ABSTRACT Solar flares produce radiation that can have an almost immediate effect on the near-Earth environment, making it crucial to forecast flares in order to mitigate their negative effects. The ...number of published approaches to flare forecasting using photospheric magnetic field observations has proliferated, with varying claims about how well each works. Because of the different analysis techniques and data sets used, it is essentially impossible to compare the results from the literature. This problem is exacerbated by the low event rates of large solar flares. The challenges of forecasting rare events have long been recognized in the meteorology community, but have yet to be fully acknowledged by the space weather community. During the interagency workshop on "all clear" forecasts held in Boulder, CO in 2009, the performance of a number of existing algorithms was compared on common data sets, specifically line-of-sight magnetic field and continuum intensity images from the Michelson Doppler Imager, with consistent definitions of what constitutes an event. We demonstrate the importance of making such systematic comparisons, and of using standard verification statistics to determine what constitutes a good prediction scheme. When a comparison was made in this fashion, no one method clearly outperformed all others, which may in part be due to the strong correlations among the parameters used by different methods to characterize an active region. For M-class flares and above, the set of methods tends toward a weakly positive skill score (as measured with several distinct metrics), with no participating method proving substantially better than climatological forecasts.
The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. ...The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.
Single‐antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts ...have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor‐specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single‐antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third‐party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death‐censored graft survival (DCGS) and risk factors for rejection. Antibody‐mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell‐mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization.
When stratifying kidney transplant recipients by sensitization history and day of transplant serum analysis, univariate and multivariate analysis reveals donor‐specific sensitization to be the most important risk factor for rejection.
Safety pharmacology screening against a wide range of unintended vital targets using in vitro assays is crucial to understand off-target interactions with drug candidates. With the increasing demand ...for in vitro assays, ligand- and structure-based virtual screening approaches have been evaluated for potential utilization in safety profiling. Although ligand based approaches have been actively applied in retrospective analysis or prospectively within well-defined chemical space during the early discovery stage (i.e., HTS screening and lead optimization), virtual screening is rarely implemented in later stage of drug discovery (i.e., safety). Here we present a case study to evaluate ligand-based 3D QSAR models built based on in vitro antagonistic activity data against adenosine receptor 2A (A2A). The resulting models, obtained from 268 chemically diverse compounds, were used to test a set of 1,897 chemically distinct drugs, simulating the real-world challenge of safety screening when presented with novel chemistry and a limited training set. Due to the unique requirements of safety screening versus discovery screening, the limitations of 3D QSAR methods (i.e., chemotypes, dependence on large training set, and prone to false positives) are less critical than early discovery screen. We demonstrated that 3D QSAR modeling can be effectively applied in safety assessment prior to in vitro assays, even with chemotypes that are drastically different from training compounds. It is also worth noting that our model is able to adequately make the mechanistic distinction between agonists and antagonists, which is important to inform subsequent in vivo studies. Overall, we present an in-depth analysis of the appropriate utilization and interpretation of pharmacophore-based 3D QSAR models for safety screening.
Longwall automation: trends, challenges and opportunities Ralston, Jonathon C.; Hargrave, Chad O.; Dunn, Mark T.
International Journal of Mining Science and Technology/International journal of mining science and technology,
09/2017, Letnik:
27, Številka:
5
Journal Article
Recenzirano
Odprti dostop
This paper explores the ongoing development and implementation of longwall automation technology to achieve greater levels of underground coal mining performance. The primary driver behind the ...research and development effort is to increase the safety, productivity and efficiency of longwall mining operations to enhance the underlying mining business. A brief review of major longwall automation challenges is given followed by a review of the insights and benefits associated with the LASC longwall shearer automation solution. Areas of technical challenge in sensing, decision support, autonomy and human interaction are then highlighted, with specific attention given to remote operating centres, proximity detection and systems-level architectures in order to motivate further automation system development. The vision for a fully integrated coal mining ecosystem is discussed with the goal of delivering a highperformance, zero-exposure and environmentally coherent mining operations.
Small-cell lung cancer (SCLC) remains the deadliest of all the lung cancer types. Its high mortality is largely attributed to the invariable development of resistance to standard ...chemo/radiotherapies, which have remained unchanged for the past 30 years, underscoring the need for new therapeutic approaches. The discovery of molecular targets for chemoprevention and treatment has been hampered by the poor understanding of SCLC progression. In recent years, comprehensive omics-based analyses have led to the discovery of recurrent alterations in patient tumors, and functional studies using genetically engineered mouse models and patient-derived tumor models have provided information about the alterations critical for SCLC pathogenesis. Defining the somatic alterations scattered throughout the SCLC genome will help to understand the underlying mechanism of this devastating disease and pave the way for the discovery of therapeutic vulnerabilities associated with the genomic alterations.
•Spectra for more than 1000 near-Earth objects (NEOs) are presented and analyzed.•NEOs originate from specific regions in the main asteroid belt, according to type.•Meteorites linked to NEO classes ...show specific escape regions from the main belt.•Distinct spectral trends are found for surface alteration by radiation and impacts.•Altered surfaces become refreshed by planetary encounters and other processes.
Advancing technology in near-infrared instrumentation and dedicated planetary telescope facilities have enabled nearly two decades of reconnoitering the spectral properties for near-Earth objects (NEOs). We report measured spectral properties for more than 1000 NEOs, representing >5% of the currently discovered population. Thermal flux detected below 2.5 µm allows us to make albedo estimates for nearly 50 objects, including two comets. Additional spectral data are reported for more than 350 Mars-crossing asteroids. Most of these measurements were achieved through a collaboration between researchers at the Massachusetts Institute of Technology and the University of Hawaii, with full cooperation of the NASA Infrared Telescope Facility (IRTF) on Mauna Kea. We call this project the MIT-Hawaii Near-Earth Object Spectroscopic Survey (MITHNEOS; myth-neos). While MITHNEOS has continuously released all spectral data for immediate use by the scientific community, our objectives for this paper are to: (1) detail the methods and limits of the survey data, (2) formally present a compilation of results including their taxonomic classification within a single internally consistent framework, (3) perform a preliminary analysis on the overall population characteristics with a concentration toward deducing key physical processes and identifying their source region for escaping the main belt. Augmenting our newly published measurements are the previously published results from the broad NEO community, including many results graciously shared by colleagues prior to formal publication. With this collective data set, we find the near-Earth population matches the diversity of the main-belt, with all main-belt taxonomic classes represented in our sample. Potentially hazardous asteroids (PHAs) as well as the subset of mission accessible asteroids (ΔV ≤ 7 km/s) both appear to be a representative mix of the overall NEO population, consistent with strong dynamical mixing for the population that interacts most closely with Earth. Mars crossers, however, are less diverse and appear to more closely match the inner belt population from where they have more recently diffused. The fractional distributions of major taxonomic classes (60% S, 20% C, 20% other) appear remarkably constant over two orders of magnitude in size (10 km to 100 m), which is eight orders of magnitude in mass, though we note unaccounted bias effects enter into our statistics below about 500 m. Given the range of surface ages, including possible refreshment by planetary encounters, we are able to identify a very specific space weathering vector tracing the transition from Q- to Sq- to S-types that follows the natural dispersion for asteroid spectra mapped into principal component space. We also are able to interpret a shock darkening vector that may account for some objects having featureless spectra. Space weathering effects for C-types are complex; these results are described separately by Lantz, Binzel, DeMeo. (2018, Icarus 302, 10–17). Independent correlation of dynamical models with taxonomic classes map the escape zones for NEOs to main-belt regions consistent with well established heliocentric compositional gradients. We push beyond taxonomy to interpret our visible plus near-infrared spectra in terms of the olivine and pyroxene mineralogy consistent with the H, L, and LL classes of ordinary chondrites meteorites. Correlating meteorite interpretations with dynamical escape region models shows a preference for LL chondrites to arrive from the ν6 resonance and H chondrites to have a preferential signature from the mid-belt region (3:1 resonance). L chondrites show some preference toward the outer belt, but not at a significant level. We define a Space Weathering Parameter as a continuous variable and find evidence for step-wise changes in space weathering properties across different planet crossing zones in the inner solar system. Overall we hypothesize the relative roles of planetary encounters, YORP spin-up, and thermal cycling across the inner solar system.
The classification of phase 3 trials as superiority or non-inferiority has become routine, and it is widely accepted that there are important differences between the two types of trial in their ...design, analysis and interpretation.
There is a clear rationale for the superiority/non-inferiority framework in the context of regulatory trials. The focus of our article is non-regulatory trials with a public health objective. First, using two examples from infectious disease research, we show that the classification of superiority or non-inferiority trials is not always straightforward. Second, we show that several arguments for different approaches to the design, analysis and interpretation of superiority and non-inferiority trials are unconvincing when examined in detail. We consider, in particular, the calculation of sample size (and the choice of delta or the non-inferiority margin), intention-to-treat versus per-protocol analyses, and one-sided versus two-sided confidence intervals. We argue that the superiority/non-inferiority framework is not just unnecessary but can have a detrimental effect, being a barrier to clear scientific thought and communication. In particular, it places undue emphasis on tests for significance or non-inferiority at the expense of estimation. We emphasise that these concerns apply to phase 3 non-regulatory trials in general, not just to those where the classification of the trial as superiority or non-inferiority is ambiguous.
Guidelines and statistical practice should abandon the sharp division between superiority and non-inferiority phase 3 non-regulatory trials and be more closely aligned to the clinical and public health questions that motivate the trial.
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