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Liver fibrosis is a pathological process caused by persistent chronic injury of the liver. Kupffer cells, natural killer (NK) cells, NKT cells, and dendritic cells (DCs), which are in close contact with T and B cells, serve to bridge innate and adaptive immunity in the liver. Meanwhile, an imbalanced inflammatory response constitutes a challenge in liver disease. The dichotomous roles of novel immune cells, including T helper 17 (Th17), regulatory T cells (Tregs), mucosa-associated invariant T cells (MAIT), and innate lymphoid cells (ILCs) in liver fibrosis have gradually been revealed. These cells not only induce damage during liver fibrosis but also promote tissue repair. Hence, immune cells have unique, and often opposing, roles during the various stages of fibrosis. Due to this heterogeneity, the treatment, or reversal of fibrosis through the target of immune cells have attracted much attention. Moreover, activation of hepatic stellate cells (HSCs) constitutes the core of fibrosis. This activation is regulated by various immune mediators, including Th17, Th22, and Th9, MAIT, ILCs, and γδ T cells, as well as their related cytokines. Thus, liver fibrosis results from the complex interaction of these immune mediators, thereby complicating the ability to elucidate the mechanisms of action elicited by each cell type. Future developments in biotechnology will certainly aid in this feat to inform the design of novel therapeutic targets. Therefore, the aim of this review was to summarize the role of specific immune cells in liver fibrosis, as well as biomarkers and treatment methods related to these cells.

Most herbal polyphenols and flavonoids reveals multiple ameliorative benefits for obesity caused by chronic metabolic disorders. Accumulated studies have revealed that preferable therapeutic effects can be obtained through clinical combination of these two kinds of natural compounds for obesity improvement. The typical representative research was the combination of quercetin and resveratrol (CQR), in which the ratio of quercetin and resveratrol is 2:1, demonstrating a synergistic effect in anti-obesity process. Although there exists reports clarifying the mechanism of the combination of two to improve obesity from the perspective of improving adipose tissue inflammation or modulating the composition of intestinal flora, there are few further studies on the mechanism of drug action from the perspective of metabolites transformation. In this research, we mainly focused on the alterations of endogenous metabolites in rats, and analyzed the urine metabolites of obese and intervention model. Therefore, a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach was applied to assess the potential effects and mechanisms of CQR at different dosages (45, 90, and 180 mg/kg) in high fat diet (HFD)-induced obesity rats. Body weight gain and visceral fat weight were reduced by CQR, as well as blood lipid and inflammatory factor levels were increased by CQR in a dose-related manner. Urinary metabolomics revealed 22 differential metabolites related to the HFD-induced obesity, which were reversed in a dose-dependent manner by CQR, of which 8 were reversed in the 45 mg/kg CQR group, 15 were reversed in the 90 mg/kg CQR group, and 18 were reversed in the 180 mg/kg CQR group. Combined with bioinformatics and pattern recognition, the results demonstrated that the key differential metabolites were basically involved in amino acid metabolism, galactose metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism and lysine degradation. In summary, our results showed significant therapeutic action by CQR administration and remarkable metabolomic changes after HFD feeding and CQR intervention. Urinary metabolomic analysis was highlighted on account of providing holistic and comprehensive insights into the pathophysiological mechanisms of the HFD-induced obesity, which also supplied clues for the future mechanism studies of CQR’s anti-obesity effects.

Chronic inflammatory pulmonary diseases are characterized by recurrent and persistent inflammation of the airways, commonly associated with poor clinical outcomes. Although their etiologies vary tremendously, airway neutrophilia is a common feature of these diseases. Neutrophils, as vital regulators linking innate and adaptive immune systems, are a double-edged sword in the immune response of the lung involving mechanisms such as phagocytosis, degranulation, neutrophil extracellular trap formation, exosome secretion, release of cytokines and chemokines, and autophagy. Although neutrophils serve as strong defenders against extracellular pathogens, neutrophils and their components can trigger various cascades leading to inflammation and fibrogenesis. Here, we review current studies to elucidate the versatile roles of neutrophils in chronic pulmonary inflammatory diseases and describe the common pathogenesis of these diseases. This may provide new insights into therapeutic strategies for chronic lung diseases.

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.

Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg−1·d−1) or atorvastatin calcium (AT, 10 mg kg−1·d−1) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic.

Introduction Virtual reality (VR) offers an innovative method to deliver non-pharmacological pain management. Distraction-based VR (VR-D) using immersive games to redirect attention has shown short-term pain reductions in various settings. To create lasting pain reduction, VR-based strategies must go beyond distraction. Guided relaxation-based VR (VR-GR) integrates pain-relieving mind–body based guided relaxation with VR, a novel therapy delivery mechanism. The primary aim of this study is to assess the impact of daily VR-GR, VR-D and 360 video (passive control) on pain intensity. We will also assess the impact of these interventions on pain unpleasantness, anxiety and opioid and benzodiazepine consumption. The secondary aim of this study will assess the impact of psychological factors (anxiety sensitivity and pain catastrophising) on pain following VR.Methods and analysis This is a single centre, prospective, randomised, clinical trial. Ninety children/adolescents, aged 8–18 years, presenting for Nuss repair of pectus excavatum will be randomised to 1 of 3 study arms (VR-GR, VR-D and 360 video). Patients will use the Starlight Xperience (Google Daydream) VR suite for 10 min. Patients randomised to VR-GR (n=30) will engage in guided relaxation/mindfulness with the Aurora application. Patients randomised to VR-D (n=30) will play 1 of 3 distraction-based games, and those randomised to the 360 video (n=30) will watch the Aurora application without audio instructions or sound. Primary outcome is pain intensity. Secondary outcomes include pain unpleasantness, anxiety and opioid and benzodiazepine consumption.Ethics and dissemination This study follows Standard Protocol Items: Recommendations for Interventional Trials guidelines. The protocol was approved by the Cincinnati Children’s Hospital Medical Center’s institutional review board. Patient recruitment began in July 2020. Written informed consent will be obtained for all participants. All information acquired will be disseminated via scientific meetings and published in peer-reviewed journals.Trial registration number NCT04351776.

Introduction: Poverty is negatively associated with health and developmental outcomes. DNA methylation (DNAm) has been proposed as a mechanism that underlies the association between adversity experienced by mothers in poverty and health and developmental outcomes in their offspring. Previous studies have identified associations between individual-level measures of stress and adversity experienced by a mother during pregnancy and infant DNAm. We hypothesized that independent of individual stresses, a mother's community-level deprivation while she is pregnant may also be associated with DNAm among the genes of her offspring that are related to stress response and/or development.Methods: Pregnant mothers (N = 53) completed assessments that measured stress, adversity, and mental health. To evaluate community-level deprivation, mothers' addresses were linked to census-level socioeconomic measures including a composite index of deprivation that combines multiple community-level indicators such as income and highest level of education received. Infant buccal cells were collected at about age 4 weeks to measure DNAm of candidate genes including NR3C1, SCG5, and SLC6A4, which are associated with the stress response and or social and emotional development. Multivariable models were employed to evaluate the association between maternal community deprivation and infant DNAm of candidate genes.Results: No significant associations were identified between maternal community-level deprivation and the methylation of NR3C1 or SCG5, however, maternal community-level deprivation was significantly associated with higher mean methylation across 8 CpG sites in SLC6A4.Conclusion: This study identified an association between community-level measures of deprivation experienced by a mother during pregnancy and DNAm in their offspring. These findings may have implications for understanding how the community context can impact early biology and potential function in the next generation.

Chinese herb Rhubarb (Dahuang), one of the most widely used traditional Chinese medicine in clinical application for over a thousand years and known as the “General (Jiang Jun)” in Chinese medical herb, currently used clinically for long-term treatment of gastrointestinal diseases and chronic liver diseases. Through previous researches, it has been identified that Rhubarb possessed a good hepatoprotective effect, which primarily protected liver from oxidation, fibrosis and cirrhosis, liver failure, hepatocellular carcinoma and various types of hepatitis. Meanwhile, it has been recently reported that long-term administration of Rhubarb preparation may undertake the risk of liver damage, which has aroused worldwide doubts about the safety of Rhubarb. Therefore, how to correctly understand the ''two-way'' effect of Rhubarb on liver protection and liver toxicity provides a basis for scientific evaluation of Rhubarb's efficacy on liver and side effects, as well as guiding clinical rational drug use. In this review, the mechanisms of Rhubarb how to play a role in hepatoprotection and why it causes hepatotoxic potential will be elaborated in detail and critically. In addition, some positive clinical guidances are also advised on how to reduce its hepatotoxicity in medical treatment.

Single event effect (SEE) induced mutual interference in CMOS circuits, including single event (SE) induced coupling effects (crosstalk) and modulation in local supply voltage on power-supply rails, was studied based on the increase in metal interconnect density. The dependence of SE vulnerability on metal interconnects was experimentally investigated using heavy ions and pulsed laser. Numerical simulation was performed to evaluate the modulation in local supply voltage induced by SEEs. Two groups of test structures with various metal interconnects between well contacts and the first metal layer were designed and fabricated. All other parts, including well contacts in the active regions, are of the same structures. Experimental results show that the upset cross section decreases with an increase in metal interconnect contact (CT) density between the active region and the first metal layer, suggesting a dominant contribution of rail voltage drop induced by charge sharing rather than SE-induced crosstalk. The differences in upset cross sections with cells of different CT hole densities appear the most evident ones under low frequency and high linear energy transfer value conditions. When transient-induced upsets play a more important role, the differences get weakened due to masking effects.

Alpinetin is a naturally occurring flavonoid from the ginger plants. We previously reported the identification of alpinetin as a ligand of human pregnane X receptor (hPXR). The current study investigated the role of alpinetin as a putative PXR activator in ameliorating chemically induced inflammatory bowel disease (IBD). We found that oral administration of alpinetin significantly alleviated the severity of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration, the levels of the pro-inflammatory mediators, and the PXR target genes in the colon. In vitro, alpinetin blocked the nuclear translocation of p-p65 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Further, alpinetin significantly upregulated PXR target genes and inhibited TNF-α-induced NF-κB-luciferase activity in LS174T colorectal cells; however, this regulatory effects were lost when cellular PXR gene was knocked down. In PXR transactivation assays, alpinetin increased both mouse and human PXR transactivation in a dose-dependent manner. Ligand occluding mutants, S247W/C284W and S247W/C284W/S208W, in hPXR-reporter assays, abrogated alpinetin-induced hPXR transactivation. Finally, alpinetin bound to the hPXR-ligand-binding domain (LBD) was confirmed by competitive ligand binding assay. The current study significantly extends prior observations by validating a PXR/NF-κB regulatory mechanism governing alpinetin’s anti-inflammatory effects in a murine model of IBD.

Acute pancreatitis (AP) is considered a cascade of immune responses triggered by acinar cell necrosis. AP involves two main processes of systemic inflammatory response syndrome and subsequent compensatory anti-inflammatory response syndrome. Although great efforts have been made regarding AP therapy, the mortality rate of AP remains high. Secondary infection acts a lethal factor in AP. Lymphocytes act as major immune mediators in immune responses in the course of this disease. However, the relationship between lymphocytes and secondary infection in AP is unclear. This review summarizes the variation of lymphocytes and infection in AP. Knowledge of the characterization of circulating lymphocyte abnormalities is relevant for understanding the pathophysiology of AP.

Serotonin, also known as 5-hydroxytryptamine (5-HT) is a signaling mediator that regulates emotion, behavior, and cognition. Previous studies have focused more on the roles of 5-HT in the central nervous system (CNS). However, 5-HT also shares a strong relationship with the pathological cases of tumor, inflammation, and pathogen infection. 5-HT participates in tumor cell migration, metastatic dissemination, and angiogenesis. In addition, 5-HT affects immune regulation via different 5-HT receptors (5-HTRs) expressed immune cells, including both innate and adaptive immune system. Recently, drugs targeting at 5-HT signaling were tested to be beneficial in mouse models and clinical trials of multiple sclerosis (MS) and inflammatory bowel disease (IBD). Thus, it is reasonable to assume that 5-HT participates in the pathogenesis of autoimmune diseases. However, the underlying mechanism by 5-HT modulates the development of autoimmune diseases has not been fully understood. Based on our previous studies and pertinent literature, we provide circumstantial evidence for an essential role of 5-HT, especially the regulation of 5-HT on immune cells in the pathogenesis of autoimmune diseases, which may provide a new point cut for the treatment of autoimmune diseases.

Combining freshwater consumption and wastewater emissions into a unified analysis framework and utilizing the epsilon-based measure (EBM) model with the characteristics of radial model and non-radial model, this paper evaluates green water use efficiency (GWUE) of 11 provincial-regions in the Yangtze River Economic Belt (YREB) and investigates its spatiotemporal differences during the period 2005-2014, on basis of which the contribution rate of each input-specific green water use inefficiency in the overall green water use efficiency and the potential of freshwater-saving and wastewater emissions reduction are also calculated. The Theil index is used to explore the sources of the provincial gap of green water use inefficiency, and a random-effect panel Tobit model is applied to test the impact of the influencing factors of green water use inefficiency in the YREB. It is found that green water use inefficiency of the YREB is relatively low and regional differences is significant during the sample period, indicating a large potential of water-saving and water pollution reduction, and narrowing BGAP and WGAP of the Upstream is the key for improving green water use inefficiency in the YREB. The panel Tobit regression results show that economic development, technological innovation, water use structure, water resources endowment, environmental regulation and regional differences all play positive/negative effects on green water use inefficiency in the YREB, while these factors' influencing direction, degree and significance are significantly different. The conclusions of our study can provide considerably valuable information for the YREB to reserve water resources and reduce wastewater emissions.

The Aedes aegypti mosquito plays an important role in the spread of diseases, including epidemic ones, such as dengue fever, Zika virus disease, yellow fever, and chikungunya disease. To control the population of Ae.aegypti, we transferred an HR3 RNAi fragment into the microalgae Chlamydomonas, which serves as food for Ae.aegypti larvae. Results showed that the HR3 RNAi transgenic algal strains were lethal to Ae.aegypti. The integumentary system of larvae fed with HR3 RNAi transgenic algal strains was severely damaged. Muscles of the larvae were unevenly distributed and disordered, and their midgut showed disintegration of the intestinal cavity. RNA-Seq results demonstrated that on the 4th day of inoculation with the transgenic algae, the abundance of early expressed genes in the 20E signal transduction pathway of larvae fed with the HR3 RNAi transgenic algal strain significantly reduced. These genes include E74, E75, E93, and 20E receptor complex EcR/USP and FTZ-F1 gene regulated by HR3. In later experiments, a scale test of 300 Ae.aegypti eggs per group was carried out for 30 days, and the survival rate of Ae.aegypti fed with the HR3 RNAi transgenic strain was only 1.3%. These results indicate that the HR3 RNAi transgenic strain exerts obvious insecticidal effect.

In practices, most industrial products are subject to sudden failure and only failure information can be collected, which presents a great challenge for reliability prediction of modern devices. To address this issue, our paper proposes a dynamic reliability estimation and control for industrial products under regular failure trials. The failure trial is performed at different operational time points of the products, which provides sole data source for evaluating the status of industrial products. We use Bayesian approach to dynamically estimate the industrial products when the failure trial is available. The estimated reliability is updated using a point estimate with new available data. To maintain the reliability of products at a desirable status, a reliability control method is presented to monitor the confidence interval of reliability distribution. The lower limit of confidence interval is maintained above a control limit, which indicates that a corresponding quality-assurance action is preferable. The proposed reliability estimation and control approach is demonstrated using a case of light-emitting diodes under failure trials at production process. The obtained results indicate the effectiveness of our estimation and control model.

Background/Aims: We sought to assess a consecutive number of patients with first-ever acute ischemic stroke (AIS), the clinical relevance in regard to functional outcome of the serum uric acid (SUA) measured at admission. Methods: In 2 prospective centers for observational study, serum concentrations of SUA were measured on admission in the serum of 710 consecutive patients with AIS. SUA concentrations were determined by high-performance liquid chromatography. SUA, NIH stroke scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome within 3 months. Results: During the follow-up, an unfavorable functional outcome (defined as a mRS score > 2) was found in 219 (30.8%) patients. The unfavorable functional outcome distribution across the SUA quartiles ranged between 12.4% (third quartile) and 50.6% (first quartile). After adjusting for all other significant outcome predictors, SUA concentration remained an independent unfavorable outcome predictor with an adjusted OR of 0.996 (95% CI, 0.993-0.998; P< 0.001). Conclusions: The data show that the U-shaped nature of the exposure-risk relationship was more prominent when the data were assessed in deciles (based on the SUA values). This model predicted the lowest relative risk of unfavorable outcome in the 67th percentile (corresponding to 309 µmol/L). SUA was significantly associated with the risk of poor functional outcomes in Chinese patients with stroke.

Abstract Background Childhood asthma is a syndrome composed of heterogeneous phenotypes; furthermore, intrinsic biologic variation among racial/ethnic populations suggests possible genetic ancestry variation in childhood asthma. The objective of the study is to identify clinically homogeneous asthma subphenotypes in a diverse sample of asthmatic children and to assess subphenotype-specific genetic ancestry in African-American asthmatic children. Methods A total of 1211 asthmatic children including 813 in the Childhood Asthma Management Program and 398 in the Childhood Asthma Research and Education program were studied. Unsupervised cluster analysis on clinical phenotypes was conducted to identify homogeneous subphenotypes. Subphenotype-specific genetic ancestry was estimated for 167 African-American asthmatic children. Genetic ancestry association with subphenotypes/clinical phenotypes were determined. Results Three distinct subphenotypes were identified: a moderate atopic dermatitis (AD) group with negative skin prick test (SPT) and preserved lung function; a high AD group with positive SPT and airway hyperresponsiveness; and a low AD group with positive SPT and lower lung function. African ancestry at asthma genome-wide association study (GWAS) SNPs differed between subphenotypes (64, 89, and 94% for the three subphenotypes, respectively) and was inversely correlated with AD; each additional 10% increase in African ancestry was associated with 1.5 fold higher in IgE and 6.3 higher odds of positive SPT (all p-values

This paper considers modal split in daily travel when there is a railroad parallel to a bottleneck-constrained road between home and a workplace. We examine the optimality and efficiency of different railroad fare and road toll (RFRT) schemes with the boundedly rational mode choice behavior of travelers. Under such behavior, commuters do not necessarily choose the mode of which the travel cost is absolutely lower than the mode of the other. A general definition of boundedly rational bi-modal equilibrium (BRBE) is presented. As the BRBE solution is not unique, the best-, worst- and average-case total travel costs under BRBE for a given RFRT scheme are proposed. The performance of each RFRT policy under different traveler levels of BR in mode choice behavior is also examined. The numerical results illustrate that system travel costs may be uncertain within the BRBE set, and the proposed RFRT schemes are able to address uncertainty due to the non-unique BRBE solution.

The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications. Bariatric surgical procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), currently provide the most effective treatment for obesity and type 2 diabetes (T2D), as well as for non-alcoholic steatohepatitis (NASH). However, the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive. Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery. This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5) in bariatric surgery. We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications. Keywords: Bile acid (BA), Bariatric surgery, Farnesoid X receptor (FXR), G protein-coupled bile acid receptor 5 (TGR5), Microbiota

Abstract Non-thermal atmospheric plasma (NTP) has shown its selective anticancer effects in many types of tumors in vitro and one of the main mechanisms is that the different increase of intracellular ROS in cancer and homologous normal cells. In this study, we report that NTP treatment reduces the proliferation in triple negative breast cancer (TNBC) and normal cell lines. Simultaneously, STAT3 pathway is inhibited by NTP effects. However, it is observed that normal cells MCF10A are more sensitive to ROS toxicity induced by NTP than cancer cells MDA-MB-231. When 5 mM of ROS inhibitor N-acetyl cysteine (NAC) is employed in NTP treatments, the proliferation of normal breast cells MCF10A recovers. Meanwhile, NTP effects remain significant inhibition of MDA-MB-231 cells. Our results further reveal that NTP can induce apoptosis in MDA-MB-231 cells through inhibiting interleukin-6 receptor (IL-6R) pathway. Moreover, the mechanism of NTP anti-cancer selectivity relates to constantly HER2/Akt activation induced by NTP especially in MCF10A cells but not in MDA-MB-231 cells. Therefore, these two different cell signaling pathways induced by NTP treatments in TNBC and homologous normal cells make NTP becoming a potential tool in future therapy.

Abstract To investigate the metabolic biomarkers of predicting the transition from pre-diabetes (pre-DM) to normal glucose regulation (NGR) and diabetes (DM) in a longitudinal cohort study. 108 participants with pre-DM were followed up for ten years and divided into 3 groups according to different glycemic outcomes. 20 participants progressed to DM, 20 regressed to NGR, and 68 remained at pre-DM. Alterations in plasma metabolites in these groups were evaluated by untargeted ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Twenty three metabolites related to glycerophospholipid metabolism, oxidation and antioxidation were associated with the process from pre-DM to NGR, while twenty two metabolites related to amino acid metabolism, glycerophospholipid metabolism and mitochondrial β-oxidation played important roles in the progression to DM. Results from stepwise logistic regression analysis showed that five biomarkers (20-Hydroxy-leukotriene E4, Lysopc(20:4), 5-methoxytryptamine, Endomorphin-1, Lysopc(20:3)) were good prediction for the restoration to NGR, and five biomarkers (Iso-valeraldehyde, linoleic acid, Lysopc(18:1), 2-Pyrroloylglycine, Dityrosine) for the development of DM. The findings suggest that the combination of these potential metabolites may be used for the prognosis of pre-DM. Targeting the pathways that involved in these prognostic biomarkers would be beneficial for the regression to NGR and the early prevention of DM among pre-DM.

Abstract Vertical sleeve gastrectomy (VSG) produces sustainable weight loss, remission of type 2 diabetes (T2D), and improvement of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the metabolic benefits of VSG have remained elusive. According to our previous results, diet-induced obesity induces epigenetic modifications to chromatin in mouse liver. We demonstrate here that VSG in C57BL/6J wild-type male mice can reverse these chromatin modifications and thereby impact the expression of key metabolic genes. Genes involved in lipid metabolism, especially omega-6 fatty acid metabolism, are up-regulated in livers of mice after VSG while genes in inflammatory pathways are down-regulated after VSG. Consistent with gene expression changes, regulatory regions near genes involved in inflammatory response displayed decreased chromatin accessibility after VSG. Our results indicate that VSG induces global regulatory changes that impact hepatic inflammatory and lipid metabolic pathways, providing new insight into the mechanisms underlying the beneficial metabolic effects induced by VSG.

Background: To investigate the effect of interleukin-6 (IL-6) gene polymorphism on pediatric pneumonia. Methods: Overall, 438 patients with pediatric pneumonia (Observation group) treated in Xuzhou Children Hospital, Cinna from July 2013 to July 2018 were randomly enrolled. Meanwhile, 423 healthy children (Control group) in the same time period were randomly selected. PCR was applied to amplify the IL-6-572 gene fragment. The IL-6-572 polymorphism was detected, and the impacts of gene polymorphism difference on pediatric pneumonia were observed. Results: There were differences in the IL-6 genotypes between the two groups (P

Background and Objective: Human papillomavirus (HPV) vaccination rates are suboptimal in young men, representing a missed opportunity to prevent cancers caused by HPV. Data about factors associated with vaccination over time are important to design interventions that improve vaccination rates. The aims of this study were to determine HPV vaccine initiation and completion rates in young men 13-26 years of age recruited from clinical and community settings from 2013-2014 and 2016-2017, and to determine factors associated with vaccination. Material and Methods: Men (N=747) were recruited from a hospital-based teen health center (THC), health department sexually transmitted disease clinic (HDSTD) and the general community. Participants completed a self-administered survey assessing demographic and behavioral factors. Vaccination status was determined using the electronic medical record and a statewide immunization registry. We determined vaccine initiation and completion rates, by recruitment site and year. We determined factors independently associated with vaccine initiation and completion, overall and stratified by recruitment year, using multivariable logistic regression. Results: Mean age was 21.2 years, 258 (34.5%) had initiated the vaccine series and 154 (20.8%) had completed it. Those recruited from the THC (vs. community and HDSTD) were more likely to initiate (71.3%, 23.2%, and 19.5%, respectively, p

The variation in childhood social-emotional development within at-risk populations may be attributed in part to epigenetic mechanisms such as DNA methylation (DNAm) that respond to environmental stressors. These mechanisms may partially underlie the degree of vulnerability (and resilience) to negative social-emotional development within adverse psychosocial environments. Extensive research supports an association between maternal adversity and offspring DNAm of the NR3C1 gene, which encodes the glucocorticoid receptor (GR). A gap in knowledge remains regarding the relationship between NR3C1 DNAm, measured in neonatal (1-month of age) buccal cells, and subsequent social-emotional development during infancy and early childhood. We conducted a longitudinal cohort study of n = 53 mother-child dyads (n = 30 with developmental outcomes formed the basis of current study) who were enrolled in a home visiting (HV) program. Higher mean DNAm of the NR3C1 exon 1F promoter was significantly associated with lower 6-month Ages and Stages Questionnaire: Social-Emotional (ASQ:SE) scores—more positive infant social-emotional functioning. A similar trend was observed at 18-months of age in a smaller sample (n = 12). The findings of this pilot study indicate that in a diverse and disadvantaged population, the level of neonatal NR3C1 DNAm is related to later social-emotional development. Limitations and implications for future research are discussed.

This paper proposes a condition-based maintenance strategy for multi-component systems under degradation failures. The maintenance decision is based on the minimum long-run average cost rate (LACR) and the maximum residual useful lifetime (RUL), respectively. The aim of this paper is to determine the optimal monitoring interval and critical level for multi-component systems under different optimization objectives. A preventive maintenance (PM) is triggered when the degradation of component exceeds the corresponding critical level. Afterwards, the paper discusses the relationship between the critical level and the monitoring interval with regards to the LACR and RUL. Methods are also proposed to determine the optimal monitoring interval and the critical level under two decision models. Finally, the impact of maintenance decision variables on the LACR and RUL is discussed through a case study. A comparison with conventional maintenance policy shows an outstanding performance of the new model.

Human papillomavirus (HPV) vaccination coverage in young men is suboptimal. The aims of this study were (a) to examine HPV vaccination and factors associated with HPV vaccination in men 13 to 26 years of age and (b) to examine and determine factors associated with accurate self-report of vaccination. Young men ( n = 400) recruited from a teen health center and a sexually transmitted disease (STD) clinic completed a survey. Accuracy was defined as correct report of at least one dose and number of doses. Mean age was 21.5 years, 104 (26.0%) received at least one vaccine dose and 49 (12.3%) received all three doses. Factors significantly associated with receipt of at least one dose in multivariable models included recruitment site (teen health center vs. STD clinic, adjusted odds ratio [AOR] = 2.75), public versus other insurance (AOR = 2.12), and age (AOR = 0.68). Most young men accurately reported their vaccination status but accuracy of report differed by age: 50.6% of 14- to 18-year-olds, 75.9% of 19- to 21-year-olds, and 93.2% of 22- to 26-year-olds. Most (293, 73.3%) accurately reported number of doses received. Age was associated with accuracy of self-report of at least one vaccine dose (AOR = 1.42), while recruitment site (STD vs. teen health center, AOR = 2.56) and age (AOR = 1.44) were associated with accuracy of self-report of number of vaccine doses. In conclusion, HPV initiation and completion in this study sample were low. Teen health center attendance, public insurance, and younger age were associated with vaccine initiation; older age and STD clinic setting were associated with accurate vaccination self-report.

Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia; its complications lead to disability and even death. Semen Cassiae is a traditional Chinese medicine, which has anti-hypertensive, anti-hyperlipidaemia, anti-oxidation, and anti-ageing properties. Our study was designed to evaluate the action of total anthraquinones of Semen Cassiae extract (SCE) on the improvement of glucose metabolism in diabetic rats and to elucidate the underlying mechanism. First, we evaluated the effect of SCE on normal rats. Next, we observed the effect of SCE using a rat model of diabetes, which was established by feeding rats with high-energy diet for 4 weeks and a single intraperitoneal injection of streptozotocin (STZ; 30 mg/kg) 3 weeks after starting the high-energy diet. Rats in different SCE groups (administered 54, 108, and 324 mg/kg/day of SCE) and metformin group (162 mg/kg/day, positive control drug) were treated with the corresponding drugs 1 week before starting high-energy diet and treatment continued for 5 weeks; meanwhile, rats in the control group were administered the same volume of sodium carboxymethyl cellulose solution (vehicle solution). One week after STZ injection, fasting blood glucose (FBG), oral glucose tolerance (OGT), fasting serum insulin (FSI) and serum lipids were quantified. Finally, the expression of proteins in the phosphatidylinositol-3-kinase (PI3K)–Akt–AS160–glucose transporter isoform 4 (GLUT4) signalling pathway was detected by western blotting. The data indicated that the levels of FBG and serum lipids were significantly lowered, and OGT and FSI were markedly increased in diabetic rats treated with SCE (108 mg/kg/day); however, SCE did not cause hypoglycaemia in normal rats. The molecular mechanisms were explored in the skeletal muscle. SCE markedly restored the decreased translocation of GLUT4 in diabetic rats. Moreover, the protein expressions of phosphorylated-AS160 (Thr642), phosphorylated-Akt (Ser473) and PI3K were significantly increased after SCE treatment in the skeletal muscle. These results indicate that SCE exerts an anti-hyperglycaemic effect by promoting GLUT4 translocation through the activation of the PI3K–Akt–AS160 signalling pathway. Our findings suggest that treatment with SCE, containing anthraquinones, could be an effective approach to enhance diabetes therapy.

Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.

Understanding where adolescents obtain information about human papillomavirus (HPV) vaccines may be helpful in designing public health interventions promoting HPV vaccination. This study assessed the following: (1) exposure to specific sources of information about HPV vaccines, (2) self-reported helpfulness of these sources of information, and (3) whether the specific source of information was associated with knowledge and perceptions about HPV vaccines among adolescent girls. There were 339 adolescent girls (mean age = 16.8 years) recruited into the study. Television advertisements, the Internet, doctors/nurses, and mothers were the most frequently reported sources of vaccine information; more than 90% of participants who received information from these sources reported they were helpful. Adolescents who received information about HPV vaccines from television advertisements, the Internet, clinicians, and mothers had higher knowledge about HPV vaccines and more positive perceptions. Assuring the accuracy of messages from these sources will be essential, given their importance in influencing adolescents’ knowledge and perceptions about HPV vaccines.

The aim of this article is to introduce a novel auction-based algorithm for grid computing wireless networks and resolve some incompetence with dynamic mechanisms. We develop a reverse online auction method to allocate grid resources, where the grid resource providers arrive dynamically and user broker has to make a multi-attribute decision whether to sell tasks or not before the end of current round. In our approach, a trade-some-with-forecast algorithm is proposed to help the user broker to utilize his forecast ability to allocate the grid resource in an online setting. Furthermore, two reverse online auction-based protocols are presented to demonstrate the resource scheduling in grid computing wireless networks. Experiments show that the reverse online auction-based with forecast protocol has better performance in comparison with the reverse online auction-based protocol. It is efficient in terms of auction stages, user satisfaction, and successful forecast.

Dialeurodes citri is a major pest in citrus producing areas, and large-scale outbreaks have occurred increasingly often in recent years. Lecanicillium attenuatum is an important entomopathogenic fungus that can parasitize and kill D. citri. We separated the fungus from corpses of D. citri larvae. However, the sound immune defense system of pests makes infection by an entomopathogenic fungus difficult. Here we used RNA sequencing technology (RNA-Seq) to build a transcriptome database for D. citri and performed digital gene expression profiling to screen genes that act in the immune defense of D. citri larvae infected with a pathogenic fungus. De novo assembly generated 84,733 unigenes with mean length of 772 nt. All unigenes were searched against GO, Nr, Swiss-Prot, COG, and KEGG databases and a total of 28,190 (33.3%) unigenes were annotated. We identified 129 immunity-related unigenes in transcriptome database that were related to pattern recognition receptors, information transduction factors and response factors. From the digital gene expression profile, we identified 441 unigenes that were differentially expressed in D. citri infected with L. attenuatum. Through calculated Log2Ratio values, we identified genes for which fold changes in expression were obvious, including cuticle protein, vitellogenin, cathepsin, prophenoloxidase, clip-domain serine protease, lysozyme, and others. Subsequent quantitative real-time polymerase chain reaction analysis verified the results. The identified genes may serve as target genes for microbial control of D. citri.

GPBAR1/TGR5 is a G protein-coupled receptor of bile acids. TGR5 is known to regulate the BA homeostasis and energy metabolism. Recent studies highlight an important role of TGR5 in alleviating obesity and improving glucose regulation, however, the mechanism of which is still unclear. Here we report that TGR5 is involved in mediating the anti-obesity and anti-hyperglycemia effect of a natural compound, oleanolic acid. By comparing the miRNA profiles between wild type and TGR5-/- livers after OA treatment, we identified miR-26a as a novel downstream target gene of TGR5 activation. The expression of miR-26a in the liver was induced in a TGR5-dependent manner after feeding the mice with a bile acid diet. TGR5 activation strongly increased the expression of miR-26a in macrophages, including the Kupffer cells in the liver. We further demonstrated that JNK pathway was required for miR-26a induction by TGR5 activation. Interestingly, we located the TGR5-responsive DNA element to a proximal region of miR-26's promoter, which was independent of the transcription of its host genes. These results unravel a new mechanism by which bile acid receptor TGR5 activates a miRNA gene expression.

Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures '89ADGES', including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the '89ADGES' discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P =

In this retrospective cohort study, we aimed to determine the incidence of intraoperative maternal hypotension during fetoscopic surgery for twin-twin transfusion syndrome (TTTS) and to evaluate the impact of intraoperative hypotension on fetal survival. A total of 328 TTTS patients with recipient twin cardiomyopathy who underwent fetoscopic surgery under epidural anesthesia were included. The exposure of interest was maternal medical therapy with nifedipine for the treatment of fetal cardiomyopathy. We found that intraoperative hypotension occurred in 53.4% (175/328 patients). There was no statistically significant difference in incidence of hypotension between nifedipine exposure and nonexposure groups (54.8% versus 50.8%, P=0.479). However, the nifedipine exposure group received a statistically significant higher dose of phenylephrine (7.04 ± 6.38 mcg/kg versus 4.70 ± 4.14 mcg/kg, P=0.018) and higher doses of other vasopressor, as counted by number of treatments (6.06 ± 4.58 versus 4.96 ± 3.42, P=0.022). There were no statistically significant differences in acute fetal survival rate (within 5 days) and fetal survival rate at birth between hypotensive and nonhypotensive patients. We concluded that preoperative exposure to nifedipine resulted in increased intraoperative maternal vasopressor requirement during fetoscopic surgery under epidural anesthesia. In patients who had intraoperative maternal hypotension, there was no correlation between the presence of maternal hypotension and postoperative fetal survival.

Several fenpropathrin-resistant predatory mites have been reported. However, the molecular mechanism of the resistance remains unknown. In the present study, the Neoseiulus barkeri (N. barkeri) transcriptome was generated using the Illumina sequencing platform, 34,211 unigenes were obtained, and 15,987 were manually annotated. After manual annotation, attentions were attracted to resistance-related genes, such as voltage-gated sodium channel (VGSC), cytochrome P450s (P450s), and glutathione S-transferases (GSTs). A polymorphism analysis detected two point mutations (E1233G and S1282G) in the linker region between VGSC domain II and III. In addition, 43 putative P450 genes and 10 putative GST genes were identified from the transcriptome. Among them, two P450 genes, NbCYP4EV2 and NbCYP4EZ1, and four GST genes, NbGSTd01, NbGSTd02, NbGSTd03 and NbGSTm03, were remarkably overexpressed 3.64–46.69-fold in the fenpropathrin resistant strain compared to that in the susceptible strain. These results suggest that fenpropathrin resistance in N. barkeri is a complex biological process involving many genetic changes and provide new insight into the N. barkeri resistance mechanism.

Objective: Whole-course nutrition management (WNM) has been proven to improve outcomes and reduce complications. We conducted this randomized controlled trial to validate its effectiveness in patients undergoing pancreatoduodenectomy (PD). Methods: From 1 December 2020, to 30 November 2023, this single-center randomized clinical trial was conducted at the Department of Hepatobiliopancreatic Surgery in a major hospital in Beijing, China. Participants who were undergoing PD were enrolled and randomly allocated to either the WNM group or the control group. The primary outcome was the incidence of postoperative complications. Subgroup analysis in patients who were at nutritional risk was performed. Finally, a 6-month follow-up was conducted and the economic benefit was evaluated using an incremental cost-effectiveness ratio (ICER). Results: A total of 84 patients were randomly assigned (1:1) into the WNM group and the control group. The incidences of total complications (47.6% vs. 69.0%, P= 0.046), total infections (14.3% vs. 33.3%, P=0.040), and abdominal infection (11.9% vs. 31.0%, P= 0.033) were significantly lower in the WNM group. In the subgroup analysis of patients at nutritional risk, 66 cases were included (35 cases in the WNM group and 31 cases in the control group). The rate of abdominal infection (11.4% vs. 32.3%, P =0.039) and postoperative length of stay (23.1 ± 10.3 vs. 30.4 ± 17.2, P=0.046) were statistically different between the two subgroups. In the 6-month follow-up, more patients reached the energy target in the WNM group (97.0% vs. 79.4%, P=0.049) and got a higher daily energy intake (1761.3 ± 339.5 vs. 1599.6 ± 321.5, P=0.045). The ICER suggested that WNM saved 31 511 Chinese Yuan (CNY) while reducing the rate of total infections by 1% in the intention-to-treat (ITT) population and saved 117 490 CNY in patients at nutritional risk, while WNM saved 31 511 CNY while reducing the rate of abdominal infections by 1% in the ITT population and saved 101 359 CNY in patients at nutritional risk. Conclusion: In this trial, whole-course nutrition management was associated with fewer total postoperative complications, total and abdominal infections, and was cost-effective, especially in patients at nutritional risk. It seems to be a favorable strategy for patients undergoing PD. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the effect of continuing care based on WeChat platform and MDT (multidisciplinary team) on outcomes and negative emotions in young and middle-aged patients with stroke sequelae. Methods: A retrospective study was conducted on clinical data of 109 young patients with post-stroke sequelae in our hospital. Based on the nursing approach, the patients were divided into two groups. Group A received conventional continued care (including reinforcing health education upon discharge, providing relevant precautions after discharge, regular follow-up of patients, and others), while Group B received continued care based on the WeChat platform and multidisciplinary team (MDT) collaboration. A comparative analysis was performed on NHISS (National Institutes of Health Stroke Scale) scores, Barthel Index (activities of daily living), FMA (Fugl-Meyer Assessment of Motor Recovery after Stroke) scores, disease awareness and attitude scores, selfefficacy scores, self-care ability scores, SAS (Self-Rating Anxiety Scale) scores, SDS (Self-Rating Depression Scale) scores, quality of life scores, and social support levels before intervention and 6 months after interventions in both groups. Results: Compared with Group A, Group B had lower NHISS scores (30.08 vs. 17.08) and higher Barthel Index (73.35 vs. 94.48) and FMA scores (68.06 vs. 90.08) (P<0.05); higher disease awareness scores (40.18±2.15 vs. 48.96±3.66) (P<0.05), higher self-efficacy scores (105.56 vs. 119.26) and self-care scores (98.18 vs. 110.06) (P<0.05), lower SAS scores (56.06 vs. 40.06) (P<0.05), higher quality of life (125.63±3.12 vs. 185.12±2.52) as well as higher nursing satisfaction scores (56.63±3.16 vs. 92.15±3.15) (P<0.05). Conclusions: Continuing care based on the WeChat platform and MDT is beneficial to promote the recovery of neurological and physical functions, improve abilities of daily living, self-efficacy, selfcare and quality of life in young and middle-aged patients with stroke sequelae, and relieve the impact of negative emotions on the recovery. [ABSTRACT FROM AUTHOR]