Discovery of novel variants underlying inherited bleeding and platelet disorders by next generation sequencing

Genetic variants that affect megakaryopoiesis and platelet formation result in inherited bleeding and platelet disorders (BPD). Only 40-60% of cases will receive a diagnosis indicating the pathway at fault [1, 2]. This thesis is the result of work undertaken to discover novel variants causative of BPD, as part of the NIHR BioResource-Rare Diseases Study (NIHR BR-RD). 1,213 BPD cases of uncertain genetic aetiology were recruited from 31 international centres. 687 samples were sent for whole exome sequencing and 1118 for whole genome sequencing. Cases were systematically phenotyped and genotype-phenotype relationships were assessed to detect causal variants in known and novel candidate BPD genes, including KDSR and ABCC4. KDSR is an early enzyme in the de novo sphingolipid synthetic pathway, and several cases have recently been reported with KDSR variants, severe skin pathology and thrombocytopenia, without evaluation of the mechanism of thrombocytopenia [3, 4]. I report a pedigree in which novel compound heterozygous variants in KDSR cosegregate with a severe phenotype of neonatal-onset thrombocytopenia in two siblings and juvenile myelofibrosis in the older sibling, without significant skin pathology. Cellular studies support roles for KDSR in the regulation of growth and apoptosis, megakaryocyte yield, maturity, size and proplatelet formation. This thesis also reports on the study of a pedigree in which coinheritance of homozygous loss of function variants in novel candidate BPD gene ABCC4 and heterozygous variant in known BPD gene P2RY12 cosegregate with a lifelong mild-to-moderate bleeding disorder. ABCC4 is a membrane-bound transport glycoprotein with broad substrate specificity that includes cAMP, a powerful inhibitor of platelet activation, and intra-platelet cAMP was elevated in affected individuals. The role of ABCC4 in megakaryopoiesis is also explored using CRISPR-Cas9-mediated inhibition of ABCC4 expression in cellular models of megakaryopoiesis. This study describes collaborative approaches to the analysis of high throughput sequencing data for the discovery of potentially pathogenic variants, and emphasises the necessity of functional validation of hypothetical associations

Genetic characterization of seedling and adult plant resistance against three rust diseases in the 22nd SAWSN CIMMYT Nursery

Relatório de estágio do mestrado em Ensino da Educação Física nos Ensinos Básico e Secundário, apresentado à Faculdade de Ciências do Desporto e Educação Física da Universidade de CoimbraEste relatório final surge a conclusão de uma formação de dois anos neste mestrado. O Estágio Pedagógico foi realizado na Escola Secundária de Anadia junto da turma D do 9º ano de escolaridade, durante o ano lectivo de 2013/14. O presente trabalho, pretende relatar e refletir sobre os procedimentos adotados em três processos por mim considerados fundamentais no processo ensino-aprendizagem, o planeamento; a realização e a avaliação. Ao longo do ano lectivo a reflexão constante sobre a prática pedagógica permitiu que me torna-se um professor em constante evolução, absorvendo a informação e tendo uma postura critica em relação a este processo. Com este relatório pretendo demonstrar o processo desenvolvido ao longo desta jornada. Um dos principais desfechos que retiro deste processo é a necessidade de ensinar e promover a aprendizagem adequada a todos os alunos. Deste o aluno que tem excesso de peso, ao que tem Necessidades Educativas Especiais, ao que não gosta de educação física, estre outros perfis. Se lhes for apresentado um ambiente adequado às suas necessidades todos eles serão munidos de uma importante bagagem. O estágio pedagógico promove a aquisição de um conjunto de saberes, de atitudes práticas e resolução de problemas pedagógicos, que servirão como base de sustentação para a integração futura no ensino e também será transversal a outras actividades ligadas ao desporto e à promoção de saúde. Por último, será abordado o tema: grupos de nível em Educação Física, apresentando como exemplo a turma do 9ºD. Que se foi confrontada ao longo do ano lectivos pela homo e heterogeneidade nos grupos formados para a aula. This final report is the conclusion of a two-year training in this Masters Degree. The Pedagogical Internship was conducted in Escola Secundária de Anadia with class D of the 9th grade during the school year 2013/14. The present study aims to report and reflect on the procedures adopted in the three cases, that i considered fundamental, teaching-learning process, planning; the implementation and evaluation. During the school year, constant reflexion about pedagogical act allow me toi became a teacher in constant improvement, absorbing all the information with na critic posture about the teaching. With this report i pretend show all the process developed during this long journey. One of the principals knowledges i reatret from this process is the need of teaching and promote na learning suitable for all students. From the student who have overweight, the one who has Special Educational Needs, the student who don’t like physical education, until the other students profile, if we gave them an suitable environment to their needs, al og them will todos eles will be provided with an important baggage. The Pedagogical Internship promotes the acquisition of an a aquisição de a set of knowledge, with practices and attitudes for solving pedagogical problems, to serve as a support base for future integration in teaching and will also be cross-linked to other activities for sport and health promotion.. Last but not least, will be approach a theme: Group levels on physical Education class, using as an example the class D from the 9th grade . Who was faced throughout the school year by the homo-and heterogeneity in groups formed for class

Identification of markers linked with stem rust resistance genes Sr33 and Sr45

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SISTEM PELAYANAN CUSTOMER SERVICE CENTER PANASONIC PADA PT. GOBEL DHARMA NUSANTARA CABANG PEKANBARU

ABSTRAK SISTEM PELAYANAN CUSTOMER SERVICE CENTER PANASONIC PADA PT. GOBEL DHARMA NUSANTARA CABANG PEKANBARU Oleh Nabila Meisa Bariana NIM 02070227300 Penulisan ini bertujuan untuk mengetahui bagaimana sistem pelayanan customer service center Panasonic PT. Gobel Dharma Nusantara Cabang Pekanbaru. Sumber data yaitu dengan melakukan observasi, wawancara secara langsung dan data sekunder yaitu dengan dokumentasi dan arsip perusahaan. peulisan ini menggunakan metode deskriptif. Berdasarkan hasil pengamatan di lapangan dapat disimpulkan bahwa PT. Gobel Dharma Nusantara Service Center Panasonic Cabang Pekanbaru terdiri dari dua proses pelayanan secara langsung dan tidak langsung. Kata Kunci : Sistem, Pelayanan, Customer Servic