Report of 2 fatal cases of adult necrotizing fasciitis and toxic shock syndrome caused by Streptococcus agalactiae.

We describe 2 cases of fatal necrotizing fasciitis and toxic shock syndrome caused by Streptococcus agalactiae-a rare entity that has been reported in only 9 patients-in 2 nonpregnant adults.published_or_final_versio

cis-Oxoruthenium complexes supported by chiral tetradentate amine (N4) ligands for hydrocarbon oxidations

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Statistical method on nonrandom clustering with application to somatic mutations in cancer

<p>Abstract</p> <p>Background</p> <p>Human cancer is caused by the accumulation of tumor-specific mutations in oncogenes and tumor suppressors that confer a selective growth advantage to cells. As a consequence of genomic instability and high levels of proliferation, many passenger mutations that do not contribute to the cancer phenotype arise alongside mutations that drive oncogenesis. While several approaches have been developed to separate driver mutations from passengers, few approaches can specifically identify activating driver mutations in oncogenes, which are more amenable for pharmacological intervention.</p> <p>Results</p> <p>We propose a new statistical method for detecting activating mutations in cancer by identifying nonrandom clusters of amino acid mutations in protein sequences. A probability model is derived using order statistics assuming that the location of amino acid mutations on a protein follows a uniform distribution. Our statistical measure is the differences between pair-wise order statistics, which is equivalent to the size of an amino acid mutation cluster, and the probabilities are derived from exact and approximate distributions of the statistical measure. Using data in the Catalog of Somatic Mutations in Cancer (COSMIC) database, we have demonstrated that our method detects well-known clusters of activating mutations in KRAS, BRAF, PI3K, and <it>β</it>-catenin. The method can also identify new cancer targets as well as gain-of-function mutations in tumor suppressors.</p> <p>Conclusions</p> <p>Our proposed method is useful to discover activating driver mutations in cancer by identifying nonrandom clusters of somatic amino acid mutations in protein sequences.</p

Structure of a bacterial type III secretion system in contact with a host membrane in situ

Many bacterial pathogens of animals and plants use a conserved type III secretion system (T3SS) to inject virulence effector proteins directly into eukaryotic cells to subvert host functions. Contact with host membranes is critical for T3SS activation, yet little is known about T3SS architecture in this state or the conformational changes that drive effector translocation. Here we use cryo-electron tomography and sub-tomogram averaging to derive the intact structure of the primordial Chlamydia trachomatis T3SS in the presence and absence of host membrane contact. Comparison of the averaged structures demonstrates a marked compaction of the basal body (4 nm) occurs when the needle tip contacts the host cell membrane. This compaction is coupled to a stabilization of the cytosolic sorting platform– ATPase. Our findings reveal the first structure of a bacterial T3SS from a major human pathogen engaged with a eukaryotic host, and reveal striking ‘pump-action’ conformational changes that underpin effector injection

Maintenance of traditional cultural orientation is associated with lower rates of obesity and sedentary behaviours among African migrant children to Australia

Background: Migrants from developing to developed countries rapidly develop more obesity than the host population. While the effects of socio-economic status on obesity are well established, the influence of cultural factors, including acculturation, is not known.Objective: To examine the association between acculturation and obesity and its risk factors among African migrant children in Australia.Design and participants: A cross-sectional study using a non-probability sample of 3- to 12-year-old sub-Saharan African migrant children. A bidimensional model of strength of affiliation with African and Australian cultures was used to divide the sample into four cultural orientations: traditional (African), assimilated (Australian), integrated (both) and marginalized (neither).Main outcome measures: Body mass index (BMI), leisure-time physical activity (PA) and sedentary behaviours (SBs) and energy density of food.Results: In all, 18.4% (95% confidence interval (CI): 14&ndash;23%) were overweight and 8.6% (95% CI: 6&ndash;12%) were obese. After adjustment for confounders, integrated (&szlig;=1.1; P&lt;0.05) and marginalized &szlig;(=1.4; P&lt;0.01) children had higher BMI than traditional children. However, integrated children had significantly higher time engaged in both PA (&szlig;=46.9, P&lt;0.01) and SBs (&szlig;=43.0, P&lt;0.05) than their traditional counterparts. In comparison with traditional children, assimilated children were more sedentary (&szlig;=57.5, P&lt;0.01) while marginalization was associated with increased consumption of energy-dense foods (&szlig;=42.0, P&lt;0.05).Conclusions: Maintenance of traditional orientation was associated with lower rates of obesity and SBs. Health promotion programs and frameworks need to be rooted in traditional values and habits to maintain and reinforce traditional dietary and PA habits, as well as identify the marginalized clusters and address their needs.<br /

Integration of Evolutionary Features for the Identification of Functionally Important Residues in Major Facilitator Superfamily Transporters

The identification of functionally important residues is an important challenge for understanding the molecular mechanisms of proteins. Membrane protein transporters operate two-state allosteric conformational changes using functionally important cooperative residues that mediate long-range communication from the substrate binding site to the translocation pathway. In this study, we identified functionally important cooperative residues of membrane protein transporters by integrating sequence conservation and co-evolutionary information. A newly derived evolutionary feature, the co-evolutionary coupling number, was introduced to measure the connectivity of co-evolving residue pairs and was integrated with the sequence conservation score. We tested this method on three Major Facilitator Superfamily (MFS) transporters, LacY, GlpT, and EmrD. MFS transporters are an important family of membrane protein transporters, which utilize diverse substrates, catalyze different modes of transport using unique combinations of functional residues, and have enough characterized functional residues to validate the performance of our method. We found that the conserved cores of evolutionarily coupled residues are involved in specific substrate recognition and translocation of MFS transporters. Furthermore, a subset of the residues forms an interaction network connecting functional sites in the protein structure. We also confirmed that our method is effective on other membrane protein transporters. Our results provide insight into the location of functional residues important for the molecular mechanisms of membrane protein transporters

Computing Highly Correlated Positions Using Mutual Information and Graph Theory for G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM) domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families