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1.
Nature ; 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942069

RESUMO

Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

2.
Ann Surg Oncol ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776702

RESUMO

PURPOSE: This study evaluated the additional value of lymph node ratio (LNR) when used in combination with the 8th American Joint Committee on Cancer (AJCC) staging system for gastric cancer (GC) to establish a new LNR-based AJCC (rAJCC) staging system. METHODS: We searched the Surveillance, Epidemiology, and End Results database to identify patients who had undergone surgery to resect nonmetastatic GC during the period from 2004 to 2013. Recursive partitioning analysis was used to identify the optimal cutoff points for LNR, and an LNR-based N classification system was designed accordingly. The two staging systems were compared in terms of discriminatory ability, as measured by the concordance index. The likelihood ratio Chi square test was used to assess prognostic homogeneity. RESULTS: A total of 13,027 patients were included in the final analysis. All of the included patients, who belonged to the 8th AJCC IIIA category, could be further classified into the rIIB, rIIIA, rIIIB, and rIIIC subgroups using the proposed rAJCC classification system. A difference in 5-year overall survival rate was found between patients classified as having rIIA disease and those classified as having rIIIC disease (66.7% vs. 5.1%). The rAJCC staging system was superior to the 8th AJCC staging system in terms of discriminatory capacity and prognostic homogeneity. CONCLUSIONS: A new rAJCC staging system is proposed, with prognostic superiority to the 8th AJCC staging system for patients with GC. The rAJCC staging system may serve as a useful tool in clinical practice.

3.
Biomed Res Int ; 2019: 3168541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737659

RESUMO

Background: Uterine contraction (UC) is the tightening and shortening of the uterine muscles which can indicate the progress of pregnancy towards delivery. Electrohysterogram (EHG), which reflects uterine electrical activities, has recently been studied for UC monitoring. In this paper, we aimed to evaluate different EHG segments for recognizing UCs using the convolutional neural network (CNN). Materials and Methods: In the open-access Icelandic 16-electrode EHG database (122 recordings from 45 pregnant women), 7136 UC and 7136 non-UC EHG segments with the duration of 60 s were manually extracted from 107 recordings of 40 pregnant women to develop a CNN model. A fivefold cross-validation was applied to evaluate the CNN based on sensitivity (SE), specificity (SP), and accuracy (ACC). Then, 1056 UC and 1056 non-UC EHG segments were extracted from the other 15 recordings of 5 pregnant women. Furthermore, the developed CNN model was applied to identify UCs using different EHG segments with the durations of 10 s, 20 s, and 30 s. Results: The CNN achieved the average SE, SP, and ACC of 0.82, 0.93, and 0.88 for a 60 s EHG segment. The EHG segments of 10 s, 20 s, and 30 s around the TOCO peak achieved higher SE and ACC than the other segments with the same duration. The values of SE from 20 s EHG segments around the TOCO peak were higher than those from 10 s to 30 s EHG segments on the same side of the TOCO peak. Conclusion: The proposed method could be used to determine the efficient EHG segments for recognizing UC with the CNN.

4.
Pharmacotherapy ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742742

RESUMO

BACKGROUND: The pathogenic mechanism of antituberculous drug-induced liver injury (ATDILI) is associated with antioxidant enzymes. The objective of the present study was to investigate the associations of ATDILI susceptibility with genetic polymorphisms of antioxidant enzyme genes including nitric oxide synthase 2 (NOS2), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 2 (SOD2), BTB domain and CNC homolog 1 (BACH1), and MAF bZIP transcription factor K (MAFK). METHODS: Thirty tag single nucleotide polymorphisms (tag-SNPs) from the all candidate genes were genotyped in a 2-stage cohort study including an initial discovery stage with 461 ATDILI patients and 466 controls and a replication stage with 216 ATDILI patients and 432 controls. The frequencies and distributions of genotypes and haplotypes were compared between the case and control groups. Three different genetic models including dominant, recessive, and additive models were used to determine the associations with susceptibility to ATDILI. RESULTS: The SNPs rs9906835, rs944725, and rs3794764 of the NOS2 gene were significantly associated with an increased risk of ATDILI. The MAFK rs3735656 SNP was significantly associated with a decreased risk for ATDILI. The AAA haplotype of the NOS2 gene was associated with susceptibility to ATDILI. The treatment outcomes of patients with tuberculosis were further affected by genetic variants of the NOS2 and MAFK genes. CONCLUSIONS: Genetic polymorphisms of NOS2 and MAFK are associated with ATDILI susceptibility in Chinese patients with tuberculosis. The variants in NOS2 and MAFK affect treatment outcomes of tuberculosis patients. Further studies are needed to better understand the molecular mechanisms of ATDILI susceptibility via regulation of the expression of ATDILI-susceptibility genes and proteins.

6.
Fish Shellfish Immunol ; 94: 934-943, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31600596

RESUMO

Really Interesting New Gene (RING) finger proteins are highly conserved molecules that participate in a variety of biological processes such as regulation of development, apoptosis and antiviral immunity in vertebrates. However, the functions of RING finger proteins are still poorly understood in crustaceans. Previously, we found that the transcript of a homolog of RING finger protein 152 (CqRNF152-like) was up-regulated in a differentially expressed transcriptome library of the haematopietic tissue (Hpt) cells from red claw crayfish Cherax quadricarinatus upon white spot syndrome virus (WSSV) infection, which is one of the most devastating viral diseases for crustaceans like shrimp and crayfish. The full-length cDNA sequence of CqRNF152-like was then identified with 975 bp, including an ORF of 685 bp that encoded a 195 amino acids protein, a 5'- UTR of 180 bp, and a 3'-UTR with a poly (A) tail of 207 bp. The conserved domain prediction showed that CqRNF152-like contained a conserved RING-finger domain. Gene expression analysis showed that CqRNF152-like was distributed in all tissues examined and the transcript is significantly up-regulated after WSSV challenge both in vivo in Hpt tissue and in vitro in cultured Hpt cells. Furthermore, the transcripts of both an immediate early gene ie1 and a late envelope protein gene vp28 of WSSV were clearly increased in the Hpt tissues, hemocytes and cultured Hpt cells after gene silencing of CqRNF152-like, which were further proved to be significantly decreased after overloading of recombinant CqRNF152-like protein in Hpt cell cultures. Meanwhile, CqRNF152-like was found to bind with WSSV envelope protein VP28 by proteins pull-down assay. Similar to most of RNF proteins, CqRNF152-like protein sequence contained a conserved RING-finger domain and showed self-ubiquitination activity in a RING finger domain dependent manner. Taken together, CqRNF152-like is likely to function as an antiviral molecular against WSSV infection through interaction with the envelope protein VP28 in a crustacean C. quadricarinatus. This is the first report that a RING finger protein with directly antiviral functions via interaction with viral protein and self-ubiquitination activity in crustacean, which sheds new light on the molecular mechanism of WSSV infection and the control of white spot disease.

7.
Materials (Basel) ; 12(20)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635405

RESUMO

Conventional carburizing has disadvantages, such as high energy consumption, large deformation of parts, and an imperfect structure of the carburizing layer. Hence, a rare earth ion pre-implantation method was used to catalyze and strengthen the carburized layer of 20Cr2Ni4A alloy steel. In this study, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), optical microscopy (OM), scanning electron microscopy (SEM), energy dispersive microanalysis (EDS), transmission electron microscopy (TEM), and Rockwell/Vickers hardness testing were used to analyze the microstructure, phase composition, retained austenite content, hardness, carburized layer thickness, and carbon diffusion. The results showed that lanthanum and yttrium ions implanted into the 20Cr2Ni4A steel formed solid solutions of rare earth ions and a large number of dislocations, which improved the diffusion coefficient of carbon elements on the carburized surface and the uniformity of the carbon distribution. Simultaneously, rare earth ion implantation improved the structure and hardness of the vacuum carburized layer. Compared to the lanthanum ion implantation, yttrium ion implantation caused the structure of the carburized layer to be finer, and the carbon diffusion coefficient increased by 1.17 times; in addition, the surface hardness of the carburized layer was 61.8 HRC.

8.
Polymers (Basel) ; 11(9)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540494

RESUMO

The respiration rate (RR) is a key vital sign that links to adverse clinical outcomes and has various important uses. However, RR signals have been neglected in many clinical practices for several reasons and it is still difficult to develop low-cost RR sensors for accurate, automated, and continuous measurement. This study aims to fabricate, develop and evaluate a novel stretchable and wearable RR sensor that is low-cost and easy to use. The sensor is fabricated using the soft lithography technique of polydimethylsiloxane substrates (PDMS) for the stretchable sensor body and inkjet printing technology for creating the conductive circuit by depositing the silver nanoparticles on top of the PDMS substrates. The inkjet-printed (IJP) PDMS-based sensor was developed to detect the inductance fluctuations caused by respiratory volumetric changes. The output signal was processed in a Wheatstone bridge circuit to derive the RR. Six different patterns for a IJP PDMS-based sensor were carefully designed and tested. Their sustainability (maximum strain during measurement) and durability (the ability to go bear axial cyclic strains) were investigated and compared on an automated mechanical stretcher. Their repeatability (output of the sensor in repeated tests under identical condition) and reproducibility (output of different sensors with the same design under identical condition) were investigated using a respiratory simulator. The selected optimal design pattern from the simulator evaluation was used in the fabrication of the IJP PDMS-based sensor where the accuracy was inspected by attaching it to 37 healthy human subjects (aged between 19 and 34 years, seven females) and compared with the reference values from e-Health nasal sensor. Only one design survived the inspection procedures where design #6 (array consists of two horseshoe lines) indicated the best sustainability and durability, and went through the repeatability and reproducibility tests. Based on the best pattern, the developed sensor accurately measured the simulated RR with an error rate of 0.46 ± 0.66 beats per minute (BPM, mean ± SD). On human subjects, the IJP PDMS-based sensor and the reference e-Health sensor showed the same RR value, without any observable differences. The performance of the sensor was accurate with no apparent error compared with the reference sensor. Considering its low cost, good mechanical property, simplicity, and accuracy, the IJP PDMS-based sensor is a promising technique for continuous and wearable RR monitoring, especially under low-resource conditions.

9.
Fish Shellfish Immunol ; 93: 580-588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398395

RESUMO

Enveloped virus usually utilizes the receptor-mediated multiple endocytic routes to enter permissive host cells for successful infection. Cellular receptors are cell surface molecules, either by helping viral attachment to cell surface followed by internalization or by triggering antiviral immunity, participate in the viral-host interaction. White spot syndrome virus (WSSV), the most lethally viral pathogen with envelope and double strand DNA genome in crustacean farming, including shrimp and crayfish, has been recently found to recruit various endocytic routes for cellular entry into host cells. Meanwhile, other than the typical pattern recognition receptors for recognition of WSSV, more and more putative cellular receptors have lately been characterized to facilitate or inhibit WSSV entry. In this review, recent findings on the endocytosis-dependent WSSV entry, viral entry mediated by putative cellular receptors, the molecular interplay between WSSV and cellular receptors, and the following anti-WSSV immunity are summarized and discussed, which may provide us a better understanding of the WSSV pathogenesis and further possible antiviral control of white spot disease in crustacean farming.

10.
Fish Shellfish Immunol ; 93: 743-751, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408731

RESUMO

White shrimp Litopenaeus vannamei are widely cultured in the world and white spot syndrome virus (WSSV) led to huge economic losses in the shrimp industry every year. In the present study, miRNAs involved in the response of shrimp L. vannamei to WSSV infection were obtained through the Illumina HiSeq 2500 high-throughput next-generation sequencing technique. A total number of 7 known miRNAs and 54 putative novel miRNAs were obtained. Among them, 14 DEMs were identified in the shrimp infected with WSSV. The putative target genes of these DEMs were related to host immune response or signaling pathways, indicating the importance of miRNAs in shrimp against WSSV infection. The results will provide information for further research on shrimp response to virus infection and contribute to the development of new strategies for effective protection against WSSV infections.

11.
Exp Ther Med ; 18(3): 1877-1883, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410149

RESUMO

microRNA (miR)-6852 has been demonstrated to suppress the progression of gastric, colorectal and cervical cancer. The mechanism by which miR-6852 regulates glioma cells is yet to be elucidated. In the present study, reverse transcription-quantitative PCR analysis was used and the results demonstrated that miR-6852 expression was reduced in glioma tissues and cells. Cell counting kit-8 and transwell assay analysis indicated that proliferation, migration and invasion of A172 cells in the miR-6852 mimic group were lower than in the miR-NC group. Compared with the Inh-NC group, A172 cells of the Inh-miR-6852 group exhibited higher proliferation, migration and invasion. Additionally, the results indicated that lymphoid enhancer binding factor 1 (LEF1) was directly inhibited by miR-6852 and LEF1 expression was negatively correlated with miR-6852 expression in glioma tissues. Furthermore, the restoration of LEF1 reversed the effects of the miR-6852 mimics. The present findings suggested that miR-6852 inhibited glioma cells proliferation, migration and invasion by targeting the suppression of LEF1.

12.
Sensors (Basel) ; 19(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394850

RESUMO

This paper presents the design and analysis of a new micro-electro-mechanical system (MEMS) tuning fork gyroscope (TFG), which can effectively improve the mechanical sensitivity of the gyroscope sense-mode by the designed leverage mechanism. A micromachined TFG with an anchored leverage mechanism is designed. The dynamics and mechanical sensitivity of the design are theoretically analyzed. The improvement rate of mechanical sensitivity (IRMS) is introduced to represent the optimization effect of the new structure compared with the conventional one. The analytical solutions illustrate that the IRMS monotonically increases with increased stiffness ratio of the power arm (SRPA) but decreases with increased stiffness ratio of the resistance arm (SRRA). Therefore, three types of gyro structures with different stiffness ratios are designed. The mechanical sensitivities increased by 79.10%, 81.33% and 68.06% by theoretical calculation. Additionally, FEM simulation demonstrates that the mechanical sensitivity of the design is in accord with theoretical results. The linearity of design is analyzed, too. Consequently, the proposed new anchored leverage mechanism TFG offers a higher displacement output of sense mode to improve the mechanical sensitivity.

13.
J Craniofac Surg ; 30(8): e790-e793, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343590

RESUMO

Conjunctival prolapse may occur following ocular, eyelid, and orbital surgeries. Conjunctival prolapse usually results as a complication of maximal levator resection or cosmetic lower eyelid blepharoplasty. Here, we describe conjunctival prolapse as an unexpected complication of frontalis muscle flap transfer for severe ptosis. On postoperative day 5, the patient experienced upper eyelid swelling after closing his eyes suddenly and standing up abruptly. The conjunctiva was reddish and ballooned up, and they protruded over the eyelids. Conjunctival prolapse persisted until postoperative day 8. The patient and surgeon were concerned that this complication would affect ptosis correction and surgical outcome. U-shaped fixations were placed to suture and force the prolapsed conjunctiva back to their normal anatomical positions. At postoperative 6 months, the patient had not experienced additional issues, and he was satisfied with the appearance of his eyes. This report describes a rare clinical case of conjunctival prolapse and provides a reference for surgeons treating similar complications.

14.
Ital J Pediatr ; 45(1): 78, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288826

RESUMO

BACKGROUND: Diagnostic value of procalcitonin (PCT) for acute appendicitis (AA) has been evaluated in adult patients, but the application in children remains controversial. The aim of this study was to evaluate the diagnostic value of PCT for overall and complicated AA in children. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Chinese National Knowledge Infrastructure, and Wanfang were searched along with reference lists of relevant articles up to January 2018 without language restrictions. Original articles that reported the performance of PCT in the diagnosis of pediatric AA and associated complications were selected. To assess the diagnostic value of PCT, sensitivity, specificity, diagnostic odds ratios (DORs), summary receiver operating characteristic (ROC) curves, area under the curve (AUC), and 95% confidence intervals (95% CIs) were estimated. RESULTS: Seven qualifying studies (504 confirmed AA and 368 controls) from 6 countries for overall AA and 4 studies (187 complicated AA and 185 uncomplicated AA) for complicated AA from 3 countries were identified. The pooled sensitivity and specificity of PCT for the diagnosis of pediatric AA were 0.62 (95% CI: 0.57-0.66) and 0.86 (95% CI: 0.82-0.89), respectively. The DOR was 21.4 (95% CI: 3.64-126.1) and the AUC was 0.955. PCT was more accurate in diagnosing complicated appendicitis, with a pooled sensitivity of 0.89 (95% CI: 0.84-0.93), specificity of 0.90 (95% CI: 0.86-0.94), and DOR of 76.73 (95% CI: 21.6-272.9). CONCLUSION: This meta-analysis showed that PCT may have potential value in diagnosing pediatric AA. Moreover, PCT had greater diagnostic value in identifying pediatric complicated appendicitis.

15.
Front Physiol ; 10: 732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316390

RESUMO

Background: It is known that the respiration-modulated photoplethysmographic (PPG) signals could be used to derive respiratory frequency (RF) and that PPG signals could be measured from different body sites. However, the accuracy of RF derived from PPG signals of different body sites has not been comprehensively investigated. Objective: This study aims to investigate the difference in the accuracy of PPG-derived RFs between measurements from different body sites, respectively, for normal and deep breathing conditions. Methods: Under normal and deep breathing patterns, the PPG signals were recorded sequentially in a randomized order from six body sites [finger, wrist under (anatomically volar), wrist upper (dorsal), earlobe, and forehead] of 36 healthy subjects. Simultaneously, the reference respiratory signal was measured by a respiratory belt on the chest. Using the frequency demodulation approach, respiratory signals were extracted from PPG signals for calculating RF by power spectral density. The bias between PPG-derived and reference RFs was then analyzed statistically using analysis of variance and non-parametric tests, Bland-Altman analysis, and linear regression to investigate the difference in RF bias between different sites. Results: The RF bias was significantly influenced by the breathing pattern and measurement site (both p < 0.001). Under normal breathing, the RF bias was insignificant in the arm, forehead, and wrist under (all p > 0.05) and significant in the other sites (all p < 0.05). Significant linear relationship between PPG-derived and reference RFs existed at all the sites (p < 0.001) except the wrist upper (p > 0.05). The linearity between PPG-derived and reference RFs was highest at the forehead (slope of best-fit line: 0.90, R 2: 0.64), followed by the earlobe, finger, arm, and wrist under (slope: 0.71, R 2: 0.40). Under deep breathing, there was no significant RF bias in all the measurement sites (p > 0.05) except forehead (p = 0.048). The effect of measurement site on RF bias was not significant (p > 0.05). The finger had the smallest RF bias and the narrowest limits of agreement. Conclusion: This study has demonstrated that the accuracy of PPG-derived RF depends on the measurement site and breathing pattern. The best sites are the forehead and finger, respectively, for normal and deep breathing patterns.

16.
Physiol Meas ; 40(7): 07TR01, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31195383

RESUMO

Respiratory rate (RR) is an important physiological parameter whose abnormality has been regarded as an important indicator of serious illness. In order to make RR monitoring simple to perform, reliable and accurate, many different methods have been proposed for such automatic monitoring. According to the theory of respiratory rate extraction, methods are categorized into three modalities: extracting RR from other physiological signals, RR measurement based on respiratory movements, and RR measurement based on airflow. The merits and limitations of each method are highlighted and discussed. In addition, current works are summarized to suggest key directions for the development of future RR monitoring methodologies.

17.
Biosci Rep ; 39(6)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31092699

RESUMO

Introduction: The treatment strategy for low-grade gliomas (LGGs) is still controversial, and there are no standardized criteria to predict the prognosis of patients with LGGs. Magnetic resonance imaging (MRI) is a routine test for preoperative diagnosis for LGG and can reflect the destructive features for the tumor. In the present study, we aimed to explore the relationship between the MRI features and prognosis in patients with LGG.Methods: Clinical data of 80 patients with pathologically proved LGGs between January 2010 and December 2016 were analyzed retrospectively. MRI features were classified as contrast enhancement pattern (focal enhancement, diffuse enhancement and ring-like enhancement), necrosis and cysts based on the preoperative MR images. Kaplan-Meier method and multivariate analysis were performed on the data by SPSS software to explore the prognostic significance of MRI features.Results: Patients with cystic LGG had a significantly longer 5-year progression-free survival (PFS) than that with no cyst (90.9 ± 8.7 vs 65.7 ± 9.1%, P=0.045). Multivariate analysis further verified cyst as an independent prognosis factor for PFS (P=0.027, hazard ratio [HR] = 0.084). Additionally, patients with ring-like enhancement exhibited significantly longer 5-year PFS time in the Kaplan-Meier survival curves (100 vs 67.2 ± 7.7%, P=0.049). There was no significant difference in PFS and overall survival (OS) between patients with or without necrosis.Conclusion: Our study suggests that cyst formation and ring-like enhancement on preoperative MR images can be useful to predict a favorable prognosis in patients with LGGs.

18.
Biochem Biophys Res Commun ; 515(1): 37-43, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31122697

RESUMO

miR-613 has been demonstrated to play critical roles in tumorigenesis and progression of a various type of cancers. However, its role and expression significance remain unclear in gastric cancer (GC). We detected the expression of miR-613 in 176 paired GC tissues and adjacent normal tissues, and found that miR-613 was significantly downregulated in GC tissues and its downregulation was correlated with T stage, lymph node invasion and advanced AJCC stages. Moreover, miR-613 expression could be an independent prognostic factor of GC. Biological function analysis indicated that miR-613 inhibited cell proliferation and invasion. Further analysis suggested that miR-613 inhibited Warburg effect of GC cells. Mechanically, we identified that miR-613 could directly bind to the 3'UTR of PFKFB2, thereby suppressing the expression of PFKFB2, which in turn, regulating glycolysis metabolism and cell growth. In conclusion, miR-613 served as a tumor suppressor by targeting PFKFB2, indicating that detecting miR-613 and modulation of miR-613 expression could be potential marker and clinical approach in GC patients.

19.
Nat Microbiol ; 4(8): 1378-1388, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31110366

RESUMO

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-ß-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.

20.
Emerg Microbes Infect ; 8(1): 734-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130074

RESUMO

Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NF-κB pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor ß-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.


Assuntos
Escherichia coli Êntero-Hemorrágica/patogenicidade , Infecções por Escherichia coli/fisiopatologia , Proteínas de Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , MAP Quinase Quinase Quinases/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Fatores de Virulência/metabolismo , Animais , Infecções por Escherichia coli/microbiologia , Células HEK293 , Humanos , Macrófagos Peritoneais , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células RAW 264.7
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