Molecular docking of potential inhibitors with the mTOR protein

The mTOR (mammalian or mechanistic Target of Rapamycin) is linked with oral cancer. Therefore, it is of interest to study the molecular docking-based binding of paclitaxel (a FDA approved drug for oral cancer) and its analogues with mTOR. Hence, we report the binding features of 10-Deacetyltaxol, 7-Epi-10-deacetyltaxol, 7-Epi-Taxol and 6alpha-Hydroxypaclitaxel with mTOR for further consideration.     

The protein circular dichroism data bank, a Web-based site for access to circular dichroism spectroscopic data

The Protein Circular Dichroism Data Bank (PCDDB) is a newly released resource for structural biology. It is a web-accessible (http://pcddb.cryst.bbk.ac.uk) data bank for circular dichroism (CD) and synchrotron radiation circular dichroism (SRCD) spectra and their associated experimental and secondary metadata, with links to protein sequence and structure data banks. It is designed to provide a public repository for CD spectroscopic data on macromolecules, to parallel the Protein Data Bank (PDB) for crystallographic, electron microscopic, and nuclear magnetic resonance spectroscopic data. Similarly to the PDB, it includes validation checking procedures to ensure good practice and the integrity of the deposited data. This paper reports on the first public release of the PCDDB, which provides access to spectral data that comprise standard reference datasets.     

Anti-superoxide and anti-peroxynitrite strategies in pain suppression

Superoxide (SO, O(2)·(-)) and its reaction product peroxynitrite (PN, ONOO(-)) have been shown to be important in the development of pain of several etiologies. While significant progress has been made in teasing out the relative contribution of SO and PN peripherally, spinally, and supraspinally during the development and maintenance of central sensitization and pain, there is still a considerable void in our understanding. Further research is required in order to develop improved therapeutic strategies for selectively eliminating SO and/or PN. Furthermore, it may be that PN is a more attractive target, in that unlike SO it has no currently known beneficial role. Our group has been at the forefront of research concerning the role of SO and PN in pain, and our current findings have led to the development of two new classes of orally active catalysts which are selective for PN decomposition while sparing SO. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Concepts and consequences of Eph receptor clustering

Polymeric receptor-ligand complexes between interacting Eph and ephrin-expressing cells are regarded as dynamic intercellular signalling scaffolds that control cell-to-cell contact: the resulting Eph-ephrin signalling clusters function as positional cues that facilitate cell navigation and tissue patterning during normal and oncogenic development. The considerable complexity of this task, coordinating a multitude of cell movements and cellular interactions, is achieved by accurate translation of spatial information from Eph and ephrin expression gradients into fine-tuned changes in cell-cell adhesion and position. Here we review emerging evidence suggesting that the required combinatorial diversity is not only achieved by the large number of possible Eph-ephrin interactions and selective use of Eph forward and ephrin reverse signals, but in particular through the composition and signal capacity of Eph-ephrin clusters, which is adjusted dynamically to reflect overall Eph and ephrin surface densities on interacting cells. Fine-tuning is provided through multi-layered cluster assembly, where homo- and heterotypic Eph and ephrin interactions define the composition - whilst intracellular signalling feedbacks determine the size and lifetime - of signalling clusters.     

Estimating P-coverage of biosynthetic pathways in DNA libraries and screening by genetic selection: biotin biosynthesis in the marine microorganism Chromohalobacter

Traditional approaches to natural product discovery involve cell-based screening of natural product extracts followed by compound isolation and characterization. Their importance notwithstanding, continued mining leads to depletion of natural resources and the reisolation of previously identified metabolites. Metagenomic strategies aimed at localizing the biosynthetic cluster genes and expressing them in surrogate hosts offers one possible alternative. A fundamental question that naturally arises when pursuing such a strategy is, how large must the genomic library be to effectively represent the genome of an organism(s) and the biosynthetic gene clusters they harbor? Such an issue is certainly augmented in the absence of expensive robotics to expedite colony picking and/or screening of clones. We have developed an algorism, named BPC (biosynthetic pathway coverage), supported by molecular simulations to deduce the number of BAC clones required to achieve proper coverage of the genome and their respective biosynthetic pathways. The strategy has been applied to the construction of a large-insert BAC library from a marine microorganism, Hon6 (isolated from Honokohau, Maui) thought to represent a new species. The genomic library is constructed with a BAC yeast shuttle vector pClasper lacZ paving the way for the culturing of libraries in both prokaryotic and eukaryotic hosts. Flow cytometric methods are utilized to estimate the genome size of the organism and BPC implemented to assess P-coverage or percent coverage. A genetic selection strategy is illustrated, applications of which could expedite screening efforts in the identification and localization of biosynthetic pathways from marine microbial consortia, offering a powerful complement to genome sequencing and degenerate probe strategies. Implementing this approach, we report on the biotin biosynthetic pathway from the marine microorganism Hon6.     

Matching in studies of classification accuracy: implications for analysis, efficiency, and assessment of incremental value

Summary.   In case–control studies evaluating the classification accuracy of a marker, controls are often matched to cases with respect to factors associated with the marker and disease status. In contrast with matching in epidemiologic etiology studies, matching in the classification setting has not been rigorously studied. In this article, we consider the implications of matching in terms of the choice of statistical analysis, efficiency, and assessment of the incremental value of the marker over the matching covariates. We find that adjustment for the matching covariates is essential, as unadjusted summaries of classification accuracy can be biased. In many settings, matching is the most efficient covariate-dependent sampling scheme, and we provide an expression for the optimal matching ratio. However, we also show that matching greatly complicates estimation of the incremental value of the marker. We recommend that matching be carefully considered in the context of these findings.