The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time

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Persistence of immunity to Nematodirus battus infection in lambs

Fifty-four Greyface Suffolk lambs aged 3 months were allocated to six groups of seven and one group of 12. Three groups were infected continuously with Nematodirus battus larvae (L3) over a 7-week period and three groups remained worm-free. One week after the last larval dose all six groups were treated with anthelmintic and challenged with a single dose of 30 000 N. battus L3 either 1, 6 or 12 weeks post-treatment (PT) and killed 10 days later. A seventh continuously infected and treated group (n = 12) was segregated into four sub-groups of three lambs which were used as tissue cell count controls and provided data on local cellular responses prior to challenge. Lambs in the first sub-group were killed immediately after anthelmintic treatment and those in the other sub-groups were killed on the same day that the lambs in the other main groups were challenged. Overall post-challenge worm burdens did not differ significantly between previously infected and challenge control groups although they were significantly reduced in both treatment groups by Week 12 PT. The principal manifestation of acquired immunity that was maintained throughout 12 weeks without further infection was retardation in larval development. There was also evidence of preferential rejection of male worms from immune lambs. Local mast cell, but not eosinophil, responses were significantly enhanced by previous infection and persisted up to Week 12 PT. The numbers of bone marrow eosinophils were significantly increased as a result of previous infection and this response persisted up to Week 12 PT. During primary infection anti-L4 and anti-adult worm IgG responses were significantly increased in the previously infected lambs by Day 42 post-infection. Eosinophil responses during this period did not differ between groups. The inflammatory cell responses, coupled with the parasitological observations, suggest that immunity to previous infection is maintained for up to 12 weeks PT without further antigenic stimulation. This 'immunological memory' may have waned partially after 6 weeks PT although the superimposition of age resistance may have masked the effect

The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

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The Angular Correlation Function of Galaxies from Early SDSS Data

The Sloan Digital Sky Survey is one of the first multicolor photometric and spectroscopic surveys designed to measure the statistical properties of galaxies within the local Universe. In this Letter we present some of the initial results on the angular 2-point correlation function measured from the early SDSS galaxy data. The form of the correlation function, over the magnitude interval 18<r*<22, is shown to be consistent with results from existing wide-field, photographic-based surveys and narrower CCD galaxy surveys. On scales between 1 arcminute and 1 degree the correlation function is well described by a power-law with an exponent of ~ -0.7. The amplitude of the correlation function, within this angular interval, decreases with fainter magnitudes in good agreement with analyses from existing galaxy surveys. There is a characteristic break in the correlation function on scales of approximately 1-2 degrees. On small scales, < 1', the SDSS correlation function does not appear to be consistent with the power-law form fitted to the 1'< theta <0.5 deg data. With a data set that is less than 2% of the full SDSS survey area, we have obtained high precision measurements of the power-law angular correlation function on angular scales 1' < theta < 1 deg, which are robust to systematic uncertainties. Because of the limited area and the highly correlated nature of the error covariance matrix, these initial results do not yet provide a definitive characterization of departures from the power-law form at smaller and larger angles. In the near future, however, the area of the SDSS imaging survey will be sufficient to allow detailed analysis of the small and large scale regimes, measurements of higher-order correlations, and studies of angular clustering as a function of redshift and galaxy type

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Funding Information: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). CG is supported by The Medical Research Council and The University of Edinburgh through the Precision Medicine Doctoral Training program. SRC is supported by the UK Medical Research Council [MR/R024065/1] and a National Institutes of Health (NIH) research grant R01AG054628. Acknowledgements The authors thank all of the STRADL and Generation Scotland participants for their time and effort taking part in this study. We would also like to thank all of the research assistants, clinicians and technicians for their help in the collecting this data.Peer reviewedPublisher PD

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Charting the elements of pedagogic frailty

Background: The concept of pedagogic frailty has been proposed as a unifying concept that may help to integrate institutional efforts to enhance teaching improvement within universities by helping to maintain a simultaneous focus on four key areas that are thought to impede development. Purpose: The variation in internal structure of the four dimensions of pedagogic frailty and the links that have been proposed to connect them are explored here through the analysis of interviews with academics working in a variety of disciplinary areas. Methods: The application of concept map-mediated interviews allows us to view the variable connections within and between these dimensions and the personal ways they are conceptualised by academics working across the heterogeneous university context. Results: The data show that academics conceptualise the discourse of teaching in various ways that have implications for the links that may be developed to integrate the elements within the model. Conclusions: Whilst the form and content of the maps representing dimensions of the pedagogic frailty model exhibit considerable variation, it is suggested that factors such as academic resilience and the explicit use of integrative concepts within disciplines may help to overcome some of the vulnerabilities that accompany pedagogic frailty. The data also raises questions about the links between factors that tend to be under individual control and those that tend towards institutional control

Methods of connecting primary care patients with community-based physical activity opportunities:A realist scoping review

Funding: NHS Fife Endowment Fund (Grant Number(s): FIF142).Deemed a global public health problem by the World Health Organization, physical inactivity is estimated to be responsible for one in six deaths in the United Kingdom (UK) and to cost the nation's economy £7.4 billion per year. A response to the problem receiving increasing attention is connecting primary care patients with community-based physical activity opportunities. We aimed to explore what is known about the effectiveness of different methods of connecting primary care patients with community-based physical activity opportunities in the United Kingdom by answering three research questions: 1) What methods of connection from primary care to community-based physical activity opportunities have been evaluated?; 2) What processes of physical activity promotion incorporating such methods of connection are (or are not) effective or acceptable, for whom, to what extent and under what circumstances; 3) How and why are (or are not) those processes effective or acceptable? We conducted a realist scoping review in which we searched Cochrane, Medline, PsycNET, Google Advanced Search, National Health Service (NHS) Evidence and NHS Health Scotland from inception until August 2020. We identified that five methods of connection from primary care to community-based physical activity opportunities had been evaluated. These were embedded in 15 processes of physical activity promotion, involving patient identification and behaviour change strategy delivery, as well as connection. In the contexts in which they were implemented, four of those processes had strong positive findings, three had moderately positive findings and eight had negative findings. The underlying theories of change were highly supported for three processes, supported to an extent for four and refuted for eight processes. Comparisons of the processes and their theories of change revealed several indications helpful for future development of effective processes. Our review also highlighted the limited evidence base in the area and the resulting need for well-designed theory-based evaluations.Publisher PDFPeer reviewe