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Alterations in gene expression and sensitivity to genotoxic stress following HdmX or Hdm2 knockdown in human tumor cells harboring wild-type p53

While half of all human tumors possess p53 mutations, inactivation of wild-type p53 can also occur through a variety of mechanisms that do not involve p53 gene mutation or deletion. Our laboratory has been interested in tumor cells possessing wild-type p53 protein and elevated levels of HdmX and/or Hdm2, two critical negative regulators of p53 function. In this study we utilized RNAi to knockdown HdmX or Hdm2 in MCF7 human breast cancer cells, which harbor wild-type p53 and elevated levels of HdmX and Hdm2 then examined gene expression changes and effects on cell growth. Cell cycle and growth assays confirmed that the loss of either HdmX or Hdm2 led to a significant growth inhibition and G1 cell cycle arrest. Although the removal of overexpressed HdmX/2 appears limited to an anti-proliferative effect in MCF7 cells, the loss of HdmX and/or Hdm2 enhanced cytotoxicity in these same cells exposed to DNA damage. Through the use of Affymetrix GeneChips and subsequent RT-qPCR validations, we uncovered a subset of anti-proliferative p53 target genes activated upon HdmX/2 knockdown. Interestingly, a second set of genes, normally transactivated by E2F1 as cells transverse the G1-S phase boundary, were found repressed in a p21-dependent manner following HdmX/2 knockdown. Taken together, these results provide novel insights into the reactivation of p53 in cells overexpressing HdmX and Hdm2

Well-balanced treatment of gravity in astrophysical fluid dynamics simulations at low Mach numbers

Accurate simulations of flows in stellar interiors are crucial to improving our understanding of stellar structure and evolution. Because the typically slow flows are merely tiny perturbations on top of a close balance between gravity and the pressure gradient, such simulations place heavy demands on numerical hydrodynamics schemes. We demonstrate how discretization errors on grids of reasonable size can lead to spurious flows orders of magnitude faster than the physical flow. Well-balanced numerical schemes can deal with this problem. Three such schemes were applied in the implicit, finite-volume Seven-League Hydro (SLH) code in combination with a low-Mach-number numerical flux function. We compare how the schemes perform in four numerical experiments addressing some of the challenges imposed by typical problems in stellar hydrodynamics. We find that the $\alpha$-$\beta$ and deviation well-balancing methods can accurately maintain hydrostatic solutions provided that gravitational potential energy is included in the total energy balance. They accurately conserve minuscule entropy fluctuations advected in an isentropic stratification, which enables the methods to reproduce the expected scaling of convective flow speed with the heating rate. The deviation method also substantially increases accuracy of maintaining stationary orbital motions in a Keplerian disk on long timescales. The Cargo-LeRoux method fares substantially worse in our tests, although its simplicity may still offer some merits in certain situations. Overall, we find the well-balanced treatment of gravity in combination with low Mach number flux functions essential to reproducing correct physical solutions to challenging stellar slow-flow problems on affordable collocated grids.Comment: Accepted for publication in A&

Theory for the coupling between longitudinal phonons and intrinsic Josephson oscillations in layered superconductors

In this publication a microscopic theory for the coupling of intrinsic Josephson oscillations in layered superconductors with longitudinal c-axis-phonons is developed. It is shown that the influence of lattice vibrations on the c-axis transport can be fully described by introducing an effective longitudinal dielectric function. Resonances in the I-V-characteristic appear at van Hove singularities of both acoustical and optical longitudinal phonon branches. This provides a natural explanation of the recently discovered subgap structures in the I-V-characteristic of highly anisotropic cuprate superconductors. The effect of the phonon dispersion on the damping of these resonances and the coupling of Josephson oscillations in different resistive junctions due to phonons are discussed in detail.Comment: submitted to Phys. Rev. B, corrections following referee repor

Motilitätsstörungen des Ösophagus

Zusammenfassung: Motilitätsstörungen des Ösophagus umfassen ein heterogenes Spektrum von Erkrankungen. Primäre Fehlbildungen des Ösophagus sind heute zwar einer verbesserten chirurgischen und gastroenterologischen Therapie zugänglich, führen jedoch zu langfristig persistierender ösophagealer Dysmotilität. Die Achalasie resultiert aus einer gestörten Relaxation des gastroösophagealen Sphinkters. Systemische Erkrankungen können mit einer sekundären ösophagealen Motilitätsstörung einhergehen. Zahlreiche neuromuskuläre Erkrankungen mit viszeraler Manifestation zeigen eine ösophageale Beteiligung. Selten kann eine Aganglionose bis in den Ösophagus reichen. Die wachsende Gruppe der Myopathien schließt metabolische und mitochondriale Störungen ein, deren zunehmende Charakterisierung genetischer Defekte vereinzelt bereits therapeutische Ansätze eröffnet. Infektbedingte Ösophagitiden zeigen besonders bei immunkompromittierten Patienten eine schwere Störung der Motilität. Immunologisch vermittelte Entzündungsprozesse im und um den Ösophagus werden allmählich besser verstanden. Schließlich können seltene Tumoren und tumorartige Läsionen eine Dysmotilität des Ösophagus verursache

What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice

BACKGROUND: The use of brand rather than generic names for medications can increase health care costs. However, little is known at a national level about how often physicians refer to drugs using their brand or generic names. OBJECTIVE: To evaluate how often physicians refer to drugs using brand or generic terminology. DESIGN AND PARTICIPANTS: We used data from the 2003 National Ambulatory Medical Care Survey (NAMCS), a nationally representative survey of 25,288 community-based outpatient visits in the United States. After each visit, patient medications were recorded on a survey encounter form by the treating physician or transcribed from office notes. MEASUREMENTS: Our main outcome measure was the frequency with which medications were recorded on the encounter form using their brand or generic names. RESULTS: For 20 commonly used drugs, the median frequency of brand name use was 98% (interquartile range, 81–100%). Among 12 medications with no generic competition at the time of the survey, the median frequency of brand name use was 100% (range 92–100%). Among 8 medications with generic competition at the time of the survey (“multisource” drugs), the median frequency of brand name use was 79% (range 0–98%; P < .001 for difference between drugs with and without generic competition). CONCLUSIONS: Physicians refer to most medications by their brand names, including drugs with generic formulations. This may lead to higher health care costs by promoting the use of brand-name products when generic alternatives are available