Biology subjects

Wang, X. M.

Publications and source records attributed to Wang, X. M..

8 recordsLinked to original sources

bioRxiv2026

A novel preclinical mouse model recapitulates progressive phenotypes of Bryant-Li-Bhoj Syndrome

Bryant-Li-Bhoj Syndrome (BLBS; OMIM: 619720, 619721) is a Mendelian neurogenetic condition, first described in 2020, with a mixed neurodevelopmental/neurodegenerative phenotype and variable systemic features. To date, 100 affected individuals with 74 unique causative variants have been published. Clinical data and prior functional work in multiple model systems have emphasized the utility of interrogating the pathogenesis of multiple causal variants to identify a convergent, therapeutically targetable mechanism. Additionally, the ability to evaluate the efficacy of future therapeutics relies on the availability of a robustly validated preclinical model. Here, we characterize the developmental and neurobehavioral phenotypes of a novel BLBS mouse model harboring one of the most recurrent causative variants (h3-3a p.T45I). H3.3T45I mice recapitulate the BLBS natural history: perinatal growth restriction, delayed developmental milestones, and progressive motor and gait impairments. Adult mice additionally display craniofacial differences, impaired nest building, hyperactivity in a social context, and male-specific elevated aggression. The non-invasive, clinically translatable endpoints established here provide a validated preclinical platform for evaluating therapeutics for a community whose current standard of care is symptom management. Summary StatementA new mouse model mirrors the developmental delays, motor decline, and behavioral changes seen in individuals with this rare, progressive genetic brain disorder, providing a foundation for testing future therapies.

genetics↗

bioRxiv2025

Emergent Leadership Driven by Asymmetric Stability Shapes Learning in Dyadic Motor Coordination

Coordinated actions are fundamental to human behavior. Even without explicit communication, stable coordination patterns and implicit leadership roles can emerge. This study examines the dynamic nature of leadership and its impact on perceptuomotor learning in a dyadic coordination task. Paired participants (dyads) controlled targets using joysticks to produce a novel coordination pattern, which was learned using visual feedback without direct communication over multiple sessions. Results showed that leadership was an emergent property of the system, dynamically shaped by the interplay between individual and system-level stability. At the system level, leadership role transitions modulated the dyads learning, characterized by distinct learning models. At the individual level, leaders maintained overall stability but exhibited occasional bursts of instability to assert control and reinforce coordination. These findings highlight the role of leader-follower dynamics in learning and performance, showing that leadership is both a limiting factor and a facilitator for coordination.

animal behavior and cognition↗

bioRxiv2024

A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental syndrome demonstrates the role of histone H3.3 in neuronal differentiation and maturation

BackgroundBryant-Li-Bhoj neurodevelopmental syndrome (BLBS) is neurogenetic disorder caused by variants in H3-3A and H3-3B, the two genes that encode histone H3.3. Ninety-nine percent of individuals with BLBS show developmental delay/intellectual disability, but the mechanism by which variants in H3.3 result in these phenotypes is not yet understood, limiting the therapeutic interventions available to individuals living with BLBS. MethodsHere, we investigate how one BLBS-causative variant, H3-3B p.Leu48Arg (L48R), affects neurodevelopment using an induced pluripotent stem cell (iPSC) model differentiated to 2D neural progenitor cells (NPCs), 2D forebrain neurons (FBNs), and 3D dorsal forebrain organoids (DFBOs). We employ a multi-omic approach in the 2D models to quantify the resulting changes in gene expression and chromatin accessibility. We used immunofluorescence (IF) staining to define the identities of cells in the 3D DFBO and whole-cell patch clamp to investigate the electrophysiological properties of neurons in DFBOs. ResultsIn the 2D systems, we found dysregulated gene expression and chromatin accessibility affecting neuronal fate, adhesion, neurotransmission, and excitatory/inhibitory balance. Immunofluorescence of DFBOs corroborated altered proportions of radial glia and mature neuronal populations. Patch clamp recordings revealed decreased electrical activity in neurons from L48R DFBOs compared to control DFBOs. ConclusionsThese data provide the first mechanistic insights into the pathogenesis of BLBS from a human-derived model of neurodevelopment, which suggest that H3.3 L48R increases H3-3B expression, resulting in the hyper-deposition of H3.3 into the nucleosome which underlies changes in gene expression and chromatin accessibility. Functionally, this causes dysregulation of cell adhesion, neurotransmission, and the balance between excitatory and inhibitory signaling. These results are a crucial step towards preclinical development and testing of targeted therapies for this and related disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/609745v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1fc16aorg.highwire.dtl.DTLVardef@d3238corg.highwire.dtl.DTLVardef@1c2ca16org.highwire.dtl.DTLVardef@1617897_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Quantifying the strength of viral fitness tradeoffs between hosts: A meta-analysis of pleiotropic fitness effects

The range of hosts a given virus can infect is widely presumed to be limited by fitness tradeoffs between alternative hosts. These fitness tradeoffs may arise naturally due to antagonistic pleiotropy if mutations that increase fitness in one host tend to decrease fitness in alternate hosts. Yet there is also growing recognition that positive pleiotropy may be more common than previously appreciated. With positive pleiotropy, mutations have concordant fitness effects such that a beneficial mutation can simultaneously increase fitness in different hosts, providing a genetic mechanism by which selection can overcome fitness tradeoffs. How readily evolution can overcome fitness tradeoffs therefore depends on the overall distribution of mutational fitness effects between hosts, including the relative frequency of antagonistic versus positive pleiotropy. We therefore conducted a systematic meta-analysis of the pleiotropic fitness effects of viral mutations reported in different hosts. Our analysis indicates that while both antagonistic and positive pleiotropy are common, fitness effects are overall positively correlated between hosts and unconditionally beneficial mutations are not uncommon. Moreover, the relative frequency of antagonistic versus positive pleiotropy may simply reflect the underlying frequency of beneficial and deleterious mutations in individual hosts. Given a mutation is beneficial in one host, the probability that it is deleterious in another host is roughly equal to the probability that any mutation is deleterious, suggesting there is no natural tendency towards antagonistic pleiotropy. The widespread prevalence of positive pleiotropy suggests that many fitness tradeoffs may be readily overcome by evolution given the right selection pressures. Lay summary Evolutionary theory suggests that fitness tradeoffs between alternative environments constrain the potential for organisms to simultaneously adapt to multiple environments. Likewise, fitness tradeoffs between alternative hosts are widely believed to limit the ability of viruses to adapt to multiple hosts and thereby expand their host range. How strongly viruses are constrained by such tradeoffs will largely depend on the fitness effects of new mutations. Fitness tradeoffs may inevitably constrain viral evolution if mutations that increase fitness in one host tend to decrease fitness in alternative hosts. However, mutations can sometimes increase fitness in multiple hosts, allowing viruses to adapt to new hosts without paying fitness costs. Geneticists refer to these two scenarios as antagonistic and positive pleiotropy depending on whether mutations have opposite or concordant fitness effects. Because the relative frequency of antagonistic versus positive pleiotropy is centrally important to viral evolution, we conducted a systematic meta-analysis of the fitness effects of mutations reported in different hosts. Our analysis reveals that cases of positive pleiotropy where mutations have beneficial effects in more than one host may be sufficiently common for evolution to resolve many apparent fitness tradeoffs between hosts.

evolutionary biology↗

bioRxiv2020

Revisiting the carbon isotope discrimination and water use efficiency relation: the influence of mesophyll conductance

SummaryThe carbon isotope discrimination (Δ) has been used widely to infer intrinsic water-use efficiency (iWUE) of C3 plants, a key parameter linking carbon and water fluxes. Despite the essential role of mesophyll conductance (gm) in photosynthesis and Δ, its effect on Δ-based predictions of iWUE has generally been neglected.Here, we derive a mathematical expression of iWUE as a function of Δ that includes gm (iWUEmes) and exploits the gm-stomatal conductance (gsc) relationship across drought-stress levels and plant functional groups (deciduous or semi-deciduous woody, evergreen woody and herbaceous species) in a global database. iWUEmes was further validated with an independent dataset of online-Δ and CO2 and H2O gas exchange measurements with seven species.Drought stress reduced gsc by 52% and gm by 45% averaged over all plant functional groups, but had no significant effect on the gsc/gm ratio, suggesting a well-constrained gsc/gm ratio of 0.79±0.07 (95%CI, n=198) across plant functional groups and drought-stress treatments. Due in part to the synchronous behavior of gsc and gm, gm was negatively correlated to iWUE. Incorporating the gsc/gm ratio in the iWUEmes model significantly improved the estimation of iWUE compared to the simple model.The inclusion of gm effects, even using a fixed gsc/gm ratio of 0.79 when gm is unknown, proved desirable to eliminate significant bias in estimating iWUE from Δ across various C3 vegetation types.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗

bioRxiv2019

Natural naphthoquinones isolated from Lithospermum erythrorhizon suppress dextran sulfate sodium-induced murine experimental colitis

The purpose of this study was to explore the effects of natural shikonin and its derivatives on mice experimental colitis induced by dextran sulfate sodium, and to investigate the underlying mechanisms in vivo. Our results suggested that, intragastric administration of single compound like shikonin and its derivatives contributed to attenuating symptoms of malignant induced by DSS. Meanwhile, shikonin or its derivatives could also remarkably reduce the disease activity index and histopathological scores, suppress the levels of pro-inflammatory cytokines (including IL-6, IL-1{beta} and TNF-), while increase that of inflammatory cytokine IL-10 in serum. Additionally, both shikonin and alkanin were found to restrain the levels of COX-2, MPO and iNOS in serum and colonic tissues. Moreover, western blotting results demonstrated that shikonin and its derivatives could inhibit the activation of the NLRP3 inflammasome and the NF-{kappa}B signaling pathway, relieve the DSS-induced disruption of colonic epithelial tight junction (TJ) in colonic tissues. Further, docking simulation had been performed to prove that shikonin and its derivatives could bind to the active sites of NLRP3 inflammasome and the NF-{kappa}B to generate an effective inflammatory effect. Taken together, our experimental data can provide some evidence for the potential use of shikonin and its derivatives to treat the inflammatory bowel disease (IBD).

biochemistry↗

bioRxiv2019

Evaluation of BMP-mediated patterning in zebrafish embryos using a growing finite difference embryo model

Bone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however it is not clear how the source-sink mechanism shapes patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo. We propose a new three-dimensional growing Partial Differential Equation (PDE)-based model to simulate the BMP patterning process during the blastula stage. This model provides a starting point to elucidate how different mechanisms and components work together in 3D to create and maintain the BMP gradient in the embryo. We also show how the 3D model fits the BMP signaling gradient data at multiple time points along both axes. Furthermore, sensitivity analysis of the model suggests that the spatiotemporal patterns of Chordin and BMP ligand gene expression are dominant drivers of shape in 3D and more work is needed to quantify the spatiotemporal profiles of gene and protein expression to further refine the models.

systems biology↗

bioRxiv2018

Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice

Background & AimsFibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.\n\nMethodsWildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.\n\nResultsFAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic {beta}-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and {beta}-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic {beta}-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.\n\nConclusionThis is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.

pathology↗