Biology subjects

Jiao, M.

Publications and source records attributed to Jiao, M..

5 recordsLinked to original sources

bioRxiv2024

Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection

cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GC{beta} polarizes to a unique localization <ookinete extrados site= (OES) until ookinete maturation and activates cGMP signaling for initiating parasite motility. However, the mechanism underlying GC{beta} translocation from cytosol to OES remains elusive. Here, we used protein proximity labeling to search the GC{beta}-interacting proteins in ookinetes of the rodent malaria parasite P. yoelii, and found the top hit Sir2A, a NAD+-dependent sirtuin family deacetylase. Sir2A interacts with GC{beta} throughout ookinete development. In mature ookinetes, Sir2A co-localizes with GC{beta} at OES in a mutually dependent manner. Parasites lacking Sir2A lose GC{beta} localization at OES, ookinete gliding, and mosquito infection, phenocopying GC{beta} deficiency. GC{beta} is acetylated at gametocytes but is deacetylated by Sir2A for OES localization at mature ookinetes. We further demonstrated that the level of NAD+, an essential co-substrate for sirtuin, increases during the ookinete development. The NAD+ at its maximal level until ookinete maturation promotes Sir2A-catalyzed GC{beta} deacetylation, ensuring GC{beta} localization at OES. This study highlights the spatiotemporal coordination of cytosolic NAD+ level and NAD+-dependent Sir2A in regulating GC{beta} deacetylation and dynamic localization for Plasmodium ookinete gliding.

microbiology↗

bioRxiv2024

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.

cancer biology↗

bioRxiv2024

Cholesterol-Dependent Membrane Deformation by Metastable Viral Capsids Facilitates Entry

Non-enveloped viruses employ unique entry mechanisms to breach and infect host cells. Understanding these mechanisms is crucial for developing antiviral strategies. Prevailing perspective suggests that non-enveloped viruses release membrane lytic peptides to breach host membranes. However, the precise involvement of the viral capsid in this entry remains elusive. Our study presents direct observations elucidating the dynamically distinctive steps through which metastable reovirus capsids disrupt host lipid membranes as they uncoat into partially hydrophobic intermediate particles. Using both live cells and model membrane systems, our key finding is that reovirus capsids actively deform and permeabilize lipid membranes in a cholesterol-dependent process. Unlike membrane lytic peptides, these metastable viral capsids induce more extensive membrane perturbations, including budding, bridging between adjacent membranes, and complete rupture. Notably, cholesterol enhances subviral particle adsorption, resulting in the formation of pores equivalent to the capsid size. This cholesterol dependence is attributed to the lipid condensing effect, particularly prominent at intermediate cholesterol level. Furthermore, our results reveal a positive correlation between membrane disruption extent and efficiency of viral variants in establishing infection. This study unveils the crucial role of capsid-lipid interaction in non-enveloped virus entry, providing new insights into how cholesterol homeostasis influences virus infection dynamics.

biophysics↗

bioRxiv2023

VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response.

Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of the VHL gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1 and HIF2 induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.

cancer biology↗

bioRxiv2022

Extended Brain Sources Estimation via Unrolled Optimization Neural Network

Electroencephalography (EEG)/Magnetoencephalography (MEG) source imaging aims to seek an estimation of underlying activated brain sources to explain the observed EEG/MEG recording. Due to the ill-posed nature of inverse problem, solving EEG/MEG Source Imaging (ESI) requires design of regularization or prior terms to guarantee a unique solution. Traditionally, the design of regularization terms is based on preliminary assumptions on the spatio-temporal structure in the source space. In this paper, we propose a novel paradigm to solve the ESI problem by using Unrolled Optimization Neural Network (UONN) (1) to improve the efficiency compared to traditional iterative algorithms; (2) to establish a data-driven way to model the source solution structure instead of using hand-crafted regularizations; (3) to learn the hyperparameter automatically in a data-driven manner. The proposed framework is based on unfolding of the iterative optimization algorithm with neural network modules. The proposed new learning framework is the first one that use the unrolled optimization neural network to solve the ESI problem. The newly designed framework can effectively learn the source extents pattern and achieved significantly improved performance compared to benchmark algorithms.

bioengineering↗