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Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China. [ABSTRACT FROM AUTHOR]

There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved antivirals (e.g., nucleoside analogues) are effective at reducing HBV replication, they have almost no impact on the existing HBV covalently closed circular DNA (cccDNA) reservoir. HBV cccDNA is a critical obstacle to the complete elimination of the virus via antiviral therapy. The true cure of HBV infection requires the eradication of viral cccDNA from HBV-infected cells; thus, the development of new agents directly or indirectly targeting HBV cccDNA is urgently needed due to the limitations of current available drugs against HBV infection. In this regard, it is the major focus of current anti-HBV research worldwide via different mechanisms to either inactivate/inhibit (functional cure) or eliminate (complete cure) HBV cccDNA. Therefore, this review discussed and summarized recent advances and challenges in efforts to inactivate/silence or eliminate viral cccDNA using anti-HBV agents from different sources, such as small molecules (including epigenetic drugs) and polypeptides/proteins, and siRNA or gene-editing approaches targeting/attenuating HBV cccDNA via different mechanisms, as well as future directions that may be considered in efforts to truly cure chronic HBV infection. In conclusion, no breakthrough has been made yet in attenuating HBV cccDNA, although a number of candidates have advanced into the phase of clinical trials. Furthermore, the overwhelming majority of the candidates function to indirectly target HBV cccDNA. No outstanding candidate directly targets HBV cccDNA. Relatively speaking, CCC_R08 and nitazoxanide may be some of the most promising agents to clear HBV infection in small molecule compounds. Additionally, CRISPR-Cas9 systems can directly target HBV cccDNA for decay and demonstrate significant anti-HBV activity. Consequently, gene-editing approaches targeting HBV cccDNA may be one of the most promising means to achieve the core goal of anti-HBV therapeutic strategies. In short, more basic studies on HBV infection need to be carried out to overcome these challenges. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases represent a global health crisis, and understanding the intricate molecular mechanisms underlying cardiac pathology is crucial for developing effective diagnostic and therapeutic strategies. Mitsugumin-53 (MG53) plays a pivotal role in cell membrane repair, has emerged as a multifaceted player in cardiovascular health. MG53, also known as TRIM72, is primarily expressed in cardiac and skeletal muscle and actively participates in membrane repair processes essential for maintaining cardiomyocyte viability. It promotes k-ion currents, ensuring action potential integrity, and actively engages in repairing myocardial and mitochondrial membranes, preserving cardiac function in the face of oxidative stress. This study discusses the dual impact of MG53 on cardiac health, highlighting its cardioprotective role during ischemia/reperfusion injury, its modulation of cardiac arrhythmias, and its influence on cardiomyopathy. MG53's regulation of metabolic pathways, such as lipid metabolism, underlines its role in diabetic cardiomyopathy, while its potential to mitigate the effects of various cardiac disorders, including those induced by antipsychotic medications and alcohol consumption, warrants further exploration. Furthermore, we examine MG53's diagnostic potential as a biomarker for cardiac injury. Research has shown that MG53 levels correlate with cardiomyocyte damage and may predict major adverse cardiovascular events, highlighting its value as a biomarker. Additionally, exogenous recombinant human MG53 (rhMG53) emerges as a promising therapeutic option, demonstrating its ability to reduce infarct size, inhibit apoptosis, and attenuate fibrotic responses. In summary, MG53's diagnostic and therapeutic potential in cardiovascular diseases presents an exciting avenue for improved patient care and outcomes. [ABSTRACT FROM AUTHOR]

Resolving the infrageneric classification of species‐rich genera has been challenging in plant taxonomy. Ilex L. is a subcosmopolitan genus with over 600 species of dioecious trees and shrubs. Many classification systems based on morphological data have been proposed during the past 250 years. However, these systems (such as Loesener's and Galle's systems) may not truly reflect Ilex's evolutionary trajectories because most of those system's infrageneric hierarchies are not monophyletic. In this study, we reconstructed a phylogeny of Ilex L. comprising 15 moderately to highly supported clades using rigorously identified samples (202 species) and closely authenticated gene sequences of three nuclear genes [internal transcribed spacer (ITS), external transcribed spacer (ETS), and nepGS]. The newly generated phylogenetic tree resembles essentially that of the nuclear tree of Manen et al., but shows conspicuous topological differences with the phylogeny of Yao et al. Closely scrutinizing morphological variation and distributional patterns of 202 species, this study found that most lineages of Ilex identified herein are well defined by a particular trait or a combination of morphological and distributional traits, displaying phylogeny–morphology–distribution conformity that has seldom been uncovered in previous studies. Given the general phylogeny–morphology–distribution conformity revealed in this genus, we put forward an updated sectional classification system for Ilex that temporarily contains 14 sections. The new classification will provide a robust framework for studying the evolution and diversification of this ecologically and economically important genus. [ABSTRACT FROM AUTHOR]

Background: Currently, skinfold thickness in studies on arm venous access ports and the effect of venous access port application are unknown. Materials and Methods: A total of 256 cancer patients who underwent primary venous access port placement in the Fourth Hospital of Hebei Medical University from September 2022 to March 2023 were selected as the study subjects. Two hundred fifty‐six patients were divided into normal skinfold thickness group and high skinfold thickness group according to skinfold thickness. The success rate of primary catheterization of arm venous port catheterization, catheterization operation time, catheterization length and incidence rate of adverse reactions were compared. Results: There was no significant difference in the basic data between the two groups. There was no significant difference in the success rate of primary catheterization between the two groups (p > 0.05), the catheterization operation time in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05), the total length of the implanted catheter in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05), and the incidence of adverse reactions in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05). Conclusion: In cancer patients, skinfold thickness can significantly affect the application effect of arm venous port, and normal skinfold thickness for arm venous port has shorter operation time, total length of implanted catheter and lower incidence of adverse reactions. [ABSTRACT FROM AUTHOR]

Industrial park is an important emission sector of PM2.5 pollution. Previous studies have provided valuable information on the impact of PM2.5 from industrial parks on human health, but relevant studies at city scale are limited. In this study, the health burden of industrial parks was evaluated based on PM2.5-related premature deaths and economic contributions. The premature deaths were calculated in terms of a novel research model by integrating the Bayesian maximum entropy (BME) model, weighted concentration-weighted trajectory (WCWT), and integrated exposure-response function (IER). Take Tianjin City for example, it was found that since the main diffusion direction of PM2.5 in Tianjin is from south to north, the industrial parks in the south of Tianjin and close to the central city with high population density have high health burden. These industrial parks need to be focused on or even relocated in the future. The research model can provide scientific basis for the health burden evaluation of industrial parks at city scale, so as to help local governments optimize the layout of industrial parks and formulate environmental responsibility management policies for industrial parks. [ABSTRACT FROM AUTHOR]

As one of the first characteristics of cancer cells, chromosomal aberrations during cell division have been well documented. Aneuploidy is a feature of most cancer cells accompanied by an elevated rate of mis-segregation of chromosomes, called chromosome instability (CIN). Aneuploidy causes ongoing karyotypic changes that contribute to tumor heterogeneity, drug resistance, and treatment failure, which are considered predictors of poor prognosis. Lung cancer (LC) is the leading cause of cancer-related deaths worldwide, and its genome map shows extensive aneuploid changes. Elucidating the role of aneuploidy in the pathogenesis of LC will reveal information about the key factors of tumor occurrence and development, help to predict the prognosis of cancer, clarify tumor evolution, metastasis, and drug response, and may promote the development of precision oncology. In this review, we describe many possible causes of aneuploidy and provide evidence of the role of aneuploidy in the evolution of LC, providing a basis for future biological and clinical research. [ABSTRACT FROM AUTHOR]

In recent years, ozone (O3) concentration has shown a decreasing trend in the Beijing–Tianjin–Hebei (BTH) region in China. However, O3 pollution remains a prominent problem. Accurate estimation of O3 exposure levels can provide support for epidemiological studies. A total of 13 variables were combined to estimate short- and long-term O3 exposure levels using the geographically weighted regression (GWR) model in the BTH region with a spatial resolution of 1 × 1 km from 2017 to 2020. Five variables were left in the GWR model. O3 concentration was positively correlated with temperature, wind speed, and SO2, whereas is was negatively correlated with precipitation and NO2. Results showed that the model performed well. Leave-one-out cross-validation (LOOCV) R2 for short- and long-term simulation results were 0.91 and 0.71, and the values for RMSE were 11.14 and 3.49 μg/m3, respectively. The annual maximum 8 h average O3 concentration was the highest in 2018 and the lowest in 2020. Decreasing concentrations of major precursors of O3 due to the regional joint prevention and control may be the reason. O3 concentration was high in the southeast of the BTH region, including in Hengshui, Handan, Xingtai and Cangzhou. [ABSTRACT FROM AUTHOR]

Ozone (O3) pollution is one of the predominant environmental problems, and exposure to high O3 concentrations has a significant negative influence on both human health and ecosystems. Therefore, it is essential to analyze spatio-temporal characteristics of O3 distribution and to evaluate O3 exposure levels. In this study, O3 monitoring and satellite data were used to estimate O3 daily, seasonal and one-year exposure levels based on the Bayesian maximum entropy (BME) model with a spatial resolution of 1 km × 1 km in the Beijing-Tianjin-Hebei (BTH) region, China. Leave-one-out cross-validation (LOOCV) results showed that R2 for daily and one-year exposure levels were 0.81 and 0.69, respectively, and the corresponding values for RMSE were 19.58 μg/m3 and 4.40 μg/m3, respectively. The simulation results showed that the heavily polluted areas included Tianjin, Cangzhou, Hengshui, Xingtai, and Handan, while the clean areas were mainly located in Chengde, Qinhuangdao, Baoding, and Zhangjiakou. O3 pollution in summer was the most severe with an average concentration of 134.5 μg/m3. In summer, O3 concentrations in 87.7% of the grids were more than 100 μg/m3. In contrast, winter was the cleanest season in the BTH region, with an average concentration of 51.1 μg/m3. [ABSTRACT FROM AUTHOR]

Purpose: To examine a screen model for detecting undergraduates with higher risk for developing psychosis (HRDP). Design and Methods: A cross‐sectional design with convenience sampling was used. The screen model included exploration stage by self‐report scales and confirmation stage by face‐to‐face interviews. Findings: A total of 273 students were detected from 4744 surveys during 4 years. Of them, 120 students with HRDP were identified and 7 had been diagnosed as schizophrenia or bipolar disorders at 12‐month follow‐up. Practice Implications: This screen model can be used in early detection for undergraduates with HRDP from large general samples. [ABSTRACT FROM AUTHOR]

Generally, instructors observed that these activities helped students develop the required skills and knowledge, as students did not require significant additional help upon resuming campus activities. Upon returning to campus, students verbally commented that "the online sessions prepared me very well for the clinical exam", indicating students self-perceived increased preparedness for clinical assessments. Keywords: Education; COVID-19; digital; online; teaching and learning; optometry EN Education COVID-19 digital online teaching and learning optometry 658 663 6 08/03/22 20220801 NES 220801 On 11 March 2020, the World Health Organisation declared a state of pandemic caused by the severe acute respiratory syndrome coronavirus 2. [Extracted from the article]

We report nano-titania modified cupric-based metal–organic frameworks (NTMCu-MOFs) by a simple and low-cost solvothermal method. The excellent properties of the NTMCu-MOFs are characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The NTMCu-MOFs have been evaluated in an on-line pass-through cleanup procedure as a sorbent prior to the analysis of phenothiazine drugs and metabolites, i.e., chlorpromazine (CPZ), promethazine (PMZ), chlorpromazine sulphoxide (CPZSO) and promethazine sulfoxide (PMZSO), in human plasma by liquid chromatography–tandem quadrupole mass spectrometry (LC-MS/MS). Endogenous matrices in human plasma samples were effectively removed by the NTMCu-MOF based on-line pass-through cleanup procedure and ion suppression effects were dramatically reduced. Under optimum conditions, satisfactory recoveries were found to be in the range of 85.6%–108%. Acceptable trueness and precision of the proposed method were also obtained, with relative errors (REs) less than 15% and within- and between-run RSDs less than 8.0%. The limits of detection (LODs) of phenothiazine drugs and metabolites were in the range of 0.012–0.024 μg L−1. The proposed method has been used for the determination of phenothiazine drugs and metabolites in the plasma samples obtained from nine schizophrenic patients undergoing chlorpromazine therapy. The results demonstrated the applicability of the proposed NTMCu-MOF on-line pass-through cleanup procedure coupled with the LC-MS/MS method to clinical studies. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines provide essential tools for the control of the COVID-19 pandemic. A number of technologies have been employed to develop SARS-CoV-2 vaccines, including the inactivated SARS-CoV-2 particles, mRNA to express viral spike protein, recombinant spike proteins, and viral vectors. Here, we report the use of the vaccinia virus Tiantan strain as a vector to express the SARS-CoV-2 spike protein. When it was used to inoculate mice, robust SARS-CoV-2 spike protein-specific antibody response and T-cell response were detected. Sera from the vaccinated mice showed strong neutralizing activity against the ancestral Wuhan SARS-CoV-2, the variants of concern (VOCs) B.1.351, B.1.617.2, and the emerging B.1.1.529 (omicron). This finding supports the possibility of developing a new type of SARS-CoV-2 vaccine using the vaccinia virus vector. [ABSTRACT FROM AUTHOR]

Fagus L. is a key component in temperate deciduous broadleaf forests of the Northern Hemisphere. However, its biogeographic history has not been examined under the framework of a fully resolved and reasonably time‐calibrated phylogeny. In this study, we sequenced 28 nuclear single/low‐copy loci (18 555 bp in total) of 11 Fagus species/segregates and seven outgroups. Phylogenetic trees were reconstructed using both concatenation‐based (maximum parsimony, maximum likelihood, and Bayesian inference) and coalescent‐based methods (StarBEAST2, ASTRAL). The monophyly of two subgenera (Fagus and Engleriana) and most sections was well supported, except for sect. Lucida, which was paraphyletic with respect to sect. Longipetiolata. We also found a major phylogenetic conflict among North American, East Asian, and West Eurasian lineages of subgen. Fagus. Three segregates that have isolated distribution (F. mexicana, F. multinervis, and F. orientalis) were independent evolutionary units. Biogeographic analysis with fossils suggested that Fagus could have originated in the North Pacific region in late early Eocene. Major diversifications coincided with a climate aberration at the Eocene/Oligocene boundary and the global cooling since mid‐Miocene. The late Miocene accelerated global cooling and the Pleistocene glaciations would have driven beeches into East Asia, North America, and West Eurasia. Meanwhile, range reduction and extinction in high latitudes, central Asia, and western North America converged to form the beech modern distribution pattern. This study provides a first attempt to disentangle the biogeographic history of beeches in the context of a nearly resolved and time‐calibrated phylogeny, which could shed new insights into the formation of the temperate biome in the Northern Hemisphere. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis and iron-metabolism are regulated by Long non-coding RNAs (lncRNAs) in ovarian cancer (OC). Therefore, a comprehensive analysis of ferroptosis and iron-metabolism related lncRNAs (FIRLs) in OC is crucial for proposing therapeutic strategies and survival prediction. Methods: In multi-omics data from OC patients, FIRLs were identified by calculating Pearson correlation coefficients with ferroptosis and iron-metabolism related genes (FIRGs). Cox-Lasso regression analysis was performed on the FIRLs to screen further the lncRNAs participating in FIRLs signature. In addition, all patients were divided into two robust risk subtypes using the FIRLs signature. Receiver operator characteristic (ROC) curve, Kaplan–Meier analysis, decision curve analysis (DCA), Cox regression analysis and calibration curve were used to confirm the clinical benefits of FIRLs signature. Meanwhile, two nomograms were constructed to facilitate clinical application. Moreover, the potential biological functions of the signature were investigated by genes function annotation. Finally, immune microenvironment, chemotherapeutic sensitivity, and the response of PARP inhibitors were compared in different risk groups using diversiform bioinformatics algorithms. Results: The raw data were randomized into a training set (n = 264) and a testing set (n = 110). According to Pearson coefficients between FIRGs and lncRNAs, 1075 FIRLs were screened for univariate Cox regression analysis, and then LASSO regression analysis was used to construct 8-FIRLs signature. It is worth mentioning that a variety of analytical methods indicated excellent predictive performance for overall survival (OS) of FIRLs signature (p < 0.05). The multivariate Cox regression analysis showed that FIRLs signature was an independent prognostic factor for OS (p < 0.05). Moreover, significant differences in the abundance of immune cells, immune-related pathways, and drug response were excavated in different risk subtypes (p < 0.05). Conclusion: The FIRLs signature can independently predict overall survival and therapeutic effect in OC patients. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy of positive feedback closed-loop management system (PFCMS) protocol in influencing parents’ decision about pregnancy continuation in pregnancies diagnosed with omphalocele. Methods This was a retrospective cohort study of patients who were diagnosed with fetal omphalocele prior to 20 weeks’ gestation by ultrasound and were referred to Fetal Care Center at a mainland Chinese medical center during an 11-year period. Two management strategies were offered during the two stages of the study period: a single consultant with a routine protocol and a multidisciplinary support team with PFCMS, respectively. We analyzed the two protocols influencing parents’ decision about pregnancy continuation. Results Forty-nine patients diagnosed with fetal omphalocele were included in this study. In Group A including 16 patients with routine protocol during the first stage of the study period, the majority opted for termination, and only five continued the pregnancy. In Group B including 33 patients with PFCMS during the second stage of the study period, less than one third chose TOP, and 23 ended in live births. There was a significantly lower TOP rate in patients treated with the PFCMS protocol. Conclusion The PFCMS protocol may be an efficient approach in managing pregnancies complicated by omphalocele, which may help in preventing unnecessary pregnancy terminations. [ABSTRACT FROM AUTHOR]

Background: The preservation or restoration of β cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D. Methods: This was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. Fifty-three participants including 33 adult-onset (≥ 18 years) and 20 juvenile-onset T1D were enrolled. Twenty-seven subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n = 26) only received standard care based on intensive insulin therapy. Data at 1-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses. Results: After 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide were not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed. Conclusion: One repeated intravenous dose of allogeneic UC-MSCs is safe in people with recent-onset T1D and may result in better islet β cell preservation during the first year after diagnosis compared to standard treatment alone. Trial registration: ChiCTR2100045434. Registered on April 15, 2021—retrospectively registered, http://www.chictr.org.cn/ [ABSTRACT FROM AUTHOR]

Soil calcium carbonate (CaCO3) content is an important soil property. The prediction of soil CaCO3 content is necessary for the sustainable management of soil fertility. In this work, we attempted to incorporate environmental variables directly and through regression models into the framework of Bayesian maximum entropy (BME) to predict CaCO3 content. Firstly, multiple linear regression (MLR) and geographically weighted regression (GWR) were used to establish a relationship between sampling data and environmental variables, including Digital Elevation Model, pH, temperature, rainfall, and fluvo-aquic soils. Prediction results of MLR and GWR served as soft data and were incorporated into the framework of BME to estimate the CaCO3 content. Secondly, soil samples and environmental variables were combined to generate probability distributions of CaCO3 at unsampled points. These probability distributions were used as soft data for the BME to predict the CaCO3 content. The results showed that the GWR method (r = 0.84, RMSE = 24.0 g kg−1) performed better than the MLR method (r = 0.73, RMSE = 30.1 g kg−1). The BME-GWR method outperformed the BME-EV and BME-MLR methods. The r values of BME-GWR, BME-EV, and BME-MLR methods were 0.87, 0.86, and 0.82, respectively, and the RMSEs of the three methods were 22.2, 23.9, and 25.2 g kg−1, respectively. The spatial distribution of CaCO3 content predicted by the above methods was similar and significantly higher in the southwest than in the northeast. [ABSTRACT FROM AUTHOR]

Initial malarial infection mostly causes symptomatic illness in humans. Infection that is not fatal induces complete protection from severe illness and death, and thus complete protection from severe illness or death is granted with sufficient exposure. However, malaria parasite immunity necessitates constant exposure. Therefore, it is important to evaluate lowered immunity and recurrent susceptibility to symptomatic disease in lower transmission areas. We aimed to investigate selection pressure based on transmission levels, antimalarial drug use, and environmental factors. We whole genome sequenced (WGS) P. falciparum clinical samples from Chinese hosts working in Ghana and compared the results with the WGS data of isolates from native Ghanaians downloaded from pf3k. The P. falciparum samples were generally clustered according to their geographic origin, and Chinese imported samples showed a clear African origin with a slightly different distribution from the native Ghanaian samples. Moreover, samples collected from two host populations showed evidence of differences in the intensity of selection. Compared with native Ghanaian samples, the China-imported isolates exhibited a higher proportion of monoclonal infections, and many genes associated with RBC invasion and immune evasion were found to be under less selection pressure. There was no significant difference in the selection of drug-resistance genes due to a similar artemisinin-based combination therapy medication profile. Local selection of malarial parasites is considered to be a result of differences in the host immunity or disparity in the transmission opportunities of the host. In China, most P. falciparum infections were imported from Africa, and under these circumstances, distinct local selective pressures may be caused by varying acquired immunity and transmission intensity. This study revealed the impact of host switching on the immune system, and it may provide a better understanding of the mechanisms that enable clinical immunity to malaria. [ABSTRACT FROM AUTHOR]

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP‐activated protein kinase (AMPK) produces anti‐inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin‐1 beta (IL‐1β), IL‐6 and tumour necrosis factor alpha (TNF‐α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP‐activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose‐dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL‐1β, IL‐6 and TNF‐α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS‐induced macrophage activation if AMPK was in deficient through siRNA‐mediated approaches. Further, the anti‐inflammatory effects produced by VitB6 or AICAR in LPS‐treated macrophages were abolished in DOK3 gene knockout (DOK3−/−) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS‐induced both systemic inflammation and acute pneumonia in wild‐type mice, but not in DOK3−/− mice. VitB6 prevents LPS‐induced acute pulmonary inflammation in mice via the inhibition of macrophage activation. [ABSTRACT FROM AUTHOR]

Background: The DENND1A gene is one of the most important sites associated with polycystic ovary syndrome (PCOS). We attempted to analyze the correlation between five single nucleotide polymorphisms (SNPs) in the DENND1A gene and the development of PCOS. Methods: A total of 346 PCOS patients and 225 normal ovulatory women were involved in the case-control study. Clinical variables and hormones were recorded. According to the Hap Map database, five tagging SNPs (rs2479106, rs2768819, rs2670139, rs2536951 and rs2479102) in the DENND1A gene were identified. The TaqMan probe and the PCR–RFLP (restriction fragment length polymorphism) methods were used for revealing these genotypes. TaqMan Genotype Software was used to analyze the alleles of the five SNPs. Results: Linkage disequilibrium and the gene frequency analysis demonstrated that the CCGGG haplotype might increase the risk of PCOS (P = 0.038, OR = 1.89, 95% CI = 1.027–3.481). Significant differences were found in genotypic and allelic distributions at the rs2536951 and rs2479102 loci between PCOS women and controls (P < 0.001). The LH levels and LH/FSH ratios were higher in PCOS patients than in the control group. A detailed analysis revealed that for the rs2479106 locus, these two values were significantly different in the control subjects who had AA, AG and GG genotypes (P = 0.013 and P = 0.007, respectively), and for the rs2468819 locus, these two values were significantly different among the PCOS patients with AA, AG and GG genotypes (P = 0.013 and 0.002, respectively). Conclusions: The tagging SNPs rs2479106 and rs2468819 in the DENND1A gene are associated with PCOS in the Chinese population, whereas rs2670139, rs2536951 and rs2479102 are not correlated with PCOS in the same population. [ABSTRACT FROM AUTHOR]

Chronic diseases often impact the quality of life of the patient, causing complications and increased mortality and medical costs. The World Health Organization proposed applying mindfulness as an important strategy to help transform the situation faced by chronic disease cases and to promote their mental flexibility and adaptability. The author reviewed the related literature on mindfulness and introduces the "SMILE" strategy in this article. This strategy includes several stages, including 1) Starting where I am, 2) Motivating patients to become self-aware of the experience of self and internal and external environment interactions, 3) Developing individual health beliefs, 4) Learning mindfulness-based health-promotion behaviors, 5) Evaluating the efficacy of mindfulness-based health-promotion behaviors and self-regulation. SMILE is a powerful strategy with the potential to promote patient wellbeing, acceptance of the need to coexist with chronic disease, and freedom. Mindfulness is an abstract concept. This article provides a reference on mindfulness intervention for healthcare providers. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To compare the effects of gliclazide, liraglutide and metformin on body composition in patients with type 2 diabetes mellitus with non‐alcoholic fatty liver disease. Materials and Methods: A total of 85 patients were randomly allocated to receive gliclazide (n = 27), liraglutide (n = 29) or metformin (n = 29) monotherapy for 24 weeks. Body composition was measured using dual‐energy X‐ray absorptiometry. Results: Liraglutide and metformin reduced total, trunk, limb, android and gynoid fat mass; this also led to weight reduction. However, gliclazide treatment produced no significant changes in weight or fat mass, likely because reductions in fat mass were concomitant with increases in lean tissue mass. Blood glucose concentrations and glycated hemoglobin levels improved in all treatment arms; levels of the latter were lower in patients treated with liraglutide and metformin. Serum alanine aminotransferase concentrations decreased in all treatment arms, whereas serum aspartate aminotransferase concentrations were reduced only by liraglutide and metformin. In all patients, weight loss and total, trunk, limb, and android fat mass reductions were positively correlated with decreases in serum alanine aminotransferase and aspartate aminotransferase levels, whereas reductions in waist circumference were positively correlated with lower serum alanine aminotransferase levels. Conclusions: Compared with gliclazide, liraglutide and metformin monotherapies result in greater weight loss, reductions in body fat mass, and better blood glucose control among type 2 diabetes mellitus patients with non‐alcoholic fatty liver disease. Reductions in weight, fat mass and waist circumference favorably affect hepatic function. This single‐center, open‐label, prospective, randomized clinical trial examined the effect of liraglutide, metformin, and gliclazide on body composition in patients with type 2 diabetes and concomitant non‐alcoholic fatty liver disease. The results show that liraglutide and metformin are superior to gliclazide in terms of reducing body weight, body mass index, and body fat mass, and in terms of improving liver function and glycosylated hemoglobin levels. In addition, liraglutide and metformin were shown to reduce fat mass rather than lean tissue mass, which is helpful in improving the body weight and glycemic control. Weight remained stable in the gliclazide group; this resulted from identical reductions in fat mass and increases in lean tissue mass. [ABSTRACT FROM AUTHOR]

MOV10 has emerged as an important host antiviral factor. MOV10 not only inhibits various viruses, including human immunodeficiency virus type 1, hepatitis C virus and vesicular stomatitis virus, but also restricts the activity of retroelements long interspersed nucleotide element-1, Alu, SVA and intracisternal A particles. Here, we report that MOV10 suppresses influenza A virus infection through interacting with viral nucleoprotein (NP), sequestering viral RNP in the cytoplasm and causing the degradation of viral vRNA. The antiviral activity of MOV10 depends on the integrity of P-bodies. We also found that the antiviral activity of MOV10 is partially countered by viral NS1 protein that interferes with the interaction of MOV10 with viral NP and causes MOV10 degradation through the lysosomal pathway. Moreover, NS1-defective influenza A virus is more susceptible to MOV10 restriction. Our data not only expand the antiviral spectrum of MOV10 but also reveal the NS1 protein as the first viral antagonist of MOV10. [ABSTRACT FROM AUTHOR]

Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study aimed to determine the role of PGIS S‐nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S‐nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of nitric oxide by carboxy‐PTIO or inhibition of S‐nitrosylation by N‐acetyl‐cysteine decreased GTN‐induced PGIS S‐nitrosylation. Enforced expression of mutated PGIS with C231/441A markedly abolished GTN‐induced PGIS S‐nitrosylation and nitrate cross‐tolerance in Apoe‐/‐ mice. Inhibition of cyclooxygenase 1 by aspirin, supplementation of PGI2 by beraprost, and inhibition of PGIS S‐nitrosylation by N‐acetyl‐cysteine improved GTN‐induced nitrate cross‐tolerance in rats. In patients, increased PGIS S‐nitrosylation was associated with nitrate tolerance. In conclusion, GTN induces nitrate cross‐tolerance through PGIS S‐nitrosylation at cysteine 231/441. [ABSTRACT FROM AUTHOR]

Introduction: Increasing the frequency of blood glucose monitoring aids the evaluation of glycemic variability and blood glucose control by antidiabetic drugs. It remains unclear, however, whether GLP-1 receptor agonists or basal insulin has a better effect on glycemic variability in type 2 diabetes mellitus (T2DM) patients who are inadequately controlled by metformin. We used a continuous glucose monitoring system (CGMS) to compare patients on a GLP-1 receptor agonist with patients on basal insulin in terms of glycemic variability.Methods: This prospective randomized study assigned T2DM patients treated with metformin (N = 39) to either exenatide treatment or insulin glargine treatment for 16 weeks. Glycemic variability was assessed using a CGMS; hemoglobin A1c (HbA1c), β-cell function, weight, body mass index (BMI), and waist circumference were also evaluated.Results: Mean blood glucose level, continuous overlapping net glycemic action, mean amplitude of glycemic excursions, percentage of the time that the blood glucose value was > 10.0 mmol/L, and highest blood glucose level (P  < 0.01-0.05) significantly decreased in both groups. Standard deviation of the mean glucose value, largest amplitude of glycemic excursions, and waist circumference significantly decreased for those treated with exenatide (P  < 0.05), while no changes were observed with insulin glargine treatment. Percentage of the time that the blood glucose value was > 7.8 mmol/L decreased after insulin glargine use (P  < 0.05) but not with the exenatide intervention. Similar decreases in fasting blood glucose and HbA1c and increases in the 1/homeostasis model assessment of insulin resistance, disposition index 30, and disposition index 120 were observed in both groups (P  < 0.01-0.05). Reductions in weight and BMI were greater with exenatide than with insulin glargine treatment (P  < 0.05).Conclusions: In overweight and obese patients with T2DM inadequately controlled by metformin, exenatide and insulin glargine have similar efficacies in terms of glycemic variability, HbA1c alleviation, and β-cell function, but exenatide has a greater effect on body weight and BMI. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes mellitus is one of risk factors of cardiovascular diseases including atherosclerosis. Whether and how diabetes promotes the formation of unstable atherosclerotic plaque is not fully understood. Here, we show that streptozotocin-induced type 1 diabetes reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout (Apoe−/−) mice. These detrimental effects of hyperglycemia on plaque stability were reversed by metformin in vivo without altering the levels of blood glucose and lipids. Mechanistically, we found that high glucose reduced the phosphorylated level of AMP-activated protein kinase alpha (AMPKα) and the transcriptional activity of activator protein 2 alpha (AP-2α), increased the expression of miR-124 expression, and downregulated prolyl-4-hydroxylase alpha 1 (P4Hα1) protein expression and collagen biosynthesis in cultured vascular smooth muscle cells. Importantly, these in vitro effects produced by high glucose were abolished by AMPKα pharmacological activation or adenovirus-mediated AMPKα overexpression. Further, adenovirus-mediated AMPKα gain of function remitted the process of diabetes-induced plaque destabilization in Apoe−/− mice injected with streptozotocin. Administration of metformin enhanced pAP-2α level, reduced miR-124 expression, and increased P4Hα1 and collagens in carotid atherosclerotic plaque in diabetic Apoe−/− mice. We conclude that streptozotocin-induced toxic diabetes promotes the formation of unstable atherosclerotic plaques based on the vulnerability index in Apoe−/− mice, which is related to the inactivation of AMPKα/AP-2α/miRNA-124/P4Hα1 axis. Clinically, targeting AMPKα/AP-2α/miRNA-124/P4Hα1 signaling should be considered to increase the plaque stability in patients with atherosclerosis.Key messages: Hyperglycemia reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout mice.Hyperglycemia destabilizes atherosclerotic plaque in vivo through an AMPKα/AP-2α/miRNA-124/P4Hα1-dependent collagen synthesis.Metformin functions as a stabilizer of atherosclerotic plaque to reduce acute coronary accent. [ABSTRACT FROM AUTHOR]

The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the zona glomerulosa (ZG) in rodents. The aim of the present study was to investigate the significance of immunohistochemical staining to detect DAB2 in the adrenal tissue of patients with APA. We investigated the expression of DAB2 in 36 adrenal glands with APA, 23 adrenal glands with cortisol-producing adenoma (CPA), and 33 adrenal glands with non-functioning adenoma (NFA). Immunohistochemical staining was performed using anti-DAB2 antibodies on paraffinembedded sections. We analysed the expression of DAB2 semiquantitatively by scoring staining intensity, and assessed the correlation of this information with the clinical findings. DAB2 mRNA expression in adenoma tissues was evaluated by RT-PCR. DAB2 was highly expressed in the ZG in normal human adrenal glands. DAB2 expression was heterogeneous in APA, with spotted, strong staining noted in most samples (25 of 36 APA). CPA and NFA also exhibited extensive low or moderate DAB2 expression. DAB2 mRNA was significantly increased and positively correlated with CYP11B2 in APA (p < 0.05). In APA, the DAB2 score adjusted for tumour volume was positively correlated with plasma aldosterone (p < 0.05). Patients with low or moderate DAB2 staining more frequently exhibited high blood pressure and were diagnosed at a younger age compared with patients with high DAB2 staining. The present study clearly demonstrates that DAB2 is a specific marker of the ZG in normal human adrenal glands but that DAB2 immunostaining is not sufficiently powerful for histopathological diagnosis of APA. DAB2 might be involved in excessive aldosterone biosynthesis and correlate with specific clinical characteristics of APA patients. [ABSTRACT FROM AUTHOR]

Enhancers frequently contain multiple binding sites for the same transcription factor. These homotypic binding sites often exhibit synergy, whereby the transcriptional output from two or more binding sites is greater than the sum of the contributions of the individual binding sites alone. Although this phenomenon is frequently observed, the mechanistic basis for homotypic binding site synergy is poorly understood. Here, we identify a bona fide cardiac-specific Prkaa2 enhancer that is synergistically activated by homotypic MEF2 binding sites. We show that two MEF2 sites in the enhancer function cooperatively due to bridging of the MEF2C-bound sites by the SAP domain-containing co-activator protein myocardin, and we show that paired sites buffer the enhancer from integration site-dependent effects on transcription in vivo. Paired MEF2 sites are prevalent in cardiac enhancers, suggesting that this might be a common mechanism underlying synergy in the control of cardiac gene expression in vivo. [ABSTRACT FROM AUTHOR]

BST-2 (tetherin, CD317, and HM1.24) is induced by interferon and restricts virus release by tethering the enveloped viruses to the cell surface. The effect of BST-2 on influenza A virus (IAV) infection has been inconclusive. In the present study, we report that BST-2 diminishes the production of IAV virus-like particles (VLPs) that are generated by viral neuraminidase and hemagglutinin proteins to a much greater degree than it inhibits the production of wild-type IAV particles. This relatively weaker inhibition of IAV is associated with reduction in BST-2 levels, which is caused by the M2 protein that interacts with BST-2 and leads to down-regulation of cell surface BST-2 via the proteasomal pathway. Similarly to the viral antagonist Vpu, M2 also rescues the production of human immunodeficiency virus-1 VLPs and IAV VLPs in the presence of BST-2. Replication of wild-type and the M2-deleted viruses were both inhibited by BST-2, with the M2-deleted IAV being more restricted. These data reveal one mechanism that IAV employs to counter restriction by BST-2. [ABSTRACT FROM AUTHOR]

The advent of nanomedicine requires novel delivery vehicles to actively target their site of action. Here, we demonstrate the development of lung-targeting drug-loaded liposomes and their efficacy, specificity and safety. Our study focuses on glucocorticoids methylprednisolone (MPS), a commonly used drug to treat lung injuries. The steroidal molecule was loaded into functionalized nano-sterically stabilized unilamellar liposomes (NSSLs). Targeting functionality was performed through conjugation of surfactant protein A (SPANb) nanobodies to form MPS–NSSLs–SPANb. MPS–NSSLs–SPANb exhibited good size distribution, morphology, and encapsulation efficiency. Animal experiments demonstrated the high specificity of MPS–NSSLs–SPANb to the lung. Treatment with MPS–NSSLs–SPANb reduced the levels of TNF-α, IL-8, and TGF-β1 in rat bronchoalveolar lavage fluid and the expression of NK-κB in the lung tissues, thereby alleviating lung injuries and increasing rat survival. The nanobody functionalized nanoparticles demonstrate superior performance to treat lung injury when compared to that of antibody functionalized systems. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is often undiagnosed or misdiagnosed clinically because of diagnostic difficulties caused by lack of laboratory-specific serological markers. In this study, we comprehensively assessed the clinical characteristics, laboratory indices, hepatotoxic drugs, risk factors and outcomes concerning DILI, and explored the similarities in mechanisms between Chinese and Western drug-induced DILI. Patients with a first diagnosis of DILI and a Roussel Uclaf Causality Assessment Method (RUCAM) score >3 points were enrolled for systematic retrospective study. Their clinical characteristics, clinical classification, risk factors, laboratory indices, hepatotoxic drugs and outcomes were analyzed. Cholestatic patients had the highest alkaline phosphatase (ALP) and prothrombin time activity (PTA) levels (P<0.05). Patients with medication time ≤30 days had significantly higher positive rate of autoantibodies than those with medication time <30 days. Odds ratio values for DILI-related factors such as hepatobiliary diseases, immune dysfunction, diabetes, hypertension, chronic alcohol consumption and age ≤45 years were 6.552, 6.130, 3.774, 2.801, 2.002 and 1.838, respectively. Pathogeneses of Chinese and Western drug-induced DILI may be substantially the same. DILI accompanied with autoantibody positivity may indicate severe liver injury outcome. Hepatobiliary diseases, diabetes and hypertension are likely to increase drug susceptibility, and more prone to cause liver injury. [ABSTRACT FROM AUTHOR]

Background: The renoprotective effect of inhibitors of renin-angiotensin system (RAS) has been identified through placebo-controlled trials. However, the effect of calcium-channel blockers (CCBs) on renal system is still controversial. Our current meta-analysis includes available evidences to compare the effect of dihydropyridine CCBs and ACEIs or ARBs on renal outcomes and mortality. We also further investigate whether CCBs can be used in combination with inhibitors of RAS to improve the prognosis of patients with chronic kidney disease (CKD).Methods and results: Electronic databases were searched up to July 2012, for clinical randomized controlled trials, assessing the effect of dihydropyridine CCBs on the incidence of end-stage renal disease (ESRD) and all-cause mortality in contrast to ACEIs or ARBs. Eight clinical trials were included containing 25,647 participants. ESRD showed significantly higher frequency with CCBs therapy compared with ACEIs or ARBs therapy, though blood pressure was decreased similarly in both groups in every trial (OR, 1.25; 95% CI, 1.05–1.48;p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEIs or ARBs exhibited better renoprotective effect compared to CCBs (OR, 0.96; 95% CI, 0.89–1.03;p = 0.24).Conclusions: CCBs did not increase all-cause mortality incidence in patients with CKD though they displayed weaker renoprotective, compared to ACEIs or ARBs therapy. Our results suggest the combination of a CCB and an ACEI or ARB should be a preferable antihypertensive therapy in patients with CKD, considering their higher effect in decreasing blood pressure and fewer adverse metabolic problems caused. [ABSTRACT FROM PUBLISHER]

Internet addiction disorder is a relatively new condition, and the criteria for its diagnosis have been developed only over the last several years. The criteria for Internet addiction remain controversial. We strive to further elucidate the clinical validity of the diagnostic criteria for Internet addiction. To test items of the diagnostic criteria for Internet addiction among adolescents, we conducted a clinical interview study of college students based on longitudinal data on their risky use of the Internet. Forty-one high-risk cases were selected from a 3-year 5-time point longitudinal survey of 716 college freshmen. We examined disputes relevant to symptoms and impairment in the DC-IA-A (Diagnostic Criteria for Internet Addiction among Taiwanese Adolescents). Of the 41 cases, 21 were diagnosed with Internet addiction via a psychiatric interview. In the Internet addiction disorder group, 23.8% of cases had a diagnosis of depression, whereas only 15.0% of the cases in the non-Internet addiction group had a diagnosis of depression. Two major criteria (A8 and A3) had low incidences in these high-risk college students and thus did not help provide a differential diagnosis between the groups. We suggest that A8, 'excessive effort spent on activities necessary to obtain access to the Internet', should be omitted, and that A3, 'tolerance: a marked increase in the duration of Internet use needed to achieve satisfaction', should be modified. A1 and A9 should be discussed regarding their role in the diagnosis of Internet addiction disorder. Additional well-designed studies examining the diagnostic criteria and the relationship between factors are needed. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Endothelin signaling is essential for neural crest development, and dysregulated Endothelin signaling is associated with several neural crest-related disorders, including Waardenburg and other syndromes. However, despite the crucial roles of this pathway in neural crest development and disease, the transcriptional effectors directly activated by Endothelin signaling during neural crest development remain incompletely elucidated. Here, we establish that the MADS box transcription factor MEF2C is an immediate downstream transcriptional target and effector of Endothelin signaling in the neural crest.We show that Endothelin signaling activates Mef2c expression in the neural crest through a conserved enhancer in the Mef2c locus and that CRISPR-mediated deletion of this Mef2c neural crest enhancer from the mouse genome abolishes Endothelin induction of Mef2c expression. Moreover, we demonstrate that Endothelin signaling activates neural crest expression of Mef2c by de-repressing MEF2C activity through a Calmodulin-CamKII-histone deacetylase signaling cascade. Thus, these findings identify a MEF2C-dependent, positive-feedback mechanism for Endothelin induction and establish MEF2C as an immediate transcriptional effector and target of Endothelin signaling in the neural crest. [ABSTRACT FROM AUTHOR]

SAMHD1 (SAM domain- and HD domain-containing protein 1) inhibits HIV-1 infection of myeloid cells and resting CD4+ Tcells. Two lineages of primate lentiviruses, the sooty mangabey SIV (simian immunodeficiency virus) (SIVsm)/macaque SIV (SIVmac)/HIV-2 lineage and the red-capped mangabey SIV (SIVrcm) lineage, carry a SAMHD1 antagonist called Vpx. Vpx recognizes SAMHD1 and recruits a ubiquitin E3 ligase complex that is composed of CUL4 (Cullin4), DDB1 (damaged DNA-binding protein 1) and a member of the DCAF (DDB1/CUL4-associated factor) family called DCAF1. This E3 ligase complex polyubiquitinates SAMHD1, which leads to proteasomal degradation of SAMHD1. As opposed to the wellcharacterized interaction of SIVmac Vpx with human SAMHD1 and DCAF1, SIVrcm Vpx adopts a different mode of interaction with SAMHD1 of red-capped mangabeys. In the present study, we have characterized the interactions that are essential for SIVrcm Vpx-mediated degradation of rcmSAMHD1 (redcapped mangabey SAMHD1). Using mutagenesis and molecular modelling, we have determined the key role of the W23LHR26 peptide of SIVrcm Vpx in recognizing rcmSAMHD1. The amino acids Phe15, Leu36, Phe52, Arg55 and Arg56 at the N-terminal domain (NtD) of rcmSAMHD1 are involved in interaction with Vpxrcm (red-capped mangabey Vpx). The molecular model of rcmSAMHD1-NtD, Vpxrcm and C-terminal domain (CtD) of DCAF1 (DCAF1-CtD) complex reveals further that rcmSAMHD1-NtD and Vpxrcm utilize an interaction interface that is different from that used by human SAMHD1-CtD and Vpxsm. These findings provide further insights into the different modes of interaction between Vpx and SAMHD1 as the result of the 'arms race' of virus and host cell. [ABSTRACT FROM AUTHOR]

It has been found that recombinant Saccharomyces cerevisiae 6525 can produce high concentration of ethanol in one-step fermentation from the extract of Jerusalem artichoke tubers or inulin. However, the utilization rate of raw materials was low and the fermentation process was costly and complicated. Therefore, in this study, after the optimum processing conditions for ethanol production in fed-batch fermentation were determined in flask, the recombinant S. cerevisiae 6525 was first used to produce ethanol from the dry powder of Jerusalem artichoke tubers in 5-L agitating fermentor. After 72 h of fermentation, around 84.3 g/L ethanol was produced in the fermentation liquids, and the conversion efficiency of inulin-type sugars to ethanol was 0.453, or 88.6 % of the theoretical value of 0.511. This study showed high feasibility of bioethanol industrial production from the Jerusalem artichoke tubers and provided a basis for it in the future. [ABSTRACT FROM AUTHOR]