132,631 research outputs found
Chapter House, Haughmond Abbey, Shropshire
No full text'CHAPTER HOUSE HAUGHMOND ABBEY Shropshire. Engrav'd by J. Greig, from a drawing by D. Parkes, Esqr. for the Beauties of England and Wales. London, Publish'd by Vernor, Hood & Sharpe, Poultry, March 1 1811.
ON-LINE CHARACTERIZATION OF CHOLINESTERASE INHIBITORS BY IMMOBILIZED ENZYME REACTORS
No full textIn the search for new therapeutics for Alzheimer’s Disease (AD), the investigation of the mechanism of action of new cholinesterase inhibitors represents a key aspect for new lead selection and subsequent optimization and development. However, the in vitro characterization of drug candidates on isolated target enzymes often requires a long operating time and a large amount of disposable expensive material. The recent development and aplication of stable immobilized enzyme reactors (IMERs) can ameliorate these concerns, and such in-solution methods should be potentially utilized in automated procedures to obtain efficient and effective higher throughput screening. In this context, the focus of this work was the development and characterization of a new IMER containing immobilized human recombinant butyrylcholinesterase (BChE) for the on-line kinetic characterization of specific, pseudo-irreversible and brain-targeted BChE inhibitors as potential drug candidates for AD. The selected phenserine and cymserine analogues were synthesized, characterized by classical ex vivo binding assays [1], and assessed by BChE-IMER.
For a pseudo-irreversible inhibitor, the kinetics constants describe the mode and duration of enzyme inhibition that will, in turn, influence the duration of the inhibitors’s in vivo pharmacological actions. The kinetic constants were determined for selected phenserine and cymserine analogues using a purposely-designed on-line procedure. Specifically, agents were inserted on to the BChE-IMER that fed directly into a HPLC system connected to a UV-Vis detector, BChE-IMER activity was determined on the basis of the Ellman reaction [2]. The carbamoylation and decarbamoylation phases at different inhibitor concentrations were then monitored continuously over time. Results allowed elucidation of the inhibition duration, mode of action and structure-activity relationships of the inhibitors of interest, which were compared to available values deriving from classical assessment.
(1) N.H. Greig, T. Utsuki, D.K. Ingram, Y. Wang, G. Pepeu, C. Scali, Q.S. Yu, I. Mamczarz, H.W. Holloway, T. Giordano, D. Chen, K. Furukawa, K. Sambamurti, A. Brossi, D.K. Lahiri: Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc Natl Acad Sci USA 2005, 102: 17213-18.
(2) G.L. Ellman, K.D. Courtney, V. Jr. Andres, R.M. Featherstone. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961, 7: 88-95
A screen for recessive speciation genes expressed in the gametes of F1 hybrid yeast
No full textDiploid hybrids of Saccharomyces cerevisiae and its closest relative, Saccharomyces paradoxus, are viable, but the sexual gametes they produce are not. One of several possible causes of this gamete inviability is incompatibility between genes from different species-such incompatible genes are usually called "speciation genes.'' In diploid F1 hybrids, which contain a complete haploid genome from each species, the presence of compatible alleles can mask the effects of ( recessive) incompatible speciation genes. But in the haploid gametes produced by F1 hybrids, recessive speciation genes may be exposed, killing the gametes and thus preventing F1 hybrids from reproducing sexually. Here I present the results of an experiment to detect incompatibilities that kill hybrid gametes. I transferred nine of the 16 S. paradoxus chromosomes individually into S. cerevisiae gametes and tested the ability of each to replace its S. cerevisiae homeolog. All nine chromosomes were compatible, producing nine viable haploid strains, each with 15 S. cerevisiae chromosomes and one S. paradoxus chromosome. Thus, none of these chromosomes contain speciation genes that were capable of killing the hybrid gametes that received them. This is a surprising result that suggests that such speciation genes do not play a major role in yeast speciation
Impact of clay particles on the cutaneous exchange of oxygen across the chorion of Atlantic salmon eggs
No full textRates of oxygen consumption for Atlantic salmon Salmo salar embryos approaching hatching were determined. Values were recorded using a 'closed system' experimental set-tip. A magnetic stirrer was used to ensure that zones of oxygen depletion did not develop in the microenvironment surrounding the respiring eggs. Recorded values of oxygen consumption ranged from 0.0024 to 0.0038 mg O-2 egg(-1) h(-1), with a mean consumption rate of 0.0032 mg 0, egg(-1) h-1. The values of oxygen consumption were similar to those reported in other studies using a closed system experimental set-up, however, they were lower than those reported in a study adopting a flow-through system. The introduction of clay-sized sediment to the incubation chamber created a thin film (<1 mm) of sediment on the egg surface, and resulted in reduced rates of oxygen consumption. The additional 0.3 g of clay sediment reduced oxygen consumption by an average of 41 % and the addition of a further 0.2 g of clay sediment reduced consumption by an average of 98%. Two explanations for the recorded reduction in consumption were proposed: (i) the creation of a low permeability seal around the eggs restricted the availability of oxygen to the incubating embryos and (ii) the clay-sized fine sediment physically blocked the micro-pore canals in the egg membrane, thereby restricting oxygen uptake
MeSH term explosion and author rank improve expert recommendations
No full textInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Curing Cholera: Pathogens, Places and Poverty in South Asia
No full textIn this paper I will seek to provide a new understanding of endemicity of disease in India. Through a study of cholera research in the twentieth century I will argue that disease and its endemicity has to be understood in biological factors as well as within a wider social and economic context. I will discuss the medical efforts at locating the causality of cholera from the nineteenth century in Indian climate, water bodies and human anatomy to show that cholera is no more a biological phenomena than water is an ecological or environmental problem. Both are essentially political and economic questions
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