Deficient and null variants of SERPINA1 are proteotoxic in a Caenorhabditis elegans model of α1-antitrypsin deficiency

α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregationprone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gainoffunction proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach

Charged Dilatonic AdS Black Branes in Arbitrary Dimensions

We study electromagnetically charged dilatonic black brane solutions in arbitrary dimensions with flat transverse spaces, that are asymptotically AdS. This class of solutions includes spacetimes which possess a bulk region where the metric is approximately invariant under Lifshitz scalings. Given fixed asymptotic boundary conditions, we analyze how the behavior of the bulk up to the horizon varies with the charges and derive the extremality conditions for these spacetimes.Comment: References update

The holographic principle

There is strong evidence that the area of any surface limits the information content of adjacent spacetime regions, at 10^(69) bits per square meter. We review the developments that have led to the recognition of this entropy bound, placing special emphasis on the quantum properties of black holes. The construction of light-sheets, which associate relevant spacetime regions to any given surface, is discussed in detail. We explain how the bound is tested and demonstrate its validity in a wide range of examples. A universal relation between geometry and information is thus uncovered. It has yet to be explained. The holographic principle asserts that its origin must lie in the number of fundamental degrees of freedom involved in a unified description of spacetime and matter. It must be manifest in an underlying quantum theory of gravity. We survey some successes and challenges in implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2: reference adde

Generating Temperature Flow for eta/s with Higher Derivatives: From Lifshitz to AdS

We consider charged dilatonic black branes in AdS_5 and examine the effects of perturbative higher derivative corrections on the ratio of shear viscosity to entropy density eta/s of the dual plasma. The structure of eta/s is controlled by the relative hierarchy between the two scales in the plasma, the temperature and the chemical potential. In this model the background near-horizon geometry interpolates between a Lifshitz-like brane at low temperature, and an AdS brane at high temperatures -- with AdS asymptotics in both cases. As a result, in this construction the viscosity to entropy ratio flows as a function of temperature, from a value in the IR which is sensitive to the dynamical exponent z, to the simple result expected for an AdS brane in the UV. Coupling the scalar directly to the higher derivative terms generates additional temperature dependence, and leads to a particularly interesting structure for eta/s in the IR.Comment: Plots and references added. Journal version of the pape

Strong Ultraviolet Pulse From a Newborn Type Ia Supernova

Type Ia supernovae are destructive explosions of carbon oxygen white dwarfs. Although they are used empirically to measure cosmological distances, the nature of their progenitors remains mysterious, One of the leading progenitor models, called the single degenerate channel, hypothesizes that a white dwarf accretes matter from a companion star and the resulting increase in its central pressure and temperature ignites thermonuclear explosion. Here we report observations of strong but declining ultraviolet emission from a Type Ia supernova within four days of its explosion. This emission is consistent with theoretical expectations of collision between material ejected by the supernova and a companion star, and therefore provides evidence that some Type Ia supernovae arise from the single degenerate channel.Comment: Accepted for publication on the 21 May 2015 issue of Natur

Universality of the Volume Bound in Slow-Roll Eternal Inflation

It has recently been shown that in single field slow-roll inflation the total volume cannot grow by a factor larger than e^(S_dS/2) without becoming infinite. The bound is saturated exactly at the phase transition to eternal inflation where the probability to produce infinite volume becomes non zero. We show that the bound holds sharply also in any space-time dimensions, when arbitrary higher-dimensional operators are included and in the multi-field inflationary case. The relation with the entropy of de Sitter and the universality of the bound strengthen the case for a deeper holographic interpretation. As a spin-off we provide the formalism to compute the probability distribution of the volume after inflation for generic multi-field models, which might help to address questions about the population of vacua of the landscape during slow-roll inflation.Comment: 24 pages, 5 figure

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Partition functions of higher spin black holes and their CFT duals

We find black hole solutions of D=3 higher-spin gravity in the hs[\lambda] + hs[\lambda] Chern-Simons formulation. These solutions have a spin-3 chemical potential, and carry nonzero values for an infinite number of charges of the asymptotic W_{\infty}[\lambda] symmetry. Applying a previously developed set of rules for ensuring smooth solutions, we compute the black hole partition function perturbatively in the chemical potential. At \lambda =0, 1 we compare our result against boundary CFT computations involving free bosons and fermions, and find perfect agreement. For generic \lambda\ we expect that our gravity result will match the partition function of the coset CFTs conjectured by Gaberdiel and Gopakumar to be dual to these bulk theories.Comment: 28 pages; v2, added re

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom