Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

<p>Background: Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.</p> <p>Methods: The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.</p> <p>Results: No growth defect under low and elevated oxygen tension, no up-or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.</p&gt

Synchronization, Diversity, and Topology of Networks of Integrate and Fire Oscillators

We study synchronization dynamics of a population of pulse-coupled oscillators. In particular, we focus our attention in the interplay between networks topological disorder and its synchronization features. Firstly, we analyze synchronization time $T$ in random networks, and find a scaling law which relates $T$ to networks connectivity. Then, we carry on comparing synchronization time for several other topological configurations, characterized by a different degree of randomness. The analysis shows that regular lattices perform better than any other disordered network. The fact can be understood by considering the variability in the number of links between two adjacent neighbors. This phenomenon is equivalent to have a non-random topology with a distribution of interactions and it can be removed by an adequate local normalization of the couplings.Comment: 6 pages, 8 figures, LaTeX 209, uses RevTe

Dynamical coupled-channel approaches on a momentum lattice

Dynamical coupled-channel approaches are a widely used tool in hadronic physics that allow to analyze different reactions and partial waves in a consistent way. In such approaches the basic interactions are derived within an effective Lagrangian framework and the resulting pseudo-potentials are then unitarized in a coupled-channel scattering equation. We propose a scheme that allows for a solution of the arising integral equation in discretized momentum space for periodic as well as twisted boundary conditions. This permits to study finite size effects as they appear in lattice QCD simulations. The new formalism, at this stage with a restriction to S-waves, is applied to coupled-channel models for the sigma(600), f0(980), and a0(980) mesons, and also for the Lambda(1405) baryon. Lattice spectra are predicted.Comment: 7 pages, 4 figure

Phenomenology of Randall-Sundrum Black Holes

We explore the phenomenology of microscopic black holes in the $S^1/Z_2$ Randall-Sundrum (RS) model. We consider the canonical framework in which both gauge and matter fields are confined to the brane and only gravity spills into the extra dimension. The model is characterized by two parameters, the mass of the first massive graviton $(m_1)$, and the curvature $1/\ell$ of the RS anti-de Sitter space. We compute the sensitivity of present and future cosmic ray experiments to various regions of $\ell$ and $m_1,$ and compare with that of Runs I and II at the Tevatron. As part of our phenomenological analysis, we examine constraints placed on $\ell$ by AdS/CFT considerations.Comment: Version to appear in Physical Review D; contains additional analysis on sensitivity of OW

Detecting Microscopic Black Holes with Neutrino Telescopes

If spacetime has more than four dimensions, ultra-high energy cosmic rays may create microscopic black holes. Black holes created by cosmic neutrinos in the Earth will evaporate, and the resulting hadronic showers, muons, and taus may be detected in neutrino telescopes below the Earth's surface. We simulate such events in detail and consider black hole cross sections with and without an exponential suppression factor. We find observable rates in both cases: for conservative cosmogenic neutrino fluxes, several black hole events per year are observable at the IceCube detector; for fluxes at the Waxman-Bahcall bound, tens of events per year are possible. We also present zenith angle and energy distributions for all three channels. The ability of neutrino telescopes to differentiate hadrons, muons, and possibly taus, and to measure these distributions provides a unique opportunity to identify black holes, to experimentally constrain the form of black hole production cross sections, and to study Hawking evaporation.Comment: 20 pages, 9 figure

Role of baryonic resonances in the dilepton emission in nucleon-nucleon collisions

Within an effective Lagrangian model, we present calculations for cross sections of the dilepton production in proton-proton and proton-neutron collisions at laboratory kinetic energies in 1-5 GeV range. Production amplitudes include contributions from the nucleon-nucleon bremsstrahlung as well as from the mechanism of excitation, propagation, and radiative decay of Delta(1232) and N*(1520) intermediate baryonic resonances. It is found that the delta isobar terms dominate the cross sections in the entire considered beam energy range. Our calculations are able to explain the data of the DLS collaboration on the dilepton production in proton-proton collisions for beam energies below 1.3 GeV. However, for incident energies higher than this the inclusion of contributions from other dilepton sources like Dalitz decay of pi0 and eta mesons, and direct decay of rho and omega mesons is necessary to describe the data.Comment: 22 pages, 7 figures, more details of the calculations added, version to appear in Phys. Rev

The modulation effect for supersymmetric dark matter detection with asymmetric velocity dispersion

The detection of the theoretically expected dark matter is central to particle physics cosmology. Current fashionable supersymmetric models provide a natural dark matter candidate which is the lightest supersymmetric particle (LSP). Such models combined with fairly well understood physics like the quark substructure of the nucleon and the nuclear form factor and the spin response function of the nucleus, permit the evaluation of the event rate for LSP-nucleus elastic scattering. The thus obtained event rates are, however, very low or even undetectable. So it is imperative to exploit the modulation effect, i.e. the dependence of the event rate on the earth's annual motion. In this review we study such a modulation effect in directional and undirectional experiments. We calculate both the differential and the total rates using symmetric as well as asymmetric velocity distributions. We find that in the symmetric case the modulation amplitude is small, less than 0.07. There exist, however, regions of the phase space and experimental conditions such that the effect can become larger. The inclusion of asymmetry, with a realistic enhanced velocity dispersion in the galactocentric direction, yields the bonus of an enhanced modulation effect, with an amplitude which for certain parameters can become as large as 0.46.Comment: 35 LATEX pages, 7 Tables, 8 PostScript Figures include

Black Holes from Cosmic Rays: Probes of Extra Dimensions and New Limits on TeV-Scale Gravity

If extra spacetime dimensions and low-scale gravity exist, black holes will be produced in observable collisions of elementary particles. For the next several years, ultra-high energy cosmic rays provide the most promising window on this phenomenon. In particular, cosmic neutrinos can produce black holes deep in the Earth's atmosphere, leading to quasi-horizontal giant air showers. We determine the sensitivity of cosmic ray detectors to black hole production and compare the results to other probes of extra dimensions. With n \ge 4 extra dimensions, current bounds on deeply penetrating showers from AGASA already provide the most stringent bound on low-scale gravity, requiring a fundamental Planck scale M_D > 1.3 - 1.8 TeV. The Auger Observatory will probe M_D as large as 4 TeV and may observe on the order of a hundred black holes in 5 years. We also consider the implications of angular momentum and possible exponentially suppressed parton cross sections; including these effects, large black hole rates are still possible. Finally, we demonstrate that even if only a few black hole events are observed, a standard model interpretation may be excluded by comparison with Earth-skimming neutrino rates.Comment: 30 pages, 18 figures; v2: discussion of gravitational infall, AGASA and Fly's Eye comparison added; v3: Earth-skimming results modified and strengthened, published versio

Quantum Fluctuation Relations for the Lindblad Master Equation

An open quantum system interacting with its environment can be modeled under suitable assumptions as a Markov process, described by a Lindblad master equation. In this work, we derive a general set of fluctuation relations for systems governed by a Lindblad equation. These identities provide quantum versions of Jarzynski-Hatano-Sasa and Crooks relations. In the linear response regime, these fluctuation relations yield a fluctuation-dissipation theorem (FDT) valid for a stationary state arbitrarily far from equilibrium. For a closed system, this FDT reduces to the celebrated Callen-Welton-Kubo formula

The adolescent and young adult (AYA) horizon study: An AYA cancer survivorship cohort

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States. Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15–39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data. Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall (N ¼ 1,679), and notably lower among minority groups compared with non-Hispanic white women. Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements. Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care