CAN-HK : An a priori crustal model for the Canadian Shield

ACKNOWLEDGMENTS The United Kingdom component of the Hudson Bay Lithospheric Experiment (HuBLE) was supported by the Natural Environment Research Council (NERC) Grant Number NE/F007337/1, with financial and logistical support from the Geological Survey of Canada (GSC), Canada-Nunavut Geoscience Office (CNGO), SEIS-UK (the seismic node of NERC), and the First Nations communities of Nunavut. J. Beauchesne and J. Kendall provided invaluable assistance in the field. I. D. B. was funded by the Leverhulme Trust and acknowledges support through Grant Number RPG-2013- 332. The authors thank three anonymous reviewers for their constructive comments.Peer reviewedPublisher PD

The Hudson Bay Lithospheric Experiment (HuBLE) : Insights into Precambrian Plate Tectonics and the Development of Mantle Keels

The UK component of HuBLE was supported by Natural Environment Research Council (NERC) grant NE/F007337/1, with financial and logistical support from the Geological Survey of Canada, Canada–Nunavut Geoscience Office, SEIS-UK (the seismic node of NERC), and First Nations communities of Nunavut. J. Beauchesne and J. Kendall provided invaluable assistance in the field. Discussions with M. St-Onge, T. Skulski, D. Corrigan and M. Sanborne-Barrie were helpful for interpretation of the data. D. Eaton and F. A. Darbyshire acknowledge the Natural Sciences and Engineering Research Council. Four stations on the Belcher Islands and northern Quebec were installed by the University of Western Ontario and funded through a grant to D. Eaton (UWO Academic Development Fund). I. Bastow is funded by the Leverhulme Trust. This is Natural Resources Canada Contribution 20130084 to its Geomapping for Energy and Minerals Program. This work has received funding from the European Research Council under the European Unions Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 240473 ‘CoMITAC’.Peer reviewedPublisher PD

Seismicity and crustal structure of the southern main Ethiopian rift: new evidence from Lake Abaya

The Main Ethiopian Rift (MER) has developed during the 18 Ma-Recent separation of the Nubian and Somalian plates. Extension in its central and northern sectors is associated with seismic activity and active magma intrusion, primarily within the rift, where shallow (urn:x-wiley:15252027:media:ggge22586:ggge22586-math-00015 km) seismicity along magmatic centers is commonly caused by fluid flow through open fractures in hydrothermal systems. However, the extent to which similar magmatic rifting persists into the southern MER is unknown. Using data from a temporary network of five seismograph stations, we analyze patterns of seismicity and crustal structure in the Abaya region of the southern MER. Magnitudes range from 0.9 to 4.0; earthquake depths are 0–30 km. urn:x-wiley:15252027:media:ggge22586:ggge22586-math-0002 ratios of urn:x-wiley:15252027:media:ggge22586:ggge22586-math-00031.69, estimated from Wadati diagram analysis, corroborate bulk-crustal urn:x-wiley:15252027:media:ggge22586:ggge22586-math-0004 ratios determined via teleseismic P-to-S receiver function H-urn:x-wiley:15252027:media:ggge22586:ggge22586-math-0005 stacking and reveal a relative lack of mafic intrusion compared to the MER rift sectors to the north. There is a clear association of seismicity with the western border fault system of the MER everywhere in our study area, but earthquake depths are shallow near Duguna volcano, implying a shallowed geothermal gradient associated with rift valley silicic magmatism. This part of the MER is thus interpreted best as a young magmatic system that locally impacts the geothermal gradient but that has not yet significantly modified continental crustal composition via rift-axial magmatic rifting

A multinuclear solid state NMR, density functional theory and X-Ray diffraction study of hydrogen bonding in Group I hydrogen dibenzoates

An NMR crystallographic approach incorporating multinuclear solid state NMR (SSNMR), X-ray structure determinations and density functional theory (DFT) are used to characterise the H bonding arrangements in benzoic acid (BZA) and the corresponding Group I alkali metal hydrogen dibenzoates (HD) systems. Since the XRD data often cannot precisely confirm the proton position within the hydrogen bond, the relationship between the experimental SSNMR parameters and the ability of gauge included plane augmented wave (GIPAW) DFT to predict them becomes a powerful constraint that can assist with further structure refinement. Both the 1H and 13C MAS NMR methods provide primary descriptions of the H bonding via accurate measurements of the 1H and 13C isotropic chemical shifts, and the individual 13C chemical shift tensor elements; these are unequivocally corroborated by DFT calculations, which together accurately describe the trend of the H bonding strength as the size of the monovalent cation changes. In addition, 17O MAS and DOR NMR form a powerful combination to characterise the O environments, with the DOR technique providing highly resolved 17O NMR data which helps verify unequivocally the number of inequivalent O positions for the conventional 17O MAS NMR to process. Further multinuclear MAS and static NMR studies involving the quadrupolar 7Li, 39K, 87Rb and 133Cs nuclei, and the associated DFT calculations, provide trends and a corroboration of the H bond geometry which assist in the understanding of these arrangements. Even though the crystallographic H positions in each H bonding arrangement reported from the single crystal X-ray studies are prone to uncertainty, the good corroboration between the measured and DFT calculated chemical shift and quadrupole tensor parameters for the Group I alkali species suggest that these reported H positions are reliable

Predictive Value of Pharmacokinetics-Adjusted Phenotypic Susceptibility on Response to Ritonavir-Enhanced Protease Inhibitors (PIs) in Human Immunodeficiency Virus-Infected Subjects Failing Prior PI Therapy

The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC50s) to the study PI were high. Median 2-week VL changes were −0.7, −0.1, and −1.0 log10 for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, −0.39 to −0.50; P ≤ 0.029). The strongest correlation with response to FPV/r was the IC50 FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = −0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Background: Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives: To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design: A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting: Thirteen UK clinical neuroscience centres. Participants: Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions: Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures: The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results: Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations: There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions: A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work: To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration: Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART):a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259

Hydrous upwelling across the mantle transition zone beneath the Afar Triple Junction

The mechanisms that drive the upwelling of chemical heterogeneity from the lower to upper mantle (e.g., thermal versus compositional buoyancy) are key to our understanding of whole mantle con- vective processes. We address these issues through a receiver function study on new seismic data from recent deployments located on the Afar Triple Junction, a location associated with deep mantle upwelling. The detailed images of upper mantle and mantle transition zone structure illuminate features that give insights into the nature of upwelling from the deep Earth. A seismic low-velocity layer directly above the mantle transition zone, interpreted as a stable melt layer, along with a prominent 520 km discontinuity sug- gest the presence of a hydrous upwelling. A relatively uniform transition zone thickness across the region suggests a weak thermal anomaly (<100 K) may be present and that upwelling must be at least partly driven by compositional buoyancy. The results suggest that the lower mantle is a source of volatile rich, chemically distinct upwellings that influence the structure of the upper mantle, and potentially the chemis- try of surface lavas

Symptomatic Social Science: Reflexivity, Recognition and Redistribution in the GBCS

The article examines methodological and theoretical issues related to the GBCS. It acknowledges its importance for the public profile of sociology, whilst arguing that it needs to develop a better sense of what it stands for not only in terms of understanding societal changes, but contributing to human betterment. To achieve this it discusses the role of reflexivity in the GBCS with reference to position and disposition and accounts of its process. It then moves on to examine its normative basis in terms of an ‘existential analytics’ and suggests a series of ways in which it might advance its insights as the work develops

CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells

Published 29 October 2015IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.Ervin E. Kara, Duncan R. McKenzie, Cameron R. Bastow, Carly E. Gregor, Kevin A. Fenix, Abiodun D. Ogunniyi, James C. Paton, Matthias Mack, Diana R. Pombal, Cyrill Seillet, Be, ne, dicte Dubois, Adrian Liston, Kelli P.A. MacDonald, Gabrielle T. Belz, Mark J. Smyth, Geoffrey R. Hill, Iain Comerford and Shaun R. McCol