A lack of effective treatment is one of the main factors contributing to gastric cancerrelated death. Discovering effective targets and understanding their underlying anticancer mechanism is key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates (OCRs) and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagyand mitophagy-associated proteins (i.e. ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a JNK-dependent and mechanistic target of rapamycin (mTOR)-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.Gastric cancer is the fifth most common type of cancer worldwide, affecting millions each year (1-4). The five-year survival rate is estimated at approximately 30% (5) making it one of the deadliest malignancies in the world and the second leading cause of cancer-related mortality in Eastern Asia (6, 7). Currently, surgery is the most effective available therapy against gastric cancer; however, its efficacy is limited to the early-stage gastric cancer patients (8, 9). For patients with late-stage tumors, surgery is not an option and despite systemic chemotherapy, the disease is deemed incurable (10)(11)(12). Considering the poor efficacy of current anticancer agents, the increasing resistance to chemotherapy drugs and the lack of treatment options for late stage patients, the development of novel and effective therapeutic approaches is of critical importance.Over the last decade, Transient Receptor Potential (TRP) channels have gained considerable attention in the field of cancer-targeted therapy (13-16). TRP channels are often altered in cancer cells and disruption in their normal function can affect various signalling pathways, ultimately leading to cancer progression and growth (17, 18). The TRP family is divided into seven subfamilies consisting of a total of 28 members. Some of members inclu...

CD8 T cells play a central role in antiviral immunity. Type I interferons are among the earliest responders after virus exposure and can cause extensive reprogramming and antigen-independent bystander activation of CD8 T cells. Although bystander activation of pre-existing memory CD8 T cells is known to play an important role in host defense and immunopathology, its impact on naïve CD8 T cells remains underappreciated. Here we report that exposure to reovirus, both in vitro or in vivo, promotes bystander activation of naïve CD8 T cells within 24 hours and that this distinct subtype of CD8 T cell displays an innate, antiviral, type I interferon sensitized signature. The induction of bystander naïve CD8 T cells is STAT1 dependent and regulated through nicotinamide phosphoribosyl transferase (NAMPT)-mediated enzymatic actions within NAD+ salvage metabolic biosynthesis. These findings identify a novel aspect of CD8 T cell activation following virus infection with implications for human health and physiology.

Manuscript Editing: The entire team with the help and advice of mentors and supervisors. AbstractPlant cell walls are comprised of cellulose, hemicellulose, and lignin, collectively known as lignocellulose. Microorganisms degrade these components to liberate sugars to meet metabolic demands. Using a metagenomic sequencing approach, we previously demonstrated that the microbiome of the North American porcupine (Erethizon dorsatum) is replete with novel lignocellulose-degrading enzymes. Here, we report the identification, synthesis and partial characterization of four genes from the porcupine microbiome encoding putative novel lignocellulose-degrading enzymes, including a β-xylanase, endoxylanase, β-glucosidase, and an ⍺-Larabinofuranosidase. These genes were identified via conserved catalytic domains associated with cellulose and hemicellulose degradation. We cloned the putative β-xylanase into the pET26b(+) plasmid, enabling inducible gene expression in Escherichia coli (E. coli) and periplasmic localization. We demonstrated IPTG-inducible accumulation of β-xylanase protein but failed to detect xylobiose degrading activity in a reporter assay. Alternative assays may be required to measure activity of this putative β-xylanase. In this report, we describe how a synthetic metagenomic pipeline can be used to identify novel microbial lignocellulose-degrading enzymes and take initial steps to introduce a hemicellulose-degradation pathway into E. coli to enable biofuel production from wood pulp feedstock. Financial Disclosure