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Introduction: The effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on quality of life (QOL) and treatment satisfaction have not been directly compared. This sub-analysis of a randomized-controlled trial with an SGLT2i, luseogliflozin, and DPP-4is compared their effects on QOL and treatment satisfaction of patients., Methods: This study recruited 623 patients with type 2 diabetes mellitus who were drug-naïve or treated with antidiabetic agents other than SGLT2is and DPP-4is. The patients were randomized into luseogliflozin or DPP-4i group and followed for 52 weeks. This sub-analysis assessed QOL and treatment satisfaction using Oral Hypoglycemic Agent Questionnaire (OHA-Q) version 2 in the drug-naïve subgroup who were drug-naïve at baseline and with monotherapy with luseogliflozin or DPP-4i throughout the observation period (256 patients) at 24 and 52 weeks and in the add-on subgroup who were treated with OHAs other than SGLT2is and DPP-4is (204 patients) at baseline, 24 and 52 weeks., Results: In the drug-naïve subgroup, total (50.8 ± 8.2 in luseogliflozin group and 53.1 ± 10.0 in DPP-4i group, p = 0.048) and somatic symptom scores (22.4 ± 5.0 in luseogliflozin group and 24.4 ± 5.8 in DPP-4i group, p = 0.005) at 52 weeks (but not at 24 weeks) were significantly higher in DPP-4i group than in luseogliflozin group. In add-on subgroup, changes in total (3.3 ± 7.8 in luseogliflozin group and 0.9 ± 7.6 in DPP-4i group, p = 0.030) and treatment convenience (1.2 ± 3.9 in luseogliflozin group and - 0.6 ± 4.2 in DPP-4i group, p = 0.002) from baseline to 24 weeks (but not at 52 weeks) were significantly greater in luseogliflozin group than in DPP-4i group. The QOL related to safety or glycemic control was comparable between the groups., Conclusions: Physicians should pay attention to side effects of SGLT2is to maintain the patients' QOL when SGLT2is are initiated or added-on. Add-on of luseogliflozin increased patients' QOL more than DPP-4is. Considering patients' QOL and treatment satisfaction is important for selecting SGLT2is or DPP-4is., Trial Registration: UMIN000030128 and jRCTs031180241., (© 2024. The Author(s).)

This study investigates the strain-induced structural transitions of η ↔ θ and the changes in electronic band structures of Au 2 X (X = S, Se, Te, Si, Ge) and Au 4 SSe. We focus on Au 2 S monolayers, which can form multiple meta-stable monolayers theoretically, including η -Au 2 S, a buckled penta-monolayer composed of a square Au lattice and S adatoms. The θ -Au 2 S is regarded as a distorted structure of η -Au 2 S. Based on density functional theory (DFT) calculations using a generalized gradient approximation, the conduction and the valence bands of θ -Au 2 S intersect at the Γ point, leading to linear dispersion, whereas η -Au 2 S has a band gap of 1.02 eV. The conduction band minimum depends on the specific Au-Au bond distance, while the valence band maximum depends on both Au-S and Au-Au interactions. The band gap undergoes significant changes during the η ↔ θ phase transition of Au 2 S induced by applying tensile or compressive in-plane biaxial strain to the lattice. Moreover, substituting S atoms with other elements alters the electronic band structures, resulting in a variety of physical properties without disrupting the fundamental Au lattice network. Therefore, the family of Au 2 X monolayers holds potential as materials for atomic scale network devices.

Cytochrome c oxidase (C c O) is part of the respiratory chain and contributes to the electrochemical membrane gradient in mitochondria as well as in many bacteria, as it uses the energy released in the reduction of oxygen to pump protons across an energy-transducing biological membrane. Here, we use time-resolved serial femtosecond crystallography to study the structural response of the active site upon flash photolysis of carbon monoxide (CO) from the reduced heme a 3 of ba 3 -type C c O. In contrast with the aa 3 -type enzyme, our data show how CO is stabilized on Cu B through interactions with a transiently ordered water molecule. These results offer a structural explanation for the extended lifetime of the Cu B -CO complex in ba 3 -type C c O and, by extension, the extremely high oxygen affinity of the enzyme.

Sulfur vacancy on an MoS 2 basal plane plays a crucial role in device performance and catalytic activity; thus, an understanding of the electronic states of sulfur vacancies is still an important issue. We investigate the electronic states on an MoS 2 basal plane by ambient-pressure X-ray photoelectron spectroscopy (AP-XPS) and density functional theory calculations while heating the system in hydrogen. The AP-XPS results show a decrease in the intensity ratio of S 2p to Mo 3d, indicating that sulfur vacancies are formed. Furthermore, low-energy components are observed in Mo 3d and S 2p spectra. To understand the changes in the electronic states induced by sulfur vacancy formation at the atomic scale, we calculate the core-level binding energies for the model vacancy surfaces. The calculated shifts for Mo 3d and S 2p with the formation of sulfur vacancy are consistent with the experimentally observed binding energy shifts. Mulliken charge analysis indicates that this is caused by an increase in the electronic density associated with the Mo and S atoms around the sulfur vacancy as compared to the pristine surface. The present investigation provides a guideline for sulfur vacancy engineering., (© 2023 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

KCR channelrhodopsins (K + -selective light-gated ion channels) have received attention as potential inhibitory optogenetic tools but more broadly pose a fundamental mystery regarding how their K + selectivity is achieved. Here, we present 2.5-2.7 Å cryo-electron microscopy structures of HcKCR1 and HcKCR2 and of a structure-guided mutant with enhanced K + selectivity. Structural, electrophysiological, computational, spectroscopic, and biochemical analyses reveal a distinctive mechanism for K + selectivity; rather than forming the symmetrical filter of canonical K + channels achieving both selectivity and dehydration, instead, three extracellular-vestibule residues within each monomer form a flexible asymmetric selectivity gate, while a distinct dehydration pathway extends intracellularly. Structural comparisons reveal a retinal-binding pocket that induces retinal rotation (accounting for HcKCR1/HcKCR2 spectral differences), and design of corresponding KCR variants with increased K + selectivity (KALI-1/KALI-2) provides key advantages for optogenetic inhibition in vitro and in vivo. Thus, discovery of a mechanism for ion-channel K + selectivity also provides a framework for next-generation optogenetics., Competing Interests: Declaration of interests The KCR variants are described in pending patent application material; these tools and all methods, protocols, clones, and sequences are freely available to nonprofit institutions and investigators. K.D. is a member of the Cell Advisory Board, a co-founder and Scientific Advisory Board member of Stellaromics and Maplight Therapeutics, and a Scientific Advisory Board member of BrightMinds Biosciences., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Evidence of a direct comparison between dipeptidyl-peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains lacking, and no clear treatment strategy or rationale has been established using these drugs. This study aimed to compare the overall efficacy and safety of DPP-4is and the SGLT2i luseogliflozin in patients with type 2 diabetes mellitus (T2DM)., Methods: Patients with T2DM who had not used antidiabetic agents or who had used antidiabetic agents other than SGLT2is and DPP-4is were enrolled in the study after written informed consent had been obtained. The enrolled patients were subsequently randomly assigned to either the luseogliflozin or DPP-4i group and followed up for 52 weeks. The primary (composite) endpoint was the proportion of patients who showed improvement in ≥ 3 endpoints among the following five endpoints from baseline to week 52: glycated hemoglobin (HbA1c), weight, estimated glomerular filtration rate (eGFR), systolic blood pressure, and pulse rate., Results: A total of 623 patients were enrolled in the study and subsequently randomized to either the luseogliflozin or DPP-4i groups. The proportion of patients who showed improvement in ≥ 3 endpoints at week 52 was significantly higher in the luseogliflozin group (58.9%) than in the DPP-4i group (35.0%) (p < 0.001). When stratified by body mass index (BMI) (< 25 or ≥ 25 kg/m 2 ) or age (< 65 or ≥ 65 years), regardless of BMI or age, the proportion of patients who achieved the composite endpoint was significantly higher in the luseogliflozin group than in the DPP-4i group. Hepatic function and high-density lipoprotein-cholesterol were also significantly improved in the luseogliflozin group compared with the DPP-4i group. The frequency of non-serious/serious adverse events did not differ between the groups., Conclusion: This study showed the overall efficacy of luseogliflozin compared with DPP-4is over the mid/long term, regardless of BMI or age. The results suggest the importance of assessing multiple aspects regarding the effects of diabetes management., Trial Registration Number: jRCTs031180241., (© 2023. The Author(s).)

Objective Mortality analyses of patients with coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation in Japan are limited. The present study therefore determined the risk factors for mortality in patients with COVID-19 requiring invasive mechanical ventilation. Methods This retrospective cohort study used the dataset from the Japanese multicenter research of COVID-19 by assembling real-word data (J-RECOVER) study that was conducted between January 1 and September 31, 2020. Independent risk factors associated with in-hospital mortality were evaluated using a multivariate logistic regression analysis. Kaplan-Meier estimates of the survival were calculated for different age groups. A subgroup analysis was performed to assess differences in survival rates according to additional risk factors, including an older age and chronic pulmonary disease. Patients A total of 561 patients were eligible. The median age was 67 (interquartile range: 56-75) years old, 442 (78.8%) were men, and 151 (26.9%) died in the hospital. Results Age, chronic pulmonary disease, and renal disease were significantly associated with in-hospital mortality. Compared with patients 18-54 years old, the adjusted odds ratios of patients 55-64, 65-74, and 75-94 years old were 3.34 (95% CI, 1.34-8.31), 7.07 (95% CI, 3.05-16.40), and 18.43 (95% CI, 7.94-42.78), respectively. Conclusion Age, chronic pulmonary disease, and renal disease were independently associated with mortality in patients with COVID-19 requiring invasive mechanical ventilation, and age was the most decisive indicator of a poor prognosis. Our results may aid in formulating treatment strategies and allocating healthcare resources.

Herein, we report nanodiamond oxide (NDOx), obtained from modified Hummers' oxidation of nanodiamond (ND), showing excellent proton conductivity and thermal stability. NDOx possesses hydrophilicity resulting in higher water adsorption and the retention of functional groups at elevated temperatures can be attributed to the high proton conductivity and thermal stability, respectively.

The rupture of macrophage phagosomes has been implicated in various human diseases and plays a critical role in immunity. However, the mechanisms underlying this process are complex and not yet fully understood. This study describes the development of a robust engineering method for rupturing phagosomes based on a well-defined mechanism. The method utilizes microfabricated microparticles composed of uncrosslinked linear poly( N -isopropylacrylamide) (PNIPAM) as phagocytic objects. These microparticles are internalized into phagosomes at 37 °C. By exposing the cells to a cold shock at 0 °C, the vast majority of the microparticle-containing phagosomes rupture. The percentage of phagosomal rupture decreases with the increase of the cold-shock temperature. The osmotic pressure in the phagosomes and the tension in the phagosomal membrane are calculated using the Flory-Huggins theory and the Young-Laplace equation. The modeling results indicate that the osmotic pressure generated by dissolved microparticles is probably responsible for phagosomal rupture, are consistent with the experimentally observed dependence of phagosomal rupture on the cold-shock temperature, and suggest the existence of a cellular mechanism for resisting phagosomal rupture. Moreover, the effects of various factors including hypotonic shock, chloroquine, tetrandrine, colchicine, and l-leucyl-l-leucine O -methyl ester (LLOMe) on phagosomal rupture have been studied with this method. The results further support that the osmotic pressure generated by the dissolved microparticles causes phagosomal rupture and demonstrated usefulness of this method for studying phagosomal rupture. This method can be further developed, ultimately leading to a deeper understanding of phagosomal rupture.

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development., (© 2022 Federation of European Biochemical Societies.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivation of pH-dependent graphene oxide (GO) nanosheets is presented. The observed virus inactivation using an authentic virus (Delta variant) and different GO dispersions at pH 3, 7, and 11 suggests that the higher pH of the GO dispersion yields a better performance compared to that of GO at neutral or lower pH. The current findings can be ascribed to the pH-driven functional group change and the overall charge of GO, favorable for the attachment between GO nanosheets and virus particles., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb -68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb -68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo., (© 2022. The Author(s).)

Transposon-encoded IscB family proteins are RNA-guided nucleases in the OMEGA (obligate mobile element-guided activity) system, and likely ancestors of the RNA-guided nuclease Cas9 in the type II CRISPR-Cas adaptive immune system. IscB associates with its cognate ωRNA to form a ribonucleoprotein complex that cleaves double-stranded DNA targets complementary to an ωRNA guide segment. Although IscB shares the RuvC and HNH endonuclease domains with Cas9, it is much smaller than Cas9, mainly due to the lack of the α-helical nucleic-acid recognition lobe. Here, we report the cryo-electron microscopy structure of an IscB protein from the human gut metagenome (OgeuIscB) in complex with its cognate ωRNA and a target DNA, at 2.6-Å resolution. This high-resolution structure reveals the detailed architecture of the IscB-ωRNA ribonucleoprotein complex, and shows how the small IscB protein assembles with the ωRNA and mediates RNA-guided DNA cleavage. The large ωRNA scaffold structurally and functionally compensates for the recognition lobe of Cas9, and participates in the recognition of the guide RNA-target DNA heteroduplex. These findings provide insights into the mechanism of the programmable DNA cleavage by the IscB-ωRNA complex and the evolution of the type II CRISPR-Cas9 effector complexes., (© 2022. The Author(s).)

Aims/introduction: Though poor glycemic control and insulin treatment are reported to be associated with sarcopenia in type 2 diabetes, type 1 diabetes may be a stronger risk for sarcopenia. We therefore studied the effect of the type of diabetes, glycemic control, and insulin therapy on the prevalence and characteristics of sarcopenia., Materials and Methods: A total of 812 Japanese patients with diabetes (type 1: n = 57; type 2: n = 755) were enrolled in this study. Sarcopenia was defined as low handgrip strength or slow gait speed and low appendicular skeletal muscle mass., Results: Among participants aged ≥65 years, the sarcopenia prevalence rate was higher among patients with type 1 diabetes (20.0%) than among those with type 2 diabetes (8.1%). The prevalence rate of low handgrip strength was higher in type 1 diabetes (50.0%) than in type 2 diabetes (28.7%). In logistic regression analysis, type 1 diabetes was significantly associated with the prevalence of low handgrip strength. In logistic regression analysis, medication with insulin was significantly associated with the prevalence of sarcopenia; this association was not retained after adjusting for HbA1c., Conclusions: The prevalence of sarcopenia in older adult patients was higher in those with type 1 diabetes than in those with type 2 diabetes. Among the components of sarcopenia, the difference was most prominent in the frequency of low handgrip strength. Poor glycemic control rather than type of diabetes or insulin treatment was revealed to be a primary risk factor for sarcopenia in diabetes mellitus., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Outer hair cell elecromotility, driven by prestin, is essential for mammalian cochlear amplification. Here, we report the cryo-EM structures of thermostabilized prestin (Pres TS ), complexed with chloride, sulfate, or salicylate at 3.52-3.63 Å resolutions. The central positively-charged cavity allows flexible binding of various anion species, which likely accounts for the known distinct modulations of nonlinear capacitance (NLC) by different anions. Comparisons of these Pres TS structures with recent prestin structures suggest rigid-body movement between the core and gate domains, and provide mechanistic insights into prestin inhibition by salicylate. Mutations at the dimeric interface severely diminished NLC, suggesting that stabilization of the gate domain facilitates core domain movement, thereby contributing to the expression of NLC. These findings advance our understanding of the molecular mechanism underlying mammalian cochlear amplification., (© 2022. The Author(s).)

Studying blood microcirculation is vital for gaining insights into vascular diseases. Blood flow imaging in deep tissue is currently achieved by acute administration of fluorescent dyes in the blood plasma. This is an invasive process, and the plasma fluorescence decreases within an hour of administration. Here, we report an approach for the longitudinal study of vasculature. Using a single intraperitoneal or intravenous administration of viral vectors, we express fluorescent secretory albumin-fusion proteins in the liver to chronically label the blood circulation in mice. This approach allows for longitudinal observation of circulation from 2 weeks to over 4 months after vector administration. We demonstrate the chronic assessment of vascular functions including functional hyperemia and vascular plasticity in micro- and mesoscopic scales. This genetic plasma labeling approach represents a versatile and cost-effective method for the chronic investigation of vasculature functions across the body in health and disease animal models., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Objective: Aging of skeletal muscle is characterized not only by a decrease of muscle quantity but also by changes in muscle quality, such as an increase in muscle stiffness. The present study aimed to investigate the effects of supplementation with quercetin glycosides (QGs), well-known polyphenolic flavonoids, combined with resistance exercise on muscle quantity and stiffness., Materials and Methods: A randomized, controlled trial was conducted in community-dwelling, Japanese people aged 50-74 years who were randomly allocated to exercise with placebo or 200 or 500 mg of QG supplementation. All participants performed low-intensity resistance training mainly targeting thigh muscles with 40% of 1-repetition maximum, 3 days per week for 24 weeks. Muscle cross-sectional area (CSA), lean mass, and vastus lateralis (VL) muscle stiffness were measured before and after the 24-week intervention., Results: Forty-eight subjects completed the 24-week intervention. There were no significant group × time interactions in thigh CSA for primary outcome, as well as lean mass. VL muscle stiffness in the stretched position was significantly lower in both the 200 mg and 500 mg QG groups than in the placebo group after the 24-week intervention ( p < 0.05). No significant correlation was observed between changes of VL muscle CSA and stiffness during the 24-week intervention., Conclusion: Quercetin glycoside supplementation combined with low-intensity resistance exercise improved passive muscle stiffness independently of muscle quantity., Clinical Trial Registration: [www.umin.ac.jp/ctr/], identifier [UMIN000037633]., Competing Interests: This study received funding from Suntory Wellness Ltd. YO, AN, TI, and MN Were employees of Suntory Wellness Ltd., which manufactures and sells health food products. The funder had the following involvement with the study: the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Otsuka, Miyamoto, Nagai, Izumo, Nakai, Fukuda, Arimitsu, Yamada and Hashimoto.)

As per the International Commission on Radiological Protection 2010 recommendation, it was stated that "interventional radiologists performing difficult procedures with high workloads may be exposed to high doses" and that education and training of medical staffs in radiation exposure is "an urgent priority." There are many reports on the textbook aspects of radiation protection, but reports on the practical aspects of radiation protection have remained to be scarce. Various methods of reducing radiation exposure are described as "useful" or "can be reduced," but the priority of these methods and the "extent" to which they contribute to reducing radiation exposure are not clear. Thus, in this article, we will look into the protection of interventional radiologist from radiation exposure in a practical way, giving priority to clarity rather than academic accuracy., Competing Interests: None, (© 2022 Japanese Society of Interventional Radiology.)

Necrotizing fasciitis is a rare and severe infectious disease that is often fatal and is characterized by the extensive necrosis of subcutaneous tissue and fascial planes. A number of clinical parameters have been intensively investigated to diagnose and assess the severity and prognosis of necrotizing fasciitis. Since it currently remains unclear whether these parameters are also abnormal before disease onset, the present study investigated this issue. We retrospectively recruited 38 patients, including 12 and 26 patients with necrotizing fasciitis and cellulitis, respectively. The results of routine blood examinations were collected at disease onset and also at baseline, which was defined as the time point before disease onset. No significant differences were observed in age or sex between the necrotizing fasciitis and cellulitis groups. However, significant differences were noted in the levels of hemoglobin, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio, sodium, creatinine, albumin, D-dimer, and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score at disease onset. Significant differences were also observed in the levels of hemoglobin, lymphocyte count, monocyte count, platelet count, creatinine, D-dimer, and LRINEC score at baseline. Hemoglobin, platelet count, C-reactive protein, creatinine, albumin, and D-dimer levels were already abnormal at baseline in the necrotizing fasciitis group. In conclusion, the present results revealed precritical abnormalities in routine blood parameters in patients with necrotizing fasciitis. Therefore, individuals predisposed to necrotizing soft tissue infection may be identified prior to disease onset., (© 2022 Japanese Dermatological Association.)

Significance: Photothrombosis is a widely used model of ischemic stroke in rodent experiments. In the photothrombosis model, the photosensitizer rose bengal (RB) is systemically introduced into the blood stream and activated by green light to induce aggregation of platelets that eventually cause vessel occlusion. Since the activation of RB is a one-photon phenomenon and the molecules in the illuminated area (light path) are subject to excitation, targeting of thrombosis is unspecific, especially in the depth dimension. We developed a photothrombosis protocol that can target a single vessel in the cortical parenchyma by two-photon excitation. Aim: We aim to induce a thrombotic stroke in the cortical parenchyma by two-photon activation of RB to confine photothrombosis within a vessel of a target depth. Approach: FITC-dextran is injected into the blood stream to visualize the cerebral blood flow in anesthetized adult mice with a cranial window. After a target vessel is chosen by two-photon imaging (950 nm), RB is injected into the blood stream. The scanning wavelength is changed to 720 nm, and photothrombosis is induced by scanning the target vessel. Results: Two-photon depth-targeted single-vessel photothrombosis was achieved with a success rate of 84.9 % ± 1.7 % and an irradiation duration of < 80    s . Attempts without RB (i.e., only with FITC) did not result in photothrombosis at the excitation wavelength of 720 nm. Conclusions: We described a protocol that achieves depth-targeted single-vessel photothrombosis by two-photon excitation. Simultaneous imaging of blood flow in the targeted vessel using FITC dextran enabled the confirmation of vessel occlusion and prevention of excess irradiation that possibly induces unintended photodamage., (© 2022 The Authors.)

Aim: We carried out a randomized controlled trial using ipragliflozin. We analyzed changes in diastolic function using echocardiography in patients with type 2 diabetes and heart failure with preserved ejection fraction., Methods: We carried out an open-label, multicenter, randomized, two-arm interventional trial. A total of eligible 68 participants were randomly assigned into two groups (ipragliflozin group n = 36; conventional treatment group n = 32). Primary end-points were the change in E/e' and e'. Secondary end-points were other parameters of echocardiography, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure., Results: After 24 weeks of follow up, E/e' decreased in both groups (ipragliflozin: 11.0 vs 10.4; conventional treatment 10.5 vs 10.1; multivariate-adjusted P = 0.95). There were no significant differences in the amount of change in E/e', e', echocardiography parameters, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure between the two groups. In the subgroup analysis, ipragliflozin treatment decreased in left ventricular mass index in patients aged ≥70 years and also decreased in NT-proBNP levels in patients with baseline NT-proBNP ≥400 pg/mL., Conclusions: In this randomized controlled study carried out in patients with type 2 diabetes and heart failure with preserved ejection fraction, 24-week ipragliflozin treatment did not improve left ventricular diastolic function compared with conventional treatment. As the subgroup, ipragliflozin treatment decreased in left ventricular mass index in participants aged ≥70 years. Geriatr Gerontol Int 2022; 22: 298-304., (© 2022 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Background: A sarcopenia diagnosis is confirmed by the presence of low muscle quantity or quality under the 2018 revised definition by the European Working Group on Sarcopenia in Older People 2. Imaging methods [i.e. magnetic resonance imaging (MRI)], dual-energy X-ray absorptiometry (DXA), and bioelectrical impedance analysis are tools to evaluate muscle quantity or quality. The present study aimed to investigate whether and how low-intensity and moderate-intensity resistance training improved both muscle quantity and quality measured by MRI, DXA, and segmental bioelectrical impedance spectroscopy (S-BIS) in middle-aged and older people., Methods: A single-blind, randomized, controlled trial was conducted. Community-dwelling people aged 50-79 years were randomly allocated to no exercise (no-Ex), low-intensity exercise (low-Ex), and moderate-intensity exercise (moderate-Ex) groups. Participants in the exercise groups performed resistance training for 24 weeks, with loads of 40% and 60% of one repetition maximum in the low-Ex and moderate-Ex groups, respectively. Cross-sectional area (CSA), lean mass, and muscle electrical properties on S-BIS were used to determine the effects of training interventions on muscle quantity and quality of the lower limbs., Results: Fifty participants (no-Ex 17, age 63.5 ± 8.5 years, women 47.1%; low-Ex 16, age 63.6 ± 8.1 years, women 50.0%; moderate-Ex 17, age 63.5 ± 8.3 years, women 52.9%) completed the 24 week exercise intervention. For the primary outcome, significant intervention effects were found in thigh muscle CSA on MRI between the moderate-Ex and no-Ex groups (+6.8 cm 2 , P < 0.01). Low-Ex for 24 weeks only increased quadriceps CSA (+2.3 cm 2 , P < 0.05). The per cent change of thigh muscle CSA (+7.0%, P < 0.01) after 24 week moderate-Ex was higher than that of leg lean mass on DXA (+2.3%, P = 0.088). Moderate-Ex for 24 weeks also improved S-BIS electrical properties related to muscle quantity and quality, including the intracellular resistance index (+0.1 cm 2 /Ω, P < 0.05), membrane capacitance (+0.7 nF, P < 0.05), and phase angle (+0.3 deg, P < 0.05); their changes were positively correlated with that of thigh muscle CSA (P < 0.01)., Conclusions: Resistance exercise with moderate intensity improved muscle quantity and quality measured by MRI and S-BIS, whereas that with low intensity only increased muscle quantity in middle-aged and older people. The comparisons among the responses to exercise between the assessment methods indicate the greater value of MRI and S-BIS to measure changes of muscle quantity and quality than of lean mass measured by DXA for assessing the local effects of resistance training., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Remarkably high mixed proton and electron conduction arising from oxidized single-wall carbon nanotubes at room temperature is demonstrated. The respective proton and electronic conductivities are 1.40 and 8.0 × 10 -2 S cm -1 in the in-plane direction, and 3.1 × 10 -2 and 1.1 × 10 -3 S cm -1 in the out-of-plane direction, indicating their potential in a wide range of solid electrolyte membranes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

ChRmine, a recently discovered pump-like cation-conducting channelrhodopsin, exhibits puzzling properties (large photocurrents, red-shifted spectrum, and extreme light sensitivity) that have created new opportunities in optogenetics. ChRmine and its homologs function as ion channels but, by primary sequence, more closely resemble ion pump rhodopsins; mechanisms for passive channel conduction in this family have remained mysterious. Here, we present the 2.0 Å resolution cryo-EM structure of ChRmine, revealing architectural features atypical for channelrhodopsins: trimeric assembly, a short transmembrane-helix 3, a twisting extracellular-loop 1, large vestibules within the monomer, and an opening at the trimer interface. We applied this structure to design three proteins (rsChRmine and hsChRmine, conferring further red-shifted and high-speed properties, respectively, and frChRmine, combining faster and more red-shifted performance) suitable for fundamental neuroscience opportunities. These results illuminate the conduction and gating of pump-like channelrhodopsins and point the way toward further structure-guided creation of channelrhodopsins for applications across biology., Competing Interests: Declaration of interests The ChRmine antibody (Fab02) and ChRmine variants are described in the pending patent application material; these tools and all methods, protocols, clones, and sequences are freely available to nonprofit institutions and investigators. K.D. is a member of the Cell advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to investigate the association between level of impaired consciousness and severe hypothermia (<28°C) and to evaluate the association between level of impaired consciousness and inhospital mortality among accidental hypothermia patients., Methods: This was a multicenter retrospective study using the J-Point registry database, which includes data regarding patients whose core body temperature was 35.0°C or less and who were treated as accidental hypothermia in emergency departments between April 1, 2011 and March 31, 2016. We estimated adjusted odds ratios of the level of impaired consciousness for severe hypothermia less than 28°C and inhospital mortality using a logistic regression model., Results: The study included 505 of 572 patients in the J-Point registry. Relative to mildly impaired consciousness (Glasgow Coma Scale [GCS] 13-15), the adjusted odds ratios for severe hypothermia less than 28°C were: moderate (GCS 9-12), 3.26 (95% confidence interval [CI], 1.69-6.25); and severe (GCS < 9), 4.68 (95% CI, 2.40-9.14). Relative to mildly impaired consciousness (GCS 13-15), the adjusted odds ratios for inhospital mortality were: moderate (GCS9-12), 1.65 (95% CI, 0.95-2.88); and severe (GCS < 9), 2.10 (95% CI, 1.17-3.78)., Conclusion: The level of impaired consciousness in patients with accidental hypothermia was associated with severe hypothermia and inhospital mortality., (© 2022 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

The key challenges for converting chitin to 5-hydroxymethylfurfural (5-HMF) include the low 5-HMF yield. Moreover, the disadvantages of traditional acid-base catalysts including complex post-treatment processes, the production of by-products, and severe equipment corrosion also largely limit the large-scale conversion of chitin to 5-HMF. In this view, herein we have demonstrated a microwave aided efficient and green conversion of chitin to 5-HMF while using polyoxometalate (POM) as a catalyst and DMSO/water as solvent. Chitin treated with H 2 SO 4 followed by ball-milling (chitin-H 2 SO 4 -BM) was selected as the starting compound for the conversion process. Four different POMs including H 3 [PW 12 O 40 ], H 3 [PMo 12 O 40 ], H 4 [SiW 12 O 40 ] and H 4 [SiMo 12 O 40 ] were used as catalysts. Various reaction parameters including reaction temperature, amount of catalyst, mass ratios of water/DMSO and reaction time have been investigated to optimize the 5-HMF conversion. The H 4 [SiW 12 O 40 ] catalyst exhibited the highest catalytic performance with 23.1% HMF yield at optimum operating conditions which is the highest among the literature for converting chitin to 5-HMF. Significantly, the disadvantages of the state of the art conversion routes described earlier can be overcome using POM-based catalysts, which makes the process more attractive to meet the ever-increasing energy demands, in addition to helping consume crustacean waste., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The interlayer spaces in two dimensional (2D) layered materials such as graphene, metal oxides and metal chalcogenides can be used in a number of roles that include the trapping of gases, for ion transfer and for water purification applications. In such spaces, "inner" pressure occurs on guest species enclosed between the layers and its variation can, in principal, be used for precisely controlling particular guest properties. In this study, a mixture of two 2D materials including graphene oxide (GO) and nickel hydroxide (Ni(OH) 2 ), was employed to yield an anisotropic GO-Ni(OH) 2 hybrid 2D sheet. The inner pressure associated with this material was able to be tuned by reduction of the GO (to yield rGO) and this in turn was shown to affect the magnetic behaviour of Ni(OH) 2 . The ferromagnetic transition temperature ( T c ) for Ni(OH) 2 decreases as the interlayer distance became shorter, which is opposite to the behaviour observed for the application of hydrostatic pressure to the hybrid sheet. The uniaxial pressure affecting the interlayer of the 2D material, and generated by the reduction of GO to rGO, has the potential to not only influence the behaviour of a range of magnetic materials, but also individual properties of other types of functional materials.

The viability of biorefining technology primarily depends on the facile cellulose conversion route with adequate conversion efficiency. Here we have demonstrated the microwave-assisted hydrolysis of cellulose to glucose using polyoxometalate (POM) clusters as acid catalysts. Two different types of POM, including Wells-Dawson and Keggin were justified as catalysts in the cellulose conversion process. In particular, the cellulose to glucose catalytic conversion using Wells-Dawson type POMs has not been reported to date. Also, even though there have been some previous reports about the catalytic biomass conversion of Keggin type POMs, the systematic study to optimize the conversion efficiency in terms of catalyst amount, reaction temperature, reaction time, and the amount of solvent is lacking. Under the experimental conditions employed, the Keggin-type catalyst showed higher cellulose conversion and glucose yield than the Wells-Dawson-type catalyst. Furthermore, the cellulose conversion efficiency and glucose yields were optimized by tuning the reaction conditions including temperature, reaction time, and the amount of solvent. Under optimized conditions, the Keggin-type POM catalyst shows a remarkably high glucose yield of 77.2% and a cellulose conversion of 90.1%. The unique complex properties of the POM catalyst, including being (i) strong acids with extremely high Brønsted and Lewis acidity and (ii) efficient microwave adsorbants which enhanced interaction between substrate and the catalyst can be attributed to the outstanding efficacy of the conversion process., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The rapid transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven infection signifies an ultimate challenge to global health, and the development of effective strategies for preventing and/or mitigating its effects are of the utmost importance. In the current study, an in-depth investigation for the understanding of the SARS-CoV-2 inactivation route using graphene oxide (GO) is presented. We focus on the antiviral effect of GO nanosheets on three SARS-CoV-2 strains: Wuhan, B.1.1.7 (U.K. variant), and P.1 (Brazilian variant). Plaque assay and real-time reverse transcription - polymerase chain reaction (RT-PCR) showed that 50 and 98% of the virus in a supernatant could be cleared following incubation with GO (100 μg/mL) for 1 and 60 min, respectively. Transmission electron microscopy (TEM) analysis and protein (spike (S) and nucleocapsid (N) proteins) decomposition evaluation confirm a two-step virus inactivation mechanism that includes (i) adsorption of the positively charged spike of SARS-CoV-2 on the negatively charged GO surface and (ii) neutralization/inactivation of the SARS-CoV-2 on the surface of GO through decomposition of the viral protein. As the interaction of S protein with human angiotensin-converting enzyme 2 (ACE2) is required for SARS-CoV-2 to enter into human cells, the damage to the S protein using GO makes it a potential candidate for use in contributing to the inhibition of the worldwide spread of SARS-CoV-2. Specifically, our findings provide the potential for the construction of an effective anti-SARS-CoV-2 face mask using a GO nanosheet, which could contribute greatly to preventing the spread of the virus. In addition, as the effect of surface contamination can be severe in the spreading of SARS-CoV-2, the development of efficient anti-SARS-CoV-2 protective surfaces/coatings based on GO nanosheets could play a significant role in controlling the spread of the virus through the utilization of GO-based nonwoven cloths, filters, and so on., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Skeletal muscle fibrosis occurs with aging and has been suggested to impair muscle performance, thereby decreasing quality of life. Recently, muscle stiffness, a surrogate measure of muscle fibrosis, was noninvasively quantified as the shear modulus using ultrasound shear wave elastography (SWE) in humans. We aimed to investigate thigh muscle stiffness in females and males, respectively, across a broad range of ages by using SWE. Eighty-six community-dwelling Japanese people who were aged 30 to 79 years and did not regularly exercise participated in this study. The vastus lateralis (VL) shear modulus was measured at three different knee joint angles: full extension, 90° of flexion, and full flexion. There were no significant main effects of sex or age on the VL shear modulus in full extension or 90° of flexion of the knee. However, the VL shear modulus in knee full flexion was significantly smaller in females than in males and increased with age from 47.9 years. The results suggest that the accelerated increase in VL stiffness that occurs after an individual passes their late 40s may be an important therapeutic target for developing effective treatments and programs that preserve and improve quality of life.

Objectives: Type 2 diabetes is a risk factor for sarcopenia. Evidence on the prevention of sarcopenia using blood glucose-lowering therapy is limited. We aimed to examine the relationship between changes in glycemic control and sarcopenia and the effect of antidiabetic agents against sarcopenia in patients with type 2 diabetes., Design: We conducted an observational longitudinal study., Setting and Participants: In total, 588 Japanese patients with diabetes of an ongoing multicenter study completed 1-year follow-up measurements for sarcopenia and clinical data., Methods: The data set of the Multicenter Study for Clarifying Evidence for Sarcopenia in patients with Diabetes Mellitus (the MUSCLES-DM study) was analyzed., Results: During the follow-up period, the frequency of sarcopenia marginally increased, and the means of skeletal muscle mass index (SMI), handgrip strength, and gait speed did not show any changes. However, on dividing into 5 groups depending on the degree of changes in glycated hemoglobin (HbA 1c ) value, the patients with a decrease of ≥1% in HbA 1c exhibited a significant increase in SMI. Our analysis revealed similar results for gait speed but not handgrip strength. Using the multiple linear regression model, we identified that a ≥1% decrease in HbA 1c value was an independent determinant of the changes in SMI and gait speed. We also determined that insulin use at baseline was an independent factor for the changes in SMI., Conclusions and Implications: Correction of poor glycemic control and use of insulin were significantly associated with the increase in skeletal muscle mass or gait speed in Japanese patients with type 2 diabetes. The current finding increases our understanding of the importance of glycemic control for the prevention of cardiovascular diseases and sarcopenia., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Channelrhodopsins (ChRs) are microbial light-gated ion channels utilized in optogenetics to control neural activity with light . Light absorption causes retinal chromophore isomerization and subsequent protein conformational changes visualized as optically distinguished intermediates, coupled with channel opening and closing. However, the detailed molecular events underlying channel gating remain unknown. We performed time-resolved serial femtosecond crystallographic analyses of ChR by using an X-ray free electron laser, which revealed conformational changes following photoactivation. The isomerized retinal adopts a twisted conformation and shifts toward the putative internal proton donor residues, consequently inducing an outward shift of TM3, as well as a local deformation in TM7. These early conformational changes in the pore-forming helices should be the triggers that lead to opening of the ion conducting pore., Competing Interests: KO, TN, TN, KY, KI, SI, JV, KH, AM, KK, TI, II, TI, RU, RE, SO, GK, TK, TK, WS, HS, TT, MT, RT, AT, RN, MF, HM, YL, EN, RT, TT, MS, TK, TS, TF, YY, SO, YJ, KT, RI, SH, HK, PH, SI, MK, TN, ON No competing interests declared, (© 2021, Oda et al.)

Bifunctional electrocatalytic properties of freeze-dried Ni/NiOx, freeze-dried NiO, and freeze-dried Ni(OH)2 are reported. Freeze-dried Ni(OH)2 was synthesized by the freeze-drying method. Freeze-dried Ni/NiOx and freeze-dried Ni were obtained from the thermal annealing of the material. Both Ni(OH)2 and Ni/NiOx could sustain with freestanding freeze-dried 3D structures without any carbon support. Freeze-dried Ni/NiOx exhibited excellent bifunctional electrocatalytic properties with the ORR performance at 0.62 V (half-wave potential) and OER at 1.47 V (η = 10 mA cm-2). Using freeze-dried metal hydroxides can be considered useful in a wide range of carbon-free applications and can improve the electrocatalytic performance. The bifunctional catalytic activities were calculated to be 0.86, 0.98 and 1.14 V for freeze-dried Ni/NiOx, freeze-dried NiO and freeze-dried Ni(OH)2, respectively. The stacking of 2D sheets into 3D mass seemed to play a vital role behind this excellent bifunctionality of freeze-dried Ni/NiOx. The material reveals possible applications in Zn-air batteries. Besides, the strategy developed herein could be justified to obtain other transition metal-oriented bifunctional electrocatalysts as alternatives to Pt- and Ir/Ru-based expensive benchmark catalysts.

We revisit the densest binary sphere packings (DBSPs) under periodic boundary conditions and present an updated phase diagram, including newly found 12 putative densest structures over the x-α plane, where x is the relative concentration and α is the radius ratio of the small and large spheres. To efficiently explore the DBSPs, we develop an unbiased random search approach based on both the piling-up method to generate initial structures in an unbiased way and the iterative balance method to optimize the volume of a unit cell while keeping the overlap of hard spheres minimized. With those two methods, we have discovered 12 putative DBSPs and thereby the phase diagram is updated, while our results are consistent with those of a previous study [Hopkins et al., Phys. Rev. E 85, 021130 (2012)]PLEEE81539-375510.1103/PhysRevE.85.021130 with a small correction for the case of 12 or fewer spheres in the unit cell. Five of the discovered 12 DBSPs are identified in the small radius range of 0.42≤α≤0.50, where several structures are competitive to each other with respect to packing fraction. Through the exhaustive search, diverse dense packings are discovered and, accordingly, we find that packing structures achieve high packing fractions by introducing distortion and/or combining a few local dense structural units. Furthermore, we investigate the correspondence of the DBSPs with crystals based on the space group. The result shows that many structural units in real crystals, e.g., LaH&#95;{10} and SrGe&#95;{2-δ} being high-pressure phases, can be understood as DBSPs. The correspondence implies that the densest sphere packings can be used effectively as structural prototypes for searching complex crystal structures, especially for high-pressure phases.

Background: Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state., Results: We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis., Conclusions: The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of K V channels.

Ion conduction through graphene oxide (GO) nanosheets that is pH-switchable between H + (in acid) and OH - (in base) ions is demonstrated. This finding is the first observation of this type for ion conductive materials and demonstrates an example of stimuli-driven ion-conduction switching.

This pilot study aimed to examine the effect of pre-meal tasteless calorie-free gum chewing on post-meal blood levels of glucose, insulin, glucagon, and gastrointestinal hormones. This was an open-label, randomized, 2-sequence, 3-period, 2-treatment crossover trial with a 1:1 allocation. Sixteen Japanese adult male volunteers aged between 30 and 49 years without diagnosed glucose metabolism disorder were enrolled. Ingestion of 200-g cooked rice after 15-min tasteless calorie-free gum chewing (GUM+ treatment) was compared to that without preceding gum chewing (GUM- treatment). Cooked rice was divided into twelve equally sized portions and consumed by chewing each portion 30 times before swallowing. Treatment sessions were separated by an at least 1-week interval and attended after an overnight fast. Circulating levels of glucose, insulin, glucagon, active glucagon-like peptide (GLP)-1 and ghrelin were measured at baseline (before treatment) and 0, 15, 30, 60, and 120 min after completion of the meal ingestion, and the postprandial change from baseline was assessed. As a result, the change in glucose levels at 0 min was significantly lower in the GUM+ treatment than in the GUM- treatment ( P  = 0.004). Furthermore, the GUM+ treatment demonstrated higher incremental insulin levels at 15 min ( P  = 0.041) and higher incremental active GLP-1 levels at 30 and 60 min ( P  = 0.018 and 0.021, respectively); whereas, postprandial glucagon and ghrelin levels were not significantly different. In conclusion, the current pilot study demonstrated that tasteless calorie-free gum chewing before rice eating had a significant but limited impact on the increase of postprandial active GLP-1 levels in male individuals without diagnosed glucose metabolism disorder., Competing Interests: Conflict of interestMitsuyoshi Takahara is a staff member of the endowed chair (Department of Diabetes Care Medicine) which received funds from AstraZeneca K.K., Mitsubishi Tanabe Pharma Co., MSD K.K., Nippon Boehringer Ingelheim Co., Novo Nordisk Pharma, Ono Pharmaceutical Co., and Taisho Toyama Pharmaceutical Co.. Masahiro Fukuda has received honoraria from Mitsubishi Tanabe Pharma Co., MSD K.K., Ono Pharmaceutical Co., Sanofi K.K., and Takeda Pharmaceutical Co., and has received research funding from Astellas Pharma, LOTTE Co., Novo Nordisk Pharma, and Sanofi K.K.. Yuji Matsuzawa declares that he has no conflict of interest. Iichiro Shimomura has received honoraria from Astellas Pharma, Eli Lilly Japan K.K., Kowa Co., Mitsubishi Tanabe Pharma Co., MSD K.K., Nippon Boehringer Ingelheim Co., Novo Nordisk Pharma, Ono Pharmaceutical Co., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., and Takeda Pharmaceutical Co., and has received subsides or donations from Astellas Pharma, AstraZeneca K.K., Daiichi Sankyo Co., Kowa Co., Kyowa Kirin Co., Mitsubishi Tanabe Pharma Co., MSD K.K., Novartis Pharmaceuticals Corp., Novo Nordisk Pharma, Ono pharmaceutical Co., Sanofi K.K., Sumitomo Dainippon Pharma., Takeda Pharmaceutical Co., Teijin Pharma, and Terumo Corporation., (© The Japan Diabetes Society 2020.)

Disruptions in the ubiquitin protein ligase E3A ( UBE3A ) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aims/introduction: Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes., Materials and Methods: Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2,067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index., Results: Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c <6.5%, 7.0%, ≥6.5% and <7.0%: 18.5%; HbA1c ≥7.0% and <8.0%: 20.3%; HbA1c ≥8.0%: 26.7%). The linear association was independent of major covariates, including anthropometric factors and duration of diabetes (HbA1c <6.5%: reference; ≥6.5% and <7.0%: odds ratio [OR] 4.38, P = 0.030; HbA1c ≥7.0% and <8.0%: 4.29, P = 0.024; HbA1c ≥8.0%: 7.82, P = 0.003). HbA1c level was specifically associated with low skeletal mass index (HbA1c ≥8.0%: OR 5.42, P < 0.001) rather than weak grip strength (OR 1.89, P = 0.058) or slow gait speed (OR 1.13, P = 0.672). No significant association was observed in the general population with a better glycemic profile., Conclusions: Poor glycemic control in patients with diabetes was associated with low muscle mass., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca 2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.

Microglia, the brain-resident macrophage, are involved in brain development and contribute to the progression of neural disorders. Despite the importance of microglia, imaging of live microglia at a cellular resolution has been limited to transgenic mice. Efforts have therefore been dedicated to developing new methods for microglia detection and imaging. Using a thorough structure-activity relationships study, we developed CDr20, a high-performance fluorogenic chemical probe that enables the visualization of microglia both in vitro and in vivo. Using a genome-scale CRISPR-Cas9 knockout screen, the UDP-glucuronosyltransferase Ugt1a7c was identified as the target of CDr20. The glucuronidation of CDr20 by Ugt1a7c in microglia produces fluorescence., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Proton-dependent oligopeptide transporters (POTs) belong to the major facilitator superfamily (MFS) and transport dipeptides and tripeptides from the extracellular environment into the target cell. The human POTs PepT1 and PepT2 are also involved in the absorption of various orally ingested drugs. Previously reported structures revealed that the bacterial POTs possess 14 helices, of which H1-H6 and H7-H12 constitute the typical MFS fold and the residual two helices are involved in the cytoplasmic linker. PepT So2 from Shewanella oneidensis is a unique POT which reportedly assembles as a 200 kDa tetramer. Although the previously reported structures suggested the importance of H12 for tetramer formation, the structural basis for the PepT So2 -specific oligomerization remains unclear owing to the lack of a high-resolution tetrameric structure. In this study, the expression and purification conditions for tetrameric PepT So2 were optimized. A single-particle cryo-EM analysis revealed the tetrameric structure of PepT So2 incorporated into Salipro nanoparticles at 4.1 Å resolution. Furthermore, a combination of lipidic cubic phase (LCP) crystallization and an automated data-processing system for multiple microcrystals enabled crystal structures of PepT So2 to be determined at resolutions of 3.5 and 3.9 Å. The present structures in a lipid bilayer revealed the detailed mechanism for the tetrameric assembly of PepT So2 , in which a characteristic extracellular loop (ECL) interacts with two asparagine residues on H12 which were reported to be important for tetramerization and plays an essential role in oligomeric assembly. This study provides valuable insights into the oligomerization mechanism of this MFS-type transporter, which will further pave the way for understanding other oligomeric membrane proteins., (open access.)

Aims/introduction: To investigate the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus, with a focus on hypoglycemia., Materials and Methods: Type 2 diabetes mellitus patients who started sitagliptin therapy and were followed for 52 weeks were enrolled in the Impact of Sitagliptin on Diabetes Mellitus in Japanese Elderly Patients study. The frequency of hypoglycemia and knowledge of hypoglycemia were analyzed using a questionnaire., Results: In total, 5,130 patients (aged 73.8 ± 6.1 years) were analyzed. A significant reduction in glycated hemoglobin (-0.7 ± 1.1%, P < 0.001) and glycoalbumin levels (-2.2 ± 3.8%, P < 0.001) was observed at week 52. The percentage of patients with hypoglycemia did not increase from the baseline (3.3%) to week 52 (2.8%) of sitagliptin administration. Hypoglycemia incidence was significantly higher for combination therapy with insulin (odds ratio 17.75, P < 0.001) or sulfonylurea (odds ratio 2.22, P < 0.001). The increase in sitagliptin dose for combination therapy with antidiabetic drug(s) increased the percentage of patients with hypoglycemia (5.6% in sitagliptin increased subgroup, 2.4% in sitagliptin maintained subgroup, P < 0.01). The awareness of hypoglycemia symptoms and attitude to carry glucose as a countermeasure to prevent hypoglycemia increased during the study., Conclusions: Sitagliptin did not increase the percentage of patients with hypoglycemia among elderly patients with type 2 diabetes mellitus. However, hypoglycemia occurred more frequently in add-on therapy to sulfonylurea or when the sitagliptin dose was increased in combination therapy, showing that sitagliptin should be used with caution., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)