Identification of FAM53C as a cytosolic-anchoring inhibitory binding protein of the kinase DYRK1A

ダウン症・自閉症関連タンパク質キナーゼDYRK1Aの抑制因子の発見 --FAM53Cタンパク質はDYRK1Aに結合して活性を低下させる--. 京都大学プレスリリース. 2023-11-24.The protein kinase DYRK1A encoded in human chromosome 21 is the major contributor to the multiple symptoms observed in Down syndrome patients. In addition, DYRK1A malfunction is associated with various other neurodevelopmental disorders such as autism spectrum disorder. Here, we identified FAM53C with no hitherto known biological function as a novel suppressive binding partner of DYRK1A. FAM53C is bound to the catalytic protein kinase domain of DYRK1A, whereas DCAF7/WDR68, the major DYRK1A-binding protein, binds to the N-terminal domain of DYRK1A. The binding of FAM53C inhibited autophosphorylation activity of DYRK1A and its kinase activity to an exogenous substrate, MAPT/Tau. FAM53C did not bind directly to DCAF7/WDR68, whereas DYRK1A tethered FAM53C and DCAF7/WDR68 by binding concurrently to both of them, forming a tri-protein complex. DYRK1A possesses an NLS and accumulates in the nucleus when overexpressed in cells. Co-expression of FAM53C induced cytoplasmic re-localization of DYRK1A, revealing the cytoplasmic anchoring function of FAM53C to DYRK1A. Moreover, the binding of FAM53C to DYRK1A suppressed the DYRK1A-dependent nuclear localization of DCAF7/WDR68. All the results show that FAM53C binds to DYRK1A, suppresses its kinase activity, and anchors it in the cytoplasm. In addition, FAM53C is bound to the DYRK1A-related kinase DYRK1B with an Hsp90/Cdc37-independent manner. The results explain for the first time why endogenous DYRK1A is distributed in the cytoplasm in normal brain tissue. FAM53C-dependent regulation of the kinase activity and intracellular localization of DYRK1A may play a significant role in gene expression regulation caused by normal and aberrant levels of DYRK1A

Graft Duodenal Perforation due to Internal Hernia after Simultaneous Pancreas-Kidney Transplantation: Report of a Case

Although complications including graft thrombosis, graft pancreatitis, and rejection have been well documented after pancreas transplantation, the occurrence of graft duodenal perforation is uncommon. In this article, we report a case of graft duodenal perforation due to internal hernia after simultaneous pancreas-kidney transplantation (SPK). A patient with type I diabetes mellitus and diabetic nephropathy had undergone SPK from a cadaveric donor. One year later, she was admitted to our hospital for severe lower abdominal pain with preshock status. She was immediately examined by abdominal computed tomography and both peripancreas graft fluid accumulation and severe dilatation of the ileum were detected. On emergency operation, two punched holes located at the graft duodenal side near the suture line and an obstruction of herniated bowel behind the graft pancreas were detected. These holes were repaired and the internal hernia was reduced. However, a control of the intraabdominal infection was very difficult despite intensive treatment with antibiotics and additional abdominal drainage. Finally, a graft pancreatectomy was unavoidably required. When complications, including symptomatic intraabdominal infection, require re-laparotomy after pancreas transplantation, the therapeutic focus should be switched from salvaging the graft to the preservation of life

Adherence to behavior changes for COVID-19 prevention in communitydwelling older adults

Background: Preventing coronavirus disease 2019 (COVID-19) in older people is an important public health issue. The purpose of this study was to investigate the relationship between the level of fear regarding COVID-19 and adherence to COVID-19 prevention measures among community-dwelling older adults.Methods: This study was a cross-sectional survey conducted from July 15 to August 19, 2020, in 127 community-dwelling older adults ≥65 years old in Japan. A questionnaire including participants’ basic attributes (age, sex, body mass index, and family structure), levels of fear regarding COVID-19, increasing adherence to four behaviors (restrictions on going out, maintaining physical distancing, wearing masks, and washing hands) for COVID-19 prevention, and its stress levels was used. We calculated the relationship between the level of fear of COVID-19 and the level of each behavioral change using Spearman’s correlation coefficient (rs).Results: About 95% of older adults displayed fear of COVID-19. Rates of adherence to all four COVID-19 prevention measures increased to approximately 80–95%. However, about 40–55% of older adults were stressed by all behavior modifications except washing hands. The increasing level of fear regarding COVID-19 correlated positively with decreasing frequency of going out (rs=0.280, p=0.001) and increasing frequency of washing hands (rs=0.336, p<0.001).Conclusion: The behavioral changes of COVID-19 prevention measures in community-dwelling older people were excellent with increasing adherence rates. While such high adherence rates may increase the preventive effect in community-dwelling older people, the new lifestyle during the COVID-19 epidemic may cause frailty due to restrictions on going out and stress regarding behavior modifications

Dual-single photon emission computed tomography and contrast-enhanced magnetic resonance imaging to evaluate dissimilar features of apical hypertrophic cardiomyopathy

Apical hypertrophic cardiomyopathy (HCM) is an uncommon variant of HCM characterized by hypertrophy located in the left ventricular apex that occurs at a rate of about 30% in the Japanese population. Although the prognosis of most patients with apical HCM is relatively benign, it can be poor if apical left ventricular aneurysms develop. However, the mechanism of aneurysmal formation is unclear. We describe two patients with apical HCM and dissimilar findings in 201Thallous chloride (201TlCl) and 123I-betamethyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) dual single-photon emission computed tomography (dual-SPECT), but no myocardial fibrosis on contrast-enhanced magnetic resonance images (MRI). One had apparently normal myocardial perfusion and metabolism, whereas the other had exercise-induced myocardial ischemia and impaired myocardial metabolism. These findings indicated that even apical HCM without myocardial fibrosis is pathophysiologically heterogeneous. Apical HCM has been evaluated by either dual-SPECT or cardiac MRI, but not by both. Thus, a combination of imaging modalities is apparently essential for elucidating the pathophysiology of apical HCM. These dissimilar findings in dual-SPECT might be important in identifying patients with apical HCM who are at high risk of forming aneurysms. (Cardiol J 2010; 17, 3: 306-311

低インスリン血症は、非糖尿病急性非代償性心不全患者において、全死亡、心血管死の独立した予後予測因子である

Background Insulin beneficially affects myocardial functions during myocardial ischemia. It increases glucose-derived ATP production, decreases oxygen consumption, suppresses apoptosis of cardiomyocytes, and promotes the survival of cardiomyocytes. Patients with chronic heart failure generally have high insulin resistance, which is correlated with poor outcomes. The role of insulin in acute decompensated heart failure (ADHF) remains unclear. This study aimed to investigate the prognostic value of serum insulin level at the time of admission for long-term outcomes in patients with ADHF. Methods and Results We enrolled 1074 consecutive patients who were admitted to our department for ADHF. Of these 1074 patients, we studied the impact of insulin on the prognosis of ADHF in 241 patients without diabetes mellitus. The patients were divided into groups according to low, intermediate, and high tertiles of serum insulin levels. Primary end points were all-cause death and cardiovascular death. During a mean follow-up of 21.8 months, 71 all-cause deaths and 38 cardiovascular deaths occurred. Kaplan-Meier analysis showed that all-cause and cardiovascular mortality was significantly higher in the low-insulin group than those in the intermediate- and high-insulin groups (log-rank P=0.0046 and P=0.038, respectively). Moreover, according to the multivariable analysis, low serum insulin was an independent predictor of all-cause and cardiovascular mortality (hazard ratio, 2.37 [95% CI, 1.24-4.65; P=0.009] and 2.94 [95% CI, 1.12-8.19; P=0.028], respectively). Conclusions Low serum insulin levels were associated with increased risk of all-cause and cardiovascular death in ADHF patients without diabetes mellitus.博士（医学）・甲第808号・令和4年3月15日© 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License(https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

日本における非代償性急性心不全患者の30日および90日以内の心不全再入院の発生率と臨床的意義 : NARA-HF研究より

Background: Countermeasure development for early rehospitalization for heart failure (re-HHF) is an urgent and important issue in Western countries and Japan.Methods and Results:Of 1,074 consecutive NARA-HF study participants with acute decompensated HF admitted to hospital as an emergency between January 2007 and December 2016, we excluded 291 without follow-up data, who died in hospital, or who had previous HF-related hospitalizations, leaving 783 in the analysis. During the median follow-up period of 895 days, 241 patients were re-admitted for HF. The incidence of re-HHF was the highest within the first 30 days of discharge (3.3% [26 patients]) and remained high until 90 days, after which it decreased sharply. Within 90 days of discharge, 63 (8.0%) patients were re-admitted. Kaplan-Meier analysis revealed that patients with 90-day re-HHF had worse prognoses than those without 90-day re-HHF in terms of all-cause death (hazard ratio [HR] 2.321, 95% confidence interval [CI] 1.654-3.174; P<0.001) and cardiovascular death (HR 3.396, 95% CI 2.153-5.145; P<0.001). Multivariate analysis indicated that only male sex was an independent predictor of 90-day re-HHF. Conclusions: The incidence of early re-HHF was lower in Japan than in Western countries. Its predictors are not related to the clinical factors of HF, indicating that a new comprehensive approach might be needed to prevent early re-HHF.博士（医学）・甲第735号・令和2年3月16日日本循環器学会の許諾を得て登録（2020年9月2日付）ジャーナル公式サイト（日本循環器学会HP内）：https://www.j-circ.or.jp/journal/公開サイト（J-STAGE）：https://www.jstage.jst.go.jp/browse/circj

急性心不全における退院時の尿素窒素分画排泄率の予後判定への有用性

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long-term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post-discharge all-cause death. Patients were divided into two groups according to a FEUN cut-off value of 35%, commonly used in pre-renal failure. The FEUN <35% (low-FEUN) group included 224 patients (48.1%), and the all-cause mortality rate for the total cohort was 37.1%. The log-rank test revealed that the low-FEUN group had a significantly higher rate of all-cause death compared to the FEUN equal to or greater than 35% (high-FEUN) group (P<0.001). Multivariate Cox proportional hazards model analysis revealed that low-FEUN was associated with post-discharge all-cause death, independently of other heart failure risk factors (hazard ratio, 1.467; 95% CI, 1.030-2.088, P=0.033). The risk of low-FEUN compared to high-FEUN in post-discharge all-cause death was consistent across all subgroups; however, the effects tended to be modified by renal function (threshold: 60 mL/min/1.73 m2, interaction P=0.069). Conclusions Our study suggests that FEUN may be a novel surrogate marker of volume status in patients with ADHF requiring diuretics.博士（医学）・甲第814号・令和4年3月15日Copyright © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made