The liquid-scintillator neutrino-detector (LSND) and mini booster neutrino experiment (MiniBooNE) experiments claim to observe the oscillation ῡ_µ→ ῡ_e, which can only be explained by additional neutrinos and is a claim that must be further tested. This thesis proposes a new accelerator and experiment called νSTORM to refute or confirm the oscillation these claims by studying the CPT-equivalent channel ν_e→ν_µ. A 3.8-GeV/c muon decay ring is proposed with neutrino detectors placed 20 m and 2000 m from the decay ring. The detector technology would be a magnetized iron sampling calorimeter, where the magnetic field is induced by a superconducting transmission line. In a frequentist study, the sensitivity of this experiment after 5 years would be >10σ. The range of the thesis discussion starts with the proton front-end design and ends with neutrino parameter estimation. After describing the phenomenology of sterile neutrinos, the facility and detector performance work is presented. Finally, the systematics are explained before the sensitivity and parameter-estimation works are explained.

Inflammation in the absence of infection (sterile inflammation) is a crucial host defence response to tissue injury, but is also considered to contribute to the pathogenesis of many diverse disease states, including stroke. Sterile inflammation is initiated by damage associated molecular patterns (DAMPs) which are endogenous molecules released from necrotic cells or that are modified during disease. The pro-inflammatory cytokines IL-1α and IL-1β are key mediators of inflammation. IL-1β release is controlled by caspase-1 which, in turn, is regulated by the inflammasome. The NOD-, LRR-, pyrin domain-containing 3 (NLRP3) inflammasome is most typically associated with sterile inflammation and the recognition of DAMPs. Thus, understanding the mechanisms of NLRP3-activating DAMP-induced inflammation may lead to the identification of novel therapeutic targets with which to treat inflammatory diseases. This thesis sought to determine how NLRP3-activating DAMPs affect the pro-inflammatory response of glia, the immune cells of the brain. Experimental models in vitro typically use a pathogen associated molecular pattern (PAMP) such as LPS to prime cells before observing their response to NLRP3-activating DAMPs. As the brain is protected by the blood brain barrier (BBB), it is unlikely glia would be exposed to PAMP priming. However it remains unclear as to how glia respond to NLRP3-activating DAMPs in the absence of priming, or what the source of endogenous priming is. Therefore, the initial hypothesis was to investigate the pro-inflammatory response of mixed glia in vitro to NLRP3-activating DAMPs in the absence of PAMP priming. It is shown here for the first time that NLRP3-activating DAMPs can initiate an IL-1-NLRP3-independent inflammatory response in mixed glia in the absence of PAMP priming. Moreover, it is shown that the acute phase protein serum amyloid A is elevated in plasma after stroke and may act as an endogenous priming signal to allow IL-1β-dependent inflammation to contribute to the damage after breakdown of the BBB.Inflammation following acute sterile injury such as stroke is augmented by persisting cell death. It was therefore hypothesised that NLRP3-activating DAMPs released after the initial injury, may initiate a form of programmed cell death that continues to drive inflammation. Using inhibitors of specific types of cell death, it was identified that NLRP3-activating DAMP induced cell death is likely to be necrosis and not programmed cell death. Further investigation into the biological importance of DAMP-induced IL-1-independent inflammation and the specific contribution of acute phase proteins to brain pathology may aid the identification of new therapeutic targets.

La thèse de doctorat porte sur la physique des neutrinos de réacteurs. L'étude de plus en plus précise des spectres d'antineutrinos des réacteurs a mis à jour une déviation entre la prédiction et les mesures qui pourrait indiquer l'existence d'un nouveau neutrino, non couplé avec l'interaction faible (un neutrino stérile) et de masse autour de 1 ₑV/c². L'expérience STEREO vise à tester l'hypothèse du neutrino stérile auprès du réacteur ILL de Grenoble. Le principe de STEREO repose sur 6 cellules de détection identiques disposées entre 9 et 11.5 m de distance du cœur du réacteur de recherche de l'ILL. Le détecteur a commencé la prise de données en novembre 2016, et les premiers résultats ont été publiés dès 2018. Le travail effectué pendant la thèse a consisté dans un premier temps à caractériser la réponse en énergie du détecteur. Pendant la première phase de prise de données, des défaillances matérielles se sont manifestées entrainant le découplage optique d'une cellule et une augmentation progressive des fuites de lumière entre cellules. Ces deux aspects ont contraint l'analyse de données à développer un algorithme de reconstruction des dépôts d'énergie qui corrige les fuites lumières au premier ordre. Un important travail sur la mesure des paramètres de cette méthode a été entrepris afin d'assurer que l'échelle en énergie soit bien reproduite dans la simulation GEANT4. L'estimation des incertitudes systématiques sur l'échelle en énergie a été effectuée en se servant des bruits de fond cosmogéniques. Le second aspect majeur abordé pendant la thèse est l'analyse statistique et la génération des contours d'exclusion de l'hypothèse du neutrino stérile. La déduction statistique a été conduite en s'inspirant de la méthode de Feldman et Cousins (1999) sur la génération d'intervalles de confiance fréquentistes. Un formalise en X² a spécialement été développé pour mener une analyse d'oscillations indépendante des prédictions de flux et de forme des spectres antineutrinos. Les erreurs statistiques et systématiques ont été propagées à l'aide de matrices de covariance et les lois de X² ont été calculées en générant des pseudo-expériences. L'ensemble des travaux menés pendant cette thèse de doctorat a contribué à la publication de trois papiers présentant les résultats de l'expérience STEREO. / The doctoral thesis focuses on the physics of reactor neutrinos. The increasingly precise study of antineutrinos spectra from reactors has revealed a deviation between the prediction and the measurements, which could indicate the existence of a new neutrino. This new neutrino state would not couple with the weak interaction (a sterile neutrino) and its mass would be around 1 ₑV/c². The STEREO experiment aims at testing the sterile neutrino hypothesis at the ILL reactor in Grenoble-France. The principle of the STEREO experiment is based on 6 identical detector cells aligned between 9 and 11.5 m distance from the core of the ILL research reactor. The detector started taking data in November 2016, and the first results were published in 2018. The work carried out during the thesis initially consisted in characterizing the detector's energy response. During the first phase of data taking, hardware failures occurred leading to the optical decoupling of a cell and a gradual increase in light cross-talk between cells. These two aspects have compelled data analysis to develop a dedicated energy deposit reconstruction algorithm that corrects first-order light leaks using a matrix formalism. Significant work on the measurement of the parameters of this method was undertaken to ensure that the energy scale was well reproduced in the GEANT4 simulation. The estimation of systematic uncertainties on the energy scale was performed using cosmogenic background events. The second major aspect addressed during the thesis is the statistical analysis and generation of exclusion contours of the sterile neutrino hypothesis. The statistical inference was built using the Feldman and Cousins (1999) method by generating frequentist confidence intervals. A formalization in X² has been specially developed to conduct the oscillation analysis independently of any flux or shape prediction of the antineutrino spectra. Statistical and systematic errors were propagated using covariance matrices and X² laws were constructed by generating pseudo-experiments. All the work carried out during this doctoral thesis contributed to the publication of three papers presenting the results of the STEREO experiment.

Whey from a commercial cheese plant, taken at draining on five separate days, from cheese made with a Mucor miehei coagulant was cooled within 1 h to 4 C. Portions were adjusted from pH 4.2 to 6.4 at .2 pH intervals and subjected to HTST pasteurization at 73.9, 76.6, and 79.5 C for 25 sec. Milk clotting activity in whey was determined before and after pasteurization. Resistance to heat in-activation increased with decreasing pH. All measurable activity was destroyed above pH 5.4 by pasteurization at 79.5 C, above pH 5.8 at 76.6 C and above pH 6.0 at 73.9 C. Milk clotting activity in Cheddar cheese mad with Mucor miehei remained unchanged for 26 weeks. Four commercial sterile liquid-milk-based consisting of infant formula, concentrated infant formula, nutritionally complete food, and diet food was aseptically inoculated with sterile Mucor miehei protease solutions to concentrations ranging from 5 x 10-3 to 1 x 10-7 chymosin units/ml of product. The samples were stored at 30 C. After 20 weeks there was no change in the nutritionally complete food. The diet food showed slight whey separation and thickening at 1 x 10-4 CU/ml and coagulation at higher concentrations. The infant formula showed definite whey separation and thickening at 1 x 10-4 CU/ml and coagulation and higher concentrations. The concentrated infant formula showed visible thickening at 1 x 10-3 CU/ml and coagulation at higher concentrations.

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Neutrino physics has been going through rapid developments since the particle was first proposed by Pauli. The observation of neutrino oscillations has prompted an investigation of the issue of neutrino mass, with the "seesaw" mechanism garnering theoretical support. The HUNTER (Heavy Unseen Neutrinos from the Total Energy-momentum Reconstruction) experiment brings together AMO, nuclear physics and high energy physics researchers from Temple University, Houston University, UCLA and Princeton University to develop an apparatus capable of probing the keV-mass range of sterile neutrinos with high precision. The HUNTER detector makes use of the well-established COLTRIMS techniques for the collection of all the decay products of a neutrino-producing decay, and the reconstruction of their initial momenta and energies. Energy and momentum conservation allow then for the reconstruction of the missing neutrino mass.Electrons produced in the decay are guided towards their detector by an optimized set of electrodes paired to a magnetic field to confine their trajectories into spirals. A magnetic shield protects the electron from external stray fields that could alter their trajectories. A thorough study on the main source of background, namely the source scattering of ions, was conducted. As an additional topic, the feasibility of a directional-sensitive dark matter search experiment has been studied. Simple models of galactic dark matter distribution suggest that the motion of the Earth in space might introduce a directional anisotropy in the WIMPs momentum distribution at the Earth. The shape of a WIMP-like recoil in a target material could be be used to extract directional information for the incident WIMP, and thus confirm the anisotropy. The peculiar microphysics of liquid Argon requires thermalization of ionization electrons for a signal to form. To determine if directional information can be extracted, one needs to understand the energy spectrum of the electrons emitted in recoil event. Then, one needs a model to determine the time scale of the thermalization, and the distance to which the electrons travel. / Physics

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Therapeutic viruses are a class of biotherapeutic which have enabled new treatments and medical advances in the areas of vaccines, cancer treatment, gene therapy, and more. In the production and purification of these products, the sterile filtration unit operation is known to have poor yields and contribute to the high cost of the final product, significantly hampering the large-scale production of some therapeutic viruses. Thus, this thesis seeks to explore various aspects of process development and fundamental understanding in the sterile filtration of therapeutic viruses. This thesis explores the mechanisms and membrane properties which govern how bacteria are retained during filtration, and applies these insights to improve the sterile filtration recovery of a therapeutic virus through proper membrane selection. To better understand the factors which cause membrane fouling and loss of virus during sterile filtration, the effect of host cell impurities on filtration performance was investigated. This revealed that small amounts of host cell protein are a major factor in both membrane fouling and reduced virus yield, and that there is a synergistic effect between the virus and the host cell protein adsorbing to the membrane surface. Recognizing that conventional polymeric membranes have many limitations, a novel ultrathin, isoporous, microfabricated silicon nitride membrane was tested for suitability as a sterile filter. Finally, the application of nanoparticles as model virus particles in filtration testing was examined, and a process was developed through which nanoparticles could be fused together to create controlled amounts of particle aggregates, similar to how viruses can be prone to aggregation. The work described here will help enable the development of next generation sterile filtration membranes and provides both insights and methodologies for improving sterile filtration performance. / Thesis / Doctor of Philosophy (PhD) / While many people are aware that viruses can be used in medicine as vaccines, there are even more new and developing ways they can be used, such as in fighting cancer or treating previously uncurable diseases. However, testing of and patient access to these new treatments is often limited due to the challenges in producing and purifying enough of the virus. Viruses are highly complex and large relative to other products, and so many of the common methods and manufacturing processes which are standard in the industry need to be significantly adapted or improved to suit the production of viruses. This study investigates one step of the purification process, sterile filtration, and considers how a variety of factors from the materials used to the properties of the virus solution can be optimized to improve performance. With a deeper understanding of the sterile filtration process, recommendations can be made to help improve the production of future virus-based therapies.

Oncolytic viruses (OVs) are a class of cancer therapy that is currently undergoing clinical trials on its way to full regulatory approval. At present, the downstream processing of OVs relies on a combination of chromatography and membrane-based processes to remove process-related (e.g. host-cell proteins and nucleic acids) and product-related impurities (e.g. aggregated virus particles). This thesis explores various methods that can potentially be used to address the challenges associated with downstream processing during the production of OVs. To this end, the Rhabdoviral vector, which is currently undergoing clinical trials (phase I/II) for use in treating advanced or metastatic solid tumors, was selected as a promising oncolytic virus. One potential improvement in the downstream process that was investigated was the use of monolithic column chromatography for Rhabdovirus purification. Two monolithic anion-exchange columns (2 and 6 µm pore size) and one hydrophobic interaction column (6 µm pore size) were used to examine how column pore size affects virus recovery and contaminant removal. This investigation ultimately inspired the development of a purification process based on monolithic hydrophobic interaction column chromatography. Furthermore, this work is also the first to investigate how additives, namely glycerol, impact the hydrophobic interaction chromatography of virus particles. The developed process could be readily implemented for the scaled-up purification of the Rhabdoviral vector. Another challenge associated with the downstream processing of OVs is membrane fouling, which is characterized by a dramatic rise in transmembrane pressure (TMP) and low virus recovery. Indeed, membrane fouling poses a significant challenge, as some recent studies have reported that it can result in viral vector titer losses of over 80%. One critical use of membranes in downstream processing is for the sterile filtration of OVs, which is a required final step that is conducted right before vialing and involves passing the virus particles through a validated sterile filter. One of the main objectives of this thesis was to develop a fundamental understanding of the sterile filtration process and to optimize it in order to achieve higher throughput and lower losses, which are both essential to the large-scale production of OVs. To this end, a dead-end sterile filtration setup was designed, and various commercially available filters were evaluated to examine how membrane morphology affects fouling and product recovery. The results of these tests showed that double-layered composite filters enabled higher virus recovery and filtration capacity compared to single-layered sterile filters. Another cause of membrane fouling is the aggregation of virus particles, which is mediated by various interactions in the solution. To study this, the above-described setup was re-designed to create an effective procedure that utilizes minimal volumes of virus solution, while also enabling the rapid assessment of microscale filtration performance and a comprehensive understanding of virus-virus and virus-membrane interactions. This setup was used to study how different additives, including various proteins (bovine serum albumin and α-lactalbumin) and polymers (polyethylene glycol and polyvinylpyrrolidone), affect the microfiltration of the Rhabdoviral vector and, consequently, the TMP profile. Furthermore, the correlation between the membrane fouling rate (via TMP profiles) and virus recovery was also investigated. This investigation revealed that proteins significantly increase virus transmission and that polymers are incapable of mimicking the effects of the proteins. To explain this phenomenon, a theory based on the biophysical structure of proteins, mainly heterogenicity in charge distribution, was proposed. Moreover, membrane surface modification tests were conducted using bovine serum albumin, with the results indicating that this approach has considerable potential for enhancing virus transmission. Due to the similarities between the test setup and actual downstream processing unit operations, the results from this part of the thesis could be easily and accurately applied to process optimization. / Thesis / Candidate in Philosophy / There is considerable interest in the development of oncolytic viruses for cancer immunotherapy. Indeed, at the time of this thesis’ writing, a Canadian team of researchers is conducting the world’s first clinical trial using a combination of two viruses to kill cancer cells and stimulate an immune response. The process of manufacturing oncolytic viruses is generally divided into two major steps: upstream processing and downstream processing. While upstream processing focuses on virus propagation, downstream processing aims at removing process-related and product-related impurities. However, research into downstream process design and optimization has largely been neglected in favour of a focus on upstream processing, aimed at increasing bioreactor yields and achieving high viral titers. Consequently, downstream processing has become the main bottleneck in virus manufacturing processes, accounting for as much as 70% production costs. This thesis aims to identify and develop a fundamental understanding of the main challenges associated with the downstream processing of oncolytic viruses and to investigate methods for addressing them. Specifically, the present work focuses on the purification and final sterile filtration steps in the manufacturing of oncolytic Rhabdoviral vectors.