2,010 research outputs found
Nutrition Derived Advanced Glycation End Products Are Bio-Social Determinants of Health That Inform on Cancer Disparities
Objectives
Through their ability to perpetuate a reactive stroma, the objective was to define the increased nutritional bioavailability of advanced glycation end products (AGEs) as a pro-tumorigenic consequence of interrelated health inequity risk factors that can influence ancestry specific tumor biology.
Methods
In vivo, ex vivo, and in vitro models were used to define the molecular effects of nutrition associated AGEs on the ancestry specific tumor microenvironment and tumor growth.
Results
The PI’s work provides the first in vivo evidence supporting an oncogenic role for AGEs. In mouse allograft models, both the chronic consumption of AGEs and pre-treatment with AGE bound peptide (p\u3c 0.0001) increased prostate tumor growth. In spontaneous tumor models, chronic AGE consumption caused rapid disease progression through prostate intra-epithelial neoplasia (p=0.049) to adenocarcinoma and metastatic disease. Mechanistically, AGEs recapitulated a regulatory program of ‘activated’ stroma similar to that observed in African American prostate tumors. Specifically, increased AGE bioavailability caused receptor for AGE (RAGE) dimerization in resident PCa fibroblasts leading to their activation and the downregulation of matrix regulatory proteins leading to rapid tumor progression.
Conclusions
When social and biological determinants of health are compromised it may increase nutritional exposure to AGEs and perpetuate a vicious cycle of AGE formation, bioavailability, and pathogenicity. As bio-social determinants of health, AGEs may represent informative and/or functional biomarkers that can be utilized across transdisciplinary studies to address the enduring complexities of cancer disparity
Multiphase PC/PL Relations: Comparison between Theory and observations
Cepheids are fundamental objects astrophysically in that they hold the key to
a CMB independent estimate of Hubble's constant. A number of researchers have
pointed out the possibilities of breaking degeneracies between Omega_Matter and
H0 if there is a CMB independent distance scale accurate to a few percent (Hu
2005). Current uncertainties in the distance scale are about 10% but future
observations, with, for example, the JWST, will be capable of estimating H0 to
within a few percent. A crucial step in this process is the Cepheid PL
relation. Recent evidence has emerged that the PL relation, at least in optical
bands, is nonlinear and that neglect of such a nonlinearity can lead to errors
in estimating H0 of up to 2 percent. Hence it is important to critically
examine this possible nonlinearity both observationally and theoretically.
Existing PC/PL relations rely exclusively on evaluating these relations at mean
light. However, since such relations are the average of relations at different
phases. Here we report on recent attempts to compare theory and observation in
the multiphase PC/PL planes. We construct state of the art Cepheid pulsations
models appropriate for the LMC/Galaxy and compare the resulting PC/PL relations
as a function of phase with observations. For the LMC, the (V-I) period-color
relation at minimum light can have quite a narrow dispersion (0.2-0.3 mags) and
thus could be useful in placing constraints on models. At longer periods, the
models predict significantly redder (by about 0.2-0.3 mags) V-I colors. We
discuss possible reasons for this and also compare PL relations at various
phases of pulsation and find clear evidence in both theory and observations for
a nonlinear PL relation.Comment: 5 pages, 8 figures, proceeding for "Stellar Pulsation: Challenges for
Theory and Observation", Santa Fe 200
The Relationship Between Luminosity and Broad-Line Region Size in Active Galactic Nuclei
We reinvestigate the relationship between the characteristic broad-line
region size (R_blr) and the Balmer emission-line, X-ray, UV, and optical
continuum luminosities. Our study makes use of the best available
determinations of R_blr for a large number of active galactic nuclei (AGNs)
from Peterson et al. Using their determinations of R_blr for a large sample of
AGNs and two different regression methods, we investigate the robustness of our
correlation results as a function of data sub-sample and regression technique.
Though small systematic differences were found depending on the method of
analysis, our results are generally consistent. Assuming a power-law relation
R_blr \propto L^\alpha, we find the mean best-fitting \alpha is about
0.67+/-0.05 for the optical continuum and the broad H\beta luminosity, about
0.56+/-0.05 for the UV continuum luminosity, and about 0.70+/-0.14 for the
X-ray luminosity. We also find an intrinsic scatter of about 40% in these
relations. The disagreement of our results with the theoretical expected slope
of 0.5 indicates that the simple assumption of all AGNs having on average same
ionization parameter, BLR density, column density, and ionizing spectral energy
distribution, is not valid and there is likely some evolution of a few of these
characteristics along the luminosity scale.Comment: 11 pages, 2 figures, emulateapj, accepted for publication in The
Astrophysical Journa
Stochastic Processes in Yellow and Red Pulsating Variables
Random changes in pulsation period are well established in cool pulsating
stars, in particular the red giant variables: Miras, semi-regulars of types A
and B, and RV Tau variables. Such effects are also observed in a handful of
Cepheids, the SX Phe variable XX Cyg, and, most recently, the red supergiant
variable, BC Cyg, a type C semi-regular. The nature of such fluctuations is
seemingly random over a few pulsation cycles of the stars, yet the regularity
of the primary pulsation mechanism dominates over the long term. The degree of
stochasticity is linked to the dimensions of the stars, the randomness
parameter 'e' appearing to correlate closely with mean stellar radius through
the period 'P', with an average value of e/P = 0.0136+-0.0005. The physical
processes responsible for such fluctuations are uncertain, but presumably
originate in temporal modifications of envelope convection in such stars.Comment: Poster given at the "Stellar Pulsation: Challenges for Theory and
Observation" conference in Santa Fe, New Mexico (2009
TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy
<p>Abstract</p> <p>Background</p> <p>Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA).</p> <p>Results</p> <p>TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1<sup>G93A </sup>mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.</p> <p>Conclusion</p> <p>These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.</p
Evidence for a Physically Compact Narrow-Line Region in the Seyfert 1 Galaxy NGC 5548
We have combined HST/FOS and ground-based spectra of the Seyfert 1 galaxy NGC
5548 to study the narrow emission lines over the 1200 -- 10,000 angstrom
region. All of the spectra were obtained when the broad emission line and
continuum fluxes were at an historic low level, allowing us to accurately
determine the contribution of the narrow-line region (NLR) to the emission
lines. We have generated multicomponent photoionization models to investigate
the relative strength of the high ionization lines compared to those in Seyfert
2 galaxies, and the weakness of the narrow Mg II 2800 line. We present evidence
for a high ionization component of NLR gas that is very close to the nucleus
(~1 pc). This component must be optically thin to ionizing radiation at the
Lyman edge (tau = 2.5) to avoid producing [O I] and Mg II in a partially
ionized zone. The very high ionization lines (N V, [Ne V], [Fe VII], [Fe X])
are stronger than the predictions of our standard model, and we show that this
may be due to supersolar abundances and/or a ``blue bump'' in the extreme
ultraviolet (although recent observations do not support the latter). An outer
component of NLR gas (at only ~70 pc from the continuum source) is needed to
produce the low ionization lines. We show that the outer component may contain
dust, which further reduces the Mg II flux by depletion and by absorption of
the resonance photons after multiple scatterings. We show that the majority of
the emission in the NLR of NGC 5548 must arise within about ~70 pc from the
nucleus. Thus, the NLR in this Seyfert 1 galaxy is very physically compact,
compared to the typical NLR in Seyfert 2 galaxies.Comment: 38 pages, Latex, includes 2 figures (postscript), to appear in Ap
Simultaneous Solutions of the Strong CP and Mu Problems
The \mu parameter of the supersymmetric standard model is replaced by \lambda
S, where S is a singlet chiral superfield, introducing a Peccei--Quinn symmetry
into the theory. Dynamics at the electroweak scale naturally solves both the
strong CP and \mu problems as long as \lambda is of order \sqrt{M_Z /M_pl} or
smaller, and yet this theory has the same number of relevant parameters as the
supersymmetric standard model. The theory will be tested at colliders: the \mu
parameter is predicted and there are long-lived superpartners that decay to
gravitinos or axinos at separated vertices. To avoid too much saxion cold dark
matter, a large amount of entropy must be produced after the electroweak phase
transition. If this is accomplished by decays of a massive particle, the reheat
temperature should be no more than a GeV, strongly constraining baryogenesis.
Cold dark matter may be composed of both axions, probed by direct detection,
and saxions, probed by a soft X-ray background arising from decays to \gamma
\gamma. There are two known possibilities for avoiding problematic axion domain
walls: the introduction of new colored fermions or the assumption that the
Peccei--Quinn symmetry was already broken during inflation. In the first case,
in our theory the colored particles are expected to be at the weak scale, while
in the second case it implies a good chance of discovering isocurvature
perturbations in the CMB radiation and a relatively low Hubble parameter during
inflation.Comment: 14 pages; v2. references added and typos correcte
340 years of atmospheric circulation characteristics reconstructed from an eastern Antarctic Peninsula ice core
Copyright @ 2006 American Geophysical Union (AGU)Precipitation delivery mechanisms for Dolleman Island (DI), located off the east coast of the Antarctic Peninsula, are investigated using reanalysis and back trajectory data. The Southern Annular Mode (SAM) and ENSO are both shown to influence precipitation delivery and event size. Precipitation delivery variability is compared against the interannual variation of chemical data from two DI ice cores. Nitrate concentration in the cores is strongly linked with the ratio of easterly to westerly back trajectories arriving at DI, as described by a Cross-Peninsula Index (CPI) defined in this paper. This CPI is used subsequently to reconstruct the atmospheric circulation characteristics for the 340-year ice core record. The analysis highlights a period of increased easterlies during 1720–1780 and an increase in westerlies for 1950–1980, the latter concomitant with a positive SAM trend and western Peninsula warming. The reconstruction also reveals periods when polynyas may have been present in the Weddell Sea
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Ultrasmall silica nanoparticles directly ligate the T cell receptor complex.
The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.These studies were supported by grants from the UK Medical Research Council (Grant number MR/R005699/1) and the Natural Sciences and Engineering Research Council of Canada, as well as through sponsorship from HS Pharmaceuticals LLC
Microstructural analysis of TRISO particles using multi-scale X-ray computed tomography
TRISO particles, a composite nuclear fuel built up by ceramic and graphitic layers, have outstanding high temperature resistance. TRISO fuel is the key technology for High Temperature Reactors (HTRs) and the Generation IV Very High Temperature Reactor (VHTR) variant. TRISO offers unparalleled containment of fission products and is extremely robust during accident conditions. An understanding of the thermal performance and mechanical properties of TRISO fuel requires a detailed knowledge of pore sizes, their distribution and interconnectivity. Here 50 nm, nano-, and 1 μm resolution, micro-computed tomography (CT), have been used to quantify non-destructively porosity of a surrogate TRISO particle at the 0.3–10 μm and 3–100 μm scales respectively. This indicates that pore distributions can reliably be measured down to a size approximately 3 times the pixel size which is consistent with the segmentation process. Direct comparison with Scanning Electron Microscopy (SEM) sections indicates that destructive sectioning can introduce significant levels of coarse damage, especially in the pyrolytic carbon layers. Further comparative work is required to identify means of minimizing such damage for SEM studies. Finally since it is non-destructive, multi-scale time-lapse X-ray CT opens the possibility of intermittently tracking the degradation of TRISO structure under thermal cycles or radiation conditions in order to validate models of degradation such as kernel movement. X-ray CT in-situ experimentation of TRISO particles under load and temperature could also be used to understand the internal changes that occur in the particles under accident conditions.Scanning and analysis was performed at the Henry Moseley X-ray Imaging Facility which has been funded through support from EPSRC under Grants EP/F007906, EP/F028431 and EP/I02249X. Imaging on the UltraXRM-L200 system was carried out at Zeiss Xradia Inc., Pleasanton, CA, USA
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