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Aim: To analyse the effect of post‐core, and cement materials and thickness of the cement lute on the stress in post‐core systems under ultrasonic vibration at different frequencies and amplitudes using three‐dimensional finite element analysis. Methodology: Eight three‐dimensional finite element models of a maxillary central incisor with post‐cores were established. Two post‐core materials (Au and Ni‐Cr alloys), two cements (glass ionomer (GI) and zinc phosphate (ZP)) and two cement layer thicknesses (50 and 150 μm) were considered. Vibration loads were applied near the neck on the buccal side of the core at frequencies of 10–40 kHz and amplitudes of 10–50 μm. The maximum shear stress of the cement layer and maximum principal stress of the roots and their distributions were investigated. Results: The stresses on cements and roots increased with an increase in the frequency and amplitude of the vibration load and elastic modulus of the cements, and decreased with increasing thickness of the cement layer and elastic modulus of the post‐core. Maximum cement stress was observed on the contralateral upper part of the loading side, whereas the maximum root stress was found on the ferrule where the load was applied. Conclusions: In this simulated model, the frequency and amplitude of ultrasound needed to remove a post‐core were positively related to the elastic modulus of the post‐core and thickness of the cement layer and negatively related to the elastic modulus of the cements. [ABSTRACT FROM AUTHOR]

Aim: To explore the health beliefs of clinical and academic nurses from Japan, Australia and China regarding wearing paper masks to protect themselves and others, and to identify differences in participants' health beliefs regarding masks. Background: The correct use of face masks and consensus among health professionals across the globe is essential for containing pandemics, and nurses need to act according to policy to protect themselves, educate the public and preserve resources for frontline health workers. Paper masks are worn by health professionals and the general public to avoid the transmission of respiratory infections, such as COVID‐19, but there appear to be differences in health beliefs of nurses within and between countries regarding these. Methods: This qualitative descriptive study used content analysis with a framework approach. Findings: There were major differences in nurse participants' beliefs between and within countries, including how nurses use paper masks and their understanding of their efficacy. In addition, there were cultural differences in the way that nurses use masks in their daily lives and nursing practice contexts. Conclusion: Nurses from different working environments, countries and areas of practice hold a variety of health beliefs about mask wearing at the personal and professional level. Implications for nursing policy and health policy: The COVID‐19 pandemic has sparked much discussion about the critical importance of masks for the safety of health professionals, and there has been considerable discussion and disagreement about health policies regarding mask use by the general public. Improper use of masks may have a role in creating mask shortages or transmitting infections. An evidence‐based global policy on mask use for respiratory illnesses for health professionals, including nurses, and the general public needs to be adopted and supported by a wide‐reaching education campaign. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to investigate whether probable rapid eye movement sleep behavior disorder (pRBD) is associated with impulse control disorders (ICDs) in drug‐naïve patients with Parkinson's disease (PD) and whether baseline pRBD is associated with a higher incidence of ICDs during follow‐up. Methods: The Parkinson's Progression Markers Initiative is an international, multicenter, prospective cohort study to identify biomarkers of PD progression. In all, 423 drug‐naïve patients with early‐stage PD were included in the cross‐sectional analysis, and 320 patients who screened negative for any ICDs or related behaviors at baseline were included in the longitudinal analysis. Results: In the cross‐sectional analysis, a significant correlation was found between pRBD and ICDs in drug‐naïve patients whilst controlling for potential confounders [odds ratio 2.56, 95% confidence interval (CI) 1.38–4.76, P = 0.003]. In the longitudinal analysis, baseline pRBD was an independent predictor of ICD development over time [hazard ratio (HR) 1.648, 95% CI 1.054–2.576; P = 0.028]. Other significant predictors of ICDs included younger age of onset (HR = 0.973, 95% CI = 0.950–0.997; P = 0.026) and greater State‐Trait Anxiety Inventory score (HR = 1.040, 95% CI = 1.020–1.061; P < 0.001). Conclusion: Our data suggest that identifying baseline pRBD in early‐stage PD may help clinicians to choose a better therapeutic strategy so as to prevent or limit neuropsychiatric complications. [ABSTRACT FROM AUTHOR]

Contents: A large number of microRNAs (miRNAs) have been detected from porcine testicular tissues thanks to the development of high‐throughput sequencing technology. However, the regulatory roles of most identified miRNAs in swine testicular development or spermatogenesis are poorly understood. In our previous study, ULK2 (uncoordinated‐51‐like kinase 2) was predicted as a target gene of miR‐26a. In this study, we aimed to investigate the role of miR‐26a in swine Sertoli cell autophagy. The relative expression of miR‐26a and ULK2 levels has a significant negative correlation (R2 = .5964, p ≤ .01) in nine developmental stages of swine testicular tissue. Dual‐luciferase reporter assay results show that miR‐26a directly targets the 3′UTR of the ULK2 gene (position 618–624). In addition, both the mRNA and protein expression of ULK2 were downregulated by miR‐26a in swine Sertoli cells. These results indicate that miR‐26a targets the ULK2 gene and downregulates its expression in swine Sertoli cells. Based on the expression of marker genes (LC3, p62 and Beclin‐1), overexpression of miR‐26a or knock‐down of ULK2 inhibits swine Sertoli cell autophagy. Taken together, these findings demonstrate that miR‐26a suppresses autophagy in swine Sertoli cells by targeting ULK2. [ABSTRACT FROM AUTHOR]

Aim: To understand Chinese nurses’ perceptions of health beliefs, their content, origin and the influence of sociocultural factors, as a basis of their evidence‐based practice. This study contributes to a larger study to establish the health beliefs of Japanese, Australian, Chinese, South Korean and Thai nurses. Background: Registered nurses teach patients and students about maintaining or attaining health are subject to the same range of influences and their health beliefs may be antithetical to current health evidence. Methods: Q‐method design using q‐sort and interview was used to explore the perspectives on a range of health beliefs of 60 nurses in four cities in China. Findings: Three factors arose from the perceptions of the participants about health and accounted for 50.2% of the total variance: (1) social impact, (2) ‘the importance of evidence’, and (3) beliefs rooted in culture. Discussion: Influence on nurses’ health beliefs was explored in terms of the internalized and frequently unconscious beliefs, values and norms tying them to their communities, reflecting the need for nurses to be aware of their health beliefs and behaviours. Conclusions: Education for nurses in practice needs to acknowledge that individual practitioners’ beliefs strongly influence health teaching for patients and families. In order to implement evidenced‐based practice and teach in line with current evidence nurses need to critically examine and reflect on the impact of culture, society and the media on their own health beliefs. Implications for nursing policy and health policy: Education policy needs to consider that culture and societal pressures affect nurses’ health beliefs and practice. Critical thinking, reflective and evidence‐based practice need to be emphasized in clinical training and nurse education. China also needs to develop policies to allow nurses to be able to assess the reliability of health information on the Internet and to make quality health research more available. [ABSTRACT FROM AUTHOR]

Parametric nonlinear regression ( PNR) models are used widely to fit weed seedling emergence patterns to soil microclimatic indices. However, such approximation has been questioned, mainly due to several statistical limitations. Alternatively, nonparametric approaches can be used to overcome the problems presented by PNR models. Here, we used an emergence data set of Phalaris paradoxa to compare both approaches. Mean squared error and correlation results indicated higher accuracy for the descriptive ability but similar poor performance for predictive ability of the nonparametric approach in comparison with the PNR approach. These results suggest that our nonparametric cumulative distribution function approach is a valuable alternative to the classical parametric nonlinear regression models to describe complex emergence patterns for P. paradoxa, but not to predict them. [ABSTRACT FROM AUTHOR]

This paper describes a Bayesian approach to make inference for aggregate loss models in the insurance framework. A semiparametric model based on Coxian distributions is proposed for the approximation of both the interarrival time between claims and the claim size distributions. A Bayesian density estimation approach for the Coxian distribution is implemented using reversible jump Markov Chain Monte Carlo (MCMC) methods. The family of Coxian distributions is a very flexible mixture model that can capture the special features frequently observed in insurance claims. Furthermore, given the proposed Coxian approximation, it is possible to obtain closed expressions of the Laplace transforms of the total claim count and the total claim amount random variables. These properties allow us to obtain Bayesian estimations of the distributions of the number of claims and the total claim amount in a future time period, their main characteristics and credible intervals. The possibility of applying deductibles and maximum limits is also analyzed. The methodology is illustrated with a real data set provided by the insurance department of an international commercial company. [ABSTRACT FROM AUTHOR]

We consider lifetime data subject to right random censorship. In this context, this paper deals with the topic of estimating the distribution function of the lifetime and the corresponding quantile function. As it has been shown that the classical Kaplan–Meier estimator of the distribution function can be improved by means of presmoothing ideas, we introduce a quantile function estimator via the presmoothed distribution function estimator studied by Cao et al. [ Journal of Nonparametric statistics, Vol. 17 (2005) pp. 31–56.] The main result of this paper is an almost sure representation of this presmoothed estimator. As a consequence, its strong consistency and asymptotic normality are established. The performance of this new quantile estimator is analyzed in a simulation study and applied to a real data example. [ABSTRACT FROM AUTHOR]

Field studies were conducted to determine the potential of multispectral classification of late-season grass weeds in wheat. Several classification techniques have been used to discriminate differences in reflectance between wheat and Avena sterilis, Phalaris brachystachys, Lolium rigidum and Polypogon monspeliensis in the 400–900 nm spectrum, and to evaluate the accuracy of performance for a spectral signature classification into the plant species or group to which it belongs. Fisher’s linear discriminant analysis, nonparametric functional discriminant analysis and several neural networks have been applied, either with a preliminary principal component analysis (PCA) or not and in different scenarios. Fisher’s linear discriminant analysis, feedforward neural networks and one-layer neural network, all showed classification percentages between 90% and 100% with PCA. Generally, a preliminary computation of the most relevant principal components considerably improves the correct classification percentage. These results are promising because A. sterilis and L. rigidum, two of the most problematic, clearly patchy and expensive-to-control weeds in wheat, could be successfully discriminated from wheat in the 400–900 nm range. Our results suggest that mapping grass weed patches in wheat could be feasible with analysis of real-time and high-resolution satellite imagery acquired in mid-May under these conditions. [ABSTRACT FROM AUTHOR]

Purpose: To compare the educational outcomes of remote instruction (RI) in impression-taking using smart glasses with those of face-to-face instruction (FI) and paper-based self-learning (SL) and analyze the educational effects, aiming to develop a remote clinical training strategy., Methods: Participants were recruited from among the dental residents who were trained in the first-year clinical program at the university hospital in 2023. The participants were divided into three groups as the original skill level was equal, and the groups were assigned RI, FI, printed guidance, and SL. All the participants took impressions of the jaw models attached to the mannequin using alginate impression material. Next, assigned instructions were provided. Then again, the trainees took impressions of the jaw models. The pre- and postinstruction impressions of each participant were evaluated, and the change in the impression score was statistically analyzed., Results: The pre- and postinstruction scores of the trainees in the RI and FI groups showed a significant increase (p < 0.05), whereas no significant difference was observed in the score changes in the SL group. In the intergroup comparisons, the score changes of the RI and FI groups were greater than those of the SL group, although no significant difference was found between the score changes of the RI and FI groups (p < 0.05)., Conclusion: RI in impression-taking using smart glasses has a greater educational effectiveness than paper-based SL. It has also been suggested that RI can have educational efficacy similar to FI., (© 2024 American Dental Education Association.)

Objectives: The digit ratio (2D:4D) is a possible marker of prenatal hormone exposure. The purpose of this study was to explore the relationships between digit ratio (2D:4D) and anthropometric indexes in Chinese children and adolescents., Methods: This study is a cross-sectional study. A school-based survey among 685 children and adolescents aged 8-15 years were conducted by stratified cluster sampling. The length of index finger (2D) and ring finger (4D) of the left hand, height, sitting height (ST), weight, chest circumference (CC), waist circumference (WC), hip circumference (HC), and abdominal skinfold thickness (AST) were measured. Pearson correlation and multivariate linear regression were used to analyze associations between 2D:4D and above indexes., Results: In girls, 2D:4D was positively related to WC, AST, waist-to-height (WHtR), waist-to-hip ratio (WHR) after adjusting for ages (p < 0.05). The WC, AST, WHtR, and WHR among girls with 2D:4D ≥ 1 were significantly higher than those among girls with 2D:4D < 1, respectively (p < 0.05). However, there was no correlations between digit ratio (2D:4D) and above anthropometric indexes in boys (p > 0.05)., Conclusions: The 2D:4D was related to anthropometric indexes in girls, which suggests that the maternal prenatal hormone exposure might be related to the anthropometric indexes of their female offspring., (© 2024 Wiley Periodicals LLC.)

Background: Left ventricular hypertrophy (LVH) is most common when driven by hypertension, and it is a strong independent risk factor for adverse cardiovascular events and death. Some animal models support a role for gut microbiota and metabolites in the development of LVH, but cohort studies confirming these findings in populations are lacking., Methods and Results: We investigated the alterations of gut microbiota and metabolites in 30 patients with hypertension, 30 patients with hypertensive LVH, and 30 matched controls on the basis of 16S rDNA and metabolomic analyses. Thirty stool and 90 serum samples were collected in fasting conditions. ANOVA/Kruskal-Wallis/Pearson's χ 2 /Fisher's exact test and Bonferroni's correction were used ( P <0.0167) for comparison among the 3 groups. A regression analysis and subgroup analysis were performed between gut microbiota and left ventricular mass index (LVMI) and metabolites and LVMI, respectively. Spearman correlation analysis was performed between metabolites and flora and metabolites and LVMI. We observed LVH-enriched Faecalitalea (β=6758.55 [95% CI, 2080.92-11436.18]; P =0.009), Turicibacter (β=8424.76 [95% CI, 2494.05-14355.47]; P =0.01), Ruminococcus torques group (β=840.88 [95% CI, 223.1-1458.67]; P =0.013), and Erysipelotrichaceae UCG-003 (β=856.37 [95% CI, 182.76-1529.98]; P =0.019) were positively correlated with LVMI. A total of 1141 (in sera) and 2657 (in feces) metabolites were identified. There was a sex-specific association between metabolites and LVMI. Significant changes in metabolic pathways in LVH were also observed, especially bile acid and lipid metabolism pathways., Conclusions: Our study demonstrated the disordered gut microbiota and microbial metabolite profiles in LVH. This highlights the roles of gut bacteria and metabolite in this disease and could lead to new intervention, diagnostic, or management paradigms for LVH., Registration: URL: https://www.chictr.org.cn; Unique Identifier: ChiCTR2200055603.

Purpose: The purpose of this study was to assess the precision and trueness of three jaw motion tracking systems, the KaVo ARCUSdigma system, SDiMatriX system, and Modjaw system, in recording mandibular movements based on optical and ultrasonic principles., Materials and Methods: Twenty-five healthy subjects were selected for the present study to measure protrosive movement and left and right lateral movements using the three jaw motion tracking systems. Each subject's mandibular movement was recorded twice with a 1-week interval. Five parameters-sagittal condylar inclination (SCI) angle, incisal guide angle, Bennett angle, lateral condylar inclination angle, and Fischer's angle-were acquired for further analysis. The precision of the jaw motion tracking systems was evaluated by comparing the results of two measurements of the same parameter. Simultaneously, cone beam computed tomography (CBCT) was utilized during the initial data acquisition and was aligned with intercuspal position (ICP) and edge-to-edge occlusion intraoral scan data. Bone landmarks were used to calculate bilateral SCI as a reference for comparison with the SCI values from each jaw motion tracking system. An independent-sample t-test was conducted to compare parameter differences, with statistical significance set at a p-value below 0.05., Results: There were no significant differences among the three jaw motion tracking systems regarding the corrected values of SCI, incisal guide angle, Bennett angle, lateral condylar inclination angle, and Fischer's angle during the 1-week interval (p > 0.05). The values of bilateral SCI obtained by CBCT were 48.57 ± 6.74 (L) and 48.35 ± 5.28 (R), respectively. No significant differences were found between the reference SCI and those parameters measured by the KaVo ARCUSdigma system and the Modjaw system (p > 0.05), while the results obtained from the SDiMatriX system indicated a significant difference compared to the reference SCI (p < 0.05)., Conclusions: The three jaw motion tracking systems exhibited favorable results in terms of precision. Regarding trueness, both the KaVo ARCUSdigma system and the Modjaw system demonstrated a satisfactory levels suitable for applications in digital prosthodontics within clinical settings. However, further refinement is needed to enhance the trueness of the SDiMatriX system., (© 2024 by the American College of Prosthodontists.)

Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death., (© 2024. The Author(s).)

Aim: To assess the relationship between dietary antioxidant intake and periodontal health in US adults and the potential role of mitochondrial function., Materials and Methods: We performed a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Dietary antioxidant intake was evaluated using three diet-related indices: dietary oxidative balance score (DOBS), dietary total antioxidant capacity (DTAC) of antioxidant vitamins and composite dietary antioxidant index (CDAI). Periodontal parameters included attachment loss (AL) and probing pocket depth (PPD). Mitochondrial dysfunction was assessed using the methylmalonic acid (MMA) level. Weighted multivariable linear regression analyses were employed to investigate the association between dietary antioxidant intake and periodontal status. Additionally, exploratory mediation analyses were conducted to determine the mediating effect of MMA on the association., Results: Totally, 5520 participants were included in our study. Participants with higher DOBS and DTAC scores had lower mean AL/PPD and MMA values. CDAI was negatively associated with mean AL and PPD. Furthermore, MMA mediated 9.4% and 4.9% of the associations between DOBS and mean AL and mean PPD, respectively. MMA also accounted for 7.2% and 3.3% of the association between DTAC and mean AL and PPD, respectively., Conclusions: The findings support that dietary antioxidant intake helps in improving periodontal health, possibly and partially by enhancing mitochondrial function., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although it is well recognized that the circadian timing system profoundly influences cognitive performance, the underlying molecular mechanisms remain poorly defined. Our previous work has found that the mitogen-activated protein kinase-interacting kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis, a conserved cellular signalling pathway regulating mRNA translation, modulates the function of the suprachiasmatic nucleus (SCN), the master circadian clock. Here, with the use of a combination of genetic, biochemical and behavioural approaches, we investigated the distribution and temporal regulation of eIF4E phosphorylation in the brain and its role in regulating the diurnal oscillations of some aspects of cognition in mice. We found that activities of the MNK-eIF4E axis, as indicated by the level of eIF4E phosphorylation at Ser209, exhibited significant circadian oscillations in a variety of brain regions, including but not limited to the prefrontal cortex, the hippocampus, the amygdala and the cerebellum. Phosphorylated eIF4E was enriched in neurons but not in astrocytes or microglia. Mice lacking eIF4E phosphorylation (eIF4E S209A/S209A ) or the MNKs (Mnk 1-/-,2-/- ), the kinases that phosphorylate eIF4E, exhibited impaired diurnal variations of novel object recognition, object location memory, Barnes maze learning and ambulatory activities. Together, these results suggest that circadian activities of the MNK-eIF4E axis contribute to the diurnal rhythms of some cognitive functions, highlighting a role for rhythmic translational control in circadian regulation of cognitive performance., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Autophagy maintains cellular homeostasis by degrading and recycling cytoplasmic components under stress conditions, which is identified to be involved in tumorigenesis and now has been recognized as novel target in cancer treatment. In present study, we gathered total autophagy-related genes and established an autophagy-related genes signature (ATGRS) through LASSO cox regression analysis in BLCA. Kaplan-Meier survival and multivariate cox regression analyses both showed the ATGRS was a robust independent prognostic factor with high accuracy. Subsequently, integrated analyses indicated that ATGRS had a strong correlation with molecular subtypes, clinicopathological characteristics and somatic mutation alteration. Moreover, ATGRS was found to be positively correlated with the infiltration of immune cells in tumour microenvironment (TME) and immune checkpoint expression, indicating the potent role of autophagy by regulating the TME. In addition, ATGRS was proved to be efficient in predicting the clinical benefit of immune checkpoint inhibitors (ICIs) based immunotherapy and chemotherapy in BLCA. Furthermore, we observed abnormal expression levels of autophagy-related genes and found the different behaviour of ATGRS in pancancer by LASSO cox regression analysis. Therefore, construction of ATGRS in BLCA could help us to interpret the underlying mechanism of autophagy and sheds a light on the clinical application for a combination of autophagy modification with targeted immunotherapy and chemotherapy in BLCA., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Our previous studies found overexpression of Musashi2 (MSI2) conduced to the progression and chemoresistance of pancreatic cancer (PC) by negative regulation of Numb and wild type p53 (wtp53). Now, we further investigated the novel signalling involved with MSI2 in PC. We identified inositol-3-phosphate synthase 1 (ISYNA1) as a novel tumour suppressor regulated by MSI2. High MSI2 and low ISYNA1 expression were prevalently observed in 91 PC tissues. ISYNA1 expression was negatively correlated with MSI2 expression, T stage, vascular permeation and poor prognosis in PC patients. What's more, patients expressed high MSI2 and low ISYNA1 level had a significant worse prognosis. And in wtp53 Capan-2 and SW1990 cells, ISYNA1 was downregulated by p53 silencing. ISYNA1 silencing promoted cell proliferation and cell cycle by inhibiting p21 and enhanced cell migration and invasion by upregulating ZEB-1. However, MSI2 silencing upregulated ISYNA1 and p21 but downregulated ZEB-1, which can be rescued by ISYNA1 silencing. Moreover, reduction of cell migration and invasion resulting from MSI2 silencing was significantly reversed by ISYNA1 silencing. In summary, MSI2 facilitates the development of PC through a novel ISYNA1-p21/ZEB-1 pathway, which provides new gene target therapy for PC., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL-1β and caspase-1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF-κB/p65 signal pathway, sUA promoted NLRP3, pro-caspase 1 and pro-IL-1β production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL-1β secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL-1β and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA., (2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: Arteriogenesis is an important mechanism that contributes to restoration of oxygen supply in chronically ischemic tissues, but remains incompletely understood due to technical limitations. This study presents a novel approach for comprehensive assessment of the remodeling pattern in a complex microvascular network containing multiple collateral microvessels., Methods: We have developed a hardware-software integrated platform for quantitative, longitudinal, and label-free imaging of network-wide hemodynamic changes and arteriogenesis at the single-vessel level. By ligating feeding arteries in the mouse ear, we induced network-wide hemodynamic redistribution and localized arteriogenesis. The utility of this technology was demonstrated by studying the influence of obesity on microvascular arteriogenesis., Results: Simultaneously monitoring the remodeling of competing collateral arterioles revealed a new, inverse relationship between initial vascular resistance and extent of arteriogenesis. Obese mice exhibited similar remodeling responses to lean mice through the first week, including diameter increase and flow upregulation in collateral arterioles. However, these gains were subsequently lost in obese mice., Conclusions: Capable of label-free, comprehensive, and dynamic quantification of structural and functional changes in the microvascular network in vivo, this platform opens up new opportunities to study the mechanisms of microvascular arteriogenesis, its implications in diseases, and approaches to pharmacologically rectify microvascular dysfunction., (© 2019 John Wiley & Sons Ltd.)

Background: Oral submucous fibrosis (OSF) is a potentially malignant lesion characterized by epithelial-mesenchymal transition (EMT). Bone morphogenetic protein 4 (BMP4) promotes EMT in fibrotic diseases, but the underlying mechanisms and its potential role in OSF are unclear. This study investigates whether BMP4 plays a role in the pathogenesis of OSF and explores the underlying mechanisms., Methods: The expression of BMP4 and the EMT proteins E-cadherin and vimentin was investigated in OSF specimens by immunohistochemical staining. Pearson's correlation analysis was conducted to explore the correlation between BMP4 and the EMT markers. Western blotting and RT-PCR assays were used to analyze the effect of arecoline (a known EMT-promoting pathogenic factor in OSF) on BMP4 and identify the transcription factor involved. Confocal microscopy was used to observe the intracellular sublocalization of the identified transcription factor, Yes-associated protein 1 (YAP1). Finally, siRNA silencing of BMP4 was used to determine its effect on YAP1 activation and arecoline-induced EMT., Results: BMP4 is overexpressed in OSF and plays a role in EMT, as its expression correlates with the expression of E-cadherin and vimentin. Arecoline induces BMP4 expression via the activation of YAP1 (through its nuclear translocation). Furthermore, the YAP1/BMP4 mechanism is the main molecular event in arecoline-induced EMT, as knockdown of BMP4 expression affects expression of the EMT markers and inhibits extracellular matrix accumulation., Conclusions: Arecoline induces EMT in OSF via the YAP1/BMP4 pathway. Thus, BMP4 could be considered as a potential therapeutic target for the treatment of OSF., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The transition from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial-mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT-related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease-free survival (DFS) than those with low risk scores. The EMT-related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT-related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT-related gene signature that has tumour-promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Immunotherapy mediated by recombinant antibodies is an effective therapeutic strategy for a variety of cancers. In a previous study, we demonstrated that the fibroblast growth factor 1 (FGF-1)-specific recombinant antibody scFv1C9 arrests the cell cycle at the G0/G1 transition by blocking the intracrine FGF-1 pathway in breast cancer cells. Here, we further show that the overexpression of scFv1C9 in MCF-7 and MDA-MB-231 breast cancer cells by lentiviral infection resulted in decreased tumourigenicity, tumour growth and lung metastasis through FGF-1 neutralization. We found that scFv1C9 resulted in the up-regulation of p21, which in turn inhibited the expression of CDK2 and blocked cell cycle progression. To explore the potential role of scFv1C9 in vivo, we delivered the gene into solid tumours by electroporation, which resulted in significant inhibition of tumour growth. In tumour tissue sections, immunohistochemical staining of the cellular proliferation marker Ki-67 and the microvessel marker CD31 showed a reduction in the proliferative index and microvessel density, respectively, upon expression of scFv1C9 compared with the appropriate controls. Thus, our data indicate a central role for scFv1C9 in blocking the intracrine pathway of FGF-1, therefore, scFv1C9 could be developed in an effective therapeutic for breast cancer., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The master circadian clock in mammals, the suprachiasmatic nucleus (SCN), is under the entraining influence of the external light cycle. At a mechanistic level, intracellular signaling via the p42/44 mitogen-activated protein kinase pathway appears to play a central role in light-evoked clock entrainment; however, the precise downstream mechanisms by which this pathway influences clock timing are not known. Within this context, we have previously reported that light stimulates activation of the mitogen-activated protein kinase effector mitogen-stress-activated kinase 1 (MSK1) in the SCN. In this study, we utilised MSK1(-/-) mice to further investigate the potential role of MSK1 in circadian clock timing and entrainment. Locomotor activity analysis revealed that MSK1 null mice entrained to a 12 h light/dark cycle and exhibited circadian free-running rhythms in constant darkness. Interestingly, the free-running period in MSK1 null mice was significantly longer than in wild-type control animals, and MSK1 null mice exhibited a significantly greater variance in activity onset. Further, MSK1 null mice exhibited a significant reduction in the phase-delaying response to an early night light pulse (100 lux, 15 min), and, using an 8 h phase-advancing 'jet-lag' experimental paradigm, MSK1 knockout animals exhibited a significantly delayed rate of re-entrainment. At the molecular level, early night light-evoked cAMP response element-binding protein (CREB) phosphorylation, histone phosphorylation and Period1 gene expression were markedly attenuated in MSK1(-/-) animals relative to wild-type mice. Together, these data provide key new insights into the molecular mechanisms by which MSK1 affects the SCN clock., (© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads., (© 2011 John Wiley & Sons A/S.)

Undecaprenyl pyrophosphate synthase is a cis-prenyltransferase enzyme, which is required for cell wall biosynthesis in bacteria. Undecaprenyl pyrophosphate synthase is an attractive target for antimicrobial therapy. We performed long molecular dynamics simulations and docking studies on undecaprenyl pyrophosphate synthase to investigate its dynamic behavior and the influence of protein flexibility on the design of undecaprenyl pyrophosphate synthase inhibitors. We also describe the first X-ray crystallographic structure of Escherichia coli apo-undecaprenyl pyrophosphate synthase. The molecular dynamics simulations indicate that undecaprenyl pyrophosphate synthase is a highly flexible protein, with mobile binding pockets in the active site. By carrying out docking studies with experimentally validated undecaprenyl pyrophosphate synthase inhibitors using high- and low-populated conformational states extracted from the molecular dynamics simulations, we show that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on the newly obtained apo-undecaprenyl pyrophosphate synthase and other crystal structures previously published, we show that the changes observed during the molecular dynamics simulation are very similar to those seen in the crystal structures obtained in the presence or absence of ligands. We believe that this is the first time that a rare 'expanded pocket' state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation., (© 2011 John Wiley & Sons A/S.)