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Human cytomegalovirus (CMV) infection is associated with hypertension and has been linked with the pathogenesis of increased arterial blood pressure (BP). Currently, whether CMV infection is associated with the progression of hypertension and hypertensive target organ damage (TOD) remains to be identified. We aimed to examine the relationship between CMV infection and the progression of hypertension and hypertensive TOD, which could provide clues on the possible mediating mechanisms, in the Han Chinese population. A total of 372 patients with hypertension and 191 healthy controls (Han participants from Xinjiang, China) were included in the study. Enzyme-linked immunosorbent assay (ELISA) and qPCR were used to detect CMV infection. C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) titers were also analyzed using an ELISA kit. Moreover, cardiovascular disease markers were evaluated by echocardiography, carotid ultrasonography, and tomographic scans. Essential hypertension (EH) patients exhibited a marked increase in CMV IgG antibody, CRP, TNF-α, and IL-6 levels. Higher grade of hypertension and hypertensive TOD had higher CMV IgG antibody and CRP levels. The CMV IgG antibody titers were positively correlated with arterial BP, greater grade of hypertension and hypertensive TOD, and CRP and IL-6 levels. The higher quartile of CMV IgG titer and CRP level were associated with the incidence of hypertension and the progression of hypertension and hypertensive TOD. In the Han Chinese population, high CMV IgG titers are associated with the progression of hypertension and hypertensive TOD. CMV IgG titer >4.25 U could be an independent predictor of hypertension and progression of hypertension, while that >4.85 U could be an independent risk factor for hypertensive TOD. The underlying mechanism may be largely mediated by chronic inflammation. [ABSTRACT FROM AUTHOR]

Background and objective: Henoch-Schönlein purpura (HSP) is an important cause of chronic kidney disease in children. This meta-analysis identified risk factors associated with renal involvement in childhood HSP. Methods: PubMed, Embase, and Web of Science were searched. The quality of all eligible studies was assessed using the Newcastle-Ottawa scale criteria. An analysis of possible risk factors was conducted to report the odds ratio (OR) and weighted mean difference (WMD). Results: Thirteen studies (2398 children) revealed 20 possible and 13 significant risk factors associated with renal involvement in HSP, with the following meta-analysis estimates of OR and WMD, with 95% confidence intervals: older age (0.90, 0.61–1.19); age > 10 y (3.13, 1.39–7.07); male gender (1.36, 1.07–1.74); abdominal pain (1.94,1.24–3.04); gastrointestinal bleeding (1.86, 1.30–2.65); severe bowel angina (3.38, 1.17–9.80); persistent purpura (4.02, 1.22–13.25); relapse (4.70, 2.42–9.14); WBC > 15 × 109/L (2.42, 1.39–4.22); platelets > 500 × 109/L (2.98, 1.22–7.25); elevated antistreptolysin O (ASO) (2.17, 1.29–3.64); and decreased complement component 3 (C3) (3.13, 1.62–6.05). Factors not significantly associated with renal involvement were: blood pressure; orchitis; elevated C-reactive protein; elevated erythrocyte sedimentation rate (ESR); and elevated serum IgA/IgE or IgG. Arthritis/arthralgia may be a risk factor according to the criteria of the American College of Rheumatology (1.41, 1.01–1.96). Conclusion: The following are associated with renal involvement in pediatric HSP: male gender; > 10 y old; severe gastrointestinal symptoms (abdominal pain, gastrointestinal bleeding, and severe bowel angina); arthritis/arthralgia; persistent purpura or relapse; WBC > 15 × 109/L; platelets > 500 × 109/L; elevated ASO; and low C3. Relevant clinical interventions for these risk factors may exert positive effects on the prevention of kidney disease during the early stages of HSP. However, the results should be interpreted cautiously due to the limitations of the studies. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter. [ABSTRACT FROM AUTHOR]

A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (Ki: 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development. [ABSTRACT FROM AUTHOR]

Community structures are ubiquitous in various complex networks, implying that the networks commonly be composed of groups of nodes with more internal links and less external links. As an important topic in network theory, community detection is of importance for understanding the structure and function of the networks. Optimizing statistical measures for community structures is one of most popular strategies for community detection in complex networks. In the paper, by using a type of self-loop rescaling strategy, we introduced a set of global modularity functions and a set of local modularity functions for community detection in networks, which are optimized by a kind of the self-consistent method. We carefully compared and analyzed the behaviors of the modularity-based methods in community detection, and confirmed the superiority of the local modularity for detecting community structures on large-size and heterogeneous networks. The local modularity can more quickly eliminate the first-type limit of modularity, and can eliminate or alleviate the second-type limit of modularity in networks, because of the use of the local information in networks. Moreover, we tested the methods in real networks. Finally, we expect the research can provide useful insight into the problem of community detection in complex networks. [ABSTRACT FROM AUTHOR]

Ascorbate-glutathione (ASA-GSH) cycle is a major pathway of H2O2 scavenging and an effective mechanism of detoxification in plants. The differences in photosynthesis, chlorophyll content (Chl), relative water content (RWC), antioxidants and antioxidative enzyme activities involved in ASA-GSH metabolism were measured between the flag leaves and spike bracts (glumes and lemmas) during grain filling under drought stress. The expression of APX1, GRC1, DHAR, MDHAR, GPX1, and GS3 in ASA-GSH cycle was also measured. Compared with the flag leaves, the spike bracts exhibited stable net photosynthetic rate (PN) and chlorophyll content (Chl), a lower accumulation of reactive oxygen species (ROS), and more enhanced percentages of antioxidant enzyme activities and key enzymes gene transcription levels involved in ASA-GSH metabolism during the grain-filling stage under drought conditions. This could be the reasonable explanation for the more stable photosynthetic capacity in spikes, and the glumes and lemmas senesced later than the flag leaves at the late grain-filling stage. Also, the function of ASA-GSH cycle could not be ignored in alleviating oxidative damage by scavenging more excess ROS in spikes under drought stress. [ABSTRACT FROM AUTHOR]

Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Characteristics of lung function impairment in bronchiectasis is not fully understood. Objectives: To determine the factors associated with lung function impairment and to compare changes in spirometry during bronchiectasis exacerbation and convalescence (1 week following 14-day antibiotic therapy). Methods: We recruited 142 patients with steady-state bronchiectasis, of whom 44 with acute exacerbations in the follow-up were included in subgroup analyses. Baseline measurements consisted of chest high-resolution computed tomography (HRCT), sputum volume, purulence and bacteriology, spirometry and diffusing capacity. Spirometry, but not diffusing capacity, was examined during acute exacerbations and convalescence. Results: In the final multivariate models, having bronchiectasis symptoms for 10 years or greater (OR = 4.75, 95%CI: 1.46–15.43, P = 0.01), sputum culture positive for Pseudomonas aeruginosa (OR = 4.93, 95%CI: 1.52–15.94, P<0.01) and HRCT total score being 12 or greater (OR = 7.77, 95%CI: 3.21–18.79, P<0.01) were the major variables associated with FEV1 being 50%pred or less; and the only variable associated with reduced DLCO was 4 or more bronchiectatic lobes (OR = 5.91, 95%CI: 2.20–17.23, P<0.01). Overall differences in FVC and FEV1 during exacerbations and convalescence were significant (P<0.05), whereas changes in other spirometric parameters were less notable. This applied even when stratified by the magnitude of FEV1 and DLCO reduction at baseline. Conclusion: Significant lung function impairment should raise alert of chest HRCT abnormality and sputum culture positive for Pseudomonas aeruginosa, in patients with predominantly mild to moderate steady-state bronchiectasis. Acute exacerbations elicited reductions in FVC and FEV1. Changes of other spirometric parameters were less significant during exacerbations. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Cough hypersensitivity has been common among respiratory diseases. Objective: To determine associations of capsaicin cough sensitivity and clinical parameters in adults with clinically stable bronchiectasis. Methods: We recruited 135 consecutive adult bronchiectasis patients and 22 healthy subjects. History inquiry, sputum culture, spirometry, chest high-resolution computed tomography (HRCT), Leicester Cough Questionnaire scoring, Bronchiectasis Severity Index (BSI) assessment and capsaicin inhalation challenge were performed. Cough sensitivity was measured as the capsaicin concentration eliciting at least 2 (C2) and 5 coughs (C5). Results: Despite significant overlap between healthy subjects and bronchiectasis patients, both C2 and C5 were significantly lower in the latter group (all P<0.01). Lower levels of C5 were associated with a longer duration of bronchiectasis symptoms, worse HRCT score, higher 24-hour sputum volume, BSI and sputum purulence score, and sputum culture positive for P. aeruginosa. Determinants associated with increased capsaicin cough sensitivity, defined as C5 being 62.5 µmol/L or less, encompassed female gender (OR: 3.25, 95%CI: 1.35–7.83, P<0.01), HRCT total score between 7–12 (OR: 2.57, 95%CI: 1.07–6.173, P = 0.04), BSI between 5–8 (OR: 4.05, 95%CI: 1.48–11.06, P<0.01) and 9 or greater (OR: 4.38, 95%CI: 1.48–12.93, P<0.01). Conclusion: Capsaicin cough sensitivity is heightened in a subgroup of bronchiectasis patients and associated with the disease severity. Gender and disease severity, but not sputum purulence, are independent determinants of heightened capsaicin cough sensitivity. Current testing for cough sensitivity diagnosis may be limited because of overlap with healthy subjects but might provide an objective index for assessment of cough in future clinical trials. [ABSTRACT FROM AUTHOR]

Rap1GAP is a GTPase-activating protein (GAP) that specifically stimulates the GTP hydrolysis of Rap1 GTPase. Although Rap1GAP is recognized as a tumor suppressor gene and downregulated in various cancers, little is known regarding the regulation of Rap1GAP ubiquitination and degradation under physiological conditions. Here, we demonstrated that Rap1GAP is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of Rap1GAP requires the PLK1 kinase and β-TrCP ubiquitin ligase complex. We revealed that PLK1 interacts with Rap1GAP in vivo through recognition of an SSP motif within Rap1GAP. PLK1 phosphorylates Ser525 in conserved 524DSGHVS529 degron of Rap1GAP and promotes its interaction with β-TrCP. We also showed that Rap1GAP was a cell cycle regulator and that tight regulation of the Rap1GAP degradation in mitosis is required for cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are common in patients with chronic lung diseases, but little is known about the prevalence in patients with bronchiectasis. A cross sectional study was conducted to investigate the prevalence and determinants associated with sleep disturbances, and the correlation between sleep disturbances and quality of life (QoL) in adults with steady-state bronchiectasis. Methods: One hundred and forty-four bronchiectasis patients and eighty healthy subjects were enrolled. Sleep disturbances, daytime sleepiness, and QoL were measured by utilizing the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and St. George Respiratory Questionnaire (SGRQ), respectively. Demographic, clinical indices, radiology, spirometry, bacteriology, anxiety and depression were also assessed. Results: Adults with steady-state bronchiectasis had a higher prevalence of sleep disturbances (PSQI>5) (57% vs. 29%, P<0.001), but not daytime sleepiness (ESS≥10) (32% vs. 30%, P = 0.76), compared with healthy subjects. In the multivariate model, determinants associated with sleep disturbances in bronchiectasis patients included depression (OR, 10.09; 95% CI, 3.46–29.37; P<0.001), nocturnal cough (OR, 1.89; 95% CI, 1.13–3.18; P = 0.016), aging (OR, 1.04; 95% CI, 1.01–1.07; P = 0.009) and increased 24-hour sputum volume (OR, 2.01; 95% CI, 1.22–3.33; P = 0.006). Patients with sleep disturbances had more significantly impaired QoL affecting all domains than those without. Only 6.2% of patients reported using a sleep medication at least weekly. Conclusions: In adults with steady-state bronchiectasis, sleep disturbances are more common than in healthy subjects and are related to poorer QoL. Determinants associated with sleep disturbances include depression, aging, nighttime cough and increased sputum volume. Assessment and intervention of sleep disturbances are warranted and may improve QoL. [ABSTRACT FROM AUTHOR]