Introduction The embrace of PET by medical clinicians has been reluctant (ΔT ≈ 20 yr) primarily due to the scale of the infrastructure that is needed. The capital cost of a cyclotron (≈ 106 USD) is now dwarfed by the demand for compliance to recent regulatory standards. This is a recurring expense, not only imposing an order-of-magnitude increase in staffing and operating costs, but damping the enthusiasm of researchers recalling the brisk pace of research in earlier days. Now an academic site, with little interest or opportunity to scale up production for wider distribution, is burdened by the new regulatory terrain of good manufacturing practice (GMP), mandated for translational studies that will reach only a few subjects. With our production resources held within a basic science department, the Medical Physics cyclotron facility at the University of Wisconsin has sought a sustainable pathway. We now anchor the operating budget by providing high-value, long-lived radionuclides to off-site users, to buffer the fluctuations of local demand for conventional PET synthons. Material and Methods: The tools of the trade The radioisotopes discussed here belong to the 3-d and 4-d sub shell, but are now moving into the rare-earths, with applications ranging from - targeted molecular imaging agents, - internal radionuclide therapy using to Auger electron-emitters, - to basic physics experiments using 163Ho (t1/2 ≈ 4500 yr) to determine the mass of the neutrino. Rather than focusing on the dozens of radionuclides produced, a number of tools deserve mention, as they support a variety of targets, reactions and products. These will be listed in order (A-G) from cyclotron to extraction to analysis. A. Two cyclotrons are used, a legacy RDS 112 (#1; 1985) and a GE PETtrace (2009). Neutron and gamma detectors are monitored during the long irradia-tions, signaling any subtle changes in the running conditions. (1). The PET-trace is fitted with a quick-change variable degrader target (2), as well as a beam-line with a 5-port (0 o, ±15 o, ±30 o) vertical switching magnet (3). The downward directed beam ports provide support for solid targets (e.g. Ga, S, Se, Te) that melt at low temperature. The irradiation of gas targets employs a generalized manifold to handle inert gases such as 36Ar for the production of 34mCl, as well as natural Kr and Xe for making Rb and Cs isotopes to act as fission product surrogates. These products are captured on a stainless steel target chamber liner, and rinsed off with warm water. The alkali metals are convenient tracers to study the ion exchange trapping process, pivotal in future 99Mo production from solution reactors (4). B. The preparation of malleable solid targets employs a 10-ton hydraulic bench press, and a jeweler’s mill to roll out foils from pellets, pressed between Nb foils to avoid contamination. C. Binary alloys are smelted in a programmable 1600o tube furnace under argon flow (eg. NiGa4). Alternatively, an induction furnace now permits highly localized heating of the binary metal charge, while allowing mechanical agitation during the smelting process. D. Electroplating onto gold discs is used for various enriched target material or the alloys above where quantitative recovery is essential, or where heat transfer from high beam current is demanding. E. The separation chemistry, prior to che-lation to targeted molecular imaging agents, is performed in LabView-driven, home-built “black boxes” resident in mini-cells (Radiation Shielding Inc.). F. Analysis of the targets after irradiation makes use of HPGe spectroscopy for gammas and characteristic X-rays of decay (e.g. rare earths). The elemental constitution of target alloys is deter-mined prior to irradiation by X-ray fluorescence analysis, excited by 109Cd and 241Am sources. G. Finally, broad-band elemental analysis at the ppb level now makes use of a microwave plasma atomic emission spectrometer (Agilent 4200), to be de-scribed elsewhere in this meeting. Results and Conclusions The tools above (A-G) are employed in the pro-duction of the expanded list of radionuclides offered by our cyclotron group to both local and off-site colleagues. The list below is ordered in terms of decreasing use, from regular production for national distribution (64Cu, 89Zr), to weekly inhouse use (44Sc, 66,68Ga, 68,69,71Ge, 72As, 61Cu, 86Y), to infrequent production for multi-site collaborations (163Ho, 95mTc, 206Bi): Radionuclide Target Employs 64Cu 64Ni/Au A, D, G 89Zr natY A, E, G 44Sc natCa A, B, E, F, G 66, 68Ga Zn/Ag A, B, D, E, F, G 68, 69, 71Ge Ga, GaO2 A, B, C, E,F 72As GeO2 A, B, E, F 52Mn natCr A, E, F, G 76, 81mBr SeO A, E, F 34mCl, Rb, Cs noble gas A, E, F 95mTc,163Ho Mo, Dy A, E, F TABLE 1. Target materials and processes. The production of long-lived radionuclides lends itself to crowd-sourcing, with distributed irradia-tion at virtually any site with a suitable accelera-tor and a relaxed beam schedule. A number of unique challenges do arise that don’t appear in the usual production of conventional cyclotron products such as 11C or 18F. Contamination by stable metals, inadvertently introduced by target pressing or beam-induced sputtering from degraders, can cause serious interference downstream limiting effective specific activity. Long-lived manganese isotopes are ubiquitous. And some very high value products are simply not within the reach of small cyclotrons, such as 52Fe and 67Cu, being too far off the line of beta stability. In conclusion, the research leading to a doctoral degree necessarily must focus on the physics and chemistry of novel radionuclides and tracers. On the other hand, clinical and translational research needs established imaging agents, with little room for innovation within the regulatory constraints. Our experience at Wisconsin has led us to a balancing act, with our routine production of clinical doses countered with our research program to provide high-value radionu-clides for our collaborative work with our basic science colleagues.

Heavy Neutral Leptons (HNLs) are the heavier counterparts of the light neutrinos of the Standard Model of particle physics. HNLs can simultaneously solve several of the problems the Standard Model cannot yet resolve, one example being that they provide a candidate for Dark Matter. This thesis work aims to shed light on the nature of HNLs and study the displaced signature the particle gives rise to at colliders. The collider of interest is the Future Circular Collider that will be colliding electrons and positrons and the signal studied is the production of an HNL and a light neutrino from an intermediate Z boson, produced from the collision of an electron and a positron. The event generation was set up through MadGraph and PYTHIA and for the detector simulations DELPHES was used. Validation of three HNL samples were carried out in a standalone framework and in the FCC framework. The samples were validated by comparing theoretically calculated lifetimes with the lifetimes attained by simulation. Kinematic studies of the transverse momentum of the HNL and its decay particles showed correlation to the mass of the HNL. Reconstruction of the number of tracks created by the HNL decay was possible and the results of two track dominance were found to correlate with theory. For the vertexing study, the reconstruction of the production vertex of the decay particles was possible where displaced vertices were observed, hence proving the possibility of implementing displaced signatures in the FCC framework for the very first time. The next step in this trajectory of the study would be to investigate vertex fitting of the reconstructed vertices in order to carry out tracking studies of the HNL. This work hence sets the foundation for further exploration of HNLs and provides stepping stones for the possibility of discovery of HNLs in the FCC-ee.

Dark matter, the unknown matter that constitutes 85% of all matter in the universe, is one of the greatest mysteries in fundamental physics. One theory that might explain dark matter predicts that there are long-lived particles known as dark pions. If these were created in a particle accelerator, they could decay inside the detector, resulting in particles that seemingly "emerge" from nothing. This phenomenon is known as emerging jets. In this study, emerging jets are simulated with various values of the dark pion average lifetime, dark pion mass, and mediator particle mass. These simulations are compared with a search for displaced vertices conducted by the ATLAS collaboration, allowing one to reinterpret the ATLAS results to constrain the parameter values that the emerging-jets model can have. This study simulates and constrains the allowed values for the dark pion mass, dark pion average life time and mediator mass with 95% confidence level. This is the first study to use results from the ATLAS experiment to constrain the emerging-jets model, as well as the first study to exclude this region of the parameter space.

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Thesis entitled Phenomenon of longevity aims to describe and define very actual today Thema longevity. There is also mentioned particularly contemporary view of the phenomenon and its historical development. This work also touches demographics and life expectancy, which is closely linked to longevity. Great attention is paid to the problem spots in the lives of very old people, especially their disadvantaged status. On this chapter is followed also the care and support of life, that is in such high age necessary. Part of the work are also two research projects that enable an insight into the past lives of long-lived seniors in their health and functional status, and especially trying to uncover the causes of longevity.

La détermination de la concentration des RadioNucléides à Vie Longue (RNVL) dans les déchets de l'industrie nucléaire est essentielle pour la gestion sur le long terme des sites de stockages. Cette étude se focalise sur la détermination de la concentration de trois RNVL : 129I, 41Ca et 10Be dans les résines échangeuses d'ions utilisées pour la purification du fluide primaire des Réacteurs à Eau Pressurisée (REP). Afin d'exploiter les potentialités de la Spectrométrie de Masse par Accélérateur (SMA) pour mesurer ces radionucléides présents en de très faibles concentrations, des procédures analytiques spécifiques ont été développées incluant : 1) la minéralisation des échantillons, 2) l'extraction sélective des analytes, 3) le conditionnement pour la mesure par SMA. Appliquées à des échantillons de résines usées provenant d'une centrale EDF (REP 900 MWe), les procédures développées ont permis l'extraction quantitative et sélective des RNVL d'intérêt vis-à-vis des émetteurs β-γ et des isobares avant leur mesure par SMA sur l'instrument national ASTER (CEREGE, Aix-en-Provence). L'iode 129, le calcium 41 et le béryllium 10 ont été mesurés dans les résines usées à des concentrations de l'ordre de 10 ng/g, 20 pg/g et 4 ng/g de résine sèche, respectivement. Pour ce qui concerne l'iode 129 et le calcium 41, ces concentrations sont en accord avec celles estimées à partir de facteurs de corrélation établis relativement à des émetteurs gamma facilement mesurables (137Cs et 60Co). Dans le cas du béryllium 10, les résultats obtenus différent significativement des valeurs attendues mais sont cohérents avec de précédentes mesures réalisées par ICP-MS. / Determining the concentration of Long-Lived RadioNuclides (LLRN) in nuclear waste is fundamental for the long term management of storage sites. This study focuses on the determination of three LLRN concentrations, i.e. 129I, 41Ca and 10Be, in ion exchange resins used for primary fluid purification in Pressurized Water Reactors (PWR). To benefit from the Accelerator Mass Spectrometry (AMS) technique allowing to measure extremely low levels of nuclide concentrations, analytical procedures including: 1) sample dissolution; 2) selective and quantitative extraction of the analyte; and, 3) analyte conditioning for AMS measurements, were developed. Applied on spent resin samples collected at a 900 MW PWR, the procedures developed for each studied LLRN allowed their quantitative recovery and their selective extraction from β-γ emitters and isobars. The concentration measurements of the LLRN of interest were then performed on the Accelerator Mass Spectrometry national facility ASTER housed by the Centre Européen de Recherche et d'Enseignement des Géosciences de l'Environnement (CEREGE, Aix-en-Provence). 129I, 41Ca and 10Be concentrations in spent resins were measured to be about 10 ng/g, 20 pg/g and 4 ng/g of dry resin, respectively. Considering 129I and 41Ca, the measured concentrations agree with those assessed from scaling factors established relatively to easily measured gamma emitters (137Cs and 60Co). For 10Be, the presented results are significantly different from expected values but are in agreement with previous ICP-MS results.

L’anticorps monoclonal anti-CD20 (Rituximab) est largement utilisé dans le traitement des maladies auto-immunes. L’analyse de la rate des patients souffrant d’un purpura thrombopénique (PTI) ou d’une anémie hémolytique auto-immune traités par anti-CD20 a mis en évidence que la déplétion lymphocytaire B favorisait la différenciation des plasmocytes (PC) normaux en plasmocytes à longue durée de vie (PLDV) auto-réactifs, expliquant en partie l’absence de réponse à ce traitement. L’enjeu de ce projet a été de savoir si la déplétion lymphocytaire B induit l’émergence de PLDV spléniques et de comprendre les processus impliqués dans la survie plasmocytaire. Pour ce faire, nous avons utilisé le modèle de souris transgénique AID-Cre-ERT2xRosa26-loxP-EYFP qui permet de marquer irréversiblement par la protéine EYFP les cellules B lors de leur passage dans un centre germinatif au cours d’une réponse immune après ingestion de tamoxifène, puis de les suivre in vivo. Les PC EYFP+ ont été générés suite à 2 immunisations avec des globules rouges de mouton. Après avoir sélectionné un set de gènes permettant d’établir les signatures plasmablastiques et plasmocytaires, nous avons comparé par RT-PCR multiplex sur cellules uniques le profil d’expression des PC EYFP+ de la rate de souris traitées ou non par anti-CD20. Nous avons ainsi caractérisé dans le contexte de déplétion B une population plasmocytaire dans la rate homogène et mature, proche des PLDV de la moelle osseuse. Ce profil était différent de celui retrouvé dans la rate des souris contrôles, plus hétérogène, comprenant une majorité de PC intermédiaires entre plasmablastes et PC matures. Nous avons observé le même processus de différenciation paradoxale plasmocytaire dans la rate sous anti-CD20 dans le modèle murin lupique NZB/W, signifiant probablement un mécanisme général, que ce soit en contexte auto-immun ou non, chez l’homme et chez la souris. Nous avons identifié le BAFF (B-cell activating factor) comme un facteur essentiel dans le processus de survie des PC de la rate dans le contexte de déplétion B. En effet, le taux de BAFF augmente dans le sérum et le tissu splénique après traitement par anti-CD20, la combinaison in vivo des traitements anti-CD20 et anti-BAFF induit une diminution drastique des PLDV de la rate, sans générer d’hypogammaglobulinémie IgG. Les granuleux Gr1+ et en particulier les neutrophiles Ly6G+ semblent être la principale source de production de BAFF dans le contexte de déplétion B. Nous avons observé un effet similaire de la combinaison anti-CD20 et anti-BAFF sur les PLDV de la rate dans le modèle lupique NZB/W. Enfin, les LT CD4+ sont un autre composant important de la niche splénique dans le contexte de déplétion B. En effet, le nombre de PC EYFP+ diminue significativement avec l’association anti-CD20 et anti-CD4. Ces résultats suggèrent donc que l’association du traitement anti-CD20 à un inhibiteur de facteur de survie plasmocytaire spécifique de la rate, en particulier BAFF, pourrait avoir un bénéfice clinique au cours des maladies auto-immunes en interférant sur le processus paradoxal de maturation des PC. Un essai clinique associant les traitements anti-CD20 et anti-BAFF au cours du PTI débutera prochainement. / Previous data suggested that the monoclonal anti-CD20 antibody induced paradoxically the settlement of autoreactive splenic long-lived plasma cells (LLPC) in the spleen of patients with auto-immune cytopenia, explaining the treatment failure. To investigate whether this process had a general relevance and decipher its mechanism, we used the AID-CreERT2-EYFP mouse model, which allows the irreversible expression of EYFP in B cells engaged in an immune response after tamoxifen regimen to follow plasma cells at different times after immunization. When analyzed by multiplex PCR at the single-cell level, while the splenic EYFP+B220-PC of untreated mice displayed an intermediate profile between short-lived and long-lived PC, the PC from anti-CD20 treated mice composed a more mature homogeneous population, similar to the long-lived bone marrow PC. The absolute number of splenic EYFP+B220-PC did not change significantly upon anti-CD20 treatment indicating that B-cell depletion promoted PC differentiation rather than a long-lived PC selection. BAFF (B-cell activating factor) and CD4+ T-cells played a major role in plasma cell survival since combination of anti-CD20 with anti-BAFF or anti-CD4 antibodies dramatically reduced the number of splenic EYFP+B220- LLPC. Anti-CD20 treatment also promoted the differentiation of LLPC in the spleen in the lupus prone NZB/W model, while a treatment combining anti-CD20 with anti-BAFF induced a marked reduction in total splenic PC numbers. These results suggest that the process of PC maturation upon anti-CD20 treatment is a general mechanism and that interfering with anti-BAFF antibody at the time of B-cell depletion might greatly improve the response rate in auto-immune disease.

The interaction of magma with continental crust at convergent margins is fundamental to understanding if and how continents grow. Isotopic and elemental data constrain the progressive stages of development of the magmatic underpinnings of the long-lived Aucanquilcha Volcanic Cluster (AVC), situated atop the thick continental crust of the central Andes in northern Chile. Whole rock data are used in conjunction with mineral compositions to infer processes that gave rise to eleven million years of intermediate, dominantly dacite, arc volcanism. A pulse of volcanic activity at the AVC between ~5 and 2 Ma is bracketed by more sluggish rates. We document chemical changes in the lavas that accompany this eruptive evolution. Trace element data suggest that crystal fractionation and magma mixing were the dominant mechanisms generating the diversity observed in the AVC whole rock data. Fractionation was dominant during early and waning stages of magmatism, and magma mixing was an important process during the high flux period. Peak thermal maturity of the AVC underpinnings coincided with the high magma flux and likely promoted open system processes during this time. Mineral compositions from zircon, amphibole, pyroxene, and Fe-Ti oxides confirm the importance of material recycling in the production of evolved AVC rocks. Various geothermometers were employed to calculate the pre-eruptive conditions of AVC magma using mineral compositions. Pressure estimates from amphibole and two-pyroxene barometry indicate crystallization depths of 1 ��� 5 kb and 4 ��� 6 kb, respectively. Temperature estimates from zircon, Fe-Ti oxides, amphiboles, and pyroxenes indicate temperatures ranging from ~700��C to 1100��C. Zircon temperatures are always the lowest (700��C - 950��C), and pyroxene temperatures are always the highest (1000��C - 1100��C), with Fe-Ti oxide and amphiboles temperatures falling in between. U-Pb ages from zircons and thermometry from individual samples evidence the thermal maturation and consolidation of the underpinnings below the AVC, presumably culminating in a large, crystal-rich mush zone where magmas were trapped and processed. It is in these middle to upper crustal zones where magmatic diversity is attenuated and giant, relatively homogeneous batholiths are formed. Isotopes of AVC lavas are similar to values observed from other central Andes volcanic centers. Lead isotopes are consistent with the AVC's location within a Pb isotope transition zone between the Antofalla and Arequipa basement terranes. Oxygen and Sr isotopic ratios are high and Nd isotopic ratios low with respect to a depleted mantle. Through time, ������Sr/������Sr values of AVC lavas progressively increase from lows of ~0.70507 to ~0.70579 (upper values of 0.70526 to 0.70680), and ��Nd values decrease from highs of -1.0 to -4.6 (lows of -1.6 to -7.3). Similarly, O isotopes (�������O) show a slight increase in base level through time from lows of 6.5��� to 7.0��� (highs of 6.75��� ��� 7.5���). Dy/Yb and Sm/Yb ratios also increased systematically from highs of 2.11 to 3.45, and 2.76 to 6.67, respectively. Despite the temporal isotopic variation, there is little isotopic variation with indices of fractionation, suggesting this signal is the consequence of deep magmatic processing, here attributed to an expanding zone of melting, assimilation, storage, and homogenization (MASH) of mantle-derived magma in the deep crust. Upward expansion brought the MASH zone into contact with rocks that were increasingly evolved with respect to Sr and Nd isotopes, explaining the isotopic shifts. Downward expansion of the MASH zone enhanced garnet stability during basalt fractionation, explaining the increased Dy/Yb and Sm/Yb ratios. Mass balance calculations involving Sr, Nd, and O isotope modeling are consistent with a crustal component making up 10 - 30% of AVC lavas, implying that although the history of central Andean magmatism is replete with large scale crustal recycling, the current phase is largely a crust formation event. / Graduation date: 2012

Un pic de 60Fe récemment observé dans une croûte ferromanganésienne a été interprété comme la trace de l'explosion d'une supernova qui aurait explosé, suffisamment proche du système solaire pour qu'elle puisse y déposer son empreinte sur la Terre, il y a 2.8 ° 0.4 millions d'années (Myr). Pour confirmer cette interprétation, d'une part avec une meilleure résolution temporelle, d'autre part en ayant accès à la mesure simultanée d'autres isotopes dans différentes phases géochimiques, les sédiments marins sont un outil particulièrement adapté. Ce travail a pour objectif de rechercher dans les sédiments marins les résidus de cette supernova sous forme d'anomalies isotopiques. Les trois principaux noyaux auxquels nous nous sommes intéressés sont l'129I, le 60Fe, et l'26Al, tous trois mesurés sous forme de rapports isotopiques par Spectrométrie de Masse par Accélérateur (SMA). Quantifier le flux des noyaux correspondant à la signature de cette supernova permettrait de mieux contraindre les modèles théoriques de nucléosynthèse stellaire. Ces résidus sont des isotopes produits par une séquence de combustions hydrostatiques pendant l'évolution stellaire et/ou par nucléosynthèse explosive lors de l'explosion de la supernova. Les conditions qui règnent au moment de l'explosion (température, densité de neutrons) permettent de penser que les supernovae pourraient être le site astrophysique du processus r.<br />L'étude en 129I a montré que la mesure de rapports 129I/127I pré-anthropogéniques nécessite un contrôle très strict des différentes sources possibles de contaminations en 129I, et ce d'autant plus lorsque l'on travaille avec de petites quantités d'iode (quelques microgrammes). Cette étude a permis de révéler un écart de plusieurs ordres de grandeurs entre la valeur pré-anthropogénique théorique et expérimentale du rapport 129I/127I dans le milieu marin. Les mesures SMA en 60Fe et 26Al ont permis d'établir, dans la phase authigène des sédiments marins, l'absence de signal en 60Fe sur la zone temporelle correspondant au signal observé dans la croûte Fe-Mn (2.4-3.2 Myr), ainsi qu'en 26Al de 2.6 à 3.2 Myr.

In the first part of this dissertation, recent efforts to understand quantum mechanical effects in biological systems are discussed. Especially, long-lived quantum coherences observed during the electronic energy transfer process in the Fenna-Matthews-Olson complex at physiological condition are studied extensively using theories of open quantum systems. In addition to the usual master equation based approaches, the effect of the protein structure is investigated in atomistic detail through the combined application of quantum chemistry and molecular dynamics simulations. To evaluate the thermalized reduced density matrix, a path-integral Monte Carlo method with a novel importance sampling approach is developed for excitons coupled to an arbitrary phonon bath at a finite temperature. In the second part of the thesis, simulations of molecular systems and applications to vibrational spectra are discussed. First, the quantum dynamics of a molecule is simulated by combining semiclassical initial value representation and density funcitonal theory with analytic derivatives. A computationally-tractable approximation to the sum-of-states formalism of Raman spectra is subsequently discussed.