POLYVIEW-MM: web-based platform for animation and analysis of molecular simulations

Molecular simulations offer important mechanistic and functional clues in studies of proteins and other macromolecules. However, interpreting the results of such simulations increasingly requires tools that can combine information from multiple structural databases and other web resources, and provide highly integrated and versatile analysis tools. Here, we present a new web server that integrates high-quality animation of molecular motion (MM) with structural and functional analysis of macromolecules. The new tool, dubbed POLYVIEW-MM, enables animation of trajectories generated by molecular dynamics and related simulation techniques, as well as visualization of alternative conformers, e.g. obtained as a result of protein structure prediction methods or small molecule docking. To facilitate structural analysis, POLYVIEW-MM combines interactive view and analysis of conformational changes using Jmol and its tailored extensions, publication quality animation using PyMol, and customizable 2D summary plots that provide an overview of MM, e.g. in terms of changes in secondary structure states and relative solvent accessibility of individual residues in proteins. Furthermore, POLYVIEW-MM integrates visualization with various structural annotations, including automated mapping of known inter-action sites from structural homologs, mapping of cavities and ligand binding sites, transmembrane regions and protein domains. URL: http://polyview.cchmc.org/conform.html

New approaches to modernization of spatial and sectorial development of Russian and Greek regional economy

The purpose of the article is to develop new highly-effective organizational and managerial approaches to conduct of modernization of spatial and sectorial development of regional economy of Russia and Greece. During conduct of the research, the authors use such scientific methods as systemic structural and comparative analysis. The authors determine the level of differentiation of the level and structure of economic development of regions of Russia and Greece in 2012 through consideration of indicators of GRP per capita of regions and GDP, as well as gross added value for regions and sectors of production. During the research, the authors come to the conclusion that modern Russia and Greece are peculiar for presence of serious disproportions in the level of economic development of regions, which is a reason for unbalanced development of economic systems of these countries, slowdown of rates of national economic growth, and crisis. This situation is caused by orientation at the use of geographical approach. As alternative, the authors offer three new approaches to modernization of spatial and sectorial development of regional economy of Russia and Greece: cluster, client-oriented, and anti-crisis and substantiate expediency of transition to their application. These approaches allow overcoming the aforementioned drawbacks and ensure well-balanced development of regional economy in the long-term, as well as its high sustainability and quick overcoming of economic crises. For provision of high effectiveness of the process of selecting the optimal approach to modernization of spatial and sectorial development of regional economy by territorial authorities, it is offered to use the corresponding proprietary algorithm of modernization of spatial and sectorial development of regional economy.peer-reviewe

IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn2+ that Promotes Pathogen Persistence in Macrophages

SummaryAlternative activation of macrophages promotes wound healing but weakens antimicrobial defenses against intracellular pathogens. The mechanisms that suppress macrophage function to create a favorable environment for pathogen growth remain elusive. We show that interleukin (IL)-4 triggers a metallothionein 3 (MT3)- and Zn exporter SLC30A4-dependent increase in the labile Zn2+ stores in macrophages and that intracellular pathogens can exploit this increase in Zn to survive. IL-4 regulates this pathway by shuttling extracellular Zn into macrophages and by activating cathepsins that act on MT3 to release bound Zn. We show that IL-4 can modulate Zn homeostasis in both human monocytes and mice. In vivo, MT3 can repress macrophage function in an M2-polarizing environment to promote pathogen persistence. Thus, MT3 and SLC30A4 dictate the size of the labile Zn2+ pool and promote the survival of a prototypical intracellular pathogen in M2 macrophages

Structure of a bacterial cell surface decaheme electron conduit

Some bacterial species are able to utilize extracellular mineral forms of iron and manganese as respiratory electron acceptors. In Shewanella oneidensis this involves decaheme cytochromes that are located on the bacterial cell surface at the termini of trans-outer-membrane electron transfer conduits. The cell surface cytochromes can potentially play multiple roles in mediating electron transfer directly to insoluble electron sinks, catalyzing electron exchange with flavin electron shuttles or participating in extracellular intercytochrome electron exchange along “nanowire” appendages. We present a 3.2-Å crystal structure of one of these decaheme cytochromes, MtrF, that allows the spatial organization of the 10 hemes to be visualized for the first time. The hemes are organized across four domains in a unique crossed conformation, in which a staggered 65-Å octaheme chain transects the length of the protein and is bisected by a planar 45-Å tetraheme chain that connects two extended Greek key split ß-barrel domains. The structure provides molecular insight into how reduction of insoluble substrate (e.g., minerals), soluble substrates (e.g., flavins), and cytochrome redox partners might be possible in tandem at different termini of a trifurcated electron transport chain on the cell surface

Identification of a heterogeneous and dynamic ciliome during embryonic development and cell differentiation.

Primary cilia are nearly ubiquitous organelles that transduce molecular and mechanical signals. Although the basic structure of the cilium and the cadre of genes that contribute to ciliary formation and function (the ciliome) are believed to be evolutionarily conserved, the presentation of ciliopathies with narrow, tissue-specific phenotypes and distinct molecular readouts suggests that an unappreciated heterogeneity exists within this organelle. Here, we provide a searchable transcriptomic resource for a curated primary ciliome, detailing various subgroups of differentially expressed genes within the ciliome that display tissue and temporal specificity. Genes within the differentially expressed ciliome exhibited a lower level of functional constraint across species, suggesting organism and cell-specific function adaptation. The biological relevance of ciliary heterogeneity was functionally validated by using Cas9 gene-editing to disrupt ciliary genes that displayed dynamic gene expression profiles during osteogenic differentiation of multipotent neural crest cells. Collectively, this novel primary cilia-focused resource will allow researchers to explore longstanding questions related to how tissue and cell-type specific functions and ciliary heterogeneity may contribute to the range of phenotypes associated with ciliopathies

Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis

Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10−7, OR = 1.70, 95%CI = 1.38 − 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10−8, OR = 0.65(0.57 − 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10−9, OR = 1.73 95%CI = (1.44 − 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10−5, OR = 1.39, 95%CI = (1.19 − 1.61)], previously demonstrated in metabolic disease and diabetes in adults. Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications

The physiological importance of photosynthetic ferredoxin NADP+ oxidoreductase (FNR) isoforms in wheat

Ferredoxin NADP+ oxidoreductase (FNR) enzymes catalyse electron transfer between ferredoxin and NADPH. In plants, a photosynthetic FNR (pFNR) transfers electrons from reduced ferredoxin to NADPH for the final step of linear electron flow, providing reductant for carbon fixation. pFNR is also thought to play important roles in two different mechanisms of cyclic electron flow around photosystem I; and photosynthetic reductant is itself partitioned between competing linear, cyclic, and alternative electron flow pathways. Four pFNR protein isoforms in wheat that display distinct reaction kinetics with leaf-type ferredoxin have previously been identified. It has been suggested that these isoforms may be crucial to the regulation of reductant partition between carbon fixation and other metabolic pathways. Here the 12 cm primary wheat leaf has been used to show that the alternative N-terminal pFNRI and pFNRII protein isoforms have statistically significant differences in response to the physiological parameters of chloroplast maturity, nitrogen regime, and oxidative stress. More specifically, the results obtained suggest that the alternative N-terminal forms of pFNRI have distinct roles in the partitioning of photosynthetic reductant. The role of alternative N-terminal processing of pFNRI is also discussed in terms of its importance for thylakoid targeting. The results suggest that the four pFNR protein isoforms are each present in the chloroplast in phosphorylated and non-phosphorylated states. pFNR isoforms vary in putative phosphorylation responses to physiological parameters, but the physiological significance requires further investigation

Interaction site prediction by structural similarity to neighboring clusters in protein-protein interaction networks

<p>Abstract</p> <p>Background</p> <p>Recently, revealing the function of proteins with protein-protein interaction (PPI) networks is regarded as one of important issues in bioinformatics. With the development of experimental methods such as the yeast two-hybrid method, the data of protein interaction have been increasing extremely. Many databases dealing with these data comprehensively have been constructed and applied to analyzing PPI networks. However, few research on prediction interaction sites using both PPI networks and the 3D protein structures complementarily has explored.</p> <p>Results</p> <p>We propose a method of predicting interaction sites in proteins with unknown function by using both of PPI networks and protein structures. For a protein with unknown function as a target, several clusters are extracted from the neighboring proteins based on their structural similarity. Then, interaction sites are predicted by extracting similar sites from the group of a protein cluster and the target protein. Moreover, the proposed method can improve the prediction accuracy by introducing repetitive prediction process.</p> <p>Conclusions</p> <p>The proposed method has been applied to small scale dataset, then the effectiveness of the method has been confirmed. The challenge will now be to apply the method to large-scale datasets.</p

SGC - Structural Biology and Human Health: A New Approach to Publishing Structural Biology Results

The Structural Genomics Consortium (SGC) is a not-for-profit, public-private partnership established to deliver novel structural biology knowledge on proteins of medical relevance and place this information into the public domain without restriction, spearheading the concept of "Open-Source Science" to enable drug discovery. The SGC is a major provider of structural information focussed on proteins related to human health, contributing 20.5% of novel structures released by the PDB in 2008. In this article we describe the PLoS ONE Collection entitled 'Structural Biology and Human Health: Medically Relevant Proteins from the SGC'. This Collection contains a series of articles documenting many of the novel protein structures determined by the SGC and work to further characterise their function. Each article in this Collection can be read in an enhanced version where we have integrated our interactive and intuitive 3D visualisation platform, known as iSee. This publishing platform enables the communication of complex structural biology and related data to a wide audience of non-structural biologists. With the use of iSee as the first example of an interactive and intuitive 3D document publication method as part of PLoS ONE, we are pushing the boundaries of structural biology data delivery and peer-review. Our strong desire is that this step forward will encourage others to consider the need for publication of three dimensional and associated data in a similar manner. © 2009 Lee et al

Computational Prediction of Heme-Binding Residues by Exploiting Residue Interaction Network

Computational identification of heme-binding residues is beneficial for predicting and designing novel heme proteins. Here we proposed a novel method for heme-binding residue prediction by exploiting topological properties of these residues in the residue interaction networks derived from three-dimensional structures. Comprehensive analysis showed that key residues located in heme-binding regions are generally associated with the nodes with higher degree, closeness and betweenness, but lower clustering coefficient in the network. HemeNet, a support vector machine (SVM) based predictor, was developed to identify heme-binding residues by combining topological features with existing sequence and structural features. The results showed that incorporation of network-based features significantly improved the prediction performance. We also compared the residue interaction networks of heme proteins before and after heme binding and found that the topological features can well characterize the heme-binding sites of apo structures as well as those of holo structures, which led to reliable performance improvement as we applied HemeNet to predicting the binding residues of proteins in the heme-free state. HemeNet web server is freely accessible at http://mleg.cse.sc.edu/hemeNet/