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Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09–0.19) for MCD, 0.33 (0.23–0.40) for FSGS, and 0.20 (0.14–0.30) for MN. FENa were 0.24 (0.09–0.68), 1.03 (0.50–2.14), and 0.78 (0.41–1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97–3.81] and HR 1.93 [95% CI 1.46–2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical significance of body weight changes on kidney outcomes among individuals with diabetes using sodium–glucose cotransporter‐2 (SGLT2) inhibitors. Materials and Methods: This is a retrospective cohort study using a nationwide epidemiological database, and we conducted an analysis involving 11 569 individuals with diabetes who were newly prescribed SGLT2 inhibitors. The main outcome was the rate of decline in estimated glomerular filtration rate (eGFR), determined through a linear mixed‐effects model with an unstructured covariance structure. Results: The median age of the patients was 52 (Q1–Q3: 47–58) years, and the median fasting plasma glucose and glycated haemoglobin (HbA1c) levels were 144 (Q1–Q3: 124–175) mg/dL and 7.4 (Q1–Q3: 6.8–8.3)%, respectively. The median estimated eGFR was 77.7 (Q1–Q3: 67.2–89.1) mL/min/1.73 m2. The median follow‐up period was 1.7 (Q1–Q3: 1.0–2.6) years. Participants were stratified into three groups based on the body mass index change rate tertiles between baseline and 1 year after (tertile 1: <−4.55%, tertile 2: −4.55% to −1.43%, tertile 3: >−1.43%). The annual change in eGFR was −0.78 (−0.94 to −0.63) mL/min/1.73 m2 in tertile 1, −0.95 (−1.09 to −0.81) mL/min/1.73 m2 in tertile 2, and −1.65 mL/min/1.73 m2 (−1.84 to −1.47) in tertile 3 (pinteraction < 0.001). A variety of sensitivity analyses confirmed the relationship between the 1‐year body mass index decrease and favourable kidney outcomes after SGLT2 inhibitor administration. Conclusions: Our analysis of a nationwide epidemiological cohort revealed that kidney outcomes following the initiation of SGLT2 inhibitors would be more favourable, with greater body weight loss observed after the initiation of SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

AgHST1 and AgHST3 genes encode sirtuins that are NAD+-dependent protein deacetylases. According to previous reports, their disruption leads to the overproduction of riboflavin in Ashbya gossypii. In this study, we investigated the potential causes of riboflavin overproduction in the AgHST1Δ and AgHST3Δ mutant strains of A. gossypii. The generation of reactive oxygen species was increasd in the mutants compared to in WT. Additionally, membrane potential was lower in the mutants than in WT. The NAD+/NADH ratio in AgHST1Δ mutant strain was lower than that in WT; however, the NAD+/NADH ratio in AgHST3Δ was slightly higher than that in WT. AgHST1Δ mutant strain was more sensitive to high temperatures and hydroxyurea treatment than WT or AgHST3Δ. Expression of the AgGLR1 gene, encoding glutathione reductase, was substantially decreased in AgHST1Δ and AgHST3Δ mutant strains. The addition of N-acetyl-L-cysteine, an antioxidant, suppressed the riboflavin production in the mutants, indicating that it was induced by oxidative stress. Therefore, high oxidative stress resulting from the disruption of sirtuin genes induces riboflavin overproduction in AgHST1Δ and AgHST3Δ mutant strains. This study established that oxidative stress is an important trigger for riboflavin overproduction in sirtuin gene-disrupted mutant strains of A. gossypii and helped to elucidate the mechanism of riboflavin production in A. gossypii. [ABSTRACT FROM AUTHOR]

Background: Exit-site infection (ESI) is a common recurring complication in patients undergoing peritoneal dialysis (PD). Sucrose and povidone–iodine (SPI) mixtures, antimicrobial ointments that promote wound healing, have been used for the treatment of ulcers and burns, but their efficacy in exit–site care is still unclear. Methods: This single-center retrospective observational study included patients who underwent PD between May 2010 and June 2022 and presented with episodes of ESI. Patients were divided into SPI and non-SPI groups and followed up from initial ESI onset until PD cessation, death, transfer to another facility, or June 2023. Results: Among the 82 patients (mean age 62, [54–72] years), 23 were treated with SPI. The median follow-up duration was 39 months (range, 14–64), with an overall ESI incidence of 0.70 episodes per patient-year. Additionally, 43.1% of second and 25.6% of third ESI were caused by the same pathogen as the first. The log-rank test demonstrated significantly better second and third ESI-free survival in the SPI group than that in the non-SPI group (p < 0.01 and p < 0.01, respectively). In a Cox regression analysis, adjusting for potential confounders, SPI use was a significant predictor of decreased second and third ESI episodes (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10–0.52 and HR, 0.22; 95%CI, 0.07–0.73, respectively). Conclusions: Our results showed that the use of SPI may be a promising option for preventing the incidence of ESI in patients with PD. Trial registration: This study was approved by the Keio University School of Medicine Ethics Committee (approval number 20231078) on August 28, 2023. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Aims Phrenic nerve injury (PNI) is the most common complication during cryoballoon ablation. Currently, two cryoballoon systems are available, yet the difference is unclear. We sought to compare the acute procedural efficacy and safety of the two cryoballoons. Methods This prospective observational study consisted of 2,555 consecutive atrial fibrillation (AF) patients undergoing pulmonary vein isolation (PVI) using either conventional (Arctic Front Advance) (AFA-CB) or novel cryoballoons (POLARx) (POLARx-CB) at 19 centers between January 2022 and October 2023. Results Among 2,555 patients (68.8 ± 10.9 years, 1,740 men, paroxysmal AF[PAF] 1,670 patients), PVIs were performed by the AFA-CB and POLARx-CB in 1,358 and 1,197 patients, respectively. Touch-up ablation was required in 299(11.7%) patients. The touch-up rate was significantly lower for POLARx-CB than AFA-CB (9.5% vs. 13.6%, p = 0.002), especially for right inferior PVs (RIPVs). The touch-up rate was significantly lower for PAF than non-PAF (8.8% vs. 17.2%, P < 0.001) and was similar between the two cryoballoons in non-PAF patients. Right PNI occurred in 64(2.5%) patients and 22(0.9%) were symptomatic. It occurred during the right superior PV (RSPV) ablation in 39(1.5%) patients. The incidence was significantly higher for POLARx-CB than AFA-CB (3.8% vs. 1.3%, P < 0.001) as was the incidence of symptomatic PNI (1.7% vs. 0.1%, P < 0.001). The difference was significant during RSPV (2.5% vs. 0.7%, P < 0.001) but not RIPV ablation. The PNI recovered more quickly for the AFA-CB than POLARx-CB. Conclusions Our study demonstrated a significantly higher incidence of right PNI and lower touch-up rate for the POLARx-CB than AFA-CB in the real-world clinical practice. [ABSTRACT FROM AUTHOR]

Two molecular structures of a complex C26H16Cl2N2Pd (1) with a benzene hemisolvate (1•0.5C6H6) and a complex C34H20Cl2N2Pd (2) revealed similar conformations: one side of the arylethynyl group is flat to the bipyridine plane while the other side of the arylethynyl group is highly twisted to the plane because rhomb-like dimer fragments are formed between respective two complexes through CH⋯π interactions. The Hirshfeld surface analysis indicates that the most important contributions for the crystal packing of 1 are from H⋯H (33.6%), C⋯H/H⋯C (28.3%), Cl⋯H/H⋯Cl (17.8%), and C⋯C (10.6%) interactions and those of 2 are from H⋯H (36.5%), C⋯H/H⋯C (26.0%), Cl⋯H/H⋯Cl (15.7%), and C⋯C (12.3%) interactions, indicating the remarkable CH⋯π and electron distribution of molecules by Cl ions. The benzene solvate molecule of 1•0.5C6H6 performs to fill the internal space instead of the naphthyl group. Detailed crystallographic and DFT studies were performed to understand the molecular structures and the corresponding supramolecular associations. [ABSTRACT FROM AUTHOR]

Context Renal sinus fat (RSF) accumulation is associated with cardiometabolic diseases, such as obesity, diabetes, hypertension, and chronic kidney disease. However, clinical implications of RSF in primary aldosteronism (PA) remain unclear. Objective We aimed to investigate relationships between RSF volume and key cardiometabolic and renin-angiotensin system (RAS) parameters in PA patients and clarify the differences in these relationships between unilateral and bilateral subtypes. Methods We analyzed data obtained from well-characterized PA patients that involved 45 unilateral (median age: 52 years; 42.2% men) and 92 bilateral patients (51 years; 42.4% men). Results RSF volume normalized by renal volume (RSF%) was greater in the unilateral group than in the bilateral group (P <.05). RSF% was greater in men than in women (P <.05). RSF% positively correlated with parameters related to cardiometabolic risk, including age, body mass index, visceral fat volume, creatinine, triglycerides/high-density lipoprotein cholesterol ratio, uric acid, fasting glucose, and C-reactive protein regardless of PA subtypes (all P <.05). Intriguingly, RSF% positively correlated with plasma aldosterone concentration (PAC), aldosterone-to-renin ratio, and intact parathyroid hormone (iPTH) (all P <.05) in bilateral patients but did not correlate with RAS parameters and even showed an opposite trend in unilateral patients. In subgroup analyses by sex, these distinctions became more evident in women. After adjustment for potential confounders, RSF% remained positively correlated with PAC and iPTH in bilateral patients. Conclusion Our results indicate that RSF accumulation is involved in cardiometabolic dysfunction associated with PA. However, there were distinct correlations between RSF volume and RAS parameters according to sex and PA subtypes. [ABSTRACT FROM AUTHOR]

Pre-emptive kidney transplantation (PEKT), i.e., transplantation performed before initiation of maintenance dialysis, is considered an ideal renal replacement therapy because there is no exposure to long-term dialysis therapy. Therefore, we summarized advantages/disadvantages of PEKT to assist in deciding whether kidney transplantation should be performed pre-emptively. This study was registered with PROSPERO, CRD42021269163. Observational studies comparing clinical outcomes between PEKT and non-PEKT were included; those involving only pediatric recipients or simultaneous multi-organ transplantations were excluded. The PubMed/MEDLINE, Cochrane Library, and Ichushi-Web databases were searched on 1 August 2021. Studies were pooled using the generic inverse-variance method with random effects model, and risk of bias was assessed using ROBINS-I. Seventy-six studies were included in the systematic review (sample size, 23–121,853; enrollment year, 1968–2019). PEKT patients had lower all-cause mortality (adjusted HR: 0.78 [95% CI 0.66–0.92]), and lower death-censored graft failure (0.81 [0.67–0.98]). Unadjusted RRs for the following outcomes were comparable between the two patient groups: cardiovascular disease, 0.90 (0.58–1.40); biopsy-proven acute rejection, 0.75 (0.55–1.03); cytomegalovirus infection, 1.04 (0.85–1.29); and urinary tract infection, 0.89 (0.61–1.29). Mean differences in post-transplant QOL score were comparable in both groups. The certainty of evidence for mortality and graft failure was moderate and that for other outcomes was very low following the GRADE classification. The present meta-analysis shows the potential benefits of PEKT, especially regarding patient and graft survival, and therefore PEKT is recommended for adults with end-stage kidney disease. [ABSTRACT FROM AUTHOR]

It is difficult to clarify the activity of swallowing-related muscles and the movement of organs. To represent the relationship between muscle activity and organ movement, a numerical simulator that reflects muscle contraction is necessary. However, no continuum organ models can identify and reflect muscle activity. In this study, a novel method was developed for obtaining the time change in the activities of all muscles involved in hyoid excursion. An organ model was developed based on four-dimensional computed tomography (4DCT) images acquired using a 320-column area detector CT, and the organ movement was analysed using a particle method. To identify the muscle activity, an evaluation function was defined and calculated considering the errors of velocities and positions of the hyoid bone, and the muscle activities to minimise the evaluation function were calculated using gradient descent. The results showed that the hyoid movement represented by the simulation model and the objective movement obtained from 4DCT images were in good agreement. The identified muscle activities were discussed through a comparison with the literature on electromyography measurements and the results of simulations using other methods. The proposed continuum organ model with muscles was considered able to clarify both muscle activity and organ movement. [ABSTRACT FROM AUTHOR]

Background: Previously, we isolated a riboflavin-overproducing Ashbya gossypii mutant (MT strain) and discovered some mutations in genes encoding flavoproteins. Here, we analyzed the riboflavin production in the MT strain, in view of flavoproteins, which are localized in the mitochondria. Results: In the MT strain, mitochondrial membrane potential was decreased compared with that in the wild type (WT) strain, resulting in increased reactive oxygen species. Additionally, diphenyleneiodonium (DPI), a universal flavoprotein inhibitor, inhibited riboflavin production in the WT and MT strains at 50 µM, indicating that some flavoproteins may be involved in riboflavin production. The specific activities of NADH and succinate dehydrogenases were significantly reduced in the MT strain, but those of glutathione reductase and acetohydroxyacid synthase were increased by 4.9- and 25-fold, respectively. By contrast, the expression of AgGLR1 gene encoding glutathione reductase was increased by 32-fold in the MT strain. However, that of AgILV2 gene encoding the catalytic subunit of acetohydroxyacid synthase was increased by only 2.1-fold. These results suggest that in the MT strain, acetohydroxyacid synthase, which catalyzes the first reaction of branched-chain amino acid biosynthesis, is vital for riboflavin production. The addition of valine, which is a feedback inhibitor of acetohydroxyacid synthase, to a minimal medium inhibited the growth of the MT strain and its riboflavin production. In addition, the addition of branched-chain amino acids enhanced the growth and riboflavin production in the MT strain. Conclusion: The significance of branched-chain amino acids for riboflavin production in A. gossypii is reported and this study opens a novel approach for the effective production of riboflavin in A. gossypii. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation. [ABSTRACT FROM AUTHOR]

Background Contrast-enhanced computed tomography (CT) is commonly used to diagnose pulmonary embolism (PE). However, a history of iodine contrast allergy presents a dilemma in the management of patients with PE. As an alternative approach, X-ray fluoroscopic video analysis has been recently reported to be useful in diagnosing PE. Case summary A 78-year-old man with dyspnoea of 1-month duration visited our hospital. His oxygen saturation was 89%, and echocardiography demonstrated right heart strain. We could not perform contrast-enhanced CT because the patient had a history of contrast allergy and refused to undergo premedicated contrast CT with anti-histamine and/or corticosteroid. Therefore, a video analysis of pulmonary circulation using dynamic chest X-ray (DCR) was performed. The reconstructed pseudo-colour video showed defects of pulmonary circulation in both lung areas. We diagnosed PE and started anticoagulant therapy. Multiple segmental defects were also observed in pulmonary perfusion scintigraphy on Day 3, which confirmed the diagnosis of PE. He was discharged on Day 9, and an improvement of the pulmonary circulation as assessed with DCR was observed. He had no symptoms at the last follow-up visit at 1 year after discharge. Discussion We describe the successful visualization of PE using DCR in a patient with iodine contrast allergy. [ABSTRACT FROM AUTHOR]

Patients with end-stage renal disease are less likely to choose peritoneal dialysis (PD) as renal replacement therapy (RRT). The reasons for this biased selection are still poorly understood. In this study, we evaluated the effect of the timing of RRT education on PD selection. This single-center retrospective observational study included patients who initiated maintenance dialysis at our hospital between April 2014 and July 2021. A logistic regression analysis was performed to investigate the association of RRT education timing with PD selection. Among the 355 participants (median age [IQR] 70 (59–79) years; 28.7% female), 53 patients (14.9%) and 302 patients (85.1%) selected PD and hemodialysis, respectively. Multivariate analysis demonstrated that high estimated glomerular filtration (eGFR) at RRT education positively predicted PD selection (p < 0.05), whereas old age (p < 0.01) and high Charlson comorbidity index (p < 0.05) were negative predictors of PD selection. Female sex (p = 0.44), welfare public assistance (p = 0.78), living alone (p = 0.25), high geriatric nutritional risk index (p = 0.10) and high eGFR at first visit to the nephrology department (p = 0.83) were not significantly associated with PD selection. Late RRT education could increase the biased selection of dialysis modality. [ABSTRACT FROM AUTHOR]

There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin–creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-β-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis. [ABSTRACT FROM AUTHOR]

Aims: Effects of a proteasome inhibitor, MG‐132, on the riboflavin production in Ashbya gossypii were investigated to elucidate the relationship of the riboflavin production with flavoprotein homeostasis. Methods and Results: The addition of MG‐132 to the liquid medium reduced the specific riboflavin production by 79% in A. gossypii at 25 μM after 24 h. The addition of the inhibitor also caused the accumulation of reactive oxygen species and ubiquitinated proteins. These results indicated that MG‐132 works in A. gossypii without any genetic engineering and reduces riboflavin production. In the presence of 25 μM MG‐132, specific NADH dehydrogenase activity was increased by 1.4‐fold compared to DMSO, but specific succinate dehydrogenase (SDH) activity was decreased to 52% compared to DMSO. Additionally, the amount of AgSdh1p (ACR052Wp) was also reduced. Specific riboflavin production was reduced to 22% when 20 mM malonate, a SDH inhibitor, was added to the culture medium. The riboflavin production in heterozygous AgSDH1 gene‐disrupted mutant (AgSDH1−/+) was reduced to 63% compared to that in wild type. Conclusions: MG‐132 suppresses the riboflavin production and SDH activity in A. gossypii. SDH is one of the flavoproteins involved in the riboflavin production in A. gossypii. Significance and Impact of the Study: This study shows that MG‐132 has a negative influence on the riboflavin production and SDH activity in A. gossypii and leads to the elucidation of the connection of the riboflavin production with flavoproteins. [ABSTRACT FROM AUTHOR]

This paper presents a method to reduce the computational time required to solve shape optimization problems. A volume minimization problem under the mean compliance constraint is chosen as an example of the shape optimization problem. To solve this problem, an iterative algorithm based on the H 1 gradient method is considered as a conventional approach. In this study, we attempt to use a method of model order reduction for solving the linear elasticity problem based on the idea by Karhunen-Loève expansion (KLE). We consider the displacements obtained by the conventional method to be sampling data of a random variable; the orthonormal bases of KLE are defined as eigenfunctions of the eigenvalue problem obtained as the optimality condition of the variance maximization problem for the random variable. The feasibility of the proposed method is illustrated by testing the numerical scheme to a linear elastic body of the connecting rod type. [ABSTRACT FROM AUTHOR]

Using a hedonic regression approach, this research aims to identify what factors affected land price fluctuations in Fukushima Prefecture following the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Station accident in 2011. In this paper, taking a long-term perspective, the analysis focuses on Iwaki City in Fukushima, where the real estate market behaved unexpectedly following the two catastrophic events, and land price fluctuation rates were rising abnormally. Results based on analysis of data for eight-year indicate the following: The impact of radiation air dose rate and distance from the nuclear power plant on land price fluctuation rate changed significantly from the fourth year after the disaster. Being located in a reconstruction base area had a negative impact on land price fluctuation rate, while access to sewers and city gas had a positive impact. It appears that the stigma associated with the accident had a little disappeared after approximately four years. [ABSTRACT FROM AUTHOR]

This study focuses on sirtuins, which catalyze the reaction of NAD+-dependent protein deacetylase, for riboflavin production in A. gossypii. Nicotinamide, a known inhibitor of sirtuin, made the color of A. gossypii colonies appear a deeper yellow at 5 mM. A. gossypii has 4 sirtuin genes (AgHST1, AgHST2, AgHST3, AgHST4) and these were disrupted to investigate the role of sirtuins in riboflavin production in A. gossypii. AgHST1∆, AgHST3∆, and AgHST4∆ strains were obtained, but AgHST2∆ was not. The AgHST1∆ and AgHST3∆ strains produced approximately 4.3- and 2.9-fold higher amounts of riboflavin than the WT strain. The AgHST3∆ strain showed a lower human sirtuin 6 (SIRT6)-like activity than the WT strain and only in the AgHST3∆ strain was a higher amount of acetylation of histone H3 K9 and K56 (H3K9ac and H3K56ac) observed compared to the WT strain. These results indicate that AgHst3 is SIRT6-like sirtuin in A. gossypii and the activity has an influence on the riboflavin production in A. gossypii. In the presence of 5 mM hydroxyurea and 50 µM camptothecin, which causes DNA damage, especially double-strand DNA breaks, the color of the WT strain colonies turned a deeper yellow. Additionally, hydroxyurea significantly led to the production of approximately 1.5 higher amounts of riboflavin and camptothecin also enhanced the riboflavin production even through the significant difference was not detected. Camptothecin tended to increase the amount of H3K56ac, but the amount of H3K56ac was not increased by hydroxyurea treatment. This study revealed that AgHst1 and AgHst3 are involved in the riboflavin production in A. gossypii through NAD metabolism and the acetylation of H3, respectively. This new finding is a step toward clarifying the role of sirtuins in riboflavin over-production by A. gossypii. Key points • Nicotinamide enhanced the riboflavin production in Ashbya gossypii. • Disruption of AgHST1 or AgHST3 gene also enhanced the riboflavin production in Ashbya gossypii. • Acetylation of H3K56 led to the enhancement of the riboflavin production in Ashbya gossypii. [ABSTRACT FROM AUTHOR]

Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease's complicated pathogenic mechanism, activation of the advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor-deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD. [ABSTRACT FROM AUTHOR]

Laboratory tests of adolescents are often interpreted by using reference intervals derived from adults, even though these populations differ in their physical and physiologic characteristics and disease susceptibility. Therefore, to examine the distribution of laboratory values specific for adolescents, we analyzed hematologic and biochemical measurements obtained from 12,023 healthy Japanese adolescents (ages 15 through 18 years; male, 9165; female, 2858) during 2009 through 2018. Distributions were shown as medians with 95% (2.5th and 97.5th percentiles) of values and were compared with those from previous studies that examined similar Asian populations. There were some differences between hematologic parameters, serum creatinine and uric acid concentration, and lipid levels of Japanese adults and adolescents. In comparison with other Asian populations, the distributions of serum uric acid and high-density–lipoprotein cholesterol in the present study were slightly higher than those in the other studies. Although further research is need, the distributions of hematologic and biochemical tests in adolescents may have the potential to facilitate the early identification and management of disease in this population. [ABSTRACT FROM AUTHOR]

The aim of the study is to analyze the stability of the energetic particle modes (EPM) and Alfven Eigenmodes (AE) in Helitron J and LHD plasma if the electron cyclotron current drive (ECCD) is applied. The analysis is performed using the code FAR3d that solves the reduced MHD equations describing the linear evolution of the poloidal flux and the toroidal component of the vorticity in a full 3D system, coupled with equations of density and parallel velocity moments for the energetic particle (EP) species, including the effect of the acoustic modes. The Landau damping and resonant destabilization effects are added via the closure relation. The simulation results show that the n = 1 EPM and n = 2 global AE (GAE) in Heliotron J plasma can be stabilized if the magnetic shear is enhanced at the plasma periphery by an increase (co-ECCD injection) or decrease (ctr-ECCD injection) of the rotational transform at the magnetic axis (). In the ctr-ECCD simulations, the EPM/AE growth rate decreases only below a given , similar to the ECCD intensity threshold observed in the experiments. In addition, ctr-ECCD simulations show an enhancement of the continuum damping. The simulations of the LHD discharges with ctr-ECCD injection indicate the stabilization of the n = 1 EPM, n = 2 toroidal AE (TAE) and n = 3 TAE, caused by an enhancement of the continuum damping in the inner plasma leading to a higher EP β threshold with respect to the co- and no-ECCD simulations. [ABSTRACT FROM AUTHOR]

The exterior Bernoulli problem is rephrased into a shape optimization problem using a new type of objective function called the Dirichlet-data-gap cost function which measures the L 2 -distance between the Dirichlet data of two state functions. The first-order shape derivative of the cost function is explicitly determined via the chain rule approach. Using the same technique, the second-order shape derivative of the cost function at the solution of the free boundary problem is also computed. The gradient and Hessian informations are then used to formulate an efficient second-order gradient-based descent algorithm to numerically solve the minimization problem. The feasibility of the proposed method is illustrated through various numerical examples. [ABSTRACT FROM AUTHOR]

The present paper describes a shape optimization procedure for designing running shoes, focusing on two mechanical properties, namely, the shock absorption and the stability keeping the right posture. These properties are evaluated from two deformations of a sole at characteristic timings during running motion. We define approximate planes for the deformations of sole's upper boundary by least squares method. Using the planes, we choose the tilt angle in the shoe width direction at the mid stance phase of running motion as an objective function representing the stability, and the sunk amount at the contact phase of running motion as a constraint function representing the shock absorption. We assume that the sole is a bonded structure of soft and hard hyper-elastic materials, and the bonding and side boundaries are variable. In this study, we apply the formulation of nonparametric shape optimization to the sole considering finite deformation and contact condition of the bottom of the sole with the ground. Shape derivatives of the cost (objective and constraint) functions are obtained using the adjoint method. The H1 gradient method using these shape derivatives is applied as an iterative algorithm. To solve this optimization problem, we developed a computer program combined with some commercial softwares. The validity of the optimization method is confirmed by numerical examples. [ABSTRACT FROM AUTHOR]

Background Coronary artery fistulas are rare and most commonly asymptomatic; however, they can become enlarged and rupture in some cases. Case summary We report a case of a 51-year-old woman who was brought to our hospital unconscious in an ambulance. Cardiac tamponade caused by the rupture of an aneurismal coronary-pulmonary artery fistula (CPAF) was detected by contrast-enhanced computed tomography and confirmed by invasive coronary angiography. Due to prompt diagnosis and subsequent surgical intervention, the patient's condition was rapidly improved, and she was discharged from the hospital. Discussion Coronary-pulmonary artery fistula aneurysm rupture requires rapid diagnosis and treatment, and thus, in cases with cardiac tamponade and coronary aneurysm, CPAF aneurysm rupture should be considered. [ABSTRACT FROM AUTHOR]

Background: Ashbya gossypii naturally overproduces riboflavin and has been utilized for industrial riboflavin production. To improve riboflavin production, various approaches have been developed. In this study, to investigate the change in metabolism of a riboflavin-overproducing mutant, namely, the W122032 strain (MT strain) that was isolated by disparity mutagenesis, genomic analysis was carried out. Results: In the genomic analysis, 33 homozygous and 1377 heterozygous mutations in the coding sequences of the genome of MT strain were detected. Among these heterozygous mutations, the proportion of mutated reads in each gene was different, ranging from 21 to 75%. These results suggest that the MT strain may contain multiple nuclei containing different mutations. We tried to isolate haploid spores from the MT strain to prove its ploidy, but this strain did not sporulate under the conditions tested. Heterozygous mutations detected in genes which are important for sporulation likely contribute to the sporulation deficiency of the MT strain. Homozygous and heterozygous mutations were found in genes encoding enzymes involved in amino acid metabolism, the TCA cycle, purine and pyrimidine nucleotide metabolism and the DNA mismatch repair system. One homozygous mutation in AgILV2 gene encoding acetohydroxyacid synthase, which is also a flavoprotein in mitochondria, was found. Gene ontology (GO) enrichment analysis showed heterozygous mutations in all 22 DNA helicase genes and genes involved in oxidation-reduction process. Conclusion: This study suggests that oxidative stress and the aging of cells were involved in the riboflavin over-production in A. gossypii riboflavin over-producing mutant and provides new insights into riboflavin production in A. gossypii and the usefulness of disparity mutagenesis for the creation of new types of mutants for metabolic engineering. [ABSTRACT FROM AUTHOR]

The solution to a free boundary problem of Bernoulli type, also known as Alt-Caffarelli problem, is studied via shape optimization techniques. In particular, a novel energy-gap cost functional approach with a state constraint consisting of a Robin condition is proposed as a shape optimization reformulation of the problem. Accordingly, the shape derivative of the cost is explicitly determined, and using the gradient information, a Lagrangian-like method is used to formulate an efficient boundary variation algorithm to numerically solve the minimization problem. The second order shape derivative of the cost is also computed, and through its characterization at the solution of the Bernoulli problem, the ill-posedness of the shape optimization formulation is proved. The analysis of the proposed formulation is completed by addressing the existence of optimal solution of the shape optimization problem and is accomplished by proving the continuity of the solution of the state problems with respect to the domain. The feasibility of the newly proposed method and its comparison with the classical energy-gap type cost functional approach is then presented through various numerical results. The numerical exploration issued in the study also includes results from a second-order optimization procedure based on a Newton-type method for resolving such minimization problem. This computational scheme put forward in the paper utilizes the Hessian information at the optimal solution and thus offers a state-of-the-art numerical approach for solving such free boundary problem via shape optimization setting. [ABSTRACT FROM AUTHOR]

Background: Low birth weight (LBW) is a risk factor for chronic kidney disease (CKD) in later life and is becoming increasingly common in developed countries, including Japan. Furthermore, a serial decrease in birth weight has been associated with an increasing prevalence of CKD stage 2 in male Japanese adolescents. Sex-specific differences affect CKD susceptibility, and the association between birth weight and CKD in women, has not been elucidated. In this study, we investigated the sex-specific effect of LBW on renal function. Methods: Annual cross-sectional data of 2417 Japanese adolescents (males 1736; females 681), aged 15–16 years, were evaluated over 8 years (2007–2014). Results: Over the study period, mean birth weights decreased significantly in males (p < 0.01) and females (p < 0.05). Furthermore, both sexes showed significant decrease in estimated glomerular filtration rates corresponding to the birth weight reduction. The prevalence of CKD stage 2 also increased in males (from 26.0 to 32.4%, p < 0.01) and females (from 6.3 to 18.5%, p < 0.05). The incidence of CKD stage 2 was significantly related to history of LBW (males: odds ratio 1.73; 95% confidence interval 1.06–2.80; p < 0.05; females: odds ratio 3.29; 95% confidence interval 1.25–8.02; p < 0.05). Conclusions: Our data revealed that renal function and birth weight have decreased over time, in healthy Japanese adolescents. In view of the recent declining trend demonstrated by birth weight in Japan, we speculate that the prevalence of CKD might increase in the future. [ABSTRACT FROM AUTHOR]

Hypertension is a global public health issue and the most important preventable cause of cardiovascular diseases. Despite the clinical availability of many antihypertensive drugs, many hypertensive patients have poor medication adherence and blood pressure control due, at least partially, to the asymptomatic and chronic characteristics of hypertension. Immunotherapeutic approaches have the potential to improve medication adherence in hypertension because they induce prolonged therapeutic effects and need a low frequency of administration. The first attempts to reduce blood pressure by using vaccines targeting the renin-angiotensin system were made more than half a century ago; however, at the time, a poor understanding of immunology and the mechanisms of hypertension and a lack of optimal vaccine technologies such as suitable antigen design, proper adjuvants, and effective antigen delivery systems meant that attempts to develop antihypertensive vaccines failed. Recent advances in immunology and vaccinology have provided potential therapeutic immunologic approaches to treat not only infectious diseases but also cancers and other noncommunicable diseases. One important biotechnology that has had a major impact on modern vaccinology is virus-like particle technology, which can efficiently deliver vaccine antigens without the need for artificial adjuvants. A human clinical trial that indicated the effectiveness and safety of a virus-like particle-based antiangiotensin II vaccine marked a turning point in the field of therapeutic antihypertensive vaccines. Here, we review the history of the development of immunotherapies for the treatment of hypertension and discuss the current perspectives in the field. [ABSTRACT FROM AUTHOR]

We propose a new shape optimization formulation of the Bernoulli problem by tracking the Neumann data. The associated state problem is an equivalent formulation of the Bernoulli problem with a Robin condition. We devise an iterative procedure based on a Lagrangian-like approach to numerically solve the minimization problem. The proposed scheme involves the knowledge of the shape gradient which is established through the minimax formulation. We illustrate the feasibility of the proposed method and highlight its advantage over the classical setting of tracking the Neumann data through several numerical examples. [ABSTRACT FROM AUTHOR]

This research aims to explore the regeneration for socio ecological production landscape in seriously environmental damaged rural area through the field survey of prior efforts around the area. In Fukushima, six years have passed since the nuclear accident, and evacuation orders for about 32,000 people living in Namie, Iitate, Tomioka and Yamakiya District of Kawamata, have been lifted by April 2017. However, since the socio ecological production landscape has lost, the lifting of this evacuation order will not lead directly to the return home of residents. The challenge is how to restore people's former life which was based on agriculture and forestry and this research looks into the ways of regenerating the socio ecological production landscape, using interview with local community representatives and field observation. The case study has revealed that the decontamination of the forest is still in a trial stage and the key obstacle is the fact that there are still a few people who wish to return because the future concrete outlook is still not visible. However, a new community has been gradually generating by the approach which a part of farmers resume farming with external researchers and volunteers with interest. It seems to lead to the potential for regeneration of the socioecological production landscape. [ABSTRACT FROM AUTHOR]

We aim to identify the geometry (i.e., the shape and location) of a cavity inside an object through the concept of thermal imaging. More precisely, we present an identification procedure to determine the geometric shape of a cavity with convective boundary condition in a heat-conducting medium using the measured temperature on a part of the surface of the object. The inverse problem of identifying the cavity is resolved by shape optimization techniques, specifically by minimizing a least-squares type cost functional over a set of admissible geometries. The computation of the first-order shape derivative or shape gradient of the cost is carried out through minimax formulation, which is then justified by the Correa-Seeger theorem coupled with function space parametrization technique. We further characterize its boundary integral form using some identities from tangential calculus. Then, we utilize the computed expression for the shape gradient to implement an effective boundary variation algorithm for the numerical resolution of the shape optimization problem. To avoid boundary oscillations or irregular shapes in our approximations, we execute the gradient-based scheme using the H1 gradient method with perimeter regularization. Also, we propose a novel application of the said method in computing the mean curvature of the free boundary appearing in the shape gradient of the cost functional. We illustrate the feasibility of the proposed method by testing the numerical scheme to several cavity identification problems. Additionally, we also give some numerical examples for the case of corrosion detection since its inverse problem interpreted in the framework of electrostatic imaging is closely related to the focused problem. [ABSTRACT FROM AUTHOR]

This study demonstrates the use of Newton method to solve topology optimization problems of density type for linear elastic bodies to minimize the maximum von Mises stress. We use the Kreisselmeier-Steinhauser (KS) function with respect to von Mises stress as a cost function to avoid the non-differentiability of the maximum von Mises stress. For the design variable, we use a function defined in the domain of a linear elastic body with no restriction on the range and assume that a density is given by a sigmoid function of the function of design variable. The main aim of this study involves evaluating the second derivative of the KS function with respect to variation of the design variable and to propose an iterative scheme based on an H1 Newton method as opposed to the H1 gradient method that was presented in previous studies. The effectiveness of the scheme is demonstrated by numerical results for several linear elastic problems. The numerical results show that the speed of the proposed H1 Newton method exceeds that of the H1 gradient method. [ABSTRACT FROM AUTHOR]

This paper presents the numerical results of a shape optimisation problem with regard to delaying the transition of a Navier-Stokes flow field from laminar to turbulent by using the theory developed by Nakazawa and Azegami. The theory was reviewed within the framework of functional analysis and updated with another expression of the shape derivative with respect to the objective function. A computer program was developed with the FreeFEM++. Numerical analyses were performed for two types of problems: a two-dimensional Poiseuille flow field with a sudden expansion and a two-dimensional uniform flow field around an isolated body. From the first example, two local minimum points of symmetric and asymmetric flow fields were determined, and the asymmetric flow field was found to be more stable. With regard to the second example, we reached the local minimum point of an elliptical shape, and infrequently determined a solution converging to an elliptical shape with the bluff in the leeward direction. By comparison, the superiority of the elliptical shape was obvious. [ABSTRACT FROM AUTHOR]

Networked control systems (NCSs) have received much attention in the field of robot teleoperation, telesurgery, and other applications. In an NCS, it is important to compress data transmitted over a limited communication network while preserving the data required for control. We address a quantized feedback system in which the output of a plant is quantized with a variable quantization interval. For such a system, we present a novel optimal quantized feedback control. The proposed approach derives not only an optimal input, but also an optimal quantization interval in the quantizer simultaneously using the model predictive control. The approach also satisfies constraints on the state, input, and quantization interval. The effectiveness of the proposed approach is validated through cart-positioning experiments. [ABSTRACT FROM PUBLISHER]