Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation

Prolonged ingestion of a cholesterol- or saturated fatty acid-enriched diet induces chronic, often systemic, auto-inflammatory responses resulting in significant health problems worldwide. In vivo information regarding the local and direct inflammatory effect of these dietary components in the intestine and, in particular, on the intestinal epithelium is lacking. Here we report that both mice and zebrafish exposed to high-fat (HFDs) or high-cholesterol (HCDs) diets develop acute innate inflammatory responses within hours, reflected in the localized interleukin-1β-dependent accumulation of myeloid cells in the intestine. Acute HCD-induced intestinal inflammation is dependent on cholesterol uptake via Niemann-Pick C1-like 1 and inflammasome activation involving apoptosis-associated Speck-like protein containing a caspase recruitment domain, which leads to Caspase-1 activity in intestinal epithelial cells. Extended exposure to HCD results in localized, inflammation-dependent, functional dysregulation as well as systemic pathologies. Our model suggests that dietary cholesterol initiates intestinal inflammation in epithelial cells

Goldstini

Supersymmetric phenomenology has been largely bound to the hypothesis that supersymmetry breaking originates from a single source. In this paper, we relax this underlying assumption and consider a multiplicity of sectors which independently break supersymmetry, thus yielding a corresponding multiplicity of goldstini. While one linear combination of goldstini is eaten via the super-Higgs mechanism, the orthogonal combinations remain in the spectrum as physical degrees of freedom. Interestingly, supergravity effects induce a universal tree-level mass for the goldstini which is exactly twice the gravitino mass. Since visible sector fields can couple dominantly to the goldstini rather than the gravitino, this framework allows for substantial departures from conventional supersymmetric phenomenology. In fact, this even occurs when a conventional mediation scheme is augmented by additional supersymmetry breaking sectors which are fully sequestered. We discuss a number of striking collider signatures, including various novel decay modes for the lightest observable-sector supersymmetric particle, gravitinoless gauge-mediated spectra, and events with multiple displaced vertices. We also describe goldstini cosmology and the possibility of goldstini dark matter.Comment: 14 pages, 7 figures; references adde

Cosmological vacuum selection and metastable susy breaking

We study gauge mediation in a wide class of O'Raifeartaigh type models where supersymmetry breaking metastable vacuum is created by gravity and/or quantum corrections. We examine their thermal evolution in the early universe and the conditions under which the susy breaking vacuum can be selected. It is demonstrated that thermalization typically makes the metastable supersymmetry breaking cosmologically disfavoured but this is not always the case. Initial conditions with the spurion displaced from the symmetric thermal minimum and a small coupling to the messenger sector can result in the realization of the susy breaking vacuum even if the reheating temperature is high. We show that this can be achieved without jeopardizing the low energy phenomenology. In addition, we have found that deforming the models by a supersymmetric mass term for messengers in such a way that the susy breaking minimum and the susy preserving minima are all far away from the origin does not change the conclusions. The basic observations are expected to hold also in the case of models with an anomalous U(1) group.Comment: 28 pages, 4 figures, plain Latex, journal versio

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry

It is well known that R-symmetric models dramatically alleviate the SUSY flavor and CP problems. We study particular modifications of existing R-symmetric models which share the solution to the above problems, and have interesting consequences for electroweak baryogenesis and the Dark Matter (DM) content of the universe. In particular, we find that it is naturally possible to have a strongly first-order electroweak phase transition while simultaneously relaxing the tension with EDM experiments. The R-symmetry (and its small breaking) implies that the gauginos (and the neutralino LSP) are pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role in making the electroweak phase transition strongly first-order. The pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac particle during freeze-out, but like a Majorana particle for annihilation today and in scattering against nuclei, thus being consistent with current constraints. Assuming a standard cosmology, it is possible to simultaneously have a strongly first-order phase transition conducive to baryogenesis and have the LSP provide the full DM relic abundance, in part of the allowed parameter space. However, other possibilities for DM also exist, which are discussed. It is expected that upcoming direct DM searches as well as neutrino signals from DM annihilation in the Sun will be sensitive to this class of models. Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure

Flavor Mediation Delivers Natural SUSY

If supersymmetry (SUSY) solves the hierarchy problem, then naturalness considerations coupled with recent LHC bounds require non-trivial superpartner flavor structures. Such "Natural SUSY" models exhibit a large mass hierarchy between scalars of the third and first two generations as well as degeneracy (or alignment) among the first two generations. In this work, we show how this specific beyond the standard model (SM) flavor structure can be tied directly to SM flavor via "Flavor Mediation". The SM contains an anomaly-free SU(3) flavor symmetry, broken only by Yukawa couplings. By gauging this flavor symmetry in addition to SM gauge symmetries, we can mediate SUSY breaking via (Higgsed) gauge mediation. This automatically delivers a natural SUSY spectrum. Third-generation scalar masses are suppressed due to the dominant breaking of the flavor gauge symmetry in the top direction. More subtly, the first-two-generation scalars remain highly degenerate due to a custodial U(2) symmetry, where the SU(2) factor arises because SU(3) is rank two. This custodial symmetry is broken only at order (m_c/m_t)^2. SUSY gauge coupling unification predictions are preserved, since no new charged matter is introduced, the SM gauge structure is unaltered, and the flavor symmetry treats all matter multiplets equally. Moreover, the uniqueness of the anomaly-free SU(3) flavor group makes possible a number of concrete predictions for the superpartner spectrum.Comment: 17 pages, 7 figures, 2 tables. v2 references added, minor changes to flavor constraints and a little discussion adde

Direct Mediation and Metastable Supersymmetry Breaking for SO(10)

We examine a metastable $\mathcal{N}=1$ Macroscopic SO(N) SQCD model of Intriligator, Seiberg and Shih (ISS). We introduce various baryon and meson deformations, including multitrace operators and explore embedding an SO(10) parent of the standard model into two weakly gauged flavour sectors. Direct fundamental messengers and the symmetric pseudo-modulus messenger mediate SUSY breaking to the MSSM. Gaugino and sfermion masses are computed and compared for each deformation type. We also explore reducing the rank of the magnetic quark matrix of the ISS model and find an additional fundamental messenger.Comment: 43 pages, Latex. Version to appear in JHEP

Assessing the psychometric and ecometric properties of neighborhood scales using adolescent survey data from urban and rural Scotland

This work was supported by NHS Health Scotland and the University of St Andrews.Background:  Despite the well-established need for specific measurement instruments to examine the relationship between neighborhood conditions and adolescent well-being outcomes, few studies have developed scales to measure features of the neighborhoods in which adolescents reside. Moreover, measures of neighborhood features may be operationalised differently by adolescents living in different levels of urban/rurality. This has not been addressed in previous studies. The objectives of this study were to: 1) establish instruments to measure adolescent neighborhood features at both the individual and neighborhood level, 2) assess their psychometric and ecometric properties, 3) test for invariance by urban/rurality, and 4) generate neighborhood level scores for use in further analysis. Methods:  Data were from the Scottish 2010 Health Behaviour in School-aged Children Survey, which included an over-sample of rural adolescents. The survey responses of interest came from questions designed to capture different facets of the local area in which each respondent resided. Intermediate data zones were used as proxies for neighborhoods. Internal consistency was evaluated by Cronbach’s alpha. Invariance was examined using confirmatory factor analysis. Multilevel models were used to estimate ecometric properties and generate neighborhood scores. Results:  Two constructs labeled neighborhood social cohesion and neighborhood disorder were identified. Adjustment was made to the originally specified model to improve model fit and measures of invariance. At the individual level, reliability was .760 for social cohesion and .765 for disorder, and between .524 and .571 for both constructs at the neighborhood level. Individuals in rural areas experienced greater neighborhood social cohesion and lower levels of neighborhood disorder compared with those in urban areas. Conclusions:  The scales are appropriate for measuring neighborhood characteristics experienced by adolescents across urban and rural Scotland, and can be used in future studies of neighborhoods and health. However, trade-offs between neighborhood sample size and reliability must be considered.Publisher PDFPeer reviewe

Theoretical and practical convergence of a self-adaptive penalty algorithm for constrained global optimization

This paper proposes a self-adaptive penalty function and presents a penalty-based algorithm for solving nonsmooth and nonconvex constrained optimization problems. We prove that the general constrained optimization problem is equivalent to a bound constrained problem in the sense that they have the same global solutions. The global minimizer of the penalty function subject to a set of bound constraints may be obtained by a population-based meta-heuristic. Further, a hybrid self-adaptive penalty firefly algorithm, with a local intensification search, is designed, and its convergence analysis is established. The numerical experiments and a comparison with other penalty-based approaches show the effectiveness of the new self-adaptive penalty algorithm in solving constrained global optimization problems.The authors would like to thank the referees, the Associate Editor and the Editor-in-Chief for their valuable comments and suggestions to improve the paper. This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT - Funda¸c˜ao para a Ciˆencia e Tecnologia within the projects UID/CEC/00319/2013 and UID/MAT/00013/2013.info:eu-repo/semantics/publishedVersio

A Complete Model of Low-Scale Gauge Mediation

Recent signs of a Standard Model-like Higgs at 125 GeV point towards large A-terms in the MSSM. This presents special challenges for gauge mediation, which by itself predicts vanishing A-terms at the messenger scale. In this paper, we review the general problems that arise when extending gauge mediation to achieve large A-terms, and the mechanisms that exist to overcome them. Using these mechanisms, we construct weakly-coupled models of low-scale gauge mediation with extended Higgs-messenger couplings that generate large A-terms at the messenger scale and viable mu/B_mu-terms. Our models are simple, economical, and complete realizations of supersymmetry at the weak scale.Comment: 33 pages; v2: refs added, minor change