Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex

Dengue virus (DENV) is the most common arboviral infection globally, infecting an estimated 390 million people each year. We employed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screen to identify host dependency factors required for DENV propagation and identified the oligosaccharyltransferase (OST) complex as an essential host factor for DENV infection. Mammalian cells express two OSTs containing either STT3A or STT3B. We found that the canonical catalytic function of the OSTs as oligosaccharyltransferases is not necessary for DENV infection, as cells expressing catalytically inactive STT3A or STT3B are able to support DENV propagation. However, the OST subunit MAGT1, which associates with STT3B, is also required for DENV propagation. MAGT1 expression requires STT3B, and a catalytically inactive STT3B also rescues MAGT1 expression, supporting the hypothesis that STT3B serves to stabilize MAGT1 in the context of DENV infection. We found that the oxidoreductase CXXC active site motif of MAGT1 was necessary for DENV propagation, as cells expressing an AXXA MAGT1 mutant were unable to support DENV infection. Interestingly, cells expressing single-cysteine CXXA or AXXC mutants of MAGT1 were able to support DENV propagation. Utilizing the engineered peroxidase APEX2, we demonstrate the close proximity between MAGT1 and NS1 or NS4B during DENV infection. These results reveal that the oxidoreductase activity of the STT3B-containing OST is necessary for DENV infection, which may guide the development of antiviral agents targeting DENV. IMPORTANCE The host oligosaccharyltransferase (OST) complexes have been identified as essential host factors for dengue virus (DENV) replication; however, their functions during DENV infection are unclear. A previous study showed that the canonical OST activity was dispensable for DENV replication, suggesting that the OST complexes serve as scaffolds for DENV replication. However, our work demonstrates that one function of the OST complex during DENV infection is to provide oxidoreductase activity via the OST subunit MAGT1. We also show that MAGT1 associates with DENV NS1 and NS4B during viral infection, suggesting that these nonstructural proteins may be targets of MAGT1 oxidoreductase activity. These results provide insight into the cell biology of DENV infection, which may guide the development of antivirals against DENV

Multi-Object Near-IR H-alpha Spectroscopy of z~1 star-forming galaxies in the HDF-N

We present preliminary results from a programme to obtain multi-object near-infrared spectroscopy of galaxies at redshifts $0.7<z<1.5$. We are using the instrument CIRPASS (the Cambridge Infra-Red PAnoramic Survey Spectrograph), in multi-object mode, to survey H-alpha in galaxies at $z\sim1$. We aim to address the true star formation history of the universe at this epoch: potentially the peak period of star formation activity. H-alpha is the same star formation measure used at low redshift, and hence we can trace star formation without the systematic uncertainties of using different calibrators in different redshift bins, or the extreme dust extinction in the rest-UV. CIRPASS has been successfully demonstrated in multi-object mode on the AAT and WHT. Here we present preliminary results from one of our fields, the Hubble Deep Field North, observed with the WHT. With 150 fibres deployed over an unvignetted field of $\sim15$arcmin, we have several detections of H-alpha from star forming galaxies at $0.8<z<1.0$ and present spectra of the seven brightest of these. By pre-selecting galaxies with redshifts such that H-alpha will appear between the OH sky lines, we can detect star formation rates of $5 h^{-2}_{70} M_{\odot} {\rm yr}^{-1}$ ($5 \sigma$ in 3-hours, $\Omega_M=0.3$, $\Omega_{\Lambda}=0.7$). It appears that star formation rates inferred from H-alpha are, on average, a factor of more than two higher than those based on the UV continuum alone.Comment: 6 pages, 3 figures, accepted for publication in MNRAS Letter

Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study

Introduction Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. Methods and Analysis The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. Ethics and Dissemination The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups

Integrating Survey and Molecular Approaches to Better Understand Wildlife Disease Ecology

Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa) population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design) versus transmission (molecular case series study design) and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37-45%). The median Salmonella DICE coefficient (or Salmonella genetic similarity) was 52% (interquartile range [IQR]: 42-62%). Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density) determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is driven by local spatial, social, density and individual factors, rather than resources. This enhanced understanding has implications for the control of diseases in wildlife populations. Attempts to manage wildlife disease using simplistic density approaches do not acknowledge the complexity of disease ecology

Delivering distribution system flexibility through micro-resilience

This study introduces the specific grid challenges faced at each of four micro-resilence sites and provides an overview of the innovative technical solutions deployed to improve grid flexibility, resilience and improve the distribution system operator customer experience. The sites were chosen due to their remote locations and reliance on a reliable electrical service due to dependent customers or lifesaving functions. Therefore, in addition to providing flexible grid services, when grid connected, there is also the opportunity to provide a reliable electrical supply to islanded pockets when there are high-voltage grid outages. The solution architecture and functions of technology such as the two-terminal power electronic devices (PEDs) and microgrid controller (MGC) are described. The combination of an energy storage system, distributed energy resources and PEDs will provide essential grid support functionality with co-ordination of devices, islanded status and data logging handled by a dedicated MGC. Also presented is the application of the Open Field Message Bus, open-standards communications framework for a field message bus, and a description of the specific interoperability use cases demonstrated within the project. This study provides valuable insights into a leading innovation project, delivered on operational networks to address practical customer issues through flexibility

Over what area did the oil and gas spread during the 2010 Deepwater Horizon oil spill?

Author Posting. © The Oceanography Society, 2016. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 29, no. 3 (2016): 96–107, doi:10.5670/oceanog.2016.74.The 2010 Deepwater Horizon (DWH) oil spill in the Gulf of Mexico resulted in the collection of a vast amount of situ and remotely sensed data that can be used to determine the spatiotemporal extent of the oil spill and test advances in oil spill models, verifying their utility for future operational use. This article summarizes observations of hydrocarbon dispersion collected at the surface and at depth and our current understanding of the factors that affect the dispersion, as well as our improved ability to model and predict oil and gas transport. As a direct result of studying the area where oil and gas spread during the DWH oil spill, our forecasting capabilities have been greatly enhanced. State-of-the-art oil spill models now include the ability to simulate the rise of a buoyant plume of oil from sources at the seabed to the surface. A number of efforts have focused on improving our understanding of the influences of the near-surface oceanic layer and the atmospheric boundary layer on oil spill dispersion, including the effects of waves. In the future, oil spill modeling routines will likely be included in Earth system modeling environments, which will link physical models (hydrodynamic, surface wave, and atmospheric) with marine sediment and biogeochemical components.This research was made possible by a grant from BP/The Gulf of Mexico Research Initiative to the CARTHE and Deep-C Consortia, and by contract M12PC00003 from the Bureau of Ocean Energy Management (BOEM)

The effect of statins on muscle symptoms in primary care:the StatinWISE series of 200 N-of-1 RCTs

Background: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis.Objectives: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related.Design: A series of 200 double-blinded N-of-1 trials.Setting: Participants were recruited from 50 general practices in England and Wales.Participants: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms.Interventions: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo.Main outcome measures: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful.Results: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods.Conclusions: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial.Future work: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications.Limitations: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations.Trial registration: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31.</p

A core outcome set for localised prostate cancer effectiveness trials

Objective: To develop a core outcome set (COS) applicable for effectiveness trials of all interventions for localised prostate cancer. Background: Many treatments exist for localised prostate cancer, although it is unclear which offers the optimal therapeutic ratio. This is confounded by inconsistencies in the selection, definition, measurement and reporting of outcomes in clinical trials. Subjects and methods: A list of 79 outcomes was derived from a systematic review of published localised prostate cancer effectiveness studies and semi-structured interviews with 15 prostate cancer patients. A two-stage consensus process involving 118 patients and 56 international healthcare professionals (HCPs) (cancer specialist nurses, urological surgeons and oncologists) was undertaken, consisting of a three-round Delphi survey followed by a face-to-face consensus panel meeting of 13 HCPs and 8 patients. Results: The final COS included 19 outcomes. Twelve apply to all interventions: death from prostate cancer, death from any cause, local disease recurrence, distant disease recurrence/metastases, disease progression, need for salvage therapy, overall quality of life, stress urinary incontinence, urinary function, bowel function, faecal incontinence, sexual function. Seven were intervention-specific: perioperative deaths (surgery), positive surgical margin (surgery), thromboembolic disease (surgery), bothersome or symptomatic urethral or anastomotic stricture (surgery), need for curative treatment (active surveillance), treatment failure (ablative therapy), and side effects of hormonal therapy (hormone therapy). The UK-centric participants may limit the generalisability to other countries, but trialists should reason why the COS would not be applicable. The default position should not be that a COS developed in one country will automatically not be applicable elsewhere. Conclusion: We have established a COS for trials of effectiveness in localised prostate cancer, applicable across all interventions which should be measured in all localised prostate cancer effectiveness trials

Statin treatment and muscle symptoms:series of randomised, placebo controlled n-of-1 trials

OBJECTIVE: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. DESIGN: Series of randomised, placebo controlled n-of-1 trials. SETTING: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. PARTICIPANTS: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. MAIN OUTCOME MEASURES: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. RESULTS: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. CONCLUSIONS: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. TRIAL REGISTRATION: ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064

Human settlement of East Polynesia earlier, incremental, and coincident with prolonged South Pacific drought

The timing of human colonization of East Polynesia, a vast area lying between Hawai‘i, Rapa Nui, and New Zealand, is much debated and the underlying causes of this great migration have been enigmatic. Our study generates evidence for human dispersal into eastern Polynesia from islands to the west from around AD 900 and contemporaneous paleoclimate data from the likely source region. Lake cores from Atiu, Southern Cook Islands (SCIs) register evidence of pig and/or human occupation on a virgin landscape at this time, followed by changes in lake carbon around AD 1000 and significant anthropogenic disturbance from c. AD 1100. The broader paleoclimate context of these early voyages of exploration are derived from the Atiu lake core and complemented by additional lake cores from Samoa (directly west) and Vanuatu (southwest) and published hydroclimate proxies from the Society Islands (northeast) and Kiribati (north). Algal lipid and leaf wax biomarkers allow for comparisons of changing hydroclimate conditions across the region before, during, and after human arrival in the SCIs. The evidence indicates a prolonged drought in the likely western source region for these colonists, lasting c. 200 to 400 y, contemporaneous with the phasing of human dispersal into the Pacific. We propose that drying climate, coupled with documented social pressures and societal developments, instigated initial eastward exploration, resulting in SCI landfall(s) and return voyaging, with colonization a century or two later. This incremental settlement process likely involved the accumulation of critical maritime knowledge over several generations