Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.

There are at least two types of adipose tissues in the body, defined as brown adipose tissues (BATs) and white adipose tissues (WATs). These tissues comprise brown and white adipocytes, respectively. The adipocytes are commonly endowed with mitochondria, but they have diverse characteristics and roles. Brown adipocytes have abundant mitochondria that contribute to the ß-oxidation of fatty acids to produce chemical energy and the production of heat via uncoupling of the mitochondrial membrane potential from ATP synthesis. Alternatively, white adipocytes have fewer mitochondria that contribute to the generation of free fatty acids via lipogenesis by providing key intermediates. Besides the described types of adipocytes, brown-like adipocytes, termed beige adipocytes, are developed in WAT depots during cold exposure. Beige adipocytes also contribute to thermogenesis. Notably, beige adipocytes may transform into white-like adipocytes after the withdrawal of cold exposure. This process is marked by the elimination of mitochondria through the activation of mitochondria autophagy (mitophagy). This review aims to describe the mitophagy that occurs during the beige-to-white transition and discuss recent insights into the molecular mechanisms of this transformation. Additionally, we describe the mitophagy monitoring strategy in adipose tissues using three independent reporter systems and discuss the availabilities and limitations of the method.

Marked gallbladder wall thickening caused by Epstein-Barr virus-induced infectious mononucleosis.

Key Clinical Message: In patients with symptoms of viral infection and marked thickening of the gallbladder wall, it is important to suspect acalculous cholecystitis due to Epstein-Barr virus-induced infectious mononucleosis. Abstract: A 35-year-old Japanese man presented with fever, abdominal right upper quadrant pain, and liver dysfunction. Positive immunoglobulin M and -G antibodies and negative nuclear antigen for Epstein-Barr virus were observed. Abdominal ultrasonography revealed a markedly thickened gallbladder wall. Acalculous cholecystitis due to Epstein-Barr virus-induced infectious mononucleosis was diagnosed.

Comprehensive analysis of non-selective and selective autophagy in yeast atg mutants and characterization of autophagic activity in the absence of the Atg8 conjugation system.

Most autophagy-related genes, or ATG genes, have been identified through studies using budding yeast. Although the functions of the ATG genes are well understood, the contributions of individual genes to non-selective and various types of selective autophagy remain to be fully elucidated. In this study, we quantified the activity of non-selective autophagy, the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy, endoplasmic reticulum (ER)-phagy and pexophagy in all Saccharomyces cerevisiae atg mutants. Among the mutants of the core autophagy genes considered essential for autophagy, the atg13 mutant and mutants of the genes involved in the two ubiquitin-like conjugation systems retained residual autophagic functionality. In particular, mutants of the Atg8 ubiquitin-like conjugation system (the Atg8 system) exhibited substantial levels of non-selective autophagy, the Cvt pathway and pexophagy, although mitophagy and ER-phagy were undetectable. Atg8-system mutants also displayed intravacuolar vesicles resembling autophagic bodies, albeit at significantly reduced size and frequency. Thus, our data suggest that membranous sequestration and vacuolar delivery of autophagic cargo can occur in the absence of the Atg8 system. Alongside these findings, the comprehensive analysis conducted here provides valuable datasets for future autophagy research.

How to Overcome the Barriers Behind Writing Case Reports for Beginners and Young General Physicians.

Background: Case reports are fundamental to clinical medicine that trace back to ancient Egypt preceding Hippocrates in the history of medicine. Case reports contribute to academic development and new clinical research. However, among cases presented at an annual academic conference for Japanese generalists, only a few cases were later published in peer-reviewed journals, highlighting potential barriers regarding the writing of case reports, such as mentorship absence. This paper aimed to offer guidance and strategies to novice and young general physicians in overcoming barriers and effectively composing case reports for international peer-reviewed journals. Methods: This paper focuses on case reports for general physicians with extensive experience in writing case reports for international peer-reviewed journals. We conducted a narrative review to help beginners and young general physicians in writing case reports and discussed strategies for overcoming these barriers. Results: We propose the following three tips as important processes for writing case reports: recognize the types of suitable cases for case reports; select a journal for submission using a list of candidate journals for general physicians; and organize the discussion section with one theme per paragraph. In addition, we provide a list of journals that specifically focus on case reports, along with important pointers for beginners and young general physicians that will assist authors in the field of general medicine in choosing appropriate journals for submission. Conclusion: We hope that understanding and applying these tips will aid beginners and young general physicians in writing case reports.

Atg44/Mdi1/mitofissin facilitates Dnm1-mediated mitochondrial fission.

Mitochondria undergo fission and fusion, and their coordinated balance is crucial for maintaining mitochondrial homeostasis. In yeast, the dynamin-related protein Dnm1 is a mitochondrial fission factor acting from outside the mitochondria. We recently reported the mitochondrial intermembrane space protein Atg44/mitofissin/Mdi1/Mco8 as a novel fission factor, but the relationship between Atg44 and Dnm1 remains elusive. Here, we show that Atg44 is required to complete Dnm1-mediated mitochondrial fission under homeostatic conditions. Atg44-deficient cells often exhibit enlarged mitochondria with accumulated Dnm1 and rosary-like mitochondria with Dnm1 foci at constriction sites. These mitochondrial constriction sites retain the continuity of both the outer and inner membranes within an extremely confined space, indicating that Dnm1 is unable to complete mitochondrial fission without Atg44. Moreover, accumulated Atg44 proteins are observed at mitochondrial constriction sites. These findings suggest that Atg44 and Dnm1 cooperatively execute mitochondrial fission from inside and outside the mitochondria, respectively.Abbreviation: ATG: autophagy related; CLEM: correlative light and electron microscopy; EM: electron microscopy; ER: endoplasmic reticulum; ERMES: endoplasmic reticulum-mitochondria encounter structure; GA: glutaraldehyde; GFP: green fluorescent protein; GTP: guanosine triphosphate: IMM: inner mitochondrial membrane; IMS: intermembrane space; OMM: outer mitochondrial membrane; PB: phosphate buffer; PBS: phosphate-buffered saline; PFA: paraformaldehyde; RFP: red fluorescent protein; WT: wild type.

Effects of a 60-Minute Lecture About Diagnostic Errors for Medical Students: A Single-Center Interventional Study.

INTRODUCTION: The danger of diagnostic errors exists in daily medical practice, and doctors are required to avoid such errors as much as possible. Although various factors, including cognitive, system-related, and patient-related factors, are involved in the occurrence of diagnostic errors, the percentage of doctors with insufficient medical knowledge among those factors is extremely low. Therefore, lectures on diagnostic errors might also be useful for medical students without experience working as doctors. This study investigated whether a 60-minute lecture on diagnostic errors would enable Japanese medical students to consider the factors involved in diagnostic errors and how their perceptions of diagnostic errors change. METHODS AND MATERIALS: This single-center interventional study was conducted in October 2022 among fourth-year medical students at the Faculty of Medicine, Saga University. A questionnaire survey was conducted before and immediately after the lecture to investigate changes in the perceptions of medical students regarding diagnostic errors. One mock case question was given on an exam the day after the lecture, and the number of responses to cognitive biases and system-related and patient-related factors involved in diagnostic errors were calculated. RESULTS: A total of 83 students were analyzed. After the lecture, medical students were significantly more aware of the existence of the concept of diagnostic error, the importance of learning about it, their willingness to continue learning about it, and their perception that learning about diagnostic errors improves their clinical skills. They were also significantly less likely to feel blame or shame over diagnostic errors. The mean numbers of responses per student for cognitive bias, system-related factors, and patient-related factors were 1.9, 3.4, and 0.9, respectively. The mean number of responses per student for all factors was 5.6. CONCLUSION: A 60-minute lecture on diagnostic errors among medical students is beneficial because it significantly changes their perception of diagnostic errors. The results of the present study also suggest that lectures may enable Japanese medical students to consider the factors involved in diagnostic errors.

Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.

Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.

Writing Case Reports Can Improve Seven Components in Clinical Reasoning.

Case reports provide scientific knowledge and opportunities for new clinical research. However, it is estimated that less than 5% of cases presented by Japanese generalists at academic conferences are published due to various barriers such as the complex process of writing articles, conducting literature searches, the significant time required, the reluctance to write in English, and the challenge of selecting appropriate journals for publication. Therefore, the purpose of this opinion paper is to provide clinicians with practical tips for writing case reports that promote diagnostic excellence. In recent years, clinical practitioners have been striving for diagnostic excellence and optimal methods to accurately and comprehensively understand the patient's condition. To write a case report, it is essential to be mindful of the elements of diagnostic excellence and consider the quality of the diagnostic reasoning process. We (the authors) are seven academic generalists who are members of the Japanese Society of Hospital General Medicine (JSHGM) - Junior Doctors Association, with a median of 7 years after graduation and extensive experience publishing case reports in international peer-reviewed journals. We conducted a narrative review and discussed ways to write case reports to promote diagnostic excellence, leveraging our unique perspectives as academic generalists. Our review did not identify any reports addressing the critical points in writing case reports that embody diagnostic excellence. Therefore, this report proposes a methodology that describes the process involved in writing diagnostic excellence-promoting case reports and provides an overview of the lessons learned. Based on our review and discussion, we explain the essential points for promoting diagnostic excellence through case reports categorized into seven components of clinical reasoning. These strategies are useful in daily clinical practice and instrumental in promoting diagnostic excellence through case reports.

Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic ß-cells from db/db mice.

Mitochondrial dysfunction in pancreatic ß-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment's effects on mQC in diabetic ß-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic ß-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db ß-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db ß-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced ß-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving ß-cell function and effective glycemic control in T2D.

How Do We Establish the Utility and Evidence of General Medicine in Japan?

Hospital Medicine in the United States has achieved significant progress in the accumulation of evidence. This development has influenced the increasing societal demand for General Medicine in Japan. Generalists in Japan actively engage in a wide range of interdisciplinary clinical practices, education, and management. Furthermore, Generalists have also contributed to advances in research. However, there is limited evidence regarding the benefits of General Medicine in Japan in all these areas, with most of the evidence derived from single-center studies. In Japan, the roles of Generalists are diverse, and the comprehensive definition of General Medicine makes it difficult to clearly delineate its scope. This results in an inadequate accumulation of evidence regarding the benefits of General Medicine, potentially making it less attractive to the public and younger physicians. Therefore, it is necessary to categorize General Medicine and collect clear evidence regarding its benefits.