Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects

Background: The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. Methodology/Principal Findings: To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Conclusions/Significance: Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling

European storminess and associated circulation weather types: future changes deduced from a multi-model ensemble of GCM simulations

A range of possible changes in the frequency and characteristics of European wind storms under future climate conditions was investigated on the basis of a multi-model ensemble of 9 coupled global climate model (GCM) simulations for the 20th and 21st centuries following the IPCC SRES A1B scenario. A multi-model approach allowed an estimation of the (un)certainties of the climate change signals. General changes in large-scale atmospheric flow were analysed, the occurrence of wind storms was quantified, and atmospheric features associated with wind storm events were considered. Identified storm days were investigated according to atmospheric circulation, associated pressure patterns, cyclone tracks and wind speed patterns. Validation against reanalysis data revealed that the GCMs are in general capable of realistically reproducing characteristics of European circulation weather types (CWTs) and wind storms. Results are given with respect to frequency of occurrence, storm-associated flow conditions, cyclone tracks and specific wind speed patterns. Under anthropogenic climate change conditions (SRES A1B scenario), increased frequency of westerly flow during winter is detected over the central European investigation area. In the ensemble mean, the number of detected wind storm days increases between 19 and 33% for 2 different measures of storminess, only 1 GCM revealed less storm days. The increased number of storm days detected in most models is disproportionately high compared to the related CWT changes. The mean intensity of cyclones associated with storm days in the ensemble mean increases by about 10 (±10)% in the Eastern Atlantic, near the British Isles and in the North Sea. Accordingly, wind speeds associated with storm events increase significantly by about 5 (±5)% over large parts of central Europe, mainly on days with westerly flow. The basic conclusions of this work remain valid if different ensemble contructions are considered, leaving out an outlier model or including multiple runs of one particular model

Resistant Hypertension and Obstructive Sleep Apnea in the Primary-Care Setting

We ascertained the prevalence of resistant hypertension (RH) among blacks and determined whether RH patients are at greater risk for obstructive sleep apnea (OSA) than hypertensives. Method. Data emanated from Metabolic Syndrome Outcome Study (MetSO), a study investigating metabolic syndrome among blacks in the primary-care setting. Sample of 200 patients (mean age = 63 ± 13 years; female = 61%) with a diagnosis of hypertension provided subjective and clinical data. RH was defined using the JNC 7and European Society guidelines. We assessed OSA risk using the Apnea Risk Evaluation System ARES), defining high risk as a total ARES score ≥6. Results. Overall, 26% met criteria for RH and 40% were at high OSA risk. Logistic regression analysis, adjusting for effects of age, gender, and medical co morbidities, showed that patients with RH were nearly 2.5 times more likely to be at high OSA risk, relative to those with hypertension (OR = 2.46, 95% CI: 1.03–5.88, P < .05). Conclusion. Our findings show that the prevalence of RH among blacks fell within the range of RH for the general hypertensive population (3–29%). However, patients with RH were at significantly greater risk of OSA compared to patients with hypertension

Bid Participates in Genotoxic Drug-Induced Apoptosis of HeLa Cells and Is Essential for Death Receptor Ligands' Apoptotic and Synergistic Effects

Background: The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. Methodology/Principal Findings: To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Conclusions/Significance: Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling

Управління виробничими запасами на підприємстві (на матеріалах ПрАТ «Детвілер Ущільнюючі Технології України»)

. The second-order matching problem is the problem of determining, for a finite set {#t i , s i # | i # I} of pairs of a second-order term t i and a first-order closed term s i , called a matching expression, whether or not there exists a substitution # such that t i # = s i for each i # I . It is well-known that the second-order matching problem is NP-complete. In this paper, we introduce the following restrictions of a matching expression: k-ary, k-fv , predicate, ground , and function-free. Then, we show that the second-order matching problem is NP-complete for a unary predicate, a unary ground, a ternary function-free predicate, a binary function-free ground, and an 1-fv predicate matching expressions, while it is solvable in polynomial time for a binary function-free predicate, a unary function-free, a k-fv function-free (k # 0), and a ground predicate matching expressions. 1 Introduction The unification problem is the problem of determining whether or not any two ter..

Relativistic Hydrodynamics around Black Holes and Horizon Adapted Coordinate Systems

Despite the fact that the Schwarzschild and Kerr solutions for the Einstein equations, when written in standard Schwarzschild and Boyer-Lindquist coordinates, present coordinate singularities, all numerical studies of accretion flows onto collapsed objects have been widely using them over the years. This approach introduces conceptual and practical complications in places where a smooth solution should be guaranteed, i.e., at the gravitational radius. In the present paper, we propose an alternative way of solving the general relativistic hydrodynamic equations in background (fixed) black hole spacetimes. We identify classes of coordinates in which the (possibly rotating) black hole metric is free of coordinate singularities at the horizon, independent of time, and admits a spacelike decomposition. In the spherically symmetric, non-rotating case, we re-derive exact solutions for dust and perfect fluid accretion in Eddington-Finkelstein coordinates, and compare with numerical hydrodynamic integrations. We perform representative axisymmetric computations. These demonstrations suggest that the use of those coordinate systems carries significant improvements over the standard approach, especially for higher dimensional studies.Comment: 10 pages, 4 postscript figures, accepted for publication in Phys. Rev.

Projections of global warming-induced impacts on winter storm losses in the German private household sector

We present projections of winter storm-induced insured losses in the German residential building sector for the 21st century. With this aim, two structurally most independent downscaling methods and one hybrid downscaling method are applied to a 3-member ensemble of ECHAM5/MPI-OM1 A1B scenario simulations. One method uses dynamical downscaling of intense winter storm events in the global model, and a transfer function to relate regional wind speeds to losses. The second method is based on a reshuffling of present day weather situations and sequences taking into account the change of their frequencies according to the linear temperature trends of the global runs. The third method uses statistical-dynamical downscaling, considering frequency changes of the occurrence of storm-prone weather patterns, and translation into loss by using empirical statistical distributions. The A1B scenario ensemble was downscaled by all three methods until 2070, and by the (statistical-) dynamical methods until 2100. Furthermore, all methods assume a constant statistical relationship between meteorology and insured losses and no developments other than climate change, such as in constructions or claims management. The study utilizes data provided by the German Insurance Association encompassing 24 years and with district-scale resolution. Compared to 1971–2000, the downscaling methods indicate an increase of 10-year return values (i.e. loss ratios per return period) of 6–35 % for 2011–2040, of 20–30 % for 2041–2070, and of 40–55 % for 2071–2100, respectively. Convolving various sources of uncertainty in one confidence statement (data-, loss model-, storm realization-, and Pareto fit-uncertainty), the return-level confidence interval for a return period of 15 years expands by more than a factor of two. Finally, we suggest how practitioners can deal with alternative scenarios or possible natural excursions of observed losses

Relativistic hydrodynamics on spacelike and null surfaces: Formalism and computations of spherically symmetric spacetimes

We introduce a formulation of Eulerian general relativistic hydrodynamics which is applicable for (perfect) fluid data prescribed on either spacelike or null hypersurfaces. Simple explicit expressions for the characteristic speeds and fields are derived in the general case. A complete implementation of the formalism is developed in the case of spherical symmetry. The algorithm is tested in a number of different situations, predisposing for a range of possible applications. We consider the Riemann problem for a polytropic gas, with initial data given on a retarded/advanced time slice of Minkowski spacetime. We compute perfect fluid accretion onto a Schwarzschild black hole spacetime using ingoing null Eddington-Finkelstein coordinates. Tests of fluid evolution on dynamic background include constant density and TOV stars sliced along the radial null cones. Finally, we consider the accretion of self-gravitating matter onto a central black hole and the ensuing increase in the mass of the black hole horizon.Comment: 23 pages, 13 figures, submitted to Phys. Rev.

Numerical simulation of small perturbation on an accretion disk due to the collision of a star with the disk near the black hole

In this paper, perturbations of an accretion disk by a star orbiting around a black hole are studied. We report on a numerical experiment, which has been carried out by using a parallel-machine code originally developed by D\"{o}nmez (2004). An initially steady state accretion disk near a non-rotating (Schwarzschild) black hole interacts with a "star", modeled as an initially circular region of increased density. Part of the disk is affected by the interaction. In some cases, a gap develops and shock wave propagates through the disk. We follow the evolution for order of one dynamical period and we show how the non-axisymetric density perturbation further evolves and moves downwards where the material of the disk and the star become eventually accreted onto the central body. When the star perturbs the steady state accretion disk, the disk around the black hole is destroyed by the effect of perturbation. The perturbed accretion disk creates a shock wave during the evolution and it loses angular momentum when the gas hits on the shock waves. Colliding gas with the shock wave is the one of the basic mechanism of emitting the $X-$rays in the accretion disk. The series of supernovae occurring in the inner disk could entirely destroy the disk in that region which leaves a more massive black hole behind, at the center of galaxies.Comment: 20pages, 8 figures, accepted for publication in Astrophysics and Space Scienc

Three Dimensional Numerical General Relativistic Hydrodynamics I: Formulations, Methods, and Code Tests

This is the first in a series of papers on the construction and validation of a three-dimensional code for general relativistic hydrodynamics, and its application to general relativistic astrophysics. This paper studies the consistency and convergence of our general relativistic hydrodynamic treatment and its coupling to the spacetime evolutions described by the full set of Einstein equations with a perfect fluid source. The numerical treatment of the general relativistic hydrodynamic equations is based on high resolution shock capturing schemes. These schemes rely on the characteristic information of the system. A spectral decomposition for general relativistic hydrodynamics suitable for a general spacetime metric is presented. Evolutions based on three different approximate Riemann solvers coupled to four different discretizations of the Einstein equations are studied and compared. The coupling between the hydrodynamics and the spacetime (the right and left hand side of the Einstein equations) is carried out in a treatment which is second order accurate in {\it both} space and time. Convergence tests for all twelve combinations with a variety of test beds are studied, showing consistency with the differential equations and correct convergence properties. The test-beds examined include shocktubes, Friedmann-Robertson-Walker cosmology tests, evolutions of self-gravitating compact (TOV) stars, and evolutions of relativistically boosted TOV stars. Special attention is paid to the numerical evolution of strongly gravitating objects, e.g., neutron stars, in the full theory of general relativity, including a simple, yet effective treatment for the surface region of the star (where the rest mass density is abruptly dropping to zero).Comment: 45 pages RevTeX, 34 figure