Anti-infective bile acids bind and inactivate a Salmonella virulence regulator.

Bile acids are prominent host and microbiota metabolites that modulate host immunity and microbial pathogenesis. However, the mechanisms by which bile acids suppress microbial virulence are not clear. To identify the direct protein targets of bile acids in bacterial pathogens, we performed activity-guided chemical proteomic studies. In Salmonella enterica serovar Typhimurium, chenodeoxycholic acid (CDCA) most effectively inhibited the expression of virulence genes and invasion of epithelial cells and interacted with many proteins. Notably, we discovered that CDCA can directly bind and inhibit the function of HilD, an important transcriptional regulator of S. Typhimurium virulence and pathogenesis. Our characterization of bile acid-resistant HilD mutants in vitro and in S. Typhimurium infection models suggests that HilD is one of the key protein targets of anti-infective bile acids. This study highlights the utility of chemical proteomics to identify the direct protein targets of microbiota metabolites for mechanistic studies in bacterial pathogens.

Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.

Characteristics, prognostic determinants of monocytes, macrophages and T cells in acute coronary syndrome: protocol for a multicenter, prospective cohort study.

BACKGROUND: Acute coronary syndrome(ACS) is the leading cause of mortality and disability worldwide. Immune response has been confirmed to play a vital role in the occurrence and development of ACS. The objective of this prospective, multicenter, observational study is to define immune response and their relationship to the occurrence and progressive of ACS. METHODS: This is a multicenter, prospective, observational longitudinal cohort study. The primary outcome is the incidence of major adverse cardiovascular events (MACE) including in-stent restenosis, severe ventricular arrhythmia, heart failure, recurrent angina pectoris, and sudden cardiac death, and stroke one year later after ACS. Demographic characteristics, clinical data, treatments, and outcomes are collected by local investigators. Furthermore, freshly processed samples will be stained and assessed by flow cytometry. The expression of S100A4, CD47, SIRPα and Tim-3 on monocytes, macrophages and T cells in ACS patients were collected. FOLLOW-UP: during hospitalization, 3, 6 and 12 months after discharge. DISCUSSION: It is expected that this study will reveal the possible targets to improve the prognosis or prevent from occurrence of MACE in ACS patients. Since it's a multicenter study, the enrollment rate of participants will be accelerated and it can ensure that the collected data are more symbolic and improve the richness and credibility of the test basis. ETHICS AND DISSEMINATION: This study has been registered in Chinese Clinical Trial Registry Center. Ethical approval was obtained from the Affiliated Hospital of Guizhou Medical University. The dissemination will occur through the publication of articles in international peer-reviewed journals. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2200066382.

Chemoproteomic Analysis of Microbiota Metabolite-Protein Targets and Mechanisms.

The microbiota have emerged as an important factor in host physiology, disease, and response to therapy. These diverse microbes (bacteria, virus, fungi, and protists) encode unique functions and metabolites that regulate intraspecies and interspecies interactions. While the mechanisms of some microbiota species and metabolites have been elucidated, the diversity and abundance of different microbiota species and their associated pathways suggest many more metabolites and mechanisms of action remain to be discovered. In this Perspective, we highlight how the advances in chemical proteomics have provided new opportunities to elucidate the molecular targets of specific microbiota metabolites and reveal new mechanisms of action. The continued development of specific microbiota metabolite reporters and more precise proteomic methods should reveal new microbiota mechanisms of action, therapeutic targets, and biomarkers for a variety of human diseases.

miR-330-5p inhibits NLRP3 inflammasome-mediated myocardial ischaemia-reperfusion injury by targeting TIM3.

BACKGROUND/AIMS: The Nod-like receptor protein-3 (NLRP3) inflammasome signalling pathway is involved in the inflammatory reaction of myocardial ischaemia-reperfusion (I/R) injury. Our previous study showed that miR-330-5p was differentially expressed in both cerebral and myocardial I/R injury, and thus might be a biomarker for I/R injury-related diseases. Another study also indicated that miR-330-5p could promote NLRP3 inflammasome activation in renal IRI. However, the role of miR-330-5p in myocardial I/R injury-induced inflammatory responses is unknown. This study aimed to investigate the role of miR-330-5p in NLRP3 inflammasome-mediated myocardial I/R injury. METHODS: Myocardial I/R injury was induced in mice by occlusion of the left anterior descending coronary artery for 45 min followed by reperfusion. For NLRP3 inflammasome stimulation in vitro, cardiomyocytes were treated with 2 h of oxygen and glucose deprivation (OGD) or LPS (100 ng/ml). Myocardial miR-330-5p expression was examined by PCR at different treatment times. A miR-330-5p antagomir and an agomir were used to regulate miR-330-5p expression. To evaluate the role of miR-330-5p in myocardial I/R injury, 2,3,5-triphenyltetrazolium chloride (TTC) staining, echocardiography, and immunoblotting were used to assess infarct volume, cardiac function, and NLRP3 inflammasome activation respectively. A luciferase binding assay was used to examine whether miR-330-5p could directly bind to the T cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM3). Finally, the role of the miR-330-5p/TIM3 axis in regulating apoptosis and NLRP3 inflammasome formation was evaluated with flow cytometry assays and immunofluorescence staining. RESULTS: Compared to that in the model group, the inhibition of miR-330-5p significantly aggravated myocardial I/R injury, resulting in increased infarct volume and more severe cardiac dysfunction. Moreover, inhibition of miR-330-5p significantly increased the levels of NLRP3 inflammasome-related proteins, including caspase-1, IL-1ß, IL-18 and TNF-α, in both in-vivo and in-vitro models. Furthermore, TIM3 was confirmed as a potential target of miR-330-5p. As predicted, suppression of TIM3 by siRNA ameliorated the anti-miR-330-5p-mediated activation of the NLRP3 inflammasome induced by OGD and LPS, thus decreasing cardiomyocyte apoptosis. CONCLUSIONS: Our study indicated that the miR-330-5p/TIM3 axis was involved in the regulatory mechanism of NLRP3 inflammasome-mediated myocardial inflammation.

Chemical Reporters for Exploring Microbiology and Microbiota Mechanisms.

The advances made in bioorthogonal chemistry and the development of chemical reporters have afforded new strategies to explore the targets and functions of specific metabolites in biology. These metabolite chemical reporters have been applied to diverse classes of bacteria including Gram-negative, Gram-positive, mycobacteria, and more complex microbiota communities. Herein we summarize the development and application of metabolite chemical reporters to study fundamental pathways in bacteria as well as microbiota mechanisms in health and disease.

Dehydration-associated chronic kidney disease: a novel case of kidney failure in China.

BACKGROUND: Mesoamerican nephropathy (MeN) is a pattern of chronic kidney disease (CKD) prevalent among Central American men who work in agriculture, and its underlying cause has not been elucidated. Currently, experts hypothesize that MeN is related to repeated episodes of occupational heat stress leading to water loss and hence it is also called dehydration-associated CKD. CASE PRESENTATION: We report a case of a 40-year-old man, whose first admission to Peking Union Medical College Hospital was due to acute kidney injury (AKI). The clinical and pathological processes were consistent with acute tubular necrosis (ATN). However, after full recovery, CKD developed 1 year later. The second renal biopsy showed characteristics of ischemic renal disease but there was no evidence of vascular disease. It is worth noting that the patient had been taking part in long-distance running without drinking adequate water for years, which would have markedly decrease his renal blood flow. Thus, this patient may have developed chronic dehydration-associated kidney disease sharing the similar etiology of MeN. CONCLUSIONS: We report here a case of dehydration-associated CKD in a Chinese patient which shared similar etiology to MeN. Even in non-agricultural areas, this etiology of CKD should be noted to obtain a relevant history and prompt diagnosis.

MiR-320a was highly expressed in postmenopausal osteoporosis and acts as a negative regulator in MC3T3E1 cells by reducing MAP9 and inhibiting PI3K/AKT signaling pathway.

BACKGROUND: Postmenopausal osteoporosis (PMO), as a frequent disease in postmenopausal women, is mainly caused by the lack of estrogen. MiR-320a has been found to abate osteoblast function and induce oxidative stress before osteoporosis. However, studies on the downstream target gene and related signaling pathway of miR-320a in PMO are still obscure. This study aims to deal with these problems. METHODS: The expression levels of miR-320a and microtubule-associated protein 9 (MAP9) in patients with osteoporosis were analyzed on the basis of the GEO database. The cells viability was determined by methylthiazolyl tetrazolium bromide (MTT). Flow cytometry and western blot were used to detect the cells apoptosis and the expression of apoptosis-related proteins, respectively. The cells differentiation-related proteins were detected by qRT-PCR and western blot. The interaction between miR-320a and MAP9 was predicted by biological software and verified by dual luciferase reporter assay and rescue assay. The expression levels of PI3K, p-PI3K, AKT and p-AKT in MC3T3-E1 cells were assessed by western blot. RESULTS: We observed that miR-320a was over-expressed in PMO patients and exhibited inhibitory effects on MC3T3-E1 cells activity and differentiation, as well as promoting effects on MC3T3-E1 cells apoptosis. MAP9 was verified as a target gene of miR-320a and was negatively regulated by miR-320a. Based on the GEO database, MAP9 was found to be lower expressed in PMO patients. Rescue assay demonstrated that down-regulation of MAP9 could alleviate the promoting effects of miR-320a inhibitor on MC3T3-E1 cells activity and differentiation and the inhibitory effects of miR-320a inhibitor on MC3T3-E1 cells apoptosis. Mechanically, miR-320a/MAP9 possibly took part in MC3T3-E1 cells viability, differentiation and apoptosis via mediating PI3K/AKT signaling pathway. CONCLUSIONS: Our outcomes demonstrated that miR-320a promoted MC3T3-E1 cells apoptosis, suppressed MC3T3-E1 cells viability and differentiation through targeting MAP9 and modulating PI3K/AKT signaling pathway, which provided theoretical support for miR-320a/MAP9 as promising targets for the treatment and prevention of PMO.

Association of polymorphisms in TNF and GRN genes with ankylosing spondylitis in a Chinese Han population.

The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18-3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population.

Association Between a CCL17 Genetic Variant and Risk of Coronary Artery Disease in a Chinese Han Population.

BACKGROUND: In the present study we investigated the effects of genetic variations in the C-C motif chemokine ligand 17 (CCL17) gene on serum CCL17 levels and risk of coronary artery disease (CAD).Methods and Results:A case-control study was conducted to determine causal inferences amongCCL17single-nucleotide polymorphisms (SNPs), serum CCL17 levels, and risk of CAD. Luciferase assays, electrophoretic mobility shift assays (EMSA), and allele-specific quantitative chromatin immunoprecipitation (ChIP) assays were used to assess the function of the SNPs. In all, 947 participants (794 with CAD, 153 without CAD) were included in the study. The T allele in rs223828, located in intron of theCCL17gene, was associated with increased serum CCL17 levels as well as increased CAD risk. A causal inference test using mediation analysis suggested that rs223828 had a significant indirect casual effect on the increased risk of CAD mediated via serum CCL17 levels. Luciferase assays confirmed that the rs223828T allele enhancesCCL17promoter activity. Protein-DNA binding studies using EMSA and allele-specific quantitative ChIP assays indicated preferential activator protein-1 (AP-1) complex formation and recruitment with the rs223828 T allele compared with the C allele. CONCLUSIONS: We propose that theCCL17SNP rs223828 is associated with increased risk of CAD, and that this site may be a potential AP-1 binding site.

Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors.

Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.

A Preliminary Study of Diastereoselectivity in the PdII -Catalyzed C(sp3 )-H Alkoxylation of Cyclic Systems.

Primary mechanism of a PdII -catalyzed 8-aminoquinoline-directed C-H alkoxylation was investigated. It was understood that the PdII -catalyzed C(sp3 )-O bond formation proceeded through a concerted reductive elimination from the PdIV intermediate in the cyclic system. Deuteration experiments and related computational studies elucidate that intrinsic conformation determined the diastereoselectivity of the PdII -catalyzed C-H alkoxylation of cyclic carboxylic acids.

Accelerated Age-Related Arterial Stiffness in Systemic Lupus Erythematosus Patients.

BACKGROUND: An increased prevalence of arterial stiffness in systemic lupus erythematosus (SLE) patients has been established, but the mechanisms of progression of arterial stiffness with increasing age have not been fully explored. OBJECTIVES: To investigate age-related progression of arterial stiffness among SLE patients relative to healthy controls. METHODS: A total of 161 female SLE patients who were enrolled in the Chinese SLE Treatment and Research group (CSTAR) registry and 135 age-matched healthy control subjects participated in this cross-sectional investigation. Traditional cardiovascular risk factors and SLE-related parameters were assessed on the day that brachial-ankle pulse wave velocity (baPWV) was examined. SAS 9.3 was used to perform all statistical analyses in this study. Linear regression and curvilinear regression models were utilized to analyze the association between age and arterial stiffness. RESULTS: Arterial stiffness based on baPWV significantly differed between the SLE patients and controls in the different age groups, and within the SLE group. The baPWV increments for each age group (<25, 25-34, 35-45, and >45) were 30 cm/s, 52 cm/s, and 121 cm/s for the controls and 61 cm/s, 132 cm/s, and 155 cm/s for the SLE patients, respectively. Curvilinear regression and linear regression revealed various trends of increased arterial stiffness among the SLE patients compared with the healthy controls. The correlation coefficients between age and arterial stiffness significantly differed among the SLE patients relative to the healthy controls (correlation coefficients of 0.46478 and 0.52612, respectively; t = 2.05; P = 0.0409). Multivariate analysis revealed that age, mean blood pressure (BP) (P < 0.0001), erythrocyte sedimentation rate (ESR) (P = 0.0073), prednisone course (P = 0.0144), and SLE disease activity (P = 0.0405) were associated with arterial stiffness among the SLE patients. Further, these patients exhibited earlier exposure to and higher frequencies of several risk factors compared with the controls in each age group (<25 years: OR = 6.3253; 25-34 years: OR = 3.1043; 35-45 years: OR = 3.1316; >45 years: OR = 3.6020). CONCLUSIONS: The mechanisms of the age-related progression of arterial stiffness differed among the SLE patients relative to the healthy controls. Furthermore, accelerated arterial stiffness was observed among the SLE patients relative to the healthy controls with advancing age.

Interarm Blood Pressure Difference in Patients With Systemic Lupus Erythematosus.

OBJECTIVES: This study was performed to determine the relationship between systemic lupus erythematosus (SLE) and the interarm blood pressure difference (IAD) and to elucidate the role of the IAD as a surrogate marker for early detection of peripheral artery disease (PAD) in patients with SLE. METHODS: In total, 135 patients with SLE and 135 age- and gender-matched subjects were enrolled. The IAD and risk of an abnormal IAD were compared between the SLE and control groups, and logistic regression analysis was performed to determine the relationship between SLE and an abnormal IAD. The specificity and sensitivity of an IAD of 10 mm Hg or greater for diagnosis of PAD (ankle brachial index of <0.90) were calculated. RESULTS: Both the systolic and diastolic IADs were significantly higher in the SLE group than in the control group (P < 0.001). After adjustment for confounding factors, SLE remained significantly associated with an abnormal IAD (P = 0.039). Both the systolic and diastolic IADs were negatively associated with the ankle brachial index. Using a systolic IAD of 10 mm Hg or greater as the cutoff point, the specificity and sensitivity for PAD were 90% and 41%, respectively. A diastolic IAD of 10 mm Hg or greater exhibited higher specificity (92%), but lower sensitivity (30%). CONCLUSIONS: Systemic lupus erythematosus is independently associated with an abnormal IAD, and an IAD of 10 mm Hg or greater predicts PAD with high specificity but low sensitivity. Blood pressure should be measured at least once in both arms in patients with SLE for early detection of asymptomatic PAD.

Association of polymorphisms in SPARC and NLRP2 genes with rheumatoid arthritis in a Chinese Han population.

OBJECTIVES: To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. RESULTS: The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. CONCLUSION: This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population.

Chylopericardium following esophagectomy: a case report and systematic review.

BACKGROUND: Chylopericardium is a rare condition characterized by the accumulation of chyle in the pericardial space. It is most commonly caused by thoracic duct injury. Chylopericardium following esophagectomy is extremely rare but can cause life-threatening complications. This report presents a case of chylopericardium post-esophagectomy, resulting in cardiac tamponade and cardiac arrest. A systematic literature review was also conducted to facilitate the understanding of this rare condition. CASE PRESENTATION: A 41-year-old male was admitted to our hospital with intermediate to highly differentiated squamous cell carcinoma of the mid-thoracic esophagus (clinical T4NxM0). He underwent thoracoscopic-laparoscopic esophagectomy with cervical anastomosis. On postoperative day 1, patient had a cardiac arrest secondary to cardiac tamponade, requiring emergency ultrasound-guided drainage. The drained fluid was initially serous but became chylous after the administration of enteral nutritional emulsion. As a result of significant daily pericardial drainage, patient subsequently underwent thoracic duct ligation. The amount of drainage was substantially reduced post-thoracic duct ligation. Over a period of 2 years and 7 months, patient recovered well and tolerated full oral diet. A comprehensive literature review was conducted and 4 reported cases were identified. Among these cases, three patients developed pericardial tamponade secondary to chylopericardium post-esophagectomy. CONCLUSION: Chylopericardium is a rare but serious complication post-esophagectomy. Prompt echocardiography and thorough pericardial fluid analysis are crucial for diagnosis. Thoracic duct ligation has been shown to be an effective management approach for this condition.

Modification of MgH2 hydrogen storage performance by nickel-based composite catalyst Ni/NiO.

In this study, the Ni/NiO catalyst was demonstrated to enhance the hydrogen storage performance of MgH2. The dehydrogenation of MgH2+10 wt% Ni/NiO started at approximately 180 °C, achieving 5.83 wt% of dehydrogenation within 10 min at 300 °C. Completely dehydrogenated, MgH2 began to rehydrogenate at about 50 °C, absorbing about 4.56 wt% of hydrogen in 10 min at 150 °C. In addition, the activation energies of dehydrogenation and rehydrogenation of MgH2+10 wt% Ni/NiO were 87.21 and 34.84 kJ/mol. During the dehydrogenation/rehydrogenation cycle, Mg2Ni/Mg2NiH4 could promote hydrogen diffusion, thus enhancing the hydrogen storage performance of Mg/MgH2.

Associations between waist circumference, central obesity, and the presence of non-valvular atrial fibrillation patients with heart failure.

Background: Reportedly, there is a clear correlation between waist circumference (WC) and atrial fibrillation (AF). However, there is no specific discussion about the relationship between WC and non-valvular AF (NVAF) patients with heart failure. Our main purpose was to study the relationship between WC, central obesity (CO), and NVAF patients with heart failure. Methods: This is a retrospective cohort study. A total of 3,435 patients with NVAF in the First Affiliated Hospital of Xinjiang Medical University from January 2015 to December 2017 were enrolled. The targeted independent variable and the dependent variable were WC and CO and the presence of NVAF with heart failure, respectively. Univariate, multiple regression, and subgroup analyses were used to analyze their relationship. We used the receiver operating characteristic (ROC) curve to choose the better predictor of NVAF with heart failure between WC and CO and calculated the proposed cut-off value of WC in males and female separately. Results: The identified risk factors of NVAF with heart failure were sex, height, WC, CO, body mass index (BMI), fasting blood glucose (FBG), homocysteine (HCY), triglyceride (TG), low-density lipoprotein cholesterol (LDLC), hypertension, diabetes mellitus (DM), stroke, vascular disease, and plaque. Then, a binary logistic regression model indicated that the occurrence of NVAF patients with heart failure increased 10% with WC increasing 1 cm and had a 2.8-fold increased risk with CO compared to those without. The predictive value [area under the ROC curve (AUC)], specificity, sensitivity, and accuracy of WC for the disease risk of NVAF with heart failure were higher than those of CO. The proposed cut-off value of WC was 91.85 cm for males and 93.15 cm for females. The diagnostic value of WC for NVAF with heart failure was higher for females than it was for males. Conclusions: Our research found that WC is related to the presence of heart failure in the patients with NYAF and can predict the presence of NVAF with heart failure. Our findings may help to improve the treatment and care strategies of NVAF individuals with abdominal obesity.

Identification of complex relationship between protein kinases and substrates during the cell cycle of HeLa cells by phosphoproteomic analysis.

Each phase of eukaryotic cell cycle is tightly controlled by multicomponent regulatory networks based on complex relationships of protein phosphorylation. In order to better understand the relationships between kinases and their substrate proteins during the progression of cell cycle, we analyzed phosphoproteome of HeLa cells during G1, S, and G2/M phases of cell cycle using our developed quantitative phosphoproteomic approaches. A total of 4776 high-confidence phosphorylation sites (phosphosites) in 1177 proteins were identified. Bioinformatics analysis for predicting kinase groups revealed that 46 kinase groups could be assigned to 4321 phosphosites. The majority of phosphoproteins harboring two or more phosphosites could be phosphorylated by different kinase groups, in which nine major kinase groups accounted for more than 90% phosphosites. Further analyses showed that approximately half of the examined two phosphosite combinations were correlatively regulated, regardless of whether the kinase groups were same or not. In general, the majority of proteins containing correlated phosphosites had solely co-regulated or counter-regulated phosphosites, and co-regulation was significantly more frequent than counter-regulation, suggesting that the former may be more important for regulating the cell cycle. In conclusion, our findings provide new insights into the complex regulatory mechanisms of protein phosphorylation networks during eukaryotic cell cycle.

An efficient palladium-catalyzed C-H alkoxylation of unactivated methylene and methyl groups with cyclic hypervalent iodine (i(3+) ) oxidants.

All the hype: The title reaction has been developed for the facile synthesis of a variety of complex alkyl ethers. Cyclic hypervalent iodine (I(3+) ) reagents serve as oxidants for this unique CH alkoxylation reaction. The reaction demonstrates excellent reactivity, good functional-group tolerance, and high yields. Q=8-aminoquinoline-derived auxiliary.