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A Role for Germline Variants in Multiple Myeloma?
(American Association for Cancer Research, 2024) Walker, Brian A.; Medicine, School of Medicine
In Blood Cancer Discovery, Thibaud and colleagues report the incidence of pathogenic germline variants (PGV) in patients with multiple myeloma and that these PGVs are associated with DNA repair pathway genes, including BRCA1 and BRCA2. They find an association of patients with PGVs and previous family or personal history of cancer, and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression-free survival than those without PGVs when they received high-dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma. See related article by Thibaud et al., p. 428.
Exploring the Antibiotic Potential of a Serine Protease from Solanum trilobatum Against Staphylococcus aureus Biofilms
(MDPI, 2025-05-07) Radhakrishnan, Manohar; Balu, Kanal Elamparithi; Karthik, Lakshminarayanan; Nagampalli, Raghavendra Sashi Krishna; Nadendla, Eswar Kumar; Krishnasamy, Gunasekaran; Biochemistry and Molecular Biology, School of Medicine
Background: Multi-antibiotic resistance has become an alarming issue in treating bacterial infections in both community and medical environments. Globally, the scientific community has been exploring multi-antibiotic techniques to find new ways to address this challenge. To address this critical challenge and explore alternative antibiotic treatments, we investigated the potential of Solanum trilobatum, an edible and medicinally important herb plant in Ayurvedic medicine.
Methods: Our research focused on a 60 kDa serine protease isolated and purified from the leaves of S. trilobatum, which showed evidence of possessing hydrolase activity. In this study, we examined the capability of the purified enzyme to eradicate preformed biofilms of S. aureus in combination with ampicillin. Additionally, we assessed the stability of the enzyme in the presence of metal ions and detergents.
Results: Enzyme kinetics revealed a Vmax of 48.63 µM/min and a Km of 14.08 µM, indicating efficient enzymatic activity. Furthermore, the enzyme exhibited maximum activity at physiological pH, suggesting its potential effectiveness under physiological conditions.
Conclusions: Our preliminary findings highlight the promising role of this enzyme as a potential agent to combat S. aureus biofilms, especially when used in conjunction with ampicillin, as an alternative antibiotic approach.
Severe osteoarthritis in aged PANX3 knockout mice: implications for a novel primary osteoarthritis model
(Oxford University Press, 2025-04-07) Wakefield, Brent; Tang, Justin; Balanta-Melo, Julián; Hutchinson, Jeffrey L.; Kanji, Rehanna; Herold, Geneva; O’Donnell, Brooke L.; Brooks, Courtney; Kiser, Patti; Grol, Matthew W.; Séguin, Cheryle A.; Plotkin, Lilian I.; Beier, Frank; Penuela, Silvia; Anatomy, Cell Biology and Physiology, School of Medicine
Osteoarthritis (OA) is a multifactorial disease associated with aging. As the molecular mechanisms underpinning the pathogenesis of this disease are unclear, there are no disease-modifying drugs to combat OA. Pannexin 3 (PANX3) has been shown to promote cartilage loss during posttraumatic OA. In contrast, the ablation of Panx3in male mice results in spontaneous full-thickness cartilage lesions at 24 mo of age. While protected from traumatic intervertebral disc (IVD) degeneration, Panx3KO mice show signs of IVD disease with altered disc mechanics. Whether the deleterious effects of ablating Panx3in aging are the result of accumulated mechanical damage is unknown. We used male and female WT and global Panx3KO C57Bl6 mice aged 18 mo of age. Mice were then randomized to sedentary (SED) or forced treadmill running (FEX) for 6 wk. Knee joint tissues, including the patellar tendon, quadriceps and distal patellar enthesis, and synovium were analyzed histologically and through micro-CT, along with lumbar spine IVDs. Half of male and female SED Panx3KO mice developed full-thickness cartilage lesions, severe synovitis, and ectopic fibrocartilage deposition and calcification of the knee joints in comparison to all other conditions. Panx3KO mice with severe OA show signs of quadriceps and patellar enthesitis, characterized by bone and marrow formation. Forced treadmill running did not seem to exacerbate these phenotypes in male or female Panx3KO mice; however, it may have contributed to the development of lateral compartment OA. The IVDs of aged Panx3KO mice displayed no apparent differences to control mice, and forced treadmill running had no further effects in either genotype. We conclude that aged Panx3KO mice show features of late-stage primary OA, including full-thickness cartilage erosion, severe synovitis, and enthesitis. These data suggest that the deletion of Panx3is deleterious to synovial joint health in aging.
Microbiome affects mice metabolic homeostasis via differential regulation of gene expression in the brain and gut
(Wiley, 2025) Milhouse, Wynne; Clapp Organski, Anna; Sun, Xun; Ai, Derek; Zhou, Baohua; Cross, Tzu-Wen L.; Ren, Hongxia; Pediatrics, School of Medicine
The gut microbiome (GMB) regulates digestion, metabolism, immunity, and energy homeostasis. This study investigates how gut microbiota integrate the regulation in the neuroendocrine and enteroendocrine systems, with a focus on G protein-coupled receptors (GPCRs) in the brain-gut axis and sex differences. Germ-free (GF) mice exhibited increased hypothalamic expression of the anorexigenic neuropeptide and decreased expression of the negative regulator of leptin signaling. GF males had significantly lower serum leptin levels compared to conventional (CON) males, highlighting a potential link between the microbiome and leptin resistance. In the gut, GF mice demonstrated heightened expression of anorexigenic gut hormones, including peptide YY (Pyy) and cholecystokinin (Cck), in addition to increased levels of G protein-coupled receptors (GPCRs) involved in gut hormone secretion and nutrient metabolism, particularly in females. While carbohydrate metabolism genes were upregulated in CON mice, lipid metabolism genes were predominantly higher in GF mice. These findings suggest that the gut microbiota downregulates genes involved in appetite suppression, modulates GPCRs linked to gut hormone secretion, and contributes to leptin resistance, particularly in males. This research underscores the importance of the gut microbiome in host metabolism and reveals potential molecular targets for novel treatments of metabolic diseases.
Active Site Characterization of a Campylobacter jejuni Nitrate Reductase Variant Provides Insight into the Enzyme Mechanism
(ACS, 2024) Yang, Jing; Mintmier, Breeanna; KC, Khadanand; Metzger, Mikayla C.; Radhakrishnan, Manohar; McGarry, Jennifer; Wilcoxen, Jarett; Basu, Partha; Kirk, Martin L.; Chemistry and Chemical Biology, School of Science
Mo K-edge X-ray absorption spectroscopy (XAS) is used to probe the structure of wild-type Campylobacter jejuni nitrate reductase NapA and the C176A variant. The results of extended X-ray absorption fine structure (EXAFS) experiments on wt NapA support an oxidized Mo(VI) hexacoordinate active site coordinated by a single terminal oxo donor, four sulfur atoms from two separate pyranopterin dithiolene ligands, and an additional S atom from a conserved cysteine amino acid residue. We found no evidence of a terminal sulfido ligand in wt NapA. EXAFS analysis shows the C176A active site to be a 6-coordinate structure, and this is supported by EPR studies on C176A and small molecule analogs of Mo(V) enzyme forms. The SCys is replaced by a hydroxide or water ligand in C176A, and we find no evidence of a coordinated sulfhydryl (SH) ligand. Kinetic studies show that this variant has completely lost its catalytic activity toward nitrate. Taken together, the results support a critical role for the conserved C176 in catalysis and an oxygen atom transfer mechanism for the catalytic reduction of nitrate to nitrite that does not employ a terminal sulfido ligand in the catalytic cycle.