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Denosumab is reported to increase bone mineral density (BMD) among haemodialysis patients; however, hypocalcaemia is a serious adverse effect among chronic kidney disease (CKD) patients. Identifying which patients will show greater improvement in BMD is important. We enrolled 84 haemodialysis patients with osteoporosis in our study. 28 patients initiated denosumab treatment between October 2019 and October 2020. We assessed BMD changes and investigated the association between baseline bone turnover marker (BTM) levels and 6-month changes in BMD after denosumab treatment. BMD was increased at 6 months in denosumab-treated patients compared with patients not treated with denosumab (lumbar spine: 5.34% vs. − 0.49%; total hip: 2.43% vs. − 0.47%). Bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) at baseline were independently associated with increased BMD in the total hip (BAP: β = 0.472, p value = 0.004; TRACP-5b: β = 0.433, p value = 0.008) and lumbar spine (BAP: β = 0.591, p value = 0.001; TRACP-5b: β = 0.613, p value = 0.0008). BAP and TRACP-5b were also independent predictors of hypocalcaemic events (OR [95% CI] 1.747 [1.084–4.604] and 1.006 [1.000–1.015], respectively). BTMs may be associated with increased BMD and hypocalcaemic events after denosumab treatment. BTM measurement may be useful for assessing the effect of denosumab on BMD; however, careful monitoring of serum calcium levels is needed.

Background/Objectives: Patients undergoing hemodialysis frequently receive oral or intravenous iron supplementation to treat iron-deficiency anemia and enhance the efficacy of erythropoiesis-stimulating agents. However, this approach may lead to iron overload. Experimental studies have suggested that iron overload may contribute to the development of sarcopenia through oxidative stress and inflammation. This study aimed to investigate the association between iron status and sarcopenia in patients undergoing hemodialysis. Methods: Serum ferritin levels were measured, and sarcopenia was assessed using the Asian Working Group for Sarcopenia criteria in 104 stable outpatients undergoing maintenance hemodialysis therapy. Results: Sarcopenia was identified in 25 (24.0%) patients. Serum ferritin levels were significantly higher in patients with sarcopenia than in those without (median: 170.6 ng/mL vs. 92 ng/mL, p = 0.023). An increase of 10 ng/mL in serum ferritin levels was independently associated with sarcopenia. The high-ferritin group (≥132 ng/mL as a cutoff value determined using receiver operating characteristic curve analysis) exhibited a higher prevalence of sarcopenia compared with the low-ferritin group (37.3% vs. 11.3%, p = 0.001). Furthermore, serum ferritin levels were negatively correlated with skeletal muscle mass and skeletal muscle strength, which constitute the components of the sarcopenia diagnostic criteria. Conclusions: Elevated serum ferritin levels were independently associated with sarcopenia in patients undergoing hemodialysis. This finding implies that excessive iron supplementation may contribute to the progression of sarcopenia. Routine evaluation of iron status and careful assessment of the necessity for iron therapy are recommended in this population.

During autophagosome formation, autophagosome-related (Atg) proteins are recruited hierarchically to organize the preautophagosomal structure (PAS). Atg13, which plays a central role in the initial step of PAS formation, consists of two structural regions, the N-terminal HORMA (from Hop1, Rev7, and Mad2) domain and the C-terminal disordered region. The C-terminal disordered region of Atg13, which contains the binding sites for Atg1 and Atg17, is essential for the initiation step in which the Atg1 complex is formed to serve as a scaffold for the PAS. The N-terminal HORMA domain of Atg13 is also essential for autophagy, but its molecular function has not been established. In this study, we searched for interaction partners of the Atg13 HORMA domain and found that it binds Atg9, a multispanning membrane protein that exists on specific cytoplasmic vesicles (Atg9 vesicles). After the Atg1 complex is formed, Atg9 vesicles are recruited to the PAS and become part of the autophagosomal membrane. HORMA domain mutants, which are unable to interact with Atg9, impaired the PAS localization of Atg9 vesicles and exhibited severe defects in starvation-induced autophagy. Thus, Atg9 vesicles are recruited to the PAS via the interaction with the Atg13 HORMA domain. Based on these findings, we propose that the two distinct regions of Atg13 play crucial roles in distinct steps of autophagosome formation: In the first step, Atg13 forms a scaffold for the PAS via its C-terminal disordered region, and subsequently it recruits Atg9 vesicles via its N-terminal HORMA domain. Significance Autophagy is a highly conserved degradative process in eukaryotes. In response to starvation, a number of autophagosome-related (Atg) proteins are recruited, and these proteins govern the process of autophagosome formation. Atg9 vesicles are thought to play an essential role in the nucleation step, but it remains unclear how Atg9 vesicles are localized to the site of autophagosome formation. In this study, we found that Atg9 interacts with the HORMA (from Hop1, Rev7, and Mad2) domain of Atg13. Atg13 mutants lacking the Atg9-binding region fail to recruit Atg9 vesicles to the site of autophagosome formation and exhibit severe defects in autophagy. Thus, the HORMA domain of Atg13 facilitates recruitment of Atg9 vesicles during autophagosome formation. Our studies provide a molecular insight into how Atg9 vesicles become part of the autophagosomal membrane.

Aortic and valvular calcification are well-known risk factors for cardio-cerebrovascular events in patients undergoing hemodialysis. We investigated the clinical impact of an angulated aorto-septal angle as a result of aortic elongation due to aortic calcification on cardio-cerebrovascular outcomes in patients undergoing hemodialysis. We investigated 306 patients (mean age 65.4 years, 68% male) who underwent pre-scheduled routine echocardiography between April and September 2018. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was quantified. We determined aortic and mitral valve calcification scores based on calcified cardiac changes; the aortic and mitral valve scores ranged between 0–9 and 0–6, respectively. The primary endpoint was a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The mean duration of dialysis among the patients in this analysis was 9.6 years. The primary endpoint was observed in 54 patients during the observational period (median 1095 days). Multivariable Cox proportional hazards analyses identified left ventricular ejection fraction (per 10% increase: hazard ratio [HR] 0.67; 95% confidential interval [CI] 0.53–0.84, P = 0.001), left ventricular mass index (per 10 g/m 2 increase: HR 1.14; 95% CI 1.05–1.24, P = 0.001), ASA (per 10 degree increase: HR 0.69; 95% CI 0.54–0.88; P = 0.003), and aortic valve calcification score (HR 1.15; 95% CI 1.04–1.26, P = 0.005) as independent determinants of the primary endpoint. Kaplan-Meier analysis showed a higher incidence of the primary endpoint in patients with ASA <119.4 degrees than those with ASA ≥119.4 degrees (Log-rank P < 0.001). An angulated aorto-septal angle is an independent risk factor for cardio-cerebrovascular events and cardio-cerebrovascular death in patients undergoing hemodialysis.

Autophagy initiates with the assembly of a preautophagosomal structure (PAS), triggered by the yeast Atg1 complex. Ohsumi, Noda and colleagues present the crystal structures of Atg13–Atg1 and Atg13–Atg17, revealing how starvation-induced dephosphorylation of Atg13 triggers formationof the Atg1 complex and PAS assembly. Assembly of the preautophagosomal structure (PAS) is essential for autophagy initiation in yeast. Starvation-induced dephosphorylation of Atg13 is required for the formation of the Atg1–Atg13–Atg17–Atg29–Atg31 complex (Atg1 complex), a prerequisite for PAS assembly. However, molecular details underlying these events have not been established. Here we studied the interactions of yeast Atg13 with Atg1 and Atg17 by X-ray crystallography. Atg13 binds tandem microtubule interacting and transport domains in Atg1, using an elongated helix-loop-helix region. Atg13 also binds Atg17, using a short region, thereby bridging Atg1 and Atg17 and leading to Atg1-complex formation. Dephosphorylation of specific serines in Atg13 enhanced its interaction with not only Atg1 but also Atg17. These observations update the autophagy-initiation model as follows: upon starvation, dephosphorylated Atg13 binds both Atg1 and Atg17, and this promotes PAS assembly and autophagy progression.

Background: The anti-Mycobacterium avium complex (MAC) antibody test measures levels of IgA antibody against the glycopeptidolipid (GPL) core in the bacterial cell walls and is a useful clinical indicator of nontuberculous mycobacterium pulmonary disease (NTM-PD). However, it is not currently possible to diagnose the disease using anti-MAC antibodies alone. Objectives: The study aim was to assess the efficacy of the combination of anti-MAC antibodies and clinical findings for diagnosing potential NTM-PD. Methods: This cross-sectional study included 938 patients tested using the anti-MAC antibody. NTM-PD was diagnosed by multiple positive cultures of the same species in sputum samples. Multivariate logistic regression models were used to identify the clinical factors related to NTM-PD. Results: Overall, 19.6% (184/938) of participants were diagnosed with NTM-PD. In multivariate analysis, positive anti-MAC antibodies, low body mass index, absence of malignancy, and cavity-forming lung lesions were significantly associated with NTM-PD at diagnosis. The positive rates of the anti-MAC antibody test were 79.4% (135/170) for MAC and 55.6% (5/9) for Mycobacterium abscessus complex, respectively. Conclusions: Bronchoscopic examinations should be performed especially in certain types of individuals from whom sputum samples cannot be obtained. Anti-MAC antibodies are also positive in patients other than those harboring MAC, but the rate may be low because of the different components in GPLs.

PURPOSE: The purpose of the present study was to investigate the effect of whole-body cryotherapy (WBC) treatment after exercise on appetite regulation and energy intake. METHODS: Twelve male athletes participated in two trials on different days. In both trials, participants performed high-intensity intermittent exercise. After 10 min following the completion of the exercise, they were exposed to a 3-min WBC treatment (−140 °C, WBC trial) or underwent a rest period (CON trial). Blood samples were collected to assess plasma acylated ghrelin, serum leptin, and other metabolic hormone concentrations. Respiratory gas parameters, skin temperature, and ratings of subjective variables were also measured after exercise. At 30 min post-exercise, energy and macronutrient intake were evaluated during an ad libitum buffet meal test. RESULTS: Although appetite-regulating hormones (acylated ghrelin and leptin) significantly changed with exercise (p = 0.047 for acylated ghrelin and p < 0.001 for leptin), no significant differences were observed between the trials. Energy intake during the buffet meal test was significantly higher in the WBC trial (1371 ± 481 kcal) than the CON trial (1106 ± 452 kcal, p = 0.007). CONCLUSION: Cold exposure using WBC following strenuous exercise increased energy intake in male athletes.

The clinical impact of ABO blood type on cardio-cerebrovascular outcomes in patients undergoing dialysis has not been clarified. A total of 365 hemodialysis patients participated in the current study. The primary endpoint was defined as a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The primary endpoint was observed in 73 patients during a median follow-up period of 1182 days, including 16/149 (11%) with blood type A, 22/81 (27%) with blood type B, 26/99 (26%) with blood type O, and 9/36 (25%) with blood type AB. At baseline, no difference was found in the echocardiographic parameters. Multivariable Cox regression analyses revealed that blood type (type A vs. non-A type; hazard ratio (HR): 0.46, 95% confidence interval (95% CI): 0.26–0.81, p = 0.007), age (per 10-year increase; HR: 1.47, 95% CI: 1.18–1.84), antiplatelet or anticoagulation therapy (HR: 1.91, 95% CI: 1.07–3.41), LVEF (per 10% increase; HR: 0.78, 95% CI: 0.63–0.96), and LV mass index (per 10 g/m2 increase; HR: 1.07, 95% CI: 1.01–1.13) were the independent determinants of the primary endpoint. Kaplan–Meier curves also showed a higher incidence of the primary endpoint in the non-A type than type A (Log-rank p = 0.001). Dialysis patients with blood type A developed cardio-cerebrovascular events more frequently than non-A type patients.

The target of rapamycin (Tor) protein plays central roles in cell growth. Rapamycin inhibits cell growth and promotes cell cycle arrest at G1 (G0). However, little is known about whether Tor is involved in other stages of the cell division cycle. Here we report that the rapamycin-sensitive Tor complex 1 (TORC1) is involved in G2/M transition in S. cerevisiae. Strains carrying a temperature-sensitive allele of KOG1 (kog1-105) encoding an essential component of TORC1, as well as yeast cell treated with rapamycin show mitotic delay with prolonged G2. Overexpression of Cdc5, the yeast polo-like kinase, rescues the growth defect of kog1-105, and in turn, Cdc5 activity is attenuated in kog1-105 cells. The TORC1-Type2A phosphatase pathway mediates nucleocytoplasmic transport of Cdc5, which is prerequisite for its proper localization and function. The C-terminal polo-box domain of Cdc5 has an inhibitory role in nuclear translocation. Taken together, our results indicate a novel function of Tor in the regulation of cell cycle and proliferation.

This paper presents the initial stage of developing an algorithm learning tool for the students of the Information Systems course at Tokyo Tech High School of Science and Technology in Japan. The tool applies the concept of Algorithm Visualization (AV) technology and was used as an aid for learning basic algorithms such as searching and sorting. Two AV types were included in the tool, one with more input options and control and the other with less. Previously proposed AV evaluation properties and the Categories of Algorithm Learning Objectives (CALO) were considered in designing the tool’s evaluation questionnaire. Written tests based on CALO were also designed. Posttest results indicate moderate improvement in the performance of the students. Test results also show that student abilities match some of the algorithm learning objectives. The students who used the AV with more options have a slightly higher gain score average in the posttest compared with those who used the AV with limited control. Overall assessment indicates a positive evaluation of the tool and signifies the students’ preferred AV characteristics. After factor analysis of the evaluation questionnaire, three factors were extracted which correspond to the suggested AV evaluation properties. These results may be used in improving the learning tool and the evaluation questionnaire.