Search

P2Y 14 receptor (P2Y 14 R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y 14 R antagonists and the crystallographic overlap study between the reported P2Y 14 R antagonist compounds 6 and 9 , a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y 14 R antagonists. The most potent antagonist, compound I-17 ( N -(1 H -benzo[ d ]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC 50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y 14 R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In vitro and in vivo evaluation demonstrated that compound I-17 had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. I-17 decreased inflammatory factor release and cell pyroptosis through the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. Thus, compound I-17 , with potent P2Y 14 R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability ( F = 75%), could be a promising lead compound for acute gouty arthritis.

Background: The P2X7 receptor (P2X7R) is known to play a significant role in regulating various pathological processes associated with immune regulation, neuroprotection, and inflammatory responses. It has emerged as a potential target for the treatment of diseases. In addition to chemically synthesized small molecule compounds, natural products have gained attention as an important source for discovering compounds that act on the P2X7R., Purpose: To explore the research progress made in the field of natural product-derived compounds that act on the P2X7R., Methods: The methods employed in this review involved conducting a thorough search of databases, include PubMed, Web of Science and WIKTROP, to identify studies on natural product-derived compounds that interact with P2X7R. The selected studies were then analyzed to categorize the compounds based on their action on the receptor and to evaluate their therapeutic applications, chemical properties, and pharmacological actions., Results: The natural product-derived compounds acting on P2X7R can be classified into three categories: P2X7R antagonists, compounds inhibiting P2X7R expression, and compounds regulating the signaling pathway associated with P2X7R. Moreover, highlight the therapeutic applications, chemical properties and pharmacological actions of these compounds, and indicate areas that require further in-depth study. Finally, discuss the challenges of the natural products-derived compounds exploration, although utilizing compounds from natural products for new drug research offers unique advantages, problems related to solubility, content, and extraction processes still exist., Conclusion: The detailed information in this review will facilitate further development of P2X7R antagonists and potential therapeutic strategies for P2X7R-associated disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Dietary absorption and digestion are influenced by the microbiota, morphology, and digestive enzymes of intestines, and fermentation is a popular and effective technique to enhance animal rearing growth performance. This study aims to explore the pivotal role of Muscovy duck probiotics fermented feedstuff (FF) in altering the growth performance by reshaping gut morphology, microorganisms and metabolism. The findings showed that FF considerably raised the levels of fatty acids (FA) and small peptides (7-19AA) in the diet. Further feeding trial data reveals that FF greatly increased the Muscovy duck average daily gain (ADG) but had no effect on their daily feed intake (DFI), and the FCR significantly dropped (P < 0.05). Additionally, it was evident that FF improved the integrity of the intestinal mucosa in Muscovy duck by increasing villus height, villus height-to-crypt depth ratio, and lowering crypt depth. Then, in comparison to the control group (NC), there was a significant increase in the gene expression of the mucosal tight junction proteins Occludin, Claudin-1, and Zo-1 in the intestine of Muscovy duck. Additionally, there was higher expression of the mucosal transport channels SGLT-1, PepT1, AQP2, AQP3, and AQP10 in the similarly colon site, jejunum, and duodenum. Furthermore, in AB-PAS/PAS-stained duodenum, jejunum, ileum, and similarly colon site, FF markedly increased relative mucus output and goblet cells while decreasing epithelial cell apoptosis. Following 16S sequencing data indicated that the intestinal microbiota was altered and the diversity and richness of gut microbes was greatly enhanced by FF. Particularly, the boost of core probiotics, such as Rothia of duodenum, Limosilactobacillus and Lentilactobacillus of jejunum, Lactococcus and Rothia of ileum, Ligilactobacillus and Entocuccus of similarly colon site, Gallibacterium of caecum. And reduced potentially pathogenic bacteria (Campylobacter, Prevotellaceae, Clostridia-vadinBB60, and Oscillospira). Nontargeted metabolomics assay for intestinal content confirmed an increased organic acids (oxidanesulfonic acid, cholic acid, gallic acid, coumaric acid, pipecollc acid, 13s-hydroxyoctadecadienoic acid) and glycosides metabolites (5-hydroxydantrolene, 3-hydroxyguanfacine glucuronide, acetylleucine, astragalin, xanthosine, taxiphylin, sinapine, denudatine, penylalanyl-tyrosine and phenylalanyl-valine). These findings demonstrated that FF, a viable option to improve Muscovy duck growth performance through reconstructed intestinal morphology, microorganisms, and metabolism, subsequently promoted the gut health and increased diet digestion and absorption. The study that is being presented offers scientific proof that FF might be a useful strategy for improving Muscovy duck growth performance., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The degradation of lignin-carbohydrate complex (LCC) esters has been proven to be crucial for the selective separation of lignocellulosic components. This study utilized Raman microspectroscopy to image the preferential degradation of lignin and LCC esters from the bamboo wall during successive NaOH (0.2 to 5.0 % w/w), H 2 SO 4 (1 to 8 % v/v), and NaClO 2 (5 to 20 min) treatments. Raman imaging showed that lignin and LCC esters were selectively removed from the middle lamella of fibers and the secondary wall of parenchyma during NaOH and NaClO 2 treatments. In contrast, H 2 SO 4 primarily caused the simultaneous removal of lignin and LCC esters from the fiber wall under harsh conditions (8 %), while the middle lamella of parenchyma was less affected, both morphologically and topochemically. Raman spectral analysis indicated that the band intensity at 1605 cm -1 for lignin and at 1173 cm -1 for LCC esters decreased by >87.0 % in the highly lignified parenchyma secondary wall after a 5.0 % NaOH treatment, while the decrease was <67 % in the fiber wall. Interestingly, a strong linear correlation was observed between LCC esters and carbohydrates in the parenchyma (R 2  > 0.912). These findings provide important insights into the graded and classified utilization of bamboo resources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA., Methods: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA., Results: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy., Conclusions: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS., Trial Registration: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577)., (© 2024. The Author(s).)

Background: Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment., Purpose: To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort., Study Type: Prospective observational study., Population: 189 hypertensive older males (mean age 64.9 ± 7.2 years)., Field Strength/sequence: TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T., Assessment: The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment., Statistical Tests: Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance., Results: TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF., Data Conclusion: The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 International Society for Magnetic Resonance in Medicine.)

The interaction of MPs and aromatic hydrocarbons in seawater and pure water was examined using experimental measurements, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations in light of the potential health risks posed by microplastic (MPs)-associated aromatic hydrocarbon pollutants. Isothermal studies and MD simulations suggested that MPs have a stronger affinity for aromatic hydrocarbons in seawater. To uncover the mechanism, MPs' surface characteristics and their intermolecular interactions with aromatic hydrocarbons were examined. According to the research, MPs in seawater have less compact structure, bigger pores, and a higher specific surface area, all of which contribute to more sorption sites. Analysis of the intermolecular interaction indicated that MPs have a greater ability for molecular interactions in seawater and the interaction energy between MPs and aromatic hydrocarbons in seawater is higher. Additionally, seawater cations may act as bridges, which also accelerate sorption in seawater. In summary, this study provides a molecular-level understanding of MPs-aromatic hydrocarbons interaction and demonstrates that the interaction is stronger in seawater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pesticides are extensively used in agricultural production, and their residues in soil, water, and agricultural products have become a threat to aquatic ecosystem. In this study, the toxicity of haloxyfop-p-methyl, an aryloxyphenoxypropionate herbicide was studied using the model animal zebrafish. The development of zebrafish larvae was affected by haloxyfop-p-methyl including spinal deformities, decreased body length, slow heart rate, and large yolk sac area. Behavior analysis revealed that behavior activity of larvae was weakened significantly including shortened displacement distance, reduced swimming speed, increased angular speed winding degrees, in accordance with higher AChE activity. Besides, exposure to haloxyfop-p-methyl could induce oxidative stress companied by the increased intents of ROS, MDA and increased activities of CAT and SOD. In immunotoxicity, haloxyfop-p-methyl not only reduced the innate immune cells such as neutrophils and macrophages, but also affected T cells mature in thymus. Furthermore, haloxyfop-p-methyl could induce neutrophils apoptosis, accompanied with the upregulation of the expression of proapoptotic protein such as Bax and P53 and the downregulation of the expression of antiapoptotic protein Bcl-2. In addition, haloxyfop-p-methyl could induce the expression of Jak, STAT and proinflammatory cytokine genes (IFN-γ, TNF-α, and IL-8). These results indicate that haloxyfop-p-methyl induces developmental toxicity, neurotoxicity, and immunotoxicity in zebrafish, providing a perspective on the toxicological mechanism of haloxyfop-p-methyl in teleosts., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Extending the benefits of tumor molecular profiling for all cancer patients requires a comprehensive analysis of tumor genomes across distinct patient populations worldwide. In this study, we perform deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We perform a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns, and the spectrum of various somatic alterations between Chinese and American patient populations. Here, we show 64% of cancers from Chinese patients in this study have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine., (© 2022. The Author(s).)

Although chlorobromoisocyanuric acid has been widely used in agriculture, its deleterious toxicity on aquatic organisms remains rare. In this study, zebrafish were exposed to chlorobromoisocyanuric acid (0, 30, 40, and 50 mg/L) from 10 to 96 h post-fertilization (hpf). We found a significant reduction in immune cell numbers (neutrophils and macrophages) and the area of thymus at 96 hpf. The expression of immune-related genes and pro-inflammatory cytokines genes were upregulated. Besides, chlorobromoisocyanuric acid triggered neutrophils cell apoptosis. The mRNA and protein levels of pro-apoptotic p53 pathway and the Bax/Bcl-2 ratio further indicated the underlying mechanism. Furthermore, the oxidative stress was observed that the accumulation of reactive oxygen species and malondialdehyde significantly increased. Subsequently, the antioxidant agent astaxanthin significantly attenuated the level of oxidative stress and the dysregulation of inflammatory response. In summary, our results showed that chlorobromoisocyanuric acid induced developmental defects and immunotoxicity of zebrafish, partly owing to oxidative stress and cell apoptosis., (© 2021 Wiley Periodicals LLC.)

Basal-like breast cancer (BLBC) accounts for approximately 15% of all breast cancer cases, and patients with BLBC have a low survival rate. Our previous study demonstrated that the KLF5 transcription factor promotes BLBC cell proliferation and tumor growth. In this study, we demonstrated that the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), increased KLF5 acetylation at lysine 369 (K369), downregulated KLF5 protein expression levels, and decreased cell viability in BLBC cell lines. HDACi target KLF5 for proteasomal degradation by promoting KLF5 protein ubiquitination. K369 acetylation of KLF5 decreases the binding between KLF5 and its deubiquitinase, BAP1. These findings revealed a novel mechanism by which HDACi suppress BLBC, and a novel crosstalk between KLF5 protein acetylation and ubiquitination., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: Studies in the general population suggest that central blood pressure (BP) may be superior to peripheral BP in risk assessment. Although ambulatory brachial BP is recognized as the most reliable BP measurement in the dialysis population, there is no comparison of office central BP with ambulatory BP regarding risk stratification in these patients., Methods: In a multicenter prospective study of dialysis patients, central BP was measured noninvasively on a midweek nondialysis day, with interdialytic ambulatory BP and predialysis BP also collected. The primary outcomes were a composite of major adverse cardiovascular events (MACE) and all-cause mortality. Agreement between central and ambulatory BP was assessed using Cohen's Kappa index and Bland--Altman plot. Linear and nonlinear Cox regression models were used to determine the association of BP parameters with outcomes., Results: A total of 368 patients were recruited and 366 underwent central BP measurement. Central BP had a moderate agreement with ambulatory BP in defining hypertension (κ = 0.42) with wide limits of agreement in Bland--Altman analysis. After a median follow-up of 51.5 months, central pulse pressure, ambulatory SBP and ambulatory pulse pressure were associated with all-cause mortality, whereas all BP parameters, except for predialysis DBP, were significant predictors of MACE. However, whenever evaluated in a stepwise variable selection Cox model, only ambulatory pulse pressure, but not any central BP, was determined as the best candidate for prediction of both all-cause mortality and MACE. Nonlinear Cox models revealed no significant nonlinear trend of the association between central BP and outcomes., Conclusion: Central BP is predictive of all-cause mortality and cardiovascular events in dialysis patients but its prognostic value does not outperform ambulatory peripheral BP. Our data support the superiority of ambulatory BP in the dialysis population., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Dietary sodium and potassium intake are associated with stroke, but the potential mechanisms are unclear. We aimed to study the association between sodium and potassium intake and subclinical cerebrovascular health in hypertensive older males using multimodal magnetic resonance imaging., Methods: A total of 189 hypertensive male subjects without previous cardiovascular or cerebrovascular disease were included. Daily urinary sodium and potassium excretion were estimated from a fasting spot urine sample using a formula approach. A dedicated cerebrovascular health imaging protocol including vessel wall imaging, angiography, arterial spin labeling imaging and T2-weighted fluid-attenuated inversion recovery imaging was performed to study intracranial atherosclerosis, vascular rarefaction (defined as fewer discernible vessels on angiography), brain perfusion and small vessel disease, respectively., Results: The mean age was 64.9 (± 7.2) years. The average daily urinary and potassium excretion was 4.7 (± 1.4) g/L and 2.1 (± 0.5) g/L, respectively. Increased urinary sodium excretion was associated with decreased cerebral blood flow and elevated urinary potassium excretion was associated with reduced prevalence of intracranial plaque. The associations remained significant after adjusting for covariates, even including blood pressure control. Quadratic regression analysis indicated a marginally significant U-shaped association between urinary sodium intake and white matter hyperintensity, which lost significance in fully adjusted models. No significant association of urinary sodium and potassium excretion with other cerebrovascular health measures was noted., Conclusion: We concluded that in hypertensive older males without overt cardiovascular disease, increased sodium intake and reduced potassium intake are associated with impaired subclinical cerebrovascular health., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Growth differentiation factor 15(GDF15) is a distant member of the superfamily of the transforming growth factor beta (TGF-β). It has been established that increased GDF15 levels are associated with an increased risk of cardiovascular disease. However, the detail effect of GDF15 on cardiovascular system in patients with chronic kidney disease (CKD) needs detail analysis., Methods: Patients with CKD who did not need dialysis were enrolled in the study. Blood pressure (BP), endothelial function, pulse wave velocity (PWV) and heart rate variability (HRV) were taken in all subjects. Plasma GDF15 concentration was measured by an enzyme-linked immunosorbent assay., Results: Among the 355 participants, the mean age was 57.4 (±14.2) years old and the mean estimated glomerular filtration rate (eGFR) was 50.1 (±33.2) mL/min/1.73m 2 . The average plasma GDF15 level was 1394.7 (±610.1) pg/mL. Higher GDF15 concentrations were significantly associated with decreased eGFR and increased urine protein-to-creatinine ratio (uPCR). In multivariable models, after adjusting for potential confounders, plasma GDF15 has negative concerning with HRV parameters including the standard deviation of the normal-to-normal (NN) interval (SDNN), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) and Triangular Index., Conclusion: We observed there was a link between increased plasma of GDF15 and decreased HRV. The mechanisms and prediction of GDF15 in the cardiovascular disease with CKD needs further discussion and study.

The van der Waals (vdW) heterostructures formed by stacking layered two-dimensional materials can improve the performance of materials and provide more applications. In our paper, six configurations of AlN/MoS 2 vdW heterostructures were constructed, the most stable structure was obtained by calculating the binding energy. On this basis, the effect of external vertical strain on AlN/MoS 2 heterostructure was analyzed, the calculated results show that the optimal interlayer distance was 3.593 Å and the band structure was modulated. Then the h-BN intercalation was inserted into the AlN/MoS 2 heterostructure, by fixing the distance between h-BN and AlN or MoS 2 , two kinds of models were obtained. Furthermore, the electronic properties of AlN/MoS 2 heterostructure can be regulated by adding h-BN intercalation layer and adjusting its position. Finally, the optical properties show that the absorption coefficient of AlN/MoS 2 heterostructure exhibits enhancement characteristic compared with that of the individual monolayers. Meantime, compared with AlN/MoS 2 , the AlN/h-BN/MoS 2 shows a redshift effect and the light absorption peak intensity increased, which indicated that h-BN intercalation layer can be used to regulate the electronic and optical properties of AlN/MoS 2 heterostructure., (© 2021 IOP Publishing Ltd.)

Sulfometuron methyl (SM) is a widely used herbicide and thus leading to accumulation in the environment. The toxicity assessments of SM in model organisms are currently rare. In the present study, zebrafish were utilized for evaluating the detrimental effects of SM in aquatic vertebrates. Zebrafish embryos were exposed to 0, 10, 20, and 40 mg/L SM from 5.5 to 72 h post-fertilization (hpf), respectively. Consequently, SM exposure resulted in increasing the mortality rate and reducing hatching rate in larval zebrafish at 10, 20, and 40 mg/L SM-treated groups. The reduced numbers of immune cells (neutrophils and macrophages) were observed after SM exposure by a dose-dependent manner. The inflammatory responses (TLR4, MYD88, IL-1β, IL-6, IL-8, IFN-γ, IL-10, and TGF-β) were measured to estimate immune responses. Anti-inflammatory factors (IL-10 and TGF-β) were down-regulated in all the treated groups and significantly altered at 40 mg/L exposure group. Additionally, behavioral tests suggested that SM treatment significantly increased the total distance, average speed, and maximum acceleration of larval zebrafish during light-dark transition and subsequently enzymology test displayed the same trend to locomotor behaviors. The content significantly increased in oxidative stress, as reflected in ROS level in all the treated groups. The numbers of cell apoptosis were significantly increased at 20, and 40 mg/L and the highest concentration group induced the substantial increment (P < 0.001) of apoptosis-related genes including p53, Bax/Bcl-2, caspase-9, and caspase-3. In summary, our results demonstrated that exposure to SM caused toxicity of development, immune system, locomotor behavior, oxidative stress, and cell apoptosis at the early developmental stages of zebrafish., (Copyright © 2021. Published by Elsevier Inc.)

Background An artificial intelligence vessel segmentation tool, Fully Automated and Robust Analysis Technique for Popliteal Artery Evaluation (FRAPPE), was used to analyze a large databank of popliteal arteries imaged through the OAI (Osteoarthritis Initiative) to study the impact of atherosclerosis risk factors on vessel dimensions and characterize remodeling patterns. Methods and Results Magnetic resonance images from 4668 subjects contributing 9189 popliteal arteries were analyzed using FRAPPE. Age ranged from 45 to 79 years (median, 61), and 58% were women. Mean lumen diameter, mean outer wall diameter, and mean wall thickness (MWT) were measured per artery. Their median values were 5.8 mm (interquartile range, 5.2-6.5 mm), 7.3 mm (interquartile range, 6.7-8.1 mm), and 0.78 mm (interquartile range, 0.73-0.84 mm) respectively. MWT was associated with multiple cardiovascular risk factors, with age (4.2% increase in MWT per 10-year increase in age; 95% CI, 3.9%-4.5%) and sex (8.6% higher MWT in men than women; 95% CI, 7.7%-9.3%) being predominant. On average, lumen and outer wall diameters increased with increasing MWT until the thickness was 0.92 mm for men and 0.84 mm for women. After this point, lumen diameter decreased steadily, more rapidly in men than women (-7.9% versus -6.1% per 25% increase in MWT; P <0.001), with little change in outer wall diameter. Conclusions FRAPPE has enabled the analysis of the large OAI knee magnetic resonance imaging data set, successfully showing that popliteal atherosclerosis is predominantly associated with age and sex. The average vessel remodeling pattern consisted of an early phase of compensatory enlargement, followed by a negative remodeling, which is more pronounced in men.

Vascular dysfunctions, including arterial stiffness and endothelial dysfunction, are prevalent in hypertensive subjects. We aimed to study their relations to subclinical intracranial vascular health in this study. A total of 200 older hypertensive males without overt cardiovascular or cerebrovascular diseases were recruited. Arterial elasticity was measured as carotid-femoral pulse wave velocity (cfPWV) and endothelial function was measured as digital reactive hyperemia index (RHI). Cerebrovascular health was evaluated using MRI in four aspects: intracranial atherosclerosis, brain perfusion as cerebral blood flow (CBF), vascular rarefaction analyzed as visible arterial branches on angiography using a custom-developed analysis technique and small vessel disease measured as white matter hyperintensity (WMH). There was a significant negative association between cfPWV and CBF, suggesting a link between arterial stiffness and CBF decline. Higher cfPWV was also associated with presence of intracranial stenotic plaque and greater WMH volume. RHI was positively related to CBF, indicating that endothelial dysfunction was associated with reduced CBF. All the associations remained significant after adjustment for confounding variables. Arterial stiffness and endothelial dysfunction are associated with reduced brain perfusion in older hypertensive males. Arterial stiffness is also associated with global cerebral vascular injury, affecting both small and medium-to-large arteries.

Objectives: The study aimed to analyze the association between hypertension control and subclinical cerebrovascular health using a comprehensive multimodal imaging approach., Methods: The study included 200 hypertensive older males without previous cardiovascular diseases. Clinic blood pressure (BP) was measured using a standard approach. Cerebrovascular health was evaluated using magnetic resonance imaging in the following four aspects: Intracranial atherosclerosis as determined by vessel wall imaging; Vascular rarefaction (defined as less discernible vessels on angiography) was evaluated using a custom-developed technique. Cerebral blood flow (CBF) and white matter hyperintensity (WMH) were assessed using arterial spin-labeling imaging and fluid-attenuated inversion recovery imaging, respectively., Results: A total of 189 subjects had MRI scans. The mean age was 64.9 (± 7.2) years. For intracranial atherosclerosis, there was a significant association between uncontrolled hypertension and presence of intracranial plaque. When systolic and diastolic BP were analyzed separately, the association remained significant for both. For vascular rarefaction, uncontrolled hypertension was associated with less discernible vessel branches or shorter vessel length on angiography. Further analysis revealed that this is due to uncontrolled diastolic BP, but not uncontrolled systolic BP. There was an association between uncontrolled hypertension and reduced CBF, which was also mainly driven by uncontrolled diastolic BP. We also found that uncontrolled diastolic BP, but not uncontrolled systolic BP, was associated with increased WMH volume., Conclusions: Uncontrolled hypertension was associated with subclinical cerebrovascular injury globally, with both small and medium-to-large arteries being affected., Key Points: • In this study, we leveraged the advantage of a series of cutting-edge MR imaging and analysis techniques and found uncontrolled hypertension is associated with subclinical globally compromised cerebrovascular health. • The detrimental consequences of uncontrolled BP affect not only the small vessels but also the medium-to-large arteries, and uncontrolled systolic and diastolic BP are both independently associated with certain types of cerebrovascular injury. • Our data suggest that cerebrovascular health is impaired globally in uncontrolled hypertension before the onset of stroke.

Introduction: The current study aimed to depict intrinsic structural changes and the spontaneous brain activity patterns in voxel level in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) by using diffusion-tensor imaging and resting-state functional magnetic resonance (MR) imaging with an amplitude of low-frequency fluctuations (ALFF) algorithm and their clinical relevance., Materials and Methods: In the study, the diffusion-tensor imaging and resting-state functional MR imaging were performed in forty-two hemodialysis patients with ESRD and 42 healthy control subjects. Neuropsychological and laboratory tests were performed in all subjects. ALFF, fraction anisotropy (FA), and mean diffusivity (MD) values were compared between the two groups. Correlations between ALFF, FA or MD values, and clinical markers were analyzed., Results: We found that ESRD patients exhibited significantly lower ALFF values in multiple areas, including medial frontal gyrus, limbic lobe, superior frontal gyrus, bilateral lingual gyri, occipital lobe, parahippocampal gyrus, precuneus, while increased ALFF values in medial frontal gyrus than healthy controls. FA values were decreased in medial frontal gyrus, parietal lobe, and left precuneus regions in the ESRD group compared with controls. Importantly, FA for the frontal and parietal lobes was negatively associated with the dialysis duration of ESRD patients, ALFF z-scores for the medial prefrontal cortex (MPFC) were positively correlated with the dialysis duration of ESRD patients and Serum calcium of ESRD patients negatively correlated with FA values in the frontal and parietal lobes ( p <0.05)., Conclusion: Our study revealed that both impaired brain structure and function in ESRD patients with routine hemodialysis distributed mainly in the parietal, temporal, and frontal lobes. ESRD patients have cognitive impairment and declined memory ability. Serum calcium and dialysis duration might be associated with the impairment of brain structure and function in patients with ESRD., Competing Interests: The authors declare no competing financial interests and no conflicts of interest in this work., (© 2021 Guo et al.)

Introduction: C-X-C motif chemokine ligand 16 (CXCL16) is an inflammatory marker that has been found to be predictive of outcomes in patients with cardiovascular disease. Our previous work has also demonstrated its relation to cardiac injury in dialysis patients. However, it is yet unclear whether there is an association between CXCL16 and adverse outcomes in dialysis patients. We aimed to evaluate its prognostic value along with several traditional inflammatory markers in the current study., Methods: This is a multicenter longitudinal study of prevalent dialysis patients. Circulating inflammatory markers including CXCL16, C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 (IL-6) were measured using a multiplex assay. The primary outcomes were all-cause mortality and a composite of major adverse cardiovascular events (MACEs). The associations between biomarkers and outcomes were analyzed using Cox proportional hazards regression models., Results: Of the 366 participants with available plasma samples, the average age was 52.5 (±12.1) years, and there were 160 (43.7%) female participants. For all-cause mortality, logarithmically transformed CXCL16, IL-6, and CRP were independent predictors after adjustment for covariates. When the 3 markers were included in the same model, CXCL16 was the only one remaining its significance. For MACEs, logarithmically transformed CXCL16 and IL-6 were significant predictors when analyzed separately and CXCL16 was an independent predictor even after adjustment for IL-6. When the biomarkers were analyzed as categorical variables, only CXCL16 was associated with both outcomes. Adding CXCL16 to established risk factors improved risk prediction as revealed by Net Reclassification Index (NRI)., Conclusion: Using a multimarker approach, we determined that CXCL16 is a potent predictor of all-cause mortality and cardiovascular events in dialysis patients. Our data suggest CXCL16 may improve risk stratification and could be a potential interventional target., (© 2021 S. Karger AG, Basel.)

Purpose: To characterize the intracranial vascular features extracted from time of flight (TOF) images and their changes from baseline to follow-up in patients undergoing carotid revascularization, using arterial spin labeling (ASL) cerebral blood flow (CBF) measurement as a reference., Methods: In this retrospective study, brain TOF and ASL images of 99 subjects, acquired before, within 48 h, and/or 6 months after, carotid revascularization surgery were analyzed. TOF images were analyzed using a custom software (iCafe) to quantify intracranial vascular features, including total vessel length, total vessel volume, and number of branches. Mean whole-brain CBF was calculated from ASL images. ASL scans showing low ASL signal in the entire flow territory of an internal carotid artery (ICA), which may be caused by labeling failure, were excluded. Changes and correlations between time points were analyzed separately for TOF intracranial vascular features and ASL CBF., Results: Similar to ASL CBF, TOF vascular features (i.e. total vessel length, total vessel volume and number of branches) increased dramatically from baseline to post-surgery, then returned to a level slightly higher than the baseline in long-term follow-up (All P < 0.05). Correlation between time points was observed for all three TOF vascular features but not for ASL CBF., Conclusion: Intracranial vascular features, including total vessel length, total vessel volume and number of branches, extracted from TOF images are useful in detecting brain blood flow changes induced by carotid revascularization surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To develop a fully automated vessel wall (VW) analysis workflow (fully automated and robust analysis technique for popliteal artery evaluation, FRAPPE) on the popliteal artery in standardized knee MR images., Methods: Popliteal artery locations were detected from each MR slice by a deep neural network model and connected into a 3D artery centerline. Vessel wall regions around the centerline were then segmented using another neural network model for segmentation in polar coordinate system. Contours from vessel wall segmentations were used for vascular feature calculation, such as mean wall thickness and wall area. A transfer learning and active learning framework was applied in training the localization and segmentation neural network models to maintain accuracy while reducing manual annotations. This new popliteal artery analysis technique (FRAPPE) was validated against manual segmentation qualitatively and quantitatively in a series of 225 cases from the Osteoarthritis Initiative (OAI) dataset., Results: FRAPPE demonstrated high accuracy and robustness in locating popliteal arteries, segmenting artery walls, and quantifying arterial features. Qualitative evaluations showed 1.2% of slices had noticeable major errors, including segmenting the wrong target and irregular vessel wall contours. The mean Dice similarity coefficient with manual segmentation was 0.79, which is comparable to inter-rater variations. Repeatability evaluations show most of the vascular features have good to excellent repeatability from repeated scans of same subjects, with intra-class coefficient ranging from 0.80 to 0.98., Conclusion: This technique can be used in large population-based studies, such as OAI, to efficiently assess the burden of atherosclerosis from routine MR knee scans., (© 2020 International Society for Magnetic Resonance in Medicine.)

The dysfunction of E3 ubiquitin ligases is important in the pathogenesis of many human diseases, as they play important roles in multiple cellular processes. In this review, we evaluated the structures, functions and clinical significance of two RING-type E3 ubiquitin ligases from the same subfamily, ring-finger protein 126 (RNF126) and breast cancer associated gene 2 (BCA2). Interestingly, the expression of RNF126 and BCA2 are regulated by multiple signaling pathways, including EGFR, ERK, AKT, and NF-κB. RNF126 and BCA2 appear to be functional mediators for not only DNA damage repair but also cancer development. Due to their significant functions in cell proliferation and DNA damage repair, RNF126 and BCA2 may be two potential diagnostic biomarkers and therapeutic targets for cancers., Competing Interests: Declaration of Competing Interest The authors declare that we have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Cognitive decline is a common non-motor symptom of Parkinson disease (PD), and cellular prion protein (PrP C ) has been suggested to play a role in this process. This study aimed to investigate the correlation between plasma exosomal prion protein and cognitive decline in PD patients., Method: A total of 60 participants, which included 23 PD patients without cognitive impairment (the PD-NCI group), 17 PD patients with cognitive impairment (the PD-CI group) and 20 health controls were included in this study. All participants received a complete evaluation of motor symptoms as well as non-motor symptoms, which include devaluations of cognitive function(assessed with the Montreal Cognitive Assessment (MoCA)) and their psychiatric state(assessed with the Hamilton Anxiety Scale(HAM-A) and Hamilton Depression Scale(HAMD-17)). We used an enzyme-linked immunosorbent assay (ELISA) to measure the plasma exosomal prion protein level. The exosomal marker Heat shock protein 70 (HSP 70) was used to normalize the protein level to the exosome content., Result: In PD patients, the plasma exosomal prion protein concentration was negatively correlated with the cognitive level. The plasma exosomal prion protein concentration was significantly higher in the PD-CI group than in the control group (p < 0.05) and the PD-NCI group (p < 0.05).Multivariate regression analysis indicated that plasma exosomal prion protein levels were significantly associated with the cognitive level (t=-3.185, P = 0.001) after adjusting for age, education, disease duration, H&Y stage and MDS-UPDRS-III scores., Conclusion: The plasma exosomal prion protein level is correlated with cognitive decline in PD patients and might be a potential biomarker for PD patients at risk for cognitive impairment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We report the synthesis of a new acyclic CB[n]-type host (1) that features a central glycoluril trimer capped by triptycene sidewalls. Host 1 has good solubility in water (≈ 3 mM) and does not undergo strong self-association (K s = 480 M -1 ). We probed the geometry of the complexes by analyzing the complexation induced changes in the 1 H NMR spectra and measured the complexation thermodynamics by isothermal titration calorimetry. The conformation of 1 and its packing in the solid state was revealed by single crystal x-ray diffraction measurements., Competing Interests: Conflicts of interest L.I. is an inventor on patents held by the University of Maryland on the use of acyclic CB[n]-type receptors in biomedical applications.

Background: Incorporation of next-generation sequencing (NGS) technology into clinical utility in targeted and immunotherapies requires stringent validation, including the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status by NGS as important biomarkers for response to immune checkpoint inhibitors., Materials and Methods: We designed an NGS assay, Cancer Sequencing YS panel (CSYS), and applied algorithms to detect five classes of genomic alterations and two genomic features of TMB and MSI., Results: By stringent validation, CSYS exhibited high sensitivity and predictive positive value of 99.7% and 99.9%, respectively, for single nucleotide variation; 100% and 99.9%, respectively, for short insertion and deletion (indel); and 95.5% and 100%, respectively, for copy number alteration (CNA). Moreover, CSYS achieved 100% specificity for both long indel (50-3,000 bp insertion and deletion) and gene rearrangement. Overall, we used 33 cell lines and 208 clinical samples to validate CSYS's NGS performance, and genomic alterations in clinical samples were also confirmed by fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR). Importantly, the landscape of TMB across different cancers of Chinese patients ( n = 3,309) was studied. TMB by CSYS exhibited a high correlation (Pearson correlation coefficient r = 0.98) with TMB by whole exome sequencing (WES). MSI measurement showed 98% accuracy and was confirmed by PCR. Application of CSYS in a clinical setting showed an unexpectedly high occurrence of long indel (6.3%) in a cohort of tumors from Chinese patients with cancer ( n = 3,309), including TP53 , RB1 , FLT3 , BRCA2 , and other cancer driver genes with clinical impact., Conclusion: CSYS proves to be clinically applicable and useful in disclosing genomic alterations relevant to cancer target therapies and revealing biomarkers for immune checkpoint inhibitors., Implications for Practice: The study describes a specially designed sequencing panel assay to detect genomic alterations and features of 450 cancer genes, including its overall workflow and rigorous clinical and analytical validations. The distribution of pan-cancer tumor mutational burden, microsatellite instability, gene rearrangement, and long insertion and deletion mutations was assessed for the first time by this assay in a broad array of Chinese patients with cancer. The Cancer Sequencing YS panel and its validation study could serve as a blueprint for developing next-generation sequencing-based assays, particularly for the purpose of clinical application., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

In this study, daidzein long-circulating liposomes (DLCL) were prepared using the ultrasonication and lipid film-hydration method. The optimized preparation conditions by the orthogonal design was as follows: 55 to 40 for the molar ratio of soybean phosphatidylcholine (SPC) to cholesterol, 1 to 10 for the mass ratio of daidzein to total lipid (SPC and cholesterol) (w:w), the indicated concentration of 5% DSPE-mPEG2000 (w:w), 50 °C for the hydration temperature, and 24 min for the ultrasonic time. Under these conditions, the encapsulation efficiency and drug loading of DLCL were 85.3 ± 3.6% and 8.2 ± 1.4%, respectively. The complete release times of DLCL in the medium of pH 1.2 and pH 6.9 increased by four- and twofold of that of free drugs, respectively. After rats were orally administered, a single dose of daidzein (30 mg/kg) and DLCL (containing equal dose of daidzein), respectively, and the MRT 0-t (mean residence time, which is the time required for the elimination of 63.2% of drug in the body), t 1/2 (the elimination half-life, which is the time required to halve the plasma drug concentration of the terminal phase), and AUC 0-t (the area under the plasma drug concentration-time curve, which represents the total absorption after a single dose and reflects the drug absorption degree) of daidzein in DLCL group, increased by 1.6-, 1.8- and 2.5-fold as compared with those in the free group daidzein. Our results indicated that DLCL could not only reduce the first-pass effect of daidzein to promote its oral absorption, but also prolong its mean resident time to achieve the slow-release effect.

Impaired orthostatic blood pressure (BP) stabilization is prevalent in patients with chronic kidney disease (CKD) and is associated with adverse outcomes. We aimed to test the hypothesis that reduced hemoglobin is an important contributor to orthostatic intolerance in CKD in the present study. This study included 262 patients with non-dialysis-dependent CKD. Seated and standing BP was measured, and orthostatic BP reduction was calculated for both systolic BP (∆ SBP) and diastolic BP (∆ DBP). The association between orthostatic BP reduction and hemoglobin was determined by multiple linear regression models. We also performed mediation analysis to test to what extent the effect of renal dysfunction on impaired orthostatic BP stabilization can be explained by reduced hemoglobin. The mean age of the patients was 57.7 (±14.5) years, and 61.5% were male. Both ∆ SBP and ∆ DBP correlated negatively with estimated glomerular filtration rate (eGFR). With adjustment for age and sex, hemoglobin level was negatively associated with ∆ SBP (β = -1.4, SE = 0.4, P < .001) and ∆ DBP (β = -0.6, SE = 0.2, P = .009). The associations remained significant with further adjustment for additional covariates. When eGFR was introduced as a covariate, it did not eliminate the significance (both P < .05). The associations remained essentially unchanged in a sensitivity analysis excluding those with concurrent erythropoietin use. Mediation analysis demonstrated that reduced hemoglobin accounted for 35.4% (P = .004) of the effect of eGFR on ∆ SBP and 47.7% (P = .032) on ∆ DBP. Our study suggests that reduced hemoglobin is a potentially important contributor to the development of orthostatic hypotension in CKD., (©2019 Wiley Periodicals, Inc.)

Endothelial-derived factors regulate a wide range of pathophysiological events. It has been reported previously that IL-33 promotes acute kidney injury (AKI) in mice although the underlying epigenetic mechanism is unclear. In the present study we investigated the role of BRG1, a chromatin remodeling protein, in AKI with a focus on its regulation of IL-33 expression in endothelial cells. Smarca4-flox mice were crossbred with Cdh5-Cre mice to achieve endothelial-specific deletion of BRG1. AKI was induced by unilateral renal ischemia followed by reperfusion. Compared to wild type (WT) littermates, endothelial conditional BRG1 knockout (CKO) mice were protected from ischemia-reperfusion induced AKI as evidenced by decreased plasma creatinine levels, attenuated caste and tubular necrosis, and diminished immune infiltrates. CKO mice also developed less severe renal fibrosis as indicated by expression levels of extracellular matrix proteins, picrosirius red staining of collagenous tissues, and quantification of renal hydroxylproline levels. Of interest, renal expression of IL-33 was down-regulated as result of endothelial BRG1 deficiency. In cultured endothelial cells, BRG1 directly bound to the IL-33 promoter to activate transcription. Endothelial cell-derived conditioned media promoted the synthesis of pro-fibrogenic proteins in renal tubular epithelial cells. Knockdown of either BRG1 or IL-33 in endothelial cells blunted the pro-fibrogenic response in renal tubular epithelial cells. In conclusion, we propose that BRG1 may contribute to ischemia-reperfusion induced renal injury and fibrosis by promoting IL-33 transcription in endothelial cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The binding ability of acyclic CB[n]-type receptors M1, M2 and macrocyclic CB[7] toward explosive materials was investigated. Acyclic M2 demonstrates an overall better binding and solubilizing ability, and lower fluorescence in the presence of aromatic explosive compounds, suggesting its future application for the detection of harmful explosive materials.

Background: The reactive hyperemia index (RHI), measured by peripheral arterial tonometry (PAT), is a novel measurement of endothelial function and has been proven to be valuable in cardiovascular risk stratification in several populations. The current study aims to explore its relation to renal function and its association with traditional cardiovascular risk factors in patients with chronic kidney disease (CKD)., Methods: Subjects with non-dialysis dependent CKD were recruited and 252 of them had a successful PAT test. In addition to general demographic and medical information, carotid-femoral pulse wave velocity (cfPWV), carotid-radial pulse wave velocity (crPWV) and augmentation index (AIx) were recorded., Results: The mean age of the study population was 57.7 (±14.7) years and 155 (61.5%) were males. The average RHI was 1.92 (±14.7) with no difference noted between males and females. There was no statistically significant correlation between RHI and eGFR (r = - 0.107, p = 0.089) or urine protein-to-creatinine ratio (r = 0.036, p = 0.570). With adjustment for age and sex, RHI was associated with systolic blood pressure (BP) (β = 0.006, p = 0.001), diastolic BP (β = 0.008, p = 0.010), heart rate (β = - 0.007, p = 0.015) crPWV (β = 0.037, p = 0.022) and AIx (β = 0.006, p = 0.001), but not with cfPWV or any other conventional risk factors analyzed. Systolic BP remained the only predictor for RHI in the stepwise regression analysis., Conclusions: RHI did not decline with reduced renal function in CKD patients and had a modest association with traditional cardiovascular risk factors. Further studies are warranted to determine if RHI could predict cardiovascular outcome in CKD patients.

Cognitive impairment is prevalent in patients with chronic kidney disease (CKD), but its underlying mechanisms are obscure. Here, we test the hypothesis that exaggerated orthostatic blood pressure reduction mediates the effects of renal failure on global cognition and memory. A total of 160 study subjects were recruited, including 80 dialysis patients and 80 controls. Global cognition was evaluated using the Montreal Cognitive Assessment (MoCA), and episodic memory was evaluated using the auditory verbal learning test (AVLT). Autonomic function was evaluated via the low-frequency to high-frequency ratio (LF/HF) through heart rate variability analysis. Compared with the controls, the dialysis patients had significantly lower MoCA and AVLT scores (including learning memory, short recall memory, and delayed recall memory) (all p < 0.001). They also showed exaggerated orthostatic systolic blood pressure reductions (all p ≤ 0.001). The maximum orthostatic systolic blood pressure reduction was independently and negatively associated with short (β = -0.05, p = 0.029) and delayed (β = -0.05, p = 0.035) recall memory in dialysis patients but not in controls. Mediation analysis demonstrated that maximum orthostatic systolic blood pressure reduction mediates 13.8% of the effect of end-stage renal disease (ESRD) on short recall memory (p = 0.04). After adjustment for LF/HF, the negative association between maximum orthostatic blood pressure reduction and short recall score remained significant (p = 0.049), while the association between maximum orthostatic blood pressure reduction and delayed recall score became nonsignificant, with a marginal p value of 0.062. Our study reveals that exaggerated orthostatic blood pressure reduction is a possible explanation for ESRD-associated memory deficits.

Atherosclerotic cardiovascular disease remains a worldwide epidemic and one of the leading causes of death nowadays. Vessel wall imaging can be used to understand the development and progression of atherosclerosis, but it is rarely done because of the high cost. We recently identified the Osteoarthritis Initiative, a large prospective cohort study of knee osteoarthritis, which might serve as a valuable source for atherosclerosis research with its serial knee magnetic resonance imaging data. We have found that these images are suitable for vessel wall image analysis of the lower extremity arteries. Here, we will introduce the Osteoarthritis Initiative data set and explain why it could be used for cardiovascular research purposes. Also, we will briefly comment on peripheral artery atherosclerosis as it is covered in the Osteoarthritis Initiative image data set and review the use of vessel wall imaging for studying atherosclerosis. We think data mining of imaging studies, not originally designed on cardiovascular research, can not only maximize the value of the imaging data set but also boost our understanding of atherosclerosis.

Oxidative stress serves an important role in hypertensive brain damage. Peroxisome proliferator‑activated receptor γ (PPAR‑γ) agonists possess antioxidative and anti‑apoptotic effects. The present study verified the possibility that rosiglitazone serves a neuroprotective role by alleviating oxidative stress and cell apoptosis in the hippocampi of spontaneously hypertensive rats (SHRs). SHRs and age‑matched Wistar‑Kyoto (WKY; both 56 weeks old) rats received gavage administration of vehicle or rosiglitazone (5 mg/kg/day) for eight weeks. Systolic blood pressure (SBP) was measured by the indirect tail‑cuff method. The expression ratio of activated astrocytes was analyzed by glial fibrillary acidic protein immunohistochemistry. PPAR‑γ, inducible nitric oxide synthase (iNOS), gp47phox, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and caspase‑3 expression were investigated by quantitative polymerase chain reaction and western blot analysis. The number of apoptotic cells in the hippocampus of four groups was detected using the terminal deoxynucleotidyl transferase‑mediated dUTP end‑labeling (TUNEL) method. Compared with the WKY group, the SHR group exhibited decreased Bcl‑2 and PPAR‑γ expression, increased SBP, increased ratio of activated astrocytes and TUNEL‑positive cells, increased expression of iNOS, gp47phox, caspase‑3 and Bax. Rosiglitazone administration increased Bcl‑2 and PPAR‑γ expression, decreased the ratio of activated astrocytes and TUNEL‑positive cells, decreased iNOS, gp47phox, caspase‑3 and Bax expression in the hippocampi of SHRs. However, rosiglitazone did not significantly decreased SBP in the SHR group. Therefore, rosiglitazone exerts neuroprotective effect through antioxidative and anti‑apoptotic pathways, which was independent of blood pressure control.

Dysfunction of microRNAs (miRs) has been implicated in the development and progression of various human cancers. Our previous study demonstrated that miR-101 inhibited bladder cancer cell proliferation and invasion through inhibition of c-FOS expression. As an miR generally has many targets, other targets of miR-101 may also serve important roles in bladder cancer progression. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to examine mRNA and protein expression, respectively. Wound healing and Transwell assays were conducted to study cell migration and invasion, respectively. The luciferase reporter gene assay was performed to verify one of the targets of miR-101. The data in the present study indicate that the expression of miR-101 is significantly reduced in bladder cancer tissues compared with that in adjacent non-tumour tissues. In addition, miR-101 expression is also downregulated in bladder cancer cell lines compared with that in normal bladder epithelial cells. Furthermore, low expression of miR-101 was significantly associated with tumour metastasis, advanced clinical stage, and poor prognosis in bladder cancer. Frizzled class receptor 4 (FZD4) was identified as a novel target of miR-101 in bladder cancer cells. The expression of FZD4 was significantly upregulated in bladder cancer tissues and cell lines. Both miR-101 overexpression and FZD4 inhibition caused a significant reduction of the migration and invasion of bladder cancer cells, whereas overexpression of FZD4 reversed the suppressive effects of miR-101 on bladder cancer cell migration and invasion. In conclusion, it was demonstrated that miR-101 downregulation is associated with bladder cancer progression and that miR-101 can inhibit bladder cancer cell migration and invasion via directly targeting FZD4. The present study expands the understanding of the molecular mechanisms underlying bladder cancer progression.

We designed and synthesized a "hybrid" molecular container 1, which is structurally related to both cucurbit[n]uril (CB[n]) and pillar[n]arene type receptors. Receptor 1 was fully characterized by 1 H NMR, 13 C NMR, IR, MS and X-ray single crystal diffraction. The self-association behavior, host-guest recognition properties of 1, and the [salt] dependence of K a were investigated in detail by 1 H NMR and isothermal titration calorimetry (ITC). Optical transmittance and TEM measurements provide strong evidence that receptor 1 undergoes co-assemble with amphiphilic guest C10 in water to form supramolecular bilayer vesicles (diameter 25.6±2.7 nm, wall thickness ≈3.5 nm) that can encapsulate the hydrophilic anticancer drug doxorubicin (DOX) and the hydrophobic dye Nile red (NR). The release of encapsulated DOX or NR from the vesicles can be triggered by hexamethonium (8 c) or spermine (10) which leads to the disruption of the supramolecular vesicles., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The strategic combination of the methylene bridged glycoluril dimer and triptycene skeletons delivers acyclic water soluble hybrid receptor 1 which is analogous to cucurbit[6]uril. The molecular recognition properties of host 1 toward hydrophobic cationic guests are investigated in detail by a combination of 1H NMR spectroscopy and isothermal titration calorimetry (ITC) studies. The fluorescence emission of 1 can be selectively and efficiently quenched upon the formation of 1·26 and 1·28 complexes.

Objective: A cross-sectional community prevalence survey was conducted to investigate the sero-epidemiological features of hepatitis B virus (HBV) infection among children aged 1-14 years in Guangdong Province in 2013, and to provide baseline data for the evaluation of HBV disease burden and the impacts of HBV control., Methods: A total of 2765 children aged 1-14 years from 16 villages/streets of eight cities in Guangdong Province were recruited as subjects. A blood sample was obtained from each subject. A chemiluminescence microparticle immunoassay (CMIA) was used to detect hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (HBsAb), and antibody to hepatitis B core antigen (HBcAb)., Results: The prevalence rates of HBsAg, HBsAb, and HBcAb among children aged 1-14 years were 1.16%, 61.63%, and 2.35%, respectively. The prevalence of HBsAg and HBcAb increased with increasing age, and the prevalence was lowest in the 1-4 years age group (0.97% for HBsAg and 1.45% for HBcAb). In contrast, the prevalence of HBsAb decreased with increasing age; however the prevalence was also highest in the 1-4 years age group (76.48%). Eastern Guangdong had the highest prevalence of HBsAg and HBcAb, and the lowest prevalence of HBsAb. The prevalence of HBsAg was under 1% in the Pearl River Delta and western Guangdong regions. Children who had received three or more doses of vaccine had a lower prevalence of HBsAg and HBcAb and a higher prevalence of HBsAb compared to those who had received fewer than three doses of vaccine., Conclusions: The prevalence of HBsAg among children aged 1-14 years in Guangdong in 2013 was 1.2%, showing a dramatic decrease compared to the 1992 provincial-level cross-sectional survey (19.9%). Children aged 1-4 years and children from the Pearl River Delta had the lowest prevalence of HBsAg positivity. High vaccination coverage among children and timely vaccination of newborns has played an important role in reducing the prevalence of HBsAg., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the changes of facial soft tissue before and after orthognathic surgery in patients with skeletal Class Ⅲ malocclusion., Methods: Between August 2016 and April 2017, 30 patients with skeletal Class Ⅲ malocclusion who underwent maxillary LeFort Ⅰ osteotomy and sagittal split mandible osteotomy were selected as study subjects. Among them, 11 were male and 19 were female with an average age of 22.6 years (range, 18-35 years). Full head CT scan and facial soft tissue three-dimensional image scan were performed within 2 weeks before surgery and at 6 months after surgery. A three-dimensional facial image model was established using Artec Studio 11.0 and CMF Proplan 3.0 software to analyze the facial soft tissue changes before and after surgery. The soft tissue anatomical landmarks in each area of the face were measured and compared before and after surgery., Results: The area of facial soft tissue change after surgery was the maxillary nose and the lower jaw area, and the two sides did not exceed the vertical boundary of the outer canthus. After surgery, the horizontal points of bilateral alar bases and bilateral cheeks changed significantly ( P <0.05). The sagittal points of subnasale, pronasale, bilateral alar bases, upper lip margin significantly forwarded ( P <0.05); the sagittal points of the bilateral cheilions, lower lip margin, midpoint of chin-lip groove, pogonion, and menton significantly backwarded ( P <0.05). The vertical points of the upper lip margin, bilateral cheilions, lower lip margin, bilateral cheeks, and bilateral inner canthus points significantly descended ( P <0.05), and the vertical point of the menton significantly elevated ( P <0.05). After surgery, the nasal column was significantly shortened, the upper lip got longer and the alar base widened when compared with those before surgery ( P <0.05)., Conclusion: The overall change of face after double jaw surgery is shorter and fuller, and the mandible of facial soft tissue change is larger than that of maxillary, which suggests that the postoperative facial changes should be taken into account in the surgical design.

The structure of cucurbit[6]uril (CB[6]), as a fascinating supramolecular receptor, is regarded as 'indestructible'. Herein, we investigated the hydrolysis of CB[6] catalysed by alkali. Our results showed that CB[6] was easily hydrolysed in 30% NaOH at 160°C within 3 h. Separation and purification of hydrolytic products demonstrated the presence of NH 3 , CO 2 , HCOONa, glycine and hydantoic acid. Based on the studies of the hydrolysis of substances similar to CB[6] including 4,5-dihydroxyethyleneurea, glycoluril and glycoluril dimer, we proposed that a plausible reaction mechanism involved a Cannizzaro reaction, which is supported by HPLC, mass spectrometry data and previous reports. Further studies are dedicated towards a controlled hydrolysis of CB[6], which will provide a new route for direct functionalization of CB[6].

It is well known that using two or more deformable mirrors (DMs) can improve the compensation ability of an adaptive optics (AO) system. However, to keep the stability of an AO system, the correlation between the multiple DMs must be suppressed during the correction. In this paper, we proposed a slope-based decoupling algorithm to simultaneous control the multiple DMs. In order to examine the validity and practicality of this algorithm, a typical woofer-tweeter (W-T) AO system was set up. For the W-T system, a theory model was simulated and the results indicated in theory that the algorithm we presented can selectively make woofer and tweeter correct different spatial frequency aberration and suppress the cross coupling between the dual DMs. At the same time, the experimental results for the W-T AO system were consistent with the results of the simulation, which demonstrated in practice that this algorithm is practical for the AO system with dual DMs.

Background: C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD., Methods: Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity., Results: Mean (±standard deviation) age of the patients were 59.9 (±14.9) years and 56.6% were male. Average plasma CNP level was 790.8 ± 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction (with vs. without endothelial dysfunction: 844.6 ± 365.5 pg/ml vs. 738.3 ± 231.8 pg/ml, p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters (SDNN, RMSSD, Triangular Index). The association of CNP with HRV persisted after adjustment for potential covariates., Conclusions: Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients.

Mechanisms underlying elevated blood pressure in dialysis patients are complex as a variety of non-traditional factors are involved. We sought to explore the association of circulating betaine, a compound widely distributed in food, with blood pressure in dialysis patients. We used baseline data of an ongoing cohort study involving patients on hemodialysis. Plasma betaine was measured by high performance liquid chromatography in 327 subjects. Blood pressure level was determined by intradialytic ambulatory blood pressure monitoring. The mean age of the patients was 52.6 ± 11.9 years, and 58.4% were male. Average interdialytic ambulatory systolic and diastolic blood pressure were 138.4 ± 22.7 mm Hg and 84.4 ± 12.5 mm Hg, respectively. Mean plasma betaine level was 37.6 μmol/L. Multiple linear regression analysis revealed significant associations of betaine with both systolic blood pressure (β = -3.66, P = .003) and diastolic blood pressure (β = -2.00, P = .004). The associations persisted even after extensive adjustment for cardiovascular covariates. Subgroup analysis revealed that the association between betaine and blood pressure was mainly limited to female patients. Our data suggest that alteration of circulating betaine possibly contributes to blood pressure regulation in these patients., (©2018 Wiley Periodicals, Inc.)

Background: Renal fibrosis is a common outcome of nearly all kinds of chronic kidney disease (CKD) and eventually progresses to end-stage renal disease. The identification of an optimal biomarker of renal fibrosis to replace the invasive renal biopsy will have important clinical implications., Methods: We isolated urinary exosomes from 50 participants and examined the exosomal protein content and particle number in 38 CKD patients with different degrees of renal fibrosis and in 12 normal individuals. We examined the levels of exosomal microRNAs (miRNAs), namely, miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-29a, miR-29b, miR-29c, miR-192, and miR-21, by sorting the exosomes and comparing the levels of proximal tubular, non-proximal tubular, and total exosomal miR-200b., Results: The exosome content was higher in the CKD group, but no differences were evident among the mild, moderate, and severe fibrosis groups. Among the 10 exosomal miRNAs, miR-200b was lower in the CKD group than in the normal group and decreased more significantly with fibrosis progression as well as in IgA nephropathy and diabetic kidney disease. CD13+ CD63+ exosomes constituted 18.6% of all urinary exosomes. Sorting the proximal tubular exosomes with the CD13 protein marker revealed that miR-200b in the CD13+ group was extremely low; however, the result was significantly different in the CD13- group but not in the CD13+ group. The magnitude of the decline was greater in the CD13- groups than in the non-sorted whole groups between the fibrosis and normal patients., Conclusions: Non-proximal renal tubule-derived urinary exosomal miR-200b is a biomarker of renal fibrosis. Exosomes can be used as a liquid biopsy and may replace the traditional invasive renal biopsy in the diagnosis of renal fibrosis., (© 2018 S. Karger AG, Basel.)

Masked uncontrolled hypertension (MUCH) has been proven to be associated with increased cardiovascular risk in the general population. We performed the current analysis to determine its prevalence in dialysis patients and its association with pulse wave velocity (PWV). From 368 participants of another cohort study, we selected 145 subjects with controlled predialysis blood pressure (BP). All subjects underwent ambulatory BP monitoring and PWV measurement. MUCH was defined as controlled predialysis BP with daytime BP⩾135/85 mm Hg (definition-1); total ambulatory BP⩾130/80 mm Hg (definition-2); and either daytime BP⩾135/85 mm Hg or nighttime BP⩾120/70 mm Hg (definition-3). The prevalence of MUCH was 43.4% (definition-1), 55.9% (definition-2) and 74.5% (definition-3). Multivariable logistic regression analysis showed that the use of antihypertensive medication was the most consistent predictor of MUCH within all 3 definitions (all odds ratio (OR)⩾4.28, P<0.001). Predialysis systolic BP (both OR>1, P⩽0.04), predialysis diastolic BP (both OR>1, P⩽0.001) and hemoglobin (both OR<1, P=0.02) were all significantly associated with MUCH in two models. Interdialytic weight gain (OR=0.52, P=0.02) was associated with MUCH under definition-2, and BMI (OR=0.86, P=0.03) was associated with MUCH under definition-3. Patients with MUCH had significantly elevated PWV compared with their counterparts according to all three definitions with or without adjusting for covariates (all P⩽0.03). In conclusion, MUCH affects a large proportion of dialysis patients with controlled predialysis BP and is associated with increased PWV. Patients on antihypertensive medications and with higher predialysis BP are more likely to have MUCH.