A user-friendly Matlab program and GUI for the pseudorotation analysis of saturated five-membered ring systems based on scalar coupling constants

Background: The advent of combinatorial chemistry has revived the interest in five-membered heterocyclic rings as scaffolds in pharmaceutical research. They are also the target of modifications in nucleic acid chemistry. Hence, the characterization of their conformational features is of considerable interest. This can be accomplished from the analysis of the (3)J(HH) scalar coupling constants. Results: A freely available program including an easy-to-use graphical user interface (GUI) has been developed for the calculation of five-membered ring conformations from scalar coupling constant data. A variety of operational modes and parameterizations can be selected by the user, and the coupling constants and electronegativity parameters can be defined interactively. Furthermore, the possibility of generating high-quality graphical output of the conformational space accessible to the molecule under study facilitates the interpretation of the results. These features are illustrated via the conformational analysis of two 4'-thio-2'-deoxynucleoside analogs. Results are discussed and compared with those obtained using the original PSEUROT program. Conclusion: A user-friendly Matlab interface has been developed and tested. This should considerably improve the accessibility of this kind of calculations to the chemical community

The solution structure and self-association properties of the cyclic lipodepsipeptide pseudodesmin A support its pore-forming potential

Pseudodesmin A is a cyclic lipodepsipeptide (CLP) of the viscosin group with a moderate in vitro biological activity. For several CLPs, including members of this group, this activity has been related to the ability to form ion pores in cellular membranes. As their size does not allow individual CLPs to span the membrane bilayer, individual monomers must somehow assemble into a larger structure. NMR spectroscopy has been used to demonstrate that in chloroform and other apolar organic solvents, pseudodesmin A monomers assemble into a supramolecular structure. These self-assembled structures can become sufficiently large to span the membrane bilayer as demonstrated with translational diffusion NMR spectroscopic measurements. With the aim to obtain more insight into the structural nature of this assembly, the solution conformation of pseudodesmin A was first determined by using ROESY (rOe) restraints measured in acetonitrile, in which no selfassociation occurs. The structure, which is found to be mostly similar to the previously described crystal structure, is shown to be retained within the supramolecular complex. Intermolecular rOe contacts obtained in chloroform together with chemical shift perturbation data provides structural insight into the organization of the selfassociated complex. Based upon this analysis, a model for the organization of pseudodesmin A monomers in the supramolecular assembly is proposed, which is in agreement with the formation of bilayer spanning hydrophilic pores and provides the basis for a structure–function relationship for this type of CLPs. Finally, it is demonstrated that the differences previously reported between the crystal and solution conformation of the white line inducing principle (WLIP), a close analogue of pseudodesmin A, are the result of the use of dimethyl sulfoxide as solvent, whose strong hydrogen-bonding capacity induces conformational exchange

Voorbij de kroniek : over het belang van theatertijdschriften

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Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer's Disease

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer’s disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD

PDBe: improved accessibility of macromolecular structure data from PDB and EMDB

© 2015 The Authors. Published by OUP. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/nar/gkv1047The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data.The Wellcome Trust [88944, 104948]; UK Biotechnology and Biological Sciences Research Council [BB/J007471/1, BB/K016970/1, BB/M013146/1, BB/M011674/1]; National Institutes of Health [GM079429]; UK Medical Research Council [MR/L007835/1]; European Union [284209]; CCP4; European Molecular Biology Laboratory (EMBL). Funding for open access charge: The Wellcome Trust.Published versio