19 research outputs found

    Combinatorial Computational Approaches to Identify Tetracycline Derivatives as Flavivirus Inhibitors

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    Limited structural information of drug targets, cellular toxicity possessed by lead compounds, and large amounts of potential leads are the major issues facing the design-oriented approach of discovering new leads. In an attempt to tackle these issues, we have developed a process of virtual screening based on the observation that conformational rearrangements of the dengue virus envelope protein are essential for the mediation of viral entry into host cells via membrane fusion. Screening was based solely on the structural information of the Dengue virus envelope protein and was focused on a target site that is presumably important for the conformational rearrangements necessary for viral entry. To circumvent the issue of lead compound toxicity, we performed screening based on molecular docking using structural databases of medical compounds. To enhance the identification of hits, we further categorized and selected candidates according to their novel structural characteristics. Finally, the selected candidates were subjected to a biological validation assay to assess inhibition of Dengue virus propagation in mammalian host cells using a plaque formation assay. Among the 10 compounds examined, rolitetracycline and doxycycline significantly inhibited plaque formation, demonstrating their inhibitory effect on dengue virus propagation. Both compounds were tetracycline derivatives with IC(50)s estimated to be 67.1 µM and 55.6 µM, respectively. Their docked conformations displayed common hydrophobic interactions with critical residues that affected membrane fusion during viral entry. These interactions will therefore position the tetracyclic ring moieties of both inhibitors to bind firmly to the target and, subsequently, disrupt conformational rearrangement and block viral entry. This process can be applied to other drug targets in which conformational rearrangement is critical to function

    Stereo-Selectivity of Human Serum Albumin to Enantiomeric and Isoelectronic Pollutants Dissected by Spectroscopy, Calorimetry and Bioinformatics

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    1–naphthol (1N), 2–naphthol (2N) and 8–quinolinol (8H) are general water pollutants. 1N and 2N are the configurational enantiomers and 8H is isoelectronic to 1N and 2N. These pollutants when ingested are transported in the blood by proteins like human serum albumin (HSA). Binding of these pollutants to HSA has been explored to elucidate the specific selectivity of molecular recognition by this multiligand binding protein. The association constants (Kb) of these pollutants to HSA were moderate (104–105 M−1). The proximity of the ligands to HSA is also revealed by their average binding distance, r, which is estimated to be in the range of 4.39–5.37 nm. The binding free energy (ΔG) in each case remains effectively the same for each site because of enthalpy–entropy compensation (EEC). The difference observed between ΔCpexp and ΔCpcalc are suggested to be caused by binding–induced flexibility changes in the HSA. Efforts are also made to elaborate the differences observed in binding isotherms obtained through multiple approaches of calorimetry, spectroscopy and bioinformatics. We suggest that difference in dissociation constants of pollutants by calorimetry, spectroscopic and computational approaches could correspond to occurrence of different set of populations of pollutants having different molecular characteristics in ground state and excited state. Furthermore, our observation of enhanced binding of pollutants (2N and 8H) in the presence of hemin signifies that ligands like hemin may enhance the storage period of these pollutants in blood that may even facilitate the ill effects of these pollutants

    Identifying knowledge gaps in seagrass research and management: An Australian perspective

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    © 2016 Elsevier Ltd Seagrass species form important marine and estuarine habitats providing valuable ecosystem services and functions. Coastal zones that are increasingly impacted by anthropogenic development have experienced substantial declines in seagrass abundance around the world. Australia, which has some of the world's largest seagrass meadows and is home to over half of the known species, is not immune to these losses. In 1999 a review of seagrass ecosystems knowledge was conducted in Australia and strategic research priorities were developed to provide research direction for future studies and management. Subsequent rapid evolution of seagrass research and scientific methods has led to more than 70% of peer reviewed seagrass literature being produced since that time. A workshop was held as part of the Australian Marine Sciences Association conference in July 2015 in Geelong, Victoria, to update and redefine strategic priorities in seagrass research. Participants identified 40 research questions from 10 research fields (taxonomy and systematics, physiology, population biology, sediment biogeochemistry and microbiology, ecosystem function, faunal habitats, threats, rehabilitation and restoration, mapping and monitoring, management tools) as priorities for future research on Australian seagrasses. Progress in research will rely on advances in areas such as remote sensing, genomic tools, microsensors, computer modeling, and statistical analyses. A more interdisciplinary approach will be needed to facilitate greater understanding of the complex interactions among seagrasses and their environment

    Client-practitioner interactions within breast care services

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    United Kingdom (UK) breast care services are delivered within one of two models. Clients presenting with breast symptoms (symptomatic) are assessed within a ‘one stop’ (all done at one hospital attendance) out-patient setting whilst asymptomatic clients currently aged 50–70 (screening) are invited for 3 yearly breast screening by the National Health Service Breast Screening Programme (NHSBSP). A proportion of the latter are recalled for further assessment should a mammographic abnormality be suspected (assessment clients). Many other health care systems around the world also offer these three breast care approaches (symptomatic, screening and assessment services), though the timeframe between screening invitations and the age range of clients varies within the screening services (see Chap. 8)

    Site fidelity and individual variation in winter location in partially migratory European shags

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    In partially migratory populations, individuals from a single breeding area experience a range of environments during the non-breeding season. If individuals show high within- and among- year fidelity to specific locations, any annual environmental effect on individual life histories could be reinforced, causing substantial demographic heterogeneity. Quantifying within- and among- individual variation and repeatability in non-breeding season location is therefore key to predicting broad-scale environmental impacts on the dynamics of partially migratory populations. We used field resightings of colour-ringed adult European shags known to have bred on the Isle of May, Scotland, to quantify individual variation and repeatability in winter location within and among three consecutive winters. In total, 3797 resightings of 882 individuals were recorded over 622km of coastline, including the Isle of May. These individuals comprised over 50% of the known breeding population, and encompassed representative distributions of ages and sexes. The distances from the Isle of May at which individuals were resighted during winter varied substantially, up to 486km and 136km north and south respectively and including the breeding colony on the Isle of May. However, resighting distances were highly repeatable within individuals; within- and among-winter repeatabilities were >0.72 and >0.59 respectively across the full September-March observation period, and >0.95 and >0.79 respectively across more restricted mid-winter periods. Repeatability did not differ significantly between males and females or among different age classes, either within or among winters. These data demonstrate that the focal shag population is partially migratory, and moreover that individuals show highly repeatable variation in winter location and hence migration strategy across consecutive winters. Such high among-individual variation and within-individual repeatability, both within and among winters, could lead to substantial life history variation, and therefore influence population dynamics and future conservation management strategies
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