Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A

The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RETC634R ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention.Peer reviewe

X-ray view of IC348 in the light of an updated cluster census

We study the properties of the coronae of the low-mass stars in the young (~2-3Myr), nearby (~310pc) open cluster IC348 combining X-ray and optical/infrared data. The four existing Chandra observations of IC348 are merged, thus providing a deeper and spatially more complete X-ray view than previous X-ray studies of the cluster. We have compiled a comprehensive catalog of IC348 members taking into account recent updates to the cluster census. Our data collection comprises fundamental stellar parameters, infrared excess indicating the presence of disks, Halpha emission as a tracer of chromospheric emission or accretion and mass accretion rates. We have detected 290 X-ray sources in four merged Chandra exposures, of which 187 are associated with known cluster members. Only four of the X-ray sources are brown dwarfs (spectral type M6 and later). The detection rate is highest for diskless Class III stars and increases with stellar mass. This may be explained with higher X-ray luminosities for higher mass and later evolutionary stage that is evident in the X-ray luminosity functions. In particular, we find that for the lowest examined masses (0.1-0.25 Msun) there is a difference between the X-ray luminosity functions of accreting and non-accreting stars (classified on the basis of their Halpha emission strength) as well as those of disk-bearing and diskless stars (classified on the basis of the slope of the spectral energy distribution). These differences disappear for higher masses. This is related to our finding that the L_x/L_bol ratio is non-constant across the mass/luminosity sequence of IC348 with a decrease towards lower luminosity stars. Our analysis of an analogous stellar sample in the Orion Nebula Cluster suggests that the decline of L_x/L_ bol for young stars at the low-mass end of the stellar sequence is likely universal.Comment: Accepted for publication in Astronomy & Astrophysic

The Low-mass Stellar Population in L1641: Evidence for Environmental Dependence of the Stellar Initial Mass Function

We present results from an optical photometric and spectroscopic survey of the young stellar population in L1641, the low-density star-forming region of the Orion A cloud south of the Orion Nebula Cluster (ONC). Our goal is to determine whether L1641 has a large enough low-mass population to make the known lack of high-mass stars a statistically-significant demonstration of environmental dependence of the upper mass stellar initial mass function (IMF). Our spectroscopic sample consists of IR-excess objects selected from the Spitzer/IRAC survey and non-excess objects selected from optical photometry. We have spectral confirmation of 864 members, with another 98 probable members; of the confirmed members, 406 have infrared excesses and 458 do not. Assuming the same ratio of stars with and without IR excesses in the highly-extincted regions, L1641 may contain as many as ~1600 stars down to ~0.1 solar mass, comparable within a factor of two to the the ONC. Compared to the standard models of the IMF, L1641 is deficient in O and early B stars to a 3-4 sigma significance level, assuming that we know of all the massive stars in L1641. With a forthcoming survey of the intermediate-mass stars, we will be in a better position to make a direct comparison with the neighboring, dense ONC, which should yield a stronger test of the dependence of the high-mass end of the stellar initial mass function upon environment.Comment: 19 pages, 21 figures. Accepted by Ap

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa

Open-ocean convection: observations, theory and models

We review what is known about the convective process in the open ocean, in which the properties of large volumes of water are changed by intermittent, deep-reaching convection, triggered by winter storms. Observational, laboratory, and modeling studies reveal a fascinating and complex interplay of convective and geostrophic scales, the large-scale circulation of the ocean, and the prevailing meteorology. Two aspects make ocean convection interesting from a theoretical point of view. First, the timescales of the convective process in the ocean are sufficiently long that it may be modified by the Earth's rotation; second, the convective process is localized in space so that vertical buoyancy transfer by upright convection can give way to slantwise transfer by baroclinic instability. Moreover, the convective and geostrophic scales are not very disparate from one another. Detailed observations of the process in the Labrador, Greenland, and Mediterranean Seas are described, which were made possible by new observing technology. When interpreted in terms of underlying dynamics and theory and the context provided by laboratory and numerical experiments of rotating convection, great progress in our description and understanding of the processes at work is being made

Hitomi (ASTRO-H) X-ray Astronomy Satellite

The Hitomi (ASTRO-H) mission is the sixth Japanese x-ray astronomy satellite developed by a large international collaboration, including Japan, USA, Canada, and Europe. The mission aimed to provide the highest energy resolution ever achieved at E  >  2  keV, using a microcalorimeter instrument, and to cover a wide energy range spanning four decades in energy from soft x-rays to gamma rays. After a successful launch on February 17, 2016, the spacecraft lost its function on March 26, 2016, but the commissioning phase for about a month provided valuable information on the onboard instruments and the spacecraft system, including astrophysical results obtained from first light observations. The paper describes the Hitomi (ASTRO-H) mission, its capabilities, the initial operation, and the instruments/spacecraft performances confirmed during the commissioning operations for about a month

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A.

The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RETC634R ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention