Biology subjects

Chai, Z.

Publications and source records attributed to Chai, Z..

12 recordsLinked to original sources

bioRxiv2026

Targeting pathogenic VWF/ADAMTS13 dysregulation attenuates CTEPH progression

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary vascular disease, characterized by persistent thrombotic obstruction and progressive pulmonary vascular remodeling, yet the molecular mechanisms linking persistent thrombosis to vascular remodeling remain incompletely understood. Clinical studies have reported elevated plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 in patients with CTEPH, but whether VWF/ADAMTS13 dysregulation contributes directly to disease pathogenesis remains unclear. Here, using newly established rat models of CTEPH, we identify a causative role for dysregulation of the VWF-ADAMTS13 axis in chronic thromboembolic progression. CTEPH rats developed persistent, unresolved VWF- and fibrin-rich thrombi accompanied by markedly increased endothelial VWF deposition. In contrast, ADAMTS13 expression and activity were significantly reduced in CTEPH rats. Consistent with these findings, genetic Adamts13 deficiency further exacerbates pulmonary microvascular thrombosis and accelerated early mortality following disease induction. Mechanistically, ultra-large (UL)-VWF accumulated on the pulmonary endothelial surface, promoting robust platelet recruitment under shear. This platelet-VWF interaction stimulated the release of platelet-derived pro-remodeling mediators, including TGF-{beta}1 and PDGF-BB. Genetic ablation of Vwf markedly reduced in situ microvascular thrombosis within pulmonary arterioles, attenuated pulmonary arterial remodeling, and improved pulmonary hemodynamics. Moreover, treatment with recombinant ADAMTS13 reduced endothelial UL-VWF accumulation, suppressed platelet activation, and effectively prevented thrombosis and platelet-driven pro-remodeling signaling in CTEPH rats. Collectively, these findings identify dysregulation of the VWF-ADAMTS13 axis as a key driver of pulmonary thrombosis and vascular remodeling in CTEPH and support therapeutic targeting of this pathway as a potential disease-modifying strategy. Key PointsO_LIVWF-ADAMTS13 dysregulation promotes persistent pulmonary thrombosis and platelet-driven arterial remodeling within pulmonary arterioles. C_LIO_LIRecombinant ADAMTS13 treatment or VWF ablation abrogates pulmonary arterial thrombosis and halts vascular remodeling in CTEPH. C_LI

pathology↗

bioRxiv2026

A Multiscale Signaling--Biophysical Framework Reveals Mechanisms of Macrophage-Mediated RBC Clearance in Sickle Cell and Gaucher Disease

Red blood cell (RBC) clearance by macrophages maintains blood homeostasis and is dysregulated in the hemolytic disorder sickle cell disease (SCD) and the lysosomal storage disorder Gaucher disease (GD), where biophysical and biochemical alterations promote premature phagocytosis. We develop a multiscale hybrid modeling framework integrating signaling dynamics, biophysical simulations, and machine learning to investigate the mechanisms governing RBC phagocytosis in these diseases. Our approach couples a systems biology model of macrophage-RBC signaling with Dissipative Particle Dynamics (DPD) simulations of molecular diffusion and membrane interactions, and leverages Physics-Informed Neural Networks (PINNs) for robust parameter inference. The DPD framework provides mechanistic insight into antibody diffusion, receptor engagement, and membrane-level interactions during macrophage-RBC contact, generating spatially resolved trajectories of CD47-SIRP signaling and antibody-receptor binding that serve as intermediate observables constraining the signaling model. The model accurately captures differential phagocytic responses between healthy and altered RBCs, revealing diminished inhibitory signaling and changes in SHP1-mediated pathways in both SCD and GD. Identifiability analysis combining Fisher Information Matrix diagnostics and profile likelihood confirms that parameters governing the CD47-SIRP-SHP1 axis are among the most robustly recoverable, and simulations of therapeutic perturbations with anti-SIRP antibodies demonstrate modulation of engulfment outcomes. We further employ Physics-Informed Kolmogorov-Arnold Networks (PIKANs) as an alternative to standard PINNs, demonstrating improved robustness under noise and sampling variability. More broadly, our multiscale platform linking biophysical simulation with systems-level inference is generalizable, offering mechanistic insights and computational tools for therapeutic exploration in diseases involving dysregulated phagocytosis. Significance statementRed blood cells are normally removed from circulation by macrophages through tightly regulated molecular signals. In diseases such as sickle cell disease and Gaucher disease, this clearance process becomes abnormal, contributing to anemia and other complications. However, the mechanisms linking the physical properties of red blood cells to immune signaling remain poorly understood. Here we develop a multiscale computational framework that combines particle-based biophysical simulations, systems biology models, and physics-informed machine learning. This approach provides a quantitative framework to interpret how changes in red blood cell mechanics and surface signaling disrupt the CD47-SIRP inhibitory pathway that normally prevents phagocytosis. The framework provides a predictive platform for studying immune clearance and may help guide therapeutic strategies targeting red blood cell-macrophage interactions.

biophysics↗

bioRxiv2025

High-resolution NMR spectroscopy of proteins in intact mitochondria

Understanding protein structure and function within mitochondria is essential for unraveling the molecular mechanisms underlying cellular energy production, stress response, and disease. Here, we present a novel approach for NMR observation of proteins within intact mitochondria by delivering proteins directly into isolated mitochondria via electroporation. Using this method, we investigate the interaction of -synuclein (-syn) with the mitochondria membrane and examine how post-translational modifications regulate this interaction. Additionally, we assessed the stability of GB1 and the dimerization of its variant within mitochondria, achieving quantitative insights into mitochondrial environmental impact on protein function. This approach offers a valuable framework for exploring mitochondrial related biomolecular events at atomic-resolution within intact mitochondria, paving the way for a more comprehensive understanding of the molecular events governing mitochondrial health and dysfunction.

biochemistry↗

bioRxiv2024

In silico biophysics and rheology of blood and red blood cells in Gaucher Disease

Gaucher Disease (GD) is a rare genetic disorder characterized by a deficiency in the enzyme glucocerebrosidase, leading to the accumulation of glucosylceramide in various cells, including red blood cells (RBCs). This accumulation results in altered biomechanical properties and rheological behavior of RBCs, which may play an important role in blood rheology and the development of bone infarcts, avascular necrosis (AVN) and other bone diseases associated with GD. In this study, dissipative particle dynamics (DPD) simulations are employed to investigate the biomechanics and rheology of blood and RBCs in GD under various flow conditions. The model incorporates the unique characteristics of GD RBCs, such as decreased deformability and increased aggregation properties, and aims to capture the resulting changes in RBC biophysics and blood viscosity. This study is the first to explore the Youngs modulus and aggregation parameters of GD RBCs by validating simulations with confocal imaging and experimental RBC disaggregation thresholds. Through in silico simulations, we examine the impact of hematocrit, RBC disaggregation threshold, and cell stiffness on blood viscosity in GD. The results reveal three distinct domains of GD blood viscosity based on shear rate: the aggregation domain, where the RBC disaggregation threshold predominantly influences blood viscosity; the transition area, where both RBC aggregation and stiffness impact on blood viscosity; and the stiffness domain, where the stiffness of RBCs emerges as the primary determinant of blood viscosity. By quantitatively assessing RBC deformability, RBC disaggregation threshold, and blood viscosity in relation to bone disease, we find that the RBC aggregation properties, as well as their deformability and blood viscosity, may contribute to its onset. These findings enhance our understanding of how changes in RBC properties impact on blood viscosity and may affect bone health, offering a partial explanation for the bone complications observed in GD patients. Author summaryIn Gaucher Disease (GD), a genetic deficiency in the enzyme glucocerebrosidase leads to the accumulation of glucosylceramide in red blood cells (RBCs), resulting in altered biomechanical properties. These changes affect blood flow characteristics, particularly blood viscosity, and may contribute to bone health issues seen in GD patients, including bone infarcts, avascular necrosis (AVN), and other bone diseases. In our study, we apply dissipative particle dynamics (DPD) simulations to explore how GD impacts RBC behavior under various flow conditions. We model GD RBCs with decreased deformability and increased aggregation, examining how these properties influence blood viscosity across three distinct shear rate domains: aggregation, transition, and stiffness. By validating our simulations with confocal imaging data and experimental RBC disaggregation thresholds, we quantitatively assess the effects of RBC stiffness, aggregation, and hematocrit levels on blood flow in GD. We find that the RBC aggregation properties, deformability and blood viscosity, may contribute to the onset of bone disease. These findings improve our understanding of how changes in RBC properties influence blood viscosity and may contribute to bone health issues, providing a partial explanation for the bone complications observed in GD patients.

biophysics↗

bioRxiv2023

Isolation and nitrogen removal characteristics of a novel aerobic denitrifying strain Achromobacter xylosoxidans GR7397

Aerobic denitrifying bacteria have the potential for engineering applications due to the efficient nitrate removal capacity from wastewater. In this study, a novel aerobic denitrifying strain was isolated and identified as Achromobacter xylosoxidans GR7397 from the activated sludge of a wastewater treatment plant, which possessed efficient nitrate removal capacity. Moreover, the denitrification capacity and properties of the strain were investigated in the presence of nitrate as the only nitrogen source. Five denitrification reductases encoding genes were harbored by strain GR7397 determined by electrophoretic analysis of PCR amplification products, consisting of periplasmic nitrate reductase (NAP), nitrate reductase (NAR), nitrite reductase (NIR), nitrous oxide reductase (NOS), and nitric oxide reductase (NOR), demonstrating that the strain has a complete denitrification metabolic pathway. The optimum denitrifying condition of strain GR7397 included sodium acetate adopted as the electron donor, COD/TN ratio at 4, pH at 8, temperature at 30{degrees}C, under which condition, the nitrate removal rate reached 14.86 mg {middle dot} L-1 {middle dot} h-1 that the [Formula] concentration decreased from 93.90 mg/L to 4.73 mg/L within 6 h with no accumulation of nitrite. In addition, the bioaugmentation performance of strain GR7397 to enhance nitrate removal was evaluated to be effective and stabilized in a sequential batch reactor (SBR). The removal rate of [Formula] was the highest during each cycle with a range of 15.48-28.56 mg{middle dot}L-1{middle dot}h-1 in the SBR with inoculating 30% of the strain concentrate. The current research demonstrated that strain GR7397 has significant potential for application in enhancing nitrogen removal in wastewater treatment.

bioengineering↗

bioRxiv2023

Distinct activation mechanisms of β-arrestin 1 revealed by 19F NMR spectroscopy

{beta}-Arrestins ({beta}arrs) are functionally versatile proteins that play critical roles in the G-protein-coupled receptor (GPCR) signaling pathways. While the classical theory of GPCR-mediated {beta}arr activation centers around the formation of a stable complex between {beta}arr and the phosphorylated receptor tail, emerging evidences highlight the indispensable contribution from membrane lipids for many receptors. Due to the intrinsic complexity of {beta}arr conformational dynamics, detailed molecular mechanisms of its activation by different binding partners remain elusive. Herein we present a comprehensive study of the structural changes of {beta}arr1 in critical structural regions during activation using 19F NMR method. We demonstrate that phosphopeptides derived from different classes of GPCRs show distinct abilities in inducing {beta}arr1 activation. We further show that the membrane phosphoinositide PIP2 independently modulates {beta}arr1 conformational dynamics without displacing its autoinhibitory carboxyl tail, leading to a distinct partially activated state. Our results delineate two activation mechanisms of {beta}arr1 by different binding partners, uncovering a highly multifaceted conformational energy landscape for this protein family.

biochemistry↗

bioRxiv2022

pCMLM: Genome Wide Association Study of Body Size Traits in Multiple Regions of Yak Based on the Provided Compressed Mixed Linear Model

ObjectiveYak is a unique large animal species living in the Qinghai-Tibet Plateau and the surrounding Hengduan Mountains, and has evolved several regional variety resources due to the special geographical and ecological environment in which it lives. Therefore, it is of great importance to investigate the genetic composition of body size traits among breeds in multiple regions for yak breeding and production. MethodA genome-wide association analysis was performed on 94 yak individuals (a total of 31 variety resources) for five body size traits (body height, body weight, body length, chest circumference, and circumference of cannon bone). The individuals were clustered following known population habitat. The kinship of grouping individuals was used in the CMLM. This provided compressed mixed linear model was named pCMLM method. ResultTotal of 3,584,464 high-quality SNP markers were obtained on 30 chromosomes. Principal component analysis using the whole SNPs do not accurately classify all populations into multiple subpopulations, a result that is not the same as the population habitat. Six SNP loci were identified in the pCMLM-based GWAS with statistically significant correlation with body height, and four candidate genes (FXYD6, SOHLH2, ADGRB2, and OSBPL6), which in the vicinity of the variant loci, were screened and annotated. Two of these genes, ADGRB2 and OSBPL6, are involved in biological regulatory processes such as body height regulation, adipocyte proliferation and differentiation. ConclusionBased on the previous population information, the pCMLM can provide more sufficient associated results when the conventional CMLM can not catch optimum clustering groups. The fundamental information for quantitative trait gene localization or candidate gene cloning in the mechanism of yak body size trait formation.

bioinformatics↗

bioRxiv2021

Calcium-independent but voltage-dependent secretion (CiVDS) mediates synaptic transmission in a mammalian central synapse

A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+-dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+-independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons, (1) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (2) CiVDS-EPSCs are independent of extracellular and intracellular Ca2+; (3) CiVDS is >100 times faster than CDS in vesicle recycling with much less short-term depression; (4) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.

neuroscience↗

bioRxiv2021

The periodic axon membrane skeleton leads to high-density sodium nanodomains but does not impact action potentials

Recent work has established that axons have a periodic skeleton structure comprising of azimuthal actin rings connected via longitudinal spectrin tetramer filaments. This structure endows the axon with structural integrity and mechanical stability. Additionally, voltage-gated sodium channels follow the periodicity of the active-spectrin arrangement, spaced [~]190 nm segments apart. The impact of this periodic sodium channel arrangement on the generation and propagation of action potentials is unknown. To address this question, we simulated an action potential using the Hodgkin-Huxley formalism in a cylindrical compartment but instead of using a homogeneous distribution of voltage-gated sodium channels in the membrane, we applied the experimentally determined periodic arrangement. We found that the periodic distribution of voltage-gated sodium channels does not significantly affect the generation or propagation of action potentials, but instead leads to high-density sodium channel nanodomains. This work provides a foundation for future studies investigating the role of the voltage-gated sodium channel periodic arrangement in the axon.

biophysics↗

bioRxiv2020

Integrative Analysis of Phenomic, Genomic, and Transcriptomic to Identify Potential Functional Genes of Yaks in Plain and Plateau

BackgroundThe yak is an important source of livelihood for the people living in the Qinghai-Tibet Plateau. Most genetics detection studies have focused on the comparison between different tissues of different breeds, both living in the Plateau and in the plains. The genetic background and complex regulatory relationship have frequently puzzled researchers. In this study, we divided a population of 10 yaks into two subgroups, namely Plateau (living in the Plateau) and Plain (living in the plains). Phenomic, genomic, and transcriptomic analyses were used to reveal the molecular genetic type in the body weight, slaughter, and beef quality of yaks. ResultsWe found a significant difference (P <0.01) between the third (60 days), fourth (90 days), fifth (120 days), and sixth (150 days) weights of Plateau and plain subpopulations. The difference in body weight was due to differences in kidney weight, meat weight, fur weight, and head weight. However, the beef quality was not significantly different. We identified 540 Differentially Expressed Genes (DEGs). Using weighted gene co-expression network analysis (WGCNA), we have constructed a co-express network, and the modules were strongly related to traits. In the genome-wide association studies (GWAS), we detected significant 156, 52, 33, 15, and 3 signals in the meat weight, head weight, fur weight, liver weight, and the last body weight traits. Based on the epigenome-wide association studies (eWAS) results, we created a link relationship between the DEGs expression level and genotype. ConclusionIn summary, our study demonstrated the effectiveness and representative of multidimensional data from a finite number of yak populations. The study highlights the underlying way, as well as a related network, to yield new information on genome genetics and pathogen-host interactions of both the living Plateau and plain yak populations.

genomics↗

bioRxiv2019

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, discovering novel VA-regulated genes

Vitamin A (VA) deficiency remains prevalent in resource limited countries, affecting over 250 million preschool aged children. Vitamin A deficiency is associated with reduced intestinal barrier function and increased risk of mortality due to mucosal infection. Using Citrobacter rodentium (C. rodentium) infection in mice as a model for diarrheal diseases in humans, previous reports showed reduced pathogen clearance and survival in vitamin A deficient (VAD) mice compared to their vitamin A sufficient (VAS) counterparts. ObjectivesTo characterize and compare the impact of preexisting VA deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. MethodsVAD mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. RNAseq were performed using the total mRNAs extracted from SI and colon. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression and co-expression patterns. ResultsDEGs compared between VAS and VAD groups detected 49 SI and 94 colon genes. By GO information, SI DEGs were significantly enriched in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, including "humoral immune response" and "complement activation" were positively associated with VA in SI. Three co-expression modules showed significant correlation with VA status in SI; these modules contained four known retinoic acid targets. In addition, other SI genes of interest (e.g. Mbl2, Cxcl14, and Nr0b2) in these modules were suggested as new candidate genes regulated by VA. Furthermore, our analysis showed that markers of two cell types in SI, mast cells and Tuft cells, were significantly altered by VA status. In colon, "cell division" was the only enriched category and was negatively associated with VA. Thus, comparison of co-expression modules between SI and colon indicated distinct networks under the regulation of dietary VA and suggest that preexisting VAD could have a significant impact on the host response to a variety of disease conditions.

physiology↗

bioRxiv2018

In vivo Chemical Reprogramming of Astrocytes into Functional Neurons

Mammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.

cell biology↗