Aβ Monomers Transiently Sample Oligomer and Fibril-Like Configurations: Ensemble Characterization Using a Combined MD/NMR Approach

Amyloid β (Aβ) peptides are a primary component of fibrils and oligomers implicated in the etiology of Alzheimer's disease (AD). However, the intrinsic flexibility of these peptides has frustrated efforts to investigate the secondary and tertiary structure of Aβ monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of Aβ aggregation. In this work, de novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale are used to characterize the structural ensembles of Aβ42, Aβ40, and M35-oxidized Aβ42, three physiologically relevant isoforms with substantially different aggregation properties. J-coupling data calculated from the REMD trajectories were compared to corresponding NMR-derived values acquired through two different pulse sequences, revealing that all simulations converge on the order of hundreds of nanoseconds-per-replica toward ensembles that yield good agreement with experiment. Though all three Aβ species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C-terminus are antiparallel β-hairpins between L17–A21, A30–L36, and V39–I41, similar to oligomer and fibril intrapeptide models that expose these hydrophobic side chains to solvent and may serve as hotspots for self-association. Compared to reduced Aβ42, the absence of a second β-hairpin in Aβ40 and the sampling of alternate β topologies by M35-oxidized Aβ42 may explain the reduced aggregation rates of these forms. A persistent V24–K28 bend motif, observed in all three species, is stabilized by buried backbone to side-chain hydrogen bonds with D23 and a cross-region salt bridge between E22 and K28, highlighting the role of the familial AD-linked E22 and D23 residues in Aβ monomer folding. These characterizations help illustrate the conformational landscapes of Aβ monomers at atomic resolution and provide insight into the early stages of Aβ aggregation pathways.     

The social position of multiracial groups in the United States: evidence from residential segregation

I use multiple perspectives on the racial order in the United States to generate hypotheses about the social position of mixed-race groups. Perspectives that view the racial order as binary, ternary with an undifferentiated middle, or ternary with a stratified middle present different expectations for the social position of multiracial groups. I use a group's level of residential segregation as an index of social position. In 2000, multiracial persons lived in neighbourhoods that were more white than the neighbourhoods of single-race minorities, though more diverse than the neighbourhoods of whites. Thus, multiracial groups appear to occupy an intermediate social position relative to blacks and whites, a finding that supports contemporary arguments about shifting colour-lines in the United States and the emergence of a triracial system of stratification. Yet, findings also suggest that the social space between blacks and whites is, itself, racially stratified.     

To converge or not to converge in environmental space: testing for similar environments between analogous succulent plants of North America and Africa

Background and Aims

Convergent evolution is invoked to explain similarity between unrelated organisms in similar environments, but most evaluations of convergence analyse similarity of organismal attributes rather than of the environment. This study focuses on the globular succulent plants of the Americas, the cacti, and their counterparts in Africa in the ice-plant, spurge and milkweed families. Though often held up as paragons of convergent morphological evolution, the environmental similarity of these plants has remained largely unexamined from a quantitative perspective.

Methods

Five hotspots (centres of high species diversity of globular succulents) were selected, two in Mexico and three in South Africa. Their environments were compared using niche modelling tools, randomization tests of niche similarity and multivariate analyses to test for environmental similarity.

Key Results

Although the sites selected have ‘similar’ but unrelated life forms, almost all our results highlighted more climate differences than similarities between the hotspots. Interprediction of niches within and between continents, a niche equivalence test, and MANOVA results showed significant differences. In contrast, a niche similarity test showed that the comparisons of Cuatrociénegas–Richtersveld, Huizache–Knersvlakte and Huizache–Richtersveld were similar.

Conclusions

Differences in rainfall and temperature regimes and the potential effect of edaphic factors may be involved in the differences between the hotspots. In addition, differences in structure, morphology and physiology of the globular succulents may coincide with some of the climatic dissimilarities; i.e. given convergence as the evolution of similar morphologies under similar conditions, then it may be that differing environments diagnose inconspicuous morphological differences. Moreover, although fine-scale differences between sites were found, a coarser perspective shows that these sites are clearly similar as drylands with relatively moderate drought and mild temperatures, illustrating how all studies of convergence must address the issue of how similar two entities must be before they are considered convergent.     

Genetic analysis of resistance to Puccinia striiformis f.sp. tritici in cv. Aflak at adult plant stage

In order to investigate heritability and gene action for yellow rust resistance in wheat, a resistance yellow rust cultivar Aflak was crossed to susceptible cultivar Avocet‘s’. Parents, F₁, F₂ and F₃ generations were cultured according to randomised complete block design with two replications in the research station of Gharakhil, Iran. Parents and other generations were inoculated with 70E0A+ race. Traits including severity and infection type were recorded and then coefficient of infection was calculated. For this trait, generations mean and variance analysis were performed and results showed that there were significant differences among generations for coefficient of infection. Results showed that in addition to additive and dominance effects, at least one kind of epistasis interaction (additive × additive) control this trait. Although additive and dominance effects control this trait, but with attention to generations variance analysis, the results showed that additive variance had important role to control this trait.     

Comparative genome sequence analysis of Sulfolobus acidocaldarius and 9 other isolates of its genus for factors influencing codon and amino acid usage

In the present study, major constraints for codon and amino acid usage of Sulfolobus acidocaldarius, Sulfolobus solfataricus, Sulfolobus tokodali, Sulfolobus islandis and 6 other isolates from islandicus species of genus Sulfolobus were investigated. Correspondence analysis revealed high significant correlation between the major trend of synonymous codon usage and gene expression level, as assessed by the “Codon Adaptation Index” (CAI). There is a significant negative correlation between Nc (Effective number of codons) and CAI demonstrating role of codon bias as an important determinant of codon usage. The significant correlation between major trend of synonymous codon usage and GC3s (G + C at third synonymous position) indicated dominant role of mutational bias in codon usage pattern. The result was further supported from SCUO (synonymous codon usage order) analysis. The amino acid usage was found to be significantly influenced by aromaticity and hydrophobicity of proteins. However, translational selection which causes a preference for codons that are most rapidly translated by current tRNA with multiple copy numbers was not found to be highly dominating for all studied isolates. Notably, 26 codons that were found to be optimally used by genes of S. acidocaldarius at higher expression level and its comparative analysis with 9 other isolates may provide some useful clues for further in vivo genetic studies on this genus.     

The activity coefficient of high density systems with hard-sphere interactions: the application of the IGCMC method

The inverse grand-canonical Monte Carlo (IGCMC) technique is used to calculate the activity coefficients of the following hard-sphere systems: one-component fluid, binary mixture and solvent primitive model (SPM) electrolyte. The calculations for a one-component fluid are performed at different densities. The components of a binary mixture differ in diameters (300 and 500 pm) with the results being presented for different density and composition of a mixture. For the SPM model, simulations are performed for a 1:1 electrolyte at different electrolyte concentrations at the packing fraction equal to 0.3. Ions and solvent molecules of the same or different sizes are considered. The results are compared with those reported by Adams (one-component fluid), with those calculated using the Ebeling and Scherwinski equation (one-component fluid and binary mixture) and with the predictions from the symmetric Poisson–Boltzmann theory and the mean spherical approximation (SPM electrolyte).     

Calculation of diffusion coefficient for supercritical carbon dioxide and carbon dioxide+naphthalene system by molecular dynamics simulation using EPM2 model

NVT ensemble molecular dynamics (MD) simulation has been applied to calculate the self-diffusion coefficients of carbon dioxide and the tracer diffusion coefficients of naphthalene in supercritical carbon dioxide. The simulation was carried out in the pressure range from 8 to 40 MPa. The elementary physical model proposed by Harris and Yung was adopted for carbon dioxide and some approximation models were used for naphthalene. The systems of MD simulation for carbon dioxide consist of 256 particles. One naphthalene molecule was added for carbon dioxide+naphthalene system. The system can be assumed to be an infinite dilution condition for carbon dioxide+naphthalene system and the mutual diffusion coefficients are equal to the tracer diffusion coefficients of naphthalene. The self-diffusion coefficients of carbon dioxide and the tracer diffusion coefficients of naphthalene in supercritical carbon dioxide can be calculated by mean square displacement. The calculated results of diffusion coefficients showed good agreement with the experimental data without adjustable parameters.     

Use of dynamic light scattering to determine second virial coefficient in a semidilute concentration regime

The present work discusses an alternative procedure to obtain static light scattering (SLS) parameters in a dilute and semidilute concentration regime from a dynamic light scattering (DLS) instrument that uses an avalanche photodiode (APD) for recording the scattered intensity signal. An APD enables one to perform both SLS and DLS measurements by photon counting and photon correlation, respectively. However, due to the associated recovery time, the APDs are susceptible to saturation (above 1000 kcps), which may limit the measurements in systems that scatter too much light. We propose an alternative way of obtaining the SLS parameters with instruments that use APD for recording signal intensities.