Extracellular fibrinogen-binding protein (Efb) from staphylococcus aureus inhibits the formation of platelet-leukocyte complexes

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Extracellular fibrinogen-binding protein (Efb) from Staphylococcus aureus inhibits platelet activation, although its mechanism of action has not been established. In this study, we discovered that the N-terminal region of Efb (Efb-N) promotes platelet binding of fibrinogen and that Efb-N binding to platelets proceeds via two independent mechanisms: fibrinogen-mediated and fibrinogen-independent. By proteomic analysis of Efb-interacting proteins within platelets and confirmation by pulldown assays followed by immunoblotting, we identified P-selectin and multimerin-1 as novel Efb interaction partners. The interaction of both P-selectin and multimerin-1 with Efb is independent of fibrinogen.Wefocused on Efb interaction with P-selectin. Excess of P-selectin extracellular domain significantly impaired Efb binding by activated platelets, suggesting that P-selectin is the main receptor for Efb on the surface of activated platelets. Efb-N interaction with P-selectin inhibited P-selectin binding to its physiological ligand, P-selectin glycoprotein ligand-1 (PSGL-1), both in cell lysates and in cell-free assays. Because of the importance of P-selectin-PSGL-1 binding in the interaction between platelets and leukocytes, we tested human whole blood and found that Efb abolishes the formation of platelet- monocyte and platelet-granulocyte complexes. In summary, we present evidence that in addition to its documented antithrombotic activity, Efb can play an immunoregulatory role via inhibition of P-selectin-PSGL-1-dependent formation of platelet- leukocyte complexes

Inference of hidden structures in complex physical systems by multi-scale clustering

We survey the application of a relatively new branch of statistical physics--"community detection"-- to data mining. In particular, we focus on the diagnosis of materials and automated image segmentation. Community detection describes the quest of partitioning a complex system involving many elements into optimally decoupled subsets or communities of such elements. We review a multiresolution variant which is used to ascertain structures at different spatial and temporal scales. Significant patterns are obtained by examining the correlations between different independent solvers. Similar to other combinatorial optimization problems in the NP complexity class, community detection exhibits several phases. Typically, illuminating orders are revealed by choosing parameters that lead to extremal information theory correlations.Comment: 25 pages, 16 Figures; a review of earlier work

Dynamic Community Detection into Analyzing of Wildfires Events

The study and comprehension of complex systems are crucial intellectual and scientific challenges of the 21st century. In this scenario, network science has emerged as a mathematical tool to support the study of such systems. Examples include environmental processes such as wildfires, which are known for their considerable impact on human life. However, there is a considerable lack of studies of wildfire from a network science perspective. Here, employing the chronological network concept -- a temporal network where nodes are linked if two consecutive events occur between them -- we investigate the information that dynamic community structures reveal about the wildfires' dynamics. Particularly, we explore a two-phase dynamic community detection approach, i.e., we applied the Louvain algorithm on a series of snapshots. Then we used the Jaccard similarity coefficient to match communities across adjacent snapshots. Experiments with the MODIS dataset of fire events in the Amazon basing were conducted. Our results show that the dynamic communities can reveal wildfire patterns observed throughout the year.Comment: 16 pages, 8 figure

Saphenofemoral arteriovenous fistula as hemodialysis access

<p>Abstract</p> <p>Background</p> <p>An upper limb arteriovenous (AV) fistula is the access of choice for haemodialysis (HD). There have been few reports of saphenofemoral AV fistulas (SFAVF) over the last 10-20 years because of previous suggestions of poor patencies and needling difficulties. Here, we describe our clinical experience with SFAVF.</p> <p>Methods</p> <p>SFAVFs were evaluated using the following variables: immediate results, early and late complications, intraoperative and postoperative complications (up to day 30), efficiency of the fistula after the onset of needling and complications associated to its use.</p> <p>Results</p> <p>Fifty-six SFAVF fistulas were created in 48 patients. Eight patients had two fistulas: 8 patent (16%), 10 transplanted (20%), 12 deaths (24%), 1 low flow (2%) and 20 thrombosis (39%) (first two months of preparation). One patient had severe hypotension during surgery, which caused thrombosis of the fistula, which was successfully thrombectomised, four thrombosed fistulae were successfully thrombectomised and revised on the first postoperative day. After 59 months of follow-up, primary patency was 44%.</p> <p>Conclusion</p> <p>SFAVF is an adequate alternative for patients without the possibility for other access in the upper limbs, allowing efficient dialysis with good long-term patency with a low complication rate.</p

Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia

<p>Abstract</p> <p>Background</p> <p>Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).</p> <p>Methods</p> <p>In this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in <it>RYR</it>1 transcripts was employed as a marker that allowed discrimination between the two alleles.</p> <p>Results</p> <p>In four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant <it>RYR</it>1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.</p> <p>Conclusion</p> <p>The data presented here revealed for the first time allele-specific differences in <it>RYR</it>1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.</p

A unified approach for a posteriori high-order curved mesh generation using solid mechanics

The paper presents a unified approach for the a posteriori generation of arbitrary high-order curvilinear meshes via a solid mechanics analogy. The approach encompasses a variety of methodologies, ranging from the popular incremental linear elastic approach to very sophisticated non-linear elasticity. In addition, an intermediate consistent incrementally linearised approach is also presented and applied for the first time in this context. Utilising a consistent derivation from energy principles, a theoretical comparison of the various approaches is presented which enables a detailed discussion regarding the material characterisation (calibration) employed for the different solid mechanics formulations. Five independent quality measures are proposed and their relations with existing quality indicators, used in the context of a posteriori mesh generation, are discussed. Finally, a comprehensive range of numerical examples, both in two and three dimensions, including challenging geometries of interest to the solids, fluids and electromagnetics communities, are shown in order to illustrate and thoroughly compare the performance of the different methodologies. This comparison considers the influence of material parameters and number of load increments on the quality of the generated high-order mesh, overall computational cost and, crucially, the approximation properties of the resulting mesh when considering an isoparametric finite element formulation

Modularity in Protein Complex and Drug Interactions Reveals New Polypharmacological Properties

Recent studies have highlighted the importance of interconnectivity in a large range of molecular and human disease-related systems. Network medicine has emerged as a new paradigm to deal with complex diseases. Connections between protein complexes and key diseases have been suggested for decades. However, it was not until recently that protein complexes were identified and classified in sufficient amounts to carry out a large-scale analysis of the human protein complex system. We here present the first systematic and comprehensive set of relationships between protein complexes and associated drugs and analyzed their topological features. The network structure is characterized by a high modularity, both in the bipartite graph and in its projections, indicating that its topology is highly distinct from a random network and that it contains a rich and heterogeneous internal modular structure. To unravel the relationships between modules of protein complexes, drugs and diseases, we investigated in depth the origins of this modular structure in examples of particular diseases. This analysis unveils new associations between diseases and protein complexes and highlights the potential role of polypharmacological drugs, which target multiple cellular functions to combat complex diseases driven by gain-of-function mutations

Immunological Basis for the Gender Differences in Murine Paracoccidioides brasiliensis Infection

This study aimed to investigate the immunological mechanisms involved in the gender distinct incidence of paracoccidioidomycosis (pcm), an endemic systemic mycosis in Latin America, which is at least 10 times more frequent in men than in women. Then, we compared the immune response of male and female mice to Paracoccidioides brasiliensis infection, as well as the influence in the gender differences exerted by paracoccin, a P. brasiliensis component with carbohydrate recognition property. High production of Th1 cytokines and T-bet expression have been detected in the paracoccin stimulated cultures of spleen cells from infected female mice. In contrast, in similar experimental conditions, cells from infected males produced higher levels of the Th2 cytokines and expressed GATA-3. Macrophages from male and female mice when stimulated with paracoccin displayed similar phagocytic capability, while fungicidal activity was two times more efficiently performed by macrophages from female mice, a fact that was associated with 50% higher levels of nitric oxide production. In order to evaluate the role of sexual hormones in the observed gender distinction, we have utilized mice that have been submitted to gonadectomy followed by inverse hormonal reconstitution. Spleen cells derived from castrated males reconstituted with estradiol have produced higher levels of IFN-γ (1291±15 pg/mL) and lower levels of IL-10 (494±38 pg/mL), than normal male in response to paracoccin stimulus. In contrast, spleen cells from castrated female mice that had been treated with testosterone produced more IL-10 (1284±36 pg/mL) and less IFN-γ (587±14 pg/mL) than cells from normal female. In conclusion, our results reveal that the sexual hormones had a profound effect on the biology of immune cells, and estradiol favours protective responses to P. brasiliensis infection. In addition, fungal components, such as paracoccin, may provide additional support to the gender dimorphic immunity that marks P. brasiliensis infection

Evolutionary genomics of a cold-adapted diatom: Fragilariopsis cylindrus

The Southern Ocean houses a diverse and productive community of organisms1, 2. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice3, 4, 5, 6, 7. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus8, 9, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean