Biology subjects

Lau, A.

Publications and source records attributed to Lau, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Neofunctionalised plastid translocon regulates chloroplast ageing in Arabidopsis

Protein import across the chloroplast outer membrane is mediated by the TOC complex and regulated by GTP hydrolysis at two receptor GTPases, large and small. The former are the {beta}-barrel-containing Toc159 family of proteins (Sun and Jarvis 2023; H. Li and Chiu 2010; Shi and Theg 2013a; Kessler and Schnell 2009). The smallest member of this family in higher plants is Toc90, which has long been regarded as functionally unimportant due to the absence of obvious phenotypes in early mutant studies (Kubis et al. 2004; Infanger et al. 2011a). It was hypothesised that Toc90 is a relic of an ancestral Toc159 protein from early green lineage organisms (Hofmann and Theg 2003; Reumann et al. 2005). Here, we challenge this view by combining genetic, biochemical, phylogenetic, and in silico structural analyses to show that Toc90 is not an ancient remnant, but rather a neofunctionalised derivative of Toc159, and likely the most recently evolved member of the family. We show that Toc90 physically associates with Toc33 as a part of a photosynthetic TOC complex. Furthermore, we identify Toc90 as a regulator of chloroplast ageing. Our findings redefine Toc90 as an active and specialised component of the chloroplast protein import machinery, playing a pivotal role in senescence, especially in reducing photosynthetic protein abundance. Together, these results highlight Toc90 as a promising target for manipulating chloroplast longevity and plant senescence, with potential to improve crop productivity and yield.

plant biology↗

bioRxiv2026

A modular generalist-specialist AI framework for ROI selection across spatial profiling workflow

Selection of regions of interest (ROIs) is often a crucial step in spatial molecular profiling and many pathology tasks, with substantial implications for research reproducibility and biological interpretability. To provide a reproducible and adaptive framework for AI-guided ROI selection, we developed a modular generalist-specialist solution across spatial profiling platforms. In a cohort comprising 55 tumor types from 160 tissue donors profiled using NanoString Digital Spatial Profiling and multiplex immunofluorescence, we first established a protein-profiling reference atlas capturing compartment-specific immune, checkpoint, stromal, and proliferation patterns. We then developed an AI Specialist Task-Oriented Model for ROI Selection (ASTROS) and tested comprehensive benchmarks considering specialist-only (ASTROS), generalist-only (PLIP/GFM), and hybrid generalist-specialist strategies, showing that the latter provides a balanced tradeoff across slide-level signal preservation, pathologist-reference concordance, within-slide placement consistency, and large-slide computational efficiency. We further demonstrated the feasibility of virtual staining for ROI preview and modular ROI placement for other spatial omics technologies, Visium and Visium HD workflows. Together, these results support our proposed framework to enable ROI selection responding to unmet needs for reducing inter-rater variability, reproducibility, and versatility in spatial profiling experiments.

pathology↗

bioRxiv2026

The IL-1 Family Controls Acute Mucosal Fungal Infection and Mucosal-Systemic Dissemination.

Candida albicans is a major opportunistic pathogen in humans that is capable of breaching mucosal barriers and causing severe systemic infections with high mortality. How the host controls mucosal infection and prevents dissemination remains unclear but is essential for improving disease outcomes. Here, we demonstrate that C. albicans induces specific IL-1 family members, which are critical for initiating mucosal protection by controlling antimicrobial peptides, IL-17, and neutrophil responses. Loss of combined IL-1 family signalling led to severe mucosal C. albicans infection, which was eventually resolved by a potent neutrophil response. However, in neutropenic conditions (a key risk patient factor) abolishing IL-1 family signalling resulted in C. albicans dissemination, predominantly to the liver, mirroring clinical disease and leading to mortality. This study highlights the IL-1 family as a key initiator of mucosal immunity, restricting mucosal invasion and cooperating with neutrophils to prevent life- threatening systemic infections.

microbiology↗

bioRxiv2025

Unveiling patterns of roadkill of a migratory amphibian in Hong Kong with implications for mitigation

Road-related mortality, particularly wildlife-vehicle collisions, poses a significant threat to amphibian populations, with billions of individuals falling victim annually. The rapid urban development in Hong Kong, China, including the forthcoming construction of a "Northern Metropolis" area, is expected to bring over 2.5 million new residents, potentially increasing traffic and posing a heightened threat to local amphibians during their migration periods. To help prevent future biodiversity loss, our study focuses on the near-threatened newt species Paramesotriton hongkongensis in Hong Kong, investigating the spatiotemporal distribution of roadkill during migration seasons. Weekly surveys at four hotspots revealed 1,563 animal carcasses, the majority of which were P. hongkongensis. Factors triggering mass mortality events were explored, although no significant correlations were found. Prediction models demonstrated moderate accuracy in detecting mass mortality events, indicating a need for further refinement. Recommendations for site-specific mitigation measures to protect amphibians during their migrations are discussed, with an emphasis on the importance of conducting fine-scale surveys for effective conservation strategies.

ecology↗

bioRxiv2025

A Transcriptomics-Based Computational Drug Repositioning Pipeline Identifies Simvastatin And Primaquine As Novel Therapeutics For Endometriosis Pain

Endometriosis has limited treatment options, prompting the search for novel therapeutics. We previously used a transcriptomics-based computational drug repositioning pipeline to analyze public bulk transcriptomic data of eutopic endometrium from cases and controls and identified several drug candidates. Fenoprofen, our top in silico candidate, was validated in a rat model of endometriosis-associated pain. Building on this, we evaluated herein two additional candidates, simvastatin (a cholesterol-lowering drug) and primaquine (an antimalarial), based on strong endometrial gene expression reversal scores and favorable safety profiles. Using the rat model, we conducted behavioral testing, bulk RNA sequencing, and differential expression analysis to assess their therapeutic potential. We also assessed endometriosis diagnosis among patients prescribed simvastatin in electronic medical records (EMR) across six University of California (UC) healthcare institutions. In vivo validation using a rat model of endometriosis demonstrated that both simvastatin and primaquine significantly reduced vaginal hyperalgesia, a surrogate marker of endometriosis-related pain. RNA-seq of uteri and lesions confirmed reversal of disease-associated gene expression signatures following treatment. Analysis of UC-wide EMR data found lower relative risk of endometriosis among those prescribed simvastatin compared to a matched control group. Overall, simvastatin and primaquine attenuated pain-associated behaviors and reversed endometriosis-related gene expression changes in an animal model. Moreover, simvastatin prescription was associated with a lower relative risk of endometriosis in our retrospective multi-center cohort study. These findings highlight their potential as repurposed therapeutics for endometriosis and support the effectiveness of computational drug repositioning in identifying new treatment strategies. One Sentence SummarySimvastatin and primaquine reduced endometriosis pain and reversed gene signatures, with simvastatin also linked to lower disease risk.

bioinformatics↗

bioRxiv2025

Gap scheduling of a PARP inhibitor and nanoparticle TOP1 agent combination avoids synergistic bone marrow toxicity

Although combinations of DNA damage response inhibitors (DDRi) and DNA damaging chemotherapy enhance cytotoxicity in cell-based systems, clinical success has been limited by overlapping bone marrow toxicities. Here, we show that a tumor-targeted nanoparticle camptothecin CRLX101, administered concurrently with DDRi, enhances anti-tumour efficacy but also increases bone marrow toxicity in preclinical models. Using rat bone marrow progenitor cells as biomarkers and leveraging differential repair kinetics of CRLX101-induced DNA damage in tumour and bone marrow, we identified a gap schedule of the PARP inhibitor olaparib and CRLX101 that enhanced efficacy over single agents but demonstrated a reduced combination marrow toxicity. A clinical trial has been designed using the gap schedule identified here and represents a template that can be used to successfully deliver DDRi with tumor-targeted chemotherapy in combination.

cancer biology↗

bioRxiv2024

Both T and B cells contribute to dysregulated activation and differentiation of CD4+ T cells in Activated PI3K delta syndrome 1

Activated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variants in PIK3CD which encodes the p110{delta} catalytic subunit of phosphoinositide 3-kinase (PI3K). APDS1 patients display a broad range of clinical manifestations and perturbations in cellular phenotype. One of the most striking features is the dysregulation of the T cell compartment characterised by an increase in memory T cells, including Tfh cells, and a concomitant decrease in naive T cells. We have previously shown that many of these changes in T cell populations were T cell extrinsic and were also induced in WT T cells that developed in the presence of PI3K GOF cells. Here we dissected the drivers of dysregulated T cell activation using a mouse model of APDS1. This revealed PI3K GOF macrophages and DCs made little contribution to the aberrant T cell activation. Instead, the loss of naive T cells was mostly driven extrinsically by PI3K GOF T cells, while the increase in Tfh cells was mediated by dysregulated PI3K GOF B cells. Surprisingly, despite previous reports of increased PI3K driving dysregulated inflammatory Tregs, we saw no evidence for Pik3cd GOF Tregs acquiring an inflammatory phenotype and driving T cell activation. These studies provide new insights into the clinical phenotype of patients with APDS1 and new understanding of the role of PI3K in immune cells.

immunology↗

bioRxiv2024

Environmental factors and host sex influence the skin microbiome structure of Hong Kong newt (Paramesotriton hongkongensis) in a coldspot of chytridiomycosis in subtropical East Asia

Chytridiomycosis, an infectious skin disease caused by the chytrid fungi, Batrachochytrium dendrobatidis and B. salamandrivorans, has been threatening global amphibian biodiversity. On the skin of chytrid-resistant amphibians, some antifungal bacteria likely defend them against chytridiomycosis, reducing the mortality of resistant amphibians. The Hong Kong newt (Paramesotriton hongkongensis) inhabits East Asia which is a suspected origin of chytrids. Asymptomatic infection in the newts suggests their long-term coexistence with chytrids. Thus, the skin microbiomes of this resistant species warrant investigation, along with other factors that can affect the microbiome. Among the 149 newts sampled in their natural habitats in Hong Kong, putative antifungal bacteria were found on all newts. There were 314 amplicon sequence variants distributed over 25 genera of putative antifungal bacteria, abundant ones included Acinetobacter, Flavobacterium, and Novosphingobium spp. The skin microbiome compositions were strongly influenced by the inter-site geographical distances. Despite inter-site differences, we identified some core skin microbes across sites, which could be vital to P. hongkongensis. The dominant cores included family Comamonadaceae, family Chitinophagaceae, and class Betaproteobacteria. Moreover, habitat elevation and host sex also exhibited significant effects on skin microbiome compositions. The antifungal bacteria found on these newts offer an important resource for conservation against chytridiomycosis, such as probiotic treatments for susceptible species.

ecology↗

bioRxiv2023

Prrx1-driven LINC complex disruption in vivo does not significantly alter bone properties in 8-week male mice nor after 6-weeks voluntary wheel running

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex serves to connect the nuclear envelope and the cytoskeleton, influencing cellular processes such as nuclear arrangement, architecture, and mechanotransduction. The role LINC plays in mechanotransduction pathways in bone progenitor cells has been well studied; however, the mechanisms by which LINC complexes govern in vivo bone formation remain less clear. To bridge this knowledge gap, we established a murine model disrupting LINC using transgenic Prx-Cre mice and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Prx-Cre mice express the Cre recombinase enzyme controlled by the paired-related homeobox gene-1 promoter (Prrx1), a pivotal regulator of skeletal development. Prx-Cre animals have been widely used in the bone field to target bone progenitor cells. Tg(CAG-LacZ/EGFP-KASH2) mice carry a lox-stop-lox flanked LacZ gene allowing for the overexpression of an EGFP-KASH2 fusion protein via cre recombinase mediated deletion of the LacZ cassette. This disrupts endogenous Nesprin-Sun binding in a dominant negative manner disconnecting nesprin from the nuclear envelope. By combining these lines, we generated a Prrx1(+) cell-specific LINC disruption model to study its impact on the developing skeleton and subsequently exercise-induced bone accrual. The findings presented here indicate Prx-driven LINC disruption (PDLD) cells exhibit no change in osteogenic and adipogenic potential compared to controls in vitro nor are there bone quality changes when compared to in sedentary animals at 8 weeks. While PDLD animals displayed increased voluntary running activity andPrrx1(+) cell-specific LINC disruption abolished the exercise-induced increases in osteoid volume and surface after a 6-week exercise intervention, no other changes in bone microarchitecture or mechanical properties were found.

bioengineering↗

bioRxiv2023

Osterix-driven LINC complex disruption in vivo diminishes bone microarchitecture in 8-week male mice but not after 6-week voluntary wheel running

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formation in vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in a Osx-driven LINC disruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potential in vitro compared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8-weeks. Upon access to a voluntary running wheel ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.

bioengineering↗

bioRxiv2022

Integrated transcriptome analysis of Huntingtons disease iPSC-derived and mouse astrocytes implicates dysregulated synaptogenesis, actin, and astrocyte maturation

Huntingtons disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat within the Huntingtin (HTT) gene having dysregulated cellular homeostasis in the central nervous system, particularly in the striatum and cortex. Astrocytes establish and maintain neuronal functions through the secretion of soluble factors and physical interactions with other neurovascular unit cell types. Under pathological conditions, astrocytes can become reactive, causing cell state transitions that affect brain function. To investigate transitions between cellular states in unaffected and HD astrocytes at high resolution, single-nuclei RNA-sequencing (snRNA-seq) was performed on human HD patient induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from a rapidly progressing HD mouse model (R6/2). Analysis of HD human and mouse astrocytes revealed both models have alterations in morphology, glutamate uptake, and dysregulation of astrocyte identity and maturation, whereas dysregulated actin-mediated signaling was unique to human iPSC-derived astrocytes. Representative proteins showed altered levels by Western. In both species, HD transcriptional changes reveal potential astrocyte maturation deficits that were potentially driven by astrogliogenesis transcription factors, including ATF3 and NFIA. When perturbed in a drosophila model of HD, knockdown of NFIA in glia rescued the climbing deficit. These data further support the hypothesis that mutant HTT induces dysregulated astrocyte cell states resulting in dysfunctional astrocytic properties, suggests that some of these states are cell autonomous and maybe unique to human HD, and implicate ATF3 and maturation deficits in HD pathogenesis.

neuroscience↗

bioRxiv2022

Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism

The complexity of affected brain regions and cell types is a challenge for Huntingtons disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

neuroscience↗

bioRxiv2021

Loss of C9orf72 perturbs the Ran-GTPase gradient and generates compositionally diverse cytoplasmic Importin β-1 granules in motor and cortical neurons in vivo

Repeat expansions in C9orf72 cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 causes neuronal specific phenotypes, disrupting the Ran-GTPase gradient both in vitro and in vivo. We describe compositionally different types of cytoplasmic Importin {beta}-1 granules that exhibit neuronal subtype-specific properties in vivo. We show that the abundance of Importin {beta}-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to bud from the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.

neuroscience↗

bioRxiv2021

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer's disease progression.

It is unknown whether specific microglia are selectively induced by amyloid-{beta} (A{beta}), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both A{beta} and tau pathologies during Alzheimers disease (AD) progression. We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both A{beta} and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

neuroscience↗

bioRxiv2021

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington's Disease Mouse Striatum

Huntingtons disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

neuroscience↗

bioRxiv2020

STUB1 is an intracellular checkpoint for interferon gamma sensing

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFN{gamma}) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFN{gamma} response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFN{gamma} sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.

cancer biology↗

bioRxiv2020

First record of the Australian redclaw crayfish Cherax quadricarinatus (von Martens 1868) in Hong Kong, China

Invasive freshwater crayfish are spreading rapidly across the world. Here, we report the first record of Australian redclaw crayfish, Cherax quadricarinatus (von Martens 1868) in Hong Kong, China. Identification of the captured crayfish was confirmed using external morphological features and molecular analyses. A total of 49 crayfish were captured from a stream pool and a reservoir in Pok Fu Lam Country Park using dip nets and funnel traps. The captured C. quadricarinatus ranged from 17.20 mm to 56.40 mm (mean = 30.70) in carapace length and the sex ratio was 1:1. Since this species is globally recognized as an invasive species, a comprehensive survey on its status and invasion front, an investigation into its potential ecological impacts, as well as the formulation of a monitoring and removal strategy, are warranted.

ecology↗

bioRxiv2019

Multi-ATOM: Ultrahigh-throughput single-cell quantitative phase imaging with subcellular resolution

A growing body of evidence has substantiated the significance of quantitative phase imaging (QPI) in enabling cost-effective and label-free cellular assay, which provides useful insights into understanding biophysical properties of cells and their roles in cellular functions. However, available QPI modalities are limited by the loss of imaging resolution at high throughput and thus run short of sufficient statistical power at the single cell precision to define cell identities in a large and heterogeneous population of cells - hindering their utility in mainstream biomedicine and biology. Here we present a new QPI modality, coined multi-ATOM that captures and processes quantitative label-free single-cell images at ultra-high throughput without compromising sub-cellular resolution. We show that multi-ATOM, based upon ultrafast phase-gradient encoding, outperforms state-of-the-art QPI in permitting robust phase retrieval at a QPI throughput of >10,000 cell/sec, bypassing the need for interferometry which inevitably compromises QPI quality under ultrafast operation. We employ multi-ATOM for large-scale, label-free, multi-variate, cell-type classification (e.g. breast cancer sub-types, and leukemic cells versus peripheral blood mononuclear cells) at high accuracy (>94%). Our results suggest that multi-ATOM could empower new strategies in large-scale biophysical single-cell analysis with applications in biology and enriching disease diagnostics.

bioengineering↗