52 research outputs found
Neuer Kopf, alte Ideen? : "Normalisierung" des Front National unter Marine Le Pen
In this article, it is investigated
whether vibrational entropy
(VE) is an important contribution to the free energy of globular proteins
at ambient conditions. VE represents the major configurational-entropy
contribution of these proteins. By definition, it is an average of
the configurational entropies of the protein within single minima
of the energy landscape, weighted by their occupation probabilities.
Its large part originates from thermal motion of flexible torsion
angles giving rise to the finite peak widths observed in torsion angle
distributions. While VE may affect the equilibrium properties of proteins,
it is usually neglected in numerical calculations as its consideration
is difficult. Moreover, it is sometimes believed that all well-packed
conformations of a globular protein have similar VE anyway. Here, we measure explicitly the VE for six different conformations from simulation data of a test protein. Estimates
are obtained using the quasi-harmonic approximation for three coordinate
sets, Cartesian, bond-angle-torsion (BAT), and a new set termed rotamer-degeneracy
lifted BAT coordinates by us. The new set gives improved estimates
as it overcomes a known shortcoming of the quasi-harmonic approximation
caused by multiply populated rotamer states, and it may serve for
VE estimation of macromolecules in a very general context. The obtained
VE values depend considerably on the type of coordinates used. However,
for all coordinate sets we find large entropy differences between
the conformations, of the order of the overall stability of the protein.
This result may have important implications on the choice of free
energy expressions used in software for protein structure prediction,
protein design, and NMR refinement
Binding Free Energy Landscape of Domain-Peptide Interactions
Peptide recognition domains (PRDs) are ubiquitous protein domains which mediate large numbers of protein interactions in the cell. How these PRDs are able to recognize peptide sequences in a rapid and specific manner is incompletely understood. We explore the peptide binding process of PDZ domains, a large PRD family, from an equilibrium perspective using an all-atom Monte Carlo (MC) approach. Our focus is two different PDZ domains representing two major PDZ classes, I and II. For both domains, a binding free energy surface with a strong bias toward the native bound state is found. Moreover, both domains exhibit a binding process in which the peptides are mostly either bound at the PDZ binding pocket or else interact little with the domain surface. Consistent with this, various binding observables show a temperature dependence well described by a simple two-state model. We also find important differences in the details between the two domains. While both domains exhibit well-defined binding free energy barriers, the class I barrier is significantly weaker than the one for class II. To probe this issue further, we apply our method to a PDZ domain with dual specificity for class I and II peptides, and find an analogous difference in their binding free energy barriers. Lastly, we perform a large number of fixed-temperature MC kinetics trajectories under binding conditions. These trajectories reveal significantly slower binding dynamics for the class II domain relative to class I. Our combined results are consistent with a binding mechanism in which the peptide C terminal residue binds in an initial, rate-limiting step
Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?
Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities
Genomic investigations of unexplained acute hepatitis in children
Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children
Localizing root causes of performance anomalies in cloud computing systems by analyzing request trace logs
Recombinant Hamster Oviductin Is Biologically Active and Exerts Positive Effects on Sperm Functions and Sperm-Oocyte Binding
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