Retinal visual prostheses ("bionic eyes") have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant ...such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration.
Clinicaltrials.gov NCT01603576.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Global increases in the occurrence of large, severe wildfires in forested watersheds threaten drinking water supplies and aquatic ecology. Wildfire effects on water quality, particularly nutrient ...levels and forms, can be significant. The longevity and downstream propagation of these effects as well as the geochemical mechanisms regulating them remain largely undocumented at larger river basin scales. Here, phosphorus (P) speciation and sorption behavior of suspended sediment were examined in two river basins impacted by a severe wildfire in southern Alberta, Canada. Fine‐grained suspended sediments (<125 μm) were sampled continuously during ice‐free conditions over a two‐year period (2009–2010), 6 and 7 years after the wildfire. Suspended sediment samples were collected from upstream reference (unburned) river reaches, multiple tributaries within the burned areas, and from reaches downstream of the burned areas, in the Crowsnest and Castle River basins. Total particulate phosphorus (TPP) and particulate phosphorus forms (nonapatite inorganic P, apatite P, organic P), and the equilibrium phosphorus concentration (EPC₀) of suspended sediment were assessed. Concentrations of TPP and the EPC₀ were significantly higher downstream of wildfire‐impacted areas compared to reference (unburned) upstream river reaches. Sediments from the burned tributary inputs contained higher levels of bioavailable particulate P (NAIP) – these effects were also observed downstream at larger river basin scales. The release of bioavailable P from postfire, P‐enriched fine sediment is a key mechanism causing these effects in gravel‐bed rivers at larger basin scales. Wildfire‐associated increases in NAIP and the EPC₀ persisted 6 and 7 years after wildfire. Accordingly, this work demonstrated that fine sediment in gravel‐bed rivers is a significant, long‐term source of in‐stream bioavailable P that contributes to a legacy of wildfire impacts on downstream water quality, aquatic ecology, and drinking water treatability.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The covalent addition of ubiquitin to target proteins is a key post-translational modification that is linked to a myriad of biological processes. Here, we report a fast, single-molecule, and ...label-free method to probe the ubiquitination of proteins employing an engineered Cytolysin A (ClyA) nanopore. We show that ionic currents can be used to recognize mono- and polyubiquitinated forms of native proteins under physiological conditions. Using defined conjugates, we also show that isomeric monoubiquitinated proteins can be discriminated. The nanopore approach allows following the ubiquitination reaction in real time, which will accelerate the understanding of fundamental mechanisms linked to protein ubiquitination.
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IJS, KILJ, NUK, PNG, UL, UM
Noting concerns about the non-clinical efficacy of the Beck Hopelessness Scale (BHS), specifically the instrument's ability to discriminate between lower levels of hopelessness, this paper describes ...the development of the General Hopelessness Scale (GHS) for use with general samples. Following a literature review an item pool assessing the breadth of the hopelessness construct domain was created. This was then placed in survey form and assessed within two independent studies. Study 1 (N = 305, 172 women, 133 men, Mage = 28.68) explored factorial structure, item performance, and convergent validity of the GHS in relation to standardised measures of self-esteem and trait hopelessness. In Study 2 (N = 326, 224 women, 102 men, Mage = 26.52), scrutiny of the GHS occurred using confirmatory factor analysis and invariance tests, alongside item performance and convergent validity analyses relative to measures of affect, optimism, and hope. Factor analysis (using minimum average partial correlations and exploratory factor analysis) within Study 1 revealed the existence of four dimensions (Negative Expectations, Hope, Social Comparison, and Futility), which met Rasch model assumptions (i.e., good item/person fit and item/person reliability). Further psychometric assessment within Study 2 found satisfactory model fit and gender invariance. Convergent validity testing revealed moderate to large associations between the GHS and theoretically relevant variables (self-esteem, trait hopelessness, affect, optimism, and hope) across Study 1 and 2. Further examination of performance (reliability and ceiling and floor effects) within Study 1 and 2 demonstrated that the GHS was a satisfactory measure in non-clinical settings. Additionally, unlike the BHS, the GHS does not assume that administrators are trained professionals capable of advising on appropriate interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide ...(TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET).
Methods: Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m2/day PO on days 1–5) and irinotecan (50 mg/m2/day IV on days 1–5) with or without bevacizumab (10 mg/kg IV on days 1 and 15).
Results: One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event‐free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative‐risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2–16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm.
Conclusion: The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three‐drug regimen demonstrated a sufficient risk reduction to warrant further investigation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This paper examines the structural action of Eduardo Torroja’s Alloz aqueduct, completed in 1939, to see whether we should think of it as acting as a beam or a shell. This is of interest regarding ...the Alloz aqueduct itself, but also in the design of similar structures in the future, where we must have a simple conceptual understanding of how we want it to work.
We apply two alternative approaches available at that time, before computers. Firstly, the membrane theory of shells, effectively assuming the aqueduct walls are infinitely flexible in bending, and secondly, the Euler–Bernoulli ‘plane sections remain plane’ elementary beam theory. We also review Torroja’s calculations which were based on an elaboration of the Euler–Bernoulli beam theory know as the Griffith–Taylor theory for the bending of cantilevers, although we are uncertain as to why he decided to use the Griffith–Taylor theory for a thin walled structure.
Both the membrane shell and Euler–Bernoulli beam theory require a prestress to be applied along the longitudinal edges of the channel. However, the level of prestress in the Alloz aqueduct is consistent with the beam theory, which seams the most appropriate approach.
Whether or not a structure of this type acts as a shell depends upon the thickness of the wall. The thinner the wall, the more it act as a shell. The wall thickness of the Alloz aqueduct is sufficient for it to act mainly as a beam.
•The structural behaviour of Torroja’s prestressed Alloz aqueduct is investigated.•Results are obtained using membrane shell theory and Euler–Bernoulli beam theory.•A comparison between our results and those by Torroja, who used the Griffith-Taylor theory.•Prestressing is a requirement for pure membrane equilibrium.•Increased prestressing reduces wall bending moments, enabling reduced wall thickness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Surface geometry plays a central role in the design of bridges, vaults and shells, using various techniques for generating a geometry which aims to balance structural, spatial, aesthetic and ...construction requirements.
In this paper we propose the use of surfaces defined such that given closed curves subtend a constant solid angle at all points on the surface and form its boundary. Constant solid angle surfaces enable one to control the boundary slope and hence achieve an approximately constant span-to-height ratio as the span varies, making them structurally viable for shell structures. In addition, when the entire surface boundary is in the same plane, the slope of the surface around the boundary is constant and thus follows a principal curvature direction. Such surfaces are suitable for surface grids where planar quadrilaterals meet the surface boundaries. They can also be used as the Airy stress function in the form finding of shells having forces concentrated at the corners.
Our technique employs the Gauss-Bonnet theorem to calculate the solid angle of a point in space and Newton's method to move the point onto the constant solid angle surface. We use the Biot-Savart law to find the gradient of the solid angle. The technique can be applied in parallel to each surface point without an initial mesh, opening up for future studies and other applications when boundary curves are known but the initial topology is unknown.
We show the geometrical properties, possibilities and limitations of surfaces of constant solid angle using examples in three dimensions.
•Constant solid angle surfaces enable the control of the slope at the boundary.•Points on a constant solid angle surfaces can be found without a mesh.•The solid angle is dimensionless and therefore useful with varying spans.•Enables surface grids in which planar quadrilaterals meet the surface boundaries.•Can be used as Airy stress functions in form finding to direct forces towards corners.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RNA-seq, the application of next-generation sequencing to RNA, provides transcriptome-wide characterization of cellular activity. Assessment of sequencing performance and library quality is critical ...to the interpretation of RNA-seq data, yet few tools exist to address this issue. We introduce RNA-SeQC, a program which provides key measures of data quality. These metrics include yield, alignment and duplication rates; GC bias, rRNA content, regions of alignment (exon, intron and intragenic), continuity of coverage, 3'/5' bias and count of detectable transcripts, among others. The software provides multi-sample evaluation of library construction protocols, input materials and other experimental parameters. The modularity of the software enables pipeline integration and the routine monitoring of key measures of data quality such as the number of alignable reads, duplication rates and rRNA contamination. RNA-SeQC allows investigators to make informed decisions about sample inclusion in downstream analysis. In summary, RNA-SeQC provides quality control measures critical to experiment design, process optimization and downstream computational analysis.
See www.genepattern.org to run online, or www.broadinstitute.org/rna-seqc/ for a command line tool.
•Wildfires have extensive and prolonged impacts on thermal regimes of streams.•Incremental effects of post-fire salvage logging remain uncertain.•Stream temperature response governed by advective and ...non-advective heat fluxes.
In 2003, the Lost Creek wildfire severely burned 21,000 hectares of forest on the eastern slopes of the Canadian Rocky Mountains. Seven headwater catchments with varying levels of disturbance (burned, post-fire salvage logged, and unburned) were instrumented as part of the Southern Rockies Watershed Project to measure streamflow, stream temperature, and meteorological conditions. From 2004 to 2010 mean annual stream temperature (Ts) was elevated 0.8–2.1°C in the burned and post-fire salvage logged streams compared to the unburned streams. Mean daily maximum Ts was 1.0–3.0°C warmer and mean daily minimum Ts was 0.9–2.8°C warmer in the burned and post-fire salvage logged streams compared to the unburned catchments. The effects of wildfire on the thermal regime of the burned catchments were persistent and trend analysis showed no apparent recovery during the study period. Temporal patterns of Ts were strongly associated with seasonal variability of surface and groundwater interactions and air temperature. Advective heat fluxes between groundwater and surface water were likely the dominant controls on Ts, though the strength of these advective controls varied among catchments highlighting the importance of simultaneous catchment-scale and process-focused research to better elucidate the physical drivers influencing Ts response to disturbance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE—RalA and RalB GTPases are important regulators of cell growth, cancer metastasis, and granule secretion. The purpose of this study was to determine the role of Ral GTPases in platelets with ...the use of platelet-specific gene-knockout mouse models.
APPROACH AND RESULTS—This study shows that platelets from double knockout mice, in which both GTPases have been deleted, show markedly diminished (≈85% reduction) P-selectin translocation to the surface membrane, suggesting a critical role in α-granule secretion. Surprisingly, however, there were only minor effects on stimulated release of soluble α- and δ-granule content, with no alteration in granule count, morphology, or content. In addition, their expression was not essential for platelet aggregation or thrombus formation. However, absence of surface P-selectin caused a marked reduction (≈70%) in platelet–leukocyte interactions in blood from RalAB double knockout mice, suggesting a role for platelet Rals in platelet-mediated inflammation.
CONCLUSIONS—Platelet Ral GTPases primarily control P-selectin surface expression, in turn regulating platelet–leukocyte interaction. Ral GTPases could therefore be important novel targets for the selective control of platelet-mediated immune cell recruitment and inflammatory disease.
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