No abstract

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

The indigenous wildcat, Felis silvestris Schreber, 1775, and the introduced domestic cat, F. catus L., have been sympatric in Britain for more than 2000 years. As a result of interbreeding, any distinction between these two forms has become obscured, although a range of morphological criteria (pelage patterns, body measurements, gut lengths, skull morphometrics) and genetic techniques (immunological distances, electrophoresis, DNA hybridization) have been used previously to distinguish between them.A sample of 333 wild-living cats in Scotland was assessed for coloration and markings of pelage, standard body measurements and weights, and (for carcasses only) limb bone lengths, intestine lengths, and skull measurements. These cats were also classi®ed as wildcat, hybrid, or domestic cat according to traditional pelage criteria.Multivariate analyses on these variables, for adult cats, failed to show any clearly distinct groups. When each of the variables was analysed separately, only the distribution of limb bone and intestine length measurements suggested the possibility that two groups might exist. Group 1 cats had short intestines and long limb bones. Group 2 consisted of cats with long intestines and short limb bones. Although the characteristics de®ning cats in Group 1 were similar to those traditionally associated with wildcats, they exhibited a much broader range of pelage and coloration than traditionally described.The groups exhibited a degree of geographical separation. The distribution of Group 1 cats was found to be related to certain environmental variables, namely mean annual temperature and land with poor potential for forestry and agriculture, suggesting that there may be a biological basis for the separation. The implications of these results on the identi®cation and taxonomy of the wildcat are signi®cant. The concept of the wildcat and the domestic cat as separate species can be challenged. The paper highlights the complexity and dif®culties for conventional taxonomy when used as a means for distinguishing between a wild type and its domesticated form where there is interbreeding.

The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.

SummaryThe proportions of milk stored within the gland cistern (cisternal milk) and within secretory alveolar tissue (alveolar milk) were determined at various intervals after milking in peak lactation cows and late lactation cows. The rate of milk secretion remained constant up to 12 h in both groups. Cisternal milk remained low (600 g or less) until after 4 h in both groups, then increased gradually to values at 12 h of 5·08 (peak lactation) and 2·60 kg (late lactation). Alveolar milk exceeded cisternal milk in both groups and at all time points up to 12 h, and was greatest in the peak lactation cows. A further measurement was made at 20 h in the late lactation group. Milk secretion rate remained constant between 12 and 20 h and most of this additional milk accumulated in the cistern. Alveolar fraction, defined as alveolar milk as a proportion of total milk, ranged from 0·43 to 0·94 at 8 h. There was a highly significant correlation between 8 h and 20 h alveolar milk fraction results, but not between 1 h and 8 h values, nor between alveolar milk at 0 h (effectively residual milk) and alveolar fraction at any time point. The milk volume results were used to construct a mathematical model describing milk flow between cisternal and alveolar compartments, and hence the pattern of milk accumulation. The results are discussed in relation to current hypotheses regarding local autocrine control of milk secretion by a feedback inhibitor in milk.