Non-thiazolidinedione antihyperglycemic agents. Part 4: synthesis of ( )-, (R)-(+)- and (S)-(-)-enantiomers of 2-oxy-3-arylpropanoic acids

. Haigh, David; Birrell, Helen C.; Cantello, Barrie C. C.; Hindley, Richard M.; Ramaswamy, Anantha; Rami, Harshad K.; Stevens, Nicola C. Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Essex, UK. Tetrahedron: Asymmetry (1999), 10(7), 1335-1351. Publisher: Elsevier Science Ltd., CODEN: TASYE3 ISSN: 0957-4166. Journal written in English. CAN 131:144536 AN 1999:369513 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract The synthesis of a new series of potent 2-oxy-3-arylpropanoic acid antihyperglycemic agents in both racemic and non-racemic form is described. (the biol. activity of these compds. was not reported here). Resoln. of racemic acids is accomplished via amide formation with either (S)-2-phenylglycinol or (S)-4-benzyl-2-oxazolidinone as complementary resolving agents. The target compds. were ?-alkoxy-4-[2-[(2-benzoxazolyl)amino]ethoxy]benzenepropanoic acid derivs.

Facile biocatalytic reduction of the carbon-carbon double bond of 5-benzylidenethiazolidine-2,4-diones. Synthesis of ( )-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2,4-dione (BRL 49653), its (R)-(+)-enantiomer and analogs.

Cantello, Barrier C. C.; Eggleston, Drake S.; Haigh, David; Haltiwanger, R. Curtis; Heath, Catherine M.; Hindley, Richard M.; Jennings, Keith R.; Sime, John T.; Woroniecki, Stefan R. SmithKline Beecham Pharmaceuticals, Surrey, UK. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1994), (22), 3319-24. Publisher: Royal Society of Chemistry, CODEN: JCPRB4 ISSN: 0300-922X. Journal written in English. CAN 122:105736 AN 1995:237497 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract A novel biotransformation system for the redn. of carbon-carbon double bonds in 5-benzylidenethiazolidine-2,4-diones to give the corresponding 5-benzylthiazolidine-1,4-diones, using whole cells of red yeasts, is described. These reduced compds., which are recovered in good yield, are of potential use in the treatment of non-insulin dependent diabetes mellitus. The mild reaction conditions developed allow redn. of 5-benzylidenethiazolidine-2,4-diones contg. other functionalities which are not compatible with alternative redn. methods. The biocatalytic redn. is enantioselective and the synthesis of R-(+)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2,4-dione by Rhodotorula rubra CBS 6469 and structure confirmation by X-ray crystallog. is detailed. Optimization of reaction conditions (including immobilization) for these whole cell redn. system is described.

Endothelin 1 Stimulates Ca2+-Sparks and Oscillations in Retinal Arteriolar Myocytes via IP3R and RyR-Dependent Ca2+ Release

PURPOSE:r/>To investigate endothelin 1 (Et1)-dependent Ca(2+)-signaling at the cellular and subcellular levels in retinal arteriolar myocytes.r/>METHODS:r/>Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using confocal laser microscopy.r/>RESULTS:r/>Basal [Ca(2+)](i), subcellular Ca(2+)-sparks, and cellular Ca(2+)-oscillations were all increased during exposure to Et1 (10 nM). Ca(2+)-spark frequency was also increased by 90% by 10 nM Et1. The increase in oscillation frequency was concentration dependent and was inhibited by the EtA receptor (Et(A)R) blocker BQ123 but not by the EtB receptor antagonist BQ788. Stimulation of Ca(2+)-oscillations by Et1 was inhibited by a phospholipase C blocker (U73122; 10 µM), two inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)Rs), xestospongin C (10 µM), 2-aminoethoxydiphenyl borate (100 µM), and tetracaine (100 µM), a blocker of ryanodine receptors (RyRs).r/>CONCLUSIONS:r/>Et1 stimulates Ca(2+)-sparks and oscillations through Et(A)Rs. The underlying mechanism involves the activation of phospholipase C and both IP(3)Rs and RyRs, suggesting crosstalk between these Ca(2+)-release channels. These findings suggest that phasic Ca(2+)-oscillations play an important role in the smooth muscle response to Et1 within the retinal microvasculature and support an excitatory, proconstrictor role for Ca(2+)-sparks in these vessels.

Stable isotope analysis of archived roach (Rutilus rutilus) scales for retrospective study of shallow lake responses to nutrient reduction

1. There is increasing interest in the use of stable isotope analysis of archived materials to study the long-term impacts of lake perturbations, including nutrient manipulation or species invasion. We tested the utility of this approach in a shallow productive lake using the zooplanktivorous early life stages of roach ( Rutilus rutilus), a fish species that is widespread throughout Eurasian lakes.

Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration

Background: Fish intake, the major source of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may reduce the risk of age-related macular degeneration (AMD). Objective: We investigated the association of oily fish and dietary DHA and EPA with neovascular AMD (NV-AMD). Design: Participants aged =65 y in the cross-sectional population-based EUREYE study underwent fundus photography and were interviewed by using a food-frequency questionnaire. Fundus images were graded by the International Classification System for Age Related Maculopathy. Questionnaire data were converted to nutrient intakes with the use of food-composition tables. Survey logistic regression was used to calculate odds ratios (ORs) and 95% CIs of energy-adjusted quartiles of EPA or DHA with NV-AMD, taking into account potential confounders. Results: Dietary intake data and fundus images were available for 105 cases with NV-AMD and for 2170 controls without any features of early or late AMD. Eating oily fish at least once per week compared with less than once per week was associated with a halving of the odds of NV-AMD (OR = 0.47; 95% CI: 0.33, 0.68; P = 0.002). Compared with the lowest quartile, there was a significant trend for decreased odds with increasing quartiles of either DHA or EPA. ORs in the highest quartiles were 0.32 (95% CI: 0.12, 0.87; P = 0.03) for DHA and 0.29 (95% CI: 0.11, 0.73; P = 0.02) for EPA. Conclusions: Eating oily fish at least once per week compared with less than once per week was associated with a halving of the OR for NV-AMD. © 2008 American Society for Nutrition.

Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia

Background-Associations between genotype and intellectual outcome in patients with phenylketonuria are complicated because intelligence is influenced by many variables, including environmental factors and other genetic determinants. Intellectual changes with age, both on and after relaxation of diet, vary within the patient population. This study aims to determine whether a significant association exists between genotype and change in intelligence after relaxation of diet.

Graham Connah - Writing About Archaeology

Review of Graham Connah Writing about archaeology. CUP book 2009.

Eochaid ua Flainn is Eochaid ua Flannucáin: Súil Úr ar an bhFianaise

The evidence for two poets on record in the tenth century is reconsidered. The argument is made that they can be identified as one person, the poet Eochaid ua Flannucáin, a member of the religious community of Armagh and founder of a dynasty which governed the centre of the Irish church for over 150 years.

Intellectual Property management in publicly funded R&D centres—A comparison of university-based and company-based research centres

Recent thinking on open innovation and the knowledge-based economy have stressed the importance of external knowledge sources in stimulating innovation. Policy-makers have recognised this, establishing publicly funded Centres of R&D Excellence with the objective of stimulating industry–science links and localised innovation spillovers. Here, we examine the contrasting IP management practices of a group of 18 university- and company-based R&D centres supported by the same regional programme. Our analysis covers all but one of the Centres supported by the programme and suggests marked contrasts between the IP strategies of the university-based and company-based centres. This suggests the potential for very different types of knowledge spillovers from publicly funded R&D centres based in different types of organisations, and a range of alternative policy approaches to the future funding of R&D centres depending on policy-makers’ objectives.

Determination of absolute ion yields from a MALDI source through calibration of an image-charge detector

MALDI (matrix-assisted laser desorption/ionization) is one of the most important techniques used to produce large biomolecular ions in the gas phase. Surprisingly, the exact ionization mechanism is still not well understood and absolute values for the ion yields are scarce. This is in part due to the unknown efficiencies of typical detectors, especially for heavy biomolecular ions. As an alternative, charged particles can be non-destructively detected using an image-charge detector where the output voltage signal is proportional to the total charge within the device. In this paper, we report an absolute calibration which provides the voltage output per detected electronic charge in our experimental arrangement. A minimum of 3 x 10(3) ions were required to distinguish the signal above background noise in a single pass through the device, which could be further reduced using filtering techniques. The calibration results have been applied to raw MALDI spectra to measure absolute ion yields of both matrix and analyte ions.

Tolstoy, stories, and facilitating insight in end of life care: Exploring ethics through vicarious experience (with Glackin M and Henry R)

Facilitating moral insight in end of life care can be challenging, and the purpose of this paper is to illustrate how this can be nurtured by means of creative literature. Tolstoy's Death of Ivan Ilych is presented as an example of such literature. Aristotle's Nichomean Ethics provides the philosophical underpinning for the method used. Sources also include the nursing literature, and students' evaluations of the impact of Tolstoy's novella on their ability to perceive the ethical issues arising in end of life care. Comments from evaluations were analysed and significant themes emerged. Students' comments clearly support the suggestion that use of this novella has facilitated insight into ethical issues at the end of life. Evaluations also indicate that vicarious experience gained through reading this novella has helped to nurture sensitivity and professional insight into the importance of compassion and offering ‘comfort’ to the dying person.