83 research outputs found
Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation
Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5âmonthâold (young adult) and 25âmonthâold (geriatric) mice healing utilizing highâthroughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days postâfracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and crossâsectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both unâfractured and 20 DPF aged mice showed increased expression of immuneâassociated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrixâassociated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time postâfracture first and age second. Clinical Significance: Greater understanding of ageâdependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149â158, 2018.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142531/1/jor23652.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142531/2/jor23652_am.pd
Suppression of Notch Signaling in Osteoclasts Improves Bone Regeneration and Healing
Owing to the central role of osteoclasts in bone physiology and remodeling, manipulation of their maturation process provides a potential therapeutic strategy for treating bone diseases. To investigate this, we genetically inhibited the Notch signaling pathway in the myeloid lineage, which includes osteoclast precursors, using a dominant negative form of MAML (dnMAML) that inhibits the transcriptional complex required for downstream Notch signaling. Osteoclasts derived from dnMAML mice showed no significant differences in early osteoclastic gene expression compared to the wild type. Further, these demonstrated significantly lowered resorption activity using bone surfaces while retaining their osteoblast stimulating ability using ex vivo techniques. Using in vivo approaches, we detected significantly higher bone formation rates and osteoblast gene expression in dnMAML cohorts. Further, these mice exhibited increased bone/tissue mineral density compared to wild type and larger bony calluses in later stages of fracture healing. These observations suggest that therapeutic suppression of osteoclast Notch signaling could reduce, but not eliminate, osteoclastic resorption without suppression of restorative bone remodeling and, therefore, presents a balanced paradigm for increasing bone formation, regeneration, and healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2089â2103, 2019Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151846/1/jor24384.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151846/2/jor24384_am.pd
Too Little, Too Late: How the Tidal Evolution of Hot Jupiters affects Transit Surveys of Clusters
The tidal evolution of hot Jupiters may change the efficiency of transit
surveys of stellar clusters. The orbital decay that hot Jupiters suffer may
result in their destruction, leaving fewer transiting planets in older
clusters. We calculate the impact tidal evolution has for different assumed
stellar populations, including that of 47~Tuc, a globular cluster that was the
focus of an intense HST search for transits. We find that in older clusters one
expects to detect fewer transiting planets by a factor of two for surveys
sensitive to Jupiter-like planets in orbits out to 0.5~AU, and up to a factor
of 25 for surveys sensitive to Jupiter-like planets in orbits out to 0.08~AU.
Additionally, tidal evolution affects the distribution of transiting planets as
a function of semi-major axis, producing larger orbital period gaps for
transiting planets as the age of the cluster increases. Tidal evolution can
explain the lack of detected exoplanets in 47~Tuc without invoking other
mechanisms. Four open clusters residing within the {\em Kepler} fields of view
have ages that span 0.4-8~Gyr--if {\em Kepler} can observe a significant number
of planets in these clusters, it will provide key tests for our tidal evolution
hypothesis. Finally, our results suggest that observers wishing to discover
transiting planets in clusters must have sufficient accuracy to detect lower
mass planets, search larger numbers of cluster members, or have longer
observation windows to be confident that a significant number of transits will
occur for a population of stars.Comment: 23 pages including 6 figures, accepted to Ap
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-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
LSST Science Book, Version 2.0
A survey that can cover the sky in optical bands over wide fields to faint
magnitudes with a fast cadence will enable many of the exciting science
opportunities of the next decade. The Large Synoptic Survey Telescope (LSST)
will have an effective aperture of 6.7 meters and an imaging camera with field
of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over
20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with
fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a
total point-source depth of r~27.5. The LSST Science Book describes the basic
parameters of the LSST hardware, software, and observing plans. The book
discusses educational and outreach opportunities, then goes on to describe a
broad range of science that LSST will revolutionize: mapping the inner and
outer Solar System, stellar populations in the Milky Way and nearby galaxies,
the structure of the Milky Way disk and halo and other objects in the Local
Volume, transient and variable objects both at low and high redshift, and the
properties of normal and active galaxies at low and high redshift. It then
turns to far-field cosmological topics, exploring properties of supernovae to
z~1, strong and weak lensing, the large-scale distribution of galaxies and
baryon oscillations, and how these different probes may be combined to
constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at
http://www.lsst.org/lsst/sciboo
The unusual M-dwarf Warm Jupiter TOI-1899~b: Refinement of orbital and planetary parameters
TOI-1899~b is a rare exoplanet, a temperate Warm Jupiter orbiting an M-dwarf,
first discovered by \citet{Canas2020_toi1899} from a TESS single-transit event.
Using new radial velocities (RVs) from the precision RV spectrographs HPF and
NEID, along with additional TESS photometry and ground-based transit follow-up,
we are able to derive a much more precise orbital period of ~d, along with a radius of ~\unit{R_{J}}. We have also improved the constraints on planet
mass, ~\unit{M_{J}}, and eccentricity, which is consistent
with a circular orbit at 2 (). TOI-1899~b
occupies a unique region of parameter space as the coolest known ( 380~K) Jovian-sized transiting planet around an M-dwarf; we show that
it has great potential to provide clues regarding the formation and migration
mechanisms of these rare gas giants through transmission spectroscopy with JWST
as well as studies of tidal evolution.Comment: 19 pages, 7 figures, 3 tables, submitted to AJ (comments welcome
Coherence Potentials: Loss-Less, All-or-None Network Events in the Cortex
Transient associations among neurons are thought to underlie memory and behavior. However, little is known about how such associations occur or how they can be identified. Here we recorded ongoing local field potential (LFP) activity at multiple sites within the cortex of awake monkeys and organotypic cultures of cortex. We show that when the composite activity of a local neuronal group exceeds a threshold, its activity pattern, as reflected in the LFP, occurs without distortion at other cortex sites via fast synaptic transmission. These large-amplitude LFPs, which we call coherence potentials, extend up to hundreds of milliseconds and mark periods of loss-less spread of temporal and amplitude information much like action potentials at the single-cell level. However, coherence potentials have an additional degree of freedom in the diversity of their waveforms, which provides a high-dimensional parameter for encoding information and allows identification of particular associations. Such nonlinear behavior is analogous to the spread of ideas and behaviors in social networks
New technologies for examining neuronal ensembles in drug addiction and fear
Correlational data suggest that learned associations are encoded within neuronal ensembles. However, it has been difficult to prove that neuronal ensembles mediate learned behaviours because traditional pharmacological and lesion methods, and even newer cell type-specific methods, affect both activated and non-activated neurons. Additionally, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviourally activated and non-activated neurons. Here, we describe three new approachesâDaun02 inactivation, FACS sorting of activated neurons and c-fos-GFP transgenic rats â that have been used to selectively target and study activated neuronal ensembles in models of conditioned drug effects and relapse. We also describe two new tools â c-fos-tTA mice and inactivation of CREB-overexpressing neurons â that have been used to study the role of neuronal ensembles in conditioned fear
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