Ab-initio simulation of high-temperature liquid selenium

Ab initio molecular dynamics simulation is used to investigate the structure and dynamics of liquid Se at temperatures of 870 and 1370~K. The calculated static structure factor is in excellent agreement with experimental data. The calculated radial distribution function gives a mean coordination number close to 2, but we find a significant fraction of one-fold and three-fold atoms, particularly at 1370~K, so that the chain structure is considerably disrupted. The self-diffusion coefficient has values ($\sim 1 \times 10^{-8}$~m~s$^{-1}$) typical of liquid metals.Comment: 10 pages, 4 Poscript figures, uses REVTE

Patient preferences regarding prophylactic cranial irradiation: A discrete choice experiment

Introduction: In patients with non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT), prophylactic cranial irradiation (PCI) is not standard practice. This study determined patient preferences for PCI with respect to survival benefit, reduction in brain metastases (BM) and acceptable toxicity.  Methods: A Discrete Choice Experiment was completed pre- and post-treatment. Patients made 15 hypothetical choices between two alternative PCI treatments described by four attributes: amount of life gained, chance of BM, ability to care for oneself, and loss of memory. Participants also chose between PCI and no PCI.  Results: 54 and 46 surveys were completed pre- and post-treatment. The most important attributes pre-treatment were: a survival benefit >6 months, of 3–6 months, avoiding severe problems with memory and self-care, avoiding quite a bit of difficulty with memory and maximally reducing BM recurrence. Post-treatment, BM reduction became more important. 90% of patients would accept PCI for a survival benefit >6 months, with a maximal reduction in BM even if severe memory/self-care problems occurred. With a 10% reduction in BM and mild problems with memory and self-care 70% of patients pre- (90% post-treatment) would accept PCI for a survival benefit of 1–3 months, and 52% pre- (78% post-treatment) for no survival benefit.  Conclusion: Improvement in survival is the most important attribute of PCI with patients willing to accept significant toxicity for maximum survival and less toxicity for less survival benefit. BM reduction became more important after treatment. The majority of patients would accept PCI for no survival benefit and a reduction in BM

Crystallization and preliminary diffraction studies of native and selenomethionine CcmG (CycY, DsbE)

t Disulfide-bond (Dsb) proteins are a family of redox proteins containing a Cys-X-X-Cys motif. They are essential for disulfide-bond exchange in the bacterial periplasm and are necessary for the correct folding and function of many secreted proteins. CcmG (DsbE) is a reducing Dsb protein required for cytochrome c maturation. Crystals of Bradyrhizobium japonicum CcmG have been obtained that diffract X-rays to 1.14 Angstrom resolution. The crystals are orthorhombic, space group P2(1)2(1)2(1), with unit-cell parameters a = 35.1, b = 48.2, c = 90.2 Angstrom. Selenomethionine CcmG was expressed without using a methionine auxotroph or methionine-pathway inhibition and was purified without reducing agents

The Fc region of an antibody impacts the neutralization of West Nile viruses in different maturation states

Flavivirus-infected cells secrete a structurally heterogeneous population of viruses because of an inefficient virion maturation process. Flaviviruses assemble as noninfectious, immature virions composed of trimers of envelope (E) and precursor membrane (prM) protein heterodimers. Cleavage of prM is a required process during virion maturation, although this often remains incomplete for infectious virus particles. Previous work demonstrated that the efficiency of virion maturation could impact antibody neutralization through changes in the accessibility of otherwise cryptic epitopes on the virion. In this study, we show that the neutralization potency of monoclonal antibody (MAb) E33 is sensitive to the maturation state of West Nile virus (WNV), despite its recognition of an accessible epitope, the domain III lateral ridge (DIII-LR). Comprehensive epitope mapping studies with 166 E protein DIII-LR variants revealed that the functional footprint of MAb E33 on the E protein differs subtly from that of the well-characterized DIII-LR MAb E16. Remarkably, aromatic substitutions at E protein residue 306 ablated the maturation state sensitivity of E33 IgG, and the neutralization efficacy of E33 Fab fragments was not affected by changes in the virion maturation state. We propose that E33 IgG binding on mature virions orients the Fc region in a manner that impacts subsequent antibody binding to nearby sites. This Fc-mediated steric constraint is a novel mechanism by which the maturation state of a virion modulates the efficacy of the humoral immune response to flavivirus infection

Resampling with neural networks for stochastic parameterization in multiscale systems

In simulations of multiscale dynamical systems, not all relevant processes can be resolved explicitly. Taking the effect of the unresolved processes into account is important, which introduces the need for paramerizations. We present a machine-learning method, used for the conditional resampling of observations or reference data from a fully resolved simulation. It is based on the probabilistic classiffcation of subsets of reference data, conditioned on macroscopic variables. This method is used to formulate a parameterization that is stochastic, taking the uncertainty of the unresolved scales into account. We validate our approach on the Lorenz 96 system, using two different parameter settings which are challenging for parameterization methods.Comment: 27 pages, 17 figures. Submitte

Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope

We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development

Structure‐guided insights on the role of NS1 in flavivirus infection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111115/1/bies201400182.pd

The Structure, Dynamics and Electronic Structure of Liquid Ag-Se Alloys Investigated by Ab Initio Simulation

Ab initio molecular-dynamics simulations have been used to investigate the structure, dynamics and electronic properties of the liquid alloy Ag(1-x)Se(x) at 1350 K and at the three compositions x=0.33, 0.42 and 0.65. The calculations are based on density-functional theory in the local density approximation and on the pseudopotential plane-wave method. The reliability of the simulations is confirmed by detailed comparisons with very recent neutron diffraction results for the partial structure factors and radial distribution functions (RDF) of the stoichiometric liquid Ag2Se. The simulations show a dramatic change of the Se-Se RDF with increasing Se content. This change is due to the formation of Se clusters bound by covalent bonds, the Se-Se bond length being almost the same as in pure c-Se and l-Se. The clusters are predominantly chain-like, but for higher x a large fraction of 3-fold coordinated Se atoms is also found. It is shown that the equilibrium fractions of Se present as isolated atoms and in clusters can be understood on a simple charge-balance model based on an ionic interpretation. The Ag and Se diffusion coefficients both increase with Se content, in spite of the Se clustering. An analysis of the Se-Se bond dynamics reveals surprisingly short bond lifetimes of less than 1 ps. The changes in the density of states with composition arise directly from the formation of Se-Se covalent bonds. Results for the electronic conductivity obtained using the Kubo-Greenwood approximation are in adequate agreement with experiment for l-Ag2Se, but not for the high Se contents. Possible reasons for this are discussed.Comment: 14 pages, Revtex, 14 Postscript figures embedded in the tex