Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase

<p>Abstract</p> <p>Background</p> <p>The tripartite motif (TRIM) proteins are a family of more than 70 members in human. However, only a few of them have been well studied. The TRIM proteins contain the conserved RING, B-box, coiled-coil, and SPRY domains, most of which are involved in protein ubiquitination. TRIM38 is a member of the TRIM protein family, which we studied in more detail here as its functions are largely unknown.</p> <p>Results</p> <p>Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation.</p> <p>Conclusions</p> <p>Our observations demonstrate that TRIM38 has E3 ubiquitin ligase activity and can be degraded during virus infection. These findings may provide insight into innate immune signaling pathways.</p

Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

<p>Abstract</p> <p>Background</p> <p>The nonstructural protein 1 (NSP1) of rotavirus has been reported to block interferon (IFN) signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs) and (or) the β-transducin repeat containing protein (β-TrCP). However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms.</p> <p>Results</p> <p>The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s) other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I), but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS), indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way.</p> <p>Conclusions</p> <p>Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.</p

Metabolic risk factors of cognitive impairment in young women with major psychiatric disorder

BackgroundCognitive performance improves clinical outcomes of patients with major psychiatric disorder (MPD), but is impaired by hyperglycemia. Psychotropic agents often induce metabolism syndrome (MetS). The identification of modifiable metabolic risk factors of cognitive impairment may enable targeted improvements of patient care.ObjectiveTo investigate the relationship between MetS and cognitive impairment in young women with MPD, and to explore risk factors.MethodsWe retrospectively studied women of 18–34 years of age receiving psychotropic medications for first-onset schizophrenia (SCH), bipolar disorder (BP), or major depressive disorder (MDD). Data were obtained at four time points: presentation but before psychotropic medication; 4–8 and 8–12 weeks of psychotropic therapy; and enrollment. MATRICS Consensus Cognitive Battery, (MCCB)—based Global Deficit Scores were used to assess cognitive impairment. Multiple logistic analysis was used to calculate risk factors. Multivariate models were used to investigate factors associated with cognitive impairment.ResultsWe evaluated 2,864 participants. Cognitive impairment was observed in 61.94% of study participants, and was most prevalent among patients with BP (69.38%). HbA1c within the 8–12 week-treatment interval was the most significant risk factor and highest in BP. Factors in SCH included pre-treatment waist circumference and elevated triglycerides during the 8–12 weeks treatment interval. Cumulative dosages of antipsychotics, antidepressants, and valproate were associated with cognitive impairment in all MPD subgroups, although lithium demonstrated a protect effect (all P &lt; 0.001).ConclusionsCognitive impairment was associated with elevated HbA1c and cumulative medication dosages. Pre-treatment waist circumference and triglyceride level at 8–12 weeks were risk factors in SCH. Monitoring these indices may inform treatment revisions to improve clinical outcomes

Phase, microstructure and service character of as-deposited and short-time heat-treated Ni-Mo alloys with mixed state.

Considering the amorphous and nano-crystalline cluster structure and their activity, on the basis of the mixed structure Ni-Mo alloys, the crystallization kinetics of the alloys and the performance of the alloys after heat treatment with different mixed structure were studied. The phase structure and composition were determined by X-ray powder diffraction. The crystallization activation energy of the mixed structure was obtained by differential scanning calorimetry. The electrochemical activity of the mixed structure alloy was determined by electrochemical analysis. The experimental results show that the structural stability of the mixed-structure alloy is better, but the crystallization activation energy is much lower than that of the amorphous alloy. The crystallization process consists of a meta-stable structure transition and a new phase formation. The electrochemical properties of the alloy indicated that the alloy with the mixed structure has higher electrochemical activity, with higher hardness and better corrosion resistance, which results from the large true contact surface and the large number of active centers in this material structure

Lysosome-associated membrane glycoprotein 3 is involved in influenza A virus replication in human lung epithelial (A549) cells

<p>Abstract</p> <p>Background</p> <p>Influenza A virus mutates rapidly, rendering antiviral therapies and vaccines directed against virus-encoded targets ineffective. Knowledge of the host factors and molecular pathways exploited by influenza virus will provide further targets for novel antiviral strategies. However, the critical host factors involved in influenza virus infection have not been fully defined.</p> <p>Results</p> <p>We demonstrated that LAMP3, a member of lysosome-associated membrane glycoprotein (LAMP) family, was significantly induced in human lung epithelial (A549) cells upon influenza A virus infection. Knockdown of LAMP3 expression by RNA interference attenuated production of viral nucleoprotein (NP) as well as virus titers. Confocal microscopy results demonstrated that viral NP is colocalized within LAMP3 positive vesicles at early stages of virus infection. Furthermore, knockdown of LAMP3 expression led to a reduction in nuclear accumulation of viral NP and impeded virus replication.</p> <p>Conclusions</p> <p>LAMP3 is an influenza A virus inducible gene, and plays an important role in viral post-entry steps. Our observations may provide insights into the mechanism of influenza virus replication and potential targets for novel anti-influenza therapeutics.</p

Social-Based Cooperative Caching in DTNs: A Contact Duration Aware Approach

Abstract—Data access is an important issue in Delay Tolerant Networks (DTNs), and a common technique to improve the performance of data access is cooperative caching. However, due to the unpredictable node mobility in DTNs, traditional caching schemes cannot be directly applied. In this paper, we propose DAC, a novel caching protocol adaptive to the challenging environment of DTNs. Specifically, we exploit the social community structure to combat the unstable network topology in DTNs. We propose a new centrality metric to evaluate the caching capability of each node within a community, and solutions based on this metric are proposed to determine where to cache. More importantly, we consider the impact of the contact duration limitation on cooperative caching, which has been ignored by the existing works. We prove that the marginal caching benefit that a node can provide diminishes when more data is cached. We derive an adaptive caching bound for each mobile node according to its specific contact patterns with others, to limit the amount of data it caches. In this way, both the storage space and the contact opportunities are better utilized. To mitigate the coupon collector’s problem, network coding techniques are used to further improve the caching efficiency. Extensive trace-driven simulations show that our cooperative caching protocol can significantly improve the performance of data access in DTNs

TRIM38 negatively regulates TLR3-mediated IFN-β signaling by targeting TRIF for degradation.

Toll-like receptors (TLRs) mediated immune response is crucial for combating pathogens and must be tightly controlled. Tripartite motif (TRIM) proteins are a family of proteins that is involved in a variety of biological and physiological processes. Some members of the TRIM family are important in the regulation of innate immunity. Although it has been shown that TRIM38 negatively regulates innate immunity, the mechanisms by which it does so have not been fully addressed. In this study, we demonstrated that TRIM38 negatively regulates Toll-like receptor 3 (TLR3)-mediated type I interferon signaling by targeting TIR domain-containing adaptor inducing IFN-β (TRIF). We found that overexpression of TRIM38 inhibits TLR3-mediated type I interferon signaling, whereas knockdown of TRIM38 has the reverse effects. We further showed that TRIM38 targets TRIF, a critical adaptor protein downstream of TLR3. TRIF is co-immunoprecipitated with TRIM38, and domain mapping experiments show that PRYSPRY of TRIM38 interacts with the N-terminus of TRIF. Overexpression of TRIM38 decreased expression of overexpressed and endogenous TRIF. This effect could be inhibited by MG132 treatment. Furthermore, the RING/B-box domain of TRIM38 is critical for K48-linked polyubiquitination and proteasomal degradation of TRIF. Collectively, our results suggest that TRIM38 may act as a novel negative regulator for TLR3-mediated type I interferon signaling by targeting TRIF for degradation

TRIM38 Negatively Regulates TLR3-Mediated IFN-β Signaling by Targeting TRIF for Degradation

Toll-like receptors (TLRs) mediated immune response is crucial for combating pathogens and must be tightly controlled. Tripartite motif (TRIM) proteins are a family of proteins that is involved in a variety of biological and physiological processes. Some members of the TRIM family are important in the regulation of innate immunity. Although it has been shown that TRIM38 negatively regulates innate immunity, the mechanisms by which it does so have not been fully addressed. In this study, we demonstrated that TRIM38 negatively regulates Toll-like receptor 3 (TLR3)-mediated type I interferon signaling by targeting TIR domain-containing adaptor inducing IFN-β (TRIF). We found that overexpression of TRIM38 inhibits TLR3-mediated type I interferon signaling, whereas knockdown of TRIM38 has the reverse effects. We further showed that TRIM38 targets TRIF, a critical adaptor protein downstream of TLR3. TRIF is co-immunoprecipitated with TRIM38, and domain mapping experiments show that PRYSPRY of TRIM38 interacts with the N-terminus of TRIF. Overexpression of TRIM38 decreased expression of overexpressed and endogenous TRIF. This effect could be inhibited by MG132 treatment. Furthermore, the RING/B-box domain of TRIM38 is critical for K48-linked polyubiquitination and proteasomal degradation of TRIF. Collectively, our results suggest that TRIM38 may act as a novel negative regulator for TLR3-mediated type I interferon signaling by targeting TRIF for degradation

Intrapulmonary lymph node metastasis is common in clinically staged IA adenocarcinoma of the lung

Background Intrapulmonary lymph nodes (LNs, stations 11–14) are usually omitted in postoperative pathological examination. Some non‐small cell lung cancer (NSCLC) patients with intrapulmonary LN metastasis are incorrectly diagnosed as N0 cases. Furthermore, underestimation of intrapulmonary LN involvement in clinically early stage NSCLC may lead to the incorrect choice of surgical procedure: lobectomy or sublobar resection. This study was conducted to determine the status of intrapulmonary LN involvement in clinically staged IA (c‐T1N0M0) peripheral adenocarcinoma of the lung. Methods Seventy‐five lobectomy specimens of c‐T1N0M0 peripheral adenocarcinoma of the lung were carefully dissected to find intrapulmonary LNs. The longest diameter of each intrapulmonary LN was measured and sent for pathological examination, together with hilar and mediastinal LNs, to investigate the relationship between LN metastasis and primary tumor size. Results Intrapulmonary LN metastasis was detected in 22.7%(17/75) of patients. Positive LNs were detected in 21.7% (10/46) of T1b patients and 45% (11/24) of T1c patients, while no metastasis (0/5) was observed in T1a patients (P = 0.036). The mean longest diameter of the 17 involved intrapulmonary LNs was only 6.5 ± 2.1 mm, which was not significantly different to the size of negative intrapulmonary LNs (5.2 ± 1.4 mm). Conclusions Intrapulmonary LN metastasis is common in clinically staged IA peripheral adenocarcinoma of the lung. LN metastasis is related to tumor size, and this should be taken into account to determine appropriate surgical procedures and postoperative treatment. Computed tomography is not a reliable method to judge LN metastasis, particularly intrapulmonary LN metastasis

DTWscore: differential expression and cell clustering analysis for time-series single-cell RNA-seq data

Abstract Background The development of single-cell RNA sequencing has enabled profound discoveries in biology, ranging from the dissection of the composition of complex tissues to the identification of novel cell types and dynamics in some specialized cellular environments. However, the large-scale generation of single-cell RNA-seq (scRNA-seq) data collected at multiple time points remains a challenge to effective measurement gene expression patterns in transcriptome analysis. Results We present an algorithm based on the Dynamic Time Warping score (DTWscore) combined with time-series data, that enables the detection of gene expression changes across scRNA-seq samples and recovery of potential cell types from complex mixtures of multiple cell types. Conclusions The DTWscore successfully classify cells of different types with the most highly variable genes from time-series scRNA-seq data. The study was confined to methods that are implemented and available within the R framework. Sample datasets and R packages are available at https://github.com/xiaoxiaoxier/DTWscore