A correction method to remove proton contamination from the electron channels of the Polar‐orbiting Operational Environmental Satellites Medium Energy Proton/Electron Detector (MEPED) is described. ...Proton contamination estimates are based on measurements in five of the MEPED proton spectral channels. A constrained inversion of the MEPED proton channel response function matrix is used to calculate proton differential flux spectra. In this inversion, the proton energy distribution is described by a weighted combination of exponential, power law, and Maxwellian distributions. Proton contamination in the MEPED electron spectral channels is derived by applying the electron channel proton sensitivities to the proton fluxes from the best fit proton spectra. Once the electron channel measurements are corrected for proton contamination, an inversion of the electron channel response function matrix is used to calculate electron differential flux spectra. A side benefit of the method is that it yields an estimate for the integrated electron flux in the energy range from 300 keV to 2.5 MeV with a center energy at ~800 keV. The final product is a differential spectrum of electron flux covering the energy range from about 10 keV to 2.5 MeV that is devoid of proton contamination except during large solar proton events. Comparisons of corrected MEPED differential fluxes to the Detection of Electromagnetic Emissions Transmitted from Earthquake Regions Instrument for Detecting Particles show that MEPED fluxes are greater than what is expected from altitude‐induced particle population changes; this is attributed at least partially to measurement differences in pitch angle range.
Key Points
A new set of POES MEPED data is produced with proton contamination removed
Differential flux for medium‐energy protons and electrons is calculated
New quantitative relativistic electron channel is output
The atmospheric effects of precipitating electrons are not fully understood, and uncertainties are large for electrons with energies greater than ~30 keV. These electrons are underrepresented in ...modeling studies today, primarily because valid measurements of their precipitating spectral energy fluxes are lacking. This paper compares simulations from the Whole Atmosphere Community Climate Model (WACCM) that incorporated two different estimates of precipitating electron fluxes for electrons with energies greater than 30 keV. The estimates are both based on data from the Polar Orbiting Environmental Satellite Medium Energy Proton and Electron Detector (MEPED) instruments but differ in several significant ways. Most importantly, only one of the estimates includes both the 0° and 90° telescopes from the MEPED instrument. Comparisons are presented between the WACCM results and satellite observations poleward of 30°S during the austral winter of 2003, a period of significant energetic electron precipitation. Both of the model simulations forced with precipitating electrons with energies >30 keV match the observed descent of reactive odd nitrogen better than a baseline simulation that included auroral electrons, but no higher energy electrons. However, the simulation that included both telescopes shows substantially better agreement with observations, particularly at midlatitudes. The results indicate that including energies >30 keV and the full range of pitch angles to calculate precipitating electron fluxes is necessary for improving simulations of the atmospheric effects of energetic electron precipitation.
Plain Language Summary
The study presented here investigates the effects from energetic electron precipitation (EEP) in the southern hemisphere winter of 2003. Electron precipitation is common during periods of enhanced geomagnetic activity and can create reactive nitrogen oxides and hydrogen oxides that can destroy ozone. Most global climate models currently do not include precipitating electrons with energies greater than 30 keV. To test whether this deficiency is important, this investigation compares observations with model simulations that included electrons with energies greater than 30 keV, as observed by the Medium Energy Proton and Electron Detector (MEPED) satellite instruments. In addition, one of the EEP data sets used in the simulations included data from just one of the telescopes on the MEPED instruments, whereas the other included data from both of the telescopes. We found that including both of the telescopes is important for capturing chemistry changes at polar and subpolar latitudes. The model simulation that only included only one of the telescopes showed significant improvement compared to a simulation with only low energy electrons. However, it did not perform as well as the model simulation that included both MEPED telescopes. This work is important because it shows that including energies >30 keV and the full range of precipitating electron pitch angles is necessary to show the impact electrons have on the atmosphere and provides an EEP data set for use in future model simulations.
Key Points
Effects of energetic electron precipitation in southern hemisphere 2003 simulated with Whole Atmosphere Community Climate Model
Simulations of middle atmosphere chemistry improve significantly by including >30‐keV precipitating electrons
Including the full range of pitch angles is necessary to capture precipitating electron impacts at subpolar latitudes
Scedosporium spp. is the most common mold infection in pneumonia resulting from near‐drowning. Three fatal scedosporiosis cases developed after solid organ transplantation, probably transmitted from ...the nearly‐drowned donor. One heart transplant recipient and two kidney transplant recipients developed fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly‐drowned victim of a suicide attempt. Genotypically, indistinguishable strains of Scedosporium auratiacum were recovered from the three recipients. Two liver transplant recipients from the same donor received prophylactic voriconazole without any subsequent signs of infection. To determine the safety of donation from nearly‐drowned donors, a national traceback investigation was also performed of the causes of deaths in all transplant recipients who received organs from drowned donors between 2001 and 2013. Over 13 years, 2600 deceased donor transplants were performed in Korea. Among these 2600 deceased donor transplants, 27 (1%) victims of drowning donated their organs. From these 27 donors, 84 patients received organ transplants and 18 died, including the above three. We found no microbiologic evidence of invasive mold transmission from the nearly‐drowned donors to the other 15 recipients. Although disseminated infection in the donor could not be demonstrated by culture, undiagnosed disseminated donor infection and transmission of Scedosporium spp. should be considered in near‐drowning events.
The authors describe their experience of one heart recipient and two kidney recipients with fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly drowned victim of a suicide attempt.
KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK ...inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antarctic and Southern Ocean science is vital to understanding natural variability, the processes that govern global change and the role of humans in the Earth and climate system. The potential for ...new knowledge to be gained from future Antarctic science is substantial. Therefore, the international Antarctic community came together to ‘scan the horizon’ to identify the highest priority scientific questions that researchers should aspire to answer in the next two decades and beyond. Wide consultation was a fundamental principle for the development of a collective, international view of the most important future directions in Antarctic science. From the many possibilities, the horizon scan identified 80 key scientific questions through structured debate, discussion, revision and voting. Questions were clustered into seven topics: i) Antarctic atmosphere and global connections, ii) Southern Ocean and sea ice in a warming world, iii) ice sheet and sea level, iv) the dynamic Earth, v) life on the precipice, vi) near-Earth space and beyond, and vii) human presence in Antarctica. Answering the questions identified by the horizon scan will require innovative experimental designs, novel applications of technology, invention of next-generation field and laboratory approaches, and expanded observing systems and networks. Unbiased, non-contaminating procedures will be required to retrieve the requisite air, biota, sediment, rock, ice and water samples. Sustained year-round access to Antarctica and the Southern Ocean will be essential to increase winter-time measurements. Improved models are needed that represent Antarctica and the Southern Ocean in the Earth System, and provide predictions at spatial and temporal resolutions useful for decision making. A co-ordinated portfolio of cross-disciplinary science, based on new models of international collaboration, will be essential as no scientist, programme or nation can realize these aspirations alone.
Context. Gamma-ray bursts (GRBs) generate an afterglow emission that can be detected from radio to X-rays during days, or even weeks after the initial explosion. The peak of this emission crosses the ...millimeter and submillimeter range during the first hours to days, making their study in this range crucial for constraining the models. Observations have been limited until now due to the low sensitivity of the observatories in this range. This situation will be greatly improved with the start of scientific operations of the Atacama Large Millimeter/submillimeter Array (ALMA). Aims. In this work we do a statistical analysis of the complete sample of mm/submm observations of GRB afterglows obtained before the beginning of scientific operations at ALMA. Methods. We present observations of 11 GRB afterglows obtained from the Atacama Pathfinder Experiment (APEX) and the SubMillimeter Array (SMA), as well as the first detection of a GRB with ALMA, still in the commissioning phase, and put them into context with a catalogue of all the observations that have been published until now in the spectral range that is covered by ALMA. Results. The catalogue of mm/submm observations collected here is the largest to date and is composed of 102 GRBs, of which 88 have afterglow observations, whereas the rest are host galaxy searches. With our programmes, we contributed with data of 11 GRBs and the discovery of 2 submm counterparts. In total, the full sample, including data from the literature, has 22 afterglow detections with redshifts ranging from 0.168 to 8.2. GRBs have been detected in mm/submm wavelengths with peak luminosities spanning 2.5 orders of magnitude, the most luminous reaching 1033erg s-1Hz-1. We observe a correlation between the X-ray brightness at 0.5 days and the mm/submm peak brightness. Finally we give a rough estimate of the distribution of peak flux densities of GRB afterglows, based on the current mm/submm sample. Conclusions. Observations in the mm/submm bands have been shown to be crucial for our understanding of the physics of GRBs, but have until now been limited by the sensitivity of the observatories. With the start of the operations at ALMA, the sensitivity has improved by more than an order of magnitude, opening a new era in the study of GRB afterglows and their host galaxies. Our estimates predict that, once completed, ALMA will detect up to ~98% of the afterglows if observed during the passage of the peak synchrotron emission.
The West Antarctic Peninsula (WAP) exhibits strong spatial and temporal oceanographic variability, resulting in highly heterogeneous biological productivity. Calcifying organisms that live in the ...waters off the WAP respond to temporal and spatial variations in ocean temperature and chemistry. These marine calcifiers are potentially threatened by regional climate change with waters already naturally close to carbonate undersaturation. Future projections of carbonate production in the Southern Ocean are challenging due to the lack of historical data collection and complex, decadal climate variability. Here we present a 6-year-long record of the shell fluxes, morphology and stable isotope variability of the polar planktic foraminifera Neogloboquadrina pachyderma (sensu stricto) from near Palmer Station, Antarctica. This species is fundamental to Southern Ocean planktic carbonate production as it is one of the very few planktic foraminifer species adapted to the marine polar environments. We use these new data to obtain insights into its ecology and to derive a robust assessment of the response of this polar species to environmental change. Morphology and stable isotope composition reveal the presence of different growth stages within this tightly defined species. Inter- and intra-annual variability of foraminiferal flux and size is evident and driven by a combination of environmental forcing parameters, most importantly food availability, temperature and sea ice duration and extent. Foraminiferal growth occurs throughout the austral year and is influenced by environmental change, a large portion of which is driven by the Southern Annular Mode and El Niño–Southern Oscillation. A distinct seasonal production is observed, with the highest shell fluxes during the warmest and most productive months of the year. The sensitivity of calcifying foraminifera to environmental variability in this region, from weeks to decades, has implications both for their response to future climatic change and for their use as palaeoclimate indicators. A longer ice-free season could increase carbonate production in this region at least while carbonate saturation is still high enough to allow for thick tests to grow.
Background Slow‐transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have ...been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples.
Methods Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images.
Key Results In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty‐three percent of STC children had low SP nerve fiber density.
Conclusions & Inferences There are age‐related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.
Alien species are the principal threat to the conservation of the Galápagos Islands, but little is known about the status of nonindigenous Galápagos insects and their effects on the biota. Currently, ...463 alien insect species have probably been introduced to the Galápagos, an increase of 186 unintentional species introductions since an inventory in 1998. Alien insects now constitute 23% of the total insect fauna. Six species are known to be invasive and a threat to the biota: two species of fire ant and two wasps, a scale insect, and an ectoparasitic dipteran. The ecological impacts of the remaining species are unknown, making the prioritization of action for conservation management difficult. Thus, a newly developed and simple scoring system is presented to predict their potential invasiveness based on trophic functional role, distribution in Galápagos, and history of invasiveness elsewhere. An additional 52 species are predicted to be highly invasive. The endemic flora is most at risk because the largest proportion (42%) of the introduced species is herbivores. Plant populations are threatened principally by vectors of plant disease and by phloem and leaf feeders. Introduced predators and parasitoids (17%) may either be affecting, or have the potential to affect, the status of terrestrial invertebrate populations. At least 10% of the species are considered to be negligible threats to Galápagos ecosystems.
Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung ...cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression. By exogenous SCUBE3 treatment or knockdown of SCUBE3 expression, we found that SCUBE3 could promote lung cancer cell mobility and invasiveness. Knockdown of SCUBE3 expression also suppressed tumorigenesis and cancer metastasis in vivo. The secreted SCUBE3 proteins were cleaved by gelatinases (matrix metalloprotease-2 (MMP-2) and MMP-9) in media to release two major fragments: the N-terminal epidermal growth factor-like repeats and the C-terminal complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. Both the purified SCUBE3 protein and the C-terminal CUB domain fragment, bound to transforming growth factor-β (TGF-β) type II receptor through the C-terminal CUB domain, activated TGF-β signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation, the increase of Smad2/3 transcriptional activity and the upregulation of the expression of target genes involved in EMT and cancer progression (such as TGF-β1, MMP-2, MMP-9, plasminogen activator inhibitor type-1, vascular endothelial growth factor, Snail and Slug), thus promoting cancer cell mobility and invasion. In conclusion, in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-β type II receptor, which could regulate TGF-β receptor signaling and modulate EMT and cancer progression.
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