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Abstract Metal homeostasis is tightly regulated in cells and organisms, and its disturbance is frequently observed in some diseases such as neurodegenerative diseases and metabolic disorders. Previous studies suggest that zinc and iron are necessary for the normal functions of pancreatic β cells. However, the distribution of elements in normal conditions and the pathophysiological significance of dysregulated elements in the islet in diabetic conditions have remained unclear. In this study, to investigate the dynamics of elements in the pancreatic islets of a diabetic mouse model expressing human islet amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis of elements using synchrotron scanning X-ray fluorescence microscopy and quantitative analysis of elements using inductively coupled plasma mass spectrometry. We found that in the islets, zinc significantly decreased in the early stage of diabetes, while iron gradually decreased concurrently with the increase in blood glucose levels of hIAPP-Tg mice. Notably, when zinc and/or iron were decreased in the islets of hIAPP-Tg mice, dysregulation of glucose-stimulated mitochondrial respiration was observed. Our findings may contribute to clarifying the roles of zinc and iron in islet functions under pathophysiological diabetic conditions.

Abstract Aims/Introduction This study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus. Materials and Methods This retrospective cross‐sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models. Results The AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis‐4 (Fib‐4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography‐diagnosed fatty liver. There was a significant interaction between BMI and Fib‐4 index; lower BMI and Fib‐4 index >2.67 showed a synergistic association with high AAC grade. Conclusions AAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib‐4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.

Background: Physical risk factors for osteochondritis dissecans (OCD) of the humeral capitellum in young baseball players have not been fully elucidated. We aimed to identify the risk factors for capitellar OCD in baseball players aged 8-14 years. Methods: Between December 2018 and December 2019, young baseball players were recruited from 8 regional baseball leagues. Ultrasonography and physical assessments were performed preseason and at the end of the study period. Bilateral passive ranges of motion (ROM) of horizontal adduction of the shoulders, internal rotation (IR) of the hips, and the thoracic kyphosis angle were measured. 1-year follow-ups were scheduled to determine the occurrence of OCD. Players with OCD were categorized into an OCD group; those without OCD and any elbow pain for one year were categorized into a non-injured group. The players’ baseline data (age, sex, position in baseball, and Rohrer's Index) were analyzed using univariate analyses. Their physical parameters were analyzed using two-way analysis of variance with repeated measures to investigate OCD-related risk factors. Results: In total, 3651 baseball players attended the 1-year follow-up. Of these, 71 (1.9%) players had OCD of the humeral capitellum. In the OCD group, a significant association was found at baseline and at the end of the study period between a higher Rohrer index at the baseline and a smaller hip IR ROM on the nondominant side. Conclusions: Loss of hip IR ROM on the nondominant side is a newly discovered risk factor related to physical function in the development of OCD.

Summary: Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

Summary: Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.

Abstract Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM. Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from Nov 15, 2017.

Abstract Background Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes. Methods We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes. Results The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P

Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote β-cell proliferation in human islets. We measured serum SerpinB1 levels in Japanese subjects with or without type 2 diabetes (T2DM). We enrolled 12 normal glucose tolerance (NGT) and 51 T2DM subjects. There was no difference in serum SerpinB1 levels between the 2 groups (T2DM, 1.3 ± 0.9 ng/mL vs. NGT, 1.8 ± 1.7 ng/mL; P = 0.146). After adjusting for age and sex, the serum SerpinB1 levels were positively correlated with HOMA2-%S (β = 0.319, P = 0.036), and negatively correlated with fasting blood glucose (β = -0.365, P = 0.010), total cholesterol (β = -0.396, P = 0.006), low-density lipoprotein (LDL) cholesterol (β = -0.411, P = 0.004), triglycerides (β = -0.321, P = 0.026), and γGTP (β = -0.322, P = 0.026) in subjects with T2DM. Thus, circulating SerpinB1 is possibly associated with insulin sensitivity and better blood glucose level in Japanese subjects with T2DM. Trial registration: UMIN Clinical Trials Registry, UMIN000020453.

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

The corneal endothelium maintains corneal transparency by its pump and barrier functions; consequently, its decompensation due to any pathological reason causes severe vision loss due to corneal haziness. Corneal transplantation is the only therapeutic choice for treating corneal endothelial dysfunction, but associated problems, such as a shortages of donor corneas, the difficulty of the surgical procedure, and graft failure, still need to be resolved. Regenerative medicine is attractive to researchers as a means of providing innovative therapies for corneal endothelial dysfunction, as it now does for other diseases. We previously demonstrated the successful regeneration of corneal endothelium in animal models by injecting cultured corneal endothelial cells (CECs) in combination with a Rho kinase (ROCK) inhibitor. The purpose of the present study was to optimize the vehicle for clinical use in cell-based therapy. Our screening of cell culture media revealed that RELAR medium promoted CEC adhesion. We then modified RELAR medium by removing hormones, growth factors, and potentially toxic materials to generate a cell therapy vehicle (CTV) composed of amino acid, salts, glucose, and vitamins. Injection of CECs in CTV enabled efficient engraftment and regeneration of the corneal endothelium in the rabbit corneal endothelial dysfunction model, with restoration of a transparent cornea. The CECs retained >85% viability after a 24 hour preservation as a cell suspension in CTV at 4°C and maintained their potency to regenerate the corneal endothelium in vivo. The vehicle developed here is clinically applicable for cell-based therapy aimed at treating the corneal endothelium. Our strategy involves the generation of vehicle from a culture medium appropriate for a given cell type by removing materials that are not favorable for clinical use.

We synthesized several protic ionic liquids (ILs) composed of onium cations and the (trifluoromethylsulfonyl)(vinylsulfonyl)amide anion. The addition of a base catalytically facilitated their transformation into zwitterions (ZIs) under solvent-free conditions, which is a convenient method for synthesizing ZIs from ILs. [ABSTRACT FROM AUTHOR]

We determined the emissivity of molten oxides using a commercially available pyrometer combined and an electromagnetic levitation system based on the liquid Fe emissivity and its melting temperature. Our method for determining molten oxide emissivity is based on immiscible molten oxides and liquid Fe. From the processes, we obtained 0.80 ± 0.03 for molten AI2O3 and 0.76 ± 0.01 for our desired molten oxide of SiO2-CaO-Mn3O4-TiO2 system with welding flux model compositions of SiO2:CaO:Mn3O4:TiO2=27:7:13:53 mass%. This is necessary when using ELF (electrostatic levitation furnace) in the ISS (International Space Station) to measure the thermophysical properties of molten oxides. We could correct the temperature monitored with emissivity set at 1 to the real temperature during density measurement by ELF in ISS using normal spectral emissivity for molten SiO2-CaO-Mn3O4-TiO2 system and we find the temperature dependence of molten oxides density of SiO2:CaO:Mn3O4:TiO2=27:7:13:53 mass%in the temperature range of 1200 K - 2000 K. We also find that the multicomponent oxide system of SiO2-CaO-Mn3O4-TiO2 has a low coefficient of density temperature dependence. [ABSTRACT FROM AUTHOR]

Background/aims: To investigate the chronological corneal changes associated with long-term rigid gas-permeable contact lens (RGP-CL) wear in patients with keratoconus (KC). Methods: Clinical records of 405 patients with KC or with KC suspect were retrospectively reviewed. Patients with mild-to-moderate KC and uneventful follow-up were classified into the CL (RGP-CL wear) and non-CL (without CL wear) groups. Inclusion criteria were (1) at least 3-year follow-up and (2) Scheimpflug-based corneal imaging examination at each visit. The anterior (ARC) and posterior (PRC) radius of curvature obtained in a 3.0 mm optical zone, the thinnest pachymetry reading of the corneal thickness (Tmin), and maximum keratometry values (Kmax) were investigated as tomographic parameters. Results: Twenty-two and 15 patients who met the inclusion criteria were included in the CL and non-CL groups, respectively (31 and 20 eyes, respectively). The mean observation periods were 75 (CL group) and 63 (non-CL group) months. A multivariable non-linear regression analysis to assess the change in tomographic parameters over the follow-up period and difference of the trend between the two groups demonstrated no significant differences in the chronological change in ARC, PRC and Tmin between the CL and non-CL groups (p=0.318, p=0.280 and p=0.874, respectively). Conclusion: Based on corneal tomographic evaluation over 5-6 years, the effects of long-term RGP-CL wear had no effect on KC progression. [ABSTRACT FROM AUTHOR]

PURPOSE: To test the detection of subclinical corneal ectasia using integrated Scheimpflug tomography and biomechanical assessment in a Japanese population. METHODS: This prospective, case-control study included 23 patients with very asymmetric ectasia (VAE) and 70 normal controls. Patients with VAE had defined clinical ectasia in one eye and a fellow eye with normal topography (VAE-NT). Objective topography for confirming normal topography in VAE-NT cases included having 0% similarity and 0% severity derived from Placido-disk based topography. Scheimpflug-based corneal tomography and corneal biomechanical assessment were performed. The Belin/Ambrósio Enhanced Ectasia Deviation index (BAD-D), Corvis Biomechanical Index (CBI), and Tomographic Biomechanical Index (TBI) were compared and their discriminating ability for detecting ectasia was assessed. RESULTS: For differentiating normal and VAE-NT eyes, the areas under the receiver operating curve for the BAD-D, CBI, and TBI were 0.668, 0.660, and 0.751, respectively. The TBI cut-off of 0.259 provided 52.17% sensitivity and 88.57% specificity. Fourteen VAE-NT cases (60.9%) were abnormal in at least one of the criteria of the BAD-D > 1.60 (39.1%), CBI > 0.5 (26.1%), or TBI > 0.29 (43.5%). Conversely, nine VAE-NT cases (39.1%) exhibited normal values for the BAD-D, CBI, and TBI. CONCLUSIONS: In the current study, 40% of VAE-NT eyes were classified as normal by the BAD-D, CBI, and TBI. Although some of these cases may truly represent unilateral ectasia, further advances are needed to enhance ectasia detection and characterize the susceptibility for ectasia progression. [ABSTRACT FROM AUTHOR]

Control over the electronic structure in -conjugated polymers is of great importance for the development of organic electronics and spintronics. In this study, we synthesized a sheathed cross-conjugated polythiophene through oxidative electrochemical polymerization. Spectroelectrochemistry has revealed that unlike linearly conjugated polythiophenes, polarons were confined in the repeating units that were segmented by cross-conjugation. [ABSTRACT FROM AUTHOR]

Recently, we reported a new synthetic approach toward a series of thiacalix[n]thiophene and thiacalix[n]dithienothiophene derivatives, cyclic homologues of sulfur-bridged cyclic oligothiophenes. A palladium-catalyzed coupling reaction of stannyl sulfide (Bu3Sn)2S and dibromothiophene/dibromodithienothiophene derivatives gave the corresponding macrocycles in good yield. Substituents at the β-position can play a key role in effective cyclization. This paper also summarizes the molecular and electronic structures of the novel macrocycles. Unlike conventional calixarenes, they exhibit distinct electron-donating properties. Furthermore, self-assembly and host-guest properties, leading to supramolecular structures, are also briefly discussed. [ABSTRACT FROM AUTHOR]

The corneal endothelium is essential for maintaining corneal transparency; therefore, corneal endothelial dysfunction causes serious vision loss. Tissue engineering-based therapy is potentially a less invasive and more effective therapeutic modality. We recently started a first-in-man clinical trial of cell-based therapy for treating corneal endothelial dysfunction in Japan. However, the senescence of corneal endothelial cells (CECs) during the serial passage culture needed to obtain massive quantities of cells for clinical use is a serious technical obstacle preventing the push of this regenerative therapy to clinical settings. Here, we show evidence from an animal model confirming that senescent cells are less effective in cell therapy. In addition, we propose that density-gradient centrifugation can eliminate the senescent cells and purify high potency CECs for clinical use. This simple technique might be applicable for other types of cells in the settings of regenerative medicine. [ABSTRACT FROM AUTHOR]

This paper proposes a thermal design procedure for micro- and nanosatellites that can be completed in one year. Two thermal design concepts keep components within their design temperature range, reducing the temperature change by using the whole structure for heat storage and reducing the temperature change of the inner structure where the most temperature-sensitive components are mounted. One- and two-nodal analysis methods are used for the former and latter concepts, respectively, to clarify the combinations of optical properties for the structures and components to keep within the design temperature range of the components. Finally, multinodal analysis is performed for detail design based on the optical properties clarified from the one- and two-nodal analyses. This thermal design procedure was applied to the Hodoyoshi-1 satellite, which is a cube about 50 cm on a side, has two inner plates and has solar cells on the body, is on a sun-synchronous orbit at an altitude of about 500 km, and is pointing to Earth. The thermal design of the Hodoyoshi-1 satellite was completed in about 10 months. [ABSTRACT FROM AUTHOR]

A new procedure for the thermal design of micro- and nano-satellites is proposed for completing the thermal design of micro- and nano-satellites within about one year. First, two concepts of thermal design are considered for maintaining the temperature change of units within an allowable range. One concept involves decreasing the temperature change of units by using the whole thermal capacity of the micro- and nano-satellite. The other concept involves decreasing the temperature change of the inner structure on which units with a narrow allowable temperature range are mounted and which is insulated conductively from the outer structure. Then, the temperatures of micro- and nano-satellites designed with the former concept are calculated using a one-node analysis method. The temperatures of micro- and nano-satellites designed with the latter concept are calculated using a two-node analysis method. The combinations of optical properties of the structures and units to maintain the temperature of units within the allowable range are obtained by using one- or two-node analysis. Finally, the multinode analyses are carried out to obtain a detailed design based on the optical properties obtained from the one-node analysis or two-node analysis. This thermal design procedure is applied to the Hodoyoshi-1 satellite, which is about 50 cm wide, 50 cm deep, 50 cm high, has a mass of about 50 kg, two inner plates, and solar cells on the body, flies on the Sun-synchronous orbit at the altitude of 500 km, and is pointing to the Earth. The thermal design of this micro-satellite was completed within about ten months. Possible problems with the procedure are tested, and the procedure is verified. [ABSTRACT FROM AUTHOR]

Self-assembly and fibrous structure formation based on pyridazine-3,6-diol-annulated tetrathiafulvalene derivative were investigated. Although the molecules formed a trimeric assembly with complementary hydrogen bonds in solution, the addition of water produced micrometer fibrous structures. On the other hand, mixing of diamines (NH2-R-NH2) promoted reorganization of the self-assembly, and various nanoobjects were formed. [ABSTRACT FROM AUTHOR]