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Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high‐fat diet and retrograde administration of sodium taurocholate were employed to establish the HP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator‐activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism‐related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin‐8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α‐amylase, total cholesterol, low‐density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high‐density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP‐1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP. [ABSTRACT FROM AUTHOR]

• Elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, and cancer among middle-aged and elderly Chinese. • The weighted genetic risk score constructed on 18 established Hcy-related genetic variants had significant interaction with Hcy on CHD mortality. • The rs7130284 and rs957140 on NOX4 gene modified the association between Hcy and mortality from CVD and CHD. • The rs154657 on DPEP1 gene modified the association between Hcy and CHD mortality. The associations of homocysteine (Hcy) and gene-Hcy interactions with the risk of all-cause and cause-specific mortality remain unclear. A total of 19,826 middle-aged and elderly Chinese adults were included from the Dongfeng-Tongji cohort in 2013–2014 and were followed-up to 31 December 2018. Cox regression was used to examine the association between Hcy and mortality. We selected 18 well-established Hcy-associated genetic variants to constructed the weighted genetic risk score (GRS) among 15,434 participants with genetic data, and interactions between genetic susceptibility and Hcy on mortality were assessed. After multivariate adjustment, elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, coronary heart disease (CHD), stroke, and cancer. We also observed a significant interaction between GRS and Hcy on CHD mortality. Moreover, the rs7130284 and rs957140 on NOX4 modified the association between Hcy and mortality from CVD and CHD, and rs154657 on DPEP1 modified the association between Hcy and CHD mortality. Elevated Hcy levels were associated with increased risk of all-cause and cause-specific mortality among middle-aged and elderly Chinese. Hcy-related genetic variants on NOX4 and DPEP1 might modify the associations of Hcy with CVD mortality or CHD mortality. [ABSTRACT FROM AUTHOR]

The associations of sleep duration and midday napping with homocysteine (Hcy) levels, and whether these sleep behaviors modify the association between genetic predisposition and Hcy levels, has yet to be investigated. We included 19,426 participants without severe health conditions at baseline from the Dongfeng–Tongji cohort. In a subgroup of 15,126 participants with genetic data, a genetic risk score (GRS) based on 18 Hcy-related loci was constructed to test the gene–sleep interactions in Hcy. Hcy levels were higher in subjects with a long sleep duration (≥9 h) and midday napping (>90 min), as compared to those who reported a moderate sleep duration (7 to <8 h) and midday napping (1–30 min) (all p values < 0.05). A long sleep duration and midday napping showed a joint effect in increasing Hcy (p for trend < 0.001). Significant interactions regarding Hcy levels were observed for a long sleep duration with GRS and MTHFR rs1801133, and long midday napping with DPEP1 rs12921383 (all p values for interaction < 0.05). Overall findings indicated that a long sleep duration and midday napping were associated with elevated serum Hcy levels, independently and jointly, and amplified the genetic susceptibility to higher Hcy. [ABSTRACT FROM AUTHOR]

To establish a gold/silica hybrid, nanomaterials (Au/SiO2) were incorporated into a gelatin methacrylate/chitosan matrix. By using FESEM, compressive strength testing, and conductivity/resistance measurements on gelatin (G)/chitosan (C), G/C-Au@SiO2 hydrogels developed. Biocompatibility investigations on osteoblasts MG-63 cells were carried out to determine whether the cell was compatible with the conductive hydrogel as it had been created. The results indicated that HNPs had improved compressive strength and conductivity without losing the favourable features such as biodegradable nature and porous shape of G/C hydrogel. The mechanical properties and Elastic modulus of composites hydrogels were enhanced twofold when hybrid nanomaterials were added to the mixture. The cyclic compressive analysis shows that pure G/C hydrogels lost their mechanical stability within the first few cycles, but G/C-Au@SiO2 hydrogels lasted for up to fifty cycles. It was demonstrated that osteoblast proliferation and adhesion were increased on the hydrogel in the CCK-8 experiment. Further, the cell survival of the hydrogels with G/C-Au@SiO2 conductivity was enhanced by 15% compared to that of pure G/C hydrogels. The morphological features of the MG-63 cells experiments were performed by using a Fluorescein diacetate hydrolysis (FDA) staining assay. This work offers a unique method for enhancing mechanical integrity and electrical properties in gelatin-based G/C hydrogels by adding bifunctional hybrid nanomaterials (HNPs) for bone fracture tissue engineering applications. [ABSTRACT FROM AUTHOR]

Objective. The aim of the study was to explore the application and the effect of the triple prerehabilitation nursing model in the perioperative period of knee arthroplasty in diabetic patients. Methods. The prospectively included 60 patients with diabetes who underwent total knee replacement were admitted from August 2021 to April 2022 and were divided into 2 groups according to the (1 : 1) ratio. The control group was mainly given routine nursing care. On the basis of the control group, the observation group received triple prerehabilitation nursing. The postoperative knee flexion, hospital for the special surgery knee score (HSS), the daily living ability (Barthel) score, the modified fall efficacy scale (MFES) score, the recovery of the lower-limb muscle strength, and the incidence of complications were compared between the two groups. Results. The knee flexion degree and lower-limb muscle recovery of the observation group were better than those of the control group at 3 d, 7 d, and 14 d after operation (P < 0.05). The HSS score, Barthel score, and MFES score of the observation group were higher than those of the control group (P < 0.05). There was no significant difference in postoperative complications between the two groups (P > 0.05). Conclusion. The triple prerehabilitation nursing care for diabetic patients undergoing total knee replacement can promote the recovery of limb function. [ABSTRACT FROM AUTHOR]

Objectives: Listeria meningoencephalitis (LMM) is very rare in healthy children. We aimed to assess the clinical features, differential diagnosis, treatment options, and outcomes of LMM in immunocompetent children through a retrospective study. Methods: The clinical symptoms, laboratory findings, imaging features, antibiotic use, and metagenomic next-generation sequencing (mNGS) results of the cerebrospinal fluid (CSF) were obtained from immunocompetent children who were diagnosed with LMM and admitted to the Xi'an Children's Hospital from May 2018 to July 2020. Results: The data from 8 immunocompetent children were retrospectively analyzed in this study. The cohort included data from 5 males and 3 females who were aged from 1 year and 7 months to 16 years and 6 months. A total of 4 patients had chilled food before onset. The complications included hyponatremia (3/8), hydrocephalus (2/8), and hemophagocytic syndrome (1/8). In total, 8 patients were diagnosed with Listeria monocytogenes by positive CSF culture or mNGS results. The positive rate of CSF culture was 62.5% (5/8). A total of 5 patients conducted CSF mNGS, and the results of the mNGS were positive in 4 patients (80%, 4/5) and suspected in 1 patient. A total of 7 patients changed their therapeutic regimen to combined antibacterial therapies that included linezolid and meropenem (5/8), or ampicillin and meropenem (2/8). A total of 5 patients had favorable outcomes (Glasgow Outcome Scale, GOSE = 5) while two patients had unfavorable outcomes (GOSE = 1) and were complicated with hyponatremia and hydrocephalus. Conclusions: Listeria meningoencephalitis (LMM) can occur in children with normal immune function and is commonly mistaken for other central nervous system infections. L. monocytogenes can be quickly and accurately detected by mNGS. Hyponatremia and hydrocephalus may indicate unfavorable outcomes. [ABSTRACT FROM AUTHOR]

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Previous research has mainly focused on the determinants of consumers' complaint channel choices. Little attention has been paid to the behavioral consequences of different complaint channels, particularly different complaint devices. Drawing on spatial crowding perception theory, this study finds that in an online complaint context, consumers' complaint intensity is shaped by complaint devices that differ in screen size. Crowding perception produced by visually restrictive tension mediates the relationship between the screen size of the complaint device and the complaint intensity. The results of secondary data confirm that consumers' complaint intensity is higher while complaining through a small-screen device (as opposed to a large-screen one). Three scenario-based experiments are conducted to examine the role of perceived spatial crowding in producing a more intense complaint behavior when complaints are submitted through smaller screen devices (as opposed to larger screen devices). The fourth experiment reveals that crowding perception can be lessened by adjusting certain design elements of the interface, ultimately mitigating the intensity of the complaint submitted through a small-screen device. Our research identifies the specific causality and underlying mechanism of the influence of device type on consumers' postconsumption behavior, thus contributing to clarify some ambiguities in the literature. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to understand the impact of American culture-oriented values, Chinese culture-oriented values and self-improvement values on luxury value perception through acculturation by examining an acculturated sample (Chinese living in the USA), a host cultural sample (Caucasian-American) and a home cultural sample (Mainland Chinese). Design/methodology/approach: In order to examine the acculturative changes of Chinese living in the USA in terms of the influence of American and Chinese culture-oriented values and self-improvement values on their luxury value perception, data were collected via three online samples: host (American), home cultural (Chinese) and acculturated (Chinese living in the USA). Effects of acculturation were tested via comparisons between acculturated to host and home cultural samples. Findings: Compared to that of Mainland Chinese and Caucasian-Americans, luxury value perception of Chinese living in the USA is jointly influenced by both American and Chinese culture-oriented values. The influence of cultural values on luxury value perception of Chinese living in the USA is not strengthened by their wish to integrate into the American culture or to maintain their Chinese culture. Nevertheless, Chinese living in the USA show more significant self-improvement (standing out) and conformity (fitting in) motives in luxury value perception when they wish to integrate into the mainstream culture. Originality/value: The authors surveyed acculturated sample, host and home cultural samples to test the bidimensional acculturation model (Berry, 1997) in the context of luxury consumption. Although the conceptual model is not fully supported, this research broadens current understanding of the effect of acculturation on luxury value perception. [ABSTRACT FROM AUTHOR]

A fully integrated dual-channel multiband RF receiver is designed and implemented for next-generation global navigation satellite systems (GNSSs) in a 0.18-\mu\ m CMOS process. Its two reconfigurable signal channels can simultaneously process any two types of 2-, 4-, or 20-MHz bandwidth signals mainly located around the RF bands of 1.2 and 1.57 GHz for GPS, Galileo, and BD-2 (aka Compass) systems, while achieving better performance (die area, noise figure, gain dynamic range) than other state-of-the-art GNSS receivers. A digital automatic gain control loop consisting of a variable gain amplifier and nonuniform 4-bit ADC is utilized to improve the receiver's robustness and performance in the presence of interferences. While drawing 25-mA current per channel from a 1.8-V supply, this RF receiver achieves a total noise figure of 2.5 dB/2.7 dB at 1.2/1.57 GHz, an image rejection of 28 dB, a maximum voltage gain of 110 dB, a gain dynamic range of 73 dB, and an input-referred 1-dB compression point of -58 dBm, with an active die area of 2.4 \ mm^2 for single channel. [ABSTRACT FROM PUBLISHER]

Abstract: The 8-SF5 analog of mefloquine was synthesized in nine steps from commercially available starting materials and in five steps from a novel ortho-SF5–substituted aniline intermediate. [ABSTRACT FROM AUTHOR]

Metals are widespread pollutants in the environment which have been reported to be associated with kidney dysfunction in many existing epidemiological studies. However, most of the studies are cross-sectional design and mainly focus on several toxic metals including arsenic, lead and cadmium. Therefore, we conducted this prospective study within the Dongfeng-Tongji cohort to evaluate the associations of plasma multiple metals with the decline in kidney function among Chinese middle-aged and elderly. In total, 1434 participants free of chronic diseases at baseline were included in analysis. We measured baseline plasma concentrations of 23 metals and calculated estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum creatinine, age, sex and ethnicity. Bonferroni correction was used for multiple testing to reduce the probability of a type I error. Principal component analysis was conducted to evaluate the combined effect of multiple metal co-exposure. Most of the plasma metal concentrations were within the literature reported reference values, whereas the concentration of lead and nickel exceeded the guideline value. We found that plasma concentrations of aluminum, arsenic, barium, lead, molybdenum, rubidium, strontium, vanadium and zinc were significantly associated with the decline in kidney function measured by annual eGFR decline, rapid renal function decline (defined as an annual decline in eGFR ≥ 5 mL/min/1.73 m2) or incident eGFR < 60 mL/min/1.73 m2, with the adjusted beta coefficients (95% CI) for annual eGFR decline 0.50 (0.30, 0.69), 0.98 (0.74, 1.23), 0.56 (0.32, 0.79), 0.21 (0.03, 0.39), 0.35 (0.16, 0.54), 0.94 (0.71, 1.17), 0.37 (0.15, 0.60), 0.78 (0.54, 1.02), and 0.74 (0.57, 0.91), respectively. The metals exposures were linked with increased risks of impaired kidney function. Associations of principal components representing these metals with the decline in kidney function were significant and suggest a possible additional health risk by co-exposure. Participants engaged in manufacturing had higher plasma levels of several metals compared with those who had been involved in management- or administration-related work. Our findings suggest that exposure to multiple metals contribute to the decline in kidney function among the middle-aged and elderly. Co-exposure to multiple metals may have synergetic effect on the kidney function. Further studies are warranted to confirm our findings and clarify the potential mechanisms. • We evaluated the associations of multiple plasma metals with kidney function decline. • We found significant positive associations between arsenic and lead levels with kidney function decline. • We also identified significant associations between other metals (zinc, rubidium, etc.) with kidney function. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Aidi injection is one of the most commonly used Chinese patent medicines for advanced non-small cell lung cancer (NSCLC). It is made from an extraction of Mylabris Phalerata, Radix Astragalus, Radix Ginseng, and Acanthopanax Senticosus. Aim of the study The objective of this study is to evaluate the efficacy and safety of Aidi injection in combination with platinum-based chemotherapy for stage IIIB/IV NSCLC. Materials and methods A systematic review and meta-analysis were performed following the PRISMA (the Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Trials were combined using Review Manager 5.3 and Comprehensive Meta-Analysis(CMA) 2.0. Dichotomous data were expressed as risk ratio (RR) and continuous outcomes as weighted mean difference (WMD), with their 95% confidence intervals (CI) respectively. All randomized controlled trials (RCTs) comparing Aidi injection plus platinum-based chemotherapy versus platinum-based chemotherapy, with efficacy and safety outcomes were selected. Disease Control Rate (DCR) was the primary outcome, Objective Response Rate (ORR), survival rate, quality of life (QOL), and toxic effects were the secondary outcomes. Results 42 RCTs recruiting 4081 patients with stage IIIB/IV NSCLC were included, with overall low-moderate methodological quality. Compared with platinum-based chemotherapy alone, Aidi injection plus platinum-based chemotherapy can increase relative benefit of DCR (RR = 1.13, 95% CI 1.09–1.16, P  < 0.00001), ORR (RR = 1.26, 95% CI 1.18–1.36, P  < 0.00001) , improve 1-, 2-, 3-year survival rates (RR = 1.14, 95% CI 1.02–1.28, P  = 0.03; RR = 1.31, 95% CI 1.05–1.64, P  = 0.02; and RR = 1.88, 95% CI 1.32–2.67, P  = 0.0005, respectively), QOL (RR = 1.80, 95% CI 1.61–2.01, P  < 0.00001), and reduce severe (grade 3 and 4) toxicities by 36% (RR = 0.64, 95% CI 0.58–0.70, P  < 0.00001). Conclusions From the available evidence, compared with platinum-based chemotherapy alone, Aidi injection plus platinum-based chemotherapy improves the clinical efficacy and alleviates the toxicity of chemotherapy in patients with stage IIIB/IV NSCLC. However, considering the intrinsic limitations of the included RCTs, well-designed, rigorously performed, high-quality trials are still required to further assess and confirm the results. [ABSTRACT FROM AUTHOR]

Evidence available on the independent and combined associations of sleep duration, bedtime, and genetic predisposition with hearing loss was lacking. The present study included 15,827 participants from the Dongfeng-Tongji cohort study. Genetic risk was characterized by polygenic risk score (PRS) based on 37 genetic loci related to hearing loss. We conducted multivariate logistic regression models to assess the odds ratio (OR) for hearing loss with sleep duration and bedtime, as well as the joint association and interaction with PRS. Results showed that hearing loss was independently associated with sleeping ≥9 h/night compared to the recommended 7 to <8 h/night, and with bedtime ≤9:00 p.m. and >9:00 p.m. to 10:00 p.m. compared to those with bedtime >10:00 p.m. to 11:00 p.m., with estimated ORs of 1.25, 1.27, and 1.16, respectively. Meanwhile, the risk of hearing loss increased by 29% for each 5-risk allele increment of PRS. More importantly, joint analyses showed that the risk of hearing loss was 2-fold in sleep duration ≥9 h/night and high PRS, and 2.18-fold in bedtime ≤9:00 p.m. and high PRS. With significant joint effects of sleep duration and bedtime on hearing loss, we found an interaction of sleep duration with PRS in those with early bedtime and an interaction of bedtime with PRS in those with long sleep duration on hearing loss ( P int <0.05), and such relationships were more evident in high PRS. Similarly, the above relationships were also observed for age-related hearing loss and noise-induced hearing loss, particularly the latter. In addition, age-modified effects of sleep patterns on hearing loss were likewise observed, with stronger estimation among those aged <65 years. Accordingly, longer sleep duration, early bedtime, and high PRS were independently and jointly related to increased risk of hearing loss, suggesting the importance of considering both genetics and sleep pattern for risk assessment of hearing loss., (Copyright © 2023 Miao Liu et al.)

This study used data from the China Health and Retirement Longitudinal Study to investigate the temporal relationship between blood lipids and sleep duration in Chinese middle-aged and older adults. We used medical examinations and questionnaire data of 5,016 Chinese middle-aged and older adults (age 45+) in 2011 and 2015. Cross-lagged path analysis was performed to examine the bidirectional relationships between blood lipids and sleep duration. Sleep duration and lipids data were analyzed as continuous variables. Temporal relationships between sleep duration and HDL-cholesterol, LDL-cholesterol, total cholesterol, and triglycerides were different. Sleep duration was negatively associated with HDL-cholesterol 4 year later (β 1 = -0.171, P = 0.005), and HDL-cholesterol was negatively associated with sleep duration 4 year later (β 2 = -0.006, P = 0.002). Longer sleep duration was associated lower levels of LDL-cholesterol (β 1 = -0.275, P = 0.097) and total cholesterol (β 1 = -0.329, P = 0.096) 4 year later. There was a positive correlation between triglycerides and sleep duration. The path coefficient from triglycerides to sleep duration 4 year later (β 2 = 0.001, P = 0.018) was greater than that from sleep duration to triglycerides 4 year later (β 1 = 0.109, P = 0.847), with P = 0.030 for the difference between β 1 and β 2 . In stratified analysis, we found that the strength and direction of the relationships may be related to age and BMI. Effects of sleep duration on blood lipids were only observed among participants aged <60 years, while the effect in the opposite direction was observed in older adults (age 60+), and the cross-lagged path coefficients were more significant in adults with BMI > 25., Competing Interests: The 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 Chen, Zhang, Duan, Mo, Liu, Ma and Yin.)

Objective: The role of lifestyle habits in patients with laryngopharyngeal reflux disease (LPRD) is comparatively underexplored. We aim to examine the specific lifestyle habits in patients with LPRD., Methods: Systematic sampling was applied to select respondents aged 18 through 80 years in otorhinolaryngology-head and neck surgery (OHNS) clinics in Nan Fang Hospital during August 2017-July 2018, 1658 eligible participants were included by a systematic sampling method. Subjects with RSI score>13 were considered as LPRD patients. The risk of reflux symptoms was estimated and multivariate calculated as odds ratios in relation to exposure to tobacco smoking, alcohol, coffee, tea, carbonated drinks, chocolate, spicy food, night sleep time, dinner-to-bed time, subjective sleep quality, and physical exercise., Results: There was a significant dose-response association between carbonated beverage and LPRD. Among people who had drinking carbonated drinks the odds ratio was 1.76 (OR 1.77, 95% CI 1.24-2.50, P = .002) compared with non-carbonated drinker. A similar positive association was found for poor subjective sleep quality and shorter night sleeping time, the odds ratio for reflux was 1.58 (95% CI 1.14 to 2.18) among those who always have poor subjective sleep quality compared with those whose have good subjective sleep quality. The odds ratio for reflux was 2.29 (95% CI 1.23-4.28, P = .015) among those who always sleep 3-5 hours every night compared with those who sleep more than 8 hours every night. Beyond that, we found high BMI may have a negative correlation with LPRD, the odds ratio for reflux was .61 (95% CI 0.39 to .95, P = .054) among those whose BMI >25 kg/m2 compared with those BMI ≤ 20 kg/m2., Conclusions: Patients with LPRD may have certain lifestyle habits, avoid carbonated beverage, poor subjective sleep quality, and lack of sleep should be advised in treatment of LPRD.

This study aimed to develop osteogenic structure assembly for modular bone treatment presentations, effect of 2-(dimethylamino)ethyl methacrylate and polyvinyl pyrrolidone combination as cell adhesive molecule with hydroxyapatite-based composite as osteoconductive constituent was inspected on bone fracture repair. The prepared injectable composite hydrogel showed significantly improved mechanical stability. The ternary composite gel was characterized for functional group modifications and chemical interactions using Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Moreover, X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analyses were performed to observe surface appearances of the hydrogel. The hydroxyapatite/2-(dimethylamino)ethyl methacrylate/poly-N-vinyl-2-pyrrolidone hydrogel played key role in supporting osteoblastic cell spread due to their bioactivity and strength abilities. The present findings revealed the significance of hydroxyapatite concentration on proliferation and osteogenic purpose of the cells. The developed performances of hydrogel have been improved cell proliferation and functions to repair bone fracture.

Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro , GNF2133 is able to proliferate both rodent and human β-cells. In vivo , GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

Background: C-reactive protein (CRP) is a well-recognized biomarker of inflammation, which can be used as a predictor of cardiovascular disease. Evidence have suggested exposure to multiple metals/metalloids may affect immune system and give rise to cardiovascular disease. However, it is lack of study to comprehensively evaluate the association of multiple metals and CRP, the interactions between metals, and the gene-metal interaction in relation to CRP levels., Aims: To explore the associations of multiple plasma metals with serum CRP, and to test the interactions between metals, and gene-metal interactions on the levels of serum CRP., Methods: We included 2882 participants from the Dongfeng-Tongji cohort, China, and measured 23 plasma metals and serum CRP concentrations. The genetic risk score (GRS) was calculated based on 7 established CRP-associated variants. For metals which were associated with the levels of CRP, we further tested the interactions between metals on CRP, and analyzed the gene-metal interactions on CRP., Results: The median level for CRP in the total population was 1.17 mg/L. After multivariable adjustment, plasma copper was positively associated with serum CRP (FDR < 0.001), whereas selenium was negatively associated with serum CRP (FDR = 0.01). Moreover, selenium and zinc attenuated the positive association between high plasma copper and CRP (P for interaction < 0.001). Participants with a higher GRS had a higher CRP level, with the increase in ln-transformed CRP per increment of 5 risk alleles were 0.64 for weighted GRS, and 0.54 for unweighted GRS (both P < 0.001). Furthermore, the genetic association with CRP was modified by copper concentration (P for interaction < 0.001)., Conclusions: Our results suggest that serum CRP is positively associated with plasma concentration of copper, and inversely associated with selenium. Plasma zinc, selenium and CRP genetic predisposition would modify the associations between plasma copper and serum CRP., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts.

Two novel SF5 analogs of the antimalarial agent mefloquine were synthesized in 5 steps and 10-23% overall yields and found to have improved activity and selectivity against malaria parasites. This work also represents the first report of SF5-substituted quinolines.