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Vpr-mediated induction of G2 cell cycle arrest has been postulated to be important for human immunodeficiency virus type 1 (HIV-1) replication, but the precise role of Vpr in this cell cycle arrest is unclear. In the present study, we have shown that HIV-1 Vpr interacts with damaged DNA binding protein 1 (DDB1) but not its partner DDB2. The interaction of Vpr with DDB1 was inhibited when DCAF1 (VprBP) expression was reduced by short interfering RNA (siRNA) treatment. The Vpr mutant (Q65R) that was defective for DCAF1 interaction also had a defect in DDB1 binding. However, Vpr binding to DDB1 was not sufficient to induce G2 arrest. A reduction in DDB1 or DDB2 expression in the absence of Vpr also did not induce G2 arrest. On the other hand, Vpr-induced G2 arrest was impaired when the intracellular level of DDB1 or Cullin 4A was reduced by siRNA treatment. Furthermore, Vpr-induced G2 arrest was largely abolished by a proteasome inhibitor. These data suggest that Vpr assembles with DDB1 through interaction with DCAF1 to form an E3 ubiquitin ligase that targets cellular substrates for proteasome-mediated degradation and G2 arrest. 相似文献
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Elana Lavine 《CMAJ》2012,184(6):666-668
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Darya A. Meshalkina Elana V. Kysil Kristina A. Antonova Konstantin A. Demin Tatiana O. Kolesnikova Sergey L. Khatsko Raul R. Gainetdinov Polina A. Alekseeva Allan V. Kalueff 《Neurochemical research》2018,43(6):1191-1199
Amitriptyline is a commonly used tricyclic antidepressant (TCA) inhibiting serotonin and norepinephrine reuptake. The exact CNS action of TCAs remains poorly understood, necessitating new screening approaches and novel model organisms. Zebrafish (Danio rerio) are rapidly emerging as a promising tool for pharmacological research of antidepressants, including amitriptyline. Here, we examine the effects of chronic 2-week exposure to 10 and 50 μg/L amitriptyline on zebrafish behavior and monoamine neurotransmitters. Overall, the drug at 50 μg/L evoked pronounced anxiolytic-like effects in the novel tank test (assessed by more time in top, fewer transition and shorter latency to enter the top). Like other TCAs, amitriptyline reduced serotonin turnover, but also significantly elevated whole-brain norepinephrine and dopamine levels. The latter effect was not reported in this model previously, and accompanied higher brain expression of tyrosine hydroxylase (a rate-limiting enzyme of catecholamine biosynthesis), but unaltered expression of dopamine-β-hydroxylase and monoamine oxidase (the enzymes of dopamine metabolism). This response may underlie chronic amitriptyline action on dopamine and norepinephrine neurotransmission, and contribute to the complex CNS profile of this drug observed both clinically and in animal models. Collectively, these findings also confirm the important role of monoamine modulation in the regulation of anxiety-related behavior in zebrafish, and support the utility of this organism as a promising in-vivo model for CNS drug screening. 相似文献
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RNA sequences that conform to the consensus sequence of 5' splice sites but are not used for splicing occur frequently in protein coding genes. Mutational analyses have shown that suppression of splicing at such latent sites may be dictated by the necessity to maintain an open reading frame in the mRNA. Here we show that stop codon frequency in introns having latent 5' splice sites is significantly greater than that of introns lacking such sites and significantly greater than the expected occurrence by chance alone. Both observations suggest the occurrence of a general mechanism that recognizes the mRNA reading frame in the context of pre-mRNA. 相似文献
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Neal E. Blair Elana L. Leithold A. N. Thanos Papanicolaou Christopher G. Wilson Laura Keefer Erin Kirton David Vinson Doug Schnoebelen Bruce Rhoads Mingjing Yu Quinn Lewis 《Biogeochemistry》2018,138(2):171-195
The damming of rivers has created hotspots for organic carbon sequestration and methane production on a global scale as the reservoirs intercept fluvial suspended and dissolved loads. To better understand how the C-biogeochemistry of a reservoir responds to watershed processes and evolves over time, Lake Decatur, located in the Intensively Managed Landscape Critical Zone Observatory (IML-CZO) was studied. Solid phase analyses (% organic C, C/N, δ13C, δ15N) of soils and sediments sampled from stream bank exposures, river suspensions, and the lake bottom were conducted to characterize organic C (OC) sources throughout the sedimentary system. Agriculturally-driven soil erosion rapidly altered lake bathymetry causing an evolution of sedimentary and OC deposition patterns, which in turn shaped where and when methane production occurred. A positive correlation between OC accumulation rate and porewater dissolved inorganic C (DIC) δ13C profiles indicates that methane generation is strongly influenced by OC burial rate. The sources of the lake bed particulate organic C (POC) have also evolved over time. Drowned vegetation and/or shoreline inputs were dominant initially in areas adjacent to the original river channel but were rapidly overwhelmed by the deposition of sediments derived from eroded agricultural soils. Eutrophication of the lake followed with the onset of heavy fertilizer application post-1960. This succession of sources is expected to be commonplace for reservoirs greater than?~?50–60 years old in agricultural settings because of the relative timing of tillage and fertilizer practices. The 13C/12C ratios of methane from Lake Decatur were more depleted in 13C than what is commonly expected for freshwater sedimentary environments. The 13C-depletion suggests that CO2-reduction is the dominant methanogenic pathway rather than the anticipated acetate dissimilation process. The isotopic observations reveal that commonly held assumptions about methane production and its C-isotopic signature in freshwater systems are over-simplified and not strictly applicable to this system. 相似文献
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Aliki Perdikari Tessa Cacciottolo Elana Henning Edson Mendes de Oliveira Julia M. Keogh I. Sadaf Farooqi 《Open biology》2022,12(3)
Obesity, defined as an excess of adipose tissue that adversely affects health, is a major cause of morbidity and mortality. However, to date, understanding the structure and function of human adipose tissue has been limited by the inability to visualize cellular components due to the innate structure of adipocytes, which are characterized by large lipid droplets. Combining the iDISCO and the CUBIC protocols for whole tissue staining and optical clearing, we developed a protocol to enable immunostaining and clearing of human subcutaneous white adipose tissue (WAT) obtained from individuals with severe obesity. We were able to perform immunolabelling of sympathetic nerve terminals in whole WAT and subsequent optical clearing by eliminating lipids to render the opaque tissue completely transparent. We then used light sheet confocal microscopy to visualize sympathetic innervation of human WAT from obese individuals in a three-dimensional manner. We demonstrate the visualization of sympathetic nerve terminals in human WAT. This protocol can be modified to visualize other structures such as blood vessels involved in the development, maintenance and function of human adipose tissue in health and disease. 相似文献
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Bas Brouwers Edson Mendes de Oliveira Maria Marti-Solano Fabiola B.F. Monteiro Suli-Anne Laurin Julia M. Keogh Elana Henning Rebecca Bounds Carole A. Daly Shane Houston Vikram Ayinampudi Natalia Wasiluk David Clarke Bianca Plouffe Michel Bouvier M. Madan Babu I. Sadaf Farooqi Jacek Mokrosiński 《Cell reports》2021,34(12):108862