The impact of past introductions on an iconic and economically important species, the red deer of Scotland

The red deer (Cervus elaphus) is an iconic species in Scotland and, due to its value as a game species, an important element of the Scottish rural economy. The native status of this species is sometimes questioned because of many recorded introductions of nonnative deer in the past that were an attempt to improve trophy size. In this study, we assessed the impact of past introductions on the genetic makeup of Scottish red deer by genotyping at 15 microsatellite loci a large number of samples (n = 1152), including mainland and island Scottish red deer and individuals from several putative external source populations used in introductions to improve trophy size. Population structure and introgression assessment analyses revealed that the impact of introductions was weak in Highland red deer populations but more prominent on the islands, especially on those where current red deer populations are mostly or entirely derived from introductions (Harris & Lewis, Arran, and Rum). Frequent imports of Central-Eastern European red deer into English deer parks were reflected in the higher genetic introgression values found in some of the individuals collected in parks

Design, Delivery, Maintenance, and Outcomes of Peer-to-Peer Online Support Groups for People With Chronic Musculoskeletal Disorders: Systematic Review

Background: Online support groups (OSGs) are one way for people with chronic diseases, their family or friends, and health professionals to communicate, gain information, and provide social support. As the number of peer-to-peer OSGs for chronic musculoskeletal conditions grows, it is important to gain insight into the different designs of groups available, who is accessing them, if and how they may be effective, and what strategies are being used to implement or increase consumer engagement. Objective: The objectives of this systematic review of people with musculoskeletal conditions were to (1) describe the design features (functions, usage options, moderation, and expert input) of peer-to-peer OSGs, (2) describe the characteristics of the individuals using peer-to-peer OSGs, (3) synthesize the evidence on outcomes of participation, and (4) identify strategies used in the delivery and maintenance of OSGs. Methods: A search comprising terms related to the population (people with musculoskeletal disorders) and the intervention (peer-to-peer OSGs) was conducted in 6 databases. Results were filtered from 1990 (internet inception) to February 2019. Studies identified in the search were screened according to predefined eligibility criteria using a 2-step process. Quantitative studies were appraised by 2 reviewers using the Risk Of Bias In Non-Randomized Studies of Interventions tool. Qualitative studies were appraised by 2 different reviewers using the Critical Appraisal Skills Programme checklist. Extracted data were synthesized narratively. Results: We examined 21 studies with low to moderate risk of bias. Of these studies, 13 studies included OSGs hosted on public platforms, 11 studies examined OSGs that were conducted in English, and 6 studies used moderators or peer leaders to facilitate engagement. Studies either reported the number of OSG members (n=1985 across all studies) or the number of posts (range: 223-200,000). The majority of OSG members were females who were not full-time employees and with varied levels of education. There were no randomized controlled trials measuring the efficacy of OSGs. Qualitative and quantitative studies identified empowerment, social support, self-management behavior, and health literacy as primary constructs to measure OSG efficacy. Neutral or marginal improvement was reported in these constructs. Sharing experiences and a greater level of engagement appeared to have an important influence on OSGs efficacy. The extent to which members posted on the website influenced engagement. Conclusions: Across a diverse range of designs, languages, included features, and delivery platforms, peer-to-peer OSGs for chronic musculoskeletal conditions attract predominantly female participants of all ages and education levels. The level of participation of a member appears to be related to their perceived benefit, health literacy, and empowerment. Future studies are needed to identify which design and maintenance strategies have superior efficacy and whether there are concomitant improvements in health outcomes for people with chronic musculoskeletal conditions resulting from participation in OSGs

Mapping the availability of translated versions of posttraumatic stress disorder screening questionnaires for adults: A scoping review

Background: The most used questionnaires for PTSD screening in adults were developed in English. Although many of these questionnaires were translated into other languages, the procedures used to translate them and to evaluate their reliability and validity have not been consistently documented. This comprehensive scoping review aimed to compile the currently available translated and evaluated questionnaires used for PTSD screening, and highlight important gaps in the literature. Objective: This review aimed to map the availability of translated and evaluated screening questionnaires for posttraumatic stress disorder (PTSD) for adults. Methods: All peer-reviewed studies in which a PTSD screening questionnaire for adults was translated, and which reported at least one result of a qualitative and /or quantitative evaluation procedure were included. The literature was searched using Embase, MEDLINE, and APA PsycInfo, citation searches and contributions from study team members. There were no restrictions regarding the target languages of the translations. Data on the translation procedure, the qualitative evaluation, the quantitative evaluation (dimensionality of the questionnaire, reliability, and performance), and open access were extracted. Results: A total of 866 studies were screened, of which 126 were included. Collectively, 128 translations of 12 different questionnaires were found. Out of these, 105 (83.3%) studies used a forward and backward translation procedure, 120 (95.2%) assessed the reliability of the translated questionnaire, 60 (47.6%) the dimensionality, 49 (38.9%) the performance, and 42 (33.3%) used qualitative evaluation procedures. Thirty-four questionnaires (27.0%) were either freely available or accessible on request. Conclusions: The analyses conducted and the description of the methods and results varied substantially, making a quality assessment impractical. Translations into languages spoken in middle- or low-income countries were underrepresented. In addition, only a small proportion of all translated questionnaires were available. Given the need for freely accessible translations, an online repository was developed

Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation

Funding Information: We thank the Arkansas Nano & Bio Materials Characterization Facility at the Institute for Nano Sciences & Engineering for our imaging studies, and Prof Yoshito Kishi (Harvard University) for the kind gift of synthetic mycolactone A/B used by S.H. and R.S. W.S. is supported by Grant No. R15GM116032 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and startup funds from the University of Arkansas. This work was also supported in part by Grant No. P30 GM103450 from the National Institute of General Medical Sciences of the NIH and by seed money from the Arkansas Biosciences Institute (ABI). S.O’K. is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme Award (BB/J014478/ 1), and S.H. holds a Welcome Trust Investigator Award in Science (204957/Z/16/Z). The alpha-1 antitrypsin work was supported by the Alpha-1 Foundation (J.I. and M.J.I.). J.I. and M.J.H. were supported by the intramural program of NCATS, National Institutes of Health, projects 1ZIATR000048-03 (J.I.) and ZIATR000063-04 (M.J.H.). R.S. holds a Welcome Trust Investigator Award in Science (202843/Z/16/Z). C.D. received funding from the Institut Pasteur, the Institut National de la Santé et de la Recherche Med́ icale, and the Fondation Raoul Follereau. N.B.’s synthesis and chemical biology studies of mycolactone were supported by CNRS, Université de Strasbourg, Fondations Potier et Follereau, and the Investisse-ment d’Avenir (Idex Unistra). V.O.P. is supported by the Academy of Finland (Grants 289737 and 314672) and the Sigrid Juselius Foundation. Funding Information: We thank the Arkansas Nano & Bio Materials Characterization Facility at the Institute for Nano Sciences & Engineering for our imaging studies, and Prof Yoshito Kishi (Harvard University) for the kind gift of synthetic mycolactone A/B used by S.H. and R.S. W.S. is supported by Grant No. R15GM116032 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and startup funds from the University of Arkansas. This work was also supported in part by Grant No. P30 GM103450 from the National Institute of General Medical Sciences of the NIH and by seed money from the Arkansas Biosciences Institute (ABI). S.O'K. is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme Award (BB/J014478/1), and S.H. holds a Welcome Trust Investigator Award in Science (204957/Z/16/Z). The alpha-1 antitrypsin work was supported by the Alpha-1 Foundation (J.I. and M.J.I.). J.I. and M.J.H. were supported by the intramural program of NCATS, National Institutes of Health, projects 1ZIATR000048-03 (J.I.) and ZIATR000063-04 (M.J.H.). R.S. holds a Welcome Trust Investigator Award in Science (202843/Z/16/Z). C.D. received funding from the Institut Pasteur, the Institut National de la Sante et de la Recherche Medicale, and the Fondation Raoul Follereau. N.B.'s synthesis and chemical biology studies of mycolactone were supported by CNRS, Universite de Strasbourg, Fondations Potier et Follereau and the Investissement d'Avenir (Idex Unistra). V.O.P. is supported by the Academy of Finland (Grants 289737 and 314672) and the Sigrid Juselius Foundation. Publisher Copyright: © 2019 American Chemical Society.Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61 alpha (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61 alpha from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61 alpha forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61 alpha provides compelling evidence that Sec61 alpha is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61 alpha is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61 alpha function and to further investigate its potential as a therapeutic target for drug discovery.Peer reviewe

The Seventh Data Release of the Sloan Digital Sky Survey

This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11663 deg^2 of imaging data, with most of the roughly 2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry over 250 deg^2 along the Celestial Equator in the Southern Galactic Cap. A coaddition of these data goes roughly two magnitudes fainter than the main survey. The spectroscopy is now complete over a contiguous area of 7500 deg^2 in the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog (UCAC-2), reducing the rms statistical errors at the bright end to 45 milli-arcseconds per coordinate. A systematic error in bright galaxy photometr is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat-fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities. (Abridged)Comment: 20 pages, 10 embedded figures. Accepted to ApJS after minor correction

NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The pathogenic mechanism of the Mycobacterium ulcerans virulence factor, mycolactone, depends on blockade of protein translocation into the ER.

Infection with Mycobacterium ulcerans is characterised by tissue necrosis and immunosuppression due to mycolactone, the necessary and sufficient virulence factor for Buruli ulcer disease pathology. Many of its effects are known to involve down-regulation of specific proteins implicated in important cellular processes, such as immune responses and cell adhesion. We have previously shown mycolactone completely blocks the production of LPS-dependent proinflammatory mediators post-transcriptionally. Using polysome profiling we now demonstrate conclusively that mycolactone does not prevent translation of TNF, IL-6 and Cox-2 mRNAs in macrophages. Instead, it inhibits the production of these, along with nearly all other (induced and constitutive) proteins that transit through the ER. This is due to a blockade of protein translocation and subsequent degradation of aberrantly located protein. Several lines of evidence support this transformative explanation of mycolactone function. First, cellular TNF and Cox-2 can be once more detected if the action of the 26S proteasome is inhibited concurrently. Second, restored protein is found in the cytosol, indicating an inability to translocate. Third, in vitro translation assays show mycolactone prevents the translocation of TNF and other proteins into the ER. This is specific as the insertion of tail-anchored proteins into the ER is unaffected showing that the ER remains structurally intact. Fourth, metabolic labelling reveals a near-complete loss of glycosylated and secreted proteins from treated cells, whereas cytosolic proteins are unaffected. Notably, the profound lack of glycosylated and secreted protein production is apparent in a range of different disease-relevant cell types. These studies provide a new mechanism underlying mycolactone's observed pathological activities both in vitro and in vivo. Mycolactone-dependent inhibition of protein translocation into the ER not only explains the deficit of innate cytokines, but also the loss of membrane receptors, adhesion molecules and T-cell cytokines that drive the aetiology of Buruli ulcer