Defective tRNA 2′- O -modification impairs translation efficiency at Phe codon in the brain and induces a neurological dysfunction.

SARS-CoV-2 infection alters cellular RNA content. Cellular RNAs are chemically modified and eventually degraded, depositing modified nucleosides into extracellular fluids such as serum and urine. Here we searched for COVID-19-specific changes in modified nucleoside levels contained in serum and urine of 308 COVID-19 patients using liquid chromatography-mass spectrometry (LC-MS). We found that two modified nucleosides, N⁶-threonylcarbamoyladenosine (t⁶A) and 2-methylthio-N⁶-threonylcarbamoyladenosine (ms²t⁶A), were elevated in serum and urine of COVID-19 patients. Moreover, these levels were associated with symptom severity and decreased upon recovery from COVID-19. In addition, the elevation of similarly modified nucleosides was observed regardless of COVID-19 variants. These findings illuminate specific modified RNA nucleosides in the extracellular fluids as biomarkers for COVID-19 infection and severity.

In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.

Over 170 types of chemical modifications have been identified in cellular RNAs across the three domains of life. Modified RNA is eventually degraded to constituent nucleosides, and in mammals, modified nucleosides are released into the extracellular space. By contrast, the fate of modified nucleosides in bacteria remains unknown. In this study, we performed liquid chromatography-mass spectroscopy (LC-MS) analysis of modified nucleosides from the RNA of 23 pathogenic bacteria, revealing 2-methyladenosine (m ² A) as a common bacteria-specific modified nucleoside detected in all bacterial RNAs. Under normal culture conditions, bacteria did not actively release most modified nucleoside species, but robustly released nucleosides, including m ² A, following addition of antibiotics or immune cells. These results indicate that m ² A is released following bacterial lysis. Intraperitoneal injection of mice with m ² A increased detectable levels of m ² A in the urine, indicating that mammals can effectively excrete m ² A. Additionally, mice infected with wild-type E. coli showed higher levels of m ² A in their urine than mice infected by m ² A-deficient rlmN KO E. coli . This suggests that m ² A from the infected bacteria is excreted in the urine. Lastly, clinical studies using urine samples from febrile patients revealed significantly elevated levels of m ² A during bacterial infections, and these values did not correlate with inflammation severity markers, such as white blood count (WBC) and C-reactive protein (CRP). This study reports the mammalian metabolism of modified nucleosides derived from bacterial RNA, and the elevation of urinary m ² A in patients with bacterial infections. IMPORTANCE: This study reveals the differences in the fate and release of modified nucleosides in bacteria and mammals. Additionally, our study highlights that external bacteria-damaging factors, such as antibiotics and phagocytosis by host immune cells, promote the release of bacteria-specific modified nucleosides. Furthermore, we found that m ² A was elevated in the urine from animal models of bacterial infection and the urine of patients with bacterial infections. Collectively, this work spans basic biology and clinical science, offering valuable insights into the fate of modified nucleosides in bacterial systems and their relevance to infectious diseases.

Evans syndrome (ES) is characterized by the development of autoimmune hemolytic anemia and immune thrombocytopenic purpura and is often linked to autoimmune diseases, such as systemic lupus erythematosus (SLE). Standard treatment includes prednisolone and intravenous immunoglobulin; however, relapse commonly occurs when prednisolone is tapered or stopped. Rituximab is increasingly used for refractory ES with SLE, although its efficacy in new-onset cases remains unclear. We herein report a 67-year-old woman with new-onset ES and SLE with lupus nephritis class IV-G whose condition improved with rituximab after prednisolone, hydroxychloroquine, and mycophenolate mofetil. The patient remained relapse-free for one year, suggesting that rituximab is a potentially viable first-line therapy.

Visceral disseminated varicella-zoster virus (VD-VZV) infection, resulting from primary infection by, or reactivation of, VZV, is a rare and severe complication in immunosuppressed patients. Because VD-VZV often develops alongside acute abdominal pain, which precedes appearance of the skin rash, diagnosis is difficult. Here, we report a case of 48-year-old woman who presented with acute abdomen, leading to a diagnosis of VD-VZV infection. The patient developed systemic lupus erythematosus 4 months earlier, and had been treated with immunosuppressants. The patient was treated successfully with a 7-day course of intravenous acyclovir. VD-VZV infection should be considered as a differential diagnosis in immunosuppressed patients with acute abdomen. Early diagnosis and prompt treatment with antivirals are crucial for improved patient outcomes.