Genetic Characteristics of Southern and Northern Brook Trout (Salvelinus fontinalis) Populations at the Zone of Contact

Population genetic evidence suggests differentiation among evolutionarily significant units of southern and northern Appalachian brook trout, with the zone of contact in southwestern Virginia. Before this differentiation was recognized, brook trout of northern origin were stocked throughout the southeastern United States. In order to determine this differentiation, established allozyme markers were used to classify 56 southwest Virginia populations as southern, northern, or introgressed. Variation at 4 polymorphic loci, including the diagnostic creatine kinase (CK-A2*) locus, indicated that 19 populations were of southern origin, 5 of northern origin, and 32 of mixed genetic origin. Data compiled among genetic studies of brook trout in the southern Appalachians showed that the southern/northern break is sharp, occurring at the New/Roanoke-James watershed divide. New River drainage populations exhibited the southern allele at high frequency, suggesting their historic native character as southern, with presence of northern alleles due to stocking or stream capture events. In conclusion, the present study suggests that management of southern Appalachian brook trout should include: (1) genetically cognizant planning of stocking events, (2) management of populations on a stream-by-stream basis, (3) prioritized conservation of pure southern brook trout populations, and (4) use of southern Appalachian hatchery stocks in restoration efforts

Molecular details of quinolone–DNA interactions: solution structure of an unusually stable DNA duplex with covalently linked nalidixic acid residues and non-covalent complexes derived from it

Quinolones are antibacterial drugs that are thought to bind preferentially to disturbed regions of DNA. They do not fall into the classical categories of intercalators, groove binders or electrostatic binders to the backbone. We solved the 3D structure of the DNA duplex (ACGCGU-NA)(2), where NA denotes a nalidixic acid residue covalently linked to the 2′-position of 2′-amino-2′-deoxyuridine, by NMR and restrained torsion angle molecular dynamics (MD). In the complex, the quinolones stack on G:C base pairs of the core tetramer and disrupt the terminal A:U base pair. The displaced dA residues can stack on the quinolones, while the uracil rings bind in the minor groove. The duplex-bridging interactions of the drugs and the contacts of the displaced nucleotides explain the high UV-melting temperature for d(ACGCGU-NA)(2) of up to 53°C. Further, non-covalently linked complexes between quinolones and DNA of the sequence ACGCGT can be generated via MD using constraints obtained for d(ACGCGU-NA)(2). This is demonstrated for unconjugated nalidixic acid and its 6-fluoro derivative. The well-ordered and tightly packed structures thus obtained are compatible with a published model for the quinolone–DNA complex in the active site of gyrases

Exploring patterns of recurrent melanoma in Northeast Scotland to inform the introduction a digital self-examination intervention

Peer reviewedPublisher PD

Design optimization of pixel sensors using device simulations for the phase-II CMS tracker upgrade

In order to address the problems caused by the harsh radiation environment during the high luminosity phase of the LHC (HL-LHC), all silicon tracking detectors (pixels and strips) in the CMS experiment will undergo an upgrade. And so to develop radiation hard pixel sensors, simulations have been performed using the 2D TCAD device simulator, SILVACO, to obtain design parameters. The effect of various design parameters like pixel size, pixel depth, implant width, metal overhang, p-stop concentration, p-stop depth and bulk doping density on the leakage current and critical electric field are studied for both non-irradiated as well as irradiated pixel sensors. These 2D simulation results of planar pixels are useful for providing insight into the behaviour of non-irradiated and irradiated silicon pixel sensors and further work on 3D simulation is underway. © 2015 Elsevier B.V

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii

Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1β/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages