Nitric oxide and peroxynitrite in health and disease

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review

Inequalities that test locality in quantum mechanics

Quantum theory violates Bell's inequality, but not to the maximum extent that is logically possible. We derive inequalities (generalizations of Cirel'son's inequality) that quantify the upper bound of the violation, both for the standard formalism and the formalism of generalized observables (POVMs). These inequalities are quantum analogues of Bell inequalities, and they can be used to test the quantum version of locality. We discuss the nature of this kind of locality. We also go into the relation of our results to an argument by Popescu and Rohrlich (Found. Phys. 24, 379 (1994)) that there is no general connection between the existence of Cirel'son's bound and locality.Comment: 5 pages, 1 figure; the argument has been made clearer in the revised version; 1 reference adde

Designing the future: strategy, design and the 4th Revolution: an introduction

This is an introduction to the special issue of California Management Review on Design Thinking (DT). This special issue joins the growing body of work exploring the idea of DT and whether DT makes a difference in terms enhancing or augmenting the impact of technology—and, as a result, innovation—in a positive way. We have chosen an interesting, relevant, and useful array of papers that provide different approaches, views, and interpretations of applied design thinking. These articles provide both management and scholarly readers with insights in how DT is used, as well as its impact and usefulness in a variety of contexts

The structure, energy, and electronic states of vacancies in Ge nanocrystals

The atomic structure, energy of formation, and electronic states of vacancies in H-passivated Ge nanocrystals are studied by density functional theory (DFT) methods. The competition between quantum self-purification and the free surface relaxations is investigated. The free surfaces of crystals smaller than 2 nm distort the Jahn-Teller relaxation and enhance the reconstruction bonds. This increases the energy splitting of the quantum states and reduces the energy of formation to as low as 1 eV per defect in the smallest nanocrystals. In crystals larger than 2 nm the observed symmetry of the Jahn-Teller distortion matches the symmetry expected for bulk Ge crystals. Near the nanocrystal's surface the vacancy is found to have an energy of formation no larger than 0.5 to 1.4 eV per defect, but a vacancy more than 0.7 nm inside the surface has an energy of formation that is the same as in bulk Ge. No evidence of the self-purification effect is observed; the dominant effect is the free surface relaxations, which allow for the enhanced reconstruction. From the evidence in this paper, it is predicted that for moderate sized Ge nanocrystals a vacancy inside the crystal will behave bulk-like and not interact strongly with the surface, except when it is within 0.7 nm of the surface.Comment: In Press at Phys. Rev.

Quantification and expert evaluation of evidence for chemopredictive biomarkers to personalize cancer treatment.

Predictive biomarkers have the potential to facilitate cancer precision medicine by guiding the optimal choice of therapies for patients. However, clinicians are faced with an enormous volume of often-contradictory evidence regarding the therapeutic context of chemopredictive biomarkers.We extensively surveyed public literature to systematically review the predictive effect of 7 biomarkers claimed to predict response to various chemotherapy drugs: ERCC1-platinums, RRM1-gemcitabine, TYMS-5-fluorouracil/Capecitabine, TUBB3-taxanes, MGMT-temozolomide, TOP1-irinotecan/topotecan, and TOP2A-anthracyclines. We focused on studies that investigated changes in gene or protein expression as predictors of drug sensitivity or resistance. We considered an evidence framework that ranked studies from high level I evidence for randomized controlled trials to low level IV evidence for pre-clinical studies and patient case studies.We found that further in-depth analysis will be required to explore methodological issues, inconsistencies between studies, and tumor specific effects present even within high evidence level studies. Some of these nuances will lend themselves to automation, others will require manual curation. However, the comprehensive cataloging and analysis of dispersed public data utilizing an evidence framework provides a high level perspective on clinical actionability of these protein biomarkers. This framework and perspective will ultimately facilitate clinical trial design as well as therapeutic decision-making for individual patients

A composite HII region luminosity function in H alpha of unprecedented statistical weight

Context. Statistical properties of HII region populations in disk galaxies yield important clues to the physics of massive star formation. Aims. We present a set of HII region catalogues and luminosity functions for a sample of 56 spiral galaxies in order to derive the most general form of their luminosity function. Methods. HII region luminosity functions are derived for individual galaxies which, after photometric calibration, are summed to form a total luminosity function comprising 17,797 HII regions from 53 galaxies. Results. The total luminosity function, above its lower limit of completeness, is clearly best fitted by a double power law with a significantly steeper slope for the high luminosity portion of the function. This change of slope has been reported in the literature for individual galaxies, and occurs at a luminosity of log L = 38.6\pm0.1 (L in erg/s) which has been termed the Stromgren luminosity. A steep fall off in the luminosity function above log L = 40 is also noted, and is related to an upper limit to the luminosities of underlying massive stellar clusters. Detailed data are presented for the individual sample galaxies. Conclusions. The luminosity functions of HII regions in spiral galaxies show a two slope power law behaviour, with a significantly steeper slope for the high luminosity branch. This can be modelled by assuming that the high luminosity regions are density bounded, though the scenario is complicated by the inhomogeneity of the ionized interstellar medium. The break, irrespective of its origin, is of potential use as a distance indicator for disc galaxies.Comment: Accepted for publication as a Letter in Astronomy & Astrophysics. Latex with postscript figures. Online-only tables and figures are included in this preprint. The HII region catalogues for 56 galaxies will be published electronically on the CDS but are available also on request from the author

Stability of undissociated screw dislocations in zinc-blende covalent materials from first principle simulations

The properties of perfect screw dislocations have been investigated for several zinc-blende materials such as diamond, Si, $\beta$-SiC, Ge and GaAs, by performing first principles calculations. For almost all elements, a core configuration belonging to shuffle set planes is favored, in agreement with low temperature experiments. Only for diamond, a glide configuration has the lowest defect energy, thanks to an sp$^2$ hybridization in the core