Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% ...of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
This report continues the practice where the IAU Working Group on Cartographic Coordinates and Rotational Elements revises recommendations regarding those topics for the planets, satellites, minor ...planets, and comets approximately every 3 years. The Working Group has now become a “functional working group” of the IAU, and its membership is open to anyone interested in participating. We describe the procedure for submitting questions about the recommendations given here or the application of these recommendations for creating a new or updated coordinate system for a given body. Regarding body orientation, the following bodies have been updated: Mercury, based on MESSENGER results; Mars, along with a refined longitude definition; Phobos; Deimos; (1) Ceres; (52) Europa; (243) Ida; (2867) Šteins; Neptune; (134340) Pluto and its satellite Charon; comets 9P/Tempel 1, 19P/Borrelly, 67P/Churyumov–Gerasimenko, and 103P/Hartley 2, noting that such information is valid only between specific epochs. The special challenges related to mapping 67P/Churyumov–Gerasimenko are also discussed. Approximate expressions for the Earth have been removed in order to avoid confusion, and the low precision series expression for the Moon’s orientation has been removed. The previously online only recommended orientation model for (4) Vesta is repeated with an explanation of how it was updated. Regarding body shape, text has been included to explain the expected uses of such information, and the relevance of the cited uncertainty information. The size of the Sun has been updated, and notation added that the size and the ellipsoidal axes for the Earth and Jupiter have been recommended by an IAU Resolution. The distinction of a reference radius for a body (here, the Moon and Titan) is made between cartographic uses, and for orthoprojection and geophysical uses. The recommended radius for Mercury has been updated based on MESSENGER results. The recommended radius for Titan is returned to its previous value. Size information has been updated for 13 other Saturnian satellites and added for Aegaeon. The sizes of Pluto and Charon have been updated. Size information has been updated for (1) Ceres and given for (16) Psyche and (52) Europa. The size of (25143) Itokawa has been corrected. In addition, the discussion of terminology for the poles (hemispheres) of small bodies has been modified and a discussion on cardinal directions added. Although they continue to be used for planets and their satellites, it is assumed that the planetographic and planetocentric coordinate system definitions do not apply to small bodies. However, planetocentric and planetodetic latitudes and longitudes may be used on such bodies, following the right-hand rule. We repeat our previous recommendations that planning and efforts be made to make controlled cartographic products; newly recommend that common formulations should be used for orientation and size; continue to recommend that a community consensus be developed for the orientation models of Jupiter and Saturn; newly recommend that historical summaries of the coordinate systems for given bodies should be developed, and point out that for planets and satellites planetographic systems have generally been historically preferred over planetocentric systems, and that in cases when planetographic coordinates have been widely used in the past, there is no obvious advantage to switching to the use of planetocentric coordinates. The Working Group also requests community input on the question submitting process, posting of updates to the Working Group website, and on whether recommendations should be made regarding exoplanet coordinate systems.
Abstract
We report comprehensive multi-wavelength observations of a peculiar Type Ia-like supernova (“SN Ia-pec”) ASASSN-15pz. ASASSN-15pz is a spectroscopic “twin” of SN 2009dc, a so-called ...“Super-Chandrasekhar-mass” SN, throughout its evolution, but it has a peak luminosity
that is
dimmer and comparable to the SN 1991T sub-class of SNe Ia at the luminous end of the normal width-luminosity relation. The synthesized
56
Ni mass of
is also substantially less than that found for several 2009dc-like SNe. Previous well-studied 2009dc-like SNe have generally suffered from large and uncertain amounts of host-galaxy extinction, which is negligible for ASASSN-15pz. Based on the color of ASASSN-15pz, we estimate a host extinction for SN 2009dc of
and confirm its high luminosity (
). The 2009dc-like SN population, which represents ∼1% of SNe Ia, exhibits a range of peak luminosities, and do not fit onto the tight width-luminosity relation. Their optical light curves also show significant diversity of late-time (≳50 days) decline rates. The nebular-phase spectra provide powerful diagnostics to identify the 2009dc-like events as a distinct class of SNe Ia. We suggest referring to these sources using the phenomenology-based “2009dc-like SN Ia-pec” instead of “Super-Chandrasekhar SN Ia,” which is based on an uncertain theoretical interpretation.
Experimental investigation of electron-ion coupling and electron heat capacity of copper in warm and dense states are presented. From time-resolved x-ray absorption spectroscopy, the temporal ...evolution of electron temperature is obtained for non-equilibrium warm dense copper heated by an intense femtosecond laser pulse. Electron heat capacity and electron-ion coupling are inferred from the initial electron temperature and its decrease over 10 ps. Data are compared with various theoretical models.
First Resolution of Microlensed Images Dong, Subo; Mérand, A.; Delplancke-Ströbele, F. ...
Astrophysical journal/The Astrophysical journal,
01/2019, Volume:
871, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
We employ Very Large Telescope Interferometer GRAVITY to resolve, for the first time, the two images generated by a gravitational microlens. The measurements of the image separation
mas, and ...hence the Einstein radius
θ
E
= 1.87 ± 0.03 mas, are precise. This demonstrates the robustness of the method, provided that the source is bright enough for GRAVITY (
K
≲ 10.5) and the image separation is of order of or larger than the fringe spacing. When
θ
E
is combined with a measurement of the “microlens parallax”
, the two will together yield the lens mass and lens–source relative parallax and proper motion. Because the source parallax and proper motion are well measured by
Gaia
, this means that the lens characteristics will be fully determined, whether or not it proves to be luminous. This method can be a powerful probe of dark, isolated objects, which are otherwise quite difficult to identify, much less characterize. Our measurement contradicts Einstein’s prediction that “the luminous circle i.e., microlensed image cannot be distinguished” from a star.
HZ-166 has previously been characterized as an α2,3-selective GABA
receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a ...series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in all models in which they were evaluated. We further evaluated KRM-II-81 in human cortical epileptic tissue where it was found to significantly-attenuate picrotoxin- and AP-4-induced increases in firing rate across an electrode array. These molecules generally had a wider margin of separation in potencies to produce anticonvulsant effects vs. motor impairment on an inverted screen test than did diazepam. Ester bioisosters of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy acting via selective positive allosteric amplification of GABA
signaling through α2/α3-containing GABA receptors. The in vivo data from the present study can serve as a guide to dosing parameters that predict engagement of central GABA
receptors.
Given its peak luminosity and early-time spectra, ASASSN-15lh was classified as the most luminous supernova ever discovered. Here, we report a UV rebrightening of ASASSN-15lh observed with Swift ...during our follow-up campaign. The rebrightening began at t ... 90 d (observer frame) after the primary peak and was followed by a ~120-d long plateau in the bolometric luminosity, before starting to fade again at t ... 210 d. ASASSN-15lh rebrightened in the Swift UV bands by ...mUVW2 ... -1.75 mag, ...mUVM2 ... -1.25 mag and ...mUVW1 ... -0.8 mag, but did not rebrighten in the optical bands. Throughout its initial decline, subsequent rebrightening and renewed decline, the spectra did not show evidence of interactions between the ejecta and circumstellar medium such as narrow emission lines. There are hints of weak Ha emission at late-times, but Margutti et al. have shown that it is narrow line emission consistent with star formation in the host nucleus. By fitting a blackbody, we find that during the rebrightening, the effective photospheric temperature increased from TBB ... 11 000 K to TBB ... 18 000 K. Over the ~ 550 d since its detection, ASASSN-15lh has radiated ~1.7 -1.9 x 10 super( 52) erg. Although its physical nature remains uncertain, the evolution of ASASSN-15lh's photospheric radius, its radiated energy and the implied event rate, are all more similar to those of H-poor superluminous supernovae than to tidal disruption events. (ProQuest: ... denotes formulae/symbols omitted.)
Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of ...both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation.
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► Deletion of Egr2 and Egr3 in lymphocytes results in a lethal autoimmune syndrome ► Deficiency in both Egr2 and Egr3 impairs antigen receptor-induced proliferation ► Egr2 and Egr3 are required for AP-1 activity by blocking Batf ► Egr2 and Egr3 induce expression of SOCS1 and SOCS3
Rac1b, an alternative splice form of Rac1, has been previously shown to be upregulated in colon and breast cancer cells, suggesting an oncogenic role for Rac1b in these cancers. Our analysis of NSCLC ...tumor and matched normal tissue samples indicates Rac1b is upregulated in a significant fraction of lung tumors in correlation with mutational status of K-ras. To directly assess the oncogenic potential of Rac1b in vivo, we employed a mouse model of lung adenocarcinoma, in which the expression of Rac1b can be conditionally activated specifically in the lung. Although expression of Rac1b alone is insufficient to drive tumor initiation, the expression of Rac1b synergizes with an oncogenic allele of K-ras resulting in increased cellular proliferation and accelerated tumor growth. Finally, we show that in contrast to our previous findings demonstrating a requirement for Rac1 in K-ras-driven cell proliferation, Rac1b is not required in this context. Given the partially overlapping spectrum of downstream effectors regulated by Rac1 and Rac1b, our findings further delineate the signaling pathways downstream of Rac1 that are required for K-ras driven tumorigenesis.
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