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^G93Amice. 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

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