Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.     

Origin of the dielectric dead layer in nanoscale capacitors

Capacitors are a mainstay of electronic integrated circuits and devices, where they perform essential functions such as storing electrical charge, and blocking direct current while allowing alternating currents to propagate. Because they are often the largest components in circuits, extensive efforts are directed at reducing their size through the use of high-permittivity insulators such as perovskite-structure SrTiO3 (refs 1, 2), which should provide more capacitance per unit area of device. Unfortunately, most experiments on thin-film SrTiO3 capacitors have yielded capacitance values that are orders of magnitude smaller than expected. The microscopic origin of this reduced capacitance, which is often discussed in terms of a low-permittivity interfacial 'dead layer', is not well understood. Whether such a dead layer exists at all, and if so, whether it is an intrinsic property of an ideal metal-insulator interface or a result of processing issues such as defects and strains, are controversial questions. Here we present fully ab initio calculations of the dielectric properties of realistic SrRuO3/SrTiO3/SrRuO3 nanocapacitors, and show that the observed dramatic capacitance reduction is indeed an intrinsic effect. We demonstrate the existence of a dielectric dead layer by calculating the dielectric profile across the interface and analyse its origin by extracting the ionic and electronic contributions to the electrostatic screening. We establish a correspondence between the dead layer and the hardening of the collective SrTiO3 zone-centre polar modes, and determine the influence of the electrode by repeating our calculations for Pt/SrTiO3/Pt capacitors. Our results provide practical guidelines for minimizing the deleterious effects of the dielectric dead layer in nanoscale devices.     

Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis

PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.     

The Foundational Role of Ergodic Theory

The foundation of statistical mechanics and the explanation of the success of its methods rest on the fact that the theoretical values of physical quantities (phase averages) may be compared with the results of experimental measurements (infinite time averages). In the 1930s, this problem, called the ergodic problem, was dealt with by ergodic theory that tried to resolve the problem by making reference above all to considerations of a dynamic nature. In the present paper, this solution will be analyzed first, highlighting the fact that its very general nature does not duly consider the specificities of the systems of statistical mechanics. Second, Khinchin’s approach will be presented, that starting with more specific assumptions about the nature of systems, achieves an asymptotic version of the result obtained with ergodic theory. Third, the statistical meaning of Khinchin’s approach will be analyzed and a comparison between this and the point of view of ergodic theory is proposed. It will be demonstrated that the difference consists principally of two different perspectives on the ergodic problem: that of ergodic theory puts the state of equilibrium at the center, while Khinchin’s attempts to generalize the result to non-equilibrium states.     

Forecasting Temperature Indices Density with Time‐Varying Long‐Memory Models

The hedging of weather risks has become extremely relevant in recent years, promoting the diffusion of weather‐derivative contracts. The pricing of such contracts requires the development of appropriate models for the prediction of the underlying weather variables. Within this framework, a commonly used specification is the ARFIMA‐GARCH. We provide a generalization of such a model, introducing time‐varying memory coefficients. Our model satisfies the empirical evidence of the changing memory level observed in average temperature series, and provides useful improvements in the forecasting, simulation, and pricing issues related to weather derivatives. We present an application related to the forecast and simulation of a temperature index density, which is then used for the pricing of weather options. Copyright © 2011 John Wiley & Sons, Ltd.     

The structural intolerance of the PrP α-fold for polar substitution of the helix-3 methionines

The conversion of the cellular prion protein (PrP^C) into its disease-associated form (PrP^Sc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity, reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206 and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes.     

Factor forecasts for the UK

Data are now readily available for a very large number of macroeconomic variables that are potentially useful when forecasting. We argue that recent developments in the theory of dynamic factor models enable such large data sets to be summarized by relatively few estimated factors, which can then be used to improve forecast accuracy. In this paper we construct a large macroeconomic data set for the UK, with about 80 variables, model it using a dynamic factor model, and compare the resulting forecasts with those from a set of standard time‐series models. We find that just six factors are sufficient to explain 50% of the variability of all the variables in the data set. These factors, which can be shown to be related to key variables in the economy, and their use leads to considerable improvements upon standard time‐series benchmarks in terms of forecasting performance. Copyright © 2005 John Wiley & Sons, Ltd.     

Aftershocks driven by a high-pressure CO2 source at depth

In northern Italy in 1997, two earthquakes of magnitudes 5.7 and 6 (separated by nine hours) marked the beginning of a sequence that lasted more than 30 days, with thousands of aftershocks including four additional events with magnitudes between 5 and 6. This normal-faulting sequence is not well explained with models of elastic stress transfer, particularly the persistence of hanging-wall seismicity that included two events with magnitudes greater than 5. Here we show that this sequence may have been driven by a fluid pressure pulse generated from the coseismic release of a known deep source of trapped high-pressure carbon dioxide (CO2). We find a strong correlation between the high-pressure front and the aftershock hypocentres over a two-week period, using precise hypocentre locations and a simple model of nonlinear diffusion. The triggering amplitude (10-20 MPa) of the pressure pulse overwhelms the typical (0.1-0.2 MPa) range from stress changes in the usual stress triggering models. We propose that aftershocks of large earthquakes in such geologic environments may be driven by the coseismic release of trapped, high-pressure fluids propagating through damaged zones created by the mainshock. This may provide a link between earthquakes, aftershocks, crust/mantle degassing and earthquake-triggered large-scale fluid flow.     

From Permanence to Total Availability: A Quantum Conceptual Upgrade

We consider the classical concept of time of permanence and observe that its quantum equivalent is described by a bona fide self-adjoint operator. Its interpretation, by means of the spectral theorem, reveals that we have to abandon not only the idea that quantum entities would be characterizable in terms of spatial trajectories but, more generally, that they would possess the very attribute of spatiality. Consequently, a permanence time shouldn’t be interpreted as a “time” in quantum mechanics, but as a measure of the total availability of a quantum entity in participating to a process of creation of a spatial localization.