Biology subjects

Chen, M.-C.

Publications and source records attributed to Chen, M.-C..

8 recordsLinked to original sources

bioRxiv2025

An Adaptive Visuomotor Transformation Reservoir Embedded in the Vertebrate Brain

Adaptive visuomotor transformation requires sensorimotor circuits to generate accurate, robust, and flexible outputs, but its underlying cellular mechanism remains poorly understood. Leveraging a zebrafish mesoscopic connectome, we built a biologically constrained spiking neural network of the optic tectum (OT), a conserved vertebrate center for visuomotor transformation, and drove the model with real retinal inputs. Integrating in silico and biological interrogations, we revealed that the OT functions as a biologically structured reservoir complemented by serotonergic systems to implement adaptive visuomotor transformation. Within the tectal reservoir, inhibitory interneurons with layer-matched axonal arborizations suppress task-unrelated pathways to ensure visuomotor accuracy, while excitatory interneurons with deep-layer terminating axons reinforce task-related pathways to enhance noise robustness. Furthermore, visually responsive OT-projecting serotonergic subsystems reweight competing pathways to confer visuomotor flexibility. Thus, our findings delineate how specific interneuron-type-embodied push-pull-like mechanisms coordinate with serotonergic neuromodulation to drive adaptive visuomotor transformation, offering a mechanistic framework for neural computational architectures.

neuroscience↗

bioRxiv2023

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

immunology↗

bioRxiv2022

Structural analyses of the plant PRT6-UBR box in the Cys-Arg/N-degron pathway and insights into the plant submergence response

The submergence response in higher plants is highly dependent on the protein stability of group VII ethylene response factors, which are primarily degraded through the oxygen-dependent Cys-Arg branch of the N-degron pathway of targeted proteolysis. Knockout of PRT6, an E3 ligase and a vital component of the N-degron pathway, improves submergence tolerance in Arabidopsis and barley but is associated with side effects such as germination deficiency. In this study, we determined structures of rice and Arabidopsis PRT6-UBR box in complex with various Arg/N-degron related peptides. We identified two highly conserved motifs in the plant PRT6-UBR box, which is responsible for Cys-Arg/N-degron recognition. Structural and mutagenesis studies revealed the importance of two conserved motifs for Cys-Arg/N-degron recognition. The phenotype of Arabidopsis seedlings with PRT6-UBR mutants in these newly identified conserved motifs showed superior submergence survival suggesting that rational manipulation of the PRT6-UBR box can improve flood tolerance. Our results provide an engineering platform for generating crops with improved submergence tolerance.

biochemistry↗

bioRxiv2022

Increased glycolysis and functional mitochondria fuel acinar-ductal metaplasia in the pancreas

Reprogramming of the cellular metabolism is a hallmark of pancreatic cancer, yet it remains unclear at what stage during carcinogenesis it occurs. Here, we investigated the metabolic requirements for acinar-to-ductal metaplasia (ADM), the first step in pancreatic carcinogenesis. We detected increased glycolytic marker expression in human ADM suggesting that a metabolic switch occurs during ADM formation. We report that this switch was similarly required for ADM formation in different oncogenic mouse models (KRAS, PI3K, and MEK1) and in ligand-induced ADM in mouse wild-type acini. In addition, we show that a functional electron transport chain (ETC), but not mitochondrial ATP production, was essential to ADM formation. We conclude that the ETC provides NAD+ for the de novo synthesis of serine from glycolysis intermediates. Our findings demonstrate that metabolic programming is essential for the initiation of pancreatic carcinogenesis and thus identifies potential targets for metabolic intervention.

cancer biology↗

bioRxiv2021

An Experimental Test of the Effects of Redacting Grant Applicant Identifiers on Peer Review Outcomes

Blinding reviewers to applicant identity has been proposed to reduce bias in peer review. This experimental test used 1200 NIH grant applications, 400 from Black investigators, 400 matched applications from White investigators, and 400 randomly selected applications from White investigators. Applications were reviewed by mail in standard and redacted formats. Redaction reduced, but did not eliminate, reviewers ability to correctly guess features of identity. The primary, pre-registered analysis hypothesized a differential effect of redaction according to investigator race in the matched applications. A set of secondary analyses (not pre-registered) used the randomly selected applications from White scientists and tested the same interaction. Both analyses revealed similar effects: Standard format applications from White investigators scored better than those from Black investigators; redaction reduced the size of the difference by about half (e.g. from a Cohens d of 0.20 to 0.10 in matched applications); redaction caused applications from White scientists to score worse but had no effect on scores for Black applications. The primary statistical test of the study hypothesis was not significant; the secondary analysis was significant. The findings support further evaluation of peer review models that diminish the influence of applicant identity.

scientific communication and education↗

bioRxiv2020

Mitochondrial ATP Synthase Trafficking along Microtubules to Cell Surface Depends on KIF5B and DRP1

Ectopic adenosine triphosphate (eATP) synthase, located on the cell surface instead of the mitochondrial inner membrane, has been discovered to be a novel target for the treatment of various types of cancer. However, the mechanism of eATP synthase trafficking toward the cell surface remains unclear. In this study, we used an integrative approach incorporating multiomics, super-resolution imaging, real-time live-cell tracing, and various functional analyses to derive a transport model of eATP synthase from the mitochondria to the plasma membrane in cancer cells. We determined that the ATP synthase complex is first assembled in the mitochondria and subsequently delivered to the cell surface through the microtubule-mediated mitochondrial transport pathway. We also found that dynamin-related protein 1 (DRP1) enhances mitochondrial fission and subsequently associates with microtubule motor protein kinesin family member 5B (KIF5B) to promote the subcellular transportation of eATP synthase. Consequently, our work provides a blueprint for eATP synthase trafficking from the mitochondria toward the cell surface.

systems biology↗

bioRxiv2020

Identification of novel differentially expressed zooxanthellal genes from Aiptasia-Symbiodinium endosymbiosis through SDS-based RNA purification

Endosymbiosis between dinoflagellates and cnidarian hosts first occurred more than 200 million years ago; however, symbiosis-specific genes and cellular processes involved in the establishment, maintenance, and breakdown of endosymbiosis remain unclear. Therefore, this study aimed to identify the zooxanthellal genes associated with the aforementioned biological processes during endosymbiosis in Aiptasia-Symbiodinium endosymbionts. Here, zooxanthellae isolates were treated with 0.02% SDS to decrease potential host RNA contamination and to enhance the identification of novel symbiosis/nonsymbiosis-associated differentially expressed zooxanthellal genes through suppressive subtractive hybridization (SSH) and next-generation sequencing (NGS) methods. Consequently, among 214 symbiosis-specific transcripts identified herein that displayed identity to only 5.6% of host-derived transcripts, 64% were well-known functional genes. In the nonsymbiotic stage, 181 differentially expressed transcripts were identified, of which 64.1% belonged to well-known functional genes. BLAST revealed that 8 categories of cellular processes were significantly induced in symbiotic or nonsymbiotic zooxanthellae. Together with the results of quantitative analysis, the results revealed that photosynthesis, flagellate biosynthesis and motility, stress-induced responses, cell wall biosynthesis, starch synthesis and transport, lipid biosynthesis and metabolism, host/symbiont immune response, intercellular communication, cell growth, and cell cycle regulation were the major cellular processes occurring in symbiotic/nonsymbiotic stages. The present results provide insights into the mechanisms involved in regulating the different physiological processes in symbiotic/nonsymbiotic zooxanthellae and may guide future studies.

bioinformatics↗

bioRxiv2019

Interplay between Desmoglein2 and hypoxia controls intravasation and circulating tumor cell clustering in breast cancer metastasis

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of Desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process as downregulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1 (HIF1). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1 repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis. Significance StatementDuring metastasis, hypoxia is a major force driving primary tumor cells to disseminate into the circulatory system. The key factors that promote circulating tumor cells (CTC) dissemination and allow them to successfully colonize distal sites are still incompletely known. We found that downregulation of DSG2 in hypoxic tumor allowed single tumor cell dissemination while DSG2 expressing tumors generated more CTC clusters. Re-induction of DSG2 expression in single CTCs may contribute to CTC survival and colonization in distant organs. These findings highlight the importance of DSG2 in breast cancer progression and metastasis.

cancer biology↗