👤 Maki Ohashi

Renal involvement in TAFRO syndrome usually is present as acute kidney injury with oligoproteinuria. Renal pathology is typically characterized by glomerular microangiopathy without immune deposits, and there have been no reports of membranous nephropathy. While idiopathic multicentric Castleman disease (iMCD), which shares a similar pathophysiology with TAFRO syndrome, has documented several cases of membranous nephropathy, the underlying mechanisms remain unclear. We present a case of TAFRO syndrome presenting with nephrotic syndrome, and kidney biopsy revealed exostosin 1/exostosin 2 (EXT1/EXT2)-associated membranous nephropathy. EXT1/EXT2 is considered a potential target antigen in autoimmune membranous nephropathy, suggesting their potential pathogenic role in this case. In iMCD cases with membranous nephropathy, IL-6 levels tend to be slightly low, while VEGF levels are significantly elevated, as seen in the present case. This cytokine profile may contribute to the differences in renal pathological findings and may also be involved in the response to treatment. This case may enhance our understanding of the pathophysiology of membranous nephropathy in TAFRO syndrome and iMCD. Show less

Physical activity benefits health, whereas physical inactivity increases the risk of age-related conditions and adverse health outcomes. Kyotango City in Japan is known for its residents' longevity, and many centenarians live there. This study investigated the physical activity associations with physical function and body composition in older adults living in this area. Community-dwelling older adults (n = 727; mean age 74.1 years; 59.4% women) participated in this study. Multiple linear regression analyses were carried out to examine objectively-measured physical activity associations with physical function (handgrip strength, knee extension strength and maximum gait speed) and body composition (skeletal muscle mass index and whole-body phase angle), adjusting for potential confounders. Additionally, isotemporal substitution models were applied to estimate changes resulting from replacing sedentary behavior with light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA). All physical function and body composition indicators were significantly associated with SB and MVPA (all P < 0.050). However, LPA was associated with only handgrip strength and body composition indicators. Replacing 30 min of SB per day with LPA was associated with a 0.176 kg increase in handgrip strength, 0.018 kg/m Older adults in a region of Japan known for longevity might maintain physical function and favorable body composition through engaging in abundant physical activity. Public health strategies should prioritize MVPA promotion while recognizing LPA's complementary role for physically inactive older adults. Geriatr Gerontol Int 2025; 25: 1511-1517. Show less

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by progressive fibrofatty replacement of the myocardium. In the Japanese population, variants of the desmoglein-2 ( A 6-year-old asymptomatic girl was diagnosed with ACM based on abnormal electrocardiogram findings, including epsilon waves, and T-wave inversions in leads V This case illustrates the potential for severe pediatric ACM associated with compound heterozygous This case underscores the genetic heterogeneity and phenotypic variability in inherited cardiomyopathies. It emphasizes the importance of comprehensive genetic testing and close monitoring of affected individuals and their families. Show less

Exostosin 1 (EXT1) and exostosin 2 (EXT2)-associated membranous nephropathy (MN) may be associated with active autoimmune disease. We encountered an elderly man who presented with EXT1/EXT2-associated lupus-like MN with full house immune deposits, monoclonal gammopathy of uncertain significance and Sjögren's syndrome. The patient exhibited various other immune abnormalities. Although he did not fulfill the criteria of clinical systemic lupus erythematosus (SLE), he met a stand-alone renal criterion of the Systemic Lupus International Collaborating Clinics (SLICC) 2012. Whether or not a stand-alone renal criterion with EXT1/EXT2 positivity, as in the present patient, can efficiently guide decisions regarding the diagnosis and treatment of SLE remains a clinical dilemma. Show less

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics. Show less

Macroautophagy/autophagy is triggered by various starvation and stress conditions. The phospholipid phosphatidylinositol-3-phosphate (PtdIns3P) is essential for the formation of the autophagosome both in yeast and mammals. The class III phosphatidylinositol 3-kinase, PIK3C3C in humans or Vps34 in yeast, produces PtdIns3P by phosphorylating the 3'-OH position of phosphatidylinositol (PtdIns). In order to synthesize PtdIns3P for the initiation of autophagy, PIK3C3/Vps34 has a heterotetrameric core, the PIK3C3 complex I (hereafter complex I) composed of PIK3C3/Vps34, PIK3R4/Vps15, BECN1/Vps30, and ATG14/Atg14. A fifth component of complex I, NRBF2 in mammals and Atg38 in yeast, was found and has been characterized in the past decade. The field has been expanding from cell and structural biology to mouse model and cohort studies. Here I will summarize the structures and models of complex I binding NRBF2/Atg38, its intracellular roles, and its involvement in health and disease. Along with this expansion of the field, different conclusions have been drawn in several topics. I will clarify what has and has not been agreed, and what is to be clarified in the future. Show less

Phosphatidylinositol-3-phosphate (PtdIns3P) is essential for generating autophagosomes and regulating endocytic trafficking. Recently, we have shown that the activities of human PIK3C3/VPS34-containing complexes I and II, which synthesize PtdIns3P, are greatly affected by three membrane physicochemical parameters: lipid unsaturation, membrane curvature, and negative charge. Both complexes are more active on membranes composed of unsaturated lipids than saturated lipids, and high membrane curvature can compensate for the negative effect of high lipid saturation. Negatively charged phosphatidylserine (PS) activates the complexes, as well as PIK3C3/VPS34 alone. The kinase activity of complex I depends critically on the ATG14 BATS domain, whereas complex II relies on the BECN1 BARA domain. Our findings highlight the importance of the membrane character as sensed by the unique membrane binding motifs/domain of the complexes for regulating PIK3C3/VPS34 activity. Show less

Epstein-Barr virus-induced gene 3 (EBI3) is a subunit common to IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function in cytokines. EBI3-deficient naive CD4+ T cells had reduced IFN-γ production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23Rα, but not another IL-23R subunit, IL-12Rβ1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23Rα expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression is inducible in T cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions. Show less

The phosphatidylinositol 3-kinase Vps34 is part of several protein complexes. The structural organization of heterotetrameric complexes is starting to emerge, but little is known about organization of additional accessory subunits that interact with these assemblies. Combining hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and electron microscopy (EM), we have characterized Atg38 and its human ortholog NRBF2, accessory components of complex I consisting of Vps15-Vps34-Vps30/Atg6-Atg14 (yeast) and PIK3R4/VPS15-PIK3C3/VPS34-BECN1/Beclin 1-ATG14 (human). HDX-MS shows that Atg38 binds the Vps30-Atg14 subcomplex of complex I, using mainly its N-terminal MIT domain and bridges the coiled-coil I regions of Atg14 and Vps30 in the base of complex I. The Atg38 C-terminal domain is important for localization to the phagophore assembly site (PAS) and homodimerization. Our 2.2 Å resolution crystal structure of the Atg38 C-terminal homodimerization domain shows 2 segments of α-helices assembling into a mushroom-like asymmetric homodimer with a 4-helix cap and a parallel coiled-coil stalk. One Atg38 homodimer engages a single complex I. This is in sharp contrast to human NRBF2, which also forms a homodimer, but this homodimer can bridge 2 complex I assemblies. Show less

Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis, and autophagy. We present the 4.4 angstrom crystal structure of the 385-kilodalton endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1), and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm, where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal conformational changes accompanying membrane binding and identify a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive. Show less

Several physical and psychological stresses frequently become triggers for gastrointestinal disorders such as ulcer. In this study, we tried to identify serum proteins as potential biomarkers for the evaluation of stress-induced gastric ulcer. By proteomic analysis using rats with gastric ulcer induced by water immersion and restraint (WIR) stress as an animal model, we found quantitative changes in several serum proteins, including creatine kinase muscle M chain (CK-M) and apolipoprotein A-IV (ApoA4) in the stressed rats. On western blotting and enzyme-linked immunosorbent assay (ELISA), we confirmed that serum CK-M was remarkably increased by WIR stress. However, ApoA4 appeared to be decreased by fasting, but not WIR stress, which is usually applied prior to WIR stress. The findings suggest that these two serum proteins might be useful as biomarkers, CK-M for stress-induced gastric ulcer and ApoA4 for starvation. Show less

Liver X receptor (LXR) is a nuclear receptor that acts as a sterol sensor and metabolic regulator of cholesterol and lipid homeostasis. The foam cell transformation of macrophages (Mvarphi) is considered a critical process in atherosclerotic lesions. The relationship, however, of the foam cell transformation of Mvarphi and LXR is not fully understood. The purpose of the present study was to examine the expression of LXRalpha, retinoid X receptor (RXR)alpha, ATP-binding cassette transporter (ABCA1), and macrophage scavenger receptor A (MSR-A), and lipid accumulation in human monocyte-derived Mvarphi. The expression of LXRalpha, ABCA1, MSR-A in 7 day cultured granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced Mvarphi (GM-Mvarphi) was significantly higher than that in 7 day cultured M-CSF-induced Mvarphi (M-Mvarphi). The expression levels of LXRalpha, ABCA1 and MSR-A protein decreased from 48 h to 5 days after the addition of lipopolysaccharide (LPS) in GM-Mvarphi, but only MSR-A protein decreased at 5 days after the addition of LPS in M-Mvarphi. Intracellular lipid accumulation was clearly observed when GM-Mvarphi was pre-stimulated with LPS for 48 h and incubated with oxidized LDL for an additional 5 days. These findings suggest that the inhibitory activity of LXRalpha, ABCA1 and MSR-A by LPS may be related to the transformation of Mvarphis, especially GM-Mvarphi into foam cells. Show less