SHEEP: The Search for the High Energy Extragalactic Population

We present the SHEEP survey for serendipitously-detected hard X-ray sources in ASCA GIS images. In a survey area of $\sim 40$ deg$^{2}$, 69 sources were detected in the 5-10 keV band to a limiting flux of $\sim 10^{-13}$ erg cm$^{-2}$ s$^{-1}$. The number counts agree with those obtained by the similar BeppoSAX HELLAS survey, and both are in close agreement with ASCA and BeppoSAX 2-10 keV surveys. Spectral analysis of the SHEEP sample reveals that the 2-10 and 5-10 keV surveys do not sample the same populations, however, as we find considerably harder spectra, with an average $\Gamma\sim1.0$ assuming no absorption. The implication is that the agreement in the number counts is coincidental, with the 5-10 keV surveys gaining approximately as many hard sources as they lose soft ones, when compared to the 2-10 keV surveys. This is hard to reconcile with standard AGN ``population synthesis'' models for the X-ray background, which posit the existence of a large population of absorbed sources. We find no evidence of the population hardening at faint fluxes, with the exception that the few very brightest objects are anomalously soft. 53 of the SHEEP sources have been covered by ROSAT in the pointed phase. Of these 32 were detected. An additional 3 were detected in the RASS. As expected the sources detected with ROSAT are systematically softer than those detected with ASCA alone, and of the sample as a whole (truncated).Comment: 36 pages, 7 figs, to appear in Ap

Polythiophene nanofilms for sensitive fluorescence detection of viruses in drinking water

Molecular imprints of the tobacco necrosis virus (TNV) have been formed within polythiophene nanofilms with an approximate thickness of 200 nm. These films have been electrochemically deposited onto conducting Au surfaces. Upon rebinding, the TNV-polythiophene complex changes the fluorescence intensity of the nanofilm. The fluorescence intensity at 410 nm was observed to be proportional to the concentration of viruses in the range of 0.1–10 ng L−1 (0.15–15 pg) with the lower calculated detection limit of 2.29 ng L−1 (3.4 pg). The intensity of the fluorescence emission is not affected by the thickness of the polythiophene film and the nature of TNV specific binding sites. Kinetic data analyses showed that the nanofilm responds to TNV within 2 min; and cross-selectivity studies with tobacco mosaic virus (TMV) showed an excellent specificity for the targeted TNV. These binding experiments demonstrate the potential of fluorescence emission for the specific, label free and rapid detection of viruses using nanofilm sensors. Taking into account the lower limit of detection, the fluorescence sensing reported here is reliable, simple to perform, rapid, cost-effective and offers a sensitive analytical method for virus detection in water resources

Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial

Background: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3–5 years in primary care patients with treatment-resistant depression. Methods: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18–75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3–5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0–63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. Findings: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5–51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means −4·7 [95% CI −6·4 to −3·0, p<0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. Interpretation: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective

TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy

<p>Abstract</p> <p>Background</p> <p>Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA).</p> <p>Results</p> <p>TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1^G93Amice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.</p> <p>Conclusion</p> <p>These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.</p

Bacteriophage Migration via Nematode Vectors: Host-Parasite-Consumer Interactions in Laboratory Microcosms

Pathogens vectored by nematodes pose serious agricultural, economic, and health threats; however, little is known of the ecological and evolutionary aspects of pathogen transmission by nematodes. Here we describe a novel model system with two trophic levels, bacteriophages and nematodes, each of which competes for bacteria. We demonstrate for the first time that nematodes are capable of transmitting phages between spatially distinct patches of bacteria. This model system has considerable advantages, including the ease of maintenance and manipulation at the laboratory bench, the ability to observe many generations in short periods, and the capacity to freeze evolved strains for later comparison to their ancestors. More generally, experimental studies of complex multispecies interactions, host-pathogen coevolution, disease dynamics, and the evolution of virulence may benefit from this model system because current models (e.g., chickens, mosquitoes, and malaria parasites) are costly to maintain, are difficult to manipulate, and require considerable space. Our initial explorations centered on independently assessing the impacts of nematode, bacterium, and phage population densities on virus migration between host patches. Our results indicated that virus transmission increases with worm density and host bacterial abundance; however, transmission decreases with initial phage abundance, perhaps because viruses eliminate available hosts before migration can occur. We discuss the microbial growth dynamics that underlie these results, suggest mechanistic explanations for nematode transmission of phages, and propose intriguing possibilities for future research

Biocatalytic approaches to a key building block for the anti-thrombotic agent ticagrelor

Three different enzymatic routes were employed to produce a precursor of the important antithrombotic agent Ticagrelor with high ee.</p