A computational study on how structure influences the optical properties in model crystal structures of amyloid fibrils

Amyloid fibrils have been shown to have peculiar optical properties since they can exhibit fluorescence in the absence of aromatic residues. In a recent study, we have shown that proton transfer (PT) events along hydrogen bonds (HBs) are coupled to absorption in the near UV range. Here, we gain more insights into the different types of hydrogen bonding interactions that occur in our model systems and the molecular factors that control the susceptibility of the protons to undergo PT and how this couples to the optical properties. In the case of the strong N–C termini interactions, a nearby methionine residue stabilizes the non-zwitterionic NH$_{2}$–COOH pair, while zwitterionic NH$_{3}$+–COO– is stabilized by the proximity of nearby crystallographic water molecules. Proton motion along the hydrogen bonds in the fibril is intimately coupled to the compression of the heavier atoms, similar to what is observed in bulk water. Small changes in the compression of the hydrogen bonds in the protein can lead to significant changes in both the ground and excited state potential energy surfaces associated with PT. Finally, we also reinforce the importance of nuclear quantum fluctuations of protons in the HBs of the amyloid proteins

Effect of discriminative plant-sugar feeding on the survival and fecundity of Anopheles gambiae

<p>Abstract</p> <p>Background</p> <p>A previous study showed for <it>Anopheles gambiae s.s</it>. a gradation of feeding preference on common plant species growing in a malaria holoendemic area in western Kenya. The present follow-up study determines whether there is a relationship between the mosquito's preferences and its survival and fecundity.</p> <p>Methods</p> <p>Groups of mosquitoes were separately given <it>ad libitum </it>opportunity to feed on five of the more preferred plant species (<it>Hamelia patens</it>, <it>Parthenium hysterophorus</it>, <it>Ricinus communis</it>, <it>Senna didymobotrya</it>, and <it>Tecoma stans</it>) and one of the less preferred species (<it>Lantana camara</it>). The mosquitoes were monitored daily for survival. Sugar solution (glucose 6%) and water were used as controls. In addition, the fecundity of mosquitoes on each plant after (i) only one blood meal (number of eggs oviposited), and (ii) after three consecutive blood meals (proportion of females ovipositing, number of eggs oviposited and hatchability of eggs), was determined. The composition and concentration of sugar in the fed-on parts of each plant species were determined using gas chromatography. Using SAS statistical package, tests for significant difference of the fitness values between mosquitoes exposed to different plant species were conducted.</p> <p>Results and Conclusion</p> <p><it>Anopheles gambiae </it>that had fed on four of the five more preferred plant species (<it>T. stans</it>, <it>S. didymobotrya</it>, <it>R. communis </it>and <it>H. patens</it>, but not <it>P. hysterophorus</it>) lived longer and laid more eggs after one blood meal, when compared with <it>An. gambiae </it>that had fed on the least preferred plant species <it>L. camara</it>. When given three consecutive blood-meals, the percentage of females that oviposited, but not the number of eggs laid, was significantly higher for mosquitoes that had previously fed on the four more preferred plant species. Total sugar concentration in the preferred plant parts was significantly correlated with survival and with the proportion of females that laid eggs. This effect was associated mainly with three sugar types, namely glucose, fructose, and gulose. Except for <it>P. hysterophorus</it>, the results suggest that feeding by mosquitoes on preferred plant species under natural conditions results in higher fitness-related benefits, and that the sugar content in preferred plant parts is largely responsible for these effects.</p

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

The role of quantum effects on structural and electronic fluctuations in neat and charged water.

In this work, we revisit the role of nuclear quantum effects on the structural and electronic properties of the excess proton in bulk liquid water using advanced molecular dynamics techniques. The hydronium ion is known to be a weak acceptor of a hydrogen bond which gives it some hydrophobic character. Quantum effects reduce the degree of this hydrophobicity which facilitates the fluctuations of the protons along the wires compared to the classical proton. Although the Eigen and Zundel species still appear to be dominant motifs, quantum fluctuations result in rather drastic events where both transient autoionization and delocalization over extended proton wires can simultaneously occur. These wild fluctuations also result in a significant change of the electronic properties of the system such as the broadening of the electronic density of states. An analysis of the Wannier functions indicate that quantum fluctuations of neat water molecules result in transient charging with subtle similarities and differences to that of the excess proton

Hydration dynamics of protein molecules in aqueous solution: Unity among diversity

Dielectric dispersion and NMRD experiments have revealed that a significant fraction of water molecules in the hydration shell of various proteins do not exhibit any slowing down of dynamics. This is usually attributed to the presence of the hydrophobic residues (HBR) on the surface, although HBRs alone cannot account for the large amplitude of the fast component. Solvation dynamics experiments and also computer simulation studies, on the other hand, repeatedly observed the presence of a non-negligible slow component. Here we show, by considering three well-known proteins (lysozyme, myoglobin and adelynate kinase), that the fast component arises partly from the response of those water molecules that are hydrogen bonded with the backbone oxygen (BBO) atoms. These are structurally and energetically less stable than those with the side chain oxygen (SCO) atoms. In addition, the electrostatic interaction energy distribution (EIED) of individual water molecules (hydrogen bonded to SCO) with side chain oxygen atoms shows a surprising two peak character with the lower energy peak almost coincident with the energy distribution of water hydrogen bonded to backbone oxygen atoms (BBO). This two peak contribution appears to be quite general as we find it for lysozyme, myoglobin and adenylate kinase (ADK). The sharp peak of EIED at small energy (at less than 2 k B T) for the BBO atoms, together with the first peak of EIED of SCO and the HBRs on the protein surface, explain why a large fraction (~ 80%) of water in the protein hydration layer remains almost as mobile as bulk water. Significant slowness arises only from the hydrogen bonds that populate the second peak of EIED at larger energy (at about 4 kBT). Thus, if we consider hydrogen bond interaction alone, only 15–20% of water molecules in the protein hydration layer can exhibit slow dynamics, resulting in an average relaxation time of about 5–10 ps. The latter estimate assumes a time constant of 20–100 ps for the slow component. Interestingly, relaxation of water molecules hydrogen bonded to back bone oxygen exhibit an initial component faster than the bulk, suggesting that hydrogen bonding of these water molecules remains frustrated. This explanation of the heterogeneous and non-exponential dynamics of water in the hydration layer is quantitatively consistent with all the available experimental results, and provides unification among diverse features.by Biman Jana, Subrata Pal and Biman Bagch