Biology subjects

Yau, T.

Publications and source records attributed to Yau, T..

4 recordsLinked to original sources

bioRxiv2026

Disrupted Sleep-Dependent Neural Oscillations and Transcriptomic Changes in the Cacna1g Loss-of-Function Mouse Model Implicated in Schizophrenia

Sleep is an essential biological process for maintaining brain function, and impaired sleep microarchitecture is a well-established feature of schizophrenia (SCZ). Rare loss-of-function variants in CACNA1G, encoding the T-type calcium channel CaV3.1, confer substantial risk for SCZ, implicating sleep-regulatory circuits in disease pathophysiology. Here, we first show that among individuals with SCZ, carriers of rare CACNA1G missense variants exhibit more pronounced alterations in sleep neurophysiology than non-carriers, identifying a human phenotype suggestive of altered channel function. Motivated by this observation, we examined the consequences of Cacna1g loss of function in mice. Cacna1g deficiency produced profound disruptions in sleep microarchitecture, including reduced sleep spindles, altered slow oscillations, impaired spindle-slow oscillation coupling, and reduced cortical synchrony--closely recapitulating neurophysiological signatures observed in individuals with schizophrenia. Beyond sleep structure, Cacna1g loss disrupted the normal coordination of brain rhythms across the 24-hour cycle, most notably abolishing diurnal modulation of theta oscillations. At the molecular level, Cacna1g loss uncoupled sleep-wake state from gene and protein regulation, producing widespread, sleep-phase-biased transcriptional and synaptic alterations across brain regions and cell types, particularly in cortical excitatory neurons. These network and molecular disruptions were accompanied by behavioral hyperactivity during the active phase. Together, these findings establish CACNA1G/CaV3.1 as a key regulator linking sleep-dependent brain dynamics to molecular homeostasis and behavior, and provide a mechanistic framework through which genetic risk for SCZ may drive disease-relevant sleep and circuit dysfunction. One Sentence SummaryLoss of CACNA1G disrupts sleep rhythms and gene regulation, creating a mismatch between brain state and behavior linked to schizophrenia.

neuroscience↗

bioRxiv2025

A New Type of Nonsuppressible Viremia Produced by HIV-Infected Macrophage

BackgroundHIV-1 RNA typically declines rapidly after initiation of antiretroviral therapy (ART); often reaching undetectable levels within a few weeks and remaining undetectable by standard assays. However, some patients on ART have persistent nonsuppressible viremia (NSV) that does not respond to treatment optimization or intensification. NSV can emerge at the time of ART initiation (primary NSV) or after being ART-suppressed (secondary NSV). Here, we examine mechanisms producing primary NSV in four people on ART. MethodsBlood samples were collected from four participants who, despite being adherent to ART, required approximately a year or more to become virologically suppressed. Viral RNA and proviral DNA genomes were sequenced to examine HIV-1 drug resistance, genome intactness and genetic diversity. The ability of HIV-1 Envs to facilitate efficient entry into cells expressing low levels of CD4 (a proxy for macrophage tropism) was assessed. ResultsBefore ART, the blood contained HIV-1 RNA genomes that were adapted to replication in CD4+ T cells and rapidly decayed after ART initiation. During ART, the blood contained HIV-1 genomes that were drug sensitive, genetically diverse, macrophage-tropic, not evolving and often had defects in vpr. ConclusionsOur results suggest that in individuals with primary NSV, ART stopped virus replication, but large pools of long-lived, HIV-infected macrophage continued to produce virus. This is mechanistically distinct from secondary NSV produced by CD4+ T cell clones. In addition, defects in vpr independently accumulation in macrophage-tropic lineages found in three participants, suggesting that vpr may impact survival of, or virus production from, HIV-infected macrophage. SUMMARYPeople with HIV-1 on ART can experience persistent, nonsuppressible viremia (NSV). We identified four people with a previously uncharacterized form of NSV that emerged at the time of ART initiation (primary NSV) and is notable for its genetic diversity, drug sensitivity, and macrophage tropism. This is mechanistically distinct from previously described cases of NSV produced by CD4+ T cells in people who were previously ART-suppressed (secondary NSV).

microbiology↗

bioRxiv2022

Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants

It has been reported that multiple SARS-CoV-2 variants of concerns (VOCs) including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) can reduce neutralisation by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralisation assays are typically performed to monitor potential vaccine breakthrough strains. However, such experimental-based methods are slow and cannot instantly validate whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone and in real time. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralisation titres. Based on this correlation, we obtained a computational model for the receptor binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralisation titres with high accuracy (~0.79). Our predicted results were comparable with experimental neutralisation titres of variants, including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.429 (Epsilon), P.1 (Gamma), B.1.526 (Iota), B.1.617.1 (Kappa), and C.37 (Lambda), as well as SARS-CoV. Here, we firstly predicted the fold of decrease of B.1.1.529 (Omicron) as 17.4-fold less susceptible to neutralisation. We visualised all 1521 SARS-CoV-2 lineages to indicate variants including B.1.621 (Mu), B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.

evolutionary biology↗

bioRxiv2019

Precise annotation of human, chimpanzee, rhesus macaque and mouse mitochondrial genomes using 5’ and 3’ end small RNAs

Using 5 and 3 end small RNAs, we annotated human, chimpanzee, rhesus macaque and mouse mitochondrial genomes at 1 base-pair (bp) resolution to cover both strands of the mammalian mitochondrial genome entirely without leaving any gaps or overlaps. The precise annotation of all coding and non-coding genes (e.g. ncMT1, MDL2 and MDL1AS) led to the discovery of novel functions and mechanisms of mitochondrion. In this study, we defined the conserved sequence block (CSB) region to span five CSBs (CSB1, CSB2, CSB3, LSP and HSP) and identified the motifs of five CSBs in the mitochondrial displacement loop (D-loop) regions of 52 mammals. The conserved arrangement of these five CSBs in 17 primates inspired us to investigate the function of the mtDNA D-loop, which has been puzzling scientists for more than 50 years. We found that 5 sRNAs of MDL1AS control the expression levels of mitochondrial genes as a whole by a negative feedback mechanism. Thus, the precise annotations of three CSBs (CSB2, LSP and HSP) in more species will help to understand the function of the mtDNA D-loop. The precision annotation of animal mitochondrial genomes also provides abundant information for studying the molecular phylogenetics and evolution of animals.

bioinformatics↗