144 research outputs found
The Lipid Kinase PIP5K1C Regulates Pain Signaling and Sensitization
SummaryNumerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in nociceptive dorsal root ganglia (DRG) neurons and if these kinases regulate pronociceptive receptor signaling. Here, we found that phosphatidylinositol 4-phosphate 5 kinase type 1C (PIP5K1C) is expressed at higher levels than any other PIP5K and, based on experiments with Pip5k1c+/− mice, generates at least half of all PIP2 in DRG neurons. Additionally, Pip5k1c haploinsufficiency reduces pronociceptive receptor signaling and TRPV1 sensitization in DRG neurons as well as thermal and mechanical hypersensitivity in mouse models of chronic pain. We identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen. UNC3230 lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw. Our studies reveal that PIP5K1C regulates PIP2-dependent nociceptive signaling and suggest that PIP5K1C is a therapeutic target for chronic pain
KELT-2Ab: A Hot Jupiter Transiting the Bright (V=8.77) Primary Star of a Binary System
We report the discovery of KELT-2Ab, a hot Jupiter transiting the bright
(V=8.77) primary star of the HD 42176 binary system. The host is a slightly
evolved late F-star likely in the very short-lived "blue-hook" stage of
evolution, with \teff=6148\pm48{\rm K}, and
\feh=0.034\pm0.78. The inferred stellar mass is
\msun\ and the star has a relatively large radius
of \rsun. The planet is a typical hot Jupiter with
period days and a mass of \mj\ and
radius of \rj. This is mildly inflated as compared
to models of irradiated giant planets at the 4 Gyr age of the system.
KELT-2A is the third brightest star with a transiting planet identified by
ground-based transit surveys, and the ninth brightest star overall with a
transiting planet. KELT-2Ab's mass and radius are unique among the subset of
planets with host stars, and therefore increases the diversity of bright
benchmark systems. We also measure the relative motion of KELT-2A and -2B over
a baseline of 38 years, robustly demonstrating for the first time that the
stars are bound. This allows us to infer that KELT-2B is an early K-dwarf. We
hypothesize that through the eccentric Kozai mechanism KELT-2B may have
emplaced KELT-2Ab in its current orbit. This scenario is potentially testable
with Rossiter-McLaughlin measurements, which should have an amplitude of
44 m s.Comment: 9 pages, 2 tables, 4 figures. A short video describing this paper is
available at http://www.youtube.com/watch?v=wVS8lnkXXlE. Revised to reflect
the ApJL version. Note that figure 4 is not in the ApJL versio
KELT-1b: A Strongly Irradiated, Highly Inflated, Short Period, 27 Jupiter-mass Companion Transiting a mid-F Star
We present the discovery of KELT-1b, the first transiting low-mass companion
from the wide-field Kilodegree Extremely Little Telescope-North (KELT-North)
survey. The V=10.7 primary is a mildly evolved, solar-metallicity, mid-F star.
The companion is a low-mass brown dwarf or super-massive planet with mass of
27.23+/-0.50 MJ and radius of 1.110+0.037-0.024 RJ, on a very short period
(P=1.21750007) circular orbit. KELT-1b receives a large amount of stellar
insolation, with an equilibrium temperature assuming zero albedo and perfect
redistribution of 2422 K. Upper limits on the secondary eclipse depth indicate
that either the companion must have a non-zero albedo, or it must experience
some energy redistribution. Comparison with standard evolutionary models for
brown dwarfs suggests that the radius of KELT-1b is significantly inflated.
Adaptive optics imaging reveals a candidate stellar companion to KELT-1, which
is consistent with an M dwarf if bound. The projected spin-orbit alignment
angle is consistent with zero stellar obliquity, and the vsini of the primary
is consistent with tidal synchronization. Given the extreme parameters of the
KELT-1 system, we expect it to provide an important testbed for theories of the
emplacement and evolution of short-period companions, and theories of tidal
dissipation and irradiated brown dwarf atmospheres.Comment: 30 pages, 19 figures. Submitted to Ap
KELT-7b: A hot Jupiter transiting a bright V=8.54 rapidly rotating F-star
We report the discovery of KELT-7b, a transiting hot Jupiter with a mass of
MJ, radius of RJ, and an orbital
period of days. The bright host star (HD33643;
KELT-7) is an F-star with , Teff K, [Fe/H]
, and . It has a mass of
Msun, a radius of Rsun, and
is the fifth most massive, fifth hottest, and the ninth brightest star known to
host a transiting planet. It is also the brightest star around which KELT has
discovered a transiting planet. Thus, KELT-7b is an ideal target for detailed
characterization given its relatively low surface gravity, high equilibrium
temperature, and bright host star. The rapid rotation of the star (
km/s) results in a Rossiter-McLaughlin effect with an unusually large amplitude
of several hundred m/s. We find that the orbit normal of the planet is likely
to be well-aligned with the stellar spin axis, with a projected spin-orbit
alignment of degrees. This is currently the second most
rapidly rotating star to have a reflex signal (and thus mass determination) due
to a planetary companion measured.Comment: Accepted to The Astronomical Journa
KELT-6b: A P~7.9 d Hot Saturn Transiting a Metal-Poor Star with a Long-Period Companion
We report the discovery of KELT-6b, a mildly-inflated Saturn-mass planet
transiting a metal-poor host. The initial transit signal was identified in
KELT-North survey data, and the planetary nature of the occulter was
established using a combination of follow-up photometry, high-resolution
imaging, high-resolution spectroscopy, and precise radial velocity
measurements. The fiducial model from a global analysis including constraints
from isochrones indicates that the V=10.38 host star (BD+31 2447) is a mildly
evolved, late-F star with T_eff=6102 \pm 43 K, log(g_*)=4.07_{-0.07}^{+0.04}
and [Fe/H]=-0.28 \pm 0.04, with an inferred mass M_*=1.09 \pm 0.04 M_sun and
radius R_star=1.58_{-0.09}^{+0.16} R_sun. The planetary companion has mass
M_P=0.43 \pm 0.05 M_J, radius R_P=1.19_{-0.08}^{+0.13} R_J, surface gravity
log(g_P)=2.86_{-0.08}^{+0.06}, and density rho_P=0.31_{-0.08}^{+0.07}
g~cm^{-3}. The planet is on an orbit with semimajor axis a=0.079 \pm 0.001 AU
and eccentricity e=0.22_{-0.10}^{+0.12}, which is roughly consistent with
circular, and has ephemeris of T_c(BJD_TDB)=2456347.79679 \pm 0.00036 and
P=7.845631 \pm 0.000046 d. Equally plausible fits that employ empirical
constraints on the host star parameters rather than isochrones yield a larger
planet mass and radius by ~4-7%. KELT-6b has surface gravity and incident flux
similar to HD209458b, but orbits a host that is more metal poor than HD209458
by ~0.3 dex. Thus, the KELT-6 system offers an opportunity to perform a
comparative measurement of two similar planets in similar environments around
stars of very different metallicities. The precise radial velocity data also
reveal an acceleration indicative of a longer-period third body in the system,
although the companion is not detected in Keck adaptive optics images.Comment: Published in AJ, 17 pages, 15 figures, 6 table
Cancer immunoediting by the innate immune system in the absence of adaptive immunity
Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting
Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred
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