Radio halos in a mass-selected sample of galaxy clusters

A fraction of galaxy clusters host Mpc-scale Radio Halos (RH), generated by ultrarelativistic electrons in the magnetized intra cluster medium (ICM). In the current view they trace turbulent regions in merging clusters, where relativistic particles are trapped and accelerated. This model has clear expectations about the statistical properties of RHs. To test these expectations large mass-selected samples of galaxy clusters with adequate radio and X-ray data are necessary. We used the Planck SZ cluster catalogue as suitable starting point of our investigation, selecting clusters with M500>6x10^14 Msun at 0.08

Using sulfur isotope fractionation to understand the atmospheric oxidation of SO 2

Sulfate aerosol plays an important but uncertain role in cloud formation and radiative forcing of the climate, and is also important for acid deposition and human health. The oxidation of SO2 to sulfate is a key reaction in determining the impact of sulfate in the environment through its effect on aerosol size distribution and composition. This thesis presents a laboratory investigation of sulfur isotope fractionation during SO2 oxidation by the most important gas-phase and heterogeneous pathways occurring in the atmosphere. The fractionation factors are then used to examine the role of sulfate formation in cloud processing of aerosol particles during the HCCT campaign in Thuringia, central Germany. The fractionation factor for the oxidation of SO2 by ·OH radicals was measured by reacting SO2 gas, with a known initial isotopic composition, with ·OH radicals generated from the photolysis of water at -25, 0, 19 and 40°C (Chapter 2). The product sulfate and the residual SO2 were collected as BaSO4 and the sulfur isotopic compositions measured with the Cameca NanoSIMS 50. The measured fractionation factor for 34S/32S during gas phase oxidation is αOH = (1.0089 ± 0.0007) − ((4 ± 5) × 10−5 )T (°C). Fractionation during oxidation by major aqueous pathways was measured by bubbling the SO2 gas through a solution of H2 O2

The characterization of the Atxn2-CAG42-knock-in mouse as a model for Spinocerebellar Ataxia Type 2

Die Ursache der neurodegenerativen Erkrankung Spinozerebelläre Ataxie Typ 2 (SCA2) ist eine expandierte Polyglutamin-Domäne im humanen ATXN2-Gen von normalerweise 22 auf über 31 CAGs. Von der Degeneration sind vorwiegend die zerebellären Purkinje Neuronen betroffen, in denen zunehmend zytoplasmatische Aggregate sichtbar werden. Auch wenn die genaue Funktion von ATXN2 und die zugrunde liegenden molekularen Mechanismen noch immer ungeklärt sind, werden ein toxischer Funktionsgewinn sowie der Verlust der normalen Proteinfunktion als mögliche Ursachen diskutiert.rnUm ein wirklichkeitsgetreues Tiermodell für die SCA2 zu haben, wurde eine knock-in Maus generiert, deren einzelnes CAG im Atxn2-Gen durch 42 CAGs ersetzt wurde. Dieses Mausmodell ist durch eine stabile Vererbung der Expansion charakterisiert. Weiterhin zeigt sie ein verringertes Körpergewicht sowie eine spät beginnende motorische Inkoordination, was dem Krankheitsbild von SCA2 entspricht. rnIm Weiteren konnte gezeigt werden, dass, obwohl die Atxn2 mRNA-Spiegel in Großhirn und Kleinhirn erhöht waren, die Menge an löslichem ATXN2 im Laufe der Zeit abnahm und dies mit einem Auftreten an unlöslichem ATXN2 korrelierte. Dieser im Kleinhirn progressive Prozess resultierte schließlich in zytoplasmatischen Aggregaten innerhalb der Purkinje Neuronen alter Mäuse. Der Verlust an löslichem ATXN2 könnte Effekte erklären, die auf einen partiellen Funktionsverlust von ATXN2 zurückzuführen sind, wobei die Aggregatbildung einen toxischen Funktionsgewinn wiederspiegeln könnte. Neben ATXN2 wurde auch sein Interaktor PABPC1 zunehmend unlöslich. Während dies im Großhirn eine Erhöhung der PABPC1 mRNA- und löslichen Proteinspiegel zur Folge hatte, konnte keine kompensatorische Veränderung seiner mRNA und zudem eine Verminderung an löslichem PABPC1 im Kleinhirn beobachtet werden. Auch PABPC1 wurde in Aggregate sequestriert. Diese Unterschiede zwischen Großhirn und Kleinhirn könnten zu der spezifischen Vulnerabilität des Kleinhirns beitragen.rnUm die Folgen auf mRNA-Prozessierung zu untersuchen, wurde ein Transkriptomprofil im mittleren sowie fortgeschrittenen Alter der Mäuse erstellt. Hierbei war eine erhöhte Expression von Fbxw8 im Kleinhirn alter Mäuse auffällig. Als Komponente eines Ubiquitin-E3-Ligase-Komplexes, hilft FBXW8 in der Degradierung von Zielproteinen und könnte somit die Toxizität des expandieren ATXN2 verringern. rnZur näheren Beschreibung der physiologischen Funktion von ATXN2, konnte in ATXN2-knock-out Mäusen gezeigt werden, dass das Fehlen von ATXN2 zu einer reduzierten globalen Proteinsyntheserate führte und somit eine Rolle als Translationsaktivator möglich erscheint. Kompensatorisch wurde eine erhöhte S6-Phosphorylierung gemessen.

New analytical LC-mass spectrometry methodologies for the quali-quantitative determination of natural substances and drugs in complex matrices

This thesis reports an integrated analytical and physicochemical approach for the study of natural substances and new drugs based on mass spectrometry techniques combined with liquid chromatography. In particular, Chapter 1 concerns the study of Berberine a natural substance with pharmacological activity for the treatment of hepatobiliary and intestinal diseases. The first part focused on the relationships between physicochemical properties, pharmacokinetics and metabolism of Berberine and its metabolites. For this purpose a sensitive HPLC-ES-MS/MS method have been developed, validated and used to determine these compounds during their physicochemical properties studies and plasma levels of berberine and its metabolites including berberrubine(M1), demethylenberberine(M3), and jatrorrhizine(M4) in humans. Data show that M1, could have an efficient intestinal absorption by passive diffusion due to a keto-enol tautomerism confirmed by NMR studies and its higher plasma concentration. In the second part of Chapter 1, a comparison between M1 and BBR in vivo biodistribution in rat has been studied. In Chapter 2 a new HPLC-ES-MS/MS method for the simultaneous determination and quantification of glucosinolates, as glucoraphanin, glucoerucin and sinigrin, and isothiocyanates, as sulforaphane and erucin, has developed and validated. This method has been used for the analysis of functional foods enriched with vegetable extracts. Chapter 3 focused on a physicochemical study of the interaction between the bile acid sequestrants used in the treatment of hypercholesterolemia including colesevelam and cholestyramine with obeticolic acid (OCA), potent agonist of nuclear receptor farnesoid X (FXR). In particular, a new experimental model for the determination of equilibrium binding isotherm was developed. Chapter 4 focused on methodological aspects of new hard ionization coupled with liquid chromatography (Direct-EI-UHPLC-MS) not yet commercially available and potentially useful for qualitative analysis and for “transparent” molecules to soft ionization techniques. This method was applied to the analysis of several steroid derivatives.

Search for high mass resonances decaying into electron-positron pairs in proton-proton collisions at sqrt(s) = 7 TeV with the ATLAS detector

The Standard Model of particle physics was developed to describe the fundamental particles, which form matter, and their interactions via the strong, electromagnetic and weak force. Although most measurements are described with high accuracy, some observations indicate that the Standard Model is incomplete. Numerous extensions were developed to solve these limitations. Several of these extensions predict heavy resonances, so-called Z' bosons, that can decay into an electron positron pair. The particle accelerator Large Hadron Collider (LHC) at CERN in Switzerland was built to collide protons at unprecedented center-of-mass energies, namely 7 TeV in 2011. With the data set recorded in 2011 by the ATLAS detector, a large multi-purpose detector located at the LHC, the electron positron pair mass spectrum was measured up to high masses in the TeV range. The properties of electrons and the probability that other particles are mis-identified as electrons were studied in detail. Using the obtained information, a sophisticated Standard Model expectation was derived with data-driven methods and Monte Carlo simulations. In the comparison of the measurement with the expectation, no significant deviations from the Standard Model expectations were observed. Therefore exclusion limits for several Standard Model extensions were calculated. For example, Sequential Standard Model (SSM) Z' bosons with masses below 2.10 TeV were excluded with 95% Confidence Level (C.L.).

The oxidation capacity of the atmosphere - OH and HO 2 radical measurements in a boreal forest environment using laser induced fluorescence spectroscopy

Das wichtigste Oxidationsmittel für den Abbau flüchtiger Kohlenwasserstoffverbindungen (VOC, engl.: volatile organic compounds) in der Atmosphäre ist das Hydroxylradikal (OH), welches sich in einem schnellen chemischen Gleichgewicht mit dem Hydroperoxylradical (HO2) befindet. Bisherige Messungen und Modellvergleiche dieser Radikalspezies in Waldgebieten haben signifikante Lücken im Verständnis der zugrundeliegenden Prozesse aufgezeigt.rnIm Rahmen dieser Doktorarbeit wurden Messungen von OH- und HO2-Radikalen mittelsrnlaserinduzierten Fluoreszensmesstechnik (LIF, engl.: laser-induced fluorescence) in einem Nadelwald in Süd-Finnland während der Messkampagne HUMPPA–COPEC–2010 (Hyytiälä United Measurements of Photochemistry and Particles in Air – Comprehensive Organic Precursor Emission and Concentration study) im Sommer 2010 durchgeführt. Unterschiedliche Komponenten des LIF-Instruments wurden verbessert. Eine modifizierte Methode zur Bestimmung des Hintergrundsignals (engl.: InletPreInjector technique) wurde in den Messaufbaurnintegriert und erstmals zur Messung von atmosphärischem OH verwendet. Vergleichsmessungen zweier Instrumente basierend auf unterschiedlichen Methoden zur Messung von OH-Radikalen, chemische Ionisationsmassenspektrometrie (CIMS - engl.: chemical ionization mass spectrometry) und LIF-Technik, zeigten eine gute Übereinstimmung. Die Vergleichsmessungen belegen das Vermögen und die Leistungsfähigkeit des modifizierten LIF-Instruments atmosphärische OH Konzentrationen akkurat zu messen. Nachfolgend wurde das LIF-Instrument auf der obersten Plattform eines 20m hohen Turmes positioniert, um knapp oberhalb der Baumkronen die Radikal-Chemie an der Schnittstelle zwischen Ökosystem und Atmosphäre zu untersuchen. Umfangreiche Messungen - dies beinhaltet Messungen der totalen OH-Reaktivität - wurden durchgeführt und unter Verwendung von Gleichgewichtszustandsberechnungen und einem Boxmodell, in welches die gemessenen Daten als Randbedingungen eingehen, analysiert. Wenn moderate OH-Reaktivitäten(k′(OH)≤ 15 s−1) vorlagen, sind OH-Produktionsraten, die aus gemessenen Konzentrationen von OH-Vorläuferspezies berechnet wurden, konsistent mit Produktionsraten, die unter der Gleichgewichtsannahme von Messungen des totalen OH Verlustes abgeleitet wurden. Die primären photolytischen OH-Quellen tragen mit einem Anteil von bis zu einem Drittel zur Gesamt-OH-Produktion bei. Es wurde gezeigt, dass OH-Rezyklierung unter Bedingungen moderater OH-Reaktivität hauptsächlich durch die Reaktionen von HO2 mit NO oder O3 bestimmt ist. Während Zeiten hoher OH-Reaktivität (k′(OH) > 15 s−1) wurden zusätzliche Rezyklierungspfade, die nicht über die Reaktionen von HO2 mit NO oder O3, sondern direkt OH bilden, aufgezeigt.rnFür Hydroxylradikale stimmen Boxmodell-Simulationen und Messungen gut übereinrn(OHmod/OHobs=1.04±0.16), während HO2-Mischungsverhältnisse in der Simulation signifikant unterschätzt werden (HO2mod/HO2obs=0.3±0.2) und die simulierte OH-Reaktivität nicht mit der gemessenen OH-Reaktivität übereinstimmt. Die gleichzeitige Unterschätzung der HO2-Mischungsverhältnisse und der OH-Reaktivität, während OH-Konzentrationen von der Simulation gut beschrieben werden, legt nahe, dass die fehlende OH-Reaktivität in der Simulation eine noch unberücksichtigte HO2-Quelle darstellt. Zusätzliche, OH-unabhängigernRO2/HO2-Quellen, wie z.B. der thermische Zerfall von herantransportiertem peroxyacetylnitrat (PAN) und die Photolyse von Glyoxal sind indiziert.

Development, characterization, and application of flowing atmospheric-pressure afterglow ionization for mass spectrometric analysis of ambient organic aerosols

Addressing current limitations of state-of-the-art instrumentation in aerosol research, the aim of this work was to explore and assess the applicability of a novel soft ionization technique, namely flowing atmospheric-pressure afterglow (FAPA), for the mass spectrometric analysis of airborne particulate organic matter. Among other soft ionization methods, the FAPA ionization technique was developed in the last decade during the advent of ambient desorption/ionization mass spectrometry (ADI–MS). Based on a helium glow discharge plasma at atmospheric-pressure, excited helium species and primary reagent ions are generated which exit the discharge region through a capillary electrode, forming the so-called afterglow region where desorption and ionization of the analytes occurs. Commonly, fragmentation of the analytes during ionization is reported to occur only to a minimum extent, predominantly resulting in the formation of quasimolecular ions, i.e. [M+H]+ and [M–H]– in the positive and the negative ion mode, respectively. Thus, identification and detection of signals and their corresponding compounds is facilitated in the acquired mass spectra. The focus of the first part of this study lies on the application, characterization and assessment of FAPA–MS in the offline mode, i.e. desorption and ionization of the analytes from surfaces. Experiments in both positive and negative ion mode revealed ionization patterns for a variety of compound classes comprising alkanes, alcohols, aldehydes, ketones, carboxylic acids, organic peroxides, and alkaloids. Besides the always emphasized detection of quasimolecular ions, a broad range of signals for adducts and losses was found. Additionally, the capabilities and limitations of the technique were studied in three proof-of-principle applications. In general, the method showed to be best suited for polar analytes with high volatilities and low molecular weights, ideally containing nitrogen- and/or oxygen functionalities. However, for compounds with low vapor pressures, containing long carbon chains and/or high molecular weights, desorption and ionization is in direct competition with oxidation of the analytes, leading to the formation of adducts and oxidation products which impede a clear signal assignment in the acquired mass spectra. Nonetheless, FAPA–MS showed to be capable of detecting and identifying common limonene oxidation products in secondary OA (SOA) particles on a filter sample and, thus, is considered a suitable method for offline analysis of OA particles. In the second as well as the subsequent parts, FAPA–MS was applied online, i.e. for real time analysis of OA particles suspended in air. Therefore, the acronym AeroFAPA–MS (i.e. Aerosol FAPA–MS) was chosen to refer to this method. After optimization and characterization, the method was used to measure a range of model compounds and to evaluate typical ionization patterns in the positive and the negative ion mode. In addition, results from laboratory studies as well as from a field campaign in Central Europe (F–BEACh 2014) are presented and discussed. During the F–BEACh campaign AeroFAPA–MS was used in combination with complementary MS techniques, giving a comprehensive characterization of the sampled OA particles. For example, several common SOA marker compounds were identified in real time by MSn experiments, indicating that photochemically aged SOA particles were present during the campaign period. Moreover, AeroFAPA–MS was capable of detecting highly oxidized sulfur-containing compounds in the particle phase, presenting the first real-time measurements of this compound class. Further comparisons with data from other aerosol and gas-phase measurements suggest that both particulate sulfate as well as highly oxidized peroxyradicals in the gas phase might play a role during formation of these species. Besides applying AeroFAPA–MS for the analysis of aerosol particles, desorption processes of particles in the afterglow region were investigated in order to gain a more detailed understanding of the method. While during the previous measurements aerosol particles were pre-evaporated prior to AeroFAPA–MS analysis, in this part no external heat source was applied. Particle size distribution measurements before and after the AeroFAPA source revealed that only an interfacial layer of OA particles is desorbed and, thus, chemically characterized. For particles with initial diameters of 112 nm, desorption radii of 2.5–36.6 nm were found at discharge currents of 15–55 mA from these measurements. In addition, the method was applied for the analysis of laboratory-generated core-shell particles in a proof-of-principle study. As expected, predominantly compounds residing in the shell of the particles were desorbed and ionized with increasing probing depths, suggesting that AeroFAPA–MS might represent a promising technique for depth profiling of OA particles in future studies.

A 2-dimensional computational model to analyze the effects of cellular heterogeinity on cardiac pacemaking

The mechanical action of the heart is made possible in response to electrical events that involve the cardiac cells, a property that classifies the heart tissue between the excitable tissues. At the cellular level, the electrical event is the signal that triggers the mechanical contraction, inducing a transient increase in intracellular calcium which, in turn, carries the message of contraction to the contractile proteins of the cell. The primary goal of my project was to implement in CUDA (Compute Unified Device Architecture, an hardware architecture for parallel processing created by NVIDIA) a tissue model of the rabbit sinoatrial node to evaluate the heterogeneity of its structure and how that variability influences the behavior of the cells. In particular, each cell has an intrinsic discharge frequency, thus different from that of every other cell of the tissue and it is interesting to study the process of synchronization of the cells and look at the value of the last discharge frequency if they synchronized.

Absence of somatostatin SST(2) receptor internalization in vivo after intravenous SOM230 application in the AR42J animal tumor model

Among clinically relevant somatostatin functions, agonist-induced somatostatin receptor subtype 2 (sst(2)) internalization is a potent mechanism for tumor targeting with sst(2) affine radioligands such as octreotide. Since, as opposed to octreotide, the second generation multi-somatostatin analog SOM230 (pasireotide) exhibits strong functional selectivity, it appeared of interest to evaluate its ability to affect sst(2) internalization in vivo. Rats bearing AR42J tumors endogenously expressing somatostatin sst(2) receptors were injected intravenously with SOM230 or with the [Tyr(3), Thr(8)]-octreotide (TATE) analog; they were euthanized at various time points; tumors and pancreas were analyzed by immunohistochemistry for the cellular localization of somatostatin sst(2) receptors. SOM230-induced sst(2) internalization was also evaluated in vitro by immunofluorescence microscopy in AR42J cells. At difference to the efficient in vivo sst(2) internalization triggered by intravenous [Tyr(3), Thr(8)]-octreotide, intravenous SOM230 did not elicit sst(2) internalization: immunohistochemically stained sst(2) in AR42J tumor cells and pancreatic cells were detectable at the cell surface at 2.5min, 10min, 1h, 6h, or 24h after SOM230 injection while sst(2) were found intracellularly after [Tyr(3), Thr(8)]-octreotide injection. The inability of stimulating sst(2) internalization by SOM230 was confirmed in vitro in AR42J cells by immunofluorescence microscopy. Furthermore, SOM230 was unable to antagonize agonist-induced sst(2) internalization, neither in vivo, nor in vitro. Therefore, SOM230 does not induce sst(2) internalization in vivo or in vitro in AR42J cells and pancreas, at difference to octreotide derivatives with comparable sst(2) binding affinities. These characteristics may point towards different tumor targeting but also to different desensitization properties of clinically applied SOM230.

Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction ¼ 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P ¼ 0.34) or histologic type (P ¼ 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30.

Kaon and D meson masses with N_f = 2+1+1 twisted mass lattice QCD

We discuss the computation of the kaon and D meson masses in the N_f = 2+1+1 twisted mass lattice QCD setup, where explicit heavy flavor and parity breaking occurs at finite lattice spacing. We present three methods suitable in this context and verify their consistency.

Development of a model-based transient calibration process for diesel engine electronic control module tables – Part 2: modelling and optimization

This is the second part of a study investigating a model-based transient calibration process for diesel engines. The first part addressed the data requirements and data processing required for empirical transient emission and torque models. The current work focuses on modelling and optimization. The unexpected result of this investigation is that when trained on transient data, simple regression models perform better than more powerful methods such as neural networks or localized regression. This result has been attributed to extrapolation over data that have estimated rather than measured transient air-handling parameters. The challenges of detecting and preventing extrapolation using statistical methods that work well with steady-state data have been explained. The concept of constraining the distribution of statistical leverage relative to the distribution of the starting solution to prevent extrapolation during the optimization process has been proposed and demonstrated. Separate from the issue of extrapolation is preventing the search from being quasi-static. Second-order linear dynamic constraint models have been proposed to prevent the search from returning solutions that are feasible if each point were run at steady state, but which are unrealistic in a transient sense. Dynamic constraint models translate commanded parameters to actually achieved parameters that then feed into the transient emission and torque models. Combined model inaccuracies have been used to adjust the optimized solutions. To frame the optimization problem within reasonable dimensionality, the coefficients of commanded surfaces that approximate engine tables are adjusted during search iterations, each of which involves simulating the entire transient cycle. The resulting strategy, different from the corresponding manual calibration strategy and resulting in lower emissions and efficiency, is intended to improve rather than replace the manual calibration process.

Thermodynamics of Forming Water Clusters at Various Temperatures and Pressures by Gaussian-2, Gaussian-3, Complete Basis Set-QB3, and Complete Basis Set-APNO Model Chemistries; Implications for Atmospheric Chemistry

The Gaussian-2, Gaussian-3, complete basis set- (CBS-) QB3, and CBS-APNO methods have been used to calculate ΔH° and ΔG° values for neutral clusters of water, (H2O)n, where n = 2−6. The structures are similar to those determined from experiment and from previous high-level calculations. The thermodynamic calculations by the G2, G3, and CBS-APNO methods compare well against the estimated MP2(CBS) limit. The cyclic pentamer and hexamer structures release the most heat per hydrogen bond formed of any of the clusters. While the cage and prism forms of the hexamer are the lowest energy structures at very low temperatures, as temperature is increased the cyclic structure is favored. The free energies of cluster formation at different temperatures reveal interesting insights, the most striking being that the cyclic trimer, cyclic tetramer, and cyclic pentamer, like the dimer, should be detectable in the lower troposphere. We predict water dimer concentrations of 9 × 1014 molecules/cm3, water trimer concentrations of 2.6 × 1012 molecules/cm3, tetramer concentrations of approximately 5.8 × 1011 molecules/cm3, and pentamer concentrations of approximately 3.5 × 1010 molecules/cm3 in saturated air at 298 K. These results have important implications for understanding the gas-phase chemistry of the lower troposphere.