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Funder: European Research Council, Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a type of blood cancer manifesting via a range of cytopenias and dysplastic changes of blood and bone marrow cells. While experts analyze cytomorphology to diagnose MDS, similar alterations can be observed in other conditions such as haematinic deficiency anemias, and definitive diagnosis requires complementary information such as blood counts, karyotype and molecular testing. However, recent works demonstrated that computational analysis of bone marrow slides predicts not only MDS or AML but also the presence of specific mutations. Here, we present and make available Haemorasis, a computational method that detects and characterizes white and red blood cells (WBC and RBC, respectively) in peripheral blood slides, and apply it to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia and iron deficiency anemia), where Haemorasis detects over half a million WBC and millions of RBC. We then show how these large sets of cell images can be used in diagnosis and prognosis, whilst identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS, and, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. Finally, we externally validate these methods, showing they generalize to other centers and scanners.

A pesquisa analisou os fatores envolvidos na expansão recente do Turismo receptivo em três localidades situadas no entorno da cidade de Campos do Jordão, na Serra da Mantiqueira - SP: Santo Antonio do Pinhal, São Bento do Sapucaí e o distrito de São Francisco Xavier, pertencente ao município de São José dos Campos. Em virtude da expressividade do fenômeno turístico na área, justifica-se avaliar os efeitos da expansão das estruturas receptivas sobre a vida das populações. A abordagem privilegiou a questão do desenvolvimento sustentável como elemento definidor das ações dos organizadores do Turismo, e avaliou junto aos moradores as formas de participação no processo. O referencial teórico apoiou-se em autores da Geografia do Turismo e outras disciplinas da área de Ciências Sociais, as quais auxiliam no estudo do fenômeno turístico. Por meio de entrevistas com os organizadores e uma amostra dos residentes, utilizou-se a fenomenologia como método para captar as percepções e opiniões dos moradores quanto ao crescimento das atividades receptivas nas três localidades. Constatouse que aos fatores de atratividade originais, o clima e a paisagem serranos, outros estão sendo adicionados à área, em razão da saturação de Campos, como a tranqüilidade dos lugarejos, a paisagem rural e os recursos associados ao meio natural. Essas mudanças na oferta atendem novas demandas e geram formas inéditas de organização do espaço turístico na área, impondo desafios às populações envolvidas. This study analyses the causes of the recent tourism growth among three sites located around the city of Campos do Jordão, on Serra da Mantiqueira, a hill area on the northeast of the state of São Paulo. The places named Santo Antonio do Pinhal, São Bento do Sapucaí e São Francisco Xavier (the latest is a district of the city of São Jose dos Campos), have their receptive structures been increased during last decade, as a consequence of the appeal of Campos do Jordão, which causes crescent demands over all that region. Due to the extention that Tourism activities are obtaining in the area, one can realize several effects over the residents living standards. As theoretical references the author used the concepts of sustainability, tourism planning, and categories such as tourist space and landscape, performing the first chapter. Study field avaliated the relations of residents which the phenomenon, using questionnaires as well as interviews with tourist authorities. The Phenomenology was the method used to analyze residents attitudes toward tourist policies and practices. Results showed that tourism activities are fastly increasing in those locations, causing new concerns and challenges to the residents.

Submitted by Luiza Arao (luizah@ccje.ufrj.br) on 2021-11-17T13:11:55Z No. of bitstreams: 1 RPBarros.LRamos.JGAReis.pdf: 7138339 bytes, checksum: bcd698c3b8a7c39c883beee0c008640d (MD5) Made available in DSpace on 2021-11-17T13:11:55Z (GMT). No. of bitstreams: 1 RPBarros.LRamos.JGAReis.pdf: 7138339 bytes, checksum: bcd698c3b8a7c39c883beee0c008640d (MD5) Previous issue date: 1992 Indisponível. Unavailable.