Biology subjects

Kwok, C.

Publications and source records attributed to Kwok, C..

3 recordsLinked to original sources

bioRxiv2026

Liver-specific loss of the transcriptional coregulator ARGLU1 protects against diet-induced obesity in mice through decreased lipid absorption

New medications that decrease food intake show promise in addressing the global obesity epidemic; however, additional therapies are needed for patients who are intolerant or unresponsive to these drugs. ARGLU1 is a transcriptional coregulator of several nuclear receptors. Herein, we detail the discovery that mice lacking ARGLU1 in hepatocytes (LKO) are resistant to diet-induced obesity, with no difference in food intake, locomotion, or energy expenditure compared to wildtype mice. Interestingly, LKO mice exhibited decreased CYP8B1, corresponding to fewer 12-hydroxylated bile acids, increasing the relative hydrophobicity of bile which decreases lipid emulsification. Notably, LKO mice have lower plasma and liver cholesterol levels, attributed to impaired lipid absorption. Furthermore, LKO mice showed preferential use of fatty acids as their fuel source. Herein, we establish a mechanistic basis for resistance of ARGLU1 LKO mice to diet-induced obesity, identifying a potential new molecular target for obesity.

physiology↗

bioRxiv2026

An ancestral haplotype of P2RX5 yields a B-cell surface marker and a promising multi-lineage immunotherapy target

While CD19- and BCMA-directed immunotherapies have improved outcomes for B-lymphoid and plasma cell malignancies, frequent relapses with antigen loss/downregulation highlight the need for new targets. Here, using transcriptomic datasets and newly-developed monoclonal antibodies, we show that P2RX5, long considered a pseudogene in humans, encodes a stable protein in 80% of individuals of African descent carrying the ancestral haplotype. Like CD19, P2RX5 displays B-cell lineage-restricted expression in normal tissues. Unlike CD19, P2RX5 is expressed not only in B-cell neoplasms, but also in T-cell leukemia (T-ALL) and multiple myeloma (MM). We developed P2RX5-directed bispecific T-cell engagers and CAR T cells, which killed T-ALL cells with no evidence of T-cell fratricide. These agents were non-inferior to FDA-approved CD19- and BCMA-directed immunotherapeutics in cell culture and xenograft models of Burkitt lymphoma and MM, while maintaining potency against CD19- and BCMA-negative variants. Hence, P2RX5 is a unique multi-lineage target for frontline or salvage immunotherapy.

cancer biology↗

bioRxiv2019

Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

The bed nucleus of stria terminalis (BNST) is a forebrain region highly sensitive to stress that expresses corticotropin-releasing hormone (CRH) neuropeptide at high levels and regulates negative valence behaviors associated with anxiety. However, how chronic stress modulates CRH signaling and neuronal activity in BNST remains unknown. We subjected C57BL6/J mice to a 6-week chronic variable mild stress (CVMS) paradigm and investigated the effects on behavior, BNST cellular neurophysiology, and BNST CRH signaling. We also utilized pharmacological infusions and optogenetics to decipher and mimic the effects of CVMS on BNST cellular neurophysiology and behavior. CVMS elevated plasma corticosterone levels, induced negative valence behaviors associated with anxiety, diminished M-currents (voltage-gated K+ currents that stabilize membrane potential and regulate neuronal excitability), and increased mEPSC amplitude in ovBNST. Additionally, the number of c-fos+, CRH+, and CRH activator pituitary adenylate cyclase-activating polypeptide (PACAP)+ cells were increased while CRH inhibitor striatal-enriched protein tyrosine phosphatase (STEP)+ cells were decreased in ovBNST. These expression data were confirmed with qPCR. CVMS also activated PKA in BNST and the electrophysiological and behavioral effects of CVMS were reversed by ovBNST infusion of the PKA-selective antagonist H89. Moreover, optogenetic activation of ovBNST directly induced negative valence behaviors associated with anxiety, mimicking the effects of CVMS. CVMS mediates effects on negative valence behaviors associated with anxiety by activating CRH signaling components and cellular excitability in ovBNST Our findings decipher an important CRH-associated stress molecular signature in BNST and advance our understanding of the neural circuitry underlying stress-induced disorders.

neuroscience↗