Abstract
We report the discovery of two ultra-faint satellites in the vicinity of the Large Magellanic Cloud (LMC) in data from the Magellanic Satellites Survey (MagLiteS ). Situated 18 deg (∼20 kpc) ...from the LMC and separated from each other by only 18 arcmin, Carina II and III form an intriguing pair. By simultaneously modelling the spatial and the colour–magnitude stellar distributions, we find that both Carina II and Carina III are likely dwarf galaxies, although this is less clear for Carina III. There are in fact several obvious differences between the two satellites. While both are well described by an old and metal poor population, Carina II is located at ∼36 kpc from the Sun, with MV ∼ −4.5 and rh ∼ 90 pc, and it is further confirmed by the discovery of 3 RR Lyrae at the right distance. In contrast, Carina III is much more elongated, measured to be fainter (MV ∼ −2.4), significantly more compact (rh ∼ 30 pc), and closer to the Sun, at ∼28 kpc, placing it only 8 kpc away from Car II. Together with several other systems detected by the Dark Energy Camera, Carina II and III form a strongly anisotropic cloud of satellites in the vicinity of the Magellanic Clouds.
Global ship-based programs, with highly accurate, full water column physical and biogeochemical observations repeated decadally since the 1970s, provide a crucial resource for documenting ocean ...change. The ocean, a central component of Earth's climate system, is taking up most of Earth's excess anthropogenic heat, with about 19% of this excess in the abyssal ocean beneath 2,000 m, dominated by Southern Ocean warming. The ocean also has taken up about 27% of anthropogenic carbon, resulting in acidification of the upper ocean. Increased stratification has resulted in a decline in oxygen and increase in nutrients in the Northern Hemisphere thermocline and an expansion of tropical oxygen minimum zones. Southern Hemisphere thermocline oxygen increased in the 2000s owing to stronger wind forcing
and ventilation. The most recent decade of global hydrography has mapped dissolved organic carbon, a large, bioactive reservoir, for the first time and quantified its contribution to export production (∼20%) and deep-ocean oxygen utilization. Ship-based measurements also show that vertical diffusivity increases from a minimum in the thermocline to a maximum within the bottom 1,500 m, shifting our physical paradigm of the ocean's overturning circulation.
Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of ...Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
During the last 30 years, there has been a continued increase in human cases of tick-borne encephalitis (TBE) in Europe, a disease caused by tick-borne encephalitis virus (TBEV). TBEV is endemic in ...an area ranging from northern China and Japan, through far-eastern Russia to Europe, and is maintained in cycles involving Ixodid ticks (Ixodes ricinus and Ixodes persulcatus) and wild vertebrate hosts. The virus causes a potentially fatal neurological infection, with thousands of cases reported annually throughout Europe. TBE has a significant mortality rate depending upon the strain of virus or may cause long-term neurological/neuropsychiatric sequelae in people affected. In this review, we comprehensively reviewed TBEV, its epidemiology and pathogenesis, the clinical manifestations of TBE, along with vaccination and prevention. We also discuss the factors which may have influenced an apparent increase in the number of reported human cases each year, despite the availability of effective vaccines.
A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude ...lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. There are a number of reasons for this, but key among ...them is the considerable heterogeneity of this disease and the paucity of molecular markers that can be used to predict clinical outcomes and responsiveness to different therapies. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of DNMT3A, IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
When combined with infrared observations with the Spitzer telescope (3 to 160 μm), the Herschel
Space Observatory now fully samples the thermal dust emission up to 500 μm and enables us to better ...estimate the total infrared-submm energy budget (L
TIR) of nearby galaxies. We present new empirical calibrations to estimate resolved and integrated total infrared luminosities from Spitzer and Herschel bands used as monochromatic or combined tracers. We base our calibrations on resolved elements of nearby galaxies (3 to 30 Mpc) observed with Herschel. We perform a resolved spectral energy distribution (SED) modelling of these objects using the Draine & Li dust models and investigate the influence of the addition of Spectral and Photometric Imaging Receiver (SPIRE) measurements in the estimation of L
TIR. We find that using data up to 250 μm leads to local L
TIR values consistent with those obtained with a complete coverage (up to 500 μm) within ±10 per cent for most of our resolved elements. We then study the distribution of energy in the resolved SEDs of our galaxies. The bulk of energy (30-50 per cent) is contained in the 70-160 μm band. The 24-70 μm fraction decreases with increasing metallicity. The 160-1100 μmsubmillimetre band can account for up to 25 per cent of the L
TIR in metal-rich galaxies. We investigate the correlation between the total infrared (TIR) surface brightnesses/luminosities and monochromatic Spitzer and Herschel surface brightnesses/luminosities. The three Photodetector Array Camera and Spectrometer (PACS) bands can be used as reliable monochromatic estimators of the L
TIR, the 100 μm band being the most reliable monochromatic tracer. There is also a strong correlation between the SPIRE 250 μm and L
TIR, although with more scatter than for the PACS relations. We also study the ability of our monochromatic relations to reproduce integrated L
TIR of nearby galaxies as well as L
TIR of z ∼ 1-3 sources. Finally, we provide calibration coefficients that can be used to derive TIR surface brightnesses/luminosities from a combination of Spitzer and Herschel surface brightnesses/fluxes and analyse the associated uncertainties.
We demonstrate the tunable enhancement of the zero phonon line of a single nitrogen-vacancy colour centre in diamond at cryogenic temperature. An open cavity fabricated using focused ion beam milling ...provides mode volumes as small as 1.24 m3 (4.7 ) and quality factor In situ tuning of the cavity resonance is achieved with piezoelectric actuators. At optimal coupling to a TEM00 cavity mode, the signal from individual zero phonon line transitions is enhanced by a factor of 6.25 and the overall emission rate of the NV− centre is increased by 40% compared with that measured from the same centre in the absence of cavity field confinement. This result represents a step forward in the realisation of efficient spin-photon interfaces and scalable quantum computing using optically addressable solid state spin qubits.
Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss‐of‐function alleles impair formation of active metabolites, resulting in reduced ...platelet inhibition. In addition, CYP2C19 loss‐of‐function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel‐treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
Clinical Pharmacology & Therapeutics (2013); 94 3, 317–323. doi:10.1038/clpt.2013.105
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
More than 74 biogeochemical profiling floats that measure water column pH, oxygen, nitrate, fluorescence, and backscattering at 10 day intervals have been deployed throughout the Southern Ocean. ...Calculating the surface ocean partial pressure of carbon dioxide (pCO2sw) from float pH has uncertainty contributions from the pH sensor, the alkalinity estimate, and carbonate system equilibrium constants, resulting in a relative standard uncertainty in pCO2sw of 2.7% (or 11 µatm at pCO2sw of 400 µatm). The calculated pCO2sw from several floats spanning a range of oceanographic regimes are compared to existing climatologies. In some locations, such as the subantarctic zone, the float data closely match the climatologies, but in the polar Antarctic zone significantly higher pCO2sw are calculated in the wintertime implying a greater air‐sea CO2 efflux estimate. Our results based on four representative floats suggest that despite their uncertainty relative to direct measurements, the float data can be used to improve estimates for air‐sea carbon flux, as well as to increase knowledge of spatial, seasonal, and interannual variability in this flux.
Key Points
Surface ocean partial pressure of carbon dioxide (pCO2sw) is calculated from pH on biogeochemical profiling floats
The relative standard uncertainty in float pCO2sw estimates is 2.7% (or 11 µatm at pCO2sw of 400 µatm)
For the first time extensive wintertime pCO2sw values are obtained in the Southern Ocean showing higher values than previous estimates
Plain Language Summary
The Southern Ocean is a key player in the global flow of carbon, yet it is hard to reach, and there are relatively few measurements there, especially in winter. Measuring the amount of carbon dioxide gas in seawater is key to advancing our understanding of the Southern Ocean. More than 74 robotic floats that use sensors to measure seawater properties have been deployed throughout the Southern Ocean, and each has a lifetime of around 5 years. It is currently not possible to directly measure carbon dioxide gas from these floats; however, it is possible to estimate carbon dioxide from things that the float can measure, like pH, a measure of ocean acidity. Here surface ocean carbon dioxide is estimated from several floats and compared to two ship‐based estimates. In some locations, the floats closely match the existing estimates, but in other locations the floats see significantly higher surface ocean carbon dioxide in the wintertime, reinforcing the idea that the Southern Ocean's role in the global carbon cycle needs a closer look. Our results show that despite not measuring carbon dioxide directly, these floats will help scientists learn a lot about the Southern Ocean's part in the global flow of carbon.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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