Biology subjects

Zhang, Z. A.

Publications and source records attributed to Zhang, Z. A..

4 recordsLinked to original sources

bioRxiv2026

A step beyond: age and sex-dependent changes in multidimensional locomotor and gait patterns of voluntary motion of C57BL/6 mice

Age-related decreases in physical activity drive frailty and reduced intrinsic capacity, promoting adverse health outcomes such as falls. Experimental tools for quantifying these metrics in preclinical models have lagged behind those used clinically; single-endpoint activity assessments (e.g., rotarod performance, treadmill activity) of rodents often require invasive handling and/or forced performance cues that may increase stress and variability, especially in aged animals. Here, we evaluated whether automated analysis of spontaneous movement using machine-learning-based software (Palmreader) could identify age-related changes in locomotor activity, gait, paw loading, or posture in male and female C57BL/6 mice across young, adult, and aged timepoints (4.5-, 7-, and 22 months of age). Parameters were quantified using the BlackBox One system during a 7-minute open-field recording. Principal component analysis demonstrated age-related separation of movement phenotypes, with individual parameters demonstrating increased hindlimb duty factor and longer stride lengths with age. Age-related changes in forelimb-to-hindlimb duty-factor imbalance, paw contact, and postural organization were also observed, and several gait alterations with age showed different patterns between males and females. Conventional measures of physical activity (e.g., distance traveled, walking time), in contrast, showed few age-related differences, particularly in females. These findings suggest that aging more consistently alters movement patterns rather than movement magnitude, and that gait and postural features may represent important age-related functional changes not captured by activity measurements alone. Automated assessment of spontaneous movement may therefore represent a useful complement to traditional physical activity testing, with the added benefit of minimal animal handling and short recording times.

animal behavior and cognition↗

bioRxiv2025

Precise Control of Switchable Chimeric Antigen Receptor T Cells Allows Enhanced Safety and Less T Cell Exhaustion

BackgroundChimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in hematologic malignancies, yet their clinical utility remains limited by safety concerns, limited persistence, and T-cell exhaustion driven by continuous receptor signaling. While switchable CAR designs provide external control, many reported systems are irreversible, strictly binary, or compromise CAR-T potency. MethodsWe engineered an optimized chemically switchable CAR platform (CSN CAR) that pharmacologically regulates antigen engagement by controlling the surface expression of the full-length CAR. An NS3 protease module was embedded within the CAR construct to enable drug-dependent stabilization of intact CAR on T cells. Using engineered CAR-T cells, we quantified drug-controlled activation, cytotoxicity, and cytokine release against CD19+ tumor cells by flow cytometry and ELISA in vitro. We further screened clinically approved NS3/4A inhibitors in CAR-HEK and CAR-T cells to identify optimal small-molecule controllers. A chronic stimulation model was established to assess CAR-T persistence and exhaustion-associated phenotypes in vitro. ResultsCSN CAR-T cells enabled precise, dose-dependent regulation of CAR surface density, cytokine production, and cytotoxicity. In the OFF state, switchable CAR-T cells showed minimal basal activity, consistent with reduced antigen-driven activation and cytokine release in the absence of drug in the experimental conditions. Upon drug addition, intact surface CAR was detectable within 1 hour, reaching [~]80% of peak observed CAR expression by 4 hours. Reversible suppression of CAR expression enabled attenuation of cytotoxicity toward normal CD19+ B cells in vitro after target-cell reduction, supporting a potential strategy to mitigate prolonged on-target/off-tumor activity. Under chronic stimulation, switchable CAR-T cells exhibited reduced exhaustion-associated markers, more stable CAR expression, and preferential differentiation toward a central memory phenotype. ConclusionTogether, these findings establish CSN CAR as a reversible and tunable switchable CAR-T platform enabled by clinically approved NS3/4A inhibitors, supporting controllable modulation of CAR activity with potential applications for improving the precision and safety of CAR-T cell therapy.

cancer biology↗

bioRxiv2021

Emergent myxobacterial behaviors arise from reversal suppression induced by kin contacts

A wide range of biological systems - from microbial swarms to bird flocks, display emergent behaviors driven by coordinated movement of individuals. To this end, individual organisms interact by recognizing their kin and adjusting their motility based on others around them. However, even in the best-studied systems, the mechanistic basis of the interplay between kin recognition and motility coordination is not understood. Here, using a combination of experiments and mathematical modeling, we uncover the mechanism of an emergent social behavior in Myxococcus xanthus. By overexpressing cell surface adhesins, TraA and TraB, involved in kin recognition, large numbers of cells adhere to one another and form organized macroscopic circular aggregates that spin clockwise or counterclockwise. Mechanistically, TraAB adhesion results in sustained cell-cell contacts that trigger cells to suppress cell reversals, and circular aggregates form as the result of cells ability to follow their own cellular slime trails. Furthermore, our in-silico simulations demonstrate a remarkable ability to predict self-organization patterns when phenotypically distinct strains are mixed. For example, defying naive expectations, both models and experiments found that strains engineered to overexpress different and incompatible traAB allelles nevertheless form mixed circular aggregates. Therefore, this work provides key mechanistic insights into M. xanthus social interactions and demonstrates how local cell contacts induce emergent collective behaviors by millions of cells. ImportanceIn many species, large populations exhibit emergent behaviors whereby all related individuals move in unison. For example, fish in schools can all dart in one direction simultaneously to avoid a predator. Currently, it is impossible to explain how such animals recognize kin through brain cognition and elicit such behaviors at a molecular level. However, microbes also recognize kin and exhibit emergent collective behaviors that are experimentally tractable. Here, using a model social bacterium, we engineer dispersed individuals to organize into synchronized collectives that create emergent patterns. With experimental and mathematical approaches we explain how this occurs at both molecular and population levels. The results demonstrate how the combination of local physical interactions triggers intracellular signaling, which in turn leads to emergent behavior on a population scale.

biophysics↗

bioRxiv2019

IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection

Administration of bacterial flagellin elicits production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede this virus. Although IL-18 and IL-22 induce each others expression, we found that IL-18 and IL-22 both impeded RV independently of each other and did so by distinct mechanisms, in both cases via activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced pyroptotic death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in levels of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that IL-18/22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

immunology↗