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Abstract Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.

Abstract Mixed-stack complexes which comprise columns of alternating donors and acceptors are organic conductors with typically poor electrical conductivity because they are either in a neutral or highly ionic state. This indicates that conductive carriers are insufficient or are mainly localized. In this study, mixed-stack complexes that uniquely exist at the neutral–ionic boundary were synthesized by combining donors (bis(3,4-ethylenedichalcogenothiophene)) and acceptors (fluorinated tetracyanoquinodimethanes) with similar energy levels and orbital symmetry between the highest occupied molecular orbital of the donor and the lowest unoccupied molecular orbital of the acceptor. Surprisingly, the orbitals were highly hybridized in the single-crystal complexes, enhancing the room-temperature conductivity (10−4–0.1 S cm−1) of mixed-stack complexes. Specifically, the maximum conductivity was the highest reported for single-crystal mixed-stack complexes under ambient pressures. The unique electronic structures at the neutral–ionic boundary exhibited structural perturbations between their electron-itinerant and localized states, causing abrupt temperature-dependent changes in their electrical, optical, dielectric, and magnetic properties.

Abstract Suppression‐burst (SB) is an electroencephalographic pattern observed in neonatal‐ and infantile‐onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB‐EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB‐EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1‐DEE) with neonatal‐ and infantile‐onset DEE who presented with SB‐EEG were retrospectively identified. Five‐minute SB‐EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1‐DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (−6.1% and −7.7%) and the median duration of suppression was longer (4.0 and 8.2 s) in patients with KCNT1‐DEE than the other five (range: −2.9% to 0.9% and 0.7‐1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1‐DEE. SB phases may influence HR regulation in patients with KCTN1‐DEE.

Abstract Aims/Introduction Understanding morning–evening variation in metabolic state is critical for managing metabolic disorders. We aimed to characterize this variation from the viewpoints of insulin secretion and insulin sensitivity, including their relevance to the circadian rhythm. Materials and Methods A total of 14 and 10 people without diabetes were enrolled, and underwent a 75‐g oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp study, respectively. Participants completed the OGTT or hyperinsulinemic‐euglycemic clamp at 08.00 hours and 20.00 hours in random order. Before each study, hair follicles were collected. In mice, phosphorylation levels of protein kinase B were examined in the liver and muscle by western blotting. Results Glucose tolerance was better at 08 .00 hours, which was explained by the higher 1‐h insulin secretion on OGTT and increased skeletal muscle insulin sensitivity on hyperinsulinemic‐euglycemic clamp. Hepatic insulin sensitivity, estimated by the hepatic insulin resistance index on OGTT, was better at 20.00 hours. The 1‐h insulin secretion and hepatic insulin resistance index correlated significantly with Per2 messenger ribonucleic acid expression. The change (evening value – morning value) in the glucose infusion rate correlated significantly with the change in non‐esterified fatty acid, but not with clock gene expressions. The change in non‐esterified fatty acid correlated significantly with E4bp4 messenger ribonucleic acid expression and the change in cortisol. In mice, phosphorylation of protein kinase B was decreased in the liver and increased in muscle in the beginning of the active period as, expected from the human study. Conclusions Glucose metabolism in each tissue differed between the morning and evening, partly reflecting lipid metabolism, clock genes and cortisol levels. Deeper knowledge of these associations might be useful for ameliorating metabolic disorders.

Abstract Background The current study aimed to reveal the correlation of beta-cell function and insulin sensitivity with glycemic control and weight control before and after medical nutrition therapy (MNT) in patients with newly-diagnosed type 2 diabetes mellitus. Methods We retrospectively analyzed consecutive 68 patients with newly-diagnosed type 2 diabetes mellitus who started MNT without antihyperglycemic medications and underwent a 75-g oral glucose tolerance test (OGTT) before and after the therapy. Beta-cell function was evaluated by the OGTT-derived disposition index, whereas insulin sensitivity was evaluated by Matsuda’s insulin sensitivity index. Results After 4.0 ± 1.5 months of MNT, mean HbA1c and body mass index significantly decreased from 9.6 ± 1.8% to 7.2 ± 1.0% and from 26.9 ± 4.1 to 25.4 ± 3.7 kg/m2 (both P

Abstract Aims/Introduction This study aimed to reveal lifestyle changes and their impact on glycemic control and weight control in patients with diabetes during the coronavirus disease 2019 (COVID‐19) pandemic in Japan. Materials and Methods We retrospectively analyzed 1,402 outpatients with diabetes at a clinic in Osaka, Japan, who responded to an interview sheet regarding lifestyle changes during the COVID‐19 pandemic between 28 March and 30 May 2020. The association of lifestyle changes with hemoglobin A1c (HbA1c) and weight changes from February to May 2020 was investigated using the linear regression model. We also investigated the association with clinically important change of HbA1c (by ≥0.3%) and bodyweight (by ≥3%), using the cumulative link model. Results Leisure time and other outside physical activities were decreased in one‐quarter of patients during the COVID‐19 pandemic, whereas the amount of meals and snacks was decreased and increased in approximately 10%, respectively. The change in leisure time physical activities was inversely associated with HbA1c and weight changes, whereas the quantitative change of meals with the decline in eating out and that of snacks were positively associated with HbA1c and weight changes (all P

Pyroelectric materials exhibiting large and nearly constant pyroelectric coefficients over a wide temperature range are highly desirable. Here, the authors develop molecular [FeCo] crystals with continuous pyroelectricity, originating from a transition between three distinct electronic structures.

Abstract Aims/Introduction Pancreatic β‐cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of β‐cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on β‐cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents β‐cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets. Materials and Methods We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin‐treated MIN6 cells and islets isolated from Wfs1−/− and db/db mice. To study the anti‐apoptotic effect of ADM, ER stress‐exposed MIN6 cells were treated with ADM peptides or transfected with ADM expression plasmid. Results Pioglitazone increased the production and secretion of ADM in islets through peroxisome‐proliferator activated receptor‐γ‐dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1−/− and db/db mice. ADM peptides and ADM overexpression protected MIN6 cells from thapsigargin‐induced apoptosis. Conclusions ER stress stimulates ADM production and secretion in islets. ADM signaling might protect β‐cells from ER stress‐induced apoptosis, and might be one of the self‐protective mechanisms. β‐Cell protection by pioglitazone is partly through induction of ADM. ADM‐based therapy could be a novel strategy for treating diabetes.

By employing THz absorption and emission spectroscopy we were able to disentangle long-range charge order with a hundreds micrometer scale and short-range charge fluctuations that occur well above the charge-order phase transition in quasi-one-dimensional organic ferroelectrics, (TMTTF)_{2}X (X=AsF_{6}, PF_{6}, and SbF_{6}). While long-range charge order melts by photoexcitation irrespective of temperature or chemical pressure, short-range fluctuations are actually enhanced close to the charge-order phase boundary for X=AsF_{6} and PF_{6}. Our findings reveal that short-range fluctuations show various photoresponses depending on both temperature and electronic parameters, providing a design strategy for nonequilibrium states.

Abstract Background Nutritional status of the older people is affected by various life-style factors. Although dietary habit is one of the life-style factors, it is unknown which of older home-care recipients’ dietary habits are associated with malnutrition. The purpose of this study was to examine the association of dietary variety, as an evaluation index for dietary habits, with malnutrition in Japanese older home-care recipients. Methods This cross-sectional study was conducted in a single city, Hyogo Prefecture, Japan between July and October 2016. Three hundred thirty-three community-dwelling older care recipients (aged 65 years or older who were receiving home-visit nursing care services) were enrolled. Their nutritional status (Mini Nutritional Assessment®-short form: MNA®-SF), dietary variety (Food frequency score [FFS]), socio-demographic characteristics (age, sex, marital status, etc.), health indicators (comorbidity [Charlson Comorbidity Index] and dysphagia status [Dysphagia Severity Scale]) were assessed. The participants were classified into two groups: malnourished (0–7 points) and non-malnourished (8–14 points), according to their MNA®-SF scores. Multivariate logistic regression analysis was used to examine the factors associated with malnutrition. Results A total of 317 participants were analyzed (118 men, 199 women, median age: 84 years). Compared to the fourth (highest) quartile of FFS, odds ratios (OR) (95% confidence intervals [CI]) of the third, second, and first (lowest) quartiles of FFS were 1.08 (0.42–2.80), 1.29 (0.56–2.98), and 2.30 (1.02–5.19), respectively (p for trend = 0.049). Higher Charlson Comorbidity Index score and the presence of dysphagia were also significantly associated with malnutrition (OR: 2.08, 95% CI: 1.08–4.00 and OR: 3.86, 95% CI: 2.08–7.17, respectively). Conclusion Lower dietary variety was significantly associated with malnutrition in Japanese older home-care recipients.

Abstract Background Treatment satisfaction and medication adherence can be improved if physicians carefully monitor the situations, check the level of difficulties patients experience when taking medications at specific times, and readjust medication regimens based on this information. However, physicians in Japan encounter difficulties in taking enough time to collect this information in clinical practice. The aim of the current study was to investigate improvements in satisfaction and adherence with the cooperation of a health insurance pharmacy in clinical practice. Methods We retrospectively analyzed 29 type 2 diabetic outpatients who were receiving their prescriptions at a medical clinic and filling prescriptions at a nearby pharmacy. The pharmacy collected information regarding satisfaction, adherence, and preferred time of taking medications, and provided these data to the clinic. The oral medication regimens for these 29 patients were readjusted based on the information obtained. Results After readjustments, the dosing frequency was decreased from 3.4 ± 1.2 to 1.8 ± 0.5 times/day, and the number of pills was reduced from 5.7 ± 2.0 to 4.5 ± 1.7 (both p

A temperature-modulated pyroelectricity measurement system for a small single crystal is developed and applied to standard sample measurements performed on a thin single crystal of lithium niobate. The modulation measurement is based on the AC technique, in which the temperature of the sample is periodically oscillated, and the synchronized pyroelectric signal is extracted using a lock-in amplifier. Temperature modulation is applied by irradiating periodic light on the sample placed in the heat exchange gas. To apply this technique to the transparent reference sample, a commercially available black resin is coated on the sample’s surface to absorb the light energy and transmits it to the specimen. The experimental results are analyzed using a two-layer heat transfer model to verify the effect of the light-absorbing layer as well as the radiative temperature modulation system.

In Wfs1−/− Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.

Through Bayesian optimization and the least absolute shrinkage and selection operator (LASSO) technique combined with first-principles calculations, we investigated the tunnel magnetoresistance (TMR) effect of Fe/disordered-MgAl_{2}O_{4}(MAO)/Fe(001) magnetic tunnel junctions (MTJs) to determine the structures of disordered-MAO that give large TMR ratios. The optimal structure with the largest TMR ratio was obtained by Bayesian optimization with 1728 structural candidates, where the convergence was reached within 300 structure calculations. Characterization of the obtained structures suggested that the in-plane distance between two Al atoms plays an important role in determining the TMR ratio. Since the Al-Al distance of disordered MAO significantly affects the imaginary part of complex band structures, the majority-spin conductance of the Δ_{1} state in Fe/disordered-MAO/Fe MTJs increases with increasing in-plane Al-Al distance, leading to larger TMR ratios. Furthermore, we found that the TMR ratio tended to be large when the ratio of the number of Al, Mg, and vacancies in the [001] plane was 2:1:1, indicating that the control of Al atomic positions is essential to enhancing the TMR ratio in MTJs with disordered MAO. The present work reveals the effectiveness and advantage of materials informatics combined with first-principles transport calculations in designing high-performance spintronic devices based on MTJs.

In vivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects of chronic synaptic activation on Aβ pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. In vivo microdialysis revealed a ∼24% increase in the hippocampal interstitial fluid Aβ42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Aβ burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ∼2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Aβ pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Aβ pathology and Alzheimer disease.

New Fe(III) compounds from qsal ligand, [Fe(qsal)2](CH3OSO3) (1) and [Fe(qsal)2](CH3SO3)·CH3OH (3), along with known compound, [Fe(qsal)2](CF3SO3) (2), were obtained as large well-shaped crystals (Hqsal = N-(8-quinolyl)salicylaldimine). The compounds 1 and 2 were in the low-spin (LS) state at 300 K and exhibited a cooperative spin crossover (SCO) transition with a thermal hysteresis loop at higher temperatures, whereas 3 was in the high-spin (HS) state below 300 K. The optical conductivity spectra for 1 and 3 were calculated from the single-crystal reflection spectra, which were, to the best of our knowledge, the first optical conductivity spectra of SCO compounds. The absorption bands for the LS and HS [Fe(qsal)2] cations were assigned by time-dependent density functional theory calculations. The crystal structures of 1 and 2 consisted of a common one-dimensional (1D) array of the [Fe(qsal)2] cation, whereas that of 3 had an unusual 1D arrangement by π-stacking interactions which has never been reported. The crystal structures in the high-temperature phases for 1 and 2 indicate that large structural changes were triggered by the motion of counter anions. The comparison of the crystal structures of the known [Fe(qsal)2] compounds suggests the significant role of a large non-spherical counter-anion or solvate molecule for the total lattice energy gain in the crystal of a charged complex.