Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1.

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Marketing secondhand goods in late medieval England

Purpose – The purpose of this paper is to identify the main practitioners, goods, customers and locations of secondhand marketing activities in late medieval England. It questions how important was the economic role played by such markets and what was the interaction with more formal market structures?

Design/methodology/approach – A broad range of evidence was examined, covering the period from 1200 to 1500: regulations, court rolls, wills, manorial accounts, literature, and even archaeology. Such material often provided mere scraps of information about marginal marketing activity and it was important to recognise the severe limitations of the evidence. Nevertheless, a wide survey of the available sources can give us an insight into medieval attitudes towards such trade, as well as reminding us that much marketing activity occurred beyond the reach of the surviving documentation.

Findings – Late medieval England had numerous outlets for secondhand items, from sellers of used clothes and furs who wandered the marketplaces to craftsmen who recycled and mended old materials. Secondhand marketing was an important part of the medieval makeshift economy, serving not only the needs of the lower sectors of society but also those aspiring to a higher status. However, it is unlikely that such trade generated much profit and the traders were often viewed as marginal, suspicious and even fraudulent.

Originality/value – There is a distinct lack of research into the extent of and significance of medieval secondhand marketing, which existed in the shadowy margins of formal markets and is thus poorly represented in the primary sources. A broad-based approach to the evidence can highlight a variety of important issues, which impact upon the understanding of the medieval English economy.

WASP-8b: a retrograde transiting planet in a multiple system

We report the discovery of WASP-8b, a transiting planet of 2.25 ± 0.08 MJup on a strongly inclined eccentric 8.15-day orbit, moving in a retrograde direction to the rotation of its late-G host star. Evidence is found that the star is in a multiple stellar system with two other companions. The dynamical complexity of the system indicates that it may have experienced secular interactions such as the Kozai mechanism or a formation that differs from the “classical” disc-migration theory.

Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 (4) as an LXR ligand. 4 recruits the steroid receptor coactivator-1 to human LXR alpha and LXRP with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.

An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism

PURPOSE:
To investigate whether variation in the distribution of the risk allele frequency of the Y402H single-nucleotide polymorphism (SNP) across various ethnicities and geographic regions reflects differences in the prevalence of late age-related macular degeneration (AMD) in those ethnicities.

METHODS:
Published data were obtained via a systematic search. Study samples were grouped into clusters by ethnicity and geographic location and the Spearman correlation coefficient of the prevalence of late AMD and risk allele frequencies was calculated across clusters.

RESULTS:
Across all ethnicities, AMD prevalence was seen to increase with age. Populations of European descent had both higher risk allele frequencies and prevalence of late AMD than did Japanese, Chinese, and Hispanic descendants. Results for African descendants were anomalous: although allele frequency was similar to that in European populations, the age-specific prevalence of late AMD was considerably lower. The correlation coefficient for the association between allele frequency and AMD prevalence was 0.40 (95% confidence interval [CI] = -0.36 to 0.84, P = 0.28) in all populations combined and 0.71 (95% CI = 0.02-0.94, P = 0.04) when people of African descent were excluded.

CONCLUSIONS:
Evidence was found at the population level to support a positive association between the Y204H risk allele and the prevalence of AMD after exclusion of studies undertaken on persons of African ancestry. Data in African, Middle Eastern, and South American populations are needed to provide a better understanding of the association of late AMD genetic risk across ethnicities.

Prevalence of Early and Late Age-Related Macular Degeneration in India: The INDEYE Study

PURPOSE. To estimate the prevalence of early and late age-related macular degeneration (AMD) in India.

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland

alpha 1-antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimer's disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5' of the AACT gene have been reported to increase the risk of developing AD, Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to bet significantly raised in cases compared to controls (t = 3.8, df = 209, p