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.

Cytopathogenesis of Sendai virus in well-differentiated primary pediatric bronchial epithelial cells

Sendai virus (SeV) is a murine respiratory virus of considerable interest as a gene therapy or vaccine vector, as it is considered nonpathogenic in humans. However, little is known about its interaction with the human respiratory tract. To address this, we developed a model of respiratory virus infection based on well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). These physiologically authentic cultures are comprised of polarized pseudostratified multilayered epithelium containing ciliated, goblet, and basal cells and intact tight junctions. To facilitate our studies, we rescued a replication-competent recombinant SeV expressing enhanced green fluorescent protein (rSeV/eGFP). rSeV/eGFP infected WD-PBECs efficiently and progressively and was restricted to ciliated and nonciliated cells, not goblet cells, on the apical surface. Considerable cytopathology was evident in the rSeV/eGFP-infected cultures postinfection. This manifested itself by ciliostasis, cell sloughing, apoptosis, and extensive degeneration of WD-PBEC cultures. Syncytia were also evident, along with significant basolateral secretion of proinflammatory chemokines, including IP-10, RANTES, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), interleukin 6 (IL-6), and IL-8. Such deleterious responses are difficult to reconcile with a lack of pathogenesis in humans and suggest that caution may be required in exploiting replication-competent SeV as a vaccine vector. Alternatively, such robust responses might constitute appropriate normal host responses to viral infection and be a prerequisite for the induction of efficient immune responses.

Talking about colds and flu: The lay diagnosis of two common illnesses among older British people

This paper reports on a study of the ways in which 54 older people in South Wales (UK) talk about the symptoms and causes of cold and influenza (flu). The study was designed to understand why older people might reject or accept the offer of seasonal flu vaccine, and in the course of the interviews respondents were also asked to express their views about the nature and causes of the two key illnesses. The latter are among the most common infections in human beings. In terms of the biomedical paradigm the common cold is caused by numerous respiratory viruses, whilst flu is caused by the influenza virus. Medical diagnosis is usually made on clinical grounds without laboratory confirmation. Symptoms of flu include sudden onset of fever and cough, and colds are characterized by sneezing, sore throat, and runny nose, but in practice the symptoms often overlap. In this study we examine the degree by which the views of lay people with respect to both diagnosis and epidemiology diverge with that which is evident in biomedical discourse. Our results indicate that whilst most of the identified symptoms are common to lay and professional people, the former integrate symptoms into a markedly different observational frame from the latter. And as far as causation is concerned it is clear that lay people emphasize the role of 'resistance' and 'immunity' at least as much as 'infection' in accounting for the onset of colds and flu. The data are analyzed using novel methods that focus on the co-occurrence of concepts and are displayed as semantic networks. As well as reporting on its findings the authors draw out some implications of the study for social scientific and policy discussions concerning lay diagnosis, lay expertise and the concept of an expert patient.

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.

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.

Combined R-matrix eigenstate basis set and finite-difference propagation method for the time-dependent Schrodinger equation: The one-electron case

In this work we present the theoretical framework for the solution of the time-dependent Schrödinger equation (TDSE) of atomic and molecular systems under strong electromagnetic fields with the configuration space of the electron’s coordinates separated over two regions; that is, regions I and II. In region I the solution of the TDSE is obtained by an R-matrix basis set representation of the time-dependent wave function. In region II a grid representation of the wave function is considered and propagation in space and time is obtained through the finite-difference method. With this, a combination of basis set and grid methods is put forward for tackling multiregion time-dependent problems. In both regions, a high-order explicit scheme is employed for the time propagation. While, in a purely hydrogenic system no approximation is involved due to this separation, in multielectron systems the validity and the usefulness of the present method relies on the basic assumption of R-matrix theory, namely, that beyond a certain distance (encompassing region I) a single ejected electron is distinguishable from the other electrons of the multielectron system and evolves there (region II) effectively as a one-electron system. The method is developed in detail for single active electron systems and applied to the exemplar case of the hydrogen atom in an intense laser field.

Creating advantage in peripheral regions: The role of publicly funded R&D centres

Regional investment in R&D, technological development and innovation is perceived as being strongly associated with productivity, growth and sustained international competitiveness. One policy instrument by which policy makers have attempted to create regional advantage has been the establishment of publicly funded research centres (PRCs). In this paper we develop a logic model for this type of regional intervention and examine the outputs and longer-term outcomes from a group of (18) publicly funded R&D centres. Our results suggest some positive regional impacts but also identify significant differences in terms of innovation, additionality and sustainability between university-based and company-based PRCs. University-based PRCs have higher levels of short-term additionality, demonstrate higher levels of organisational innovation but prove less sustainable. Company-based PRCs demonstrate more partial additionality in the short-term but ultimately prove more sustainable.