Neuronal process remodeling occurs widely in the construction of both invertebrate and vertebrate nervous systems. During Drosophila metamorphosis, gamma neurons of the mushroom bodies (MBs), the center for olfactory learning in insects, undergo pruning of larval-specific dendrites and axons followed by outgrowth of adult-specific processes. To elucidate the underlying molecular mechanisms, we conducted a genetic mosaic screen and identified one ultraspiracle (usp) allele defective in larval process pruning. Consistent with the notion that USP forms a heterodimer with the ecdysone receptor (EcR), we found that the EcR-B1 isoform is specifically expressed in the MB gamma neurons, and is required for the pruning of larval processes. Surprisingly, most identified primary EcR/USP targets are dispensable for MB neuronal remodeling. Our study demonstrates cell-autonomous roles for EcR/USP in controlling neuronal remodeling, potentially through novel downstream targets.
The pleiotropic functions of small GTPase Rho present a challenge to its genetic analysis in multicellular organisms. We report here the use of the MARCM (mosaic analysis with a repressible cell marker) system to analyze the function of RhoA in the developing Drosophila brain. Clones of cells homozygous for null RhoA mutations were specifically labeled in the mushroom body (MB) neurons of mosaic brains. We found that RhoA is required for neuroblast (Nb) proliferation but not for neuronal survival. Surprisingly, RhoA is not required for MB neurons to establish normal axon projections. However, neurons lacking RhoA overextend their dendrites, and expression of activated RhoA causes a reduction of dendritic complexity. Thus, RhoA is an important regulator of dendritic morphogenesis, while distinct mechanisms are used for axonal morphogenesis.
Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests (CA125 and transvaginal sonography [TVS]). Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current lim its. This study estimates the mortality reduction, years of life saved and cost-effectiveness achievable by annual multimodal screening using rising CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counter parts with better performance characteristics. An existing stochastic micro-simulation model is refined and used to screen a virtual cohort of 1 million women from age 45 to 85. Each woman is assigned a detailed disease course and screening results timeline. The pre-clinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are performed in order to evaluate the impact of these factors on overall screening performance and costs. Our results demonstrate that when applied to women at average risk, annual screening using rising CA125 to select women for TVS achieves modest mortality reduction (~13%) and falls with in currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first line test that perform s substantially better than CA125 and has similar costs is required in order for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective.
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