2,255 research outputs found
Core excitations across the neutron shell gap in ²⁰⁷Tl
The single closed-neutron-shell, one proton-hole nucleus 207Tl was populated in deep-inelastic collisions of a 208Pb beam with a 208Pb target. The yrast and near-yrast level scheme has been established up to high excitation energy, comprising an octupol
Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling
Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio
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The relationship between parent and child dysfunctional beliefs about sleep and child sleep
Cognitive theories emphasise the role of dysfunctional beliefs about sleep in the development and maintenance of sleep-related problems (SRPs). The present research examines how parents' dysfunctional beliefs about children's sleep and child dysfunctional beliefs about sleep are related to each other and to children's subjective and objective sleep. Participants were 45 children aged 11 -12 years and their parents. Self-report measures of dysfunctional beliefs about sleep and child sleep were completed by children, mothers and fathers. Objective measures of child sleep were taken using actigraphy. The results showed that child dysfunctional beliefs about sleep were correlated with father (r=.43, p<.05) and mother (r=.43, p<.05) reported child SRPs, and with Sleep Onset Latency (r=.34, p<.05). Maternal dysfunctional beliefs about child sleep were related to child SRPs as reported by mothers (r=.44, p<.05), and to child dysfunctional beliefs about sleep (r=.37, p<.05). Some initial evidence was found for a mediation pathway in which child dyfunctional beliefs mediate the relationship between parent dysfunctional beliefs and child sleep. The results support the cognitive model of SRPs and contribute to the literature by providing the first evidence of familial aggregation of dysfunctional beliefs about sleep
The spectral variability of FSRQs
The optical variability of 29 flat spectrum radio quasars in SDSS Stripe 82
region are investigated by using DR7 released multi-epoch data. All FSRQs show
variations with overall amplitude ranging from 0.24 mag to 3.46 mag in
different sources. About half of FSRQs show a bluer-when-brighter trend, which
is commonly observed for blazars. However, only one source shows a
redder-when-brighter trend, which implies it is rare in FSRQs. In this source,
the thermal emission may likely be responsible for the spectral behavior.Comment: 4 pages, 1 figure, to be published in Journal of Astrophysics and
Astronomy, as a proceeding paper of the conference "Multiwavelength
Variability of Blazars", Guangzhou, China, September 22-24, 201
Pulmonary ORMDL3 is critical for induction of Alternaria -induced allergic airways disease
Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma.
Objective
We sought to investigate in vivo the functional role of ORMDL3 in disease inception.
Methods
An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice.
Results
Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease.
Conclusions
This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses
Endothelin-1 directs airway remodeling and hyper-reactivity in a murine asthma model
BACKGROUND: The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators. METHODS: Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-β and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization. RESULTS: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1β levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes. CONCLUSIONS: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design
Thick primary melanoma has a heterogeneous tumor biology: an institutional series
<p>Abstract</p> <p>Background</p> <p>Thick melanomas (TM) ≥4 mm have a high risk for nodal and distant metastases. Optimal surgical management, prognostic significance of sentinel node biopsy (SLNB), and benefits of interferon (IFN) for these patients are unclear. As a continuum of increasing tumor thickness is placed into a single TM group, differences in biologic and clinical behavior may be lost. The purpose of this study was to better characterize the diverse biology in TM, including the value of increasing thickness and nodal status information, potentially identifying high risk TM subgroups that may warrant more aggressive treatment/follow up.</p> <p>Methods</p> <p>155 consecutive TM patients treated at a single institution between 1971 and 2007 were retrospectively reviewed. Patient, disease and treatment features were analyzed with respect to disease-free (DFS) and overall survival (OS).</p> <p>Results</p> <p>Median patient age was 66 years and 68% of patients were men. The trunk was the most common TM location (35%), followed by the head and neck (29%) and lower extremities (20%). Median thickness was 6 mm and 61% were ulcerated. 6% patients had stage IV disease, 12% had clinical nodal metastases. Clinically negative lymph node basins were treated by observation (22 patients - 15.4%), elective lymph node dissection (ELND) (24 patients - 17.6%) or SLNB (91 patients - 67%). 75% of ELND's and 53% of SLNB's were positive. Completion node dissection was performed in 38 SLNB+ patients and 22% had additional positive nodes. 17% of the study patients received IFN. At median follow up of 26 months, 5 year DFS and OS were 42% and 43.6%. For SLNB positive vs negative, median DFS were 22 vs 111 months (p = 0.006) and median OS were 41 vs 111 months (p = 0.006). When stratified by tumor thickness ≤ vs > 6 mm, 5 year DFS was 58.3% vs 20% (p < 0.0001) and OS was 62% vs 20% (P < 0.0001). IFN had no impact on DFS or OS (p = 0.98 and 0.8 respectively).</p> <p>Conclusion</p> <p>Within the high risk group of patients with TM, cases with tumor thickness > 6 mm or a positive SLNB had a significantly worse DFS and OS (p < .0001, <.0001 and .006, .006).</p
[89Zr]Oxinate4 for long-term in vivo cell tracking by positron emission tomography
Purpose 111In (typically as [111In]oxinate3) is a gold standard
radiolabel for cell tracking in humans by scintigraphy. A long
half-life positron-emitting radiolabel to serve the same purpose
using positron emission tomography (PET) has long
been sought. We aimed to develop an 89Zr PET tracer for cell
labelling and compare it with [111In]oxinate3 single photon
emission computed tomography (SPECT).
Methods [89Zr]Oxinate4 was synthesised and its uptake and
efflux were measured in vitro in three cell lines and in human
leukocytes. The in vivo biodistribution of eGFP-5T33 murine
myeloma cells labelled using [89Zr]oxinate4 or [111In]oxinate3
was monitored for up to 14 days. 89Zr retention by living
radiolabelled eGFP-positive cells in vivo was monitored by
FACS sorting of liver, spleen and bone marrow cells followed
by gamma counting.
Results Zr labelling was effective in all cell types with yields
comparable with 111In labelling. Retention of 89Zr in cells
in vitro after 24 h was significantly better (range 71 to
>90 %) than 111In (43–52 %). eGFP-5T33 cells in vivo
showed the same early biodistribution whether labelled with
111In or 89Zr (initial pulmonary accumulation followed by
migration to liver, spleen and bone marrow), but later translocation
of radioactivity to kidneys was much greater for 111In.
In liver, spleen and bone marrow at least 92 % of 89Zr
remained associated with eGFP-positive cells after 7 days
in vivo.
Conclusion [89Zr]Oxinate4 offers a potential solution to the
emerging need for a long half-life PET tracer for cell tracking
in vivo and deserves further evaluation of its effects on survival
and behaviour of different cell types
On the kinematics of the Local cosmic void
We collected the existing data on the distances and radial velocities of
galaxies around the Local Void in the Aquila/Hercules to examine the peculiar
velocity field induced by its underdensity. A sample of 1056 galaxies with
distances measured from the Tip of the Red Giant Branch, the Cepheid
luminosity, the SNIa luminosity, the surface brightness fluctuation method, and
the Tully-Fisher relation has been used for this purpose. The amplitude of
outflow is found to be ~300 km/s. The galaxies located within the void produce
the mean intra-void number density about 1/5 of the mean external number
density of galaxies. The void's population has a lower luminosity and a later
morphological type with the medians: M_B = -15.7^m and T = 8 (Sdm),
respectively.Comment: Version 1. 14 pages, 8 figures, 2 tables. Accepted to Astrophysics,
Volume 54, Issue
Lessons from the decoupling limit of Horava gravity
We consider the so-called "healthy" extension of Horava gravity in the limit
where the Stuckelberg field decouples from the graviton. We verify the alleged
strong coupling problem in this limit, under the assumption that no large
dimensionless parameters are put in by hand. This follows from the fact that
the dispersion relation for the Stuckelberg field does not have the desired z =
3 anisotropic scaling in the UV. To get the desired scaling and avoid strong
coupling one has to introduce a low scale of Lorentz violation and retain some
coupling between the graviton and the Stuckelberg field. We also make use of
the foliation preserving symmetry to show how the Stuckelberg field couples to
some violation of energy conservation. We source the Stuckelberg field using a
point particle with a slowly varying mass and show that two such particles feel
a constant attractive force. In this particular example, we see no Vainshtein
effect, and violations of the Equivalence Principle. The latter is probably
generic to other types of source and could potentially be used to place lower
bounds on the scale of Lorentz violation.Comment: 18 pages, 1 figure. Version to appear in JHEP. Conclusions with
respect to strong coupling modified - our strong coupling analysis does not
apply to a low scale of Lorentz violation. Expanded Equivalence Principle
violation discussion, noting it presents a challenge to low scale Lorentz
violation, exactly the scenario designed to cure strong coupling. Other minor
corrections and references adde
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