Dissertation zur Erlangung des akademischen Grades Dr. med. Charakterisierung des XIAP-Gens bei zwei Familien mit X-chromosomalem lymphoproliferativem Syndrom Eingereicht von: Peter Christian Horn geboren am 04.08.1982 in Freiburg Angefertigt an: Der Universitätsklinik und Poliklinik für Kinder und Jugendliche Leipzig und dem Zentrum für familiären Brust- und Eierstockkrebs der technischen Universität München Betreuer: Prof. Dr. med. Volker Schuster (Universität Leipzig) Prof. Dr. rer. nat. Alfons Meindl (TU München) Eingereicht im Dezember 2014 Das X-linked-inhibitor-of-apoptosis Protein XIAP nimmt eine zentrale Rolle in der Hemmung von Apoptoseprozessen beim Menschen ein. In Abwesenheit von XIAP kann eine defekte Immunabwehr gegenüber viralen Infektionen beobachtet werden. In Folge können lebensbedrohliche Immunreaktionen wie hämophagozytäre Lymphhistiozytose, aplastische Anämie und persistierende Hypogammaglobulinämie auftreten. Im Rahmen dieser Arbeit wurde untersucht, ob bei einem Patientenkollektiv mit lymphoproliferativem Syndrom Mutationen im XIAP-Gen Auslöser der Erkrankung sind. Es wurde eine molekulargenetische Sequenzierung und Auswertung des XIAP- 5 Zusammenfassung der Arbeit 53 Gens bei 36 Verdachtsfällen eines X-chromosomal vererbten lymphoproliferativen Syndroms durchgeführt. In allen Fällen wurde der gesamte exonische Abschnitt des Gens sequenziert und auf Polymorphismen und Mutationen untersucht. Bei zwei Proben wurden Mutationen im XIAP-Gen gefunden. Weiter konnten Mutter und Bruder eines der Betroffenen untersucht werden, so dass insgesamt drei Knaben mit XIAP-Gendefekt sowie eine heterozygote Konduktorin identifiziert wurden. Nach der Identifikation der Mutationsträger erfolgte eine Auswertung der Krankenge- schichte und ein Vergleich mit den verfügbaren Beschreibungen von XIAP-Defizienz. Die beiden neu identifizierten Mutationen verursachen ein Krankheitsbild, das mit den wenigen verfügbaren Beschreibungen von XIAP-Defizienz vereinbar ist. Die Auswer- tung der Klinik der drei Betroffenen unterstützt die Hypothese, dass bei XIAP- Defizienz keine Lymphome auftreten. Die Therapieentscheidung bei XIAP-Defizienz ist einzelfallabhängig. Die Arbeit ver- gleicht den Krankheitsverlauf der neu beschriebenen Patienten mit der Literatur und unterstreicht, dass die Entscheidung zu einer Knochenmarkstransplantation gut begrün- det werden muss. Es sind inzwischen mehr Patienten bekannt, die ohne Therapie oder unter IVIG-Gabe asymptomatisch sind, als solche, die eine Knochenmarkstransplantati- on überlebt haben. Alle hier beschriebenen Patienten konnten ohne Transplantation be- handelt werden. Eine Stammzelltransplantation kann jedoch erfolgreich sein. Bei kon- servativ behandelten Patienten können Rezidive auftreten. Kritisch zu sehen sind im Licht der Erfahrung mit den XIAP-defizenten Patienten An- strengungen, XIAP-Inhibitoren zur Tumortherapie am Menschen zu entwickeln – dies könnte als Nebenwirkung paradoxe Folgen wie Lymphoproliferation oder HLH haben. Die in der Arbeit beschriebenen Patienten waren die ersten Patienten mit XIAP- Defizienz, die im deutschsprachigen Raum identifiziert wurden. Die beiden Mutationen die bei den Familien gefunden wurden, waren bisher nicht beschrieben.

This thesis is an investigation of ruthenium-catalyzed [2+2] cycloaddition reactions of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with unsymmetrical alkynes. Yields of up to 90% were obtained though regioselectivity was modest. Select cycloadducts could be separated and used to access a highly functionalized [3.2.0] bicyclic structure through reductive cleavage of the N-O bond. These ring-opened products displayed a chemical exchange phenomenon in 1D carbon NMR and required characterization by 2D NMR techniques. In addition, a haloalkynylation reaction was found to occur when 1-iodo-2-phenylethyne and the 3-aza-2-oxabicyclo[2.2.1]hept-5-ene were submitted to the cycloaddition conditions. An effort was made to optimize the reaction between 1-iodo-2-phenylethyne and norbornadiene in favour of the addition product. / Government of Ontario, NSERC

Thesis (M.A.)--University of California, San Diego, 2009. / The 1st work for violin, clarinet, violoncello; the 2nd for piano with chamber orchestra; the 3rd for 2 flutes (1 doubling on piccolo), 2 clarinets, 2 violoncellos. Title from first page of PDF file (viewed July 7, 2009). Available via ProQuest Digital Dissertations. Accompanying disc contains PDF file of thesis and recordings of performances.

Thesis--Chicago Musical College. / "Original two-piano music": p. 340-362. "Recorded two-piano music": p. 363-373. "Annotated bibliography": p. 374-384.

A irradiação de alimentos já foi aprovada e vem sendo utilizada em diversos países para aplicações e finalidades de uma ampla variedade de alimentos. Seus benefícios abrangem o aumento do prazo de validade, melhoria de higiene dos alimentos e consequentemente menor deterioração e perdas se comparado com alimentos que não sofrem radiação. Além disto, os alimentos após irradiados apresentam-se seguros em termos nutritivos e de redução de patógenos. Porém, alimentos que contem de médio a alto teor de gordura induzem a formação de um subproduto denominado 2-Alcilciclobutanonas, a qual sabemos que parte destes compostos ingeridos são normalmente excretados através das fezes, porém parte permanece depositada nos tecidos adiposos. Trabalhos realizados com estes compostos anteriormente apresentaram efeitos citotóxicos e genotóxicos em células de cólon. Desta forma, o objetivo do presente trabalho foi investigar os efeitos citotóxicos realizados em testes de viabilidade celular, testes genotóxicos em micronúcleo e testes mutagênicos com a técnica de Ames em condições experimentais in vitro dos compostos 2-dDCB e 2-tDCB. Para isso, o fígado foi o órgão de escolha para avaliar os possíveis efeitos destes compostos, uma vez que este órgão é geralmente acometido pelo acumulo de gordura. Foram utilizadas três linhagens hepáticas: HepG2, BRL3A e HTC. A análise dos resultados da viabilidade celular, revelou que as 2-dDCBs apresentaram discreto efeito citotóxico na concentração de 500 μM e as 2-tDCBs apresentaram danos baixos a partir de 100 μM e maiores em 500 μM, mostrando ser dose dependentes. Nos resultados de mutagenicidade, os compostos não apresentaram quaisquer efeitos mutagênicos nas concentrações e doses utilizadas, detectados pelo teste de Ames. Por fim, o ensaio de micronúcleo correspondeu às expectativas não demonstrando efeitos genotóxicos na linhagem, doses e tempos testados. Com base nos resultados atingidos, as 2 ACBs podem ser consumidas com relativa segurança, sob a ótica de possíveis efeitos mutagênicos e genotóxicos nas concentrações avaliadas. / Food irradiation has already been approved and has been used in several countries for applications and purposes of a wide variety of foods. Its benefits include increased shelf life, improved food hygiene and consequently less deterioration and losses compared to foods that do not undergo into radiation. In addition, food after irradiation is safe in terms of nutrients and pathogen reduction. However, foods that contain medium to high fat levels, induce the formation of a by-product called 2-Alkylcyclobutanones, which we know that part of these ingested compounds are normally excreted through the feces, but part remains deposited in the adipose tissues. Work performed with these compounds previously showed cytotoxic and genotoxic effects on colon cells. Thus, the objective of the present work was to investigate the cytotoxic effects performed in cell viability tests, genotoxic tests in micronucleus and mutagenic tests with Ames technique under in vitro experimental conditions of 2-dDCB and 2-tDCB compounds. Hence, the liver was the chosen organ to evaluate the possible effects of these compounds, since this organ is usually affected by accumulation of fat. Three hepatic cell lines were used: HepG2, BRL3A and HTC. Analysis of the cell viability results revealed that the 2-dDCBs presented a discrete cytotoxic effect at the concentration of 500 μM and the 2-tDCBs presented low damages from 100 μM and larger at 500 μM, showing to be dose dependent. In the mutagenicity results, the compounds did not show any mutagenic effects at the concentrations and doses used, detected by the Ames test. Finally, the micronucleus test corresponded to expectations demonstrating no genotoxic effects in the cell line, doses and times tested. Based on the results achieved, the 2 ACBs can be consumed with relative safety, from the perspective of possible mutagenic and genotoxic effects in the evaluated concentrations.

Les macrophages sont une cible cellulaire importante du VIH-1 et sont impliqués dans la propagation virale et la constitution du réservoir. Les patients infectés par le VIH-2 présentent un contrôle naturel de l'infection qui est généralement absent chez les patients infectés par le VIH-1. Nous avons étudié ici la relation entre les macrophages et le VIH-2 afin d'évaluer leur contribution à la physiopathologie de l'infection. L'assemblage de particules virales dans des macrophages dérivés de monocytes (MDM) infectés par le VIH-2 se fait au niveau de la membrane de compartiments internes semblables aux VCC documentés dans les MDM infectés par le VIH-1. Les VCC des MDM infectés par le VIH-1 et le VIH-2 partagent la même composition protéique, et la même morphologie. Contrairement à Gag du VIH-1, la protéine Gag du VIH-2 est absente du cytosol et presque exclusivement localisée dans les VCC, ce qui suggère que Gag du VIH-2 est rapidement transportée vers le VCC une fois synthétisée dans le cytosol. Les particules de VIH-2 produites de novo par les MDM peuvent mûrir, mais sont faiblement infectieuses et se transmettent inefficacement aux cellules T activés. Cette faible infectiosité n'est pas associée avec l'expression du facteur de restriction BST-2 et n'est pas non plus améliorée par une baisse des niveaux d'expression de BST-2 induite par Vpu. Nos données suggèrent que les macrophages infectés par le VIH-2 ne contribuent probablement pas à la production et à la dissémination du virus in vivo. Cependant, les macrophages infectés par le VIH-2 peuvent représenter une source potentielle d'antigènes viraux qui pourraient stimuler les réponses des cellules T spécifiques du virus. / Macrophages are an important cellular target of HIV-1 and are potentially involved in viral spreading and constitution of the viral reservoir. HIV-2-infected patients exhibit a natural virological control of the infection that is generally absent from HIV-1-infected patients. Here, we studied the relationship between macrophages and HIV-2 to approach their potential contribution to the physiopathology of HIV-2 infection. Viral particles assembly in HIV-2-infected monocyte-derived macrophages (MDMs) occurred at the limiting membrane of internal compartments similar to virus-containing compartments (VCCs) documented in HIV-1-infected MDMs. Indeed, VCCs from HIV-1 and HIV-2-infected MDMs shared protein composition, as seen by confocal microcopy, and morphology, as seen by electron microscopy. Strikingly, HIV-2 Gag was mostly absent from the cytosol and almost exclusively localized to the VCCs, whereas HIV-1 Gag was distributed in both locations, suggesting that HIV-2 Gag is rapidly transported to the VCC membranes once synthesized in the cytosol. HIV-2 particles produced de novo by MDMs can mature, but are poorly infectious and inefficiently transmitted to activated T cells. This low infectivity neither correlate with expression of the restriction factor BST-2, nor was improved by Vpu-induced down-modulation of BST-2 levels. Our data suggest that, HIV-2-infected macrophages are unlikely to contribute to viral production and dissemination in vivo. However, HIV-2-infected macrophages accumulate large amounts of intracellular virus that may represent a potential source of viral antigens that could stimulate virus specific T cell responses.

The objective of this study is to assess the diagnostic accuracy of the personality of the Mexican criminal with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). The inventory was administered to 1,740 Mexican participants of which 870 (728 male and 142 female) are prison inmates, processed and/or sentenced for various crimes from various prisons in Mexico City, and the other 870 participants (728 male and 142 female) are not prison inmates. The ROC (Receiver Operating Characteristic) curve analysis was used to assess the level of diagnostic accuracy through indexes of the Area below the curve (ABC), sensitivity (S) and specificity (E). The analysis was differentiated by gender and showed significant differences / El objetivo de este estudio es poder apreciar la precisión diagnóstica de la personalidad del delincuente mexicano con la prueba del Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Se administró la prueba a un total de 1740 participantes mexicanos de los que 870 (728 varones y 142 mujeres) son reclusos, procesados y/o sentenciados por diferentes delitos, procedentes de diversas cárceles del Estado y Distrito Federal, y otros 870 (728 varones y 142 mujeres) son personas no reclusas. Se utilizó el análisis de la curva ROC (Receiver Operating Characteristic) para apreciar el nivel de precisión diagnóstica a través de sus índices del Área Bajo la Curva (ABC), su Sensibilidad (S) y Especificidad (E). El análisis, diferenciado por género, mostró notables diferencias. / O objetivo do presente estudo consiste em avaliar a precisão diagnóstica da personalidade do delinquente mexicano através da prova Minnesota Multiphasic Personality Inventory-2 (MMPI-2). A prova foi administrada a 1.740 participantes mexicanos, dos quais 870 (728 homens e 142 mulheres) são reclusos, julgados e condenados por diferentes delitos, procedentes de diferentes estabelecimentos prisionais da cidade do México, e outros 870 (728 homens e 142 mulheres) são pessoas não reclusas. Foi utilizada uma análise da curva de ROC (Receiver Operating Characteristics) para avaliar o nível de precisão diagnóstica através dos índices da Área Abaixo da Curva (ABC), sua sensibilidade (S) e Especificidade (E). A análise de diferenciação entre sexos revelou diferenças significativas.

Ces travaux de thèse portent sur le développement de la première synthèse du squelette des 10-silastéroïdes, et cela grâce à une cascade cycloaddition [2+2+2]/extension de cycle. Après quelques rappels sur la chimie du silicium et sur son utilisation comme bioisostère du carbone en chimie médicinale, une vue d’ensemble de la littérature concernant les extensions de cycles tendus sera réalisée. Celle-ci nous amènera à détailler notre stratégie et ses trois défis importants qui seront abordés dans les chapitres suivants. Le premier est la préparation de silanes polyinsaturés susceptibles de réaliser notre cascade réactionnelle. Pour cela, le silicium doit porter quatre groupements différents. Dans ce but, trois synthèses ont été mises au point afin d’améliorer sans cesse la préparation de ces silanes. Le second défi de ce projet est l’accès au benzosilacyclobutène par cycloaddition [2+2+2], ceci étant la première étape de notre cascade. Cela est réalisé à l’aide d’une catalyse au NbCl3.DME, permettant ainsi la synthèse de benzosilacyclobutènes hautement fonctionnalisés avec de très bons rendements. Cette nouvelle synthèse est plus performante que la seule voie de synthèse existante dans la littérature, que se soit au niveau des rendements, de la fonctionnalisation des substrats, mais aussi grâce à des conditions plus douces. Le troisième défi est le contrôle de la régiosélectivité de la réaction d’extension de cycle des benzosilacyclobutènes. Cette régiosélectivité est grandement influencé par le métal utilisé. Ainsi, l’utilisation du catalyseur de cobalt CpCo(CO)2 pour notre cascade conduit au silapolycycle linéaire. La catalyse avec RhCl(PPh3)3 permet quant à elle d’accéder au silapolycycle angulaire désiré, possédant un atome de silicium en jonction de cycle, et donc au premier squelette de 10-silastéroïde. / This PhD work deals with the development of the first synthesis of the 10-silasteroids scaffold, using a cascade [2+2+2] cycloaddition/ring expansion. An overview of silicon chemistry and its use as a carbon bioisoster in medicinal chemistry is covered, followed by a description of the literature on ring expansion. Then, we will explain our strategy and its three main challenges will be discussed in the following chapters. The first one is the preparation of polyunsaturated silanes wich is capable of performing our cascade reaction. For this purpose, the silicon atom must have four different substituents. To reach this goal, three synthesis were developed in order to gradually increase the preparation of the silanes. The second challenge is the access to benzosilacyclobutenes by a [2+2+2] cycloaddition reaction, this reaction being the first step of our cascade reaction. It was done using NbCl3.DME catalysis, allowing the formation of highly functionalized benzosilacyclobutenes in high yields. This new synthesis is more efficient than the previously described literature synthesis, in means of yields, substrat functionnalizations, and mild reaction condition. The third challenge is the control of the regioselectivity of the ring expansion of the benzosilacyclobutenes. This regioselectivity mainly depends on the metal used. For exemple, the use of CpCo(CO)2 catalyst gives to the linear silapolycycle. Whereas, RhCl(PPh3)3 catalysis yields to the desired angular silapolycycle, containing the silicon atom at the ring junction, leading to the first synthesis of the 10-silasteroids scaffolds.

In this paper, we initiate the study of a variant of Roman dominating functions. For a graph G=(V,E), a Roman {2}-dominating function f:V→{0,1,2} has the property that for every vertex v∈V with f(v)=0, either v is adjacent to a vertex assigned 2 under f, or v is adjacent to least two vertices assigned 1 under f. The weight of a Roman {2}-dominating function is the sum Σv∈Vf(v), and the minimum weight of a Roman {2}-dominating function f is the Roman {2}-domination number. First, we present bounds relating the Roman {2}-domination number to some other domination parameters. In particular, we show that the Roman {2}-domination number is bounded above by the 2-rainbow domination number. Moreover, we prove that equality between these two parameters holds for trees and cactus graphs with no even cycles. Finally, we show that associated decision problem for Roman {2}-domination is NP-complete, even for bipartite graphs.

Från slutet av 1990-talet har en stor mängd av de icke-separerade 13 meter breda vägarna byggts om till mötesseparerade vägar, där trafiken i varje riktning separeras med en mittremsa. Mötesseparerade vägar har varit ett mycket lyckat projekt för trafiksäkerheten och bidragit med en stor minskning av svårt skadade och döda i trafiken. Det finns många mötesseparerade vägar i Sverige. Vid olyckor på 2+1-vägar blir det svårt för trafiken att vända på vägen vilket leder till stopp och gör det även svårt för Blåljusmyndigheten samt bärgningsbilar att ta sig fram. Dessa olyckor leder till förseningstimmar och i sin tur till samhällskostnader. Det här examensarbetet är skrivet för Trafikverket för att granska 2+1-vägar i Trafikverkets Region Öst. Rapporten tar fram och jämför minskning av förseningskostnader efter en ombyggnad från 2+1- till 2+2-väg, rapporten tar även fram och jämför förseningskostnaden med investeringskostnaden för ombyggnationen. Resultatet för den här studien har framförts genom litteraturstudier, analys av data från Trafikledningen, webbverktyg och genom användning av Microsoft Excel för kalkylering av förseningstimmar och -kostnader för utvalda vägar och sträckor. Resultatet från rapporten visar om det är värt att undersöka en 2+1-väg för ombyggnation från 2+1- till 2+2-väg ur förseningskostnadsperspektiv. Detta redovisas genom en generell jämförelse per mil 2+1-väg baserad på väg 50, 55 och 56 i Trafikverkets Region Öst. Rapporten innehåller även en analys över de fem mest drabbade olycksplatserna på E18:s 2+1 sträckor. Analysen av dessa visade att alla fem sträckor låg mellan Köping och Västerås i Västmanland. / From the late 1990s, a large part of the non-separated 13-meter-wide roads have been reconstructed into meeting separated roads, where traffic in each direction is separated by a middle strip. Meeting separated roads have been a very successful project for road safety and have contributed to a large reduction in severely injured and casualties in traffic. There are many meeting separated roads in Sweden. In the case of accidents on 2+1-roads, it becomes difficult for the traffic to turn around on the road, which leads to a stop and makes it difficult for the emergency services and tow trucks to reach the scene of the accident. These accidents lead to delay hours and, in turn, to community costs. This thesis is written for the Swedish Transport Administration to review 2+1 roads in the Swedish Transport Administration’s Region East. The report produces and compares the reduction of delay costs after rebuilding a road from 2+1- to 2+2-standard, the report also presents and compares the delay cost with the investment cost for the reconstruction. This study is based on literature studies, analysis of data from the “Traffic Management”, internet-based programs and through the use of Microsoft Excel for calculating delay hours and -costs for selected roads and routes. The result of the report shows whether it is worth investigating in a reconstruction from 2+1- to 2+2-road from delay cost perspective. This is presented through a general comparison per Scandinavian mile of 2+1-road based on roads 50, 55 and 56 in the Swedish Transport Administration’s Region East. The report also contains an analysis of the five most affected accident sites on the E18's 2+1-routes. The analysis of these accident sites showed that all five were between Köping and Västerås in Västmanland county.