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Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking.

Pt is a well-known benchmark catalyst in the acidic oxygen reduction reaction (ORR) that drives electrochemical O2-to-H2O conversion with maximum chemical energy-to-electricity efficiency. Once dispersing bulk Pt into isolated single atoms, however, the preferential ORR pathway remains a long-standing controversy due to their complex local coordination environment and diverse site density over substrates. Herein, using a set of carbon nanotube supported Pt–N–C single-atom catalysts, we demonstrate how the neighboring N dopants regulate the electronic structure of the Pt central atom and thus steer the ORR selectivity; that is, the O2-to-H2O2conversion selectivity can be tailored from 10% to 85% at 0.3 V versus reversible hydrogen electrode. Moreover, via a comprehensive X-ray-radiated spectroscopy and shell-isolated nanoparticle-enhanced Raman spectroscopy analysis coupled with theoretical modeling, we reveal that a dominant pyridinic- and pyrrolic-N coordination within the first shell of Pt–N–C motifs favors the 4e–ORR, whereas the introduction of a second-shell graphitic-N dopant weakens *OOH binding on neighboring Pt sites and gives rise to a dominant 2e–ORR. These findings underscore the importance of the chemical environment effect for steering the electrochemical performance of single-atom catalysts.

● Development of a three-step learning strategy for alloy design with high efficiency, transparency and interpretation. ● Realization of the trade-off between strength and plasticity at elevated temperature. ● Identification and validation of key factors influencing the content and distribution of Laves phase in ferrite steels. ● Extraction of composition-structure-property linkage by adaptive learning and local-interpolation learning. ● Development of new 15Cr ferrite steels that have low cost and excellent mechanical properties at 650 °C. 15Cr ferrite steels are urgently required in advanced Ultra-supercritical power plants but meet design challenges in balancing excellent strength and plasticity at high temperatures. We developed a three-step learning strategy based on mutually driven machine learning and purposeful experiments to complete this multi-objective task. Compared with traditional adaptive learning and local-interpolation learning, this step-by-step modular manner provides good transparency and interpretability of the information flow, which is ensured by identifying essential factors from an exquisitely prepared composition-microstructure dataset, and learning valuable knowledge about the composition-property relationship. The requirement of only two groups of experiments indicates the low cost and high efficiency of the strategy. Performing the strategy, we found that Ti is another key element affecting the Laves phase besides Mo and W, and their effects on ultimate tensile strength (UTS) and elongation were also uncovered. Importantly, several low-cost steels free of Co were successfully designed, and the best steel exhibited 156%, 31%, and 62% higher UTS and elongation at 650 °C than the typical 9Cr, 15Cr, and 20Cr steels, respectively. Based on the advantages and success of the strategy in terms of alloy improvement, we believe the strategy suits other multi-objective design tasks in more materials systems. [Display omitted] [ABSTRACT FROM AUTHOR]

The dendritic neural model (DNM) is computationally faster than other machine-learning techniques, because its architecture can be implemented by using logic circuits and its calculations can be performed entirely in binary form. To further improve the computational speed, a straightforward approach is to generate a more concise architecture for the DNM. Actually, the architecture search is a large-scale multiobjective optimization problem (LSMOP), where a large number of parameters need to be set with the aim of optimizing accuracy and structural complexity simultaneously. However, the issues of irregular Pareto front, objective discontinuity, and population degeneration strongly limit the performances of conventional multiobjective evolutionary algorithms (MOEAs) on the specific problem. Therefore, a novel competitive decomposition-based MOEA is proposed in this study, which decomposes the original problem into several constrained subproblems, with neighboring subproblems sharing overlapping regions in the objective space. The solutions in the overlapping regions participate in environmental selection for the neighboring subproblems and then propagate the selection pressure throughout the entire population. Experimental results demonstrate that the proposed algorithm can possess a more powerful optimization ability than the state-of-the-art MOEAs. Furthermore, both the DNM itself and its hardware implementation can achieve very competitive classification performances when trained by the proposed algorithm, compared with numerous widely used machine-learning approaches.

Introduction:Comprehensive data on the risk of hospital-acquired (HA) acute kidney injury (AKI) among adult users of opioid analgesics are lacking. This study aimed to systematically compare the risk of HA-AKI among the users of various opioid analgesics. Methods:This multicenter, retrospective real-world study analyzed 255,265 adult hospitalized patients who received at least one prescription of opioid analgesic during the first 30 days of hospitalization. The primary outcome was the time from the first opioid analgesic prescription to HA-AKI occurrence. 12 subtypes of opioid analgesics were analyzed, including 9 for treating moderate-to-severe pain and 3 for mild-to-moderate pain. We examined the association between the exposure to each subtype of opioid analgesic and the risk of HA-AKI using Cox proportional hazards models, using the most commonly used opioid analgesic as the reference group. Results:As compared to dezocine, the most commonly used opioid analgesic for treating moderate-to-severe pain, exposure to morphine, but not the other 7 types of opioid analgesics, was associated with a significantly increased risk of HA-AKI (adjusted hazard ratio: 1.56, 95% confidence interval: 1.40–1.78). The association was consistent in stratified analyses and in a propensity-matched cohort. There were no significant differences in the risk of HA-AKI among the opioid analgesic users with mild-to-moderate pain after adjusting for confounders. Conclusion:The use of morphine was associated with an increased risk of HA-AKI in adult patients with moderate-to-severe pain. Opioid analgesics other than morphine should be chosen preferentially in adult patients with high risk of HA-AKI when treating moderate-to-severe pain.

Regenerative cooling by endothermic hydrocarbon fuel (EHF) is one of the most promising techniques for thermal management of supersonic or hypersonic aircraft. How to maintain the fuel working in proper states is an important issue to maximize the cooling potential of EHT. This work proposes a novel working state map, including risking zone (RZ), thermal cracking zone (TCZ), supercritical zone (SupZ) and subcritical zone (SubZ), to differentiate possible working states of an EHF during regenerative cooling. Using n-decane flowing in a circular tube as an example, the boundaries of four zones are determined by numerical simulation covering different heat fluxes (0.2–4.0 MW·m−2) and mass flow rates (0.5–10.5 g·s−1) under two operating pressures (3.45 and 5.00 MPa). Empirical correlations for three boundary lines are obtained and the maximum cooling capacity is identified, as well as the identification of the pressure effect. The revelation of such new perspective of regenerative cooling is of great implication to the design and optimization of cooling system for future thermal management.

This article addresses the distributed consensus control for multiple Euler–Lagrange systems under directed networks with time-varying transmission delays. Only some followers can access the information of the leader; communication is directed between agents. A distributed adaptive event-triggered control protocol is designed for the two cases where the generalized velocity of the leader is constant/time varying. When the generalized velocity of the leader is time varying, a distributed adaptive observer is designed to make followers obtain the time-varying information of the leader. Then, Lyapunov stability theory and the Linear matrix inequality algorithm prove the tracking errors can converge to zero in a completely distributed chattering-free manner. With the event-triggered mechanism, the number of communications can be decreased, and the system update frequency and the energy consumption can be reduced effectively. Meanwhile, the elimination of the Zeno behavior is also proved. Finally, the simulation results verify the effectiveness of the two controllers.

The aim of this study was to explore the associations of moderate-to-vigorous-intensity physical activity (MVPA) time and sedentary (SED) time with a history of cardiovascular disease (CVD) and multifactorial (i.e., blood pressure (BP), body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), and glycated hemoglobin A1c (HbA1c)) control status among type 2 diabetes mellitus (T2DM) patients in China. A cross-sectional analysis of 9152 people with type 2 diabetes from the Multifactorial Intervention on Type 2 Diabetes (MIDiab) study was performed. Patients were grouped according to their self-reported MVPA time (low, < 150 min·week−1; moderate, 150 to < 450 min·week−1; high, ≥ 450 min·week−1) and SED time (low, < 4 h·d–1; moderate, 4 to < 8 h·d–1; high, ≥ 8 h·d–1). Participants who self-reported a history of CVD were identified as having a CVD risk. Odds ratios (ORs) and 95% confidence intervals (CIs) of CVD risk and multifactorial control status associated with MVPA time and SED time were estimated using mixed-effect logistic regression models, adjusting for China’s geographical region characteristics. The participants had a mean ± standard deviation (SD) age of (60.87 ± 8.44) years, 44.5% were women, and 25.1% had CVD. After adjustment for potential confounding factors, an inverse association between high MVPA time and CVD risk that was independent of SED time was found, whereas this association was not observed in the moderate-MVPA group. A higher MVPA time was more likely to have a positive effect on the control of BMI. Compared with the reference group (i.e., those with MVPA time ≥ 450 min·week−1and SED time < 4 h·d–1), CVD risk was higher in the low-MVPA group: The OR associated with an SED time < 4 h·d–1was 1.270 (95% CI, 1.040–1.553) and that associated with an SED time ≥ 8 h·d–1was 1.499 (95% CI, 1.149–1.955). We found that a high MVPA time (i.e., ≥ 450 min·week−1) was associated with lower odds of CVD risk regardless of SED time among patients with T2DM.

In this article, we propose a system that can fuse inertial measurement unit (IMU), light detection and ranging (LiDAR), and intermittent global positioning system (GPS) measurements to achieve high precision localization and mapping in large-scale environment. The iterated error-state Kalman filter is used to fuse IMU and LiDAR measurements to estimate relative motion information quickly. Based on the factor graph, LiDAR, GPS measurements, and loop closure are transformed into constraints for joint optimization to construct global map. A real-time GPS outlier detection method based on the IMU preintegration theory and residual chi-square test is designed. In addition, the use of robust kernel is supported to implicitly reduce the impact of undetected GPS outliers on the system. A LiDAR-based loop-closure detector is designed, which can search for a pair of point clouds with similar geometric information. Importantly, the performance of the proposed method is compared with state-of-the-art methods through a series of experiments. The experimental results show that the method is robust and accurate to complete the task of localization and mapping in large-scale environment.

Nationwide estimates of the impact of common modifiable risk factors on mortality remain crucial. We aim to assess the influence of social determinants, lifestyle, and metabolic factors on mortality in 174,004 adults aged ≥40 years from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We reveal that 17 modifiable factors are independently associated with mortality, accounting for 64.8% of all-cause mortality, 77.4% of cardiovascular mortality, and 44.8% of cancer mortality. Low education emerges as the leading factor for both all-cause and cancer mortality, while hypertension is predominant for cardiovascular mortality. Moreover, low gross domestic product per capita and high ambient particulate matter with a diameter of <2.5 μm (PM2.5) air pollution account for 7.8% and 4.3% for all-cause mortality, respectively, using a different method. Gender-specific analyses reveal distinct patterns, with women’s mortality primarily associated with social determinants and men exhibiting stronger associations with lifestyle factors. Targeted health interventions are essential to mitigate mortality risks effectively in China.

ABSTRACTIn this paper, the event-triggered formation-containment control of multiple Euler-Lagrange systems over directed networks is addressed. First, an auxiliary system is introduced for each agent to make its relative position and velocity converge to zero, allowing the measurement of velocity errors between adjacent agents to be avoided. To solve the problem of input saturation in the system, the formation-containment control algorithm is designed for leaders and followers. The control algorithm ensures that the saturation boundary of the control input is limited and has no link to the adjacent agents. Because of an event-triggered mechanism, the system will not update countless times and will eliminate unexpected Zeno behaviors; thus, the utilization rate of all the resources is improved. Finally, the validity of the proposed algorithm is verified by simulation experiments.

BackgroundEducation attainment can improve life expectancy and guide healthy behaviours throughout an entire lifetime. A nationwide longitudinal study of the association of education status with the risk of hypertension and its control in China is lacking.MethodsThe China Cardiometabolic Disease and Cancer Cohort Study is a multicentre, population-based, prospective cohort study. We performed the baseline survey from 2011 to 2012. A follow-up visit was conducted during 2014–2016. 101 959 subjects were included in the final data analyses. Cox proportional hazards regression was used to examine the associations of education levels with the risk of hypertension and uncontrolled hypertension.ResultsDuring follow-up, 11 189 (19.9%) participants had developed hypertension among subjects without hypertension at baseline. Among the participants with hypertension at baseline, only 40.6% had controlled hypertension. Compared with the participants’ education level at elementary school and below, the multivariable-adjusted HR for incident hypertension was 0.76 (95% CI, 0.72 to 0.80) in those with a middle school education level and 0.67 (95% CI, 0.63 to 0.70) in those with a high school degree or above. Correspondingly, multivariable-adjusted HRs associated with uncontrolled hypertension were 0.90 (95% CI, 0.87 to 0.92) in participants with a middle school education level and 0.85 (95% CI, 0.82 to 0.88) in participants with a high school degree or above level.ConclusionParticipants with education attainment at elementary school and below exhibited excess risks of newly diagnosed hypertension and worse blood pressure control compared with individuals with education attainment at middle school or above.

Kdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a(LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/−increased H3K36me2 levels at the Pparglocus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/−mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/−macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/−mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

Atmospheric water harvesting is a practical strategy that is achieved by removing materials from air moisture to relieve global water scarcity. Here we design a water-harvester (i.e., MOF-303/thiolated polymer composite (MTC)) by using a metal–organic framework (MOF-303) and thiolated chitosan (TC) skeleton. Intermolecular hydrogen bonding between TC and MOF-303 facilitates porous structures with enlarged air–polymer interfaces for long cycling life and high capacity at low relative humidity. Benefiting from synergetic effects on porosity and anchorage for accelerating the uptake-release of moisture, MTC exhibits a rapid water uptake capacity of 0.135 g/g in 60 min under 12.5 RH% and ultrafast water desorption kinetics of 0.003 g/g/min at 8.5 RH%, which is superior to the as-reported MOF-303 based adsorbents. At low heat (∼40 °C), the water desorption and collection rate, respectively, are 0.0195 and 0.0168 g/g/min within 210 min, showing ultrahigh harvesting efficiency. These results highlight the enormous potential as promising materials for solving the world’s water scarcity crisis. This study offers an insight into the design of AWH materials, which can be extended into applications in some realms, e.g., freshwater development for industry in arid areas, water engineering-related devices and systems, etc.

Purpose: Obese individuals have an increased risk of hypothyroidism. This study investigated the sex-specific association between obesity phenotypes and the development of hypothyroidism. Methods: The study population was derived from a health management cohort in Shandong Provincial Hospital from 2012 to 2016. In total, 9011 baseline euthyroid adults were included and classified into four groups according to obesity phenotype: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). The median follow-up time was 1.92 (1.00–2.17) years. Incidence density was evaluated and a generalized estimation equation method was used to investigate the associations between obesity phenotypes and the development of hypothyroidism. Results: The incidence densities of hypothyroidism in males with a consistent obesity phenotype were 12.19 (8.62–16.76), 15.87 (11.39–21.56), 14.52 (6.74–27.57), and 19.88 (14.06–27.34) per 1000 person-years in the MHNO, MHO, MUNO, and MUO groups, respectively. After adjusting for confounding factors, compared with the MHNO phenotype, the MHO, MUNO, and MUO phenotypes were independent risk factors for developing hypothyroidism in males. In the subgroup analysis, the MHO and MUO phenotypes were independent risk factors for developing hypothyroidism in males under 55 years, while the MUNO phenotype was an independent risk factor in males over 55 years. The MHO, MUNO, and MUO phenotypes were not independent risk factors for hypothyroidism in females. Conclusion: Both obesity and metabolic abnormities are associated with a higher risk of hypothyroidism in males. The underlying mechanism of the sex and age differences in this association needs further investigation.

Purpose: The role of thyroid autoimmunity in the association between obesity and hyperthyrotropinaemia remains unclear. We aimed to assess the relationship between obesity, autoimmunity, and hyperthyrotropinaemia. Methods: In this population-based cross-sectional study, 12531 Chinese individuals (18–80 years) with thyroid function test were categorized into three groups by body mass index (BMI) and were categorized into three layers by thyroid autoantibodies. Multivariate logistic regression was employed to assess the correlation and interaction effect. Results: There was no significant difference in prevalence of hyperthyrotropinaemia (P= 0.637) among three BMI groups. After stratification, the difference of serum thyrotropin (P&lt; 0.01) and prevalence of hyperthyrotropinaemia (P&lt; 0.01) between the three groups have significant linear trends at the positive levels of thyroid peroxidase antibody (TPOAb) or/and thyroglobulin antibody (TgAb). When TPOAb and TgAb were positive, the risk of hyperthyrotropinaemia increased 1.857-fold in overweight group and 2.201-fold in obese group compared with normal group. Compared with negative TPOAb and TgAb, the risk of hyperthyrotropinaemia for individuals with two positive antibodies increased 3.310-fold, 4.969-fold, and 5.122-fold in the three BMI groups. The adjusted OR (95% CI) for interaction were 1.033 (0.752–1.419) for overweight and one positive antibodies, 1.935 (1.252–2.990) for overweight and two positive antibodies, 1.435 (0.978–2.105) for obesity and one positive antibodies and 2.191 (1.252–3.832) for obesity and two positive antibodies. Conclusion: Overweight and obesity were associated with hyperthyrotropinaemia only in presence of thyroid autoimmunity, and obesity might aggravate the pathogenic effect of autoimmunity on hyperthyrotropinaemia. There was an interaction effect between obesity and autoimmunity on the prevalence of hyperthyrotropinaemia.

Herein, we report a new molecule structure modification strategy for non-fullerene small-molecule electron acceptors (NFAs) for solar cells through trifluoromethylation of end-capping groups. The synthesized trifluoromethylated acceptor ITCF3 exhibits narrower band gap, stronger light absorption, lower molecular energy levels, and better electron transport property compared to the reference NFA without the trifluoromethyl group (ITIC). Bulk heterojunction solar cells based on ITCF3 combined with the PM6 polymer donor exhibit a significantly improved power conversion efficiency of 13.3% compared with the ITIC-based device (8.4%). This work reveals great potential of trifluoromethylation in the design of efficient photovoltaic acceptor materials.

National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes.

ABSTRACTAdiposity is caused by an imbalance between energy intake and consumption. Promotion of the browning of white fat increases energy expenditure and could combat adiposity. Thyroid-stimulating hormone (TSH) has been confirmed to positively correlate with adiposity. However, the putative connection between TSH and white adipose browning has never been explored. In this study, we sought to assess the effect of TSH on white adipose tissue browning and energy metabolism. Subclinical hypothyroidism mice, thyroid-specific Tshr-knockout mice injected with TSH, adipocyte-specific and global Tshr-knockout micewere subjected to morphological, physiological, genetic or protein expression analyses and metabolic cages to determine the role of TSH on the browning of white adipose tissue and metabolism. 3T3-L1 and primary SVF cells were used to verify the effects and mechanism of TSH on the browning of white adipocytes. We show that increased circulation TSH level decreases energy expenditure, promotes adiposity, impairs glucose and lipid metabolism. Knockout of Tshrdecreases adiposity, increases energy expenditureand markedly promotes the development of beige adipocytesin both epididymal and inguinal subcutaneous white fat via a mechanism that likely involves AMPK/PRDM16/PGC1α. Our results reveal an important role of TSH in regulating energy balance and adiposity by inhibiting the browning of white fat.

IMPORTANCE: Whether optimal cardiovascular health metrics may counteract the risk of cardiovascular events among patients with prediabetes or diabetes is unclear. OBJECTIVE: To investigate the associations of ideal cardiovascular health metrics (ICVHMs) with subsequent development of cardiovascular disease (CVD) among participants with prediabetes or diabetes as compared with participants with normal glucose regulation. DESIGN, SETTING, AND PARTICIPANTS: The China Cardiometabolic Disease and Cancer Cohort Study was a nationwide, population-based, prospective cohort study of 20 communities from various geographic regions in China. The study included 111 765 participants who were free from CVD or cancer at baseline. Data were analyzed between 2011 and 2016. EXPOSURES: Prediabetes and diabetes were defined according to the American Diabetes Association 2010 criteria. Seven ICVHMs were adapted from the American Heart Association recommendations. MAIN OUTCOMES AND MEASURES: The composite of incident fatal or nonfatal CVD, including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure. RESULTS: Of the 111 765 participants, 24 881 (22.3%) had normal glucose regulation, 61 024 (54.6%) had prediabetes, and 25 860 (23.1%) had diabetes. Mean (SD) age ranged from 52.9 (8.6) years to 59.4 (8.7) years. Compared with participants with normal glucose regulation, among participants with prediabetes, the multivariable-adjusted hazard ratio for CVD was 1.34 (95% CI, 1.16-1.55) for participants who had 1 ICVHM or less and 0.57 (95% CI, 0.43-0.75) for participants who had at least 5 ICVHMs; among participants with diabetes, the hazard ratios for CVD were 2.05 (95% CI, 1.76-2.38) and 0.80 (95% CI, 0.56-1.15) for participants who had 1 ICVHM or less and at least 5 ICVHMs, respectively. Such pattern of association between ICVHMs and CVD was more prominent for participants younger than 55 years (prediabetes and at least 5 ICVHMs: hazard ratio [HR], 0.32; 95% CI, 0.16-0.63; 1 ICVHM or less: HR, 1.58; 95% CI, 1.13-2.21; diabetes and at least 5 ICVHMs: HR, 0.99; 95% CI, 0.44-2.26; 1 ICVHM or less: HR, 2.46; 95% CI, 1.71-3.54; compared with normal glucose regulation) than for participants 65 years or older (prediabetes and at least 5 ICVHMs: HR, 0.80; 95% CI, 0.50-1.26; 1 ICVHM or less: HR, 1.01; 95% CI, 0.79-1.31; diabetes and at least 5 ICVHMs: HR, 0.79; 95% CI, 0.46-1.35; 1 ICVHM or less: HR, 1.73; 95% CI, 1.36-2.22, compared with normal glucose regulation; P values for interaction ≤.02). Additionally, the hazard ratio for CVD per additional ICVHM was 0.82 (95% CI, 0.79-0.86) among participants with prediabetes and was 0.85 (95% CI, 0.80-0.89) among participants with diabetes. CONCLUSIONS AND RELEVANCE: Participants with prediabetes or diabetes who had 5 or more ICVHMs exhibited lower or no significant excess CVD risks compared with the participants with normal glucose regulation.

Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.

Subclinical hypothyroidism is associated with cardiovascular diseases, yet the underlying mechanism remains largely unknown. Herein, in a common population (n = 1,103), TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness. Consistently, TSH receptor ablation in ApoE−/− mice attenuated atherogenesis, accompanied by decreased vascular inflammation and macrophage burden in atherosclerotic plaques. These results were also observed in myeloid-specific Tshr-deficient ApoE−/− mice, which indicated macrophages to be a critical target of the proinflammatory and atherogenic effects of TSH. In vitro experiments further revealed that TSH activated MAPKs (ERK1/2, p38α, and JNK) and IκB/p65 pathways in macrophages and increased inflammatory cytokine production and their recruitment of monocytes. Thus, the present study has elucidated the new mechanisms by which TSH, as an independent risk factor of atherosclerosis, aggravates vascular inflammation and contributes to atherogenesis.

Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor(FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2promoter, thus preventing FoxO1 from repressing SREBP-2gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCRnascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

AbstractThe aim of this cross-sectional study was to investigate whether abnormal glycemic status (diabetes and prediabetes) is associated with increased prevalence of thyroid disorders in North China. A total of 10,860 adult participants were enrolled based on the REACTIONstudy [Ning G. J Diabetes. 2012;4(2):172–173]. They were divided into three groups by glucose levels according to the American Diabetes Association 2010 criteria. The basic characteristics of the study population were analyzed. The prevalence and effects of thyroid disorders, cardio-cerebrovascular disease, and risk factors of thyroid disorders, among the study groups, were investigated. The study population comprised 2994 diabetic patients (27.57%) and 6386 prediabetic patients (58.80%), with the mean age of 55.37 ± 8.82 years. Compared to those subjects with normal glucose status (8.11%), thyroid disorders were more common in the diabetic (15.97%) and prediabetic patients (13.48%) (P < 0.001). Impacts of female gender related to the presence of thyroid disorders were even more profound in the diabetic patients than in those with other glucose status. The results indicate that screening for thyroid disorders among patients with diabetes or prediabetes should be regularly performed, especially in females.

Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.

Despite the current guideline’s recommendation of a timely stepwise intensification therapy, the “clinical inertia”, termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic β cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.

A palladium-catalyzed one-pot two-step radical mediated carbonylative cyclization of 1,7-enynes with perfluoroalkyl iodides and Mo(CO)6has been developed for the construction of polycyclic 3,4-dihydroquinolin-2(1H)-one scaffolds. This method realizes a facile synthesis of various polycyclic 3,4-dihydroquinolin-2(1H)-one derivatives containing perfluoroalkyl and carbonyl units in high yields. Moreover, modifications of several bioactive molecules were demonstrated using this protocol.

The Ni61Fe10Cr10Al17Mo2high entropy alloys (HEAs) with low density have been developed with great potentials for applications. The forging process is one of the important methods for fabricating components. Accordingly, the study of the deformation behavior of HEAs is the essence in the processing and molding of this material for using in industry. Moreover, there are multiple phases with hierarchical structures in the as-cast Ni61Fe10Cr10Al17Mo2alloys, with the face-centered cubic (FCC) phase as the matrix phase accompanied with hard body-centered cubic (BCC) B2 phase. Here, the hot deformation behaviors of the homogenized Ni61Fe10Cr10Al17Mo2alloy were investigated at strain rates ranging from 0.001 to 1.0 s−1and temperatures ranging from 1000 to 1200 °C via isothermal compression tests. The true stress-strain curves were used to reveal the relationship between the flow stress and the deformation temperature and strain rate. The constitutive equations describing the correlations between the flow stress and hot compression parameters were constructed. At the same time, the dynamic material model and instability criterion were used to plot the hot processing map. Furthermore, the deformed microstructures and the dynamic recrystallization of alloy were investigated. Combined with the processing map, the optimal processing route is obtained.

Internal waves (IWs) generated by tidal flow over the seafloor play a critical role in ocean circulation and climate. We determine the dependence of the radiated IW power on topographic parameters in numerical simulations of tidal flow over two‐dimensional random topographic profiles that have the spectrum of oceanic abyssal hills. The IW power increases as the horizontal spatial resolution scale is decreased, but below a certain spatial scale the power saturates at a level less than the linear theory prediction. For increasing topographic RMS height Hrmsthe emergent interference of the tide and the IWs from different generation sites leads to a transition in the IW power dependence on Hrmsfrom quadratic to linear. This transition in the scaling of the IW power depends on the slopes of a valley's nearest neighboring peaks. Our results should guide the modeling of IW generation by tidal flow over small‐scale ocean topography. Wave interference suppresses internal waves (IWs) generated by random topographyWith increasing topographic resolution, IW power saturates at a level less than linear theory predictsIW power scales linearly with the height of supercritical random topography

Although previous studies suggest that amino acids (AAs) and microbiota-related metabolites (MRMs) are associated with type 2 diabetes mellitus (T2DM), the results remain unclear among normoglycemic populations. We test 28 serum AAs and 22 MRMs in 3,414 subjects with incident diabetes and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. In fully adjusted logistic regression models, per SD increment of branched-chain AAs, aromatic AAs, asparagine, alanine, glutamic acid, homoserine, 2-aminoadipic acid, histidine, methionine, and proline are positively associated with incident T2DM. In the MRM panel, serum carnitines, N-acetyltryptophan, and uric acid are positively associated with incident T2DM. Causal mediation analyses indicate 34 significant causal mediation linkages, with 88.2% through obesity and lipids. Variances explained in the serum metabolites are modestly limited in the comprehensive catalog of risk factor–metabolite–diabetes associations. These findings reveal that systematic AAs and MRMs change profile before T2DM onset and support a potential role of metabolic alterations in the pathogenesis of diabetes.

Context:Subclinical hypothyroidism (SCH) is an important public health problem worldwide for its increasing prevalence and potential deleterious effects, whereas its etiology has not been fully elucidated. Lipotoxicity exerts extensive and serious impact on human health, but so far, the potential effect of lipotoxicity on thyroid is unclear.Objective:The objective of the study was to assess the association between serum triglyceride levels and the risk for SCH.Design, Participants, and Methods:We conducted a population-based case-control study. A total of 24 100 subjects with similar and stable iodine nutrition status were recruited from China. Cases of 5033 SCH patients were identified and equal controls were matched by age, gender, and region. Conditional logistic regression was used to analyze the association between serum triglyceride levels and risk for SCH.Results:Hypertriglyceridemia was associated with an approximately 35% increased risk for SCH in both men (odds ratio 1.325; 95% confidence interval 1.002–1.753) and women (odds ratio 1.397; 95% confidence interval 1.217–1.604), even after adjustment for potential confounders. Notably, the risk for SCH increased progressively following the elevation of serum triglyceride levels. Compared with individuals with serum triglyceride levels less than 0.97 mmol/L, the risk for SCH increased approximately 1.9-fold in men and 1.4-fold in women, respectively, when triglyceride levels were greater than 1.99 mmol/L.Conclusion:Our findings suggested that hypertriglyceridemia was positively associated with the risk for SCH.

Cholesterol homeostasis is strictly regulated through the modulation of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis. Phosphorylation of HMGCR inactivates it and dephosphorylation activates it. AMP-activated protein kinase (AMPK) is the major kinase phosphorylating the enzyme. Our previous study found that thyroid-stimulating hormone (TSH) increased the hepatocytic HMGCR expression, but it was still unclear whether TSH affected hepatic HMGCR phosphorylation associated with AMPK. We used bovine TSH (bTSH) to treat the primary mouse hepatocytes and HepG2 cells with or without constitutively active (CA)-AMPK plasmid or protein kinase A inhibitor (H89), and set up the TSH receptor (Tshr)-KO mouse models. The p-HMGCR, p-AMPK, and related molecular expression were tested. The ratios of p-HMGCR/HMGCR and p-AMPK/AMPK decreased in the hepatocytes in a dose-dependent manner following bTSH stimulation. The changes above were inversed when the cells were treated with CA-AMPK plasmid or H89. In Tshr-KO mice, the ratios of liver p-HMGCR/HMGCR and p-AMPK/AMPK were increased relative to the littermate wild-type mice. Consistently, the phosphorylation of acetyl-CoA carboxylase, a downstream target molecule of AMPK, increased. All results suggested that TSH could regulate the phosphorylation of HMGCR via AMPK, which established a potential mechanism for hypercholesterolemia involved in a direct action of the TSH in the liver.

Hydrogen sulfide (H2S) is a newly identified endogenous gasotransmitter that has been implicated in the pathophysiology of several biologic systems. However, the role of H2S in the pathogenesis of diabetic vascular injury remains unclear. The aims of this study were to determine the effect of H2S on the high glucose (HG)–induced expression of intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells and to explore the possible underlying mechanisms. Human umbilical vein endothelial cells were exposed either to a normal concentration of D-glucose (5.5 mmolL) or to HG (16.7 mmolL) in the absence or presence of NaHS for the indicated periods. The ICAM-1 protein and messenger RNA (mRNA) levels were analyzed by Western blotting and real-time reverse transcriptase–polymerase chain reaction, respectively. Exposure to HG for 48 or 72 hours significantly increased ICAM-1 expression at both the protein and mRNA levels, and these increases correlated with increases in both the production of intracellular reactive oxygen species and the activation of nuclear factor-B. Pretreatment with NaHS inhibited HG-induced ICAM-1 expression at both the protein and mRNA levels and resulted in a reduction in the intracellular reactive oxygen species level and the suppression of nuclear factor-B activity. NaHS also inhibited tumor necrosis factor-–induced ICAM-1 protein expression, which was similar to the effect of antioxidant N-acetyl-L-cysteine. These findings indicate that H2S might protect against HG-induced vascular damage by down-regulating ICAM-1 expression in endothelial cells.

Hydrogen sulfide (H2S) is the third endogenous gaseous mediator identified after nitric oxide and carbon monoxide. It has been demonstrated that H2S has protective effects on myocardial ischemiareperfusion-induced cell apoptosis. To date, little is known about the role of H2S in the pathophysiology of diabetic vascular complications. In this study, we investigated the effects of sodium hydrosulfide on high-glucose–induced apoptosis of primary human umbilical vein endothelium cells. Exposure to high glucose (25 mmoleL) for 48 hours resulted in the induction of apoptosis by 41.6 ± 1.01, which was attenuated by pretreatment with sodium hydrosulfide (50 moleL) for 30 minutes. Further investigation of the apoptotic mechanisms in the cells demonstrated that high glucose upregulated the ratio of BaxBcl-2 and activated caspase-3 and also increased the levels of reactive oxygen species and malondialdehyde while reducing superoxide dismutase activity. All the above responses could be prevented by pretreatment with 50 moleL of sodium hydrosulfide. These results indicated that the protective effects of H2S on endothelial cells in the condition of high glucose might involve an antioxidative stress mechanism.