Modeling, design, chiral aspects and role of para-substituents in aryloxypropranolamine based beta-blockers.

The conformation of the beta-blockers viz. metoprolol, atenolol, bisoprolol, betaxolol and celiprolol has been investigated using Perturbative Configuration Interaction of Localized Orbitals (PCILO) method. The conformational energy maps have been constructed for both the enantiomers (R and S) by rotating the molecule from the para-substituent end. The aryloxypropranolamine moiety adopts the same conformation for all antagonists. The graphical view of R- and S- form of these antagonists in the lowest energy conformation reveals that it is only in the S- form of beta-blockers, all the three functionalities--aromatic moiety, amino and beta-hydroxyl groups are available for interaction with beta-adrenoceptors. The para-substituents of the beta-blockers adopt a conformation which is perpendicular to the aryloxy moiety resulting in an L-shaped structure. The beta-antagonists possibly partition into the lipid bilayer through the para-substituents and the aryloxypropranolamine moiety containing the functionalities, thus, lies parallel to the plane of lipid bilayer for interaction with beta-adrenoceptors. Superimposition of S-bisoprolol in lowest energy conformation with the 3rd putative transmembranous segment of the beta-adrenoceptors reveals that the aromatic moiety, amino and beta-hydroxyl groups of antagonists are involved in interaction with the side chains of Trp-109, Asp-113 and Thr-110 respectively. This has been further substantiated by the interaction studies on the model systems.     

Actives from MMV Open Access Boxes? A suggested way forward

It is estimated that more than 1 billion people across the world are affected by a neglected tropical disease (NTD) that requires medical intervention. These diseases tend to afflict people in areas with high rates of poverty and cost economies billions of dollars every year. Collaborative drug discovery efforts are required to reduce the burden of these diseases in endemic regions. The release of “Open Access Boxes” is an initiative launched by Medicines for Malaria Venture (MMV) in collaboration with its partners to catalyze new drug discovery in neglected diseases. These boxes are mainly requested by biology researchers across the globe who may not otherwise have access to compounds to screen nor knowledge of the workflow that needs to be followed after identification of actives from their screening campaigns. Here, we present guidelines on how to move such actives beyond the hit identification stage, to help in capacity strengthening and enable a greater impact of the initiative.     

Enzyme polymorphism in Mansonia uniformis, a mosquito vector of brugian filariasis

Three temporal samples of a wild population of Mansonia uniformis were analysed for genetic variation at six gene-enzyme systems. Adenylate kinase, hexokinase (3 loci) and cathodal malate dehydrogenase were monomorphic. Phosphoglucomutase, glucose phosphate isomerase, isocitrate dehydrogenase and anodal malate dehydrogenase were polymorphic. Each of the polymorphic loci was represented by three alleles. The average heterozygosity or gene diversity was 0.0437.     

Sub millimetre flexible fibre probe for background and fluorescence free Raman spectroscopy

Using the shifted-excitation Raman difference spectroscopy technique and an optical fibre featuring a negative curvature excitation core and a coaxial ring of high numerical aperture collection cores, we have developed a portable, background and fluorescence free, endoscopic Raman probe. The probe consists of a single fibre with a diameter of less than 0.25 mm packaged in a sub-millimetre tubing, making it compatible with standard bronchoscopes. The Raman excitation light in the fibre is guided in air and therefore interacts little with silica, enabling an almost background free transmission of the excitation light. In addition, we used the shifted-excitation Raman difference spectroscopy technique and a tunable 785 nm laser to separate the fluorescence and the Raman spectrum from highly fluorescent samples, demonstrating the suitability of the probe for biomedical applications. Using this probe we also acquired fluorescence free human lung tissue data.     

The Ph gene and the origin of tetraploid wheats

None of the diploid species of Triticum and Aegilops, from which tetraploid emmer and timopheevii wheats were presumably derived, presently possess a Ph gene identical to that on the long arm of chromosome 5B of T. aestivum. This suggests that the Ph gene originated at the tetraploid level. Both emmer and Timopheevii completely compensate for the absence of chromosome 5B of T. aestivum clearly due to the presence of a Ph gene identical to that on chromosome 5B. The presence of a similar Ph gene in both the tetraploids and its absence in the putative diploid parents suggests that the tetraploids diverged from a common amphiploid ancestor after the origin of the Ph gene. The possibility of independent origin of the tetraploids involving an unidentified common B genome donor with the Ph gene at the diploid level, however, can not be completely ruled out.     

Protein variation and systematics of three subgenera of Malayan rats (Rodentia: Muridae, genus Rattus Fischer).

1. Nine erythrocyte proteins coded by a separate locus each were analysed in and among seven Malayan species of Rattus belonging to three subgenera. 2. Electrophoretic data obtained confirm the specific status of the seven taxa and divide the seven species into three groups which correspond with Ellerman's (1949) subgenera Stenomys, Maxomys and Leopoldamys. 3. A comparative study together with 11 other species of Malayan Rattus previously analysed show that, with few exceptions, the overall relationships among the 18 species based on electrophoretic data correspond well with conclusions based on morphological evidence. 4. Malayan species of Rattus are relatively very diverse genetically (S = 0.27, range 0.01-0.94).