Prediction of peptide and protein propensity for amyloid formation

Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔGº values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation

Forced Moves or Good Tricks in Design Space? Landmarks in the Evolution of Neural Mechanisms for Action Selection

This review considers some important landmarks in animal evolution, asking to what extent specialized action-selection mechanisms play a role in the functional architecture of different nervous system plans, and looking for “forced moves” or “good tricks” (see Dennett, D., 1995, Darwin’s Dangerous Idea, Penguin Books, London) that could possibly transfer to the design of robot control systems. A key conclusion is that while cnidarians (e.g. jellyfish) appear to have discovered some good tricks for the design of behavior-based control systems—largely lacking specialized selection mechanisms—the emergence of bilaterians may have forced the evolution of a central ganglion, or “archaic brain”, whose main function is to resolve conflicts between peripheral systems. Whilst vertebrates have many interesting selection substrates it is likely that here too the evolution of centralized structures such as the medial reticular formation and the basal ganglia may have been a forced move because of the need to limit connection costs as brains increased in size

Quality Control of Cement Deep Soil Mixing Work for the Port of Oakland Projects

The Cement Deep Soil Mixing (CDSM) method is an in situ soil treatment technology that introduces and mixes cementitious materials with native soils using hollow-stem rotating shafts equipped with a cutting tool at the tip and mixing paddles above the tip. The successful use of the soil-cement produced by CDSM relies on the selection of acceptance criteria and construction quality control during the in situ soil mixing process. Two CDSM projects for the Port of Oakland are used as case examples to present the acceptance criteria set and the execution of the quality control program for the soil mixing work. This quality control program ensures that the geometric and material design parameters of the CDSM structure have been obtained. The data acquired from these two projects are presented and compared with strength data from two other projects to illustrate the influence of acceptance criteria over the CDSM products

AFM study of morphology and mechanical properties of a chimeric 2 spider silk and bone sialoprotein protein for bone regeneration

Atomic force microscopy (AFM) was used to assess a new chimeric protein consisting of a fusion protein of the consensus repeat for Nephila clavipes spider dragline protein and bone sialoprotein (6merþBSP). The elastic modulus of this protein in film form was assessed through force curves, and film surface roughness was also determined. The results showed a significant difference among the elastic modulus of the chimeric silk protein, 6merþBSP, and control films consisting of only the silk component (6mer). The behavior of the 6merþBSP and 6mer proteins in aqueous solution in the presence of calcium (Ca) ions was also assessed to determine interactions between the inorganic and organic components related to bone interactions, anchoring, and biomaterial network formation. The results demonstrated the formation of protein networks in the presence of Ca2þ ions, characteristics that may be important in the context of controlling materials assembly and properties related to bone formation with this new chimeric silk-BSP protein.Silvia Games thanks the Foundation for Science and Technology (FCT) for supporting her Ph.D. grant, SFRH/BD/28603/2006. This work was carried out under the scope of the European NoE EXPERTISSUES (NMP3-CT-2004-500283), the Chimera project (PTDC/EBB-EBI/109093/2008) funded by the FCT agency, the NIH (P41 EB002520) Tissue Engineering Resource Center, and the NIH (EB003210 and DE017207)

Sentinel network for monitoring in vitro susceptibility of Plasmodium falciparum to antimalarial drugs in Colombia: a proof of concept

Drug resistance is one of the principal obstacles blocking worldwide malaria control. In Colombia, malaria remains a major public health concern and drug-resistant parasites have been reported. In vitro drug susceptibility assays are a useful tool for monitoring the emergence and spread of drug-resistant Plasmodium falciparum. The present study was conducted as a proof of concept for an antimalarial drug resistance surveillance network based on in vitro susceptibility testing in Colombia. Sentinel laboratories were set up in three malaria endemic areas. The enzyme linked immunosorbent assay-histidine rich protein 2 and schizont maturation methods were used to assess the susceptibility of fresh P. falciparum isolates to six antimalarial drugs. This study demonstrates that an antimalarial drug resistance surveillance network based on in vitro methods is feasible in the field with the participation of a research institute, local health institutions and universities. It could also serve as a model for a regional surveillance network. Preliminary susceptibility results showed widespread chloroquine resistance, which was consistent with previous reports for the Pacific region. However, high susceptibility to dihydroartemisinin and lumefantrine compounds, currently used for treatment in the country, was also reported. The implementation process identified critical points and opportunities for the improvement of network sustainability strategies.PAHO [057-1-3144141]; COLCIENCIAS [ID 2229-405-20319]info:eu-repo/semantics/publishedVersio

Optical Trapping with High Forces Reveals Unexpected Behaviors of Prion Fibrils

Amyloid fibrils are important in diverse cellular functions, feature in many human diseases and have potential applications in nanotechnology. Here we describe methods that combine optical trapping and fluorescent imaging to characterize the forces that govern the integrity of amyloid fibrils formed by a yeast prion protein. A crucial advance was to use the self-templating properties of amyloidogenic proteins to tether prion fibrils, enabling their manipulation in the optical trap. At normal pulling forces the fibrils were impervious to disruption. At much higher forces (up to 250 pN), discontinuities occurred in force-extension traces before fibril rupture. Experiments with selective amyloid-disrupting agents and mutations demonstrated that such discontinuities were caused by the unfolding of individual subdomains. Thus, our results reveal unusually strong noncovalent intermolecular contacts that maintain fibril integrity even when individual monomers partially unfold and extend fibril length.National Institutes of Health (U.S.) (Grant GM025874)National Science Foundation (U.S.). CAREER (Award 0643745

Homolytic N-H activation of ammonia: hydrogen transfer of parent iridium ammine, amide, imide, and nitride species

The redox series [Ir-n(NH(x))(PNP)] (n = II-IV, x = 3-0; PNP = N(CHCHPtBu(2))(2)) was examined with respect to electron, proton, and hydrogen atom transfer steps. The experimental and computational results suggest that the Ir-III imido species [Ir(NH) (PNP)] is not stable but undergoes to the respective Ir-II amido and Ir-III nitrido species. N-H bond strengths are estimated upon reaction with hydrogen atom transfer reagents to rationalize this observation and are used to discuss the reactivity of these compounds toward E-H bond activation

Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]

Prions are proteins that can access multiple conformations, at least one of which is beta-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers