REGULATION OF THE EXPRESSION OF HETEROMERIC RECEPTOR SUBUNITS BY MODULATION OF MRNA STABILITY ¿ A CASE STUDY OF TRC40 RECEPTOR

In recent years, the mechanisms of post-transcriptional regulation of gene expression have gained increased attention, including their importance in oligomeric protein assembly. The ER based proteins CAML and WRB have been described to form a heteromeric protein complex that functions as a receptor for the TRC40 ATPase, mediating the post-translational insertion of tail-anchored proteins into the ER membrane. A recent study showed that, even if the two proteins are not in a stoichiometric equilibrium - CAML is in ~5-fold excess over WRB -, the transient siRNA mediated depletion of each one of the two subunits, in HeLa cells, leads to the depletion of the second one. Interestingly, the silencing of CAML leads not only to the depletion of WRB protein but also to the depletion and strong destabilization of WRB mRNA, revealing a novel mechanism for the regulation of the expression of different subunits of a protein complex. In this thesis, I have followed up on this work, trying to unveil the mechanisms involved in the co-regulation of the expression and assembly of the TRC40 receptor complex. My results demonstrate that the interplay observed at the transcript level is not reciprocal, i.e. CAML mRNA is not affected by WRB siRNA mediated depletion, and that the CAML-sensitivity of the WRB transcript is attributable to a relatively small portion (370 nt) of its 3' untranslated sequence (UTR), as shown by the results obtained with the dual-luciferase reporter system. Moreover, co-IP experiments show that CAML is indeed in excess over WRB and that a WRB-free population of CAML exists. It remains however unclear, what mechanism may explain the depletion of CAML upon WRB silencing. Finally, I propose a model according to which, on the one hand, CAML protein either directly or indirectly interacts with the 3\u2019UTR of WRB, promoting is stability, which is lost when CAML is silenced. On the other hand, CAML may be inserted in the ER membrane in an unusual way, via the TRC40 pathway, meaning that it would require a functional TRC40 receptor complex, which is lost when WRB is silenced. The resulting non-inserted CAML molecules would then be degraded by the ubiquitinproteasome system. Future work is required to further understand the precise mechanisms involved in the co-regulation of the expression of the two subunits of the TRC40 receptor. This work could pave the way for the discovery of new posttranscriptional co-regulatory mechanisms for the expression and assembly of oligomeric protein subunits, which could very well be relevant to many different protein complexes

Tratamiento de fracturas diafisarias inestables de fémur con clavo intramedular encerrojado tipo FMRP

Un grupo de 26 fracturas conminutas de fémur, rotacionalmente inestables, fueron tratadas con clavo intramedular encerrojado tipo FMRP. En 22 casos la conminución afectaba a más del 50% de la cortical. Del total de enclavados, 22 fueron estáticos y 4 dinámicos. La consolidación desde el punto de vista clínico y radiológico ocurrió en el 92% de los casos. En 2 casos se desarrolló un pseudoartrosis. Sólo un paciente mostró un acortamiento mayor de 1 cm. Una angulación mayor de 10° en cualquiera de los planos del espacio fue apreciada en 5 pacientes. No se produjo en ningún caso deformidad rotacional. El clavo intramedular encerrojado ha aumentado las indicaciones del enclavado intramedular en el tratamiento de las fracturas inestables de fémur. La incidencia de infección y pseudoartrosis es baja. La estabilidad del montaje permite una movilización inmediata del paciente, rehabilitación temprana y menor estancia intrahospitalaria. El clavo FMRP disminuye el tiempo de fluoroscopia, un fresado con instrumentos flexibles y es más barato que otros sistemas similares.Twenty six comminuted and rotationally unstable fractures of the femur were treated with the FMBP intramedullary locked nail. Twenty two of the fractures had comminution involving more than 50% of the cortex. Of the nailings, 22 were static and 4 dynamic. Clinical and radiographic union occurred in 92% of cases. There were 2 nonunions. There was one case of deep wound infection. Only one patient had a shortening greater than 1 cm. Angulation in any plane greater than 10° was noted in 5 patients. There were no instances of rotatory deformities. The interlocking nail has expanded the indications for the use of closed intramedullary nailing in the treatment of unstable femoral fractures. The incidence of infection and nonunion is low. Stability of the fractures allows immediate mobilization of the patients, early rehabilitation of the limb and shorter hospital stay. The FMRP nail eliminated fluoroscopy, flexible reamers and is cheaper as compared to other systems

Hadronic τ\tau decay, the renormalization group, analiticity of the polarization operators and QCD parameters

The ALEPH data on hadronic tau-decay is throughly analysed in the framework of QCD. The perturbative calculations are performed in 1-4-loop approximation. The analytical properties of the polarization operators are used in the whole complex q^2 plane. It is shown that the QCD prediction for R_{tau} agrees with the measured value R_{tau} not only for conventional Lambda^{conv}_3 = (618+-29) MeV but as well as for Lambda^{new}_3 = (1666+-7) MeV. The polarization operator calculated using the renormgroup has nonphysical cut [-Lambda^2_3, 0]. If Lambda_3 = Lambda^{conv}_3, the contribution of only physical cut is deficient in the explanation of the ALEPH experiment. If Lambda_3 = Lambda^{new}_3 the contribution of nonphysical cut is very small and only the physical cut explains the ALEPH experiment. The new sum rules which follow only from analytical properties of polarization operators are obtained. Basing on the sum rules obtained, it is shown that there is an essential disagreement between QCD perturbation theory and the tau-lepton hadronic decay experiment at conventional value Lambda_3. In the evolution upwards to larger energies the matching of r(q^2) (Eq.(12)) at the masses J/psi, Upsilon and 2m_t was performed. The obtained value alpha_s(-m^2_z) = 0.141+-0.004 (at Lambda_3 = Lambda^{new}_3) differs essentially from conventional value, but the calculation of the values R(s) = sigma(e+e- -> hadrons)/sigma(e+e- -> mu+mu-), R_l = Gamma(Z -> hadrons)/Gamma(Z -> leptons), alpha_s(-3 GeV^2), alpha_s(-2.5 GeV^2) does not contradict the experiments.Comment: 20 page

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307