Modulatory effect of Cytomegalovirus latency and sex on peripheral biomarkers and cognitive performance in old people

“Successful aging” - defined as long life in a good mental and physical health, requires appropriate immune function. However, dysregulated immunity in later life, known as “immunosenescence,” results in compromised immune functions and disturbed pro- and anti-inflammatory balance. The impact of these age-related immune alterations on physical and mental health, and hence successful aging, is currently not well understood. With few exceptions, the studies on aging have not attempted to integrate psycho-neurological, metabolic, and endocrine parameters with immune function in order to dissect out which influences which. Few have taken CMV-infection into account and even gender has not always been considered. The present dissertation contributes to this developing research field both conceptually and empirically. It is publication-oriented and consists of four publications. Publication I presents data obtained from a subgroup of the Berliner Aging Study participants, which show significant age-associated differences of T-cell subset distribution. The modulatory impact of both sex and CMV-infection on T-cell naïve and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells, were found. For the first time, the frequency of the TSCM phenotype and of PD-1+ T-cells in peripheral circulation has been investigated, and the effects of age, CMV-serostatus, and sex on their frequency have been examined. Publication II reviews the relevant literature on the dynamic neuroimmune interactions between the immune and the nervous systems. Bringing these two strands of research together, we propose that immunosenescence and peripheral low-grade inflammation at least partly contribute to neuroinflammation inducing neurodegeneration and age-related cognitive impairments. We review and discuss possible interventions that can prevent or at least postpone these age-related changes. Publication III characterizes the baseline inflammatory status of aged individuals, recruited to undergo the cognitive, physical, and combined training interventions. By analyzing multiple circulating peripheral biomarkers and measures of objective cognitive function, we show that both CMV-serostatus and sex may modulate inflammatory immune factors, cognitive performance, and the relationship between the two domains, and should therefore be considered in comparative and interventional studies with elderly people. In study IV, we propose a new strategy that allows the quantitative investigation of multiple interactions between different cytokines, receptor molecules, metabolic and neurotrophic factors, hormones, immune cells, and measures of cognitive performance. Using a graph-theoretical approach enables us not only to visualize biologically meaningful interconnections between different variables but also to compare the network topology dynamics between different groups of CMV-seronegative and -seropositive men and women in a statistically sound manner. In summary, results obtained from the studies III and IV suggest that highly integrated and segregated networks have optimal neuroimmune interactions. Taken together, this dissertation contributes to the study of age-related functional alterations of immune and related physiological functions in two major ways. First, it expands the analysis methods that have been used to investigate markers of immunosenescence. Second, it has generated new findings on the modulatory effects of CMV-latency and sex on multiple peripheral biomarkers and cognitive function in older men and women

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

The Modulatory Effect of Gender and Cytomegalovirus-Seropositivity on Circulating Inflammatory Factors and Cognitive Performance in Elderly Individuals

Aging is characterized by a chronic increase in the systemic levels of inflammatory cytokines even in ostensibly healthy individuals. The drivers of age-related increase in systemic inflammation are unclear but one potential contributor may be a persistent infection with Cytomegalovirus (CMV). In this study, we characterized the inflammatory status of 161 older participants recruited to undergo a six-month training intervention. We investigated the influence of gender and CMV-seropositivity on the main inflammatory and anti-inflammatory circulating biomarkers, such as cytokines, receptor antagonist, soluble receptor, immune cells, and relevant metabolic markers. We found that both gender and CMV-seropositivity modulate circulating peripheral biomarkers, and that CMV-infection modifies associations among the latter. Moreover, we observed an interaction between CMV-serostatus and gender associations with cognitive abilities: gender differences in fluid intelligence (Gf) and working memory (WM) were noted only in CMV-negative individuals. Finally, we found that in the CMV-seronegative participants Gf, episodic memory (EM), and WM correlated negatively with pro-inflammatory tumor necrosis factor (TNF); and EM correlated positively with anti-inflammatory interleukin (IL)-10. In CMV-seropositive individuals EM and Gf correlated negatively with pro-inflammatory IL-6, while EM, Gf, and WM correlated negatively with anti-inflammatory IL-1RA. We conclude that both CMV-serostatus and gender may modulate neuroimmune factors, cognitive performance and the relationship between the two domains and should therefore be considered in comparative and interventional studies with elderly people

Phenotypic characterization and prognostic impact of circulating γδ and αβ T-cells in metastatic malignant melanoma

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

π0\pi ^{0} and η\eta meson production in proton-proton collisions at s=8\sqrt{s}=8 TeV

An invariant differential cross section measurement of inclusive $\pi ^{0}$ and $\eta$ meson production at mid-rapidity in pp collisions at $\sqrt{s}=8$  TeV was carried out by the ALICE experiment at the LHC. The spectra of $\pi ^{0}$ and $\eta$ mesons were measured in transverse momentum ranges of $0.33.5$   $\text{ GeV/c }$ . However, a deviation from this empirical scaling rule is observed for transverse momenta below $p_{ \text{ T }} <3.5$   $\text{ GeV/c }$ in the $\eta /\pi ^0$ ratio with a significance of $6.2\sigma$

Systematic studies of correlations between different order flow harmonics in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The correlations between event-by-event fluctuations of anisotropic flow harmonic amplitudes have been measured in Pb-Pb collisions at sNN=2.76 TeV with the ALICE detector at the Large Hadron Collider. The results are reported in terms of multiparticle correlation observables dubbed symmetric cumulants. These observables are robust against biases originating from nonflow effects. The centrality dependence of correlations between the higher order harmonics (the quadrangular v4 and pentagonal v5 flow) and the lower order harmonics (the elliptic v2 and triangular v3 flow) is presented. The transverse momentum dependences of correlations between v3 and v2 and between v4 and v2 are also reported. The results are compared to calculations from viscous hydrodynamics and a multiphase transport (AMPT) model calculations. The comparisons to viscous hydrodynamic models demonstrate that the different order harmonic correlations respond differently to the initial conditions and the temperature dependence of the ratio of shear viscosity to entropy density (η/s). A small average value of η/s is favored independent of the specific choice of initial conditions in the models. The calculations with the AMPT initial conditions yield results closest to the measurements. Correlations among the magnitudes of v2, v3, and v4 show moderate pT dependence in midcentral collisions. This might be an indication of possible viscous corrections to the equilibrium distribution at hadronic freeze-out, which might help to understand the possible contribution of bulk viscosity in the hadronic phase of the system. Together with existing measurements of individual flow harmonics, the presented results provide further constraints on the initial conditions and the transport properties of the system produced in heavy-ion collisions