CTLA-4 blockade induces tumor pyroptosis via CD8+ T cells in head and neck squamous cell carcinoma.

Immune checkpoint blockade (ICB) treatment has demonstrated excellent medical effects in oncology, and it is one of the most sought after immunotherapies for tumors. However, there are several issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasdermin-mediated pyroptosis is a typical inflammatory death mode. We discovered that increased expression of gasdermin protein was linked to a favorable tumor immune microenvironment and prognosis in head and neck squamous cell carcinoma (HNSCC). We used the mouse HNSCC cell lines 4MOSC1 (responsive to CTLA-4 blockade) and 4MOSC2 (resistant to CTLA-4 blockade) orthotopic models and demonstrated that CTLA-4 blockade treatment induced gasdermin-mediated pyroptosis of tumor cells, and gasdermin expression positively correlated to the effectiveness of CTLA-4 blockade treatment. We found that CTLA-4 blockade activated CD8+ T cells and increased the levels of interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) cytokines in the tumor microenvironment. These cytokines synergistically activated the STAT1/IRF1 axis to trigger tumor cell pyroptosis and the release of large amounts of inflammatory substances and chemokines. Collectively, our findings revealed that CTLA-4 blockade triggered tumor cells pyroptosis via the release of IFN-γ and TNF-α from activated CD8+ T cells, providing a new perspective of ICB.

Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer.

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.

A Cytoplasm-Specific Fluorescent Ligand for Selective Imaging of RNA G-Quadruplexes in Live Cancer Cells.

The development of site-specific, target-selective and biocompatible small molecule ligands as a fluorescent tool for real-time study of cellular functions of RNA G-quadruplexes (G4s), which are associated with human cancers, is of significance in cancer biology. We report a fluorescent ligand that is a cytoplasm-specific and RNA G4-selective fluorescent biosensor in live HeLa cells. The in vitro results show that the ligand is highly selective targeting RNA G4s including VEGF, NRAS, BCL2 and TERRA. These G4s are recognized as human cancer hallmarks. Moreover, intracellular competition studies with BRACO19 and PDS, and the colocalization study with G4-specific antibody (BG4) in HeLa cells may support that the ligand selectively binds to G4s in cellulo. Furthermore, the ligand was demonstrated for the first time in the visualization and monitoring of dynamic resolving process of RNA G4s by the overexpressed RFP-tagged DHX36 helicase in live HeLa cells.

A method of gas-related pollution source layout based on multi-source data: A case study of shaanxi province, China.

The location and layout of enterprises have an important impact on local air quality. However, a few studies on exploring of the optimal layout of gas-related enterprises from the perspective of optimizing the layout of air pollution sources. This study developed a method for the evaluation of air pollution source layout based on air pollutant emission inventory data, atmospheric self-purification capacity data, and satellite remote sensing air quality data. Taking Shaanxi Province as an example, the Moran's I index and GIS spatial analysis techniques were used to evaluate the layout of air pollution sources, analyze the spatial variation characteristics of air pollution sources, and propose specific countermeasures to optimize the layout of air pollution sources. Results showed that northern Shaanxi and Guanzhong Plain are the most unsuitable for the distribution of NOx and CO sources, accounting for 13.78% and 21.77% of the total area, respectively. The most suitable area for the distribution of NOx is southern Shaanxi, accounting for 65.77% of the total area, mainly concentrated in Hanzhong and Ankang regions. The most suitable area for the distribution of CO is southern Shaanxi, accounting for 40.97% of the total area, mainly concentrated in Hanzhong and Shangluo regions. The findings of this study could supplement and improve the evaluation of the layout of industrial enterprises in China from technical and methodological aspects, and provide new insight for local governments to adjust and optimize the layout of air pollution sources.

Cost-benefits analysis of ultra-low emissions standard on air quality and health impact in thermal power plants in China.

As China's largest energy infrastructure, thermal power plant consumed approximately half of China's coal over the past decade and threatened air quality, human health and socioeconomic development. Thus, a series of control policies have been implemented to alleviate those impacts in China. Particularly, China has witnessed unprecedented declines in air pollutant emissions from thermal power plants since the ultra-low emissions (ULE) standards were implemented. In contrast, the effect of the ULE policy on air quality, health and cost benefits remains poorly understood. Therefore, this study estimates the improved air quality and associated health and economic benefits under the ULE standards in the thermal power sector by using a measure-specific approach, combining a bottom-up emission inventory, an atmospheric model, a health assessment model and a cost analysis model. The results show that all the control measures lead to reduced air pollution, and renovating pre-existing units (RPU) is the most effective. Compared to without implementing the ULE policy, the population-weighted average PM2.5 and O3 concentrations decreased by 1.50 µg/m3 and 0.87 ppm, and 67,831 premature deaths could be avoided nationally. Furthermore, the results also show the net economic benefits of combining health benefits and costs due to control measures are 109.92 billion Yuan (in 2015 value) in China. The comprehensive results reveal that the health benefits outweigh the direct policy. Based on these empirical findings and the specific circumstances of China, we suggest that RPU should be further promoted to the entire of China, and if necessary, establish a long-term compensation mechanism for inter-provincial interests and institute and enforce comprehensive policies that carefully consider the health impacts of policies. This study provides strong arguments for China's policy-making and considering tightening emission standards for thermal power plants worldwide.

Health effects of future dioxins emission mitigation from Chinese municipal solid waste incinerators.

Dioxins (including 2,3,7,8-tetrachlorodibenzo-p-dioxin, as Group 1 Carcinogen) in the atmosphere mainly originate from incomplete combustion during municipal solid waste (MSW) incineration. To significantly reduce dioxins emission from the MSW incineration industry, China has promulgated a set of ambitious plans regulating MSW-related pollution; however, the emission reduction potentials and concomitant environmental and health impacts associated with the implementation of these programs on a national scale remain unknown. Here, we use real measurements from official environmental impact assessment systems and continuous emissions monitoring systems (covering 96.6% of national MSW incinerators) to estimate unit-level dioxins emission and concomitant environmental and health impacts. We find that in 2018, 99.3% and 66.7% of Chinese incinerators met such concentration and temperature standards, respectively, controlling the total emissions to 19.6 g toxic equivalency quantity and maintaining carcinogenic and noncarcinogenic risks significantly below safety levels nationwide. Fully achieving both current standards and future regulations will reduce emissions and health risks by 67.7% and 62.6%, respectively, with waste sorting program contributing the majority. This study reveals substantial benefits from curbing MSW-related dioxins pollution and underscores the promise of ongoing management.

[Application of precision-cut lung slice technology to study the role of DDR2 in pulmonary fibrosis].

Pulmonary fibrosis is a severe lung interstitial disease characterized by the destruction of lung tissue structure, excessive activation and proliferation of fibroblasts, secretion and accumulation of a large amount of extracellular matrix (ECM), and impaired lung function. Due to the complexity of the disease, a suitable animal model to mimic human pulmonary fibrosis has not yet been established. Precision-cut lung slice (PCLS) has been a widely used in vitro method to study lung physiology and pathogenesis in recent years. This method is an in vitro culture technology at the level between organs and cells, because it can preserve the lung tissue structure and various types of airway cells in the lung tissue, simulate the in vivo lung environment, and conduct the observation of various interactions between cells and ECM. Therefore, PCLS can compensate for the limitations of other models such as cell culture. In order to explore the role of discoidin domain receptor 2 (DDR2) in pulmonary fibrosis, Ddr2flox/flox mice were successfully constructed. The Cre-LoxP system and PCLS technology were used to verify the deletion or knockdown of DDR2 in mouse PCLS. Transforming growth factor ß1 (TGF-ß1) can induce fibrosis of mouse PCLS in vitro, which can simulate the in vivo environment of pulmonary fibrosis. In the DDR2 knock down-PCLS in vitro model, the expression of various fibrosis-related factors induced by TGF-ß1 was significantly reduced, suggesting that knocking down DDR2 can inhibit the formation of pulmonary fibrosis. The results provide a new perspective for the clinical study of DDR2 as a therapeutic target in pulmonary fibrosis.

[Differential expressions of seminal plasma piRNAs in men and its significance].

OBJECTIVE: To study the differential expressions of piRNAs in the seminal plasma of men and the role of piRNAs in spermatogenesis. METHODS: We sequenced the seminal plasma samples collected from 187 male infertility patients and 58 normal healthy men, obtained differentially expressed piRNAs, and detected the relative expressions of piRNAs in different types of sperm by RT-qPCR to explore their significance in the diagnosis of male infertility. Using histopathology, RNA-protein pull-down and Western blot, we investigated the action mechanism of piRNAs in spermatogenesis in the mouse model. RESULTS: RT-qPCR of the seminal plasma samples revealed a high expression of hsa_piR_000478 in teratozoospermia and ROC curve analysis showed an auxiliary significance of hsa_piR_000478 in the diagnosis of the disease (AUC = 0.7549). Transfection of hsa_piR_000478 and its homologous sequence piR_mmu_54800729 into the seminiferous tubules of the mouse model significantly decreased sperm motility, increased the percentage of morphologically abnormal sperm and destroyed the testicular structure. Molecular biological experiments exhibited a close correlation between piRNAs and the energy metabolism-related pathway, which elevated the level of cell glycolysis and interfered with normal spermatogenesis. CONCLUSION: hsa_piR_000478 has an auxiliary significance in the diagnosis of male infertility, and piRNAs may interfere with spermatogenesis by affecting the glycolysis-related pathway in the spermatogenic microenvironment of the testis.

Population Pharmacokinetics of Caspofungin and Dose Simulations in Heart Transplant Recipients.

The effect of heart transplantation (HTx) on the pharmacokinetics (PK) of caspofungin is not well-characterized. The aim of this study was to investigate the population PK of caspofungin in HTx and non-HTx patients and to identify covariates that may affect the PK of caspofungin. Seven successive blood samples were collected before administration and at 1, 2, 6, 10, 16, and 24 h after the administration of caspofungin for at least 3 days. This study recruited 27 HTx recipients and 31 non-HTx patients with 414 plasma concentrations in total. A nonlinear mixed-effects model was used to describe the population PK of caspofungin. The PK of caspofungin was best described by a two-compartment model. The clearance (CL) and volume of the central compartment (Vc) of caspofungin were 0.385 liter/h and 4.27 liters, respectively. The intercompartmental clearance (Q) and the volume of the peripheral compartment (Vp) were 2.85 liters/h and 6.01 liters, respectively. In the final model, we found that albumin (ALB) affected the CL of caspofungin with an adjustment factor of -1.01, and no other covariates were identified. In this study, HTx was not found to affect the PK of caspofungin. Based on the simulations, the dose of caspofungin should be proportionately increased in patients with decreased ALB levels.

Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries.

The Shank family proteins are enriched at the postsynaptic density (PSD) of excitatory glutamatergic synapses. They serve as synaptic scaffolding proteins and appear to play a critical role in the formation, maintenance and functioning of synapse. Increasing evidence from genetic association and animal model studies indicates a connection of SHANK genes defects with the development of neuropsychiatric disorders. In this review, we first update the current understanding of the SHANK family genes and their encoded protein products. We then denote the literature relating their alterations to the risk of neuropsychiatric diseases. We further review evidence from animal models that provided molecular insights into the biological as well as pathogenic roles of Shank proteins in synapses, and the potential relationship to the development of abnormal neurobehavioral phenotypes.

Relocating Industrial Plants Delivers Win-Win Emission Reduction Benefits to Origin and Destination Regions.

Relocating pollution-intensive factories is one of the most effective measures to meet mandatory environmental regulations in developed cities while simultaneously imposing environmental pressure on the receiving cities. Existing studies often assume that relocated plants produce the same or higher emissions when relocated. However, the current pollution mitigation policies enforce even higher emission standards in the destination after plant relocation. We employ a bottom-up pollution accounting approach to assess the impact of intraregional or interregional relocation of iron and steel plants in China's Beijing-Tianjin-Hebei (BTH) area on various air pollutants; specifically, seven policy scenarios are modeled, based on stringency, implementation scope, and production technologies. We find that relocation combined with emission standards enforcement and shifts from BOF (basic oxygen furnace) to EAF (electric arc furnace) production technology may significantly reduce emissions within and outside BTH areas by as much as 28.8% compared to business as usual. The observed reduction is mainly due to the requirement of meeting ultralow emission standards directly or indirectly after relocation. Both origin and destination cities benefit from the relocation, with limited emission spillovers (+9.1%) for destinations outside BTH and even a net reduction (9.4%) in Tangshan. We conclude that combining factory relocation with stricter emission standards and production technological innovation could circumvent the Pollution Haven Hypothesis and deliver win-win air pollution reduction benefits for both origins and destinations.

ML365 inhibits TWIK2 channel to block ATP-induced NLRP3 inflammasome.

Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2I289A/L290A/Y308A) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC50 value of 4.07 ± 1.5 µM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 µM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with F value of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.

A case report of acute testicular pain secondary to segmental testicular infarction.

BACKGROUND: Segmental testicular infarction is a rare condition that often occurs in the upper pole of the left testicle and usually presents with acute onset of scrotal pain. Contrast-enhanced ultrasound and MR are essential for diagnosing and differentiating segmental testicular infarction in clinical practice, and conservative treatment can only be adopted after a definitive diagnosis. In the present case, after conservative treatment, the infarct volume was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. We performed a correlation analysis to investigate the causes of these changes. CASE PRESENTATION: A 33-year-old male, without any specific disease history, was admitted to the hospital with a 5-day history of left testicular pain, and the imaging showed focal necrosis of the left testicle with hemorrhage. He was diagnosed with segmental testicular infarction after differentiating and excluding it from malignant tumors. Conservative medical treatment was given, and the symptoms of testicular pain were relieved after treatment. After discharge, regular reexamination at follow-ups showed that the infarct's size was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. CONCLUSION: Conservative treatment has become the standard treatment currently adopted after confirming the diagnosis of segmental testicular infarction through contrast-enhanced ultrasound and MR. The blood flow changes in and around the focus of testicular infarction can be related to various factors. At present, relevant conclusions of the underlying mechanisms were mainly deduced from infarction studies of other related organs such as the heart and brain; thus, the specific pathological mechanism needs further experimental verification.

Effects of air pollutant emission on the prevalence of respiratory and circulatory system diseases in Linyi, China.

As a typical industrial city, Linyi has suffered severe atmospheric pollution in recent years. Meanwhile, a high incidence of respiratory and circulatory diseases has been observed in Linyi. The relationship between air pollutants and the prevalence of respiratory and circulatory system diseases in Linyi is still unclear, and therefore, there is an urgent need to assess the human health risks associated with air pollutants. In this study, the number of outpatient visits and spatial distribution of respiratory and circulatory diseases were first investigated. To clarify the correlation between diseases and air pollutant emissions, the residential intake fraction (IF) of air pollutants was calculated. The results showed that circulatory and respiratory diseases accounted for 62.32% of the total causes of death in 2015. The incidence of respiratory diseases was high in the winter, and outpatient visits were observed for more males (60.9%) than females (39.1%). The spatial distribution suggested that outpatient visits for respiratory and circulatory diseases were concentrated in the main urban area of Linyi, including the Hedong District, Lanshan District, and Luozhuang District, and especially at the junction of these three areas. After calculating the IF combined with the characteristics of pollution sources, meteorological conditions, and population data, a high IF value was concentrated in urban and suburban areas, which was consistent with the high incidence of diseases. Moreover, high R values and a significant correlation (R > 0.6, p < 0.05) between outpatient visits and residential IF of air pollutants imply similar spatial distributions of outpatient visits and IF value of residents. The spatial similarity of air pollution and outpatient visits suggested that future air pollution control policies should better reflect the health risks of spatial hotspots. This study can provide a potentially important reference for environmental management and air pollution-related health interventions.

Who is a good neighbor? Analysis of frontrunner cities with comparative advantages in low-carbon development.

A well-developed economy and low-carbon emission intensity are important characteristics of low-carbon cities; they also represent important tasks for achieving global climate change mitigation goals. It is seldom discussed, however, how we should identify frontrunner cities from which low-carbon development experiences can be gleaned and then implemented in neighboring cities. This study, therefore, proposed a simple indicator-the "good neighbor index"-to identify frontrunner cities in low-carbon transformation based on economic and emission performance. Based on this indicator, we identified "good neighbors" in static and dynamic views for China. The results showed that the static good neighbors in 2015 were mostly large cities with higher incomes and better industrial structures whereas the dynamic neighbors achieved better economic growth and emission reductions from 2005 to 2015, though their economic and emissions statuses were generally worse. The good neighbor list is not consistent with the list of national low-carbon pilot cities, which has largely overlooked the experiences of some fast-growing cities. These results have policy implications for the Chinese government in terms of promoting the low-carbon transformation of cities. The study can also provide a reference for other countries in addressing climate change at the city level.

[Preparation of evodiamine-glycyrrhizic acid micelles with glycyrrhizic acid as carrier and their anti-hepatic fibrosis activity].

This study aimed to prepare evodiamine-glycyrrhizic acid(EVO-GL) micelles to enhance the anti-hepatic fibrosis activity of evodiamine. Firstly, EVO-GL micelles were prepared with use of thin film dispersion method. With particle size, encapsulation efficiency, loading capacity of micelles and the solubility of evodiamine as the indexes, the effect of different factors on micelles was observed to screen the optimal preparation methods and process. Then the pharmaceutical properties and the therapeutic effects of EVO-GL micelles prepared by optimal process were evaluated on CCl_4-induced hepatic fibrosis. The results showed that the micelles prepared by the thin film dispersion method had an even size, with an average particle size of(130.80±12.40)nm, Zeta potential of(-41.61±3.12) mV, encapsulation efficiency of 91.23%±1.22%, drug loading of 8.42%±0.71%, high storage stability at 4 ℃ in 3 months, and slow in vitro release. Experimental results in the treatment of CCl_4-induced hepatic fibrosis in rats showed that EVO-GL micelles had a synergistic anti-hepatic fibrosis effect, which significantly reduced the liver function index of hepatic fibrosis rats. In conclusion, the EVO-GL micelles prepared with glycyrrhizic acid as a carrier would have a potential application prospect for the treatment of hepatic fibrosis.

Design of Multi-Metallic-Based Electrocatalysts for Enhanced Water Oxidation.

Electrochemical water splitting by renewable energy resources is an efficient and green approach for hydrogen gas production. However, the anodic oxygen evolution reaction (OER) largely impedes the industrial application due to its sluggish four-electron-transition kinetics. Although various materials have been developed to accelerate the OER rate, still some issues should be addressed to meet the industrial demand: (i) considerable 200-300 mV overpotential as extra onset energy input, (ii) limited survival and performance in acidic electrolyte for the majority of oxide/hydroxide composite materials, (iii) unsatisfying long-term durability and (iv) the need for facile and scalable preparation methods. Here, we emphasize on multi-metallic composites with enhanced OER activity based on both precious and nonprecious elements that outperform the unary and binary composites. The regulation effect from multi-metal incorporation is also summarized systematically: (i) introducing foreign metal atoms to the host material boosts the physical properties such as conductivity, surface area, defect density, morphology, wettability, etc., (ii) metal doping can synergistically regulate the electronic features of the host material, e. g. oxygen vacancy, eg orbit filling, coordinative number and covalence state, which can optimize the absorption/desorption energy of the M-O intermediate, (iii) chaotic impact from the added atoms twists the catalyst lattice into a more aggressive and higher energy state, which is more feasible to transform to an active intermediate with lower required energy supply. This review aims to provide a practical approach to further improve the OER performance via multi-metallic-based catalysts.

Processable Surface Modification of Nickel-Heteroatom (N, S) Bridge Sites for Promoted Alkaline Hydrogen Evolution.

Nickel-heteroatoms bridge sites are important reaction descriptors for many catalytic and electrochemical processes. Herein we report the controllable surface modification of nickel-nitrogen (Ni-N) bridge sites on metallic Ni particles via a simplified vapor-assisted treatment approach. X-ray absorption spectroscopy (XAS) and Operando Raman spectroscopy verifies the interaction between Ni and surface-anchored N, which leads to distorted Ni lattice structure with improved wettability. The Ni-N bridge sites with appropriate N coverage level plays a critical role in the enhanced hydrogen evolution reaction (HER) and the optimized electrode (Ni-N0.19 ) has demonstrated superior HER performances with low overpotential merely of 42 mV for achieving a current density of 10 mA cm-2 , as well as favorable reaction kinetics and excellent durability in alkaline electrolyte. DFT calculations revealed that the appropriate N-coverage level can lead to the most favorable ΔGH* kinetics for both adsorption of H* and release of H2 , while high N coverage (Ni-N0.59 ) results in weaker H* adsorption, thus a decreased HER activity, corresponding well to our experimental observations. Furthermore, this generic synthetic approach can also be applied to prepare S-modified Ni HER catalyst by generating hydrogen sulfide vapor.

Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients.

Background and Purpose- Trimethylamine N-oxide (TMAO)-a gut derived metabolite-has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods- We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results- After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02-1.46). Consistently, compared with participants in the lowest tertile (<1.79 µmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 µmol/L; odds ratio, 1.34; 95% CI, 1.00-1.81) or in TMAO tertile 3 (≥3.19 µmol/L; odds ratio, 1.43; 95% CI, 1.02-2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions- Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Low-Temperature Synthesis of Cuboid Silver Tetrathiotungstate (Ag2WS4) as Electrocatalyst for Hydrogen Evolution Reaction.

Ternary bimetallic sulfide silver tetrathiotungstate (Ag2WS4) was prepared by a simple low-temperature precipitation method. The structure of Ag2WS4 was determined using the data from powder X-ray diffraction, which is in space group I4̅2 m (I-phase) with a tetragonal unit cell of a = b = 5.950 71 Å and c = 9.562 65 Å, containing layers of edge-sharing AgS4 and WS4 tetrahedra. The Ag2WS4 was also used as an electrocatalyst for the hydrogen evolution reaction (HER) in acid electrolyte. The results demonstrated that, attributed to its unique composition, large electrochemical active surface area, and high electric conductivity, the Ag2WS4 exhibited superior electrocatalytic activity for HER, in comparison with the ternary counterparts of WS2 and Ag2S with a low onset potential and small Tafel slope. The Ag2WS4 also presented superior stability and maintained the electrocatalytic activity of HER for at least 24 h in 0.5 M H2SO4.