Boreal forest riparian zones regulate stream sulfate and dissolved organic carbon

In boreal forest catchments, solute transfer to streams is controlled by hydrological and biogeochemical processes occurring in the riparian zone (RZ). However, RZs are spatially heterogeneous and information about solute chemistry is typically limited. This is problematic when making inferences about stream chemistry. Hypothetically, the strength of links between riparian and stream chemistry is time-scale dependent. Using a ten-year (2003 − 2012) dataset from a northern Swedish catchment, we evaluated the suitability of RZ data to infer stream dynamics at different time scales. We focus on the role of the RZ versus upslope soils in controlling sulfate (SO42−) and dissolved organic carbon (DOC). A priori, declines in acid deposition and redox-mediated SO42− pulses control sulfur (S) fluxes and pool dynamics, which in turn affect dissolved organic carbon (DOC). We found that the catchment is currently a net source of S, presumably due to release of the S pool accumulated during the acidification period. In both, RZ and stream, SO42 − concentrations are declining over time, whereas DOC is increasing. No temporal trends in SO42 − and DOC were observed in upslope mineral soils. SO42 − explained the variation of DOC in stream and RZ, but not in upslope mineral soil. Moreover, as SO42 − decreased with time, temporal variability of DOC increased. These observations indicate that: (1) SO42 − is still an important driver of DOC trends in boreal catchments and (2) RZ processes control stream SO42 − and subsequently DOC independently of upslope soils. These phenomena are likely occurring in many regions recovering from acidification. Because water flows through a heterogeneous mosaic of RZs before entering the stream, upscaling information from limited RZ data to the catchment level is problematic at short-time scales. However, for long-term trends and annual dynamics, the same data can provide reasonable representations of riparian processes and support meaningful inferences about stream chemistry

CUBES: application of image slicers to reformat the field for two spectral resolving powers

The Cassegrain U-Band Efficient Spectrograph (CUBES) is a high-efficiency spectrograph designed for observations from 305 to 400nm. It will be integrated at a Cassegrain focus of the Very Large Telescope (VLT). The image slicer technology is applied to reformat the field of view reducing the spectrograph entrance slit etendue and minimising the spectrograph volume and weight without slit losses. Two image slicers will provide CUBES with two spectral resolving powers: R≥20,000 for high resolution (HR) and R≥5,000 for low resolution (LR). Both image slicers are composed of two arrays of six spherical mirrors. For the HR mode, a rectangular field of view of 1.5arcsec by 10arcsec is reorganised into a slit of 0.19mm × 88mm; for the LR mode, a field of view of 6arcsec by 10arcsec is reformatted into a slit of 0.77mm × 88mm, with slicer mirrors of width 0.5mm and 2mm, respectively. CUBES is currently in the Preliminary Design Phase (Phase B). This communication presents the Conceptual (Phase A) design and the main performance for the HR and LR image slicers addressing the following technological challenges: compact layout with the minimum number of optical components to optimise throughput, near diffraction limited optical quality, telecentric design with overlapped exit pupils for all slices of the field of view, distribution of the slicer mirrors to reduce shadows and selection of the best substrate for the very short wavelengths at which CUBES will operate

Segmentation of plate coupling, fate of subduction fluids, and modes of arc magmatism in Cascadia, inferred from magnetotelluric resistivity

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 15 (2014): 4230–4253, doi:10.1002/2014GC005509.Five magnetotelluric (MT) profiles have been acquired across the Cascadia subduction system and transformed using 2-D and 3-D nonlinear inversion to yield electrical resistivity cross sections to depths of ∼200 km. Distinct changes in plate coupling, subduction fluid evolution, and modes of arc magmatism along the length of Cascadia are clearly expressed in the resistivity structure. Relatively high resistivities under the coasts of northern and southern Cascadia correlate with elevated degrees of inferred plate locking, and suggest fluid- and sediment-deficient conditions. In contrast, the north-central Oregon coastal structure is quite conductive from the plate interface to shallow depths offshore, correlating with poor plate locking and the possible presence of subducted sediments. Low-resistivity fluidized zones develop at slab depths of 35–40 km starting ∼100 km west of the arc on all profiles, and are interpreted to represent prograde metamorphic fluid release from the subducting slab. The fluids rise to forearc Moho levels, and sometimes shallower, as the arc is approached. The zones begin close to clusters of low-frequency earthquakes, suggesting fluid controls on the transition to steady sliding. Under the northern and southern Cascadia arc segments, low upper mantle resistivities are consistent with flux melting above the slab plus possible deep convective backarc upwelling toward the arc. In central Cascadia, extensional deformation is interpreted to segregate upper mantle melts leading to underplating and low resistivities at Moho to lower crustal levels below the arc and nearby backarc. The low- to high-temperature mantle wedge transition lies slightly trenchward of the arc.Phil Wannamaker and Virginie Maris gratefully acknowledge funding by the U.S. National Science Foundation under grants EAR08–43725 and EAR08–38043 through the Earthscope and Geophysics programs. The 2D inversion capability received development support under U.S. Department of Energy contract DE-PS36-04GO94001. Rob Evans was supported through Earthscope grant EAR08–44041 and Shane McGary through a National Defense Science and Engineering Graduate (NDSEG) fellowship. Fieldwork in Canada was made possible by an NSERC Discovery Grant and a Canadian Foundation for Innovation award to Martyn Unsworth.2015-05-1

Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig®) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company's submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naïve indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company's revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of £31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and £26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was £33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to £11,727 per QALY gained compared with re-induction chemotherapy and between £7892 and £31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to £7156 to £29,995 per QALY gained versus BSC and to less than £5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS

The P2X1 receptor and platelet function

Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1 receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques

Early influences on cardiovascular and renal development

The hypothesis that a developmental component plays a role in subsequent disease initially arose from epidemiological studies relating birth size to both risk factors for cardiovascular disease and actual cardiovascular disease prevalence in later life. The findings that small size at birth is associated with an increased risk of cardiovascular disease have led to concerns about the effect size and the causality of the associations. However, recent studies have overcome most methodological flaws and suggested small effect sizes for these associations for the individual, but an potential important effect size on a population level. Various mechanisms underlying these associations have been hypothesized, including fetal undernutrition, genetic susceptibility and postnatal accelerated growth. The specific adverse exposures in fetal and early postnatal life leading to cardiovascular disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life may underlie the complex associations of fetal growth retardation and low birth weight with cardiovascular disease in later life. To estimate the population effect size and to identify the underlying mechanisms, well-designed epidemiological studies are needed. This review is focused on specific adverse fetal exposures, cardiovascular adaptations and perspectives for new studies. Copyrigh

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure