Biology subjects

Wang, X.-T.

Publications and source records attributed to Wang, X.-T..

4 recordsLinked to original sources

bioRxiv2024

Calcium Homeostasis Modulator 2 Constitutes an ATP-regulation Pore in Mitochondria

Recent structural analyses showed that the calcium homeostasis modulator-2 (CALHM2) forms a mega channel, but its cellular location and endogenous function are yet unknown. We found that native CALHM2 resides on the mitochondrial inner membrane and constitutes an ATP-regulated ATP release channel. CALHM2 knockdown/knockout decreases cytosolic ATP concentration, and thereby compromises energy-sensitive processes, such as intracellular Ca2+ handling. However, CALHM2 loss-of-function elevates ATP concentration in the mitochondrial matrix, dephosphorylates key enzymes in the mammalian target of rapamycin (mTOR) pathway, and promotes longevity in CALHM2 knockout mice. These findings reveal that CALHM2 constitutes a novel regulator of mitochondrial metabolism, which may have important implications in aging and diseases.

cell biology↗

bioRxiv2024

Spatial chromosome organization and adaptation of Escherichia coli under heat stress

The spatial organization of bacterial chromosomes is crucial for cellular functions. It remains unclear how bacterial chromosomes adapt to high temperature stress. This study delves into the 3D genome architecture and transcriptomic responses of Escherichia coli under heat stress condition to unravel the intricate interplay between chromosome structure and environmental cues. By examining the role of macrodomains, chromosome interaction domains (CIDs), and nucleoid-associated proteins (NAPs), this work unveils the dynamic changes in chromosome conformation and gene expression patterns induced by high temperature stress. It was observed that under heat stress, short-range interaction frequency of chromosome decreased, while the long-range interaction frequency of the Ter macrodomain increased. Furthermore, two metrics, namely, Global Compactness (GC) and Local Compactness (LC), were devised to measure and compare the compactness of chromosomes based on their 3D structure models. The findings in this work shed light on the molecular mechanisms underlying thermal adaptation and chromosomal organization in bacterial cells, offering valuable insights into the complex interrelationships between environmental stimuli and genomic responses.

systems biology↗

bioRxiv2023

Increasing the reliability of functional connectivity by predicting long-scan functional connectivity based on short-scan functional connectivity: model exploration, explanation, validation, and application.

Functional connectivity (FC) is a widely used imaging parameter of functional magnetic resonance imaging (fMRI). However, low reliability has been a concern among researchers, particularly in small-sample-size studies. Previous studies have shown that FC based on longer fMRI scans was more reliable, therefore, a feasible solution is to predict long-scan FCs using existing short-scan FCs. This study explored three different generalized linear models (GLMs) using the human connectome project (HCP) dataset. We found that the GLM based on individual short-scan FC could effectively predict long-scan individual FC value, while GLMs based on whole-brain FCs and dynamic FC performed better in predicting long-scan summed FC value of whole brain. The models were explained through visualization of weights in models. Besides, the differences in three GLMs could be explained as differences in distribution features of FC matrices predicted by them. Results were validated in different datasets, including the Consortium for Reliability and Reproducibility (CoRR) project and our local dataset. These models could be applied to improve the test-retest reliability of FC and to improve the performance of connectome-based predictive models (CPM). In conclusion, we developed three GLMs that could be used to predict long-scan FC from short-scan FC, and these models were robust across different datasets and could be applied to improve the test-retest reliability of FC and the performance of CPM.

neuroscience↗

bioRxiv2022

Preclinical Characterization of Relatlimab, a Human LAG-3-Blocking Antibody, Alone or in Combination With Nivolumab

Novel therapeutic approaches combining immune checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen like protein-1, and to reverse LAG-3-mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced anti-tumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase 2/3 trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrated superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma. SynopsisPreclinical studies demonstrate that relatlimab specifically blocks the interaction between LAG-3 and its ligands, and provide a biological rationale for combining relatlimab with the anti-PD-1 antibody nivolumab as an effective cancer immunotherapeutic strategy.

cancer biology↗