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61.
62.
Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 interactome network. Notably, in non-infected cells, TRAF3 was found associated with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cis-Golgi apparatus. Upon dsRNA and dsDNA sensing however, the Golgi apparatus fragmented into cytoplasmic punctated structures containing TRAF3 allowing its colocalization and interaction with Mitochondrial AntiViral Signaling (MAVS), the essential mitochondria-bound RIG-I-like Helicase (RLH) adaptor. In contrast, retention of TRAF3 at the ER-to-Golgi vesicular transport system blunted the ability of TRAF3 to interact with MAVS upon viral infection and consequently decreased type I IFN response. Moreover, depletion of Sec16A and p115 led to a drastic disorganization of the Golgi paralleled by the relocalization of TRAF3, which under these conditions was unable to associate with MAVS. Consequently, upon dsRNA and dsDNA sensing, ablation of Sec16A and p115 was found to inhibit IRF3 activation and anti-viral gene expression. Reciprocally, mild overexpression of Sec16A or p115 in Hec1B cells increased the activation of IFNβ, ISG56 and NF-κB -dependent promoters following viral infection and ectopic expression of MAVS and Tank-binding kinase-1 (TBK1). In line with these results, TRAF3 was found enriched in immunocomplexes composed of p115, Sec16A and TBK1 upon infection. Hence, we propose a model where dsDNA and dsRNA sensing induces the formation of membrane-bound compartments originating from the Golgi, which mediate the dynamic association of TRAF3 with MAVS leading to an optimal induction of innate immune responses.  相似文献   
63.
G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that, via trimetric guanine nucleotide-binding proteins (G-proteins), initiate some signaling pathways in the eukaryotic cell. Many diseases involve malfunction of GPCRs making their role evident in drug discovery. Thus, the automatic prediction of GPCRs can be very helpful in the pharmaceutical industry. However, prediction of GPCRs, their families, and their subfamilies is a challenging task. In this article, GPCRs are classified into families, subfamilies, and sub-subfamilies using pseudo-amino-acid composition and multiscale energy representation of different physiochemical properties of amino acids. The aim of the current research is to assess different feature extraction strategies and to develop a hybrid feature extraction strategy that can exploit the discrimination capability in both the spatial and transform domains for GPCR classification. Support vector machine, nearest neighbor, and probabilistic neural network are used for classification purposes. The overall performance of each classifier is computed individually for each feature extraction strategy. It is observed that using the jackknife test the proposed GPCR–hybrid method provides the best results reported so far. The GPCR–hybrid web predictor to help researchers working on GPCRs in the field of biochemistry and bioinformatics is available at http://111.68.99.218/GPCR.  相似文献   
64.
Specific activation of amino acids by aminoacyl-tRNA synthetases (aaRSs) is essential for maintaining fidelity during protein translation. Here, we present crystal structure of malaria parasite Plasmodium falciparum tryptophanyl-tRNA synthetase (Pf-WRS) catalytic domain (AAD) at 2.6 Å resolution in complex with L-tryptophan. Confocal microscopy-based localization data suggest cytoplasmic residency of this protein. Pf-WRS has an unusual N-terminal extension of AlaX-like domain (AXD) along with linker regions which together seem vital for enzymatic activity and tRNA binding. Pf-WRS is not proteolytically processed in the parasites and therefore AXD likely provides tRNA binding capability rather than editing activity. The N-terminal domain containing AXD and linker region is monomeric and would result in an unusual overall architecture for Pf-WRS where the dimeric catalytic domains have monomeric AXDs on either side. Our PDB-wide comparative analyses of 47 WRS crystal structures also provide new mechanistic insights into this enzyme family in context conserved KMSKS loop conformations.  相似文献   
65.
The regulation of protein function is often achieved through post-translational modifications including phosphorylation, methylation, ubiquitination, and acetylation. The role of acetylation has been most extensively studied in the context of histones, but it is becoming increasingly evident that this modification now includes other proteins. The Sir2 family of NAD-dependent deacetylases was initially recognized as mediating gene silencing through histone deacetylation, but several family members display non-nuclear sub-cellular localization and deacetylate non-histone protein substrates. Although many structural and enzymatic studies of Sir2 proteins have been reported, how substrate recognition is achieved by this family of enzymes is unknown. Here we use in vitro deacetylase assays and a variety of potential substrates to examine the substrate specificity of yeast homologue Hst2. We show that Hst2 is specific for acetyl-lysine within proteins; it does not deacetylate small polycations such as acetyl-spermine or acetylated amino ter-mini of proteins. Furthermore we have found that Hst2 displays conformational rather than sequence specificity, preferentially deacetylating acetyl-lysine within unstructured regions of proteins. Our results suggest that this conformational requirement may be a general feature for substrate recognition in the Sir2 family.  相似文献   
66.
Floristic inventory of wild plants comprised of total 129 plant species belonging to 42 families and 101 genera. Location wise UAP contributed greater amount of plant species (53%), followed by PFI (29%), UoP (15%) and Islamia College (3%). Majority of the plants were annual herbs (58%), followed by perennial herbs (29%), trees (10%) and shrubs (3%), respectively. The leading families included Poaceae, contributed 18% of all the plant species. Habitat wise, 44% of them grew in grassy plains, abandoned lands and mismanaged lawns, followed by roadsides (34%), undulating grassy plains (15%) and stony grounds with uneven topography along with stream banks and drainage ditches (7%). Still some of plant species were used as ornamentals, while some shrubs were use in fencing around fields; others were utilized as green manure, for fishing, sheltering and religious purposes. Exploring and identifying the wild flora of the campus and compiling as a handbook would help to monitor new plants introductions particularly of noxious invasive weeds in the campuses in future.  相似文献   
67.
Mesenchymal stem cells (MSCs) have therapeutic potential for treatment of diabetes. However, in vitro behavior of MSCs in high glucose condition as well as presence of glucose lowering agents is not fully understood. Because MSCs have an important role in tissue repair, we examined the effects of metformin and celecoxib on viability of MSCs in different glucose conditions. MSCs, from umbilical cord blood, were cultured in normoglycemic (glucose 5.5 mM), midglycemic (glucose 10 mM), and hyperglycemic (glucose 25 mM) conditions, and the cell viability was evaluated by MTT assay. The cytotoxicity and secretion of GDF‐15 were further tested in MSCs treated with metformin and celecoxib in various glucose concentrations. Our results showed that high glucose condition lowered viability of MSCs. Metformin treatment also inhibited proliferation of MSCs, but its toxicity was not changed in high glucose condition. Celecoxib induced cytotoxicity in MSCs, and the toxicity was increased in high glucose condition. Metformin and celecoxib induced release from MSCs; however, high glucose inhibited the metformin‐induced GDF‐15 release. These findings suggested that metformin did not increase the cytotoxicity of high glucose condition in MSCs. Moreover, celecoxib treatment in diabetic condition can reduce the viability of MSCs to proliferate and regenerate perhaps via change in release of GDF‐15.  相似文献   
68.
The phenomena related to brain function occur as the interplay of various modules at different spatial and temporal scales. Particularly, the integration of the dynamical behavior of cells within the complex brain topology reveals a heterogeneous multi-scale problem, which has, to date, mainly been addressed by methods of statistical physics such as mean-field approximations. In contrast, the present study introduces an abstract mathematical model of a deterministic nature that provides a robust integral transformation of the microscopic activities into macroscopic spatiotemporal patterns. The existence of the transformation operator is guaranteed by the convergence of a repetitive patching of the network domain with its fundamental domains that express the local topologies of the tissue. Depending on the choice of the local connectivity function, this framework represents a computationally efficient generalization of the classical Kirchhoff’s, Hebbian, and Hopfield’s approaches. The capabilities of this multi-scale method have been evaluated within the structure of the dorsal striatum of rats, a brain region with major involvement in motor and cognitive information processing. Numerical simulations suggest the formation of characteristic spatiotemporal patterns due to the activation of cholinergic interneurons.  相似文献   
69.
70.

Background  

Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours?  相似文献   
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