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Little is known about the subtypes of type 2 diabetes (T2D) and their association with clinical outcomes in Asians. We performed data-driven cluster analysis in patients with newly diagnosed drug-naive T2D (n = 756) from the Korean Genome and Epidemiology Study. Clusters were based on five variables (age at diagnosis, BMI, HbA1c, and HOMA2 β-cell function, and insulin resistance). We identified four clusters of patients with T2D according to k-means clustering: cluster 1 (22.4 %, severe insulin-resistant diabetes [SIRD]), cluster 2 (32.7 %, mild age-related diabetes [MARD]), cluster 3 (32.7 %, mild obesity-related diabetes [MOD]), and cluster 4 (12.3 %, severe insulin-deficient diabetes [SIDD]). During 14 years of follow-up, individuals in the SIDD cluster had the highest risk of initiation of glucose-lowering therapy compared to individuals in the other three clusters. Individuals in the MARD and SIDD clusters showed the highest risk of chronic kidney disease and cardiovascular disease, and individuals in the MOD clusters showed the lowest risk after adjusting for other risk factors (P < 0.05). Patients with T2D can be categorized into four subgroups with different glycemic deterioration and risks of diabetes complications. Individualized management might be helpful for better clinical outcomes in Asian patients with different T2D subgroups. [Display omitted] • Patients with type 2 diabetes can be categorized into four clusters with different diabetes-related outcomes. • Glycemic deterioration needed to initiate anti-diabetic therapy was earlier in severe insulin-deficient diabetes patients. • Patients with mild age-related diabetes and severe insulin-deficient diabetes showed the highest risk of complications. [ABSTRACT FROM AUTHOR]

Recent studies have shown that dysregulation of autophagy is involved in the development of nonalcoholic fatty liver disease (NAFLD). Transcription factors E3 (TFE3) and EB (TFEB) are master regulators of the transcriptional response of basic cellular processes such as lysosomal biogenesis and autophagy. Here, we investigated the role of fenofibrate, a PPARα agonist, in promotion of intracellular lipid clearance by upregulation of TFEB/TFE3. We investigated whether the effects of fenofibrate on livers were dependent on TFEB in high fat diet (HFD)-fed mice and in vivo Tfeb knockdown mice. These mice were analyzed for characteristics of obesity and diabetes; the effects of fenofibrate on hepatic fat content, glucose sensitivity, insulin resistance, and autophagy functional dependence on TFEB were investigated. HepG2, Hep3B, TSC2+/+ and tsc2−/− MEFs, tfeb wild type- and tfeb knockout-HeLa cells were used for in vitro experiments. Fenofibrate treatment activated autophagy and TFEB/TFE3 and reduced hepatic fat accumulation in an mTOR-independent manner. Knockdown of TFEB offset the effects of fenofibrate on autophagy and hepatic fat accumulation. In addition, fenofibrate treatment induced lysosomal Ca2+ release through mucolipin 1, activated calcineurin and the CaMKK β -AMPK-ULK1 pathway, subsequently promoted TFEB and TFE3 dephosphorylation and nuclear translocation. Treatment with calcium chelator or knockdown of mucolipin 1 in hepatocytes offset the effects of fenofibrate treatment on autophagy and hepatic fat accumulation. Activation of PPARα ameliorates hepatic fat accumulation via activation of TFEB and lipophagy induction. Lysosomal calcium signaling appears to play a critical role in this process. In addition, activation of TFEB by modulating nuclear receptors including PPARα with currently available drugs or new molecules might be a therapeutic target for treatment of NAFLD and other cardiometabolic diseases. • Activation of PPARα with fenofibrate induces lipophagy and improves hepatic steatosis. • Fenofibrate treatment mobilizes intracellular Ca2+ via lysosomal calcium channel mucolipin 1. • Fenofibrate treatment upregulates the CaMKK β -AMPK pathway and calcineurin and subsequently, increases TFEB activation. [ABSTRACT FROM AUTHOR]

Plasma-enhanced atomic layer deposition (PEALD) has demonstrated its superiority at coating ultra-conformal high dielectric thin-films, which are essential to the fin field-effect transistors (FinFETs) as well as the advanced 3D V-NAND (vertical Not-AND) flash memory cells. Despite the growing research interest, the exploration of the optimal operation policies for PEALD remains a complicated and expensive task. Our previous work has constructed a comprehensive 3D multiscale computational fluid dynamics (CFD) model for the PEALD process and demonstrated its potential to enhance the understanding of the process. Nevertheless, the limitation of computational resources and the relatively long computation time restrict the efficient exploration of the operating space and the optimal operating strategy. Thus, in this work, we apply a 2D axisymmetric reduction of the previous 3D model of PEALD reactors with and without the showerhead design. Furthermore, a data-driven model is derived based on a recurrent neural network (RNN) for process characterization. The developed integrated data-driven model is demonstrated to accurately characterize the key aspects of the deposition process as well as the gas-phase transport profile while maintaining computational efficiency. The derived data-driven model is further validated with the results from a full 3D multiscale CFD model to evaluate model discrepancy. Using the data-driven model, an operational strategy database is generated, from which the optimal operating conditions can be determined for the deposition of Hafnium Oxide (HfO 2) thin-film based on an elementary cost analysis. [ABSTRACT FROM AUTHOR]

Background Context: Vertebral fracture is related to an increased risk for subsequent and recurrent osteoporotic fracture as well as increased mortality. However, no study has investigated the exact incidence and mortality of subsequent vertebral fractures.Objective: The purpose of our study was to determine trends in the incidence and mortality of subsequent vertebral fractures after first-time vertebral fracture in Koreans older than 50 years using the national claims database.Study Design: Retrospective cohort study.Patient Sample: Data from the Korea National Health Insurance Service database from 2007 to 2016.Outcome Measures: The incidence of subsequent vertebral fracture during a 4-year follow-up period. The mortality and standardized mortality ratio (SMR) after subsequent vertebral fractures during the 1-year period after fracture were also determined. Analysis was restricted to patients older than 50 years.Methods: The national claims data set was analyzed to find all new visits and revisits after 6 months from the last claim to a hospital or clinic for vertebral fractures and revisits in men and women aged 50 years or older between 2007 and 2016. The number of first-time vertebral fractures in 2012 was investigated to determine subsequent vertebral fractures. The incidence, mortality rates, and SMR of subsequent vertebral fractures were calculated. There were no sources of funding and no conflicts of interest associated with this study.Results: During the 4-year follow-up period, the overall cumulative incidence of subsequent vertebral fractures were 27.53%. According to sex, the cumulative incidence of subsequent vertebral fractures was 20.09% in men and 29.98% in women. The cumulative mortality rate over the first year after subsequent vertebral fractures was 5%. The mortality rates over 1 year were 10.04% for men and 3.81% for women. The overall SMR at the 1-year follow-up after subsequent vertebral fractures was 10.58 (95% confidence interval: 9.29-12.05) in men and 3.88 (95% confidence interval: 3.5-4.3) in women.Conclusions: Our study showed that subsequent vertebral fractures were more common in women, with an incidence rate of 29.98% over 4 years. However, the mortality rate was higher in men, reaching 10.04% in 1 year. Subsequent vertebral fractures occurred in large numbers, and the mortality rates were relatively high. Thus, first vertebral fracture may be considered as an early warning of high risk for future subsequent vertebral fractures, especially in women. [ABSTRACT FROM AUTHOR]

Aster spathulifolius Maxim (AS), a perennial herb of the genus Aster within the family Asteraceae, induced weight loss in a rat model of diet-induced obesity. We hypothesized that AS could also reduce body weight in obese humans. Therefore, we performed a randomized, double-blind, placebo-controlled clinical trial in Korea to evaluate the effect of AS extract (ASE) on body weight and fat mass and its safety in obese humans. Forty-four obese participants (body mass index [BMI], 25-30 kg/m 2 ) aged ≥ 20 years were randomly assigned to the placebo or ASE group (700 mg/d of ASE) and were instructed to take a once-daily pill for 12 weeks. Weight, BMI, waist circumference, fat mass (measured using bioimpedance, dual-energy X-ray absorptiometry, and computed tomography), and laboratory tests were assessed at baseline and at 12 weeks. Body weight significantly decreased after 12 weeks of treatment in the ASE group (placebo vs ASE: − 0.08 ± 2.11 kg vs − 3.30 ± 3.15 kg, P < .05), and so did body fat mass (placebo vs ASE; bioimpedance method: − 0.51 ± 1.89 kg vs − 2.38 ± 2.30 kg, P < .05; dual-energy X-ray absorptiometry: 0.38 ± 1.59 kg vs − 2.26 ± 2.37 kg, P < .05). Changes in lipid profiles, fasting plasma glucose, and hemoglobin A1c did not differ between the 2 groups. No drug-related adverse events were observed during the study. In conclusion, ASE significantly decreases body weight and fat mass in obese humans, suggesting that ASE may be a potential therapeutic candidate for reducing obesity. [ABSTRACT FROM AUTHOR]

Aims Inflammatory processes are involved in bone remodeling. C-reactive protein (CRP) is an acute phase reactant that reflects different degrees of inflammation. Accumulating evidence suggests that CRP is an inflammatory marker and a direct cause of disease. Therefore, we examined the direct effects of CRP on bone cells. Main methods We used RAW 264.7 cells to evaluate the direct effects of CRP on osteoclast differentiation. We carried out alkaline phosphatase (ALP) and bone nodule formation assays using MC3T3-E1 cells to evaluate osteoblast differentiation. Expression of osteoclast-specific and osteoblast-specific genes and effects on cell signaling pathways associated with cell differentiation were analyzed by reverse transcription polymerase chain reaction and Western blotting. Key findings CRP significantly and dose-dependently inhibited TRAP-positive multinucleated cell formation in RANKL-induced RAW 264.7 cell cultures. We observed suppression of p38, ERK and AKT mitogen-activated protein kinases induced by RANKL in Western blots after CRP treatment of RAW 264.7 cells. CRP also suppressed ALP activity and mineralization by Alizarin red S staining of MC3T3-E1 cell cultures. CRP suppressed osteoclast-specific and osteoblast-specific genes. Furthermore, CRP increased interferon beta (IFN-β) mRNA expression and protein levels in RAW 264.7 and MC3T3-E1 cells, and these effects were suppressed by oxPAPC, an inhibitor of Toll-like receptor (TLR) signaling. Significance These data indicated that CRP may have a direct role on osteoclast and osteoblast differentiation via TLR signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Bisphenol A (BPA), a major component of epoxy resins used in protective coatings, is a known endocrine-disrupting chemical. BPA has the ability of binding to estrogen receptors. In the current paper, we examine the direct effects of bisphenol A on in vitro osteoclast and osteoblast culture systems. Main methods: We evaluated the effects of BPA on osteoclast formation using bone marrow-derived macrophages and RAW 264.7 cells and on osteoblast differentiation using MC3T3-E1 cells. Key findings: BPA significantly inhibited RANKL-induced, TRAP-positive multinucleated cell formation in bone marrow-derived macrophages and RAW 264.7 cell cultures in a dose-dependent manner (0.5μM to 12.5μM). We observed suppression of ERK, JNK, AKT, and p38 mitogen-activated protein kinases induced by RANKL in Western blotting after BPA treatment in RAW 264.7 cells. Furthermore, BPA suppressed Bcl-2 (anti-apoptotic) while stimulating Bax (pro-apoptotic) protein expression in RAW 264.7 cells. Bisphenol A also significantly suppressed ALP activities and bone nodule formation in MC3T3-E1 cell cultures. Specifically, the expression of Bcl-2 protein was decreased, and changes in expression of caspases 3, 8, and 9 were detected by BPA treatment in both cells. Significance: We found that bisphenol A directly suppressed both osteoclastic and osteoblastic activities in vitro. Our data suggest that bisphenol A suppresses cell differentiation and survival. [Copyright &y& Elsevier]

Abstract: Both IFG and IGT are prediabetic conditions that can progress to type 2 DM. However, previous studies have shown that these are not identical. This study was conducted on 307 drug naïve prediabetic adults who did not meet the diagnostic criteria for diabetes based on the OGTT. According to the OGTT, the subjects were divided into isolated IFG (i-IFG), isolated IGT (i-IGT), and combined glucose intolerance (CGI) group. We also measured insulin resistance indices (HOMA-IR, WBISI), an insulin secretion indices (insulinogenic index [IGI], AUC I/G0–120, disposition index [DI]), and compared each of the three groups. The OGTT measurements showed that 87 subjects were diagnosed with i-IFG, 75 subjects had i-IGT, and 145 subjects had CGI. With respect to the insulin resistance indices, HOMA-IR and WBISI were not significantly different. However, insulin secretory capacity, the IGI and DI were significantly higher for the i-IFG group. Moreover, after confounders were adjusted, HOMA-IR, IGI, AUC I/G0–120, and the DI were significantly higher for the i-IFG group and WBISI was significantly higher for the i-IGT group. These results demonstrate that the pathogenesis of IFG is more closely associated with insulin resistance, and the pathogenesis of IGT is more closely associated with impaired insulin secretion. [ABSTRACT FROM AUTHOR]

Objectives: Macrophage inflammatory protein-1α (MIP-1α), an osteoclast (OCL) stimulatory factor produced by primary multiple myeloma (MM) cells, increases bone destruction and tumor burden in murine models of MM. Several chemokine receptors (CCR1, CCR5, and CCR9) mediate the effects of MIP-1α. In this study, we determined which of these mediates the effects of MIP-1α on human OCL formation and myeloma cells. Methods: We employed RT-PCR analysis, neutralizing antibodies to CCR1 and CCR5 as well as a CCR1-specific antagonist and OCL formation assays to identify the MIP-1α receptors involved in MIP-1α''s effects on myeloma cells and OCL formation. Results: RT-PCR analysis demonstrated that both CCR1 and CCR5 were expressed by highly purified human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1α-induced OCL formation. Furthermore, monocyte chemotactic protein-3 (MCP-3), which binds CCR1 but not CCR5 and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1α. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of β1 integrin mRNA in myeloma cells induced by MIP-1α, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells. Conclusion: These data demonstrate that MIP-1α utilizes either CCR1 or CCR5 for its effects on OCL formation and myeloma cells, and that blocking either CCR1 or CCR5 inhibits OCL formation and myeloma cell adhesion to stromal cells. [Copyright &y& Elsevier]