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1.
Medicine (Baltimore) ; 98(38): e17274, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568007

RESUMO

BACKGROUND: Weight status and autism spectrum disorder (ASD) are rising public health concerns. An increasing number of reports indicate that individuals with ASD may have unhealthy weight status, but the evidence is mixed. To understand the weight status in individuals with ASD and provide strategies for prevention and intervention, we describe the protocol for a systematic review and meta-analysis aimed at assessing the prevalence of obesity, overweight, and underweight in ASD. METHODS: A broad range of key bibliographic databases including MEDLINE (PubMed), Embase, Cochrane, and ISI Web of Science will be searched to identify studies reporting the prevalence of obesity, overweight, and underweight in patients with ASD. Retrieved records will be independently screened by 2 authors and relevant estimates will be extracted from studies reporting data on obesity, overweight, and underweight prevalence among individuals with ASD. The assessment of study quality will be conducted primarily using the Newcastle-Ottawa scale and checklist proposed by the Joanna Briggs Institute. Prevalence estimates of obesity and overweight will be separately pooled using random-effects model. The pooled estimates will be summarized and presented by regional groupings. Subgroup analysis will be conducted for variables (such as study setting, participants' age, and geographical region) across studies, depending on data availability. Between-study heterogeneity will be assessed using the I statistic and explored through subgroup analyses. This systematic review and meta-analysis will be reported following the preferred reporting items for systematic reviews and meta-analyses checklist and the meta-analysis of observational studies in epidemiology statements guidelines for meta-analysis and systematic reviews of observational studies. RESULTS: In this study, we will outline details of the aims and methods on the meta-analysis of weight status of individuals with ASD. CONCLUSION: The results of this study will summarize the current data of weight status of individuals with ASD. REGISTRATION: PROSPERO-National Institute of Health Research (NIHR) Prospective Register of Systematic Reviews (CRD42019130790).

2.
Artigo em Inglês | MEDLINE | ID: mdl-31597381

RESUMO

Dam-break flooding is a potential hazard for reservoirs that poses a considerable threat to human lives and property in downstream areas. Assessing the dam-break flood risk of the Zipingpu Reservoir in Chengdu, Sichuan Province, China, is critically important because this reservoir is located on the Longmen Shan fault, which experiences high seismic activity. In this paper, we develop an approach based on the protected object for dam-break flood risk management. First, we perform a numerical simulation of dam-break flooding in four possible dam break scenarios. Next, the flood areas are divided into 71 analysis units based on the administrative division. Based on the numerical simulation results and the socio-economic demographic data affected by a flood, the importance and risk level of each analysis unit is confirmed, and the flood risk map is established according to the classification results. Finally, multi-level flood risk management countermeasures are proposed according to the results of the unit classification shown in the map.

3.
ACS Infect Dis ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588734

RESUMO

Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill non-growing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyl depsipeptide scaffold is subject to rapid metabolism. Herein, we explore alteration of the potentially metabolically reactive α,ß unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of S. aureus ClpP and show activity against Gram-positive bacteria, including S. aureus biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides, but with a decreased metabolic liability. While removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl urea depsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators, with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.

4.
Pediatr Surg Int ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31576470

RESUMO

PURPOSE: To identify potential metabolic biomarkers for distinguishing malignant and benign thyroid nodules in children and adolescents using a metabolomics approach. METHODS: A total of 96 consecutive patients (median age 14.29 ± 2.31 years, range 9-18 years) who underwent thyroidectomy and 40 healthy controls were enrolled. Patients were assigned to the papillary thyroid carcinoma and benign thyroid adenoma groups according to postoperative pathologic biopsy. Plasma samples were preoperatively collected, and multivariate analysis was performed to identify differential metabolites. RESULTS: Papillary thyroid carcinoma could be distinguished not only from healthy serum but also from benign thyroid adenoma according to the metabolic profiles. A total of 17 metabolites were identified. Compared with those from benign thyroid adenoma patients and healthy controls, the metabolites from papillary thyroid carcinoma patients, including leucine, lactate, alanine, glycine, acetate, lysine and choline, were increased, while glucose was decreased. CONCLUSION: The metabolomics method based on proton nuclear magnetic resonance has great potential for identifying papillary thyroid carcinoma in children and adolescents. Lactate and glycine may be used as potential serum markers for the diagnosis of papillary thyroid carcinoma.

5.
Dis Markers ; 2019: 6514608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583029

RESUMO

Neuroblastoma is the most common seen solid neural tumor in children less than age one. As mutation in the miR-34b/c gene is observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that polymorphism in the miR-34b/c gene might predispose to neuroblastoma. Here, we conducted this replication study by genotyping rs4938723 T>C from miR-34b/c in Hunan children (162 subjects with neuroblastoma and 270 control subjects) and examined its effect on the risk of neuroblastoma. We determined such association using logistic regression, adjusted for age and gender. Relative to those with TT genotype, subjects with C allele had reduced neuroblastoma risk (TC vs. TT: adjusted OR = 0.46, 95%CI = 0.30-0.71; additive model: adjusted OR = 0.64, 95%CI = 0.47-0.88; TC/CC vs. TT: adjusted OR = 0.49, 95%CI = 0.33-0.73). Stratified analysis revealed that rs4938723 TC/CC carriers were less likely to develop neuroblastoma for patients in the subgroups of age ≤ 18 months, age > 18 months, females, males, tumors in retroperitoneal, tumors in other sites, and clinical stages II, III, IV, and III+IV. Our findings verified miR-34b/c rs4938723 C variant allele as a protective factor for the risk of neuroblastoma. Further investigation of how miR-34b/c rs4938723 T>C might modify neuroblastoma risk is warranted.

6.
Mol Pharmacol ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31585985

RESUMO

Withaferin A (WIT) is a natural product possessing a wide range of pharmacological activities. Previous studies have reported covalent binding of WIT to tubulin and downregulation of tubulin protein levels although the underlying mechanisms remain to be established. In the current investigation, we showed that WIT induces downregulation of tubulin in a post-transcriptional manner, suggestive of direct and potent activity in tubulin degradation. The N,N'-Ethylenebis(iodoacetamide) assay and competitive binding experiments with four colchicine site-targeted tubulin inhibitors further revealed that WIT interacts with the colchicine site of tubulin to promote degradation. WIT irreversibly inhibited tubulin polymerization and mass spectrometry results disclosed binding to Cys239 and Cys303 sites of ß-tubulin. Interestingly, WIT promoted degradation of the ß-tubulin isoforms containing Cys239 (ß2,ß4 and ß5(ß)) but had no effect on those containing Ser239 (ß3 and ß6). Moreover, a C239S but not C303S mutation in ß-tubulin completely abolished the degradation effect of WIT, suggesting that the Cys239-WIT covalent bond accounts for this activity. Our collective results clearly demonstrate that covalent interactions between WIT and Cys239 of ß-tubulin promote tubulin degradation, supporting its potential utility as a therapeutic compound. SIGNIFICANCE STATEMENT: Withaferin A(WIT), a natural product possessing a wide range of pharmacological activities, covalently binds to Cys239 of ß-tubulin near the colchicine site and the WIT-Cys239 covalent bond accounts for WIT induced tubulin degradation, fully clarifying the underlying mechanisms and supporting its potential utility a therapeutic compound.

7.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3773-3779, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602952

RESUMO

The aim of this paper was to explore the mechanism of Shenxiong Glucose Injection antagonizing apoptosis of H9 c2 cells induced by H_2O_2. H9 c2 cells were pretreated with 1. 7%,3. 4% and 6. 8% Shenxiong Glucose Injection,and then H_2O_2 was introduced to induce apoptosis in vitro. Cell viability was detected by MTS assay,morphological changes of apoptosis were observed by AO/EB fluorescence staining,apoptosis rate was detected by Annexin/PI method,cell expression profile was detected by gene chip technology,the mRNA of PIK3 CA,Bcl-2,Bax,caspase-3 and GAPDH were detected by qRT-PCR,the protein expression levels of PIK3 CA,AKT,P-AKT,Bcl-2,Bax and caspase-3 were detected by Western blot,and the contents of LDH and MDA were detected by kit. The results showed that Shenxiong Glucose Injection of different concentrations significantly increased the viability of H9 c2 cells treated with H_2O_2( P<0. 01),and reversed H_2O_2-induced apoptosis( P< 0. 01). The microarray experiments showed that 138 genes were altered in H9 c2 cells after treatment with Shenxiong Glucose Injection. The differential expression fold of PIK3 CA associated with PI3 K/AKT pathway was 3. 59. The results of qRT-PCR and Western blot showed that Shenxiong Glucose Injection could down-regulate the mRNA and protein expression levels of caspase-3( P<0. 01),up-regulate the mRNA and protein expression level of PIK3 CA and Bcl-2( P<0. 01),and up-regulate the phosphorylation levels of AKT( P<0. 01) in H_2O_2-treated H9 c2 cells. The protective effect of Shenxiong Glucose Injection on H_2O_2 cells injury was significantly inhibited by LY294002,a PI3 K/AKT pathway inhibitor. The results suggested that Shenxiong Glucose Injection may inhibit H_2O_2-induced H9 c2 cells apoptosis by regulating PI3 K/AKT signaling pathway.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31603618

RESUMO

A subgroup analysis of the nationwide, cross-sectional 3B STUDY was performed to understand the current blood pressure (BP) control status and treatment patterns in Chinese diabetes patients as well as to identify factors associated with BP control. The demographic data, anthropometric parameters, and laboratory results were collected from 24 512 type 2 diabetes patients. The BP goal was a systolic BP <130 mm Hg and a diastolic BP <80 mm Hg regardless of a history of hypertension or current antihypertensive treatment. The overall prevalence of hypertension was 59.9% with geographical differences. Among the diabetes patients with hypertension, 76.9% received antihypertensive medicines. Calcium channel blockers (39.3%), angiotensin II receptor antagonists (26.6%), and then ß-blockers (14.0%) or angiotensin-converting enzyme inhibitors (13.6%) were frequently used for BP control. Only 17.5% (n = 2658) of diabetes patients with hypertension reached the recommended target BP. Body mass index <24 kg/m2 , urban resident, frequent physical activity, good adherence to medication, comorbidity with cardiovascular disease, achieving glycemic goal (HbA1c <7.0%), achieving lipid goal (low-density lipoprotein cholesterol <2.59 mmol/L) were independent factors that predicted achievement of target BP goal. On the contrary, comorbidity with chronic kidney disease predicted failure to achieve target BP goal. Patients who were treated in a cardiology department or lived in the North were more likely to achieve BP goals. A considerable proportion of diabetic patients failed to achieve guideline-recommended BP targets. More aggressive efforts should be made to overcome the diverse barriers and facilitate the optimization of diabetes management.

9.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

10.
Nat Commun ; 10(1): 4420, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594923

RESUMO

Azoxy bond is an important chemical bond and plays a crucial role in high energy density materials. However, the biosynthetic mechanism of azoxy bond remains enigmatic. Here we report that the azoxy bond biosynthesis of azoxymycins is an enzymatic and non-enzymatic coupling cascade reaction. In the first step, nonheme diiron N-oxygenase AzoC catalyzes the oxidization of amine to its nitroso analogue. Redox coenzyme pairs then facilitate the mutual conversion between nitroso group and hydroxylamine via the radical transient intermediates, which efficiently dimerize to azoxy bond. The deficiency of nucleophilic reactivity in AzoC is proposed to account for the enzyme's non-canonical oxidization of amine to nitroso product. Free nitrogen radicals induced by coenzyme pairs are proposed to be responsible for the efficient non-enzymatic azoxy bond formation. This mechanism study will provide molecular basis for the biosynthesis of azoxy high energy density materials and other valuable azoxy chemicals.

11.
Int J Nanomedicine ; 14: 7489-7502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571860

RESUMO

Background: 3,5,4'-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated. Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated. Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues. Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31562084

RESUMO

Image enhancement is an important pre-processing step for many computer vision applications especially regarding the scenes in poor visibility conditions. In this work, we develop a unified two-pathway model inspired by the biological vision, especially the early visual mechanisms, which contributes to image enhancement tasks including low dynamic range (LDR) image enhancement and high dynamic range (HDR) image tone mapping. Firstly, the input image is separated and sent into two visual pathways: structure-pathway and detail-pathway, corresponding to the M-and P-pathway in the early visual system, which code the low-and high-frequency visual information, respectively. In the structure-pathway, an extended biological normalization model is used to integrate the global and local luminance adaptation, which can handle the visual scenes with varying illuminations. On the other hand, the detail enhancement and local noise suppression are achieved in the detail-pathway based on local energy weighting. Finally, the outputs of structure-and detail-pathway are integrated to achieve the low-light image enhancement. In addition, the proposed model can also be used for tone mapping of HDR images with some fine-tuning steps. Extensive experiments on three datasets (two LDR image datasets and one HDR scene dataset) show that the proposed model can handle the visual enhancement tasks mentioned above efficiently and outperform the related state-of-the-art methods.

13.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

14.
Transl Stroke Res ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515743

RESUMO

Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3 h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50 Hz repeated every 200 ms, intensity at 200 G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3 h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.

15.
ACS Nano ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31490650

RESUMO

Biofilm infections can induce chronic inflammation and stall the normal orchestrated course of wound-healing cascades. Herein, pH-switchable antimicrobial hydrogel with nanofiber networks for biofilm eradication and rescuing stalled healing in chronic wounds is reported on the basis of the self-assembly of a designed octapeptide (IKFQFHFD) at neutral pH. This hydrogel is biocompatible and exhibits an acidic pH (pathological environment of infected chronic wounds)-switchable broad-spectrum antimicrobial effect via a mechanism involving cell wall and membrane disruption. The antimicrobial activity of hydrogel is derived from its acidic pH-dependent nanofiber network destabilization and activated release of IKFQFHFD, which is antimicrobial only at acidic pH due to the antimicrobial peptide-like molecular structure. In addition, supramolecular nanofiber networks loaded with drugs of cypate (photothermal agent) and proline (procollagen component) are further developed. In vitro experiments show that loaded drugs exhibit acidic pH (pH ∼ 5.5)-responsive release profiles, and synergistic biofilm eradication and subsequent healing cascade activation of cells proliferation are achieved on the basis of the supramolecular nanofiber networks. Remarkably, the nanofiber networks of hydrogel enable in vivo complete healing of MRSA biofilm infected wound in diabetic mice within 20 days, showing great potential as promising chronic wound dressings. The proposed synergistic strategy for eradicating biofilm and activating subsequent healing cascades may offer a powerful modality for the management of clinical chronic wounds.

16.
Math Biosci Eng ; 16(5): 5687-5696, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31499732

RESUMO

Background: The current standard approach to the treatment of patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitizing mutations has been the treatment with a first-generation EGFR-TKIs. While, with resistance developed against first-generation EGFR-TKIs, second/third-generation TKIs have attracted all the attention, and replaced first-generation EGFR- TKIs upon disease progression due to the greater efficacy and more favorable tolerability. In the past few years, this strategy has been challenged by clinical evidence when next-generation EGFR-TKIs are used in patients with advanced NSCLC. Objective: In this study, we performed a meta- analysis to investigate the efficacy of next-generation TKIs comparison with first-generation TKIs in the treatment of NSCLC. Methods: The multiple databases including Pubmed, Embase, Cochrane library databases were adopted to search for the relevant studies, and full-text articles involving to comparison of next-generation TKIs and first-generation TKIs were reviewed. After rigorous reviewing on quality, the data was extracted from eligible randomized controlled trial (RCT). Meta-analysis Revman 5.3 software was used to analyze the combined pooled ORs with the corresponding 95% confidence interval using fixed- or random-effects models according to the heterogeneity. Results: A total of 5 randomized controlled trials were included in this analysis. The group of next-generation TKIs did achieved benefit in progression-free survival (PFS) (OR = 0.58, 95%CI = 0.45-0.75, P<0.0001), overall survival (OS) (OR = 0.76, 95%CI = 0.65-0.90, P = 0.001) as well with the objective response rate (ORR) (OR = 1.27, 95%CI = 1.01-1.61, P = 0.04), respectively. In the results of subgroup analysis of PFS with EGFR mutations, there is also significant differences with exon 19 deletion (OR = 0.56, 95%CI = 0.41-0.77, P = 0.0003) and exon 21 (L858R) mutation (OR = 0.60, 95%CI = 0.49-0.75, P<=0.00001). While, the treatment-related severe adverse event (SAE) between the next-generation TKIs and first-generation TKIs did not have statistical significance (OR = 1.48, 95%CI = 0.62-3.55, P = 0.38). Conclusion: The next-generation TKIs significantly improved efficacy outcomes in the treatment of EGFR mutation-positive advanced NSCLC compared with the first-generation TKIs, with a manageable safety profile. These results are potentially important for clinical decision making for these patients.

17.
J Pineal Res ; : e12611, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31541591

RESUMO

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7 and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38 and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2 and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

18.
New Phytol ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545519

RESUMO

•Variation in temperature (T) is usually accompanied by changes in leaf water potential (Ψleaf ), which may influence mesophyll conductance (gm ). However, the effects of Ψleaf on gm have not yet been considered in models of the gm response to temperature. •Temperature responses of gm and Ψleaf and the response of gm to Ψleaf were studied in rice and wheat, then an empirical model of Ψleaf was incorporated into an existing gm -T model. •In wheat, Ψleaf was dramatically decreased with increasing T, while in rice Ψleaf was less sensitive or insensitive to T. Without taking Ψleaf into account, gm for wheat showed no response to T. However, at a given Ψleaf , gm was significantly higher at high temperature compared to low. After incorporating the function of Ψleaf into the gm -T model, we suggest that the gm -T relationship can be influenced by the activation and deactivation energy for membrane permeability, Ψleaf gradient between temperatures, and the sensitivity of gm to Ψleaf , below a threshold (Ψleaf,0 ). •The data presented here suggest that Ψleaf plays an important role in the gm -T relationship, and should be considered in future studies related to the temperature response of gm and photosynthesis.

19.
Rev Sci Instrum ; 90(8): 083904, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472619

RESUMO

We describe the design, fabrication, and use of a ceramic bulk preparation system, applied to the very high-throughput batching and molding for solid ceramic powders. Through the principle on precise volume controlling of powder materials, up to 100 ceramic block samples with maximum 6 components could be prepared in one time through 100 channels with Φ5 × 5 mm forming molds. The automatic control stage has been built to fill the target powder in a limited size and discrete small volume range. Here, we have designed a mechanical structure and software program so that rotary silo powder feeding amount could be controlled at 5-100 ml/time and the feeding precision can reach 0.005 g. Finally, the equipment is verified by preparing several infrared ceramic samples of different components.

20.
Am J Crit Care ; 28(5): 370-376, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474607

RESUMO

BACKGROUND: High-flow oxygen therapy has been widely adopted, but its use for weaning patients from mechanical ventilation has not been reported. OBJECTIVE: To evaluate whether high-flow oxygen therapy improves the efficiency of weaning patients from mechanical ventilation. METHODS: In a single-center, prospective study, patients receiving mechanical ventilation were randomly assigned to 1 of 3 groups (T-tube, pressure support ventilation, or high-flow oxygen) during 2-hour spontaneous breathing trials in a 14-day study. Participants were followed up until hospital discharge or death. RESULTS: Of 268 patients included, 90 were assigned to the T-tube group, 96 to the pressure support ventilation group, and 82 to the high-flow oxygen group. The first-day 2-hour spontaneous breathing trial passing rates were higher in the pressure support ventilation and high-flow oxygen groups than in the T-tube group (P < .05). The time needed to pass the spontaneous breathing trial was less in the pressure support ventilation and high-flow oxygen groups than in the T-tube group (P < .05). The reintubation rate was lower and the successful weaning rate on the first day was higher in the high-flow oxygen group than in the T-tube and pressure support ventilation groups (P < .05). During the 14-day study period, the weaning time was less in the high-flow oxygen group than in the T-tube and pressure support ventilation groups (P < .05). CONCLUSION: High-flow oxygen therapy can reduce the time needed to wean patients from mechanical ventilation by shortening the time needed to pass a spontaneous breathing trial and by decreasing the reintubation rate.

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