Synthesis of heteroatom-doped ZnO nanoparticles as an efficient visible light photocatalyst and its photoelectrochemical performance

Heteroatom-doped ZnO nanoparticles (Zn1-xNixO NPs) have been synthesized by a simple solvothermal approach. The photocatalytic activity of the products has been evaluated by a photoassisted degradation of Rhodamine B in aqueous solution under visible light irradiation. All the heteroatom-doped semiconductors exhibit better photocatalytic activities than pure ZnO, with the 1 mol% Ni2+-doped ZnO showing the best photocatalytic activity. From the transient photocurrent response and electrochemical impedance spectroscopic experiments it is observed that the photogenerated charges of the Ni-doped ZnO show longer lifetime and higher separation than that of pure ZnO, leading to its superior visible light photoactivity. The active species tests indicate that the hydroxyl radical and active holes were primarily responsible for the enhanced photocatalytic performance of Rhodamine B, and the superoxide radical takes part partially in the oxidation process. A possible photocatalytic mechanism is proposed. Good photostability and reusability of the product show that the studied nanoparticles have potential application in dye wastewater treatment

Involvement of CYP2E1 in the Course of Brain Edema Induced by Subacute Poisoning With 1,2-Dichloroethane in Mice

This study was designed to explore the role of cytochrome P4502E1 (CYP2E1) expression in the course of brain edema induced by subacute poisoning with 1,2-dichloroethane (1,2-DCE). Mice were randomly divided into five groups: the control group, the 1,2-DCE poisoned group, and the low-, medium- and high-dose diallyl sulfide (DAS) intervention groups. The present study found that CYP2E1 expression levels in the brains of the 1,2-DCE-poisoned group were upregulated transcriptionally; in contrast, the levels were suppressed by DAS pretreatment in the intervention groups. In addition, the expression levels of both Nrf2 and HO-1 were also upregulated transcriptionally in the brains of the 1,2-DCE-poisoned group, while they were suppressed dose-dependently in the intervention groups. Moreover, compared with the control group, MDA levels and water contents in the brains of the 1,2-DCE-poisoned group increased, whereas NPSH levels and tight junction (TJ) protein levels decreased significantly. Conversely, compared with the 1,2-DCE- poisoned group, MDA levels and water contents in the brains of the intervention groups decreased, and NPSH levels and TJ protein levels increased significantly. Furthermore, pathological changes of brain edema observed in the 1,2-DCE-poisoned group were markedly improved in the intervention groups. Collectively, our results suggested that CYP2E1 expression could be transcriptionally upregulated in 1,2-DCE-poisoned mice, which might enhance 1,2-DCE metabolism in vivo, and induce oxidative damage and TJ disruption in the brain, ultimately leading to brain edema

Towards Structural Systems Pharmacology to Study Complex Diseases and Personalized Medicine

Genome-Wide Association Studies (GWAS), whole genome sequencing, and high-throughput omics techniques have generated vast amounts of genotypic and molecular phenotypic data. However, these data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, which continues along a one-drug-one-target-one-disease paradigm. As a partial consequence, both the cost to launch a new drug and the attrition rate are increasing. Systems pharmacology and pharmacogenomics are emerging to exploit the available data and potentially reverse this trend, but, as we argue here, more is needed. To understand the impact of genetic, epigenetic, and environmental factors on drug action, we must study the structural energetics and dynamics of molecular interactions in the context of the whole human genome and interactome. Such an approach requires an integrative modeling framework for drug action that leverages advances in data-driven statistical modeling and mechanism-based multiscale modeling and transforms heterogeneous data from GWAS, high-throughput sequencing, structural genomics, functional genomics, and chemical genomics into unified knowledge. This is not a small task, but, as reviewed here, progress is being made towards the final goal of personalized medicines for the treatment of complex diseases

Functional Connectivity Density, Local Brain Spontaneous Activity, and Their Coupling Strengths in Patients With Borderline Personality Disorder

In this study, combining degree centrality (DC) and fractional amplitude of low frequency fluctuation (fALFF) analyses of resting state (rs)-functional magnetic resonance imaging (fMRI) data, we aimed to explore functional connectivity density, local brain spontaneous activity, and their coupling strengths in borderline personality disorder (BPD). Forty-three BPD patients and 39 demographically-matched controls underwent rs-fMRI after completing a series of psychological tests. Two-sample t-tests were performed to compare DC and fALFF between these two groups. Across-voxel correlation analysis was conducted to assess DC-fALFF coupling strengths in each group. Imaging parameters and psychological variables were correlated by Pearson correlation analysis in the BPD group. Altered DC and fALFF values in the BPD group, compared with the control group, were distributed mainly in default mode network (DMN), and DC-fALFF coupling strengths were decreased in the left middle temporal gyrus (MTG) and right precuneus in the BPD group. Additionally, insecure attachment scores correlated positively with left precuneus DC and negatively with fALFF of the right posterior cingulate cortex (PCC) in the BPD group. These altered DC and fALFF findings indicate that the BPD patients had disturbed functional connectivity density and local spontaneous activity in the DMN compared with control subjects. Their decreased connectivity-amplitude coupling suggests that the left MTG and right precuneus may be functional impairment hubs in BPD. Disturbed rs function in the left precuneus and right PCC might underlie insecure attachment in BPD

MicroRNA-150 modulates intracellular Ca2+ levels in naïve CD8+ T cells by targeting TMEM20

Regulation of intracellular Ca2+ signaling is a major determinant of CD8+ T cell responsiveness, but the mechanisms underlying this regulation of Ca2+ levels, especially in naïve CD8+ T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca2+ levels in naïve CD8+ T cells required for activation by suppressing TMEM20, a negative regulator of Ca2+ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca2+ levels in naïve CD8+ T cells. The subsequent increase in Ca2+ levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8+ T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8+ T cells reduced intracellular Ca2+ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca2+ level and activation in naïve CD8+ T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca2+ levels115Ysciescopu

Continuous theta burst stimulation over right cerebellum for speech impairment in Parkinson’s disease: study protocol for a randomized, sham-controlled, clinical trial

BackgroundSpeech impairment is a common symptom of Parkinson’s disease (PD) that worsens with disease progression and affects communication and quality of life. Current pharmacological and surgical treatments for PD have inconsistent effects on speech impairment. The cerebellum is an essential part of sensorimotor network that regulates speech production and becomes dysfunctional in PD. Continuous theta-burst stimulation (cTBS) is a non-invasive brain stimulation technique that can modulate the cerebellum and its connections with other brain regions.ObjectiveTo investigate whether cTBS over the right cerebellum coupled with speech-language therapy (SLT) can improve speech impairment in PD.MethodsIn this randomized controlled trial (RCT), 40 patients with PD will be recruited and assigned to either an experimental group (EG) or a control group (CG). Both groups will receive 10 sessions of standard SLT. The EG will receive real cTBS over the right cerebellum, while the CG will receive sham stimulation. Blinded assessors will evaluate the treatment outcome at three time points: pre-intervention, post-intervention, and at a 12-week follow-up. The primary outcome measures are voice/speech quality and neurobehavioral parameters of auditory-vocal integration. The secondary outcome measures are cognitive function, quality of life, and functional connectivity determined by resting-state functional magnetic resonance imaging (fMRI).SignificanceThis trial will provide evidence for the efficacy and safety of cerebellar cTBS for the treatment of speech impairment in PD and shed light on the neural mechanism of this intervention. It will also have implications for other speech impairment attributed to cerebellar dysfunctions.Clinical trial registrationwww.chictr.org.cn, identifier ChiCTR2100050543

Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030