Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends ...testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
A large and complex suite of 295 legacy and new halogenated persistent organic pollutants (POPs) were investigated in fat or liver tissue samples of polar bears collected in 2013–2014 from Southern ...(SHB) and Western (WHB) subpopulations of the Canadian Arctic contaminants hotspot of Hudson Bay. A total of 210 POPs were detected and/or quantifiable with some frequency in all fat or liver samples. POP profile and concentration differences were investigated both within (e.g. age and sex) and between the two subpopulations. Two time-point comparisons were made relative to POPs reported for Hudson Bay polar bears harvested in 2007–2008. ΣPolychlorinated biphenyl (PCB) concentrations at both time points were the most concentrated of the POP groups, and were spatially uniform with no detectable influence of sex or age, as were concentrations of the dominant congener CB153. ΣChlordanes (ΣCHLs, 74–79% oxychlordane) and the Σperfluoroalkyl substances (ΣPFASs, ≈60% perfluorooctane sulfonate (PFOS)) had the second greatest POP group concentrations in SHB and WHB respectively, with ΣPFASs and ΣCHLs being significantly influenced by age and/or sex. ΣCHLs were spatially uniform but ΣPFASs were greater in the SHB bears, as were e.g. some flame retardants, due to e.g. local contamination and/or changes in bear behavior and diet. Endosulfans and hexabromocyclododecane were detectable in samples from 2007–2008 but not from 2013–2014, which is consistent with their global POP regulations. ΣPolychlorinated naphthalenes (ΣPCNs) were consistently detected at relatively high concentrations compared to other arctic wildlife, however these concentrations were low relative to legacy POPs. ΣShort-chain chlorinated paraffins (ΣSCCPs) were major contributors to the overall POPs burden with concentrations comparable to other legacy POPs, though there was no significant difference between or within subpopulations for PCNs or SCCPs. Except for octachlorostyrene, POPs concentrations were generally lower in female and male bears from SHB in 2013–2014 relative to 2007–2008, however those of WHB males were greater over the same timeframe for almost all POPs.
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•210 out of 295 legacy and new POPs were present in Hudson Bay (HB) polar bears.•ΣPCBs, ΣCHLs and PFOS were the dominant POPs in fat or liver samples.•Some POPs (e.g. ΣPFASs and ΣCHLs) were influenced by age, sex and/or subpopulation.•Some new POP concentrations were comparable (ΣSCCPs) and some lower (ΣPCNs) to legacy POPs.
The Moderate Resolution Imaging Spectroradiometer (MODIS) aboard both NASA's Terra and Aqua satellites is making near-global daily observations of the earth in a wide spectral range (0.41-15 k m). ...These measurements are used to derive spectral aerosol optical thickness and aerosol size parameters over both land and ocean. The aerosol products available over land include aerosol optical thickness at three visible wavelengths, a measure of the fraction of aerosol optical thickness attributed to the fine mode, and several derived parameters including reflected spectral solar flux at the top of the atmosphere. Over the ocean, the aerosol optical thickness is provided in seven wavelengths from 0.47 to 2.13 k m. In addition, quantitative aerosol size information includes effective radius of the aerosol and quantitative fraction of optical thickness attributed to the fine mode. Spectral irradiance contributed by the aerosol, mass concentration, and number of cloud condensation nuclei round out the list of available aerosol products over the ocean. The spectral optical thickness and effective radius of the aerosol over the ocean are validated by comparison with two years of Aerosol Robotic Network (AERONET) data gleaned from 132 AERONET stations. Eight thousand MODIS aerosol retrievals collocated with AERONET measurements confirm that one standard deviation of MODIS optical thickness retrievals fall within the predicted uncertainty of Dt = c0.03 c0.05t over ocean and Dt = c0.05 c 0.15t over land. Two hundred and seventy-one MODIS aerosol retrievals collocated with AERONET inversions at island and coastal sites suggest that one standard deviation of MODIS effective radius retrievals falls within Dr eff = c0.11 k m. The accuracy of the MODIS retrievals suggests that the product can be used to help narrow the uncertainties associated with aerosol radiative forcing of global climate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Biogeochemical signatures preserved in ancient sedimentary rocks provide clues to the nature and timing of the oxygenation of the Earth's atmosphere. Geochemical data suggest that oxygenation ...proceeded in two broad steps near the beginning and end of the Proterozoic eon (2,500 to 542 million years ago). The oxidation state of the Proterozoic ocean between these two steps and the timing of deep-ocean oxygenation have important implications for the evolutionary course of life on Earth but remain poorly known. Here we present a new perspective on ocean oxygenation based on the authigenic accumulation of the redox-sensitive transition element molybdenum in sulphidic black shales. Accumulation of authigenic molybdenum from sea water is already seen in shales by 2,650 Myr ago; however, the small magnitudes of these enrichments reflect weak or transient sources of dissolved molybdenum before about 2,200 Myr ago, consistent with minimal oxidative weathering of the continents. Enrichments indicative of persistent and vigorous oxidative weathering appear in shales deposited at roughly 2,150 Myr ago, more than 200 million years after the initial rise in atmospheric oxygen. Subsequent expansion of sulphidic conditions after about 1,800 Myr ago (refs 8, 9) maintained a mid-Proterozoic molybdenum reservoir below 20 per cent of the modern inventory, which in turn may have acted as a nutrient feedback limiting the spatiotemporal distribution of euxinic (sulphidic) bottom waters and perhaps the evolutionary and ecological expansion of eukaryotic organisms. By 551 Myr ago, molybdenum contents reflect a greatly expanded oceanic reservoir due to oxygenation of the deep ocean and corresponding decrease in sulphidic conditions in the sediments and water column.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this trial, patients with previously treated and relapsed chronic lymphoid leukemia who received ibrutinib had significantly improved progression-free survival, overall survival, and response ...rate, as compared with those who received ofatumumab.
Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features.
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Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy.
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,
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Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies.
Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab,
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ofatumumab,
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or investigational agents.
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–
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Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had . . .
We use Mars Atmosphere and Volatile EvolutioN observations of the upstream solar wind, and Mars Express observations of ionospheric electron densities and magnetic fields, to study how the topside ...ionosphere (>320 km) of Mars is affected by variations in solar wind dynamic pressure. We find that high solar wind dynamic pressures result in the topside ionosphere being depleted of plasma at all solar zenith angles, coincident with increased induced magnetic field strengths. The depletion of topside plasma in response to high solar wind dynamic pressures is observed in both weak and strong crustal magnetic field regions. Taken together, our results suggest that high solar wind dynamic pressures lead to ionospheric compression, increased ion escape, and reduced day‐to‐night plasma transport in the high‐altitude nightside ionosphere.
Plain Language Summary
Mars lacks a global dipole magnetic field to hold off the solar wind. As a consequence, the solar wind can significantly affect the structure of the topside ionosphere. Previous studies detailing these effects, however, have primarily focused on impulsive space weather events. In this work, we use observations from two spacecraft (MAVEN and Mars Express) to statistically study how the solar wind dynamic pressure affects the topside ionosphere. We find that, during times of high solar wind dynamic pressure, the ionosphere is globally depleted of plasma, which suggests that the ionosphere is compressed and plasma escape is enhanced.
Key Points
The topside ionosphere is globally depleted of plasma during times of high solar wind dynamic pressure
The topside ionosphere responds to changes in solar wind dynamic pressure in regions of both weak and strong crustal magnetic fields
Day‐to‐night plasma transport in the high‐altitude nightside ionosphere is reduced during times of high solar wind dynamic pressure
Measurements from the Terra satellite launched in December of 1999 provide a global record of the recent interannual variability of tropospheric air quality: carbon monoxide (CO) from the Measurement ...of Pollution in the Troposphere (MOPITT) instrument and aerosol optical depth (AOD) from the Moderate‐Resolution Imaging Spectroradiometer (MODIS). This paper compares and contrasts these data sets with a view to understanding the general features of the overall pollutant loading of the Northern Hemisphere (NH). We present a detailed examination of the seasonal and recent interannual variability of the fine mode AOD and CO column, first considering the variation of the global zonal average for both quantities, and then concentrating on several geographical regions with the aim of isolating different emissions. In a zonal sense, the principal NH sources are related to anthropogenic urban and industrial activity. We show that both the CO and the AOD zonal seasonal variations reflect the atmospheric oxidant concentration, which determines the primary sink of CO and the production of sulfate aerosol. As a consequence, the seasonal cycles are several months out of phase, with perturbations resulting from sporadic wildfire or biomass‐burning emissions. In these cases, carbonaceous particles dominate the AOD, and this results in the best correlation with the CO column. Of the 4 years of data available from the Terra satellite, the winter and spring of 2002–2003 showed anomalously high NH pollution compared to the previous years. This was a result of fires in western Russia in the late summer and fall of 2002 and intense fires in the southeast of Russia in the spring and summer of 2003. We examine these events using fire counts from MODIS to indicate the burning regions and investigate how the timing of the fires in relation to atmospheric oxidant concentrations affects the resultant seasonal pollutant loadings. Finally, we trace the emissions from these fires to indicate how intense local pollution sources can impact continental‐ and global‐scale air quality.
Moderate Resolution Imaging Spectroradiometer (MODIS) measurements (7 channels: 0.47–2.1 μm, 250–500 m resolutions) provide us with new insights into the characteristics of global aerosols. MODIS ...retrieves not only aerosol loading but also the fraction of fine mode particle. In this paper we demonstrate MODIS capability for use in monitoring global, regional, and local air pollution. Three case studies in northern Italy, Los Angeles, and Beijing showed the conclusive results of applying MODIS‐derived aerosol optical depths (τa) to regional and local air pollution in terms of accuracy (Δτa = ±0.05 ± 0.2τa) and spatial sensitivity of the retrievals. Under stagnant condition, accumulated aerosol abundance can reach τa > 1 (at 0.55 μm) before being removed by wind or precipitation. The correlation found between Aerosol Robotic Network (AERONET) daily averaged τa and 24‐hour PM10 (particulate matter with diameter <10 μm) concentration (μg/m3) in northern Italy is encouraging with correlation coefficient ∼0.82. The derivation of PM concentration from satellite measurements may be possible once we know the detailed aerosol vertical distribution. To compare aerosol loading in different regions of the globe, we choose the two most populated regions (eastern China and India) and the two most industrialized regions (the eastern United States/Canada and western Europe). The time series of MODIS monthly mean τa from July 2000 to May 2001 depicts a strong seasonal variation with maxima in the spring/summer and minima in the winter. The clear separation between (1) the eastern United States/Canada and western Europe and (2) eastern China and India shows that the τa values in (2) are 50% to 2–3 times higher compared to those in (1). The enhancements of aerosol loading were due to smoke as originated from Montana/Idaho forest fires transported to the eastern United States in late August 2000 and dust outbreaks from Taklimakan and Gobi Deserts to eastern China as well as smoke from Southeast Asia to southern China in February–April 2001.
A measurement of electron antineutrino oscillation by the Daya Bay Reactor Neutrino Experiment is described in detail. Six 2.9-GWth nuclear power reactors of the Daya Bay and Ling Ao nuclear power ...facilities served as intense sources of ν¯e’s. Comparison of the ν¯e rate and energy spectrum measured by antineutrino detectors far from the nuclear reactors (∼1500–1950 m) relative to detectors near the reactors (∼350–600 m) allowed a precise measurement of ν¯e disappearance. More than 2.5 million ν¯e inverse beta-decay interactions were observed, based on the combination of 217 days of operation of six antineutrino detectors (December, 2011–July, 2012) with a subsequent 1013 days using the complete configuration of eight detectors (October, 2012–July, 2015). The ν¯e rate observed at the far detectors relative to the near detectors showed a significant deficit, R=0.949±0.002(stat)±0.002(syst). The energy dependence of ν¯e disappearance showed the distinct variation predicted by neutrino oscillation. Analysis using an approximation for the three-flavor oscillation probability yielded the flavor-mixing angle sin22θ13=0.0841±0.0027(stat)±0.0019(syst) and the effective neutrino mass-squared difference of |Δmee2|=(2.50±0.06(stat)±0.06(syst))×10−3 eV2. Analysis using the exact three-flavor probability found Δm322=(2.45±0.06(stat)±0.06(syst))×10−3 eV2 assuming the normal neutrino mass hierarchy and Δm322=(−2.56±0.06(stat)±0.06(syst))×10−3 eV2 for the inverted hierarchy.
Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies ...in mice. Further, studies with PAD4 - deficient mice have shown that PAD4 deficiency does not lead to increased infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is associated with a number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88 Å resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.
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