El modelo sueco de carrera docente e investigadora

Es necesario hacer unas aclaraciones previas. En lo que sigue me referiré frecuentemente al NFR (Secretaría para la Investigación). Es éste un órgano, formado por científicos, dependiente del Ministerio de Educación y Ciencia sueco, que lleva casi todo el peso de la financiación de la investigación en todos los campos. El órgano rector se elige democráticamente entre los profesores universitarios, por lo cual su composición no esta ligada al partido en el poder en cada momento

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters

This is the final version of the article. Available from Portland Press via the DOI in this record.There is another ORE record for this publication: http://hdl.handle.net/10871/32310Precise homoeostasis of the intracellular concentration of Cl- is achieved via the co-ordinated activities of the Cl- influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl- co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr1048)]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of 86Rb+ uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr5 in KCC1/KCC3 and Thr6 in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser96). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl- influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl- extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states.This work was supported by the Medical Research Council and the Wellcome Trust [grant number 091415] as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer). K.T.K. is supported by the Manton Center for Orphan Diseases at Children's Hospital Boston at Harvard Medical School, and the Harvard/MIT Joint Research Grants Program in Basic Neuroscience

Including Systematic Uncertainties in Confidence Interval Construction for Poisson Statistics

One way to incorporate systematic uncertainties into the calculation of confidence intervals is by integrating over probability density functions parametrizing the uncertainties. In this note we present a development of this method which takes into account uncertainties in the prediction of background processes, uncertainties in the signal detection efficiency and background efficiency and allows for a correlation between the signal and background detection efficiencies. We implement this method with the Feldman & Cousins unified approach with and without conditioning. We present studies of coverage for the Feldman & Cousins and Neyman ordering schemes. In particular, we present two different types of coverage tests for the case where systematic uncertainties are included. To illustrate the method we show the relative effect of including systematic uncertainties the case of dark matter search as performed by modern neutrino tel escopes.Comment: 23 pages, 10 figures, replaced to match published versio

Low-mass e+e- pair production in 158 A GeV Pb-Au collisions at the CERN SPS, its dependence on multiplicity and transverse momentum

We report a measurement of low-mass electron pairs observed in 158 GeV/nucleon Pb-Au collisions. The pair yield integrated over the range of invariant masses 0.2 < m < 2.0 GeV is enhanced by a factor of 3.5 +/- 0.4 (stat) +/- 0.9 (syst) over the expectation from neutral meson decays. As observed previously in S-Au collisions, the enhancement is most pronounced in the invariant-mass region 300-700 MeV. For Pb-Au we find evidence for a strong increase of the enhancement with centrality. In addition, we show that the enhancement covers a wide range in transverse momentum, but is largest at the lowest observed pt.Comment: 17 pages, 4 figures, submitted to Phys.Lett.

e+e--pair production in Pb-Au collisions at 158 GeV per nucleon

We present the combined results on electron-pair production in 158 GeV/n {Pb-Au} ($\sqrt{s}$= 17.2 GeV) collisions taken at the CERN SPS in 1995 and 1996, and give a detailed account of the data analysis. The enhancement over the reference of neutral meson decays amounts to a factor of 2.31$\pm0.19 (stat.)\pm0.55 (syst.)\pm0.69 (decays)$ for semi-central collisions (28% $\sigma/\sigma_{geo}$) when yields are integrated over $m>$ 200 MeV/$c^2$ in invariant mass. The measured yield, its stronger-than-linear scaling with $N_{ch}$, and the dominance of low pair $p_t$ strongly suggest an interpretation as {\it thermal radiation} from pion annihilation in the hadronic fireball. The shape of the excess centring at $m\approx$ 500 MeV/$c^2$, however, cannot be described without strong medium modifications of the $\rho$ meson. The results are put into perspective by comparison to predictions from Brown-Rho scaling governed by chiral symmetry restoration, and from the spectral-function many-body treatment in which the approach to the phase boundary is less explicit.Comment: 39 pages, 40 figures, to appear in Eur.Phys.J.C. (2005

The AMANDA Neutrino Telescope and the Indirect Search for Dark Matter

With an effective telescope area of order 10^4 m^2, a threshold of ~50 GeV and a pointing accuracy of 2.5 degrees, the AMANDA detector represents the first of a new generation of high energy neutrino telescopes, reaching a scale envisaged over 25 years ago. We describe its performance, focussing on the capability to detect halo dark matter particles via their annihilation into neutrinos.Comment: Latex2.09, 16 pages, uses epsf.sty to place 15 postscript figures. Talk presented at the 3rd International Symposium on Sources and Detection of Dark Matter in the Universe (DM98), Santa Monica, California, Feb. 199

The AMANDA Neutrino Telescope: Principle of Operation and First Results

AMANDA is a high-energy neutrino telescope presently under construction at the geographical South Pole. In the Antarctic summer 1995/96, an array of 80 optical modules (OMs) arranged on 4 strings (AMANDA-B4) was deployed at depths between 1.5 and 2 km. In this paper we describe the design and performance of the AMANDA-B4 prototype, based on data collected between February and November 1996. Monte Carlo simulations of the detector response to down-going atmospheric muon tracks show that the global behavior of the detector is understood. We describe the data analysis method and present first results on atmospheric muon reconstruction and separation of neutrino candidates. The AMANDA array was upgraded with 216 OMs on 6 new strings in 1996/97 (AMANDA-B10), and 122 additional OMs on 3 strings in 1997/98.Comment: 36 pages, 23 figures, submitted to Astroparticle Physic