Investigating substitutions in antibody–antigen complexes using molecular dynamics: a case study with broad-spectrum, Influenza A antibodies

In studying the binding of host antibodies to the surface antigens of pathogens, the structural and functional characterization of antibody–antigen complexes by X-ray crystallography and binding assay is important. However, the characterization requires experiments that are typically time consuming and expensive: thus, many antibody–antigen complexes are under-characterized. For vaccine development and disease surveillance, it is often vital to assess the impact of amino acid substitutions on antibody binding. For example, are there antibody substitutions capable of improving binding without a loss of breadth, or antigen substitutions that lead to antigenic escape? The questions cannot be answered reliably from sequence variation alone, exhaustive substitution assays are usually impractical, and alanine scans provide at best an incomplete identification of the critical residue–residue interactions. Here, we show that, given an initial structure of an antibody bound to an antigen, molecular dynamics simulations using the energy method molecular mechanics with Generalized Born surface area (MM/GBSA) can model the impact of single amino acid substitutions on antibody–antigen binding energy. We apply the technique to three broad-spectrum antibodies to influenza A hemagglutinin and examine both previously characterized and novel variant strains observed in the human population that may give rise to antigenic escape. We find that in some cases the impact of a substitution is local, while in others it causes a reorientation of the antibody with wide-ranging impact on residue–residue interactions: this explains, in part, why the change in chemical properties of a residue can be, on its own, a poor predictor of overall change in binding energy. Our estimates are in good agreement with experimental results—indeed, they approximate the degree of agreement between different experimental techniques. Simulations were performed on commodity computer hardware; hence, this approach has the potential to be widely adopted by those undertaking infectious disease research. Novel aspects of this research include the application of MM/GBSA to investigate binding between broadly binding antibodies and a viral glycoprotein; the development of an approach for visualizing substrate–ligand interactions; and the use of experimental assay data to rescale our predictions, allowing us to make inferences about absolute, as well as relative, changes in binding energy

Finsler geometry on higher order tensor fields and applications to high angular resolution diffusion imaging.

We study 3D-multidirectional images, using Finsler geometry. The application considered here is in medical image analysis, specifically in High Angular Resolution Diffusion Imaging (HARDI) (Tuch et al. in Magn. Reson. Med. 48(6):1358–1372, 2004) of the brain. The goal is to reveal the architecture of the neural fibers in brain white matter. To the variety of existing techniques, we wish to add novel approaches that exploit differential geometry and tensor calculus. In Diffusion Tensor Imaging (DTI), the diffusion of water is modeled by a symmetric positive definite second order tensor, leading naturally to a Riemannian geometric framework. A limitation is that it is based on the assumption that there exists a single dominant direction of fibers restricting the thermal motion of water molecules. Using HARDI data and higher order tensor models, we can extract multiple relevant directions, and Finsler geometry provides the natural geometric generalization appropriate for multi-fiber analysis. In this paper we provide an exact criterion to determine whether a spherical function satisfies the strong convexity criterion essential for a Finsler norm. We also show a novel fiber tracking method in Finsler setting. Our model incorporates a scale parameter, which can be beneficial in view of the noisy nature of the data. We demonstrate our methods on analytic as well as simulated and real HARDI data

Living conditions of Czech farmers according to the EU statistics on income

The paper deals with the assessment of income situation of the Czech households with the head person working or self-employed in the farm sector. Actual analyses result from initial consideration of the rise and dynamics of income disparities in our country. Primary data source are obtained from the European Union survey project - Statistics on Income and Living Conditions (EU-SILC). Our reference period, in view of data availability at the time of the article processing, is represented by the 2007 year. The core studied variable is represented by the volume of the income calculated for each household. The information obtained by study of this variable was complemented by other variables enabling the logical validity check and analysis of the socioeconomic environment of households under examination. Main findings and conclusions are derived from the analysis of the decile and quintile classification of the relevant equivalized income datasets. The prime goal of the study was to quantify the share of the Czech agriculture related households living on the monthly income less then 60 % of the nationwide median value of the income variable under consideration. The households identified with such income position are referred as “households-at-risk-of-income poverty“

Structure and Determinants of Consumer Expenditures

The local and worldwide present economic situation is often judged and discussed on the basis of the consumer expenditures development. Consumer expenditures or a buying behaviour outcome of each individual market subject is in marketing defined as a product and service seeking, from that consumers expect satisfying of their needs. On the basis of the introduced determination authors conducted a marketing research. Results in combination with a marketing insight into consumer expenditures realization served as a starting-point for an analysis of factors forming a consumer's buying decision. The introduced results are naturally just a view into the potential of the realized research result analysis. Development and testing of hypotheses has continually been proceedin

Measuring surface-area-to-volume ratios in soft porous materials using laser-polarized xenon interphase exchange NMR

We demonstrate a minimally invasive nuclear magnetic resonance (NMR) technique that enables determination of the surface-area-to-volume ratio (S/V) of soft porous materials from measurements of the diffusive exchange of laser-polarized 129Xe between gas in the pore space and 129Xe dissolved in the solid phase. We apply this NMR technique to porous polymer samples and find approximate agreement with destructive stereological measurements of S/V obtained with optical confocal microscopy. Potential applications of laser-polarized xenon interphase exchange NMR include measurements of in vivo lung function in humans and characterization of gas chromatography columns.Comment: 14 pages of text, 4 figure

Low Carbon Steel Processed by Equal Channel Angular Warm Pressing

Low carbon steel AISI 10 was subjected to a severe plastic deformation technique called Equal Angular Channel Pressing (ECAP) at different increased temperatures. The steel was subjected to ECAP with channel’s angle j = 90°, at different temperature in range of 150 - 300 °C. The number of passes at each temperature was N = 3. Light, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) of thin foils were used to study the formation of substructure and ultrafine grains in deformed specimens. The size of newly born polygonized grains (subgrains and/or submicrocrystalline grains) is in range of 300 - 500 mm. The formation of such of predominant submicrocrystalline structure resulted in significant increase of yield stress [Re] and tensile strength of the steel [Rm]

Effetti della diluizione sulla microstruttura e comportamento ad usura di una lega Fe-C-B-Cr-Mo

Generalmente tra le leghe hardfacing a base ferro quelle ipereutettiche, composte da carburi primari in unastruttura eutettica, offrono le migliori prestazioni ad usura. L’ottimizzazione della composizione chimica di talileghe, però, deve tener conto del fenomeno della diluizione. Durante la deposizione, la diffusione di elementi dilega e la fusione del substrato possono modificare la sequenza di solidificazione della lega. Ciò porta ad unadiminuzione della frazione dei carburi primari e alla variazione delle proprietà del rivestimento.Lo scopo della ricerca è stato quello di analizzare gli effetti della diluizione. In un primo approccio la diluizioneviene simulata tramite la fusione di una lega ipereutettica Fe-C-B–Cr-Mo con aggiunte crescenti di ferro puro.Successivamente è stata analizzata la fusione della lega direttamente in crogioli di acciaio. I risultati derivanti dallasimulazione sono infine messi a confronto con quelli ottenuti dalla deposizione della lega tramite un processoindustriale di spin casting. L’evoluzione microstrutturale dopo diluizione è stata studiata tramite microscopiaottica, elettronica, diffrazione dei raggi X, misure DSC e di microdurezza, mentre la resistenza ad usura è stataanalizzata attraverso prove pin-on-disc

ESR, raman and conductivity studies on fractionated poly(2-methoxyaniline-5-sulfonic acid)

Synthesis methods used to produce poly(2-methoxyaniline-5-sulfonic acid) (PMAS), a water soluble, self-doped conducting polymer, have been shown to form two distinctly different polymer fractions with molecular weights of approximately 2 kDa and 8 -10 kDa. The low molecular weight (LMWT) PMAS fraction is redox inactive and non-conducting while the high molecular weight (HMWT) PMAS is electro-active with electrical conductivities of 0.94 0.05 S cm-1. Previous investigations have illustrated the different photochemical and electrochemical properties of these fractions, but have not correlated these properties with the structural and electronic interactions that drive them. Incomplete purification of the PMAS mixture, typically via bag dialysis, has been shown to result in a mixture of approximately 50:50 HMWT:LMWT PMAS with electrical conductivity significantly lower at approximately 0.10 to 0.26 S cm-1. The difference between the electrical conductivities of these fractions has been investigated by the controlled addition of the non-conducting LMWT PMAS fraction into the HMWT PMAS composite film with the subsequent electronic properties investigated by solid-state ESR and Raman spectroscopies. These studies illustrate strong electronic intereactions of the insulating LMWT PMAS with the emeraldine salt HMWT PMAS to substantially alter the population of the electronic charge carriers in the conducting polymer. ESR studies on these mixtures, when compared to HMWT PMAS, exhibited a lower level of electron spin in the presence of LMWT PMAS indicative of the the formation of low spin bipolarons without a change the oxidation state of the conducting HMWT fraction