Using atomic clustering based on structural and electronic descriptors that consider surrounding environment to evaluate local properties of DFT functionals.

We developed a method for evaluating the accuracies of the local properties of DFT functionals in detail using a clustering method based on machine learning and structural/electronic descriptors. We generated 36 clusters consistent with human intuition using 30,436 carbon atoms from the QM9 dataset. The results were used to evaluate 13C NMR chemical shifts calculated using 84 DFT functionals. Carbon atoms were grouped based on their similar environments, reducing errors within these groups. This enables more accurate assessment of the accuracy using a specific DFT functional. Therefore, the present atomic clustering provides more detailed insight into accuracy verification.

Thiocholine-Mediated One-Pot Peptide Ligation and Desulfurization.

Thiol catalysts are essential in native chemical ligation (NCL) to increase the reaction efficiency. In this paper, we report the use of thiocholine in chemical protein synthesis, including NCL-based peptide ligation and metal-free desulfurization. Evaluation of thiocholine peptide thioester in terms of NCL and hydrolysis kinetics revealed its practical utility, which was comparable to that of other alkyl thioesters. Importantly, thiocholine showed better reactivity as a thiol additive in desulfurization, which is often used in chemical protein synthesis to convert Cys residues to more abundant Ala residues. Finally, we achieved chemical synthesis of two differently methylated histone H3 proteins via one-pot NCL and desulfurization with thiocholine.

RAQET: Large-scale two-component relativistic quantum chemistry program package.

The Relativistic And Quantum Electronic Theory (RAQET) program is a new software package, which is designed for large-scale two-component relativistic quantum chemical (QC) calculations. The package includes several efficient schemes and algorithms for calculations involving large molecules which contain heavy elements in accurate relativistic formalisms. These calculations can be carried out in terms of the two-component relativistic Hamiltonian, wavefunction theory, density functional theory, core potential scheme, and evaluation of electron repulsion integrals. Furthermore, several techniques, which have frequently been used in non-relativistic QC calculations, have been customized for relativistic calculations. This article introduces the brief theories and capabilities of RAQET with several calculation examples. © 2018 Wiley Periodicals, Inc.

Cognitive and self-regulation skills for employment among people with brain injury: A comparison of employed and non-employed people using mixed analysis.

BACKGROUND: Employment for people with brain injuries is challenging, and identifying the factors that can be improved by rehabilitation and establishing appropriate intervention methods are imperative. OBJECTIVE: To examine whether differences in cognitive functions and self-regulation skills exist between employed and non-employed people with brain injuries. In addition, we explored the self-regulation skills characteristic of employed people by qualitatively comparing them to those of non-employed people. METHODS: Using a mixed research method, demographic data, neuropsychological tests, self-efficacy, and self-regulation skills were compared between 38 people with brain injuries (16 employed and 22 unemployed) in the community. Subsequently, self-regulation skills were assessed by the Self-Regulation Skills Interview (SRSI), and participants' responses were qualitatively compared. RESULTS: No significant differences were observed in demographic data and neuropsychological tests, but employed people showed significantly better SRSI scores than unemployed people (p <  0.01). The qualitative analysis of the SRSI showed that employed people recognised themselves as having more specific symptoms than unemployed people. For example, they recognised the behaviour 'when having more than one errand, forgetting it', whereas non-employed people only recognised the category 'failure of prospective memory'. Furthermore, employed people reviewed their behaviour and developed ingenious coping strategies, such as 'looking back on appointments that have been made', 'writing down as soon as having a schedule', whereas unemployed people only exhibited categories such as 'writing schedules on the cell phone'. CONCLUSIONS: Self-regulation skills, such as recognising specific symptoms and developing relevant coping strategies, are effective for gaining employment.

Analytical energy gradient based on spin-free infinite-order Douglas-Kroll-Hess method with local unitary transformation.

In this study, the analytical energy gradient for the spin-free infinite-order Douglas-Kroll-Hess (IODKH) method at the levels of the Hartree-Fock (HF), density functional theory (DFT), and second-order Møller-Plesset perturbation theory (MP2) is developed. Furthermore, adopting the local unitary transformation (LUT) scheme for the IODKH method improves the efficiency in computation of the analytical energy gradient. Numerical assessments of the present gradient method are performed at the HF, DFT, and MP2 levels for the IODKH with and without the LUT scheme. The accuracies are examined for diatomic molecules such as hydrogen halides, halogen dimers, coinage metal (Cu, Ag, and Au) halides, and coinage metal dimers, and 20 metal complexes, including the fourth-sixth row transition metals. In addition, the efficiencies are investigated for one-, two-, and three-dimensional silver clusters. The numerical results confirm the accuracy and efficiency of the present method.

Efficacy and safety of a telemedicine system in subjects with gestational diabetes mellitus (TELEGLAM): Study protocol for a randomized controlled trial.

Background: Strict glycemic control is important to prevent perinatal complications in patients with gestational diabetes mellitus (GDM). Patients often require insulin injection, and frequent hospital visits are necessary to adjust the dose of insulin, which is considered burdensome for pregnant patients. Telemedicine may reduce the burden of hospital visits, and previous studies have reported its safety in GDM patients. This study aimed to evaluate the efficacy of telemedicine in GDM patients, focusing on patient satisfaction and health economic indicators. Methods: This is a single-center, two-arm, randomized, open-label parallel-group study. Subjects will be selected from the patient population attending the Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Japan. Patients diagnosed with GDM by an oral glucose tolerance test (OGTT) by 29 weeks and 6 days of gestation who have undergone self-monitoring of blood glucose (SMBG) and insulin injection are eligible for inclusion. In the intervention group, telemedicine will be administered using the MeDaCa telemedicine system developed by the Medical Data Card, Inc., Tokyo, Japan. Subjects in the control group will be examined face-to-face every 2-3 weeks, as usual. We set health economic indicators and patient satisfaction as the primary endpoints, and will perform a cost-consequence analysis. Glycemic control indicators and perinatal outcomes will be evaluated as secondary endpoints. Conclusions: Eligible patients are currently being recruited. Recruitment will be completed when the expected number of patients are enrolled.

Newly developed type 1 diabetes after coronavirus disease 2019 vaccination: A case report.

The vaccine for the coronavirus disease 2019 (COVID-19) has been reported to potentially cause or worsen diabetes. A 73-year-old Japanese woman received two doses of Moderna COVID-19 vaccine. Four weeks after the second vaccination, her glycemic control began to deteriorate, and 8 weeks after the second vaccination, the patient was diagnosed with new-onset type 1 diabetes that was strongly positive for autoantibodies and showed a disease-susceptible human leukocyte antigen haplotype, DRB1*04:05:01-DQB1*04:01:01. The glucagon stimulation test suggested an insulin-dependent state, and induction of intensive insulin therapy brought about fair glycemic control. The time period from the COVID-19 vaccination to the development of type 1 diabetes was relatively longer than to the onset or exacerbation of type 2 diabetes, as previously reported, suggesting the complicated immunological mechanisms for the destruction of ß-cells associated with the vaccination. In recipients with the disease-susceptible haplotypes, one should be cautious about autoimmune responses for several months after the vaccination.

A Set of Highly Sensitive Sirtuin Fluorescence Probes for Screening Small-Molecular Sirtuin Defatty-Acylase Inhibitors.

Human sirtuins (SIRT1-7) regulate not only deacetylation but also deacylation of fatty acid-derived acyl moieties (defatty-acylation) at the ε-amino group of lysine residues. SIRT-subtype-specific defatty-acylase activity modulators are needed for detailed investigation of the biological roles of these enzymes, and to find suitable small molecules, we require appropriate screening systems. Here, we designed and synthesized a set of SIRT defatty-acylase activity probes with various quencher moieties and peptide sequences based on our previously developed one-step FRET-based SIRT probe SFP3, using improved methodology. Scanning of this set of probes with SIRT isozymes revealed that certain probe/isozyme combinations showed especially high responses. To illustrate the utility of the combinations thus identified, we applied compound 18/SIRT2 for inhibitor screening of a large chemical library. This enabled us to discover a new small molecule SIRT2-specific defatty-acylase inhibitor.

Bile acid binding resin prevents fat accumulation through intestinal microbiota in high-fat diet-induced obesity in mice.

BACKGROUND: Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. PROCEDURES: Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. MAIN FINDINGS: The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. CONCLUSIONS: Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity.

GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice.

AIMS: Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. METHODS: Anti-CD3 antibody was administered to female BALB/c and C.B-17-scid mice with or without reconstitution by naïve CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. RESULTS: The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17-scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo, and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. CONCLUSIONS: Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.

Implementation of Analytical Energy Gradient of Spin-Dependent General Hartree-Fock Method Based on the Infinite-Order Douglas-Kroll-Hess Relativistic Hamiltonian with Local Unitary Transformation.

An analytical energy gradient for the spin-dependent general Hartree-Fock method based on the infinite-order Douglas-Kroll-Hess (IODKH) method was developed. To treat realistic systems, the local unitary transformation (LUT) scheme was employed both in energy and energy gradient calculations. The present energy gradient method was numerically assessed to investigate the accuracy in several diatomic molecules containing fifth- and sixth-period elements and to examine the efficiency in one-, two-, and three-dimensional silver clusters. To arrive at a practical calculation, we also determined the geometrical parameters of fac-tris(2-phenylpyridine)iridium and investigated the efficiency. The numerical results confirmed that the present method describes a highly accurate relativistic effect with high efficiency. The present method can be a powerful scheme for determining geometries of large molecules, including heavy-element atoms.

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver.

AIMS: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. RESULTS: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.