Title: Study of the rare B-meson decays with the ATLAS experiment Author: Marek Biroš Institute: Institute of Particle and Nuclear Physics Supervisor: RNDr. Pavel Řezníček, Ph.D., Institute of Particle and Nuclear Physics Abstract: The rare B0 d → K∗0 (892) μμ decay is one of the B-physics channels sensitive to Beyond Standard Model effects. The potential deviation from Standard Model predictions could be observed in the angular distribution of this decay. The work compiles several sub-tasks at the initial stage of this complex analysis: decay angles fit validation and signal event preselection. The fit functions used in the analysis are verified on generated toy Monte Carlo data. Ranges of parameters, for which are these functions positive, are established and within this parametric space, the testing of possible intrinsic fit biases is evaluated. A dependence of the fit bias with respect to the collected number of events (expected in Run 2 as well as at HL-LHC) and to the different signal-to- background ratio is studied. The second part of the thesis deals with processing of raw reconstructed data from the detector into n-tuples resulting in a more compact dataset that would be used in the final analysis. Within the process, baseline cuts are applied in order to minimize size of final datasets by reducing...

This study aimed to investigate lipoprotein metabolism in male hamsters fed diets considered to be atherogenic in humans. Livers from adult male hamsters were selected to study aspects of apolipoprotein B metabolism. Isolated hepatocytes in suspension were compared with those maintained under tissue culture conditions. Liver slices were also prepared and compared with isolated suspended hepatocytes. Freshly prepared hepatocytes from the animals were incubated with radiolabelled precursors in suspension, or they were maintained under tissue culture conditions; liver slices were also investigated. The rates of total protein synthesis were of the same order in each of these systems, but protein secretion was impaired in liver slices, probably as a result of diffusion problems associated with the altered architecture of the sliced tissue. Albumin constituted 40 - 50% of the secreted proteins in each system. The rates of VLDL synthesis were increased in cells and slices prepared from animals previously fed sucrose- or fat-rich diets, but the secretion of VLDL was inhibited when diets contained unsaturated fat. The overall synthesis of apolipoprotein B was enhanced by fat-feeding; in the case of suspended hepatocytes, secretion of this protein was decreased when the preceding diet contained fats that were unsaturated; while in the case of liver slices, secretion was paradoxically enhanced. Apolipoprotein B was not degraded at significant rates in hepatocytes prepared from either control or fat-fed hamsters.

During the different stages of its development, wheat is possible infected by many plant pathogens. One of the most common is Zymoseptoria tritici, the causal agent of the disease called Septoria Tritici Blotch (STB). The most common strategy in the Z. tritici disease management is treating plants with fungicides. Unfortunately, this plant pathogen as many others evolved resistance towards some of the most commonly used fungicidal classes. The aim of this study was to detect the resistance of Z. tritici to strobilurin fungicide azoxystrobin. During the April 2017, around 300 plant samples were collected from 11 geographical regions in the Czech Republic. From those plant samples, 52 monosporic Z. tritici isolates were obtained and tested for the presence of the resistance. The fungicide resistance was measured and detected by laboratory agar dilution biotest and molecular methods as a CAPS marker (Cleaved Amplified Polymorphic Sequences) and qPCR (Quantitative Polymerase Chain Reaction). By agar dilution biotest, resistance to azoxystrobin was confirmed in 54% of total 52 analysed isolates. By CAPS marker analysis, the presence of G143A mutant allele of the mitochondrial cytochrome b gene, linked to the fungicide resistance, was confirmed in all selected isolates marked as resistant in the biotest. The DNA of one infected leaf sample collected from the field marked as 17Zt212 was isolated and tested by the qPCR method. In the field sample (17Zt212), the 4% of the Z. tritici population was found to be resistant to fungicide azoxystrobin.

Submitted to the faculty of Indiana University In partial fulfillment of the requirements for the degree Master in Bioinformatics In the School of Informatics, Indiana University, December 2004 / The aggregation rate of B-Lactoglobulin (BLG) was studied using turbidimetry and dynamic light scattering in the range 5.8<pH,3.5 at a fixed ionic strength of 4.5 mM, and in the range 4.5 - 500mM NACl at a fixed pH of 5.0. The initial slope of turbidity vs time curve was used to define an initial rate. The highest initial rates of aggregation were observed in the pH range 4.50 to 4.75 but the increase in aggregation rate when the pH was reduced from 5.0 to 4.69 was large compared to its decrease when the pH was reduced from pH 4.69 to 4.20; i.e. the dependence of initial rate on pH was highly asymmetric. The rate of aggregation at pH 5.0 strongly increased with decrease in ionic strength I from 100 to 4.5 mM and was found to be nearly linear with 1/ I. QELS measurements at pH 5.22 and 5.40 at I = 4.5mM revealed that particle size increased with time. Eventual appearances of bimodal distributions showed fast and slow modes corresponding to the BLG dimer and to hydrodynamic diameter 100-800 nm. Measurements at 4.0 and 4.2 indicated the consumption of dimers in the first few minutes to form higher order aggregates. Electrostatic modeling via Delphi was used to visualize the electrostatic poetnetial around the BLG dimer in order to elucidate the pH and ionic strength dependence of BLG aggregation rates. The aggregation process appears to comprise firstly an initial fast consumption of dimer, whose dependence on pH and I arises from the interaction of the positive and negative domains of interacting dimers; and secondly, the slow formation of much larger aggregates with relatively little sensitivity to pH and I. The open-ended nature of BLG aggregation is thought to arise from the asymmetry of the dimer charge distribution in the range 4.2<pH<5.2. Polyanions appear to inhibit aggregation. However, the role of polyanions in minimizing BLG aggregation was observed immediately after the addition of polyanioin to the protein. / Bioinformatics

Cette thèse porte sur la vérification des règles ajoutées de l'Atelier B en utilisant une plate-forme appelée BCARe qui repose sur un plongement de la théorie sous-jacente à la méthode B (théorie de B) dans l'assistant à la preuve Coq. En particulier, nous proposons trois approches pour prouver la validité d'une règle, ce qui revient à prouver une formule exprimée dans la théorie de B. Ces trois approches ont été évaluées sur les règles de la base de règles de SIEMENS IC-MOL. La première approche dite autarcique est développée avec le langage de tactiques de Coq Ltac.  Elle repose sur une première étape qui consiste à déplier tous les opérateurs ensemblistes pour obtenir une formule de la logique du premier ordre. Puis nous appliquons une procédure de décision qui met en oeuvre une heuristique naïve en ce qui concerne les instanciations. La deuxième approche, dite sceptique,appelle le prouveur automatique de théorèmes Zenon après avoir effectué l'étape de normalisation précédente. Nous vérifions ensuite les preuves trouvées par Zenon dans le plongement profond de B en Coq.  La troisième approche évite l'étape de normalisation précédente grâce à une extension de Zenon utilisant des règles d'inférence spécifiques à la théorie de B. Ces règles sont obtenues grâce à la technique de superdéduction. Cette dernière approche est généralisée en une extension de Zenon à toute théorie grâce à un calcul dynamique des règles de superdéduction. Ce nouvel outil, appelé Super Zenon, peut par exemple prouver des problèmes issus de la bibliothèque de problèmes TPTP. / The purpose of this thesis is the verification of Atelier B added rules using the framework named BCARe which relies on a deep embedding of the B theory within the logic of the Coq proof assistant. We propose especially three approaches in order to prove the validity of a rule, which amounts to prove a formula expressed in the B theory. These three approaches have been assessed on the rules coming from the rule database maintained by Siemens IC-MOL.  To do so, the first approach, so-called autarkic approach, is developed thanks to the Coq tactic language, Ltac. It rests upon a first step which consists in unfolding the set operators so as to obtain a first order formula.  A decision procedure which implements an heuristic is applied afterwards to deal with instantiation.  We propose a second approach, so-called skeptic approach, which uses the automated first order theorem prover Zenon, after the previous normalization step has been applied.  Then we verify the Zenon proofs in the deep embedding of B in Coq. A third approach consists in using anextension of Zenon to the B method thanks to the superdeduction. Superdeduction allows us to add the axioms of the B theory by means of deduction rules in the proof mechanism of Zenon. This last approach is generalized in an extension of Zenon to every theory thanks to a dynamic calculus of the superdeduction rules. This new tool, named Super Zenon, is able to prove problems coming from the problem library TPTP, for example.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by autoantibody production, inflammation and end organ damage resulting from an overactivation of the immune system through mechanisms that are still not completely understood. One critical component of this pernicious cycle is a loss of tolerance to self-antigen that precedes disease manifestations. Importantly, there has only been one FDA approved treatment for SLE in the last 60 years, though an additional treatment has recently been approved for lupus nephritis. Therefore, there is a need to understand how pathogenic pathways are regulated in the context of SLE. This thesis focused on not only further understanding how interferon regulatory factor 5 (IRF5) drives pathogenicity in a mouse of model of lupus but also discerning the molecular pathways important for blood dendritic cell antigen 2 (BDCA2) inhibition of type I interferon (IFN-I) release from plasmacytoid dendritic cells (pDCs). Gain-of-function polymorphisms in the transcription factor IRF5 are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. This work shows that monoallelic IRF5 deficiency in B cells markedly reduces disease in the FcγRIIB−/−Yaa mouse model of lupus. Mechanistically, B cell receptor and TLR7 signaling synergize to promote IRF5 phosphorylation through IRAK4, and also increase IRF5 protein expression, with these processes being independently regulated. This synergy increases B cell-intrinsic IL-6 and TNF-𝛂 production, both key requirements for germinal center responses, with IL-6 and TNF-𝛂 production in vitro and in vivo being substantially lower with loss of one allele of IRF5. Moreover, this thesis further strengthens the notion of IRF5 as a target for the treatment of SLE by therapeutically targeting IRF5 in the FcγRIIB−/−Yaa mouse lupus model. This work shows that tamoxifen driven deletion of IRF5 after disease associated manifestations have already developed confers protection in the FcγRIIB−/−Yaa mouse model. IFN-I is a family of pleotropic cytokines that are thought to be pathogenic in the context of SLE. PDCs are a major source of IFN-I. As such, they have been shown to play a major role in anti-viral immunity and are thought to be pathogenic in context of SLE. I used the anti-BDCA2 antibody 24F4A to ligate the receptor in a human pDC cell line (Gen 2.2) and applied a variety of proteomics methods, including profiling of post-translational modifications, to evaluate signaling downstream of BDCA2. I found that phosphorylation of phosphoinositide 3-kinase adapter protein 1 (PIK3AP1)/ B cell adaptor protein (BCAP) was increased after BDCA2 engagement by 24F4A. Deletion of BCAP from Gen2.2 cells reversed BDCA2 mediated AKT phosphorylation and IFN inhibition, suggesting that PI3 kinase (PI3K) may be important for BDCA2 mediated IFN inhibition. Treatment of human pDCs with PI3kinase inhibitor followed by TLR9 stimulation confirmed that PI3K activity is critical for BDCA2 mediated IFN inhibition. This work describes a critical threshold of IRF5 expression in B cells necessary for the development of the lupus like disease in the FcγRIIB−/−Yaa mice and that systemic deletion of IRF5 after disease onset reduces the disease manifestations in the same mouse model. Additionally, this work demonstrated that BCAP and PI3K are important pathways to mediate the IFN inhibition observed with engagement of the BDCA2 pathway. This work supports IRF5 as a therapeutic target in SLE and furthermore, describes a molecular pathway important for BDCA2 mediated IFN-I inhibition from pDCs.

Indiana University-Purdue University Indianapolis (IUPUI) / Acute skeletal muscle injury leads to increases in activin B levels and when selectively neutralized with a monoclonal antibody, there is augmented skeletal muscle repair.

The basic helix-loop-helix protein, activated B-cell factor-l (ABF-l), is a transcription factor involved in cellular proliferation and differentiation. ABF-1 shows patterns of expression that are stimulated in activated B cells, which may suggest ABF-1 is involved in the regulation of B-cell differentiation. To investigate the functional role of ABF-1, we have generated a human plasmacytoma cell line with inducible expression of ABF-1. We were able to induce expression of ABF-1 by using the tetracycline repressor system (teton/off). With addition of tetracycline we were able to stimulate the expression of the full-length ABF-1 in the cells. We also got induction of the truncated form of ABF-1, lacking the protein dimerization domain (HLH), with the addition of tetracycline. We then compared these two cell lines to uninduced cells. We confirmed that ABF-1 expression was induced by western blot analysis. We conclude that we have developed a human plasmacytoma cell line with inducible expression of ABF-1 and can use this cell line for further studies.

Activated B-cell Factor-I (ABF-1) is a class II basic helix-loop-helix protein expressed in activated B-cells, EBV -immortalized lymphoblastoid cell lines and embryonic skeletal muscle in mice. ABF -1 dimerizes with another bHLH protein E4 7 to form a transcriptional repressor ofE2A, which is a gene essential to the proper development of B- and T -cells. In an effort to study genes in B-cells regulated by ABF- 1, I have attempted to construct a Burkitt Lymphoma cell line allowing tetracycline regulated expression of ABF-1. The tetracycline repressor gene was first added to these cells, creating a parental line oftet repression. Next, both a full-length and a truncated version of ABF -1 were added to the cell line. The truncated version of the protein is expressed in the presence of tetracycline, but completely repressed in its absence, demonstrating a tightly-regulated system of inducible expression. The full-length version of ABF-1 has yet to be expressed in this cell line; however, it has been expressed in a HeLa cell line, demonstrating that the construct has been properly made.

M.Med.(Haematology), Faculty of Health Sciences, University of the Witwatersrand, 2008 / This study aimed to identify the relevance of these prognostic features in the modern treatment era in South African children. A retrospective analysis of the presentation clinical and laboratory features and treatment outcomes of all children treated for Precursor B cell ALL at the Johannesburg Hospital was performed. Between January 1997 and May 2007, 100 children were reviewed. Clinical features (age, race and gender) emerged as significant prognostic variables. Laboratory features (white cell count and genetic features) lacked significance. Early morphologic response on day 15 identified a subgroup associated with a favourable outcome. However the presence of > 5% blasts was not significantly predictive of relapse or death at this time point. Minimal residual disease (MRD) detection by modified immunoglobulin gene rearrangement and flow cytometry techniques did not improve the predictive value of the morphological assessment. In a low resource setting, the challenge is to design cost effective MRD detection methods to improve the identification of patients at risk for relapse.