The effect of force-field parameters on properties of liquids:Parametrization of a simple three-site model for methanol

A simple rigid three-site model for methanol compatible with the simple point charge (SPC) water and the GROMOS96 force field is parametrized and tested. The influence of different force-field parameters, such as the methanol geometry and the charge distribution on several properties calculated by molecular dynamics is investigated. In particular an attempt was made to obtain good agreement with experimental data for the static dielectric constant and the mixing enthalpy with water. The model is compared to other methanol models from the literature in terms of the ability to reproduce a range of experimental properties.<br/

Formation of long, multicenter pi-[TCNE](2)(2-) dimers in solution: solvation and stability assessed through molecular dynamics simulations

Purely organic radical ions dimerize in solution at low temperature, forming long, multicenter bonds, despite the metastability of the isolated dimers. Here, we present the first computational study of these pi-dimers in solution, with explicit consideration of solvent molecules and finite temperature effects. By means of force-field and ab initio molecular dynamics and free energy simulations, the structure and stability of pi-[TCNE](2)(2-) (TCNE = tetracyanoethylene) dimers in dichloromethane have been evaluated. Although the dimers dissociate at room temperature, they are stable at 175 K and their structure is similar to the one in the solid state, with a cofacial arrangement of the radicals at an inter-planar separation of approximately 3.0 angstrom. The pi-[TCNE](2)(2-) dimers form dissociated ion pairs with the NBu4+ counterions, and their first solvation shell comprises approximately 20 CH2Cl2 molecules. Among them, the eight molecules distributed along the equatorial plane of the dimer play a key role in stabilizing the dimer through bridging C-H center dot center dot center dot N contacts. The calculated free energy of dimerization of TCNE center dot- in solution at 175 K is -5.5 kcal mol(-1). These results provide the first quantitative model describing the pairing of radical ions in solution, and demonstrate the key role of solvation forces on the dimerization process

Genetics of Systemic Sclerosis: An Update

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation, and fibrosis of the skin and internal organs. Over the past few years, a role for genetics in the susceptibility for SSc has been established. This review aims to provide an update on the progress made in the past year or so within the field of SSc genetics research. This year has been of particular interest due to the publication of a large genome-wide association study, further investigations into gene–gene interactions, and the tendency to validate genetic results in functional models

Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis.

BACKGROUND: Gastrointestinal tract (GIT) involvement is a common cause of debilitating symptoms in patients with systemic sclerosis (SSc). There are no disease modifying therapies for this condition and the treatment remains symptomatic, largely owing to the lack of a clear understanding of its pathogenesis. AIMS: To investigate novel aspects of the pathogenesis of gastrointestinal involvement in SSc. To summarise existing knowledge regarding the cardinal clinical gastrointestinal manifestations of SSc and its pathogenesis, emphasising recent investigations that may be valuable in identifying potentially novel therapeutic targets. METHODS: Electronic (PubMed/Medline) and manual Google search. RESULTS: The GIT is the most common internal organ involved in SSc. Any part of the GIT from the mouth to the anus can be affected. There is substantial variability in clinical manifestations and disease course and symptoms are nonspecific and overlapping for a particular anatomical site. Gastrointestinal involvement can occur in the absence of cutaneous disease. Up to 8% of SSc patients develop severe GIT symptoms. This subset of patients display increased mortality with only 15% survival at 9 years. Dysmotiity of the GIT causes the majority of symptoms. Recent investigations have identified a novel mechanism in the pathogenesis of GIT dysmotility mediated by functional anti-muscarinic receptor autoantibodies. CONCLUSIONS: Despite extensive investigation, the pathogenesis of gastrointestinal involvement in systemic sclerosis remains elusive. Although treatment currently remains symptomatic, an improved understanding of novel pathogenic mechanisms may allow the development of potentially highly effective approaches including intravenous immunoglobulin and microRNA based therapeutic interventions

Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase

A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs