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1.
Biomed Chromatogr ; : e4697, 2019 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-31495945

RESUMO

A liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method was developed and validated to measure GDC-0084 in human plasma and cerebrospinal fluid (CSF). Reverse-phase chromatography with gradient elution was performed by using a C18 column (50 × 2.0 mm, 3 µm). Solid-phase extraction of plasma and CSF was employed to give excellent recovery. MS detection was performed with positive ion screening in multiple reaction monitoring mode. The precursor to the product ions (Q1→Q3) selected for GDC-0084 and GDC-0084-d6 were 383.2→353.2 and 389.2→353.2, respectively. A separate calibration curve was established for human plasma and CSF. Both calibration curves, ranging from 0.2 to 200 ng/mL, were linear and had acceptable intra-day and inter-day precision and accuracy. The lower limit of quantitation and limit of detection for GDC-0084 in human plasma were 0.2 ng/mL (signal/noise ≥ 47) and 0.005 ng/mL (signal/noise ≥ 3.5), respectively, and for GDC-0084 in human CSF were 0.2 ng/mL (signal/noise ≥ 19.7) and 0.04 ng/mL (signal/noise ≥ 7.2). This method was successfully applied to analyze serial plasma samples obtained from children with diffuse intrinsic pontine gliomas and other midline gliomas who participated in pharmacokinetic studies as part of a phase I clinical trial of GDC-0084.

2.
J Mol Cell Biol ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31504682

RESUMO

The release and nuclear translocation of the intracellular domain of NOTCH receptor (NICD) is the prerequisite for Notch signaling mediated transcriptional activation. NICD is subjected to various post-translational modifications including ubiquitination. Here we surprisingly found NUMB proteins stabilize the intracellular domain of NOTCH1 receptor (N1ICD) by regulating the ubiquitin-proteasome machinery, which is independent of NUMB's role in modulating endocytosis. BAP1, a deubiquitinating enzyme (DUB), was further identified as a positive N1ICD regulator, and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD. Intriguingly, BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function. BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells. Thus, NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1-BRCA1 complex.

3.
Med Sci Monit ; 25: 6454-6461, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31456594

RESUMO

BACKGROUND Circular RNA circMTO1 has been reported to inhibit the progression of many types of cancers. However, the role of circMTO1 in the progression of glioblastoma remains unclear. The purpose of our study was to explore the potential involvement of circMTO1 in glioblastoma. MATERIAL AND METHODS The expression of circMTO1 in human glioblastoma tissues was determined via quantitative real-time polymerase chain reaction (qRT-PCR). The effect of circMTO1 on proliferation of human glioblastoma cell line U251 was assessed through the Cell Counting Kit-8 (CCK-8) and colony formation assay. The regulatory interaction between circMTO1 and miR-92 was explored by bioinformatics prediction and luciferase reporter assay. RESULTS We showed that circMTO1 was markedly downregulated in glioblastoma tissues compared with adjacent normal tissues. Lower circMTO1 level was significantly associated with shorter overall survival among patients with glioblastoma. In addition, circMTO1 inhibited proliferation of cell U251 cells. Mechanistically, circMTO1 upregulates the expression of WWOX in U251 cells, and WWOX mediates circMTO1-induced inhibition of proliferation of U251 cells. In addition, miR-92 downregulates the expression of WWOX by the targeting its mRNA 3' UTR. More importantly, circMTO1 directly interact with miR-92, and subsequently serves as a miRNA sponge to upregulate WWOX expression. CONCLUSIONS Our results demonstrate that circMTO1 inhibits the proliferation of glioblastoma cells via the miR-92/WWOX signaling pathway.

4.
Infect Dis Poverty ; 8(1): 68, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362789

RESUMO

BACKGROUND: Echinococcosis caused by Echinococcus is one of the most major infectious diseases in north-west highland of China. E. granulosus sensu strict, E. multilocularis, and E. canadensis are known to be the only three species related to human health transmitting in the areas. To achieve targeted treatment and control of echinococcosis, the accurate identification and discrimination of the species are important. However, currently the available diagnostic approaches do not present ideal results either in accuracy or efficiency. METHODS: In the study, a set of primers were designed to aim at the three human-pathogenic Echinococcus species in China. The one-step multiplex PCR assay was developed and evaluated for the specificity and sensitivity. A total of 73 parasitic lesions and 41 fecal materials obtained from human and various animals collected in the clinic and the field were tested to assess the applicability of this method. RESULTS: The multiplex PCR effectively detected the individual DNA from the targeted species and their random mixtures generating with distinguishable expected size of products. The detection limit of the assay for each of the three species was 5 pg/µl when they were tested separately. When DNA mixtures of the targeted species containing the same concentration were used as templates, the lowest amount of DNA which can be detected was 50 pg/µl, 10 pg/µl and 5 pg/µl for E. granulosus s. s., E. multilocularis, and E. canadensis respectively. No cross-reactivity was observed when DNA from eight genetically close species was used as control templates. The multiplex PCR identifications of all samples were in line with the original sequencing results except for those infected with E. shiquicus, which showed negative signals in the developed assay. Of all the tested stool materials, 16 were previously found positive for Echinococcus by visual and microscopic examination. Among these 16 samples, 13 were confirmed by the multiplex PCR, and the other three tested negative. Additionally, the multiplex PCR identified another 14 positive feces from the remained 25 stool samples which absence of worms. CONCLUSIONS: The developed multiplex PCR shows advantages in fast diagnosis and large-scale epidemiological investigation, which proven to be a promising tool utilized in clinic and surveillance system.

5.
Acta Trop ; : 105133, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31415736

RESUMO

Data in China on human Taenia infections, including Taenia solium cysticercosis, is largely lacking. We aimed to determine the prevalence of taeniasis with all three human Taenia species as well as T. solium cysticercosis in primary school-aged children in minority areas of western Sichuan, China. During April 2016 to December 2017, we did a cross-sectional study in five western Sichuan Province primary schools in Liangshan (3 schools), Ganzi (1 school) and Aba (1 school) prefectures. Diagnosis of taeniasis was made by stool microscopy for presence of Taenia eggs, as well as recovery of taeniid tapeworms or proglottids by medicinal treatment followed by species identification using multiplex PCR. Diagnosis of T. solium cysticercosis was made serologically using an ELISA with low-molecular-weight antigens purified from T. solium cyst fluid to detect specific IgG antibodies. A total of 1,672 children were screened for taeniasis and 1,639 were evaluated for cysticercosis antibodies. Overall prevalence of taeniasis was 7.5% but was as high as 15.6% at one school site (e.g., Shuiluo). Of the three known human Taenia species, adult T. solium tapeworms were detected in 42 children from four of the five schools (all three schools in Liangshan and one in Aba), giving a prevalence of T. solium taeniasis of 2.5% (95% confidence interval 0-6.7%). Cysticercosis antibody seropositivity by school varied from 2.3% to 15.6% (overall 7.5%). T. solium taeniasis carriers were more likely to have cysticercosis antibodies than chlidren without T. solium taeniasis (43.6% vs 6.6%). Schools with higher prevalences of T. solium taeniasis were more likely to have children with human cysticercosis IgG antibodies. This study discloses a high prevalence of taeniasis and T. solium cysticercosis in primary school-aged children in minority areas of western Sichuan, suggesting an urgent necessity for school-based disease control.

6.
Nat Prod Res ; : 1-6, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429297

RESUMO

A phytochemical investigation on the whole plant of Plantago maxima Juss. ex Jacq led to the isolation of a new and rare chlorinated iridoid glycoside named plantomoside (1), along with three known compounds, geniposidic acid (2), 10-deoxygeniposidic acid (3), and viteoid II (4). The structure of 1 was determined through 1 D and 2 D NMR spectroscopic data analysis, HR-ESI-MS, and acid hydrolysis.

7.
Acta Trop ; 199: 105132, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404523

RESUMO

A literature review was performed to define the history of transmission of human parasitic diseases and the evolution of control measures adopted in Sichuan Province during the past several decades. In particular, monitoring data related to soil-transmitted helminth (STH) infections collected since 2006 were analyzed to determine prevalence based on the current control measures and strategies. It was observed that high STH infections, existing mostly in hilly and mountain areas where cultural and economic development has been slower than that in the plain areas, present a continuing challenge to the prevention and control of STHs. For example, it was found that health knowledge, awareness and preventive behavior rates are low in residents over 50 years old, contributing to positive correlations between high infection and low efficacy of control in rural areas. Financial resources of the government at various levels have not been adequate to provide sufficient budget support and personnel dedicated to prevention and control including human deworming in endemic areas. Recent initiatives of the central government have been directed at addressing both parasitic diseases and poverty and, together, present opportunities for the implementation of more effective and integrated control activities.

8.
Nat Commun ; 10(1): 3233, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324787

RESUMO

MAVS is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood. Here, we show that NLK inhibits the antiviral immune response during viral infection by targeting MAVS for degradation. NLK depletion promotes virus-induced antiviral cytokine production and decreases viral replication, which is potently rescued by the reintroduction of NLK. Moreover, the depletion of NLK promotes antiviral effects and increases the survival times of mice after infection with VSV. NLK interacts with and phosphorylates MAVS at multiple sites on mitochondria or peroxisomes, thereby inducing the degradation of MAVS and subsequent inactivation of IRF3. Most importantly, a peptide derived from MAVS promotes viral-induced IFN-ß production and antagonizes viral replication in vitro and in vivo. These findings provide direct insights into the molecular mechanisms by which phosphorylation of MAVS regulates its degradation and influences its activation and identify an important peptide target for propagating antiviral responses.

9.
Parasitology ; 146(12): 1595-1601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31307567

RESUMO

Echinococcus granulosus sensu stricto (s.s.), Echinococcus multilocularis and Echinococcus canadensis are the common causes of human echinococcosis in China. An accurate species identification tool for human echinococcosis is needed as the treatments and prognosis are different among species. The present work demonstrates a method for the simultaneous detection of these three Echinococcus species based on multiplex polymerase chain reaction (mPCR). Specific primers of this mPCR were designed based on the mitochondrial genes and determined by extensive tests. The method can successfully detect either separated or mixed target species, and generate expected amplicons of distinct size for each species. Sensitivity of the method was tested by serially diluted DNA, showing a detection threshold as less as 0.32 pg for both E. granulosus s.s. and E. canadensis, and 1.6 pg for E. multilocularis. Specificity assessed against 18 other parasites was found to be 100% except weakly cross-react with E. shiquicus. The assay was additionally applied to 69 echinococcosis patients and 38 healthy persons, confirming the high reliability of the method. Thus, the mPCR described here has high application potential for clinical identification purposes, and can further provide a useful tool for evaluation of serology and imaging method.

11.
Ultrason Sonochem ; 56: 77-83, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31101291

RESUMO

Classification and prediction of ultrasound-induced microbubble inertial cavitation (IC) activity may play an important role in better design of ultrasound treatment strategy with improved efficiency and safety. Here, a new method was proposed by combining support vector machine (SVM) algorithm with passive cavitation detection (PCD) measurements to fulfill the tasks of IC event classification and IC dose prediction. By using the PCD system, IC thresholds and IC doses were firstly measured for various ultrasound contrast agent (UCA) solutions exposed to pulsed high-intensity focused ultrasound (pHIFU) at different driving pressures and pulse lengths. Then, after trained and tested by measured data, two SVM models (viz. C-SVC and ε-SVR) were established to classify the likelihood of IC event occurrence and predict IC dose, respectively, under different parameter conditions. The findings of this study indicate that the combination of SVM and PCD could be used as a useful tool to optimize the operation strategy of cavitation-facilitated pHIFU therapy.

12.
J Immunol ; 203(1): 259-268, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127032

RESUMO

The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-ß-activated kinase 1 (TAK1)-mediated NF-κB activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-α- and IL-1ß-triggered NF-κB activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-α- and IL-1ß-triggered NF-κB activation and transcription of downstream genes, whereas USP19 deficiency had the opposite effects. Usp19-/- mice produced higher levels of inflammatory cytokines and were more susceptible to TNF-α- and IL-1ß-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-α- or IL-1ß-dependent manner and specifically deconjugated K63- and K27-linked polyubiquitin chains from TAK1, leading to the impairment of TAK1 activity and the disruption of the TAK1-TAB2/3 complex. Our findings provide new insights to the complicated molecular mechanisms of the attenuation of the inflammatory response.

13.
Acta Parasitol ; 64(2): 360-366, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31077030

RESUMO

INTRODUCTION: Haemaphysalis longicornis is an important ectoparasite of domestic and wild animals that can transmit many pathogens including viruses, fungi, bacteria and protozoa. MATERIALS AND METHODS: In this study, we examined genetic variation and population genetics in three mitochondrial (mt) genes [cox1 (cytochrome c subunit 1), rrnL (large subunit ribosomal RNA) and nad5 (NADH dehydrogenase 5)] among four H. longicornis populations from China. RESULTS: The sizes of the partial sequences of cox1, rrnL and nad5 were 776 bp, 409 bp, 510 bp, respectively. Among the obtained sequences, we identified 22 haplotypes for cox1, 2 haplotypes for rrnL and 17 haplotypes for nad5. Low gene flow and significant genetic differentiation (66.2%) were detected among H. longicornis populations. There was no rapid expansion event in the demographic history of four H. longicornis populations in China. In addition, phylogenetic analyses confirmed that all the Haemaphysalis isolates were H. longicornis which were segregated into two major clades. CONCLUSION: The mt DNA genes provide a potential novel genetic marker for molecular epidemiology of H. longicornis and assist in the control of tick and tick-borne diseases in humans and animals.

14.
ACS Appl Mater Interfaces ; 11(20): 18626-18636, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30969106

RESUMO

Lithium aluminum silicate (LAS) nanoparticles have been successfully loaded on graphene nanosheets by adding a silane coupling agent KH-550 by sol-gel process, hydrothermal reaction, and heat treatment process. By regulating the complex permittivity of reduced graphene oxide (rGO) by LAS nanoparticles and KH-550, LAS/rGO-KH-550 possesses excellent microwave absorption performance. The maximum reflection loss of LAS/rGO-KH-550 reaches -62.25 dB at 16.48 GHz with thickness of only 2.7 mm, and the widest bandwidth is up to 6.64 GHz below -10 dB. The LAS/rGO-KH-550 has effective absorption (99.9%) below -20 dB at all X and Ku bands (8-18 GHz). Also, the added quantity of composites in the paraffin matrix is only 20 wt %. The results demonstrate that the interfacial polarization, the Debye dipolar relaxation, the well-matched characteristic impedance, and the quarter-wavelength matching all play important roles in improving the microwave absorption properties of LAS/rGO-KH-550 nanocomposites. Consequently, the LAS/rGO-KH-550 nanocomposites can be readily applied as an ultra-wide-band, light weight, and ultra-high-performance microwave-absorbing material.

15.
Int J Biol Macromol ; 133: 1187-1193, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30980876

RESUMO

In our search for soluble epoxide hydrolase (sEH) inhibitors from plants, we found that water extracts of Scutellaria baicalensis Georgi displayed significant inhibitory activity against sEH in vitro. Extracts of S. baicalensiswere separated, resulting in the isolation of thirty compounds (1-30), including six lignins (1-6), sixteen flavones (7-22), and five amides (23-27). Their structures were determined on the basis of1H and13C NMR and MS spectra. Compounds 1-6 were first reported in the genus Scutellaria. All the isolated compounds were assayed for their inhibitory activities against sEH. Compounds 25-27 showed significant inhibitory activities against sEH with IC50 values of 6.06 ±â€¯0.12, 7.83 ±â€¯0.52, and 6.32 ±â€¯0.31 µM, respectively, and compounds 3-6, 12, 18, and 22 displayed moderate inhibitory activities against sEH with IC50 values from 20.82 ±â€¯0.78 µM to 56.61 ±â€¯0.98 µM. The inhibition kinetic analysis results indicated that compounds 25-27 were all uncompetitive. Molecular docking studies were performed to get insights into inhibition mechanisms of compounds 25-27 against sEH.

16.
PLoS Pathog ; 15(4): e1007680, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30943264

RESUMO

Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49-/- mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49+/+ mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation.


Assuntos
Herpes Simples/prevenção & controle , Imunidade Inata/imunologia , Lisina/metabolismo , Proteínas de Membrana/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Antivirais , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1 , Humanos , Lisina/química , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Células THP-1 , Ubiquitina Tiolesterase/genética , Ubiquitinação , Replicação Viral
17.
Appl Opt ; 58(4): 1101-1109, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30874159

RESUMO

For bonnet polishing of an aspheric surface, the tool influence function (TIF) is inevitably time varying, induced by the different surface curvatures on the aspheric surface. Accordingly, this paper investigated how the surface curvature affects the bonnet-workpiece contact area, and then presented a time-varying TIF model. The time-varying TIF was modeled based on the finite element analysis and kinematics analysis methods, and validated by experiments. The experimental results exhibited good agreement with the theoretical results. The proposed method can forecast the TIF for different polishing positions on aspheric surfaces, and provide the theoretical foundation for dynamic compensation of aspheric surface polishing.

18.
Nature ; 567(7749): 525-529, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30814730

RESUMO

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.

19.
J Colloid Interface Sci ; 546: 113-121, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904687

RESUMO

Oxygen reduction reaction (ORR) is a key process in renewable energy conversion and storage technologies, including fuel cells and metal-air batteries. Pt is a highly efficient ORR electrocatalyst, but its large-scale application is severely prohibited by the high cost. In the pursuit of cost-effective electrocatalysts, it is urgent to develop non-noble metal ORR catalysts. Herein, we report a facile strategy for synthesizing an ORR electrocatalyst based on ultrafine bimetallic FeCo nanoparticles (NPs) anchoring on N-doped porous carbon matrix (FeCo-NC). By optimizing the ratio of Fe and Co, the FeCo-NC-1 catalyst exhibits excellent performance for ORR with the half-wave potential of 0.84 V and limiting current density of -5.3 mA cm-2, which is comparable to the commercial Pt/C catalyst. When applied to Zn-air batteries, FeCo-NC-1 catalyst possesses a high open-circuit potential (1.50 V) and large specific capacity (726.2 mA h g-1) with a good long-term stability and methanol-tolerant capability, which are even superior to the commercial Pt/C catalyst. The first-principle calculations indicate the bimetallic FeCo-NC has stronger O2 adsorption than the single metal nitrogen-doped carbon catalysts (Fe-NC and Co-NC), which is the primary reason for the better ORR performance. We believe this work can be helpful for the development of inexpensive and high-efficient ORR electrocatalysts.

20.
J Immunol ; 202(8): 2397-2406, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30814308

RESUMO

Mediator of IRF3 activation ([MITA] also known as STING) is a direct sensor of cyclic dinucleotide and critically mediates cytoplasmic DNA--triggered innate immune signaling. The activity of MITA is extensively regulated by ubiquitination and deubiquitination. In this study, we report that USP20 interacts with and removes K48-linked ubiquitin chains from MITA after HSV-1 infection, thereby stabilizing MITA and promoting cellular antiviral responses. Deletion of USP20 accelerates HSV-1-induced degradation of MITA and impairs phosphorylation of IRF3 and IκBα as well as subsequent induction of type I IFNs and proinflammatory cytokines after HSV-1 infection or cytoplasmic DNA challenge. Consistently, Usp20 -/- mice produce decreased type I IFNs and proinflammatory cytokines, exhibit increased susceptibility to lethal HSV-1 infection, and aggravated HSV-1 replication compared with Usp20 +/+ mice. In addition, complement of MITA into Usp20 -/- cells fully restores HSV-1-triggered signaling and inhibits HSV-1 infection. These findings suggest a crucial role of USP20 in maintaining the stability of MITA and promoting innate antiviral signaling.

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