Coarse Graining of Nonbonded Inter-particle Potentials Using Automatic Simplex Optimization to Fit Structural Properties

We implemented a coarse-graining procedure to construct mesoscopic models of complex molecules. The final aim is to obtain better results on properties depending on slow modes of the molecules. Therefore the number of particles considered in molecular dynamics simulations is reduced while conserving as many properties of the original substance as possible. We address the problem of finding nonbonded interaction parameters which reproduce structural properties from experiment or atomistic simulations. The approach consists of optimizing automatically nonbonded parameters using the simplex algorithm to fit structural properties like the radial distribution function as target functions. Moreover, any mix of structural and thermodynamic properties can be included in the target function. Different spherically symmetric inter-particle potentials are discussed. Besides demonstrating the method for Lennard--Jones liquids, it is applied to several more complex molecular liquids such as diphenyl carbonate, tetrahydrofurane, and monomers of poly(isoprene).Comment: 24 pages, 3 tables, 14 figures submitted to the Journal of Chemical Physics (JCP

Necrotizing soft tissue infections - a multicentre, prospective observational study (INFECT) : Protocol and statistical analysis plan

Background: The INFECT project aims to advance our understanding of the pathophysiological mechanisms in necrotizing soft tissue infections (NSTIs). The INFECT observational study is part of the INFECT project with the aim of studying the clinical profile of patients with NSTIs and correlating these to patient-important outcomes. With this protocol and statistical analysis plan we describe the methods used to obtain data and the details of the planned analyses. Methods: The INFECT study is a multicentre, prospective observational cohort study. Patients with NSTIs are enrolled in five Scandinavian hospitals, which are all referral centres for NSTIs. The primary outcomes are the descriptive variables of the patients. Secondary outcomes include identification of factors associated with 90-day mortality and amputation; associations between affected body part, maximum skin defect and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score and 90-day mortality; 90-day mortality in patients with and without acute kidney injury (AKI) and LRINEC score of six and above or below six; and association between affected body part at arrival and microbiological findings. Exploratory outcomes include univariate analyses of baseline characteristics associations with 90-day mortality. The statistical analyses will be conducted in accordance with the predefined statistical analysis plan. Conclusion: Necrotizing soft tissue infections result in severe morbidity and mortality. The INFECT study will be the largest prospective study in patients with NSTIs to date and will provide important data for clinicians, researchers and policy makers on the characteristics and outcomes of these patients.</p

Preparation, structural characterisation and antibacterial properties of Ga-doped sol-gel phosphate-based glass

A sol-gel preparation of Ga-doped phosphate-based glass with potential application in antimicrobial devices has been developed. Samples of composition (CaO)(0.30)(Na2O)(0.20-x) (Ga2O3) (x) (P2O5)(0.50) where x = 0 and 0.03 were prepared, and the structure and properties of the gallium-doped sample compared with those of the sample containing no gallium. Analysis of the P-31 MAS NMR data demonstrated that addition of gallium to the sol-gel reaction increases the connectivity of the phosphate network at the expense of hydroxyl groups. This premise is supported by the results of the elemental analysis, which showed that the gallium-free sample contains significantly more hydrogen and by FTIR spectroscopy, which revealed a higher concentration of -OH groups in that sample. Ga K-edge extended X-ray absorption fine structure and X-ray absorption near-edge structure data revealed that the gallium ions are coordinated by six oxygen atoms. In agreement with the X-ray absorption data, the high-energy XRD results also suggest that the Ga3+ ions are octahedrally coordinated with respect to oxygen. Antimicrobial studies demonstrated that the sample containing Ga3+ ions had significant activity against Staphylococcus aureus compared to the control

Diabetes and necrotizing soft tissue infections—A prospective observational cohort study : Statistical analysis plan

Background: Necrotizing soft tissue infections (NSTIs) are rare but carry a high morbidity and mortality. The multicenter INFECT project aims to improve the understanding of the pathogenesis, clinical characteristics, diagnosis, and prognosis of NSTIs. This article describes the study outline and statistical analyses that will be used. Methods: Within the framework of INFECT project, patients with NSTI at 5 Scandinavian hospitals are enrolled in a prospective observational cohort study. The goal is to evaluate outcome and characteristics for patients with NSTI and diabetes compared to patients with NSTI without diabetes. The primary outcome is mortality at 90 days after inclusion. Secondary outcomes include days alive and out of ICU and hospital, SAPS II, SOFA score, infectious etiology, amputation, affected body area, and renal replacement therapy. Comparison in mortality between patients with diabetes type 1 and 2 as well as between insulin-treated and non-insulin–treated diabetes patients will be made. Clinical data for diabetic patients with NSTI will be reported. Conclusion: The study will provide important data on patients with NSTI and diabetes.</p

PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

BACKGROUND: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases.

We have calculated the reorganization energy for the intramolecular electron transfer between the reduced type 1 copper site and the peroxy intermediate of the trinuclear cluster in the multicopper oxidase CueO. The calculations are performed at the combined quantum mechanics and molecular mechanics (QM/MM) level, based on molecular dynamics simulations with tailored potentials for the two copper sites. We obtain a reorganization energy of 91-133 kJ/mol, depending on the theoretical treatment. The two Cu sites contribute by 12 and 22 kJ/mol to this energy, whereas the solvent contribution is 34 kJ/mol. The rest comes from the protein, involving small contributions from many residues. We have also estimated the energy difference between the two electron-transfer states and show that the reduction of the peroxy intermediate is exergonic by 43-87 kJ/mol, depending on the theoretical method. Both the solvent and the protein contribute to this energy difference, especially charged residues close to the two Cu sites. We compare these estimates with energies obtained from QM/MM optimizations and QM calculations in a vacuum and discuss differences between the results obtained at various levels of theory

Interferon-γ-producing immature myeloid cells confer protection against severe invasive group A Streptococcus infections

Cytokine-activated neutrophils are known to be essential for protection against group A Streptococcus infections. However, during severe invasive group A Streptococcus infections that are accompanied by neutropenia, it remains unclear which factors are protective against such infections, and which cell population is the source of them. Here we show that mice infected with severe invasive group A Streptococcus isolates, but not with non-invasive group A Streptococcus isolates, exhibit high concentrations of plasma interferon-γ during the early stage of infection. Interferon-γ is necessary to protect mice, and is produced by a novel population of granulocyte–macrophage colony-stimulating factor-dependent immature myeloid cells with ring-shaped nuclei. These interferon-γ-producing immature myeloid cells express monocyte and granulocyte markers, and also produce nitric oxide. The adoptive transfer of interferon-γ-producing immature myeloid cells ameliorates infection in wild-type and interferon-γ-deficient mice. Our results indicate that interferon-γ-producing immature myeloid cells have a protective role during the early stage of severe invasive group A Streptococcus infections

Protein C Inhibitor—A Novel Antimicrobial Agent

Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity

Antibodies against a Surface Protein of Streptococcus pyogenes Promote a Pathological Inflammatory Response

Streptococcal toxic shock syndrome (STSS) caused by Streptococcus pyogenes is a clinical condition with a high mortality rate despite modern intensive care. A key feature of STSS is excessive plasma leakage leading to hypovolemic hypotension, disturbed microcirculation and multiorgan failure. Previous work has identified a virulence mechanism in STSS where M1 protein of S. pyogenes forms complexes with fibrinogen that activate neutrophils to release heparin-binding protein (HBP), an inducer of vascular leakage. Here, we report a marked inter-individual difference in the response to M1 protein–induced HBP release, a difference found to be related to IgG antibodies directed against the central region of the M1 protein. To elicit massive HBP release, such antibodies need to be part of the M1 protein–fibrinogen complexes. The data add a novel aspect to bacterial pathogenesis where antibodies contribute to the severity of disease by promoting a pathologic inflammatory response