Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.     

General practitioner fundholding: experience in Grampian.

Proposals for fundholding were greeted with scepticism by many general practitioners, and in Scotland the BMA persuaded the government to allow a scheme to test the arrangements as a demonstration project operating "shadow" practice funds. This allowed the six selected practices to set up administrative and computer systems without the worry of dealing with real money. The shadow fundholding scheme has since been extended to small practices and to a trial of fundholding for all services except accident and emergency. The six practices in the original pilot have all become fundholders and are beginning to effect improvements in the service to their patients. However, with more practices becoming fundholders negotiating contracts with providers is becoming increasingly complicated and more time and money needs to be put into this aspect.     

Fine‐scale distribution modeling of avian malaria vectors in north‐central Kansas

Infectious diseases increasingly play a role in the decline of wildlife populations. Vector‐borne diseases, in particular, have been implicated in mass mortality events and localized population declines are threatening some species with extinction. Transmission patterns for vector‐borne diseases are influenced by the spatial distribution of vectors and are therefore not uniform across the landscape. Avian malaria is a globally distributed vector‐borne disease that has been shown to affect endemic bird populations of North America. We evaluated shared habitat use between avian malaria vectors, mosquitoes in the genus Culex and a native grassland bird, the Greater Prairie‐Chicken (Tympanuchus cupido), by (1) modeling the distribution of Culex spp. occurrence across the Smoky Hills of north‐central Kansas using detection data and habitat variables, (2) assessing the occurrence of these vectors at nests of female Greater Prairie‐Chickens, and (3) evaluating if shared habitat use between vectors and hosts is correlated with malarial infection status of the Greater Prairie‐Chicken. Our results indicate that Culex occurrence increased at nest locations compared to other available but unoccupied grassland habitats; however the shared habitat use between vectors and hosts did not result in an increased prevalence of malarial parasites in Greater Prairie‐Chickens that occupied habitats with high vector occurrence. We developed a predictive map to illustrate the associations between Culex occurrence and infection status with malarial parasites in an obligate grassland bird that may be used to guide management decisions to limit the spread of vector‐borne diseases.     

Disentangling genetic and epigenetic determinants of ultrafast adaptation

A major rationale for the advocacy of epigenetically mediated adaptive responses is that they facilitate faster adaptation to environmental challenges. This motivated us to develop a theoretical–experimental framework for disclosing the presence of such adaptation‐speeding mechanisms in an experimental evolution setting circumventing the need for pursuing costly mutation–accumulation experiments. To this end, we exposed clonal populations of budding yeast to a whole range of stressors. By growth phenotyping, we found that almost complete adaptation to arsenic emerged after a few mitotic cell divisions without involving any phenotypic plasticity. Causative mutations were identified by deep sequencing of the arsenic‐adapted populations and reconstructed for validation. Mutation effects on growth phenotypes, and the associated mutational target sizes were quantified and embedded in data‐driven individual‐based evolutionary population models. We found that the experimentally observed homogeneity of adaptation speed and heterogeneity of molecular solutions could only be accounted for if the mutation rate had been near estimates of the basal mutation rate. The ultrafast adaptation could be fully explained by extensive positive pleiotropy such that all beneficial mutations dramatically enhanced multiple fitness components in concert. As our approach can be exploited across a range of model organisms exposed to a variety of environmental challenges, it may be used for determining the importance of epigenetic adaptation‐speeding mechanisms in general.