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

Multifaceted contributions : health workers and smallpox eradication in India

Smallpox eradication in South Asia was a result of the efforts of many grades of health-workers. Working from within the confines of international organisations and government structures, the role of the field officials, who were of various nationalities and also drawn from the cities and rural enclaves of the countries in these regions, was crucial to the development and deployment of policies. However, the role of these personnel is often downplayed in official histories and academic histories, which highlight instead the roles played by a handful of senior officials within the World Health Organization and the federal governments in the sub-continent. This article attempts to provide a more rounded assessment of the complex situation in the field. In this regard, an effort is made to underline the great usefulness of the operational flexibility displayed by field officers, wherein lessons learnt in the field were made an integral part of deploying local campaigns; careful engagement with the communities being targeted, as well as the employment of short term workers from amongst them, was an important feature of this work

Convergence Acceleration via Combined Nonlinear-Condensation Transformations

A method of numerically evaluating slowly convergent monotone series is described. First, we apply a condensation transformation due to Van Wijngaarden to the original series. This transforms the original monotone series into an alternating series. In the second step, the convergence of the transformed series is accelerated with the help of suitable nonlinear sequence transformations that are known to be particularly powerful for alternating series. Some theoretical aspects of our approach are discussed. The efficiency, numerical stability, and wide applicability of the combined nonlinear-condensation transformation is illustrated by a number of examples. We discuss the evaluation of special functions close to or on the boundary of the circle of convergence, even in the vicinity of singularities. We also consider a series of products of spherical Bessel functions, which serves as a model for partial wave expansions occurring in quantum electrodynamic bound state calculations.Comment: 24 pages, LaTeX, 12 tables (accepted for publication in Comput. Phys. Comm.

Higgs After the Discovery: A Status Report

Recently, the ATLAS and CMS collaborations have announced the discovery of a 125 GeV particle, commensurable with the Higgs boson. We analyze the 2011 and 2012 LHC and Tevatron Higgs data in the context of simplified new physics models, paying close attention to models which can enhance the diphoton rate and allow for a natural weak-scale theory. Combining the available LHC and Tevatron data in the ZZ* 4-lepton, WW* 2-lepton, diphoton, and b-bbar channels, we derive constraints on the effective low-energy theory of the Higgs boson. We map several simplified scenarios to the effective theory, capturing numerous new physics models such as supersymmetry, composite Higgs, dilaton. We further study models with extended Higgs sectors which can naturally enhance the diphoton rate. We find that the current Higgs data are consistent with the Standard Model Higgs boson and, consequently, the parameter space in all models which go beyond the Standard Model is highly constrained.Comment: 37 pages; v2: ATLAS dijet-tag diphoton channel added, dilaton and doublet-singlet bugs corrected, references added; v3: ATLAS WW channel included, comments and references adde

Inorganic chlorine partitioning in the summer lower stratosphere: Modeled and measured [ClONO_2]/[HCl] during POLARIS

We examine inorganic chlorine (Cl_y,) partitioning in the summer lower stratosphere using in situ ER-2 aircraft observations made during the Photochemistry of Ozone Loss in the Arctic Region in Summer (POLARIS) campaign. New steady state and numerical models estimate [ClONO_2]/[HCl] using currently accepted photochemistry. These models are tightly constrained by observations with OH (parameterized as a function of solar zenith angle) substituting for modeled HO_2 chemistry. We find that inorganic chlorine photochemistry alone overestimates observed [ClONO_2]/[HCl] by approximately 55–60% at mid and high latitudes. On the basis of POLARIS studies of the inorganic chlorine budget, [ClO]/[ClONO_2], and an intercomparison with balloon observations, the most direct explanation for the model-measurement discrepancy in Cl_y, partitioning is an error in the reactions, rate constants, and measured species concentrations linking HCl and ClO (simulated [ClO]/[HCl] too high) in combination with a possible systematic error in the ER-2 ClONO_2 measurement (too low). The high precision of our simulation (±15% 1σ for [ClONO_2]/[HCl], which is compared with observations) increases confidence in the observations, photolysis calculations, and laboratory rate constants. These results, along with other findings, should lead to improvements in both the accuracy and precision of stratospheric photochemical models

Mathematical Properties of a New Levin-Type Sequence Transformation Introduced by \v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la. I. Algebraic Theory

\v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la [J. Math. Phys. \textbf{44}, 962 - 968 (2003)] introduced in connection with the summation of the divergent perturbation expansion of the hydrogen atom in an external magnetic field a new sequence transformation which uses as input data not only the elements of a sequence $\{s_n \}_{n=0}^{\infty}$ of partial sums, but also explicit estimates $\{\omega_n \}_{n=0}^{\infty}$ for the truncation errors. The explicit incorporation of the information contained in the truncation error estimates makes this and related transformations potentially much more powerful than for instance Pad\'{e} approximants. Special cases of the new transformation are sequence transformations introduced by Levin [Int. J. Comput. Math. B \textbf{3}, 371 - 388 (1973)] and Weniger [Comput. Phys. Rep. \textbf{10}, 189 - 371 (1989), Sections 7 -9; Numer. Algor. \textbf{3}, 477 - 486 (1992)] and also a variant of Richardson extrapolation [Phil. Trans. Roy. Soc. London A \textbf{226}, 299 - 349 (1927)]. The algebraic theory of these transformations - explicit expressions, recurrence formulas, explicit expressions in the case of special remainder estimates, and asymptotic order estimates satisfied by rational approximants to power series - is formulated in terms of hitherto unknown mathematical properties of the new transformation introduced by \v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la. This leads to a considerable formal simplification and unification.Comment: 41 + ii pages, LaTeX2e, 0 figures. Submitted to Journal of Mathematical Physic

Comparison of modeled and observed values of NO_2 and JNO_2 during the Photochemistry of Ozone Loss in the Arctic Region in Summer (POLARIS) mission

Stratospheric measurements of NO, NO_(2), O_(3), ClO, and HO_(2) were made during spring, early summer, and late summer in the Arctic region during 1997 as part of the Photochemistry of Ozone Loss in the Arctic Region in Summer (POLARIS) field campaign. In the sunlit atmosphere, NO_(2) and NO are in steady state through NO2 photolysis and reactions involving O_(3), ClO, BrO, and HO_(2). By combining observations of O_(3), ClO, and HO_(2), observed and modeled values of the NO_(2) photolysis rate coefficient (JNO_(2)), and model estimates of BrO, several comparisons are made between steady state and measured values of both NO_(2) and JNO_(2). An apparent seasonal dependence in discrepancies between calculated and measured values was found; however, a source for this dependence could not be identified. Overall, the mean linear fits in the various comparisons show agreement within 19%, well within the combined uncertainties (±50 to 70%). These results suggest that photochemistry controlling the NO_(2)/NO abundance ratio is well represented throughout much of the sunlit lower stratosphere. A reduction in the uncertainty of laboratory determinations of the rate coefficient of NO + O_(3) → NO_(2) + O_(2) would aid future analyses of these or similar atmospheric observations