Sleep is vital for optimal physical and mental health, as well as cognitive and social functioning. Young adults with developmental disabilities (DD) are at greater risk for physical and mental health disorders and experience limitations in cognitive and social functioning in ways that can prevent participation in meaningful activities associated with young adulthood. Sleep literature has reflected that persons with DD experience worse sleep than persons without DD. Suboptimal sleep could compromise functionality and thus participation in young adulthood activities. Not much is known however of the nature of sleep problems experienced by young adults with DD. This study is a short-term longitudinal descriptive study on the sleep of young adults with DD using actigraphy. Results identify potential sleep problems with getting enough sleep and maintaining sleep. With a better understanding of sleep issues, efforts can be made to improve the sleep, functionality, and outcomes for young adults with DD.

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The pathogen Francisella tularensis subsp. tularensis has been classified as a Center for Disease Control (CDC) select agent. However, little is still known of what makes the bacteria cause dis-ease, especially the highly virulent type A1 strains. The work in this dissertation focused on type A1 strains from the Inzana laboratory, including a wildtype virulent strain TI0902, an avirulent chemical mutant strain TIGB03 with a Single Nucleotide Polymorphism in the wbtK gene, and several complemented mutants, [wbtK+]TIGB03, with dramatic differences in virulence and growth rates. One of the complemented clones (Clone12 or avp-[wbtK+]TIGB03-C12) was aviru-lent, but protected mice against challenge of a lethal dose of TI0902 and was considered as a possible vaccine strain. Whole genome sequencing was performed to identify genetic differences between the virulent, avirulent and protective strains using both Roche/454 and Illumina next-generation sequencing technologies. Additionally, RNASeq analysis was performed to identify differentially expressed genes between the different strains. This comprehensive genomic analysis revealed the critical role of transposable elements in inducing genomic instability resulting in large du-plications and deletions in the genomes of the chemical mutant and the complemented clones that in turn affect gene dosage and expression of genes known to regulate virulence. For exam-ple, whole genome sequencing of the avirulent chemical mutant TIGB03 revealed a large 75.5 kb tandem duplication flanked by transposable elements, while the genome of a virulent Clone01 (vir-[wbtK+]TIGB03-C1) lost one copy of the 75.5 kb tandem duplicated region but gained a tandem duplication of another large 80kb region that contains a virulence associated transcription factor SspA. RNAseq data showed that the dosage effect of this extra region in Clone1 suppresses expression of MglA regulated genes. Since MglA regulates genes that are known to be crucial for virulence, including the well-studied Francisella Pathogenicity Island (FPI), these results suggest that gene dosage effects arising from large duplications can trigger unknown virulence mechanisms in F. tularensis subsp. tularensis. These results are important especially when designing live vaccine strains that have repeated insertion elements in their genomes. / Ph. D.

Secondary xylem, commonly known as wood, is a valuable commercial commodity. Among the major components of wood are the elongated, thick-walled water-conducting cells known as tracheary elements. Understanding tracheary element differentiation and maturation is of scientific and commercial importance as it may lead to broad understanding of cellular differentiation processes as well as ways to increase both the quality and quantity of wood produced by economically important tree species. One way to begin to understand the regulation of tracheary element differentiation is to identify elements that control expression of genes associated with tracheary elements. In Arabidopsis thaliana, Xylem Cysteine Protease 1 (XCP1) is specifically expressed in tracheary elements where it catalyzes microautolysis. Thus XCP1 can serve as a useful model for identifying factors that regulate tracheary element-specific gene expression. A deletion analysis of the XCP1 promoter was conducted to identify promoter elements that are necessary and sufficient for tracheary element-restricted gene expression. Two regions required for tracheary element-specific gene expression were identified. One of these was assembled as a multimeric bait construct and used in yeast one-hybrid assays to identify candidate transcription factors that bind to the XCP1 promoter region. Subsequently, a southwestern blot analysis was used to identify transcription factors displaying specific binding to a previously reported cis-element, CTTCAAAGCCA, found in the XCP1 promoter and other tracheary element-associated genes from multiple species. / Master of Science

Background: Bernard-Soulier syndrome (BSS) is a severe congenital bleeding disorder characterized by thrombocytopenia, thrombocytopathy and decreased platelet adhesion. BSS results from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. Methods: We report on a patient demonstrating typical BSS phenotype (thrombocytopenia with giant platelets, bleeding symptoms). However, BSS was not diagnosed until he reached the age of 39 years. Results: Flow cytometry of the patient’s platelets revealed absence of GPIb/IX/V receptor surface expression. In addition, immunofluorescence analysis of patient’s platelets demonstrated very faint staining of GPIX. A novel homozygous deletion comprising 11 nucleotides starting at position 1644 of the GPIX gene was identified using molecular genetic analysis. Conclusions: The novel 11-nucleotide deletion (g.1644_1654del11) was identified as causing the bleeding disorder in the BSS patient. This homozygous deletion includes the last 4 nucleotides of the Kozak sequence as well as the start codon and the following 4 nucleotides of the coding sequence. The Kozak sequence is a region indispensable for the initiation of the protein translation process, thus preventing synthesis of functional GPIX protein in the case of deletion. / Hintergrund: Das Bernard-Soulier-Syndrom (BSS) ist eine angeborene Blutungsstörung, die mit Thrombozytopenie, Thrombozytopathie und verminderter Thrombozytenadhäsion assoziiert ist. BSS wird durch genetische Veränderungen des Glykoprotein(GP)-Ib/IX/V-Komplexes verursacht. Methoden: Wir berichten über einen Patienten mit typischem BSS-Phänotyp (Thrombozytopenie mit Riesenthrombozyten, Blutungssymptome). Dennoch wurde die Diagnose BSS erst im Alter von 39 Jahren gestellt. Ergebnisse: Die Durchflusszytometrie der Thrombozyten des Patienten ergab eine fehlende Oberflächenexpression des GPIb/IX/V-Rezeptors. Zusätzlich zeigten Immunfluoreszenz-Analysen der Thrombozyten eine nur sehr schwache Anfärbung von GPIX. In der molekulargenetischen Analyse wurde eine noch nicht bekannte homozygote Deletion von 11 Nukleotiden (beginnend an Position 1644 im GPIX-Gen) identifiziert. Schlussfolgerungen: Diese neue Deletion von 11 Nukleotiden (g.1644_1654del11) wurde als Ursache für die vermehrte Blutungsneigung bei dem BSS-Patienten identifiziert. Von der homozygoten Deletion betroffen sind die letzten 4 Nukleotide der Kozak-Sequenz sowie das Startkodon und weitere 4 Nukleotide des kodierenden Bereichs. Die Kozak-Sequenz ist unerlässlich für die Initiation der Translation in der Proteinbiosynthese, so dass die bei dem Patienten nachgewiesene Deletion die Synthese des funktionellen GPIX-Proteins verhindert. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

La leucémie aiguë à cellules dendritiques plasmacytoïdes (BPDCN) fait partie des cancers incurables pour lesquels les mécanismes impliqués dans la pathogénèse restent inconnus. Dans ce travail, nous avons identifié le gène NR3C1 (5q31), qui code pour le récepteur des glucocorticoïdes (GCR), et un long ARN non-codant inter-génique (appelé ici lincRNA-3q), comme étant des cibles d'altération géniques ou de dérégulation transcriptionnelles dans les BPDCN. La translocation/délétion de NR3C1 est associée avec un temps de survie extrêmement court et des activités anormales du réseau de régulation des gènes GCR, EZH2 et FOXP3. Nous avons découvert que lincRNA-3q code pour une forme nucléaire d'ARN non-codant qui est activé de façon ectopique dans les BPDCN et les AML à haut risque. Dans les cancers myéloïdes, une déplétion de lincRNA-3q induit un arrêt du cycle cellulaire qui coïncide avec la suppression des signatures d'expression génique de E2F1/Rb et des gènes spécifiques aux cellules souches leucémiques. Nos résultats démontrent qu'une inhibition des protéines à bromodomaine BET supprime sélectivement l'expression lincRNA-3q, indiquant une stratégie thérapeutique potentielle pour contrer l'activité oncogénique de cet ARN non-codant. Ce travail défini, un nouveau cadre de recherche pour comprendre la pathogénèse et la résistance au traitement dans les BPDCN. / Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an incurable malignancy for which disease mechanisms are unknown. Here, we identify the NR3C1 gene (5q31), encoding the glucocorticoid receptor (GCR), and a long, intergenic, non-coding RNA gene (named here lincRNA-3q), respectively, as targets for genetic alteration or transcriptional deregulation in BPDCN. NR3C1 translocation/deletion was associated to critically short survival in BPDCN and to abnormal activity of GCR, EZH2, and FOXP3 gene regulatory networks. LincRNA-3q, was found to encode a nuclear, non- coding RNA that is ectopically activated in BPDCN and high-risk AML. Depletion of lincRNA-3q in myeloid cancer cells induced cell cycle arrest, coincident to suppression of E2F1/Rb and leukemia stem cell-specific gene expression signatures. BET bromodomain protein inhibition could selectively suppress lincRNA-3q indicating a treatment strategy for counteracting oncogenic activity of this non- coding RNA. Thus, this work defines a new framework for understanding disease pathogenesis and treatment resistance in BPDCN.

Background: Bernard-Soulier syndrome (BSS) is a severe congenital bleeding disorder characterized by thrombocytopenia, thrombocytopathy and decreased platelet adhesion. BSS results from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. Methods: We report on a patient demonstrating typical BSS phenotype (thrombocytopenia with giant platelets, bleeding symptoms). However, BSS was not diagnosed until he reached the age of 39 years. Results: Flow cytometry of the patient’s platelets revealed absence of GPIb/IX/V receptor surface expression. In addition, immunofluorescence analysis of patient’s platelets demonstrated very faint staining of GPIX. A novel homozygous deletion comprising 11 nucleotides starting at position 1644 of the GPIX gene was identified using molecular genetic analysis. Conclusions: The novel 11-nucleotide deletion (g.1644_1654del11) was identified as causing the bleeding disorder in the BSS patient. This homozygous deletion includes the last 4 nucleotides of the Kozak sequence as well as the start codon and the following 4 nucleotides of the coding sequence. The Kozak sequence is a region indispensable for the initiation of the protein translation process, thus preventing synthesis of functional GPIX protein in the case of deletion. / Hintergrund: Das Bernard-Soulier-Syndrom (BSS) ist eine angeborene Blutungsstörung, die mit Thrombozytopenie, Thrombozytopathie und verminderter Thrombozytenadhäsion assoziiert ist. BSS wird durch genetische Veränderungen des Glykoprotein(GP)-Ib/IX/V-Komplexes verursacht. Methoden: Wir berichten über einen Patienten mit typischem BSS-Phänotyp (Thrombozytopenie mit Riesenthrombozyten, Blutungssymptome). Dennoch wurde die Diagnose BSS erst im Alter von 39 Jahren gestellt. Ergebnisse: Die Durchflusszytometrie der Thrombozyten des Patienten ergab eine fehlende Oberflächenexpression des GPIb/IX/V-Rezeptors. Zusätzlich zeigten Immunfluoreszenz-Analysen der Thrombozyten eine nur sehr schwache Anfärbung von GPIX. In der molekulargenetischen Analyse wurde eine noch nicht bekannte homozygote Deletion von 11 Nukleotiden (beginnend an Position 1644 im GPIX-Gen) identifiziert. Schlussfolgerungen: Diese neue Deletion von 11 Nukleotiden (g.1644_1654del11) wurde als Ursache für die vermehrte Blutungsneigung bei dem BSS-Patienten identifiziert. Von der homozygoten Deletion betroffen sind die letzten 4 Nukleotide der Kozak-Sequenz sowie das Startkodon und weitere 4 Nukleotide des kodierenden Bereichs. Die Kozak-Sequenz ist unerlässlich für die Initiation der Translation in der Proteinbiosynthese, so dass die bei dem Patienten nachgewiesene Deletion die Synthese des funktionellen GPIX-Proteins verhindert. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The D1-class receptors (D1R, D5R) each possess distinct signaling characteristics; however, pharmacological selectivity between them remains elusive. The third intracellular loops (IL3) of D1R and D5R harbour divergent residues that may contribute to their individual signalling phenotypes. Here we probe the function of central region of IL3 of D1R and D5R using deletion mutagenesis. Radioligand binding and whole cell cAMP assays suggest that the N-terminal and C-terminal moieties of the central IL3 oppositely contribute to the constitutive and agonist-dependant activity of D1-Class receptors. Whereas the N-terminal deletions ablated constitutive activity and decreased DA-induced activation, C-terminal deletions induced robust increases. These data, interpreted in concert with structural predictions generated from homology modeling implicate the central IL3 as playing an important role in the activation and subtype-specific characteristics of the D1-class receptors. This study may serve as a basis for the development of novel drugs targeting the central IL3 region.