Biochemical and molecular characterisation of purine transporters of Trypanosoma brucei brucei

This thesis describes the elucidation and comparison of substrate recognition relationships for the H2 nucleobase transporter of T. b. brucei and the main nucleobase transporter of human erythrocytes. Using standard transport kinetics, application of the Cheng-Prusoff equation and a derivation of the Nernst equation, it was possible to determine the Gibbs free energy (DG°) for the interactions of purine analogues with each transporter, which allowed predictions about the nature of the interactions that are essential for uptake. A range of unusual tricyclic and "fleximer" purine analogues was also assayed for ability to interact with the various purine transporters in T. b. burcei and human erythrocytes. This provided further insights into the extent that the substrate-binding pocket can accommodate unusual and large substrates. Some of the purine analogues used for the substrate-recognition study also displayed limited trypanocidal activity in vitro. More importantly, these results provide a foundation for the design and development of purine nucleobase analogues with anti-trypanosomal action that are efficiently and selectively accumulated by the parasite. One of the main aims of the project was to clone and characterise nucleobase transporters from T. b. brucei. The initial functional complementation strategy in nucleobase-transport deficient trypanosomes proved unsuccessful due to the presence of an additional, previously uncharacterised purine transporter in the trypanosome selection background and other technical obstacles. Homology searching of the T. b. brucei genome database led to the identification of a sequence with substantial similarity to the Adenosine Transporter 1 (TbAT1) gene previously shown to be responsible for the P2 nucleoside transport activity. The AT-like sequence was cloned, functionally expressed in heterologous systems (Saccharomyces cerevisiae and Xenopus oocytes), and characterised as the high-affinity Nucleobase Transporter 1 (TbNBT1). This also marked the first time a nucleobase-specific transporter had been cloned and characterised from any protozoan

Cancer experience in the relatives of an unselected series of breast cancer patients

First- and second-degree relatives of an unselected series of 402 breast cancer patients have been studied for their cancer experience. In the first-degree relatives an excess of all cancers is seen [overall relative risk (RR) = 1.28, P = 0.002; males RR = 1.26, P = 0.047; females RR = 1.30, P = 0.022). There is a marked excess of sarcoma (RR = 4.26, P = 0.0064); females are at high risk of breast cancer (RR = 2.68, P < 0.0001) and males have an excess of carcinoma of the lip, oral cavity and pharynx (RR = 4.22, P = 0.0032). Second-degree relatives have a non-significant excess of all cancers (RR = 1.14, P = 0.14); females have a borderline excess of breast cancer (RR = 1.53, P = 0.08) and an excess of carcinoma of the kidney (RR = 7.46, P = 0.0012) and males have an excess of carcinoma of the trachea and lung (RR = 1.50, P = 0.032). No excess of prostate or ovarian carcinoma was seen. Relatives are at slightly higher risk if the index patient is diagnosed between the ages of 40 and 49 (first-degree RR = 1.64, P = 0.007; second-degree RR = 1.43, P = 0.02). The excess of cancers, including breast cancers, is not limited to a few high-risk families, but appears to be spread across many. These observations may be accounted for by shared environmental factors within families or a common predisposing gene with low penetrance

An idealized numerical study of tropical cyclogenesis and evolution at the Equator

Tropical cyclone formation and evolution at, or near, the Equator is explored using idealized three‐dimensional model simulations, starting from a prescribed, initial, weak counterclockwise rotating vortex in an otherwise quiescent, nonrotating environment. Three simulations are carried out in which the maximum tangential wind speed (5 m surn:x-wiley:qj:media:qj3701:qj3701-math-0001) is specified at an initial radius of 50, 100, or 150 km. After a period of gestation lasting between 30 and 60 hr, the vortices intensify rapidly, the evolution being similar to that for vortices away from the Equator. In particular, the larger the initial vortex size, the longer the gestation period, the larger the maximum intensity attained, and the longer the vortex lifetime. Beyond a few days, the vortices decay as the cyclonic vorticity source provided by the initial vortex is depleted and negative vorticity surrounding the vortex core is drawn inwards by the convectively driven overturning circulation. In these negative vorticity regions, the flow is inertially/centrifugally unstable. The vortex evolution during the mature and decay phases differs from that in simulations away from the Equator, where inertially unstable regions are much more limited in area. Vortex decay in the simulations appears to be related intimately to the development of inertial instability, which is accompanied by an outward‐propagating band of deep convection. The degree to which this band of deep convection is realistic is unknown

Stochastic model for the dynamics of interacting Brownian particles

Using the scheme of mesoscopic nonequilibrium thermodynamics, we construct the one- and two- particle Fokker-Planck equations for a system of interacting Brownian particles. By means of these equations we derive the corresponding balance equations. We obtain expressions for the heat flux and the pressure tensor which enable one to describe the kinetic and potential energy interchange of the particles with the heat bath. Through the momentum balance we analyze in particular the diffusion regime to obtain the collective diffusion coefficient in terms of the hydrodynamic and the effective forces acting on the Brownian particles.Comment: latex fil

Stem cell factor (SCF) and c-kit in the ovine fetal testis in normal and nutrition perturbed pregnancies

Stem cell factor (SCF) and c-kit in the ovine fetal testis in normal and nutrition perturbed pregnancie

Comparison of US County-Level Public Health Performance Rankings With County Cluster and National Rankings: Assessment Based on Prevalence Rates of Smoking and Obesity and Motor Vehicle Crash Death Rates

Importance: Health departments can be grouped together based on sociodemographic characteristics of the population served. Comparisons within these groups can then help with monitoring and improving the health of their populations. Objective: To compare county-level percentile rankings on outcomes of smoking, motor vehicle crash deaths, and obesity within sociodemographic peer clusters vs nationwide rankings. Design, Setting, and Participants: This cross-sectional, population-based study of demographic and health data from the 2014 Behavioral Risk Factor Surveillance System and the 2016 Robert Wood Johnson Foundation County Health Rankings data set was conducted at 3139 of 3143 US counties and county-equivalents. Four locations were excluded due to incomplete data. Data analysis was conducted between January and August 2017. Exposures: Random forest algorithms were used to identify sociodemographic characteristics most associated with the outcomes of interest. These characteristics were race and ethnicity, educational attainment, age, marital status, employment status, sex, and health insurance status. k-means clustering was used to cluster counties based on these sociodemographic characteristics and the percentage of the county classified as rural. Main Outcomes and Measures: County-level smoking prevalence, motor vehicle crash death rate, and obesity prevalence. County percentile rankings on the outcomes of interest were compared in the national context and the within-cluster context. Results: A total of 318 856 967 individuals (mean [SD] individuals per county, 101 579.2 [326 315]; 161 911 910 women [50.8%]) were represented by the 3139 counties used in this analysis. Eight distinct sociodemographic clusters throughout the United States were found. Cluster-specific percentile rankings for both smoking prevalence and motor vehicle crash death rates improved more than 70 percentile points for several counties in the rural, American Indian cluster compared with the nationwide percentiles. Conversely, the young, urban, middle to high socioeconomic status cluster included counties with cluster-specific percentile rankings that declined by 60 percentile points or more compared with the nationwide rankings for all 3 outcomes of interest. Conclusions and Relevance: Comparing county health outcomes on a nationwide or statewide basis fails to adequately account for sociodemographic context. Clustering counties by sociodemographic factors related to the outcome of interest allows a better understanding of other factors that may be shaping the prevalence of health outcomes. These groupings may also aid learning exchange

Trends in cyclones in the high-latitude North Atlantic during 1979-2016

We report an increase in winter (DJF) cyclone densities in the areas around Svalbard and in northwestern Barents Sea and a decrease in cyclone densities in southeastern Barents Sea during 1979-2016. Despite high interannual variability, the trends are significant at the 90% confidence level. The changes appear as a result of a shift into a more meridional winter storm track in the high-latitude North Atlantic, associated with a positive trend in the Scandinavian Pattern. A significant decrease in the Brunt-Vaisala frequency east of Svalbard and a significant increase in the Eady Growth Rate north of Svalbard indicate increased baroclinicity, favouring enhanced cyclone activity in these regions. For the first time, we apply composite analysis to explicitly address regional consequences of these wintertime changes in the high-latitude North Atlantic. We find a tendency toward a warmer and more moist atmospheric state in the Barents Sea and over Svalbard with increased cyclone activity around Svalbard.Peer reviewe

Towards a population of HMXB/NS microquasars as counterparts of low-latitude unidentified EGRET sources

The discovery of the microquasar LS 5039 well within the 95% conficence contour of the Unidentified EGRET Source (UES) 3EG J1824-1514 was a major step towards the possible association between microquasars (MQs) and UESs. The recent discovery of precessing relativistic radio jets in LS I +61 303, a source associated for long time with 2CG 135+01 and with the UES 3EG J0241+6103, has given further support to this idea. Finally, the very recently proposed association between the microquasar candidate AX J1639.0-4642 and the UES 3EG J1639-4702 points towards a population of High Mass X-ray Binary (HMXB)/Neutron Star (NS) microquasars as counterparts of low-latitude unidentified EGRET sources.Comment: 12 pages, 7 figures. Proceedings of the Conference "The Multiwavelength Approach to Unidentified Gamma-ray Sources", to appear in the journal Astrophysics and Space Scienc

New directions in island biogeography

Aim: Much of our current understanding of ecological and evolutionary processes comes from island research. With the increasing availability of data on distributions and phylogenetic relationships and new analytical approaches to understanding the processes that shape species distributions and interactions, a re-evaluation of this ever-interesting topic is timely. Location: Islands globally. Methods: We start by arguing that the reasons why island research has achieved so much in the past also apply to the future. We then critically assess the current state of island biogeography, focusing on recent changes in emphasis, including research featured in this special issue of Global Ecology and Biogeography. Finally, we suggest promising themes for the future. We cover both ecological and evolutionary topics, although the greater emphasis on island ecology reflects our own backgrounds and interests. Results: Much ecological theory has been directly or indirectly influenced by research on island biotas. Currently, island biogeography is renascent, with research focusing on, among other things, patterns and processes underlying species interaction networks, species coexistence and the assembly of island communities through ecological and evolutionary time. Continuing island research should provide additional insight into biological invasions and other impacts of human activities, functional diversity and ecosystem functioning, extinction and diversification, species pools and more. Deeper understanding of the similarities and differences between island and mainland systems will aid transferability of island theory to continental regions. Main conclusions: As research in biogeography and related fields expands in new directions, islands continue to provide opportunities for developing insights, both as natural laboratories for ecology and evolution and because of the exceptions islands often present to the usual ‘rules’ of ecology. New data collection initiatives are needed on islands world-wide and should be directed towards filling gaps in our knowledge of within-island distributions of species, as well as the functional traits and phylogenetic relationships of island species