Biology subjects

Chau, A.

Publications and source records attributed to Chau, A..

7 recordsLinked to original sources

bioRxiv2026

Extracting interpretable single-cell metabolic states with graph-guided representation learning

Metabolism shapes cellular function and state, yet measuring single-cell metabolic states at scale remains a challenge. We present Metabolic Representation Net (MeRN), a graph-guided variational autoencoder that leverages prior metabolic knowledge as a topology graph to learn latent representations of metabolic state and reaction activity from single-cell transcriptomes. MeRN's scalable estimation of reaction activity enables the definition of data-driven pathways (DDPs): context-specific metabolic modules supported by transcriptomic evidence and agnostic of standard pathway definitions. Using DDPs, we introduce the weakest link analysis to identify metabolic network rewiring. MeRN recovers metabolic zonation in the mouse intestine, links a folate deficiency-induced break in de novo purine synthesis to embryonic neural tube defects, shows cytokines with similar non-metabolic effects can elicit divergent T cell metabolism, and identifies metabolic drivers of T cell exhaustion and therapy response in human cancers. Our results establish MeRN as a unified method for metabolic analysis of single-cell transcriptomes.

bioinformatics↗

bioRxiv2026

Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm

Despite long-standing epidemiological associations, the mechanism linking folate availability to gestational neural tube defects remains unclear, partly because measuring and interpreting metabolic activity in dynamic biological systems remains challenging. Here, we apply a deep-learning-based graph-guided variational autoencoder (MeRN; Metabolic Representation Network) to infer single-cell metabolic activity and states from scRNA-seq data of mouse embryogenesis. By analyzing folate-deficient embryogenesis from E7.0 to E9.0, we identify a transient state within the nascent neural lineage that is acutely sensitive to folate availability, leading to an interconnected disruption between key bioenergetic pathways and de novo purine biosynthesis. Moreover, metabolically induced growth defects lead to permanent morphological disruptions along the dorsal-ventral axis, which we confirm by generating whole-embryo fate maps using a prime-editing-based lineage recorder (PEtracer). Collectively, our results establish a highly scalable framework for interpreting dynamic changes in embryonic metabolism and elucidating the mechanistic bases underlying environmentally linked congenital disorders.

genomics↗

bioRxiv2026

Concordant transcriptional and morphological remodeling revealed by in vivo Perturb-CLEAR

The principle that form follows function has long guided thinking in biology and architecture alike. In the nervous system, however, form does more than reflect function: neuronal morphology actively constrains input patterns, synaptic integration, and circuit wiring. During postnatal neurodevelopment, dendritic architectures are assembled and remodeled through genetically encoded programs and activities, transforming molecular programs into circuit architecture. However, dendritic morphogenesis has been difficult to quantify at scale while systematically testing how genetic variants, including neurodevelopmental disorder (NDD) risk genes, alter these structures in vivo. We developed Perturb-CLEAR, which integrates pooled CRISPR screening and whole-mount imaging to quantify brain-wide cytoarchitecture, and paired it with Perturb-seq to link structural phenotypes to transcriptomic changes. Applying Perturb-CLEAR to the developing mouse cortex revealed morphogenesis trajectories accompanied by transcriptomic dynamics. Moreover, systematic perturbation of NDD risk genes uncovered gene-specific multimodal phenotypes. Adnp perturbation remodels basal dendrites in L4/5 IT (intratelencephalic) neurons but not other dendritic compartments or cell types, alongside consistent transcriptional shifts. Combined morphology and transcriptome analyses link NDD risk genes to concordant multimodal cellular phenotypes in the developing brain, highlighting diverse paths of perturbation effect propagation across modalities.

neuroscience↗

bioRxiv2024

Evidence for distinct networks underlying symptom clusters of posttraumatic stress disorder

BackgroundClinical and psychometric evidence has long supported a multidimensional model of PTSD, with symptom subcategories derived from factor analytic methods. Although research on the biological bases of PTSD as a unitary construct is profuse, comparatively few studies have examined the neural mechanisms underlying subcategories of PTSD symptoms. The present study aimed to provide the first evidence of causal relationships between brain structure and PTSD symptom subcategories, using a lesion-behavior mapping approach. MethodsUsing a group of male combat veterans with focal penetrating traumatic brain injuries (n = 177), we determined the effects of focal damage on the PTSD symptom subcategories of hyperarousal, avoidance, and re-experiencing. ResultsOur findings revealed two distinct networks that underlie symptom subcategories of PTSD: (1) an amygdala-ventromedial prefrontal cortex network underlying hyperarousal and avoidance symptoms, in which amygdala damage acts as a risk factor for the development of these symptoms, while vmPFC damage acts as a protective factor against the same symptoms; and (2) a hippocampal network underlying re-experiencing and avoidance, in which hippocampal damage acts as a protective factor against these symptoms. ConclusionsThe present study provides novel insights regarding the causal role of key brain regions in the heterogeneous expression of PTSD symptoms. Results not only contribute to a more complete picture of the neural mechanisms underlying PTSD, but may also aid in the future development of individualized therapeutic strategies that target specific symptom profiles.

neuroscience↗

bioRxiv2022

Resting EEG power spectra across middle to late life: Associations with age, cognition, APOE-ε4 carriage and cardiometabolic burden

We investigated how resting EEG measures are associated with risk factors for late-life cognitive impairment and dementia, including age, Apolipoprotein E {varepsilon}4 (APOE-{varepsilon}4) carriage and cardiometabolic burden. Resting EEG was recorded from 86 adults (50-80 years of age). Participants additionally completed the Addenbrookes Cognitive Examination (ACE) III and had blood drawn to assess APOE-{varepsilon}4 carriage status and cardiometabolic burden. EEG power spectra were decomposed into sources of periodic and aperiodic activity to derive measures of aperiodic component slope and alpha (7-14 Hz) and beta (15-30 Hz) peak power and peak frequency. Alpha and beta peak power measures were corrected for aperiodic activity. The aperiodic component slope was correlated with ACE-III scores but not age. Alpha peak frequency decreased with age. Individuals with higher cardiometabolic burden had lower alpha peak frequencies and lower beta peak power. APOE-{varepsilon}4 carriers had lower beta peak frequencies. Our findings suggest that the slope of the aperiodic component of resting EEG power spectra is more closely associated with measures of cognitive performance rather than chronological age in older adults.

neuroscience↗

bioRxiv2021

Substantial Differences in SARS-CoV-2 Antibody Responses Elicited by Natural Infection and mRNA Vaccination

We analyzed data from two ongoing COVID-19 longitudinal serological surveys in Orange County, CA., between April 2020 and March 2021. A total of 8,476 finger stick blood specimens were collected before and after an aggressive mRNA vaccination campaign. IgG levels were determined using a multiplex antigen microarray containing 10 SARS-CoV-2 antigens, 4 SARS, 3 MERS, 12 Common CoV, and 8 Influenza antigens. Twenty-six percent of 3,347 specimens from unvaccinated Orange County residents in December 2020 were SARS-CoV-2 seropositive. The Ab response was predominantly against nucleocapsid (NP), full length spike and the spike S2 domain. Anti-receptor binding domain (RBD) reactivity was low and there was no cross-reactivity against SARS S1 or SARS RBD. An aggressive mRNA vaccination campaign at the UCI Medical Center started on December 16, 2020 and 6,724 healthcare workers were vaccinated within 3 weeks. Seroprevalence increased from 13% in December to 79% in January, 93% in February and 99% in March. mRNA vaccination induced much higher Ab levels especially against the RBD domain and significant cross-reactivity against SARS RBD and S1 was also observed. Nucleocapsid protein Abs can be used to distinguish individuals in a population of vaccinees to classify those who have been previously infected and those who have not, because nucleocapsid is not in the vaccine. Previously infected individuals developed higher Ab titers to the vaccine than those who have not been previously exposed. These results indicate that mRNA vaccination rapidly induces a much stronger and broader Ab response than SARS-CoV-2 infection.

immunology↗

bioRxiv2020

An Xist-dependent protein assembly mediates Xist localization and gene silencing

Nuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNA Xist establishes the inactive-X-chromosome (Xi)-compartment, we found that the Xist RNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence of Xist. The E-repeat-sequence of Xist serves a multivalent binding-platform for these proteins. Without the E-repeat, Xist initially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to {Delta}E-Xist rescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal that Xist sequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.

molecular biology↗