoagulants and intravenous immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to a lack of comparative clinical trials or animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies due to their ability to disrupt VITT IgG-PF4 binding. Here, we examined the effects of various anticoagulants (including unfractionated (UF) heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the Fc{gamma}RIIa receptor-blocking antibody, IV.3, in relation to VITT pathophysiology. Our investigation focused on VITT IgG-PF4 binding, platelet activation, thrombocytopenia, and thrombosis. Danaparoid, at therapeutic doses, was the sole anticoagulant that reduced VITT IgG-PF4 binding, verified by purified anti-PF4 specific VITT IgG. Low-dose UF heparin (< 2U/mL) augmented VITT IgG binding to PF4 on platelets. While danaparoid and high-dose UF heparin (10 U/mL) inhibited platelet activation, none of the anticoagulants significantly affected thrombocytopenia in our VITT animal model, and all prolonged bleeding time. IVIg and all anticoagulants, except UF heparin, protected VITT mice from thrombosis. Direct Fc{gamma}RIIa receptor inhibition with IV.3 antibody proved the most effective approach for managing both thrombosis and thrombocytopenia in VITT. Our results underscore the necessity of animal model investigations to inform patient treatment strategies. This study provides compelling evidence for developing Fc{gamma}RIIa receptor blockers to treat VITT and other Fc{gamma}RIIa-related thrombotic inflammatory disorders. Key pointsO_LINon-heparin anticoagulants and IVIg reduce thrombosis in vivo by varying degrees whereas heparin exacerbates thrombosis. C_LIO_LIDirect blocking of Fc{gamma}RIIa receptor is the most effective strategy to treating both thrombosis and thrombocytopenia in VITT. C_LI

immunology↗

bioRxiv2022

Identifying Novel Candidate Defense Genes Against Rice Blast By Disease-Resistance Transcriptome Analysis

A blast-resistance rice mutant, GR978, generated by gamma-irradiation of indica cultivar IR64 was used to characterize the disease resistance transcriptome of rice to gain a better understanding of genes or chromosomal regions contributing to broad-spectrum disease resistance. GR978 was selected from the IR64 mutant collection at IRRI. To facilitate phenotypic characterization of the collection, a set of controlled vocabularies (CV) documenting mutant phenotypes in [~]3,700 entries was developed. In collaboration with the Tos17 rice mutant group at National Institute of Agrobiological Sciences, Japan, a merged CV set with 91 descriptions that map onto public ontology databases (PO, TO, OBO) is implemented in the IR64 mutant database. To better characterize the disease resistance transcriptome of rice, gene expression data from a blast resistant cultivar, SHZ-2, was incorporated in the analysis. Disease resistance transcriptome parameters, including differentially expressed genes (DEGs), regions of correlated gene expression (RCEs), and associations between DEGs and RCEs were determined statistically within and between genotypes using MAANOVA, correlation, and fixed ratio analysis. Twelve DEGs were found within the inferred physical location of the recessive gene locus on a [~]3.8MB region of chromosome 12 defined by genetic analysis of GR978. Highly expressed DEGs ([≥] 2fold difference) in GR978 or SHZ-2 and in common between the two, are mostly defense-response related, suggesting that most of the DEGs participate in causing the resistance phenotype. Comparing RCEs between SHZ-2 and GR978 showed that most RCEs between genotypes did not overlap. However, an 8-gene RCE in chromosome 11 was in common between SHZ2 and GR978. Gene annotations and GO enrichment analysis showed a high association with resistance response. This region has no DEGs nor is it associated with known blast resistance QTLs. Association analyses between RCEs and DEGs show that there was no enrichment of DEGs in the RCEs within a genotype and across genotypes as well. Association analysis of blast-resistance QTL (Bl-QTLs) regions (assembled from published literature; data courtesy of R. Wisser, pers comm., Cornell University) with DEGs and RCEs showed that while Bl- QTLs are not significantly associated with DEGs, they are associated with genotype-specific RCEs; GR978- RCEs are enriched within Bl-QTLs. The analysis suggested that examining patterns of correlated gene expression patterns in a chromosomal context (rather than the expression levels of individual genes) can yield additional insights into the causal relationship between gene expression and phenotype. Based on these results, we put forward a hypothesis that QTLs with small or moderate effects are represented by genomic regions in which the genes show correlated expression. It implies that gene expression within such a region is regulated by a common mechanism, and that coordinated expression of the region contributes to phenotypic effects. This hypothesis is testable by co segregation analysis of the expression patterns in well-characterized backcross and recombinant inbred lines.

plant biology↗

bioRxiv2022

Strong genotype by environment interactions in the rice Global MAGIC population across seedling stage drought

Crop adaptation is required to sustainably increase the rate of yield gains to meet projected future needs under the challenging conditions of climate change and competition for resources. Future adaptation will likely need to harness both highly polygenic traits and genotype-by-environment interactions (GxE), the study of which is aided by complex recombinant populations. We used the diverse Oryza sativa Global Multiparent Advanced Generation InterCross (MAGIC) population to study the genetic architecture and contributions of seedling emergence, establishment, and development to yield components under dry-direct seeding and seedling stage drought across three growing seasons. Dry-direct seeding is an establishment practice that has the potential to reduce methane emissions, water use, and labor demands for rice farmers, but increases the possibility of early-season drought conditions. We found substantial evidence for large roles of environmental variation and GxE in controlling trait variation. Maintenance of shoot growth during seedling stage drought was positively correlated with crown root number and both directly and indirectly influenced agronomic traits. Other than the major green revolution locus sd1, most allelic effects were conditionally neutral (affecting trait values in some environments but not others) and most alleles had their strongest effect in an environmental extreme. This discovery is both a challenge and a potential opportunity: with variable genetic architecture, selection in any one environment may not result in stable trait gains across environments. However, conditionally neutral GxE is a potential route to sustainable yield stability through allele pyramiding.

genetics↗

bioRxiv2021

Identification of Fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no FDA-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 years of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo, and that it inhibits activation of the NLRP3-ASC inflammasome in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other anti-depressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies triangulate to link fluoxetine as a potential drug repurposing candidate for a major unmet medical need that causes blindness in millions of people in the United States and across the world. Significance StatementDry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no FDA-approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents the assembly and activation of the NLRP3-ASC inflammasome. As a result, it also blocks the degeneration of retinal pigmented epithelium (RPE) cells in an animal model of dry AMD. Furthermore, we demonstrate through an analysis of health insurance databases that use of this FDA-approved anti-depressant drug is associated with reduced incidence of dry AMD. These studies identify that fluoxetine is a potential repurposing candidate for AMD, a prevalent cause of blindness.

immunology↗

bioRxiv2019

Twelve Platinum-Standard Reference Genomes Sequences (PSRefSeq) that complete the full range of genetic diversity of Asian rice

As the human population grows from 7.8 billion to 10 billion over the next 30 years, breeders must do everything possible to create crops that are highly productive and nutritious, while simultaneously having less of an environmental footprint. Rice will play a critical role in meeting this demand and thus, knowledge of the full repertoire of genetic diversity that exists in germplasm banks across the globe is required. To meet this demand, we describe the generation, validation and preliminary analyses of transposable element and long-range structural variation content of 12 near-gap-free reference genome sequences (RefSeqs) from representatives of 12 of 15 subpopulations of cultivated rice. When combined with 4 existing RefSeqs, that represent the 3 remaining rice subpopulations and the largest admixed population, this collection of 16 Platinum Standard RefSeqs (PSRefSeq) can be used as a pan-genome template to map resequencing data to detect virtually all standing natural variation that exists in the pan-cultivated rice genome.

genomics↗

bioRxiv2019

cis dominantly explains regulatory divergence between two indica rice genotypes; drought further enhances regulatory differences

Abstract cis and/or trans regulatory divergence within or between related taxa on a genome-wide scale has been largely unexamined in crops, more so, the effect of stress on cis/trans architecture. In this study, the indica genotypes IR64, an elite drought-susceptible lowland variety, and Apo (IR55423-01 or NSIC RC9), a moderate drought-tolerant upland genotype together with their hybrid (IR64 x Apo) were exposed to non- and water-stress conditions. Evidence of cis and/or trans regulatory differences was tested between these two indica rice genotypes. By sequencing (RNA-seq) the parents and their hybrid, we are able to map genes diverging in cis and/or trans factors between the two genotypes. Under non-stress conditions, cis dominantly explains (11.2%) regulatory differences, followed by trans (8.9%). Further analysis showed that water-limiting conditions largely affect trans and cis + trans factors. Between the two inbred lines, Apo appears to exhibit higher expression fold change of genes enriched in "response to stress" and "photosynthesis" under non- and water-stress conditions. On the molecular level, cis and/or trans regulatory divergence explains their genotypic differences and differential drought response. Parent-hybrid RNA-seq has the potential to identify genes diverging in cis and/or trans factors even between intra-sub-specifically related genotypes. By comparing cis/trans landscape under stressed and unstressed conditions, this approach has the ability to assess the impact of drought on gene expression. Computational analysis and association of several drought-yield QTL markers with cis-diverging genes provide converging evidences suggestive of a potential approach to identify trait-associated candidate genes using hybrids and their parents alone. Key Messagecis dominantly explains divergence of two indica rice genotypes, IR64 and Apo under normal conditions while trans and cis + trans regulatory factors are largely affected by drought

plant biology↗