Biology subjects

Huang, A. S.

Publications and source records attributed to Huang, A. S..

8 recordsLinked to original sources

bioRxiv2026

Pre-existing levels of pro-survival proteins and induction of BCL-XL dictate cell fate after p53 activation

TP53 (also called TRP53 or p53) is a critical tumour suppressor that prevents cancer development by inducing a transcriptional program which can lead to diverse cellular responses, most prominently, cell proliferation arrest/senescence with survival of cells or cell death by apoptosis. Why distinct cell types undergo different outcomes after p53 activation remains unclear. Using integrated RNA-sequencing, proteomic and functional analyses across a diverse range of murine primary cell types, we demonstrate that cell fate is governed by the balance between pro-survival BCL-2 and pro-apoptotic BH3-only proteins. Cells resistant to apoptosis displays a higher starting ratio of pro-survival BCL-2 to pro-apoptotic BH3-only proteins, along with transcriptional upregulation of the pro-survival gene Bcl2l1, encoding BCL-XL. This control of cell fate is also seen in human wild-type p53 cancer cell lines. These findings reveal the mechanism for understanding p53-driven cell fate decisions, suggest therapeutic strategies to shift p53-induced cell proliferation arrest/senescence toward apoptotic cell death and allowed generation of an RNAseq data-based predictor of outcome for cancer cells after p53 activation.

cancer biology↗

bioRxiv2025

Vis-OCT Explorer: an open-source software for visible-light optical coherence tomography data processing

Background and objectivesVisible-light optical coherence tomography (vis-OCT) has enabled the visualization of retinal structures and functions beyond the capabilities of conventional OCTs. However, to reconstruct high-quality images, vis-OCT requires special post-processing, including balanced detection. An open-source, standardized vis-OCT data processing software is essential for clinical applications and translation of vis-OCT. MethodsWe developed Vis-OCT Explorer, an open-source, modular Python-based software for processing vis-OCT images. In addition to the standard spectral-domain OCT processing pipeline - including k-space resampling, dispersion compensation, and fast Fourier transformation - Vis-OCT Explorer offers unique dual-spectrometer balanced detection, short-time-Fourier transformation (STFT) based dispersion compensation coefficient optimization, and GPU-accelerated processing. We evaluated the reconstruction performance by quantifying a quality index extracted from individual B-scan images. We also assessed the repeatability of retinal thickness measurements by five operators on images acquired from different testing sites using the intraclass correlation coefficient (ICC) analysis. ResultsBalanced detection and STFT-based dispersion compensation significantly increased the quality index of reconstructed B-scan images. ICC values of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness measurements from four testing sites exceeded 0.8 in 87.5% of the macular-centered images. The ICC of RNFL thickness measurements on all optic nerve head-centered images is above 0.8, showing strong repeatability across users. ConclusionsVis-OCT Explorer provides high-quality image processing and enables highly repeatable measurements on vis-OCT human retinal images. It facilitates future multicenter clinical tests to validate vis-OCTs clinical efficacy.

bioengineering↗

bioRxiv2025

Machine-learning-based automated Schlemms canal volumetric segmentation for optical coherence tomography

Volumetric segmentation of Schlemms Canal (SC) in optical coherence tomography (OCT) is time-consuming, creating a barrier to experiments studying glaucoma and the anatomy of the trabecular outflow pathways in vivo. To this end, we developed an automated segmentation tool, Schlemms Canal-Localization and Semantic Segmentation (SC-LSS), for the volumetric segmentation of SC in in vivo mice eyes from visible-light OCT (vis-OCT). SC-LSS first localizes the boundaries of SC and subsequently determines the boundaries of SC within the localized region. We used 324 B-scans from 16 mouse eyes for training, validation, and testing the model, and 203 additional B-scans from 16 mouse eyes to evaluate the models accuracy. We found that the Dice coefficient between segmentations generated by SC-LSS and manual expert graders was 0.70 {+/-} 0.20 and that the Dice coefficient between two expert graders was 0.73 {+/-} 0.18 (p = 0.10). Furthermore, SC-LSS captured decreases in SC size with increasing intraocular pressure, yielding a 51.5% decrease in SC size at 20 mmHg compared to 5 mmHg. SC-LSS also identified a 20.1% increase in SC size following the administration of pilocarpine. We anticipate that SC-LSS will accelerate studies on factors regulating the trabecular outflow pathways and their role in glaucoma development and management.

bioengineering↗

bioRxiv2025

Subtyping psychotic disorders using a data-driven approach reveals divergent cortical and cellular signatures

Structural brain abnormalities in psychosis are well-replicated but heterogenous posing a barrier to uncovering the pathophysiology, etiology, and treatment of psychosis. To parse neurostructural heterogeneity and assess for the presence of anatomically-derived subtypes, we applied a data-driven method, similarity network fusion (SNF), to structural neuroimaging data in a broad cohort of individuals with psychosis (schizophrenia spectrum disorders (SSD) n=280; bipolar disorder with psychotic features (BD) n=101). SNF identified two transdiagnostic subtypes in psychosis (subtype 1: n=158 SSD, n=75 BD; subtype 2: n=122 SSD, n=26 BD) that exhibited divergent patterns of abnormal cortical surface area and subcortical volumes. Compared to controls (n=243), subtype 1 showed moderate enlargement of surface area in frontal and parietal areas and larger dorsal striatal volumes, whereas subtype 2 demonstrated markedly smaller surface areas in frontal and temporal areas and subcortical volumes, including hippocampus, amygdala, thalamus and ventral striatum. When comparing subtypes on clinical characteristics, subtype 2 had more severe negative symptoms, greater neuropsychological impairment, and lower estimated premorbid intellectual functioning compared to subtype 1. Integrating cell-type data imputed from gene expression in the Allen Human Brain Atlas revealed an association between interregional reductions in surface area and layer 5 glutamatergic neuron abundance, critical for corticostriatal network connectivity and cognitive function, whereas reductions in cortical thickness spatially coupled with glia cell and interneuron abundance, in subtype 2. These outcomes indicate that regional variations in surface area, linked to different cell-types than cortical thickness, may be an important biomarker for understanding the pathophysiological trajectories of psychotic disorders.

neuroscience↗

bioRxiv2025

Characterizing massa intermedia morphology in schizophrenia: associations with aging, neuropsychological functioning, and atypical hippocampal development

The massa intermedia (MI) is a midline structure connecting the left and right thalamus that typically develops during the 2nd trimester of pregnancy. Missing and smaller MI has been linked to neurodevelopmental disorders, including schizophrenia (SZ), and subtle deficits in cognition. However, findings are inconsistent and the association between MI and other anatomical variants linked to atypical brain development in SZ, including incomplete hippocampal inversion (IHI), is unclear. Presence/absence and morphology of the MI were ascertained on structural T1-weighted MRI images obtained at 3T in SZ (n = 223) and healthy individuals (n = 194) and compared between groups. Associations between MI morphology, cognitive function, and incomplete hippocampal inversion (IHI) were assessed. Prevalence of missing MI was 1.7% and did not differ between groups. MI was significantly smaller in SZ (p <.001). However, follow-up analyses revealed that smaller MI size in SZ was due to a significant Diagnosis x Age interaction characterized by a stronger negative age effect in SZ. IHI was significantly more common in individuals with missing MI. Neurocognition was not correlated with MI size when controlling for age and diagnosis. Stronger effects of age on MI size in SZ suggests that abnormal MI size measured in adulthood may not be a reliable static indicator of atypical neurodevelopment, but may reflect disease progression or accelerated aging. Missing MI was rare in our sample. Conversely, missing MI is associated with IHI suggesting a shared neurodevelopmental disruption in the 2nd trimester.

neuroscience↗

bioRxiv2024

Transcription of HIV-1 at sites of intact latent provirus integration

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.

immunology↗

bioRxiv2022

E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.

cell biology↗

bioRxiv2019

Organogenesis and Distribution of the Ocular Lymphatic Vessels in the Anterior Eye: Implication to Glaucoma Surgery Site Selection

Glaucoma surgeries, such as trabeculectomy, are performed to lower the intraocular pressure to reduce the risk of vision loss. The surgeries create a new passage in the eye that reroutes the aqueous humor outflow to the subconjunctival space, where the fluid is presumably absorbed by the conjunctival lymphatics. However, the current knowledge of these ocular surface lymphatics remains limited. Here, we characterized the biology and function of the ocular lymphatics using transgenic lymphatic reporter mice and rats. We found that the limbal and conjunctival lymphatic networks are progressively formed by a primary lymphatic vessel that grows out from the nasal-side medial canthus region at the time of birth. This primary lymphatic vessel immediately branches out and invades the limbus and conjunctiva, and then simultaneously encircles the cornea in a bidirectional manner. As a result, the distribution of the ocular lymphatic is significantly polarized toward the nasal side, and the limbal lymphatics are directly connected to the conjunctival lymphatics. New lymphatic spouts are mainly produced from the nasal-side limbal lymphatics, posing the nasal side of the eye more responsive to fluid drainage and inflammatory stimuli. Consistently, when a fluorescent tracer was injected, fluid clearance was much more efficient in the nasal side than the temporal side of the eyes. In comparison, blood vessels are evenly distributed on the front surface of the eyes. We found that these distinct vascular distribution patterns were also conserved in human eyes. Together, our study demonstrated that the ocular surface lymphatics are more densely present in the nasal side and uncovered the potential clinical benefits in selecting the nasal side as a surgical site for glaucoma surgeries to improve the fluid drainage.

developmental biology↗