Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

Identification of complex metabolic states in critically injured patients using bioinformatic cluster analysis

IntroductionAdvances in technology have made extensive monitoring of patient physiology the standard of care in intensive care units (ICUs). While many systems exist to compile these data, there has been no systematic multivariate analysis and categorization across patient physiological data. The sheer volume and complexity of these data make pattern recognition or identification of patient state difficult. Hierarchical cluster analysis allows visualization of high dimensional data and enables pattern recognition and identification of physiologic patient states. We hypothesized that processing of multivariate data using hierarchical clustering techniques would allow identification of otherwise hidden patient physiologic patterns that would be predictive of outcome.MethodsMultivariate physiologic and ventilator data were collected continuously using a multimodal bioinformatics system in the surgical ICU at San Francisco General Hospital. These data were incorporated with non-continuous data and stored on a server in the ICU. A hierarchical clustering algorithm grouped each minute of data into 1 of 10 clusters. Clusters were correlated with outcome measures including incidence of infection, multiple organ failure (MOF), and mortality.ResultsWe identified 10 clusters, which we defined as distinct patient states. While patients transitioned between states, they spent significant amounts of time in each. Clusters were enriched for our outcome measures: 2 of the 10 states were enriched for infection, 6 of 10 were enriched for MOF, and 3 of 10 were enriched for death. Further analysis of correlations between pairs of variables within each cluster reveals significant differences in physiology between clusters.ConclusionsHere we show for the first time the feasibility of clustering physiological measurements to identify clinically relevant patient states after trauma. These results demonstrate that hierarchical clustering techniques can be useful for visualizing complex multivariate data and may provide new insights for the care of critically injured patients

Phenomenology of non-standard Z couplings in exclusive semileptonic b -> s transitions

The rare decays $B\to K^{(*)}\ell^+\ell^-$, $B\to K^{(*)}\nu\bar\nu$ and $B_s\to\mu^+\mu^-$ are analyzed in a generic scenario where New Physics effects enter predominantly via $Z$ penguin contributions. We show that this possibility is well motivated on theoretical grounds, as the $\bar sbZ$ vertex is particularly susceptible to non-standard dynamics. In addition, such a framework is also interesting phenomenologically since the $\bar sbZ$ coupling is rather poorly constrained by present data. The characteristic features of this scenario for the relevant decay rates and distributions are investigated. We emphasize that both sign and magnitude of the forward-backward asymmetry of the decay leptons in $\bar B\to \bar K^*\ell^+\ell^-$, ${\cal A}^{(\bar B)}_{FB}$, carry sensitive information on New Physics. The observable ${\cal A}^{(\bar B)}_{FB}+{\cal A}^{(B)}_{FB}$ is proposed as a useful probe of non-standard CP violation in $\bar sbZ$ couplings.Comment: Minor modifications; version to appear in Phys. Rev.

Final State Interactions and New Physics in B -> pi K Decays

Within the Standard Model, and if one assumes that soft rescattering effects are negligible, the CP asymmetry A^dir_CP (B^\pm -> \pi^\pm K) is predicted to be very small and the ratio R = BR(B_d -> \pi^\mp K^\pm)/BR(B^\pm -> \pi^\pm K) provides a bound on the angle \gamma of the unitarity triangle, sin^2 \gamma \leq R. We estimate the corrections from soft rescattering effects using an approach based on Regge phenomenology, and find effects of order 10% with large uncertainties. In particular, we conclude that A^dir_CP \sim 0.2 and sin^2 \gamma \sim 1.2 R could not be taken unambiguously to signal New Physics. Using SU(3) relations, we suggest experimental tests that could constrain the size of the soft rescattering effects thus reducing the related uncertainty. Finally, we study the effect of various models of New Physics on A^dir_CP and on R.Comment: 20 pages, RevTex, no figures; a few typos corrected, references added, brief additional discussion of uncertanties is adde

Testing new physics with the electron g-2

We argue that the anomalous magnetic moment of the electron (a_e) can be used to probe new physics. We show that the present bound on new-physics contributions to a_e is 8*10^-13, but the sensitivity can be improved by about an order of magnitude with new measurements of a_e and more refined determinations of alpha in atomic-physics experiments. Tests on new-physics effects in a_e can play a crucial role in the interpretation of the observed discrepancy in the anomalous magnetic moment of the muon (a_mu). In a large class of models, new contributions to magnetic moments scale with the square of lepton masses and thus the anomaly in a_mu suggests a new-physics effect in a_e of (0.7 +- 0.2)*10^-13. We also present examples of new-physics theories in which this scaling is violated and larger effects in a_e are expected. In such models the value of a_e is correlated with specific predictions for processes with violation of lepton number or lepton universality, and with the electric dipole moment of the electron.Comment: 34 pages, 7 figures. Minor changes and references adde

Limits on scalar leptoquark interactions and consequences for GUTs

A colored weak singlet scalar state with hypercharge 4/3 is one of the possible candidates for the explanation of the unexpectedly large forward-backward asymmetry in t tbar production as measured by the CDF and D0 experiments. We investigate the role of this state in a plethora of flavor changing neutral current processes and precision observables of down-quarks and charged leptons. Our analysis includes tree- and loop-level mediated observables in the K and B systems, the charged lepton sector, as well as the Z to b bbar decay width. We perform a global fit of the relevant scalar couplings. This approach can explain the (g-2)_mu anomaly while tensions among the CP violating observables in the quark sector, most notably the nonstandard CP phase (and width difference) in the Bs system cannot be fully relaxed. The results are interpreted in a class of grand unified models which allow for a light colored scalar with a mass below 1TeV. We find that the renormalizable SU(5) scenario is not compatible with our global fit, while in the SO(10) case the viability requires the presence of both the 126- and 120-dimensional representations.Comment: 26 pages, 7 figures; version as publishe

Second Generation Leptoquark Search in p\bar{p} Collisions at s\sqrt{s} = 1.8 TeV

We report on a search for second generation leptoquarks with the D\O\ detector at the Fermilab Tevatron $p\bar{p}$ collider at $\sqrt{s}$ = 1.8 TeV. This search is based on 12.7 pb$^{-1}$ of data. Second generation leptoquarks are assumed to be produced in pairs and to decay into a muon and quark with branching ratio $\beta$ or to neutrino and quark with branching ratio $(1-\beta)$. We obtain cross section times branching ratio limits as a function of leptoquark mass and set a lower limit on the leptoquark mass of 111 GeV/c$^{2}$ for $\beta = 1$ and 89 GeV/c$^{2}$ for $\beta = 0.5$ at the 95%\ confidence level.Comment: 18 pages, FERMILAB-PUB-95/185-

Search for Top Squark Pair Production in the Dielectron Channel

This report describes the first search for top squark pair production in the channel stop_1 stopbar_1 -> b bbar chargino_1 chargino_1 -> ee+jets+MEt using 74.9 +- 8.9 pb^-1 of data collected using the D0 detector. A 95% confidence level upper limit on sigma*B is presented. The limit is above the theoretical expectation for sigma*B for this process, but does show the sensitivity of the current D0 data set to a particular topology for new physics.Comment: Five pages, including three figures, submitted to PRD Brief Report

Mass-Matching in Higgsless

Modern extra-dimensional Higgsless scenarios rely on a mass-matching between fermionic and bosonic KK resonances to evade constraints from precision electroweak measurements. After analyzing all of the Tevatron and LEP bounds on these so-called Cured Higgsless scenarios, we study their LHC signatures and explore how to identify the mass-matching mechanism, the key to their viability. We find singly and pair produced fermionic resonances show up as clean signals with 2 or 4 leptons and 2 hard jets, while neutral and charged bosonic resonances are visible in the dilepton and leptonic WZ channels, respectively. A measurement of the resonance masses from these channels shows the matching necessary to achieve $S\simeq 0$. Moreover, a large single production of KK-fermion resonances is a clear indication of compositeness of SM quarks. Discovery reach is below 10 fb$^{-1}$ of luminosity for resonances in the 700 GeV range.Comment: 28 pages, 18 figure

Asymmetric Dark Matter from Leptogenesis

We present a new realization of asymmetric dark matter in which the dark matter and lepton asymmetries are generated simultaneously through two-sector leptogenesis. The right-handed neutrinos couple both to the Standard Model and to a hidden sector where the dark matter resides. This framework explains the lepton asymmetry, dark matter abundance and neutrino masses all at once. In contrast to previous realizations of asymmetric dark matter, the model allows for a wide range of dark matter masses, from keV to 10 TeV. In particular, very light dark matter can be accommodated without violating experimental constraints. We discuss several variants of our model that highlight interesting phenomenological possibilities. In one, late decays repopulate the symmetric dark matter component, providing a new mechanism for generating a large annihilation rate at the present epoch and allowing for mixed warm/cold dark matter. In a second scenario, dark matter mixes with the active neutrinos, thus presenting a distinct method to populate sterile neutrino dark matter through leptogenesis. At late times, oscillations and dark matter decays lead to interesting indirect detection signals.Comment: 32 pages + appendix, references added, minor change