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What are the potential clinical benefits of embryo culture and assessment in a time-lapse incubator compared with a standard incubator using static assessment?This large multicentre, single-blinded, randomized controlled study included 1224 participants randomly assigned (1:1) to the time-lapse or standard incubator group. In all patients one or two embryos were transferred on day 3. The primary outcome was the implantation rate in the first embryo transfer cycle. Secondary outcomes included the cumulative implantation rate, live birth rate in the first embryo transfer cycle and cumulative live birth rate.Among 1224 participants recruited, 1182 underwent embryo transfer. The number of successfully implanted embryos in the first transfer cycle was significantly higher in the time-lapse incubator group (time-lapse group: 52.35%, standard incubator group: 47.11%, P = 0.014). The implantation rate in the first embryo transfer cycle was still significantly higher in the time-lapse group than the standard incubator group after adjusting for age, body mass index, medical centre and embryo status (relative risk 1.11, 95% confidence interval 1.02-1.20, P = 0.020). However, the cumulative implantation rate, live birth rate in the first embryo transfer cycle and cumulative live birth rate were not statistically different between the groups.The implantation rate in the first embryo transfer cycle was significantly improved in the time-lapse group, but the effect of the time-lapse system on the cumulative implantation rate or cumulative live birth rate was not significant. The embryo assessment method offered by time-lapse systems rather than an undisturbed environment may play an important role in improving the implantation rate in the first embryo transfer cycle. These results are only applicable to young patients.

To investigate how the National Health Commission of China (NHCC)-recommended Chinese medicines (CMs) modulate the major maladjustments of coronavirus disease 2019 (COVID-19), particularly the clinically observed complications and comorbidities.By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology (hyperinflammations, viral replication), complications (pain, headache) and comorbidities (hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database. The experimentally-determined targets and the activity values of the chemical ingredients of these CMs were from the Natural Product Activity and Species Source Database. The approved and clinical trial drugs against these targets were searched from the Therapeutic Target Database and DrugBank Database. Pathways of the targets was obtained from Kyoto Encyclopedia of Genes and Genomes and additional literature search.Overall, 9 CMs modulated 6 targets discovered by the COVID-19 target discovery studies, 8 and 11 CMs modulated 8 and 6 targets of the approved or clinical trial drugs for the treatment of the major COVID-19 complications and comorbidities, respectively.The coordinated actions of each NHCC-recommended CM against a few targets of the major COVID-19 pathophysiology, complications and comorbidities, partly have common mechanisms with the conventional medicines.

Prenatal exposure to ambient air pollution has been associated with adverse perinatal outcomes in previous studies. However, few studies have examined the interaction between air pollution and the season of conception on term low birth weight (TLBW) or macrosomia. Birth registry data of singleton live births in Wenzhou, China, between January 2015 and December 2016 were accessed from the Wenzhou Maternal and Child Health Information Management platform, and data on the ambient air pollutants in Wenzhou were obtained from the Chinese Air Quality Online Monitoring and Analysis Platform. Single-/two-pollutant binary logistic regression models were used to assess the associations between ambient air pollutants (PM

It is emerging that autophagy-related proteins regulate the adaptive response to DNA damage in maintaining genome stability at multiple pathways. Here, we discuss recent insights into how autophagy-related proteins participate in DNA damage repair processes, influence chromosomal instability, and regulate the cell cycle through autophagy-dependent and independent actions. There is increasing awareness of the importance of these pathways mediated by autophagy-related proteins to DNA damage response (DDR), and disturbances in these regulatory connections may be linked to genomic instability participated in various human diseases, such as cancer and aging.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare endocrine disease characterized by gonadal dysplasia. According to whether the sense of smell is affected, this disorder is classified into Kallmann syndrome (KS) and normosmic isolated hypogonadotropic hypogonadism (nIHH). In this study, we reported a case of nIHH patient and explored the pathogenic mechanism of FGFR1 in nIHH. A FGFR1 variant (c.2008GA, p.E670K) and a CEP290 variant (c.964GA, p.D322N) were detected by the whole exome sequencing in this nIHH patient. Bioinformatic analysis revealed that this FGFR1 variant (c.2008GA) causes structural perturbations in TK2 domain demonstrating that this variant result in FGFR1 loss-of-function and abnormal signaling. The identification of an additional CEP290 variant (c.964GA) indicated that CEP290 might play a potential role in developmental abnormalities and inhibition of GnRH neuron release. A protein interaction network analysis showed that CEP290 was predicted to interact with FGFR1. In summary, our study identified the potential pathogenic mechanism(s) of the novel FGFR1 variant and indicated that CEP290 might play a role in the GnRH neuron migration route. Our findings expand the mutation spectrum of FGFR1 and CEP290 and provide a reference for clinical diagnosis and treatment of IHH.特发性低促性腺激素性性腺功能减退症(idiopathic hypogonadotropic hypogonadism, IHH)是由于促性腺激素释放激素(gonadotropin-releasing hormone, GnRH)缺乏或作用缺陷引起以性腺发育不良为特征的内分泌罕见病。依据是否并发嗅觉障碍可以分为嗅觉正常特发性低促性腺激素性性腺功能减退症(normosmic isolated hypogonadotropic hypogonadism, nIHH)和嗅觉障碍的卡尔曼综合征(Kallmann syndrome, KS)。本研究收集并分析了1例nIHH散发病例的临床资料。全外显子测序证实患儿同时携带FGFR1基因变异(c.2008GA, p.E670K)和遗传于其母亲的CEP290基因变异(c.964GA, p.D322N)。生物信息学分析发现FGFR1基因突变(c.2008GA)改变FGFR1蛋白TK2结构域,影响FGFR1受体的功能及下游细胞信号转导通路的激活。CEP290基因(c.964GA)可能影响GnRH神经元的正确迁徙途径导致IHH,CEP290蛋白与FGFR1蛋白之间存在相互作用。本研究结果扩展了IHH致病基因表达谱,为探究IHH的致病机制提供了新的方向,并为该类疾病的临床精准诊疗提供了借鉴和参考。.

Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.

Background The COVID-19 pandemic and relevant prevention and control measures may affect the mental health and induce depressive symptoms in fathers with concurrent partner delivery exposure. This study aims to investigate the prevalence of depression in fathers with simultaneous exposure to COVID-19 pandemic and the effects of family functions on paternal perinatal depression (PPD) risk. Methods A cross-sectional study was conducted among the perinatal fathers recruited in a large tertiary hospital in Wuhan across the whole pandemic period from 31 December 2019 to 11 April 2020. Edinburgh Postnatal Depression Scale (EPDS) and APGAR family function scale were used to evaluate PPD and family function, respectively. Chi-square test and multivariable-adjusted logistic regression model were applied for data analysis. Results Among the 1187 participants, the prevalence of PPD was 13.82% throughout the COVID-19 pandemic. Compared with that in the time period before the announcement of human-to-human transmission on 19 January 2020, the depression risk was significantly lower during the traffic restriction (OR = 0.54, 95% CI: 0.34, 0.86) and public transportation reopening periods (OR = 0.29, 95% CI: 0.14, 0.59). Poor/fair family functions was associated with elevated depression risk (OR = 2.93, 95% CI: 1.90, 4.52). Individuals reporting a low family income and smoking had high depression risks. Conclusions A declined risk of PPD was observed over the traffic restriction period of the COVID-19 pandemic. An improved family function may help alleviate the risk of PPD during the pandemic. Health authorities are recommended to formulate targeted prevention and control strategies to handle PPD.

Background The placental barrier protects the fetus from exposure to some toxicants and is vital for drug development and risk assessment of environmental chemicals. However, in vivo experiments for assessing the placental barrier permeability of chemicals is not ethically acceptable. Although ex vivo placental perfusion methods provide good alternatives for the assessment of placental barrier permeability, the application to a large number of test chemicals could be time- and resource-consuming. Computational prediction models for ex vivo placental barrier permeability are therefore desirable. Methods A total of 87 chemicals and corresponding 1444 physicochemical properties were divided into training and test datasets. Three types of algorithms including linear regression, random forest, and ensemble models were applied to develop prediction models for ex vivo placental barrier permeability. Results Among the tested models, the ensemble model integrating the previous two methods performed best for predicting ex vivo human placental barrier permeability with correlation coefficients of 0.887 and 0.825 when considering the applicability domain. An additional test on seven newly curated chemicals from the literature showed a good correlation coefficient of 0.879 which was further improved to 0.921 by considering the variation of experiments. Conclusion In this study, the first valid predicting model for ex vivo human placental barrier permeability was developed following the OECD guideline. The model is expected to be useful for assessing the human placental barrier permeability and can be integrated with developmental toxicity prediction models for investigating the toxic effects of chemicals on the fetus.

Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving individualized treatment of epilepsy. A sensitive, accurate and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of 15 antiseizure medications in human plasma (carbamazepine, gabapentin, pregabalin, phenytoin, zonisamide, oxcarbazepine, tiagabine, lamotrigine, topiramate, phenobarbital, lacosamide, primidone, 10,11-Dihydro-10-hydroxy carbamazepine, ethosuximide, and levetiracetam). The sample preparation procedure was an one-step protein precipitation with methanol. Mass detection was performed in ionization polarity switching mode (positive-negative-positive) using multiple reaction monitoring mode. A "boot-shaped" gradient elution program was applied to separate and concentrate those target analytes, resulting in symmetrical peak shapes within 10 min, without endogenous interference. The method showed great linearity over the concentration ranges with acceptable correlation coefficients (0.9966-0.9996). The precision and accuracy values for intra- and inter-assays were within ±15%. Consequently, the method was successfully implemented on pediatric patients undergoing mono- or polytherapy for epilepsy and provided timely concentration results to ordering clinicians.

Background GnRHa treatment was established for improving final adult height (FAH) in children presenting with Idiopathic central precocious puberty (ICPP) up to age 8, while several controversies remained for older age groups. The primary objective was to evaluate whether boys diagnosed with ICPP over 9 years of chronological age (CA) could achieve a height benefit from GnRHa treatment. Methods We retrospectively evaluated the medical records of 23 boys treated for idiopathic central precocious puberty between January 2018 and January 2021 at Jiangsu Children’s Medical Center. All patients started treatment with intramuscular depot GnRHa at a dose of 80–100 μg/kg, followed by continuous intramuscular injection every 28 days at a dose of 60–80 μg/kg. The hormonal parameters, bone age/chronological age ratio, FAH, growth velocity (GV), tanner staging and body mass index (BMI) were assessed during the treatment period. Results After one course of treatment (3 months), the basal FSH and testosterone levels were reduced, while the basal LH value was not significantly changed compared with those before treatment. Furthermore, the mean BA/CA ratio reduction was statistically significant at month 12. The mean PAH following administration of GnRHa after 12 months was statistically improved compared with those at baseline. In addition, the clinical sign of puberty and GV were significantly improved and the BMI remained unchanged as desired at month 12. Conclusions This analysis highlighted the positive outcome on the decrease in the rate of bone maturation, with a favorable effect on progression of clinical signs of puberty. Furthermore, our study confirmed PAH was improved even in the older children at onset of treatment (ages 9–10), emphasizing the importance of personalized treatment in such population.

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

Background Currently, there is no cure for Alzheimer’s disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown. Methods The senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses. Results The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1–40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain. Conclusions Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

To explore Chinese late-life immigrants' perceptions of loneliness and social isolation.A qualitative descriptive methodology underpinned this study. In-depth individual interviews were conducted in Mandarin with purposively recruited participants. The twenty-three participants in the study had all emigrated from China, were 65-80 years old on arrival and had lived in New Zealand for between 2.5 and 16 years. An inductive thematic analytic process was undertaken. The COREQ checklist was followed to ensure study rigour.Three themes, 'high value placed on meeting family obligations', 'feeling a deep sense of imbalanced intergenerational reciprocity' and 'moving away from filial expectations', were identified. Confucianist values of 'women's domestic duty of caring for grandchildren', 'filial piety', and 'saving face' to be accepted and respected by others negatively attributed to participants' understandings and experiences of loneliness. To plan for increasing frailty and to avoid family conflict while ameliorating potential loneliness, some participants reluctantly discarded prior customary filial piety expectations in favour of formal aged care options.Participants' profound sense of loneliness was seen to be attributed to their deeply rooted cultural values and backgrounds from having lived for a significant period of time in China. Loneliness occurred as a result of the resettlement process in later life. These experiences highlight the importance of using cultural framing that takes into account beliefs and adaptations to host societies anticipated during the process of late-life immigration.

Background The current surveillance system only focuses on notifiable infectious diseases in China. The arrival of the big-data era provides us a chance to elaborate on the full spectrum of infectious diseases. Methods In this population-based observational study, we used multiple health-related data extracted from the Shandong Multi-Center Healthcare Big Data Platform from January 2013 to June 2017 to estimate the incidence density and describe the epidemiological characteristics and dynamics of various infectious diseases in a population of 3,987,573 individuals in Shandong province, China. Results In total, 106,289 cases of 130 infectious diseases were diagnosed among the population, with an incidence density (ID) of 694.86 per 100,000 person-years. Besides 73,801 cases of 35 notifiable infectious diseases, 32,488 cases of 95 non-notifiable infectious diseases were identified. The overall ID continuously increased from 364.81 per 100,000 person-years in 2013 to 1071.80 per 100,000 person-years in 2017 (χ2 test for trend, P P Conclusions Infectious diseases remain a substantial public health problem, and non-notifiable diseases should not be neglected. Multi-source-based big data are beneficial to better understand the profile and dynamics of infectious diseases.

To evaluate the clinical therapeutic effect of electroacupuncture (EA) atThe data of 318 patients undergoing anal fistula surgery were analyzed retrospectively. In accordance with whether accepted the combined treatment with EA at bilateralFor VAS score, there was an interaction between therapeutic method and treatment duration (Electroacupuncture at

Background:Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment.Methods:We searched PubMed for citations published in English using the terms “methotrexate”, “transporter”, “acute lymphoblastic leukemia”, “polymorphisms”, and “therapeutic drug monitoring”. The retrieval papers were critically reviewed and summarized according to the aims of this mini-review.Results:Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied.Conclusion:Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.

The active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid–liquid phase separation, a mechanism for the formation of membrane-less subcellular compartments. Here, we show that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation in transfected HEK293T cells. Condensate formation is triggered by Liprin-α3 PKC-phosphorylation at serine-760, and RIM and Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies establish phosphorylation of Liprin-α3 serine-760 in transfected cells and mouse brain tissue. In primary hippocampal neurons of newly generated Liprin-α2/α3 double knockout mice, synaptic levels of RIM and Munc13 are reduced and the pool of releasable vesicles is decreased. Re-expression of Liprin-α3 restored these presynaptic defects, while mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented this rescue. Finally, PKC activation in these neurons acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. Our findings indicate that PKC-mediated phosphorylation of Liprin-α3 triggers its phase separation and modulates active zone structure and function., Liquid–liquid phase separation may be a mechanism for organizing the presynaptic nerve terminal. Here, the authors show that PKC-mediated phosphorylation of Liprin-α3 triggers phase separation in cell lines and modulates active zone structure and function in primary hippocampal neurons.

This study investigated the effects and mechanisms of miR-132 related to the permeability and mobility of human retinal pigment epithelium ARPE-19 cells in high-glucose (HG) condition. ARPE-19 cells were cultured in normal and HG condition and identified by immunofluorescence staining. Cell viability was assessed by the MTT assay, cell permeability was assessed by the FITC-dextran assay and cell mobility was assessed by the wound healing assay. Different miRNA and mRNA expression levels were determined by quantitative real-time polymerase chain reaction (RT-qPCR). The expression of tight junction-related proteins was determined by Western blot assay and immunofluorescence. The interaction between occludin and miR-132 was confirmed by a dual-luciferase reporter assay. We revealed that HG-treated ARPE-19 cells exhibited significantly increased miR-132 expression, decreased expression of the tight-junction markers including occludin and E-cadherin, and increased cell mobility and permeability. Occludin is a direct target of miR-132, which could regulate cell viability, mobility and permeability under HG condition through the JAK/STAT3 signaling pathway. These are the first data to suggest that miR-132 may contribute to the progression of diabetic retinopathy (DR) and that targeting the effect of miR-132 on occudin and the JAK/STAT3 pathway could represent a novel effective DR-treatment strategy.

To observe the clinical effect of acupuncture at lower-A total of 123 IBS-D patients with syndrome of liver depression and spleen deficiency were randomly divided into an acupuncture+TXYF group, a TXYF group and a medication group, 41 cases in each group. The patients in TXYF group were treated with oral administration of TXYF, three times a day. The patients in acupuncture+TXYF group were treated with oral administration of TXYF and routine acupuncture at Shangjuxu (ST 37), Tianshu (ST 25), Taichong (LR 3), Sanyinjiao (SP 6) and Zusanli (ST 36), once a day. The patients in medication group were treated with oral administration of pinaverium bromide, 50 mg, three times a day. All the treatment was given for four weeks. The total score of TCM syndrome scale, self-rating anxiety scale (SAS), self-rating depression scale (SDS) scores as well as the expression of calcitonin gene-related peptide (CGRP), vasoactive peptide (VIP) and MAPK signal pathway indicators of ERK1 mRNA and ERK2 mRNA were compared before and after treatment; the clinical effect was also compared.After treatment, the total score of TCM syndrome scale and SAS and SDS scores in each group were significantly reduced (The acupuncture at lower

Vascular calcification refers to the pathological deposition of calcium and phosphate minerals into the vasculature. It is prevalent in atherosclerosis, ageing, type 2 diabetes mellitus and chronic kidney disease, thus, increasing morbidity and mortality from these conditions. Vascular calcification shares similar mechanisms with bone mineralization, with smooth muscle cells playing a critical role in both processes. In the last decade, a variety of microRNAs have been identified as key regulators for the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition in vascular smooth muscle cells during vascular calcification. Therefore, this review mainly discusses the roles of microRNAs in the pathophysiological mechanisms of vascular calcification in smooth muscle cells and describes several interventions against vascular calcification by regulating microRNAs. As the exact mechanisms of calcification remain not fully elucidated, having a better understanding of microRNA involvement in vascular calcification may give impetus to development of novel therapeutics for the control and treatment of vascular calcification.

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2(−/−) mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.

Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain cancer. The disease is essentially incurable, with glioblastomas characterized by resistance to both chemotherapy and radiotherapy, as well as by rapid tumor progression, all of which are mainly ascribed to glioma stem-like cells (GSLCs). In the present study, an improved model that is more similar to clinical GBM was constructed. Twenty clinical glioma samples were collected to obtain primary low-grade tumor cells. The cells were either maintained in serum-free medium as primary glioma-based cells (PGBCs) or cultured in the same medium with CHIR99021 as GSLCs. Then, the molecular and ultrastructural differences between the two cell groups were determined. Furthermore, the proliferation and migration of the GSLCs were examined and the potential mechanisms were investigated. Finally, temozolomide resistance in vitro and in the mouse model was assessed to study the properties of the induced GSLCs. The primary low-grade tumor cells extracted from surgical samples were enriched with GSLC properties, with high expression levels of CD133 and Nestin in 100 nM CHIR99021. The GSLCs exhibited high proliferation and migration. Furthermore, the expression of the PI3K/AKT signaling pathway and that of related genes and proteins were significantly enhanced by CHIR99021. The animal study also revealed high levels of STAT3, mTOR, NF-κB, and VEGF in the GSLC-transplanted mice. CHIR99021 could stably enhance GSLC properties in patient-derived glioma samples. It may provide a useful model for further study, helping to understand the pathogenesis of therapeutic resistance and to screen drug candidates.

Background The function of miR-20a-5p in pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanism remains largely unknown. Methods C57BL/6J mice and PASMCs were used for constructing pulmonary artery hypertension (PAH) animal and cell models, respectively. Reverse transcription polymerase chain reaction (RT-PCR) was employed to detect miR-20a-5p and ATP-binding cassette subfamily A member 1 (ABCA1) messenger RNA expression. CCK-8, Transwell, and TUNEL experiments were used to determine PASMCs proliferation, migration, and apoptosis. The relationship between miR-20a-5p and ABCA1 was detected by luciferase reporter experiment, Western blot analysis, and qRT-PCR. Results miR-20a-5p was remarkably elevated in PASMCs of PAH mice and human PASMCs treated by hypoxia, while ABCA1 was remarkably decreased. After transfection of miR-20a-5p mimics, PASMCs proliferation and migration were promoted and PASMCs apoptosis was suppressed. ABCA1 was confirmed to be a target of miR-20a-5p and restoration of ABCA1 reversed the function of miR-20a-5p. Conclusion miR-20a-5p enhances the proliferation and migration of PASMCs to promote the development of PAH via targeting ABCA1.

To compare the perioperative outcomes and hemodynamic effects at induction of general laryngeal mask airway (LMA) anesthesia with lumbar plexus-sciatic nerve block (LPSB) and general anesthesia with endotracheal intubation (ET) in elderly patients undergoing hip surgery.A total of 63 patients having open reduction internal fixation of an intertrochanteric fracture were randomly assigned to receive LMA anesthesia with LPSB or general anesthesia with ET. Perioperative and postoperative outcomes were compared between the 2 groups.Compared with the LMA/block group, there were significant reductions in systolic blood pressure, diastolic blood pressure, and mean arterial pressure at induction in the general endotracheal group (all, P 0.001). In the general ET group, 84% of the patients experienced at least one episode of significant hypotension, whereas no patient in the LMA/block group had significant hypotension (P 0.001). There were no changes in cardiac output, cardiac index, stroke volume, and stroke volume index of the LMA/block group, whereas significant changes were noted in the general anesthesia ET group. Significantly fewer complications were noted in the LMA/block group, and LMA block was associated with shorter weaning time, fewer returns to the intensive care unit, and less postoperative pain.General LMA anesthesia with LPSB provides better outcomes that general ET anesthesia in elderly patients undergoing hip surgery.

Peripheral nerve injury is a complex biological process that involves the expression changes of various coding and non-coding RNAs. Previously, a number of novel miRNAs that were dysregulated in rat sciatic nerve stumps after peripheral nerve injury were identified and functionally annotated by Solexa sequencing. In the current study, we studied one of these identified novel miRNAs, miR-3075, in depth. Results of transwell-based cell migration assay showed that increased expression of miR-3075 suppressed the migration rate of Schwann cells while decreased expression of miR-3075 elevated the migration rate of Schwann cells, demonstrating that miR-3075 inhibited Schwann cell migration. Results of BrdU cell proliferation assay showed that neither miR-3075 mimic nor miR-3075 inhibitor would affect Schwann cell proliferation. We further studied candidate target genes of miR-3075 by using bioinformatic tools and analyzing gene expression patterns and found that miR-3075 might target contactin 2 (Cntn2). Previous study showed that Cntn2 regulated cell migration and myelination. Our current observation suggested that the biological effects of miR-3075 on Schwann cell phenotype might by through the negative regulation of Cntn2. Overall, our study revealed the function of a novel miRNA, miR-3075, and expanded our current understanding of the molecular mechanisms underlying peripheral nerve injury and regeneration.

The prevalence of cardiovascular disease (CVD) is higher in patients with schizophrenia than in the general population. We aimed to investigate whether atypical antipsychotics (AAP) increase the levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), thereby increasing the risk of CVD. The data were from inpatients aged 18-60 years with a diagnosis of schizophrenia according to ICD-10 at the Affiliated Brain Hospital of Nanjing Medical University who underwent physical examination between 1 October 2014 and 30 September 2016. A retrospective cohort study was used to analyse the correlation between AAP, Lp-PLA2 levels and the CVD risk (it was determined that Lp-PLA2 values >200 ng/mL were defined as high CVD risk) in patients treated with monotherapy, olanzapine, clozapine or quetiapine. Data were collected for 452 patients with eligible schizophrenia: 163 treated with clozapine, 186 treated with olanzapine, 47 treated with quetiapine and 56 receiving no medication. Compared with the no-medication patients, AAP administration in patients with olanzapine, clozapine or quetiapine had higher serum Lp-PLA2 levels when age, sex, BMI and fasting glucose level were matched. AAP were significantly associated with serum Lp-PLA2 level by Spearman's correlation coefficients. The results of logistic regression analysis showed that AAP administration was an independent factor of CVD risk when adjusted by potential confounding factors. This study is the first to confirm that AAP administration, especially clozapine and olanzapine, could increase Lp-PLA2 levels and CVD risk, independent of drug-induced weight gain in schizophrenia. The extent and the factors of increasing Lp-PLA2 level and CVD risk in olanzapine, clozapine and quetiapine are discrepant. The possible effects of AAP on Lp-PLA2 in schizophrenia patients are involved in pro-inflammatory cytokines and hormones.

Objective Clinical decision making in children with congenital and acquired heart disease relies on measurements of cardiac structures using two-dimensional echocardiography. We aimed to establish z-score regression equations for right heart structures in healthy Chinese Han children. Methods Two-dimensional and M-mode echocardiography was performed in 515 patients. We measured the dimensions of the pulmonary valve annulus (PVA), main pulmonary artery (MPA), left pulmonary artery (LPA), right pulmonary artery (RPA), right ventricular outflow tract at end-diastole (RVOTd) and at end-systole (RVOTs), tricuspid valve annulus (TVA), right ventricular inflow tract at end-diastole (RVIDd) and at end-systole (RVIDs), and right atrium (RA). Regression analyses were conducted to relate the measurements of right heart structures to 4body surface area (BSA). Right ventricular outflow-tract fractional shortening (RVOTFS) was also calculated. Several models were used, and the best model was chosen to establish a z-score calculator. Results PVA, MPA, LPA, RPA, RVOTd, RVOTs, TVA, RVIDd, RVIDs, and RA (R2 = 0.786, 0.705, 0.728, 0.701, 0.706, 0.824, 0.804, 0.663, 0.626, and 0.793, respectively) had a cubic polynomial relationship with BSA; specifically, measurement (M) = β0 + β1 × BSA + β2 × BSA2 + β3 × BSA.3 RVOTFS (0.28 ± 0.02) fell within a narrow range (0.12–0.51). Conclusions Our results provide reference values for z scores and regression equations for right heart structures in Han Chinese children. These data may help interpreting the routine clinical measurement of right heart structures in children with congenital or acquired heart disease. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound, 2017

Background Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury. Objective The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD). Methods APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice. Results Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice. Conclusion MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression.

Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.

Nanochannel/nanopre based analysis methods have attracted increasing interest in recent years due to their exquisite ability to reveal changes in molecular volume. In this work, a highly asymmetric nanochannel–ionchannel hybrid coupled with an electrochemical technique was developed for copper ion (Cu2+) detection. Polyglutamic acid (PGA) was modified in a nanochannel array of porous anodic alumina (PAA). When different concentrations of Cu2+ were introduced into the nanochannel–ionchannel hybrid in a neutral environment, a Cu2+–PGA chelation reaction occurs, resulting in varied current–potential (I–V) properties of the nanochannel–ionchannel hybrid. When PAA was immersed in a low pH solution, the Cu2+–PGA complex dissociated. On the basis of the change in ionic current, a label-free assay for Cu2+ was achieved along with the ability to regenerate and reuse the constructed platform. Because of the unique mass transfer property of the nanochannel–ionchannel hybrid combined with the highly amplified ionic c...

The present study aimed to identify altered genes and pathways associated with four histotypes of ovarian cancer, according to the systematic tracking of dysregulated modules of reweighted protein‑protein interaction (PPI) networks. Firstly, the PPI network and gene expression data were initially integrated to infer and reweight normal ovarian and four types of ovarian cancer (endometrioid, serous, mucinous and clear cell carcinoma) PPI networks based on Spearman's correlation coefficient. Secondly, modules in the PPI network were mined using a clique‑merging algorithm and the differential modules were identified through maximum weight bipartite matching. Finally, the gene compositions in the altered modules were analyzed, and pathway functional enrichment analyses for disrupted module genes were performed. In five conditional‑specific networks, universal alterations in gene correlations were revealed, which leads to the differential correlation density among disrupted module pairs. The analyses revealed 28, 133, 139 and 33 altered modules in endometrioid, serous, mucinous and clear cell carcinoma, respectively. Gene composition analyses of the disrupted modules revealed five common genes (mitogen‑activated protein kinase 1, phosphoinositide 3‑kinase‑encoding catalytic 110‑KDα, AKT serine/threonine kinase 1, cyclin D1 and tumor protein P53) across the four subtypes of ovarian cancer. In addition, pathway enrichment analysis confirmed one common pathway (pathways in cancer), in the four histotypes. This systematic module approach successfully identified altered genes and pathways in the four types of ovarian cancer. The extensive differences of gene correlations result in dysfunctional modules, and the coordinated disruption of these modules contributes to the development and progression of ovarian cancer.

The evaluation of developmental and reproductive toxicity of food contact materials (FCMs) is an important task for food safety. Since traditional experiments are both time-consuming and labor-intensive, only a small number of FCMs have sufficient toxicological data for evaluating their effects on human health. While computational methods such as structural alerts and quantitative structure-activity relationships can serve as first-line tools for the identification of chemicals of high toxicity concern, models with binary outputs and unsatisfied accuracy and coverage prevent the use of computational methods for prioritizing chemicals of high concern. This study proposed a genetic algorithm-based method to develop a weight-of-evidence (WoE) model leveraging complementary methods of structural alerts, quantitative structure-activity relationships and in silico toxicogenomics models for chemical prioritization. The WoE model was applied to evaluate 623 food contact chemicals and identify 26 chemicals of high toxicity concern, where 13 chemicals have been reported to be developmental or reproductive toxic and further experiments are suggested for the remaining 13 chemicals without toxicity data related to developmental and reproductive effects. The proposed WoE model is potentially useful for prioritizing chemicals of high toxicity concern and the methodology may be applied to toxicities other than developmental and reproductive toxicity.

Background: Recent studies have demonstrated that coronary microcirculation dysfunction (CMVD) is closely correlated with adverse clinical outcomes. In this study, quantitative stress myocardial contrast echocardiography (MCE) was used to evaluate the CMVD and to investigate its association with the prognosis of patients with nonobstructive coronary artery disease (CAD). Material and methods: From 2006 to 2014, 227 consecutive patients with chest pain and a diagnostic coronary angiography without significant coronary artery stenosis (

In order to understand the sources and health risks of polycyclic aromatic hydrocarbons in the PM

Background Diagnosis of tuberculosis (TB) in children is challenging. Epidemiological data of childhood pulmonary tuberculosis (PTB) are urgently needed. Methods We described trends in epidemiology, clinical characteristics, and treatment outcomes in seven cities of Shandong province, China, during 2005–2017. Data were collected from the China Information System for Disease Control and Prevention. Results Among 6283 (2.4% of all PTB) PTB cases aged

This study aimed to analyze the epidemiology of pulmonary tuberculosis (PTB) and gained insight into the future TB control plan in China. We extracted epidemiological, clinical, and geographic data from TB prevention and control institutions in 6 cities of Shandong province, China, during 2005 to 2017. Among 224,480 diagnosed PTB, rural residents accounted for 93%, smear-positive PTB 52%, and new cases 92%. The incidence rate of overall PTB declined from 40.8 to 26.25 per 100,000 during 2005 to 2017. Except smear-negative PTB (7.57–19.87 per 100,000), the incidence of smear-positive PTB and all that stratified by age, sex, and treatment history decreased. With 80% reduction, the incidence of smear-positive PTB (6.38 per 100,000) and relapse cases (1.01 per 100,000) were already very low in 2017. With persistent efforts to combat TB, the disease burden had shifted from smear-positive PTB to smear-negative PTB. While new cases need continuous attention, further reducing the incidence of smear-negative PTB and elderly patients may have a greater impact on future TB control.

In this work, we developed a simple electrochemical method for ultrasensitive and label-free detection of circulating tumor cells (CTCs) based on direct plasmon-enhanced electrochemistry (DPEE). After plasmonic gold nanostars (AuNSs) were modified on the glassy carbon (GC) electrode, the aptamer probe was immobilized on the AuNSs surface, which can selectively capture the CTCs in samples. Upon localized surface plasmon resonance (LSPR) excitation, the electrochemical current response can be enhanced remarkably due to efficient hot electrons transport from AuNSs to the external circuit. The captured cells on the AuNSs surface will influence the hot electrons transport efficiency, leading to a decreased current response. Using ascorbic acid (AA) as the electroactive probe, it was found that the current responses of the AuNSs/GC electrode upon light irradiation decrease with the cell concentration. Due to the special molecular recognition of the aptamer and enhanced electrochemical performance of the plasmon, the proposed method enables an ultrasensitive and label-free detection of CTCs with excellent selectivity. The experimental results show that CCRF-CEM cell concentrations as low as 5 cells/mL can be successfully detected, which is superior to most reported work up to now. Using the present method, MCF-7 cells as low as 10 cells/mL can be also successfully detected, indicating the universality of the proposed method for CTCs detection. Furthermore, the cytosensor can successfully distinguish CTCs from normal cells in blood samples. The as-proposed strategy provides a promising application of DPEE in the development of novel biosensors for nondestructive analysis of biological samples.

Pristimerin (Pris), which is a natural triterpenoid compound extracted from the Celastraceae plant, has an effect on intestinal inflammation, but its mechanism needs further study. Human genome-wide analysis found that the expression of microRNA-155 in the blood and colon tissue of patients with IBD was increased. Therefore, we studied the effect of Pris on a model of DSS-induced colitis in mice and investigated whether Pris inhibited the expression of microRNA-155. We obtained a mouse model of acute experimental colitis by allowing the mice to drink a 3% by mass DSS solution freely for 7 days. Pris solutions at different concentrations were injected via the abdomen to simulate the therapeutic effect of Pris on colitis. The body weight and faeces were measured and recorded daily. The mice were sacrificed by the cervical dislocation method after the experiment, and the colon length and histological changes, as well as the changes in Nrf2 in the colon tissue, were measured. The activities of the antioxidant enzymes GSH, GSH-Px and SOD were examined. The expression levels of microRNA-155, IL-1β, IL-6, IL-17, and TNF-α in the colon were detected by RT-PCR technology, and the expression of NF-κB p65 in the colon was detected by western blotting. Our study shows that Pris can reduce the DAI score, obviously alleviate weight loss, and decrease the colon pathological tissue damage caused by DSS. Pris can inhibit the increase in microRNA-155 expression induced by DSS-induced colitis. Our study has shown that Pris may reduce DSS-induced colitis in mice by inhibiting the expression of microRNA-155, and further inhibition of the inflammatory response and oxidative stress occurred.

Few studies have investigated the use of dexmedetomidine in patients with a high risk of postoperative nausea and vomiting (PONV) following gynaecological laparoscopic surgery.To investigate if the intra-operative use of dexmedetomidine could reduce the incidence of PONV in this patient population.A randomised, double-blind, placebo-controlled trial.A tertiary hospital in Beijing, China.130 adult patients scheduled for gynaecological laparoscopic surgery.Patients in the dexmedetomidine group (Dex group, n = 65) received a loading dose of dexmedetomidine (0.5 μg kg over 10 min) before induction of anaesthesia, followed by a continuous infusion (0.1 μg kg h) until the end of surgery. Patients in the control group (Ctrl group, n = 65) received volume-matched normal saline. Propofol and remifentanil were used for induction and maintenance of anaesthesia. Intravenous patient-controlled analgesia with morphine was provided after surgery.The incidence of 24-h PONV.The incidence of nausea within the first 2 postoperative hours was lower in the Dex group than in the Ctrl group [0% (0/65) vs. 9% (6/65), P = 0.037]. The overall incidence of PONV within the first 2 postoperative hours was slightly lower in the Dex group than in the Ctrl group, but the difference was not statistically significant [5% (3/65) vs. 14% (9/65), P = 0.069]. There was no significant difference between the two groups regarding the incidence of 24-h PONV.For adult patients undergoing gynaecological laparoscopic surgery, supplemental use of dexmedetomidine during general anaesthesia reduced the incidence of early postoperative nausea but not vomiting within the 24 h after surgery.Chinese Clinical Trial Registry ChiCTR-IPR-15006914.

A high quality diet is believed to play a functional role in promoting the healthy growth of mankind and preventing many kinds of chronic degenerative diseases, including cancer, cardiovascular disease, diabetes, and obesity. Adherence to a high quality diet has been strongly associated with a lower risk of mortality. To help promote healthy lifestyles and physical strength, the Chinese government has produced a new revised version of the Dietary Guidelines for Chinese Residents (2016) and the Chinese Food Pagoda, as guidance for dietary intake among its population. Similarly, the Japanese government has produced the Japanese Food Guide Spinning Top Model, and the US government has recently published revised dietary recommendations in its 2015–2020 eighth edition of Dietary Guidelines for Americans. The evidence from all respective cohort studies involved in producing these guidelines shows a reduced risk of many chronic diseases and mortality if the guidelines are followed. All scientific findings support encouraging the general population to consume a broad variety of food on the basis of nutrient and food intakes in order to prevent deficiency diseases and a surplus of energy and nutrients, and recommend daily physical activity for health promotion.

Endothelial dysfunction plays a principal role in the pathogenesis of pulmonary arterial hypertension (PAH), which is a fatal disease with limited effective clinical treatments. Mitochondrial dysregulation and oxidative stress are involved in endothelial dysfunction. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1α in hypoxia-induced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1α expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1α in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1α inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1α decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NF-κB activation and increased ATP formation and endothelial nitric oxide synthase (eNOS) phosphorylation. Furthermore, hypoxia-induced changes in the mean pulmonary arterial pressure and right heart hypertrophy were nearly normal after intervention. These results suggest that PGC-1α is associated with endothelial function in hypoxia-induced PAH and that improved endothelial function is associated with improved cellular mitochondrial respiration, reduced inflammation and oxygen stress, and increased PGC-1α expression. Taken together, these findings indicate that PGC-1α may be a new therapeutic target in PAH.

Background/aims Hypertension is a common public health problem due to its high morbidity and potential risk, which is related to inflammatory actions. Kaempferol (KAE) has anti-inflammation activities. Herein, we explored the effects of KAE on LPS-induced inflammatory injury in human aortic endothelial cells (HAECs). Methods HAECs were treated with KAE before stimulated with LPS or AngII. After miR-203 inhibitor transfection, cell viability and apoptosis were detected by CCK-8 and flow cytometry. The accumulated levels of apoptotic proteins, nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways related proteins, MyD88 and toll-like receptor 4 (TLR4) were both determined by western blot. The concentrations of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were detected by ELISA. Expression of miR-203 was analyzed by qRT-PCR. The target of miR-203 was achieved by luciferase assay. Results LPS successfully induced inflammatory injury as evidenced by decreasing cell viability, increasing apoptosis, and also increasing IL-6, TNF-α concentrations. The apoptotic proteins p53 and cleaved-Caspase-3 were both upregulated while Bcl-2 was downregulated. Moreover, LPS activated NF-κB and MAPK pathways. However KAE reversed the results led by LPS. KAE increased miR-203 expression in LPS or AngII-disposed HAECs. More experiments revealed that transfection with miR-203 inhibitor impaired the inflammation-alleviating effects of KAE. MyD88 and TLR4 were predicated as a target of miR-203, which might be implicated in the protective functions of KAE on HAECs. Conclusion KAE exerted the protective impacts on HAECs against inflammatory injury through inactivation of NF-κB and MAPK pathways, as well as upregulation of miR-203.

Background Few studies have investigated the associations between outdoor air pollution and outpatient visits for respiratory diseases (RDs) in general population. Methods We collected daily outpatient data of primary RDs from five hospitals in Jinan during January 2012 and December 2016, as well as daily measurements of air pollutants from the Jinan Environmental Monitoring Center and daily meteorological variables from the China Meteorological Data Sharing Service System. A generalized additive model (GAM) with quasi-Poisson regression was constructed to estimate the associations between daily average concentrations of outdoor air pollutants (PM2.5,PM10, SO2, NO2, CO and O3) and daily outpatient visits of RDs after adjusting for long-time trends, seasonality, the “day of the week” effect, and weather conditions. Subgroup analysis stratified by gender, age group and the type of RDs was conducted. Results A total of 1,373,658 outpatient visits for RDs were identified. Increases of 10 μg/m3 in PM2.5, PM10, NO2, CO and O3 were associated with0.168% (95% CI, 0.072–0.265%), 0.149% (95% CI, 0.082–0.215%), 0.527% (95% CI, 0.211–0.843%), 0.013% (95% CI, 0.003–0.023%), and 0.189% (95% CI, 0.032–0.347%) increases in daily outpatient visits for RDs, respectively. PM2.5 and PM10 showed instant and continuous effects, while NO2, CO and O3 showed delayed effects on outpatient visits for RDs. In stratification analysis, PM2.5 and PM10 were associated with acute RDs only. Conclusions Exposure to outdoor air pollutants including PM2.5, PM10, NO2, CO and O3 associated with increased risk of outpatient visits for RDs. Electronic supplementary material The online version of this article (10.1186/s12931-018-0958-x) contains supplementary material, which is available to authorized users.

Background and Purpose The Na+/Ca2+ exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca2+ ([Ca2+]i) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been developed and studied in ischaemic tissue injury but barely examined in glioblastoma for the purpose of anti‐tumour therapy. We assessed the effect of NCX blockers on glioblastoma growth and whether NCX can become a therapeutic target. Experimental Approach Patch‐clamp recording, Ca2+ imaging, flow cytometry, and Western blot were used to study the effects of specific and non‐specific NCX blockers on cultured glioblastoma cells. In vivo bioluminescent imaging was used to measure effects on grafted glioblastoma. Key Results Selectively blocking the reverse NCX with SEA0400, SN‐6, and YM‐244769 did not affect tumour cell viability. Blocking the forward NCX with bepridil, CB‐DMB, or KB‐R7943 elevated [Ca2+]i and killed glioblastoma cells. Bepridil and CB‐DMB caused Ca2+‐dependent cell cycle arrest together with apoptosis, which were all attenuated by a Ca2+ chelator BAPTA‐AM. Systemic administration of bepridil inhibited growth of brain‐grafted glioblastoma. Bepridil did not appear to have a cytotoxic effect on human astrocytes, which have higher functional expression of NCX than glioblastoma cells. Conclusions and Implications Low expression of the NCX makes glioblastoma cells sensitive to disturbance of [Ca2+]i. Interventions designed to block the forward NCX can cause Ca2+‐mediated injury to glioblastoma thus having therapeutic potential. Bepridil could be a lead compound for developing new anti‐tumour drugs.

To determine Z-score equations and reference ranges for Doppler flow velocity indices of cardiac outflow tracts in normal fetuses. A prospective cross-sectional echocardiographic study was performed in 506 normal singleton fetuses from 18 to 40 weeks. Twelve pulsed-wave Doppler (PWD) measurements were derived from fetal echocardiography. The regression analysis of the mean and the standard deviation (SD) for each parameter were performed against estimated fetal weight (EFW) and gestational age (GA), in order to construct Z-score models. The correlation between these variables and fetal heart rate were also investigated. Strong positive correlations were found between the twelve PWD indices and the independent variables. A linear-quadratic regression model was the best description of the mean and SD of most parameters, with the exception of the velocity time interval (VTI) of ascending aorta against EFW, which was best fitted by a fractional polynomial. Z-score equations and reference values for PWD indices of fetal cardiac outflow tracts were proposed against GA and EFW, which may be useful for quantitative assessment of potential hemodynamic alternations, particularly in cases of intrauterine growth retardation and structural cardiac defects.

Computational prioritization of chemicals for potential skin sensitization risks plays essential roles in the risk assessment of environmental chemicals and drug development. Given the huge number of chemicals for testing, computational methods enable the fast identification of high-risk chemicals for experimental validation and design of safer alternatives. However, the development of robust prediction model requires a large dataset of tested chemicals that is usually not available for most toxicological endpoints, especially for human data. A small training dataset makes the development of effective models difficult with insufficient coverage and accuracy. In this study, an ensemble tree-based multitask learning method was developed incorporating three relevant tasks in the well-defined adverse outcome pathway (AOP) of skin sensitization to transfer shared knowledge to the major task of human sensitizers. The results show both largely improved coverage and accuracy compared with three state-of-the-art methods. A user-friendly prediction server was available at https://cwtung.kmu.edu.tw/skinsensdb/predict . As AOPs for various toxicity endpoints are being actively developed, the proposed method can be applied to develop prediction models for other endpoints.

Penicillin is the most widely used and longest-lived antibiotic in the pharmaceutical industry. It belongs to the bio-fermentation chass of drugs, with a large amount of fermentation exhaust containing volatile organic compounds (VOCs) generated during the process of penicillin production, which have a serious impact on the environment. In this study, the pollution characteristics of the fermented exhaust are studied by using investigation and testing the souces of the pollution and via a health risk assessment model. The main results show that 23 kinds of VOCs were detected in the penicillin fermentation exhaust. The main pollutants included vinyl acetate trifluorotrichloroethane, dichlorotetrafluoroethane, and methylene chloride. In the heating stage, holding stage, cooling stage, and fermentation stage, the proportion of chlorinated hydrocarbons was the highest, followed by esters, and the total amount of these two kinds of substances accounted for more than 90% of total volatile organic compounds (TVOCs). Using the model of health risk assessment, the noncarcinogenic risk value of the total fermented exhaust was 4.98×10