Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted. Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRA

Neutralino Dark Matter Elastic Scattering in a Flat and Accelerating Universe

In SUGRA inspired supersymmetric models with universal boundary conditions for the soft masses, the scalar cross section $\sigma_{scalar}$ for the elastic neutralino--nucleon scattering is in general several orders of magnitude below the sensitivity of current experiments. For large $\tan \beta$ and low $M_{1/2}, m_0$ values, the theoretically predicted $\sigma_{scalar}$ can approach the sensitivity of these experiments ($\approx 10^{-6} pb$) being at the same time in agreement with recent cosmological data, which impose severe restrictions on the CDM relic density, and with accelerator experiments which put lower bounds on sparticle and Higgs boson masses. Further improvement of the sensitivity of DAMA and CDMS experiments will probe the large $\tan \beta$ region of the parameter space in the vicinity of the boundaries of the parameter space allowed by chargino and Higgs searches.Comment: 15 pages, 9 figures. A note added; version to appear in MPL

Synthesis of accelerograms compatible with the Chinese GB 50011-2001 design spectrum via harmonic wavelets: artificial and historic records

A versatile approach is employed to generate artificial accelerograms which satisfy the compatibility criteria prescribed by the Chinese aseismic code provisions GB 50011-2001. In particular, a frequency dependent peak factor derived by means of appropriate Monte Carlo analyses is introduced to relate the GB 50011-2001 design spectrum to a parametrically defined evolutionary power spectrum (EPS). Special attention is given to the definition of the frequency content of the EPS in order to accommodate the mathematical form of the aforementioned design spectrum. Further, a one-to-one relationship is established between the parameter controlling the time-varying intensity of the EPS and the effective strong ground motion duration. Subsequently, an efficient auto-regressive moving-average (ARMA) filtering technique is utilized to generate ensembles of non-stationary artificial accelerograms whose average response spectrum is in a close agreement with the considered design spectrum. Furthermore, a harmonic wavelet based iterative scheme is adopted to modify these artificial signals so that a close matching of the signals’ response spectra with the GB 50011-2001 design spectrum is achieved on an individual basis. This is also done for field recorded accelerograms pertaining to the May, 2008 Wenchuan seismic event. In the process, zero-phase high-pass filtering is performed to accomplish proper baseline correction of the acquired spectrum compatible artificial and field accelerograms. Numerical results are given in a tabulated format to expedite their use in practice

Partial wave treatment of Supersymmetric Dark Matter in the presence of CP - violation

We present an improved partial wave analysis of the dominant LSP annihilation channel to a fermion-antifermion pair which avoids the non-relativistic expansion being therefore applicable near thresholds and poles. The method we develop allows of contributions of any partial wave in the total angular momentum J in contrast to partial wave analyses in terms of the orbital angular momentum L of the initial state, which is usually truncated to p-waves, and yields very accurate results. The method is formulated in such a way as to allow easy handling of CP-violating phases residing in supersymmetric parameters. We apply this refined partial wave technique in order to calculate the neutralino relic density in the constrained MSSM (CMSSM) in the presence of CP-violating terms occurring in the Higgs - mixing parameter \mu and trilinear A coupling for large tanb. The inclusion of CP-violating phases in mu and A does not upset significantly the picture and the annihilation of the LSP's to a b b_bar, through Higgs exchange, is still the dominant mechanism in obtaining cosmologically acceptable neutralino relic densities in regions far from the stau-coannihilation and the `focus point'. Significant changes can occur if we allow for phases in the gaugino masses and in particular the gluino mass.Comment: 23 pages LaTeX, 10 eps figures, version to appear in PR

Neutrino Fluxes from CMSSM LSP Annihilations in the Sun

We evaluate the neutrino fluxes to be expected from neutralino LSP annihilations inside the Sun, within the minimal supersymmetric extension of the Standard Model with supersymmetry-breaking scalar and gaugino masses constrained to be universal at the GUT scale (the CMSSM). We find that there are large regions of typical CMSSM $(m_{1/2}, m_0)$ planes where the LSP density inside the Sun is not in equilibrium, so that the annihilation rate may be far below the capture rate. We show that neutrino fluxes are dependent on the solar model at the 20% level, and adopt the AGSS09 model of Serenelli et al. for our detailed studies. We find that there are large regions of the CMSSM $(m_{1/2}, m_0)$ planes where the capture rate is not dominated by spin-dependent LSP-proton scattering, e.g., at large $m_{1/2}$ along the CMSSM coannihilation strip. We calculate neutrino fluxes above various threshold energies for points along the coannihilation/rapid-annihilation and focus-point strips where the CMSSM yields the correct cosmological relic density for tan(beta) = 10 and 55 for $\mu$ > 0, exploring their sensitivities to uncertainties in the spin-dependent and -independent scattering matrix elements. We also present detailed neutrino spectra for four benchmark models that illustrate generic possibilities within the CMSSM. Scanning the cosmologically-favored parts of the parameter space of the CMSSM, we find that the IceCube/DeepCore detector can probe at best only parts of this parameter space, notably the focus-point region and possibly also at the low-mass tip of the coannihilation strip.Comment: 32 pages, 13 figures. v2: updated/expanded discussion of IceCube/DeepCor

Spatial variability of precipitation regimes over Turkey

Turkish annual precipitation regimes are analysed to provide large-scale perspective and redefine precipitation regions. Monthly total precipitation data are employed for 107 stations (1963–2002). Precipitation regime shape (seasonality) and magnitude (size) are classified using a novel multivariate methodology. Six shape and five magnitude classes are identified, which exhibit clear spatial structure. A composite (shape and magnitude) regime classification reveals dominant controls on spatial variability of precipitation. Intra-annual timing and magnitude of precipitation is highly variable due to seasonal shifts in Polar and Subtropical zones and physiographic factors. Nonetheless, the classification methodology is shown to be a powerful tool that identifies physically-interpretable precipitation regions: (1) coastal regimes for Marmara, coastal Aegean, Mediterranean and Black Sea; (2) transitional regimes in continental Aegean and Southeast Anatolia; and (3) inland regimes across central and Eastern Anatolia. This research has practical implications for understanding water resources, which are under ever growing pressure in Turkey

An Enhanced Cosmological Li6 Abundance as a Potential Signature of Residual Dark Matter Annihilations

Residual late-time dark matter particle annihilations during and after Big Bang Nucleosynthesis (BBN) may alter the predicted cosmological abundances of the light elements. Within the constrained minimal supersymmetric extension of the Standard Model (the CMSSM) with a neutralino LSP, we find negligible effects on the abundances of Deuterium, He3, He4 and Li7 predicted by homogeneous BBN, but potentially a large enhancement in the predicted abundance of Li6. This enhancement may be as much as two orders of magnitude in the focus-point WMAP strip and in the coannihilation and funnel regions for large tan beta for small m_{1/2}, and the effect is still significant at large m_{1/2}. However, the potential Li6 enhancement is negligible in the part of the coannihilation strip for tan beta = 10 that survives the latest LHC constraints. A similar enhancement of the \li6 abundance may also be found in a model with common, non-universal Higgs masses (the NUHM1).Comment: 24 pages 9 figure

Bound-State Effects on Light-Element Abundances in Gravitino Dark Matter Scenarios

If the gravitino is the lightest supersymmetric particle and the long-lived next-to-lightest sparticle (NSP) is the stau, the charged partner of the tau lepton, it may be metastable and form bound states with several nuclei. These bound states may affect the cosmological abundances of Li6 and Li7 by enhancing nuclear rates that would otherwise be strongly suppressed. We consider the effects of these enhanced rates on the final abundances produced in Big-Bang nucleosynthesis (BBN), including injections of both electromagnetic and hadronic energy during and after BBN. We calculate the dominant two- and three-body decays of both neutralino and stau NSPs, and model the electromagnetic and hadronic decay products using the PYTHIA event generator and a cascade equation. Generically, the introduction of bound states drives light element abundances further from their observed values; however, for small regions of parameter space bound state effects can bring lithium abundances in particular in better accord with observations. We show that in regions where the stau is the NSP with a lifetime longer than 10^3-10^4 s, the abundances of Li6 and Li7 are far in excess of those allowed by observations. For shorter lifetimes of order 1000 s, we comment on the possibility in minimal supersymmetric and supergravity models that stau decays could reduce the Li7 abundance from standard BBN values while at the same time enhancing the Li6 abundance.Comment: 22 pages 6 figure

Besov priors for Bayesian inverse problems

We consider the inverse problem of estimating a function $u$ from noisy, possibly nonlinear, observations. We adopt a Bayesian approach to the problem. This approach has a long history for inversion, dating back to 1970, and has, over the last decade, gained importance as a practical tool. However most of the existing theory has been developed for Gaussian prior measures. Recently Lassas, Saksman and Siltanen (Inv. Prob. Imag. 2009) showed how to construct Besov prior measures, based on wavelet expansions with random coefficients, and used these prior measures to study linear inverse problems. In this paper we build on this development of Besov priors to include the case of nonlinear measurements. In doing so a key technical tool, established here, is a Fernique-like theorem for Besov measures. This theorem enables us to identify appropriate conditions on the forward solution operator which, when matched to properties of the prior Besov measure, imply the well-definedness and well-posedness of the posterior measure. We then consider the application of these results to the inverse problem of finding the diffusion coefficient of an elliptic partial differential equation, given noisy measurements of its solution.Comment: 18 page