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- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 3. |
- Grim, Jonathan E., et al.
(författare)
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Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase
- 2008
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 181:6, s. 913-920
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Tidskriftsartikel (refereegranskat)abstract
- The SCF(FBW7) ubiquitin ligase degrades proteins involved in cell division, growth, and differentiation and is commonly mutated in cancers. The Fbw7 locus encodes three protein isoforms that occupy distinct subcellular localizations, suggesting that each has unique functions. We used gene targeting to create isoform-specific Fbw7-null mutations in human cells and found that the nucleoplasmic Fbw7alpha isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and sterol regulatory element binding protein 1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, and this correlates with changes in cyclin E-cyclin-dependent kinase 2 (CDK2)-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation. These data suggest that oscillations in cyclin E-CDK2-specific activity during the cell cycle regulate the timing of cyclin E degradation. Moreover, they highlight the utility of adeno-associated virus-mediated gene targeting in functional analyses of complex loci.
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| 4. |
- Whitmer, R. A., et al.
(författare)
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Central obesity and increased risk of dementia more than three decades later
- 2008
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 71:14, s. 1057-1064
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Tidskriftsartikel (refereegranskat)abstract
- Background: Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. Methods: A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. Results: A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33–3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58–2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98–3.81) vs those with low SAD (<25 cm) and normal BMI (18.5–24.9 kg/m2), whereas those both obese (BMI >30 kg/m2) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85–4.55). Conclusions: Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.
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