Measurement of CP asymmetry in muon-tagged D0->K-K+ and D0->pi-pi+ decays at LHCb

This thesis presents the measurement of the time-integrated CP asymmetries in D0->K-K+ and D0->pi-pi+ decays. The analysis uses data corresponding to an integrated luminosity of 3 fb^-1 collected at the LHCb experiment in proton-proton collision at centre-of-mass energies of 7 TeV and 8 TeV. The D0 mesons are produced in semileptonic b-hadron decays, where the charge of the accompanying muon determines the initial flavour of the D0 meson. By taking the difference of the observed asymmetries in the selected D0->K-K+ and D0->pi-pi+ samples, production and detection asymmetries cancel. The difference in CP asymmetries between the two final states is measured to be DeltaACP = AcpKK - Acppipi = (+0.14+-0.16(stat)+-0.08(syst))%. In order to obtain a measurement of AcpKK, large samples of Cabibbo-favoured D+ meson decays are used to determine production and detection asymmetries to a high precision. The CP asymmetry is found to be AcpKK = (-0.06+-0.15(stat)+-0.10(syst))%, where the correlation coefficient between DeltaACP and AcpKK is rho=0.28. By combining these results, the CP asymmetry in decays D0->pi-pi+ is derived to be Acppipi = (-0.20+-0.19(stat)+-0.10(syst))%. The results of this thesis show that there is no significant CP violation in D0->K-K+ and D0->pi-pi+ decays at the level of 10^-3

Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo

BACKGROUND Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified "circulatory shock" as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation. RESULTS To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3$^{tm1-Jfz}$ VE-Cadherin(PAC)-cerERT2) led to baseline Tie2 suppression inducing spontaneous vascular leak. On the contrary, the transient overexpression of GATA3 in the pulmonary endothelium (jet-PEI plasmid delivery platform) was sufficient to increase Tie2 at baseline and completely block its hypotension-induced acute drop. On the functional level, the Tie2 protection by GATA3 overexpression abrogated the development of pulmonary capillary leakage. CONCLUSIONS The data suggest that the GATA3-Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies

Explaining Age-Differences in Working Memory: The Role of Updating, Inhibition, and Shifting

Working memory (WM) represents the capacity to store and process a limited amount of information. Better understanding developmental changes of WM forms a key topic in research on neuropsychology of aging. Previous studies reveal age-differences in WM and in executive functions (EFs). Although EFs are seen as essential mechanisms in WM, the specific relation between the two cognitive constructs so far remains unclear. The present study set out to investigate the unique roles of the three main facets of EFs (i.e., updating, inhibition, and shifting) in accounting for age-related variability in WM. Therefore, one-hundred seventy-five younger and 107 older adults performed a battery of cognitive tests including measures of WM, EFs, and processing speed. A set of statistical approaches including regression analyses and path models was used to examine the cognitive correlates that could explain individual and age-related variance in WM. Significant age-differences were found on WM and on EF measures. Regression analyses and path models showed that updating and inhibition but not shifting played a major role in explaining age-related variance in WM. In sum, findings suggest that updating and inhibition are most influential for age-differences in WM. They further show that age and processing speed do not significantly contribute to variability in WM performance beyond executive resource. The present findings have implications for conceptual and developmental theories of WM and may further offer an initial empirical basis for developing possible trainings to improve older adults’ WM performance by strengthening the efficiency of updating and inhibitory processes