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Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; (3)H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RT(G)) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G). Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio. Canagliflozin lowered RT(G) and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.

Aims/Introduction Maternal hyperglycemia is associated with heavy for date (HFD) infants. Considering the association between body composition and hyperglycemia, we investigated the changes in maternal body composition and their relationship with HFD infants in pregnant women with diabetes. Materials and Methods Body composition was measured during pregnancy using a bioelectrical impedance analysis system. This retrospective study included 151 pregnant women; 27 women had type 1 diabetes mellitus (DM), 21 had type 2 DM, 101 were diagnosed with gestational DM, and 2 had overt DM. The number of HFD infants was 40. Results In the non‐type 1 DM group, change in fat mass (ΔFM) (P < 0.01) and pre‐pregnancy BMI (P < 0.05) were risk factors for HFD. In the insulin group, ΔFM, pre‐pregnancy BMI, and age (all P < 0.05) were risk factors for HFD. The area under the curve was 0.813 for the predictive model combined with ΔFM and pre‐pregnancy BMI in the non‐type 1 DM group and 0.818 for the model combined with ΔFM, pre‐pregnancy BMI, and age in the insulin group. Conclusions The combination of body composition parameters and clinical data may predict HFD in pregnant women with diabetes. This study evaluated the association between maternal body composition changes and heavy for date infants in diabetic pregnancies. Fat mass gain (ΔFM), pre‐pregnancy BMI, and maternal age were significant predictors of HFD. Combining these factors may help identify high‐risk pregnancies and guide early nutritional interventions.

Cesarean wound healing is influenced by surgeon experience, suture type, and technique. This study utilized a simulation model to quantify these effects. Obstetricians–gynecologists and junior residents performed two-layer continuous suturing on uterine models, forming eight groups based on experience level (expert, novice), suture type (conventional, barbed), and technique (Albert–Lembert, layer-to-layer). The ideal wound condition was defined as that achieved by an expert using barbed sutures and the layer-to-layer technique. Wound characteristics were quantified and compared to this ideal. Experts using barbed sutures in Albert–Lembert suturing showed higher wound density but greater deformation and larger endometrial openings (both P < 0.01). Novices using barbed sutures in Albert–Lembert suturing showed similar wound density but significantly greater deformation and opening (both P < 0.01). Novices using conventional sutures in layer-to-layer suturing showed the lowest wound density and longest suturing time (both P < 0.01). Notably, novices using barbed sutures achieved wound characteristics comparable to experts using conventional sutures in Albert–Lembert suturing and results closer to the ideal in layer-to-layer suturing. These findings establish a quantifiable standard for cesarean suturing and suggest that optimizing suture types and techniques may help compensate for differences in surgical expertise.

Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity. Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats. In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity. Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

Y chromosomes are different from other chromosomes because of a lack of recombination. Until now, complete sequence information of Y chromosomes has been available only for some primates, although considerable information is available for other organisms, e.g., several species of DROSOPHILA: Here, we report the gene organization of the Y chromosome in the dioecious liverwort Marchantia polymorpha and provide a detailed view of a Y chromosome in a haploid organism. On the 10-Mb Y chromosome, 64 genes are identified, 14 of which are detected only in the male genome and are expressed in reproductive organs but not in vegetative thalli, suggesting their participation in male reproductive functions. Another 40 genes on the Y chromosome are expressed in thalli and male sexual organs. At least six of these genes have diverged X-linked counterparts that are in turn expressed in thalli and sexual organs in female plants, suggesting that these X- and Y-linked genes have essential cellular functions. These findings indicate that the Y and X chromosomes share the same ancestral autosome and support the prediction that in a haploid organism essential genes on sex chromosomes are more likely to persist than in a diploid organism.

The study aimed to evaluate visualization-based training's effects on lung auscultation during clinical clerkship (CC) in the Department of Respiratory Medicine on student skills and confidence. The study period was December 2020-November 2021. Overall, 65 students attended a lecture on lung auscultation featuring a simulator (Mr. Lung™). Among them, 35 (visualization group) received additional training wherein they were asked to mentally visualize lung sounds using a graphical visualized lung sounds diagram as an example. All students answered questions on their self-efficacy regarding lung auscultation before and after four weeks of CC. They also took a lung auscultation test with the simulator at the beginning of CC (pre-test) and on the last day of the third week (post-test) (maximum score: 25). We compared the answers in the questionnaire and the test scores between the visualization group and students who only attended the lecture (control group, n = 30). The Wilcoxon signed-rank test and analysis of covariance were used to compare the answers to the questionnaire about confidence in lung auscultation and the scores of the lung auscultation tests before and after the training. Confidence in auscultation of lung sounds significantly increased in both groups (five-point Likert scale, visualization group: pre-questionnaire median 1 [Interquartile range 1] to post-questionnaire 3 [1], p<0.001; control group: 2 [1] to 3 [1], p<0.001) and was significantly higher in the visualization than in the control group. Test scores increased in both groups (visualization group: pre-test 11 [2] to post-test 15 [4], p<0.001; control group: 11 [5] to 14 [4], p<0.001). However, there were no differences between both groups' pre and post-tests scores (p = 0.623). Visualizing lung sounds may increase medical students' confidence in their lung auscultation skills; this may reduce their resistance to lung auscultation and encourage the repeated auscultation necessary to further improve their long-term auscultation abilities.

Background Auscultation is a simple physical examination that provides important clinical information. Many educational materials are available to facilitate students’ understanding of lung auscultation. Some studies and teaching materials have visualized lung sounds as spectrograms. However, their effectiveness as educational tools remains unclear. Accordingly, this study evaluates the effect of auscultation education using lung sound visualization on medical students’ diagnostic skills. Methods Participants were medical students completing their four-week clinical clerkship (CC) in the Department of Respiratory Medicine of Chiba University Hospital. Sixty-three students participated in this study between November 2022 and July 2023. They were divided into two groups: the full-term visualization group ( n  = 31) and the half-term visualization group ( n  = 32). Although both groups were taught lung sound visualization using simple diagrams, there was a two-week difference in the length of exposure. We taught visualization to the full-term visualization group on the first day of the CC, and to the half-term visualization group after the midpoint test. Thus, the full-term visualization group practiced lung auscultations with visualization for four weeks, while the half-term visualization group had two weeks of practice. All the students performed lung auscultation tests with a simulator three times: pre-test at the beginning, midpoint at the end of the second week, and post-test at the end of CC. In addition, they responded to questionnaires regarding lung auscultation at the beginning and end of CC. Results The score gain from baseline in the lung auscultation tests at the midpoint was 0.5; p  = 0.018). The increase in scores at the post-test was not significantly different between the two groups (median full-term, + 3.6; half-term, + 2.3; p  = 0.060). The self-reported confidence, clinical reasoning ability, activity, and frequency of lung auscultation improved in both groups. The questionnaire responses indicated that the students accepted the value of lung sound visualization. Conclusions Differing the duration of exposure to lung sound visualization (two weeks and four weeks) showed no significant difference in medical students’ auscultation skills.

Competitive hydrogen evolution and multiple proton-coupled electron transfer reactions limit photoelectrochemical CO 2 reduction in aqueous electrolyte. Here, oxygen-terminated lightly boron-doped diamond (BDD L ) thin films were synthesized as a semiconductor electron source to accelerate CO 2 reduction. However, BDD L alone could not stabilize the intermediates of CO 2 reduction, yielding a negligible amount of reduction products. Silver nanoparticles were then deposited on BDD L because of their selective electrochemical CO 2 reduction ability. Excellent selectivity (estimated CO:H 2 mass ratio of 318:1) and recyclability (stable for five cycles of 3 h each) for photoelectrochemical CO 2 reduction were obtained for the optimum silver nanoparticle-modified BDD L electrode at −1.1 V vs. RHE under 222-nm irradiation. The high efficiency and stability of this catalyst are ascribed to the in situ photoactivation of the BDD L surface during the photoelectrochemical reaction. The present work reveals the potential of BDD L as a high-energy electron source for use with co-catalysts in photochemical conversion.

PurposeAuto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs.MethodsWe evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs.ResultsThree of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor.ConclusionAuto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection–triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1–expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)–containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.