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Mello, Curtis

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Mello, Curtis

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2017 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.c50f1aca-c08f-4d1f-bd5d-f8dd096bd354

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    Insights about variation in meiosis from 31,228 human sperm genomes
    (Springer Nature, 2019-05-02) Bell, Avery; Mello, Curtis; Nemesh, James; Brumbaugh, Sara A; Wysoker, Alec; McCarroll, Steven
    Meiosis, while critical for reproduction, is also variable and error-prone: crossover rates vary among gametes, between the sexes, and among humans of the same sex, and chromosome mis-segregation leads to aneuploidy1-8. To study diverse meiotic outcomes and how they co-vary across chromosomes, gametes, and humans, we developed Sperm-seq, a way to simultaneously sequence the genomes of thousands of individual sperm. We analyzed the genomes of 31,228 human gametes from 20 sperm donors, identifying 813,122 crossovers and 787 aneuploid chromosomes. Sperm donors had aneuploidy rates ranging from 0.01 to 0.05 aneuploidies per gamete; crossovers partially protected chromosomes from nondisjunction at meiosis I. Some chromosomes and donors underwent more-frequent non-disjunction during the meiosis I cell division, while other chromosomes and donors showed more segregation failures during meiosis II; many genomic anomalies that could not be explained by simple nondisjunction also occurred. Diverse recombination phenotypes – from crossover rates to crossover location and separation (a measure of crossover interference) – co-varied strongly across individuals and cells. Our results can be incorporated with earlier observations into a unified model in which a core mechanism – the variable physical compaction of meiotic chromosomes – generates inter-individual and cell-to-cell variation in diverse meiotic phenotypes.
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    Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
    (Springer Nature, 2017) Merkle, Florian; Ghosh, Sulagna; Kamitaki, Nolan; Mitchell, Jana; Avior, Yishai; Mello, Curtis; Kashin, Seva; Mekhoubad, Shila; Ilic, Dusko; Sweetnam, Maura; Saphier Belfer, Genevieve; Handsaker, Robert; Genovese, Giulio; Bar, Shiran; Benvenisty, Nissim; McCarroll, Steven; Eggan, Kevin
    Background: Depressive disorders are the second-leading cause of global disability, and an area of increasing focus in international health efforts. We describe a community health worker (CHW) program rolled out in a stepped-wedge design during the course of routine patient care to 74 patients with depression in 4 communities in rural Mexico. Methods: We used random effects models to calculate the change in Patient Health Questionnaire-9 (PHQ-9) scores, an internationally validated measure of depression, before and after the CHW program was introduced. As a secondary outcome, we also examined the change pre- and post-intervention in the proportion of patients who had a mean of at least one visit per month for depression follow-up, in accordance with clinic visit guidelines. Results: In multivariate mixed-effects regression, the introduction of the CHW program was associated with a 2.1-point decrease in PHQ-9 score (95% CI: -3.7 to -0.50) followed by a decrease in PHQ-9 score of 0.19 points per month (95% CI: -0.41 to 0.02), beyond standard care. There was strong evidence that patients were far more likely to attend a mean of at least one visit per month (adjusted OR = 8.5, 95% CI: 7.2 to 9.7) after the intervention was introduced in a community. Conclusions: Our results suggest an association between the introduction of a CHW program and improved depression outcomes and appointment adherence. Our findings are limited by missing data. Future research is necessary to develop evidence-based mental health interventions implementable in low-resource settings.