Radio Spectra and NVSS Maps of Decametric Sources

We constructed radio spectra for ~1400 UTR-2 sources and find that 46% of them have concave curvature. Inspection of NVSS maps of 700 UTR sources suggests that half of all UTR sources are either blends of two or more sources or have an ultra-steep spectrum (USS). The fraction of compact USS sources in UTR may be near 10%. Using NVSS and the Digitized Sky Survey(s) we expect to double the UTR optical identification rate from currently ~19%.Comment: 2 pages, no figures; to appear in Proc. "Observational Cosmology with the New Radio Surveys", eds. M. Bremer, N. Jackson & I. Perez-Fournon, Kluwer Acad. Pres

Modelling the free energy profile of the mitochondrial ADP/ATP carrier.

The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational changes. These changes are prevented in the absence of substrate by a large energy barrier due to the need for sequential disruption and formation of a matrix and cytoplasmic salt bridge network that are located on either side of the central cavity. In analogy to enzyme catalysis, substrate lowers the energy barrier by binding tighter in the intermediate state. Here we provide an in-silico kinetic model that captures the free energy profile of these conformational changes and treats the carrier as a nanomachine moving stochastically from the matrix to cytoplasmic conformation under the influence of thermal energy. The model reproduces the dependency of experimentally determined kcat and KM values on the cytoplasmic network strength with good quantitative accuracy, implying that it captures the transport mechanism and can provide a framework to understand the structure-function relationships of this class of transporter. The results show that maximum transport occurs when the interaction energies of the cytoplasmic network, matrix network and substrate binding are approximately equal such that the energy barrier is minimized. Consequently, the model predicts that there will be other interactions in addition to those of the cytoplasmic network that stabilise the matrix conformation of the ADP/ATP carrier

Genetic Tests for Ecological and Allopatric Speciation in Anoles on an Island Archipelago

From Darwin's study of the Galapagos and Wallace's study of Indonesia, islands have played an important role in evolutionary investigations, and radiations within archipelagos are readily interpreted as supporting the conventional view of allopatric speciation. Even during the ongoing paradigm shift towards other modes of speciation, island radiations, such as the Lesser Antillean anoles, are thought to exemplify this process. Geological and molecular phylogenetic evidence show that, in this archipelago, Martinique anoles provide several examples of secondary contact of island species. Four precursor island species, with up to 8 mybp divergence, met when their islands coalesced to form the current island of Martinique. Moreover, adjacent anole populations also show marked adaptation to distinct habitat zonation, allowing both allopatric and ecological speciation to be tested in this system. We take advantage of this opportunity of replicated island coalescence and independent ecological adaptation to carry out an extensive population genetic study of hypervariable neutral nuclear markers to show that even after these very substantial periods of spatial isolation these putative allospecies show less reproductive isolation than conspecific populations in adjacent habitats in all three cases of subsequent island coalescence. The degree of genetic interchange shows that while there is always a significant genetic signature of past allopatry, and this may be quite strong if the selection regime allows, there is no case of complete allopatric speciation, in spite of the strong primae facie case for it. Importantly there is greater genetic isolation across the xeric/rainforest ecotone than is associated with any secondary contact. This rejects the development of reproductive isolation in allopatric divergence, but supports the potential for ecological speciation, even though full speciation has not been achieved in this case. It also explains the paucity of anole species in the Lesser Antilles compared to the Greater Antilles

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Ethnicity and attitudes to deceased kidney donation: a survey in Barbados and comparison with Black Caribbean people in the United Kingdom

<p>Abstract</p> <p>Background</p> <p>Black minority ethnic groups in the UK have relatively low rates of deceased donation and report a higher prevalence of beliefs that are regarded as barriers to donation. However there is little data from migrants' countries of origin. This paper examines community attitudes to deceased kidney donation in Barbados and compares the findings with a survey conducted in a disadvantaged multi-ethnic area of south London.</p> <p>Methods</p> <p>Questionnaires were administered at four public health centres in Barbados and at three private general practices. Adjusted odds ratios were calculated to compare attitudinal responses with a prior survey of 328 Caribbean and 808 White respondents in south London.</p> <p>Results</p> <p>Questionnaires were completed by 327 respondents in Barbados (93% response); 42% men and 58% women, with a mean age of 40.4 years (SD 12.6). The main religious groups were Anglican (29%) and Pentecostal (24%). Educational levels ranged from 18% not completing 5th form to 12% with university education. Attitudes to the notion of organ donation were favourable, with 73% willing to donate their kidneys after their death and only 5% definitely against this. Most preferred an opt-in system of donation. Responses to nine attitudinal questions identified 18% as having no concerns and 9% as having 4 or more concerns. The highest level of concern (43%) was for lack of confidence that medical teams would try as hard to save the life of a person who has agreed to donate organs. There was no significant association between age, gender, education or religion and attitudinal barriers, but greater knowledge of donation had some positive effect on attitudes. Comparison of attitudes to donation in south London and Barbados (adjusting for gender, age, level of education, employment status) indicated that a significantly higher proportion of the south London Caribbean respondents identified attitudinal barriers to donation.</p> <p>Conclusions</p> <p>Community attitudes in Barbados are favourable to deceased donation based on a system of informed consent. Comparison with south London data supports the hypothesis that the relatively high prevalence of negative attitudes to deceased donation among disadvantaged ethnic minorities in high income countries may reflect feelings of marginalisation and lack of belonging.</p

Statistical methods to correct for verification bias in diagnostic studies are inadequate when there are few false negatives: a simulation study

<p>Abstract</p> <p>Background</p> <p>A common feature of diagnostic research is that results for a diagnostic gold standard are available primarily for patients who are positive for the test under investigation. Data from such studies are subject to what has been termed "verification bias". We evaluated statistical methods for verification bias correction when there are few false negatives.</p> <p>Methods</p> <p>A simulation study was conducted of a screening study subject to verification bias. We compared estimates of the area-under-the-curve (AUC) corrected for verification bias varying both the rate and mechanism of verification.</p> <p>Results</p> <p>In a single simulated data set, varying false negatives from 0 to 4 led to verification bias corrected AUCs ranging from 0.550 to 0.852. Excess variation associated with low numbers of false negatives was confirmed in simulation studies and by analyses of published studies that incorporated verification bias correction. The 2.5^th– 97.5^thcentile range constituted as much as 60% of the possible range of AUCs for some simulations.</p> <p>Conclusion</p> <p>Screening programs are designed such that there are few false negatives. Standard statistical methods for verification bias correction are inadequate in this circumstance.</p

The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons

Background: A major pathological hallmark of AD is the deposition of insoluble extracellular b-amyloid (Ab) plaques. There are compelling data suggesting that Ab aggregation is catalysed by reaction with the metals zinc and copper. Methodology/Principal Findings: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Ab1–40 and Ab1–42. This action of MT-2A appears to involve a metal-swap between Zn 7MT-2A and Cu(II)-Ab, since neither Cu 10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Ab aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Ab induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. Conclusions/Significance: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Ab aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Ab leaving a metal-free Ab that can readily bind metals again, we believe that MT-2A might represent a different therapeuti