Thesis (M.A.)--University of Wisconsin--Madison, 1972. / Title from title screen (viewed Nov. 8, 2007). Includes bibliographical references. Online version of the print original.

Thesis (M.A.)--University of Wisconsin--Madison, 1972. / Includes bibliographical references.

Thesis (Th. M.)--Calvin Theological Seminary, 1949.

Jazz is a distinctive stylistic influence in twentieth-century American organ music. Organ music in the United States during this period may be classified into four diverse categories: German-influenced; French-influenced; program music; and new styles that include twentieth-century techniques, such as serialism, chance (aleatoric), atonality, and jazz. The organ is an ideal instrument for jazz performance since the organ can provide diverse timbres, such as reeds (clarinets, trumpets, and trombones), strings (violin, viola, and cello), and overtone-rich sounds from mutations and mixtures.This document presents an analysis of jazz elements in twentieth-century American organ works, especially focused on the following selected organ works: Charles Ives' Variations on "America" (1891), William Albright's Sweet Sixteenths: Concert Rag for Organ (1975), and William Bolcom's Sometimes I Feel, and Free Fantasia on "O Zion Haste" and "How Firm a Foundation" from Gospel Preludes, Book IV (1984). The first chapter introduces jazz, including its definition, historical background, and styles. The next four chapters discuss brief biographical material, musical styles, compositions of each composer, and comprehensive musical analysis of their selected organ works, including form, melody, harmony, rhythm, timbre, and registration.

A síndrome de McCune Albrigth (SMA) é uma doença genética não hereditária, com incidência estimada entre 1/100.000 e 1/1.000.000 casos/ano. A SMA caracteriza-se clinicamente pela tríade: displasia óssea fibrosa (FD), manchas cutâneas café-com-leite e hiperfunção endócrina tais como: síndrome de Cushing, pseudo-puberdade precoce, hipertiroidismo, acromegalia. O diagnóstico da SMA clássica é usualmente baseado no quadro clínico associado a dosagens hormonais e exames de imagem, principalmente cintilografia do esqueleto. No entanto, quadros atípicos e formas parciais muitas vezes dificultam o diagnóstico preciso da síndrome. O objetivo deste estudo foi padronizar dentre as técnicas de PNA (peptide nucleic acid) e PCT em Tempo Real, para a detecção de polimorfismos de base única (SNPs), a técnica mais sensível para a discriminação das mutações ativadoras da subunidade da proteína G. Para este estudo foram selecionados 32 pacientes, 1 masculino e 31 femininos, com SMA, todos em seguimento no Hospital das Clínicas da Faculdade de Medicina da USP. Como resultado positivo, apresentamos nesse trabalho pela primeira vez o uso do RT-PCR genotipagem na detecção das mutações ativadoras da proteína G, em DNA extraído de tecidos afetados e em leucócitos de sangue periférico, sendo a técnica considerada sensível o suficiente para discriminar de forma simples e rápida as mutações ativadoras da PGs. Sugerimos nesse estudo o uso da técnica de discriminação alélica pelo sistema Taqman. Essa técnica possibilita a detecção destas mutações gsp no sangue periférico mesmo numa baixa porcentagem, uma vez que nem sempre o tecido afetado (gônada, osso, hipófise) é disponível. / The McCune-Albright Syndrome (MAS) is a genetic disease, with incidence estimated at 1/100.000 and 1/1000000 cases per year. MAS is clinically characterized by the triad: bone fibrous dysplasia (FD) café-au-lait skin spots and endocrine hyperfunction, such as: precocious puberty (PP), Cushing's syndrome, hyperthyroidism and acromegaly. The diagnosis of MAS is originally based on clinical characteristics associated with hormonal and imaging studies. However, atypical and partial forms often hamper the accurate diagnosis of the syndrome. For this study we selected 32 patients, 1male and 31 females, all being treated in Hospital das Clínicas, School of Medicine, University of São Paulo. As a positive result, we showed for the first time the use of Real Time PCR/genotyping for the detection of activating mutations of the stimulatory G protein, using blood leucocytes DNA. This technique was sensible and can bring fast results for the patient and the physician, making the diagnosis easier. Our study proposes the use of allelic discrimination by Taqman system, which can be used as a probe that allows the identification of specific genotypes. These techniques could help detect these mutations in peripheral blood when the affected tissue is not available.

A síndrome de McCune Albrigth (SMA) é uma doença genética não hereditária, com incidência estimada entre 1/100.000 e 1/1.000.000 casos/ano. A SMA caracteriza-se clinicamente pela tríade: displasia óssea fibrosa (FD), manchas cutâneas café-com-leite e hiperfunção endócrina tais como: síndrome de Cushing, pseudo-puberdade precoce, hipertiroidismo, acromegalia. O diagnóstico da SMA clássica é usualmente baseado no quadro clínico associado a dosagens hormonais e exames de imagem, principalmente cintilografia do esqueleto. No entanto, quadros atípicos e formas parciais muitas vezes dificultam o diagnóstico preciso da síndrome. O objetivo deste estudo foi padronizar dentre as técnicas de PNA (peptide nucleic acid) e PCT em Tempo Real, para a detecção de polimorfismos de base única (SNPs), a técnica mais sensível para a discriminação das mutações ativadoras da subunidade da proteína G. Para este estudo foram selecionados 32 pacientes, 1 masculino e 31 femininos, com SMA, todos em seguimento no Hospital das Clínicas da Faculdade de Medicina da USP. Como resultado positivo, apresentamos nesse trabalho pela primeira vez o uso do RT-PCR genotipagem na detecção das mutações ativadoras da proteína G, em DNA extraído de tecidos afetados e em leucócitos de sangue periférico, sendo a técnica considerada sensível o suficiente para discriminar de forma simples e rápida as mutações ativadoras da PGs. Sugerimos nesse estudo o uso da técnica de discriminação alélica pelo sistema Taqman. Essa técnica possibilita a detecção destas mutações gsp no sangue periférico mesmo numa baixa porcentagem, uma vez que nem sempre o tecido afetado (gônada, osso, hipófise) é disponível. / The McCune-Albright Syndrome (MAS) is a genetic disease, with incidence estimated at 1/100.000 and 1/1000000 cases per year. MAS is clinically characterized by the triad: bone fibrous dysplasia (FD) café-au-lait skin spots and endocrine hyperfunction, such as: precocious puberty (PP), Cushing's syndrome, hyperthyroidism and acromegaly. The diagnosis of MAS is originally based on clinical characteristics associated with hormonal and imaging studies. However, atypical and partial forms often hamper the accurate diagnosis of the syndrome. For this study we selected 32 patients, 1male and 31 females, all being treated in Hospital das Clínicas, School of Medicine, University of São Paulo. As a positive result, we showed for the first time the use of Real Time PCR/genotyping for the detection of activating mutations of the stimulatory G protein, using blood leucocytes DNA. This technique was sensible and can bring fast results for the patient and the physician, making the diagnosis easier. Our study proposes the use of allelic discrimination by Taqman system, which can be used as a probe that allows the identification of specific genotypes. These techniques could help detect these mutations in peripheral blood when the affected tissue is not available.

Thesis advisor: Charles Hoffman / In both mammals and fission yeast, control of cAMP levels is maintained by adenylyl cyclases (ACs), which synthesize cyclic nucleotide, and by cyclic nucleotide phosphodiesterases (PDEs), which are responsible for its degradation. AC activity is regulated by G proteins, which respond to signals from G protein-coupled receptors (GPCRs) that detect extracellular signaling factors such as hormones. cAMP is a second messenger that has several effectors, with protein kinase A (PKA) being a primary target of activation that phosphorylates several downstream targets and results in modulation of pathways such as cell growth and gluconeogenesis. Aberrant cAMP regulation has been linked to several human disease states, such as McCune-Albright Syndrome, which is the result of elevated cAMP levels. Whereas the targeting of PDEs with drugs and selective inhibitors has been very successful, the AC-inhibiting compounds identified to date are unfavorable for clinical use. Inhibitors may not necessarily bind to and inhibit a given AC directly but instead act on a regulatory pathway such as calmodulin signaling. Theoretically, they also may bind to the G protein, interfere with the AC-G protein stimulatory complex, or regulate a factor of AC transcription. Since more than one AC species is expressed in many human cell types, it is difficult to selectively reduce cAMP levels. Therefore, for an AC inhibitor to be favored as a candidate for drug development, it is likely that the compound should directly bind to and inhibit the AC. This thesis describes my studies on a scaffold of 41 structurally related BCAC compounds, called the BCAC51 scaffold, that was identified in a high-throughput screen (HTS) with Schizosaccharomyces pombe strains transformed with GNAS and either mammalian AC4 or AC7. I carried out a series of experiments to examine whether the compounds bind to and inhibit mammalian ACs directly. The most active compounds were further characterized for potency and specificity against a panel of ACs. Several compounds significantly reduced cAMP production, but it could not be determined if the compounds directly or indirectly altered AC activity. I also cloned and constructed strains expressing the human wild-type AC5 gene and the AC5 R418W mutant, which has shown an increased sensitivity to GNAS. cAMP assays on these strains using various BCAC compounds showed that while most compounds had similar effects on both forms of AC5, BCAC62 was significantly more effective on the wild-type enzyme than on the mutant AC5, although the reason for this is unclear. To test whether the compounds could reduce AC activity in the absence of GNAS (basal activity), a flow cytometry study was carried out using a PKA-repressed GFP reporter. Results suggested that BCAC compounds do reduce basal-AC activity and therefore do not act by binding to and inhibiting GNAS, by interfering with the AC-GNAS stimulatory complex, nor by stimulating PDE. Finally, I developed a molecular genetic screen for mutant alleles of an AC gene that confer compound-resistance. One cycle of the screen is near completion, and the screen provides a foundation for future examination of compound-resistant AC candidates. The results presented in this thesis serve as a basis for further research into members of the BCAC51 compound series being putative direct inhibitors of mammalian ACs. / Thesis (BS) — Boston College, 2022. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Scholar of the College. / Discipline: Biology.

No description available.

INTRODUÇÃO: A primeira doença humana atribuída à resistência hormonal foi o pseudo-hipoparatireoidismo (PHP), uma doença rara caracterizada por hipocalcemia, hiperfosfatemia e níveis elevados de hormônio paratireoidiano (PTH) na presença de função renal normal, quadro condizente com resistência ao PTH. A classificação original do PHP leva em consideração a osteodistrofia hereditária de Albright (AHO): presente no PHP1a e ausente no PHP1b. Na medida em que as bases moleculares do PHP têm sido compreendidas, uma classificação baseada no genótipo tem surgido. Segundo ela, pacientes com PHP1a apresentam mutações na região codificadora da Gsalfa do GNAS e o padrão de herança é autossômico dominante relacionado à transmissão materna. Por outro lado, o PHP1b é caracterizado por alterações nas regiões diferencialmente metiladas (DMRs) do GNAS por mecanismos não completamente esclarecidos, limitando a previsão do seu padrão de herança. Pacientes que apresentam a AHO na ausência de resistência hormonal têm o diagnóstico de pseudopseudo-hipoparatireoidismo (PPHP) e seu padrão de herança é autossômico dominante relacionado à transmissão paterna de mutações na região codificadora da Gsalfa do GNAS. OBJETIVOS: Classificar 25 pacientes com PHP com base em defeitos no GNAS e caracterizar seu fenótipo. Pesquisar mutações no GNAS nos quatro pacientes com PPHP e também caracterizar seu fenótipo. MÉTODOS: A avaliação fenotípica incluiu análise das resistências hormonais, pesquisa de repercussões crônicas da hipocalcemia/hiperfosfatemia (calcificações em sistema nervoso central: SNC e catarata) e identificação da AHO. A análise do GNAS foi feita por sequenciamento automático e MLPA (região codificadora da Gsalfa) e por MS-MLPA (região regulatória: DMRs). RESULTADOS: Resistência ao PTH foi identificada nos 25 pacientes com PHP e resistência ao TSH em 17/25. Calcificações em SNC e catarata estiveram presentes em 18 e 10 pacientes com PHP, respectivamente. A AHO foi caracterizada por: face arredondada (n=18), braquidactilia (n=11), baixa estatura (n=8), ossificações subcutâneas (n=6), obesidade (n=9) e retardo mental (n=3). Identificamos oito mutações (cinco novas) na região codificadora da Gsalfa em 10 pacientes com PHP1a e quatro pacientes com PPHP. Quinze pacientes apresentaram alteração no padrão de metilação das DMRs (genótipo: PHP1b). O fenótipo dos pacientes foi semelhante nos dois grupos. DISCUSSÃO E CONCLUSÃO: Nenhuma das classificações do PHP foi capaz de predizer gravidade ou o curso clínico da doença. Porém, o diagnóstico do PHP1a baseado no genótipo possibilitou a identificação precoce de uma paciente, a exclusão de PHP1a na filha de outra paciente e o aconselhamento genético em duas famílias. O diagnóstico de PHP1b em uma paciente só foi possível graças ao genótipo, visto que seu perfil laboratorial osteometabólico era inconclusivo. Com base no fenótipo, 8/15 pacientes com PHP1b seriam classificados como PHP1a considerando a presença de dois ou mais estigmas da AHO, podendo levar a falhas no aconselhamento genético. Portanto, concluímos que a classificação do PHP baseada na análise do GNAS é mais informativa do que a baseada no fenótipo, permitindo o diagnóstico precoce e o aconselhamento genético de casos familiais de PHP1a. A identificação do PHP1b deve ser promissora na medida em que seus mecanismos de transmissão forem mais bem entendidos / BACKGROUND: The first human disease attributed to hormone resistance was pseudohypoparathyroidism (PHP), a rare disease characterized by hypocalcemia, hyperphosphatemia and elevated parathyroid hormone (PTH) levels in the presence of normal renal function, consistent picture of PTH resistance. The original classification of PHP takes into account the Albright hereditary osteodystrophy (AHO): present in PHP1a and absent in PHP1b. As the molecular bases of PHP have been understood, a classification based on genotype has emerged. According to it, PHP1a patients present mutations in the Gsalpha coding region of the GNAS and the pattern of inheritance is autosomal dominant related to maternal transmission. On the other hand, PHP1b is characterized by alterations in differentially methylated regions (DMRs) of the GNAS by mechanisms not completely clear, limiting the prediction of the pattern of inheritance. Patients who present AHO in the absence of hormone resistance have the diagnosis of pseudopseudohypoparathyroidism (PPHP) and their pattern of inheritance is autosomal dominant related to paternal transmission of mutations in the Gsalfa coding region of the GNAS. OBJECTIVE: To classify 25 patients with PHP based on GNAS molecular defects and to characterize their phenotype. To search for GNAS mutations in four patients with PPHP and also to characterize their phenotype. METHODS: The phenotypic evaluation included analysis of hormone resistances, research of chronic repercussions of hypocalcemia/hyperphosphatemia (calcifications in central nervous system: CNS and cataract) and identification of AHO. The analysis of the GNAS was done by automated sequencing and MLPA (Gsalphaa coding region) and by MS-MLPA (regulatory region: DMRs). RESULTS: PTH resistance was identified in 25 patients with PHP and TSH resistance in 17/25. Calcifications in CNS and cataract were present in 18 and 10 patients with PHP, respectively. AHO was characterized by: rounded face (n=18), brachydactyly (n=11), short stature (n=8), subcutaneous ossifications (n=6), obesity (n=9) and mental retardation (n=3). We identified eight mutations (five novels) in the Gsalpha coding region in 10 patients with PHP1a. Fifteen patients presented alterations in the methylation pattern of DMRs (genotype: PHP1b). The phenotype of patients was similar in both groups. DISCUSSION AND CONCLUSION: None of the PHP classifications was able to predict the severity or clinical course of the disease. However, the diagnosis of PHP1a based on genotype allowed the early identification of one patient, the exclusion of PHP1a in the daughter of another patient and genetic counseling in two families. The PHP1b diagnosis in one patient was only possible due to the genotype, as her bone metabolism profile was inconclusive. Based on phenotype, 8/15 PHP1b patients would have been classified as PHP1a considering the presence of two or more AHO stigmas, being able to lead to failures in genetic counseling. Therefore, we conclude that the PHP classification based on GNAS analysis is more informative than that based on phenotype, allowing the early diagnosis and the genetic counseling for familial cases of PHP1a. The identification of PHP1b may be promising as its transmission mechanisms are better clarified

La Néoplasie Endocrinienne Multiple de type 1 (NEM1) est une maladie génétique qui associe hyperparathyroïdie primaire, tumeurs neuroendocrines digestives et adénomes hypophysaires. Elle est due à des mutations non récurrentes du gène MEN1, parfois difficile à classer. Nous avons rassemblé et analysé les données cliniques et génétiques de 1676 patients français porteurs d’une variation de MEN1 des 4 laboratoires experts du groupe TENGEN. De ce travail, nous avons alimenté une base de données de variants (UMD MEN1) et établir le profil mutationnel de MEN1 en France. Dans une seconde partie, nous avons établi des recommandations pour la classification des variants faux sens de MEN1 en adaptant les Guidelines de l’ACMG-AMP (American College of Medical Genetics).Le Syndrome de McCune-Albright (SMA) est du à des mutations postzygotiques activatrices récurrentes du gène GNAS, responsables d’un mosaïcisme somatique, souvent indétectables dans le sang. En utilisant une technique de PCR quantitative ultrasensible, le taux de détection des mutations R201C et R201H est de 50% dans le sang de 16 patients présentant 1 à 3 lésions majeures du SMA. Pour la 1ere fois, nous avons retrouvé ces mutations dans l’ADN circulant de 3/4 patients testés.Ces mutations sont retrouvées aussi dans 30 à 40% des adénomes somatotropes. Le locus GNAS est soumis à empreinte parentale, responsable d’une expression mono-allélique de GNAS dans certains tissus comme l’hypophyse. Dans une série de 57 adénomes somatotropes nous avons montré une perturbation de l’empreinte de GNAS, associée à une relâche de l’empreinte mais n’entraînait pas d’augmentation de l’expression du gène GNAS. / The Multiple Endocrine Neoplasia 1 (MEN1) is due to MEN1 mutations and characterized by a broad spectrum of lesions including hyperparathyroidism, pituitary adenomas and neuroendocrine tumors. Missense variants are frequent and could lead wrong interpretation. We collected and analyzed all the 370 variants of 1676 patients sequenced for ten years by the TENGEN network (French oncogenetics of neuroendocrine tumors). We registered them in the UMD MEN1 database. Then, consensus was reached to validate adjustments to the ACMG-AMP guidelines for MEN1 locus-specific interpretation of missense variants. The McCune-Albright syndrome (MAS) is a rare pediatric mosaic genetic disorder. MAS results from recurrent post-zygotic GNAS mutations, not detectable in blood DNA by Sanger. We develop an ultrasensitive quantitative PCR using digital droplet PCR™ (ddPCR™) in order to target the R201C and R201H GNAS mutations. After a validation study, we clinically evaluated ddPCR™ in the whole blood DNA or circulating cell-free DNA (ccfDNA) of patients presented with at least 1 MAS lesion. First we detected in ccfDNA the mosaic somatic GNAS mutant. The ddPCR™ showed a mutation detection rate of 50% in blood DNA of the 16 included patients and 3/4 in ccfDNA.GNAS mutations are also reported in 30 to 40% of somatotroph tumors. GNAS is encoded by an imprinted locus, responsible for a mono-allelic expression in pituitary. We explored the GNAS locus methylation status of 57 somatotroph adenomas and showed disturbance. We studied the impact on GNAS, SST2R and AIP expression of this disturbance. We showed an imprinting relaxation not associated with an increased expression of GNAS.