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21.
Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids. 相似文献
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23.
Mikhail S. Novikov Vladimir T. Valuev-Elliston Denis A. Babkov Maria P. Paramonova Alexander V. Ivanov Sergey A Gavryushov Anastasia L. Khandazhinskaya Sergey N. Kochetkov Christophe Pannecouque Graciela Andrei Robert Snoeck Jan Balzarini Katherine L. Seley-Radtke 《Bioorganic & medicinal chemistry》2013,21(5):1150-1158
A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC50 = 0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs. 相似文献
24.
Mikhail S. Novikov Denis A. Babkov Maria P. Paramonova Anastasia L. Khandazhinskaya Alexander A. Ozerov Alexander O. Chizhov Graciela Andrei Robert Snoeck Jan Balzarini Katherine L. Seley-Radtke 《Bioorganic & medicinal chemistry》2013,21(14):4151-4157
HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5–12 μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure–activity relationship for the linker region. 相似文献
25.
Daniel?SchmitterEmail author Paulina?Wachowicz Daniel?SageEmail author Anastasia?Chasapi Ioannis?Xenarios Viesturs?Simanis Michael?Unser 《Cell division》2013,8(1):6
Background
The yeast Schizosaccharomyces pombe is frequently used as a model for studying the cell cycle. The cells are rod-shaped and divide by medial fission. The process of cell division, or cytokinesis, is controlled by a network of signaling proteins called the Septation Initiation Network (SIN); SIN proteins associate with the SPBs during nuclear division (mitosis). Some SIN proteins associate with both SPBs early in mitosis, and then display strongly asymmetric signal intensity at the SPBs in late mitosis, just before cytokinesis. This asymmetry is thought to be important for correct regulation of SIN signaling, and coordination of cytokinesis and mitosis. In order to study the dynamics of organelles or large protein complexes such as the spindle pole body (SPB), which have been labeled with a fluorescent protein tag in living cells, a number of the image analysis problems must be solved; the cell outline must be detected automatically, and the position and signal intensity associated with the structures of interest within the cell must be determined.Results
We present a new 2D and 3D image analysis system that permits versatile and robust analysis of motile, fluorescently labeled structures in rod-shaped cells. We have designed an image analysis system that we have implemented as a user-friendly software package allowing the fast and robust image-analysis of large numbers of rod-shaped cells. We have developed new robust algorithms, which we combined with existing methodologies to facilitate fast and accurate analysis. Our software permits the detection and segmentation of rod-shaped cells in either static or dynamic (i.e. time lapse) multi-channel images. It enables tracking of two structures (for example SPBs) in two different image channels. For 2D or 3D static images, the locations of the structures are identified, and then intensity values are extracted together with several quantitative parameters, such as length, width, cell orientation, background fluorescence and the distance between the structures of interest. Furthermore, two kinds of kymographs of the tracked structures can be established, one representing the migration with respect to their relative position, the other representing their individual trajectories inside the cell. This software package, called “RodCellJ”, allowed us to analyze a large number of S. pombe cells to understand the rules that govern SIN protein asymmetry. (Continued on next page)(Continued from previous page)Conclusions
“RodCellJ” is freely available to the community as a package of several ImageJ plugins to simultaneously analyze the behavior of a large number of rod-shaped cells in an extensive manner. The integration of different image-processing techniques in a single package, as well as the development of novel algorithms does not only allow to speed up the analysis with respect to the usage of existing tools, but also accounts for higher accuracy. Its utility was demonstrated on both 2D and 3D static and dynamic images to study the septation initiation network of the yeast Schizosaccharomyces pombe. More generally, it can be used in any kind of biological context where fluorescent-protein labeled structures need to be analyzed in rod-shaped cells.Availability
RodCellJ is freely available under http://bigwww.epfl.ch/algorithms.html.26.
27.
28.
Anastasios Kollias Isidoros Psilopatis Eirini Karagiaouri Maria Glaraki Evangelos Grammatikos Emmanouel E. Grammatikos Anastasia Garoufi George S. Stergiou 《Obesity (Silver Spring, Md.)》2013,21(5):1013-1017
Objective:
In children and adolescents with cardiovascular risk factors, the assessment of subclinical target‐organ damage is of paramount importance. This study investigated factors associated with carotid intima‐media thickness (cIMT) in adolescents.Design and Methods:
A cross‐sectional study was performed in 448 apparently healthy adolescents recruited from schools (mean age 14 ± 2.2 years, 211 boys), which involved cIMT measurements (common carotid artery) and assessment of lipid profile, glucose, and blood pressure (BP).Results:
The prevalence of overweight/obesity was 28.1%/12.7% and of BP ≥95th percentile 19.6%. Left cIMT was correlated with age (r = 0.10), waist circumference (WC) (0.15), and BP (0.21/0.13, systolic/diastolic) (all P < 0.05). Right cIMT was correlated with waist to hip ratio (WHR) (0.10), whereas the mean of left and right cIMT was correlated with WC (0.12), WHR (0.12), and systolic BP (0.14) (all P < 0.05). After the age of 13 years, boys tended to have higher cIMT than girls, which was significant in the 13‐15 years subgroup (P < 0.05). In stepwise multivariate analysis (independent variables: age, gender, WC, WHR, body mass index z‐score, lipid parameters, glucose, BP), left cIMT was independently associated with systolic BP; right cIMT with WHR; mean left and right cIMT with WC. Adolescents with BP ≥90th percentile had higher left cIMT than those <90th percentile (0.63 ± 0.09 vs. 0.61 ± 0.09 mm respectively, P < 0.05).Conclusion:
Central adiposity and systolic BP appear to be independently associated with increased cIMT values in apparently healthy adolescents. Left side cIMT appears to be superior to right side measurements in terms of association with cardiovascular risk factors. 相似文献29.
Marc Tebruegge Anastasia Pantazidou Duncan MacGregor Gena Gonis David Leslie Luigi Sedda Nicole Ritz Tom Connell Nigel Curtis 《PloS one》2016,11(1)
Background
There are limited data on the epidemiology, diagnosis and optimal management of nontuberculous mycobacterial (NTM) disease in children.Methods
Retrospective cohort study of NTM cases over a 10-year-period at a tertiary referral hospital in Australia.Results
A total of 140 children with NTM disease, including 107 with lymphadenitis and 25 with skin and soft tissue infections (SSTIs), were identified. The estimated incidence of NTM disease was 0.6–1.6 cases / 100,000 children / year; no increasing trend was observed over the study period. Temporal analyses revealed a seasonal incidence cycle around 12 months, with peaks in late winter/spring and troughs in autumn. Mycobacterium-avium-complex accounted for most cases (77.8%), followed by Mycobacterium ulcerans (14.4%) and Mycobacterium marinum (3.3%). Polymerase chain reaction testing had higher sensitivity than culture and microscopy for acid-fast bacilli (92.0%, 67.2% and 35.7%, respectively). The majority of lymphadenitis cases underwent surgical excision (97.2%); multiple recurrences in this group were less common in cases treated with clarithromycin and rifampicin compared with clarithromycin alone or no anti-mycobacterial drugs (0% versus 7.1%; OR:0.73). SSTI recurrences were also less common in cases treated with two anti-mycobacterial drugs compared with one or none (10.5% versus 33.3%; OR:0.23).Conclusions
There was seasonal variation in the incidence of NTM disease, analogous to recently published observations in tuberculosis, which have been linked to seasonal variation in vitamin D. Our finding that anti-mycobacterial combination therapy was associated with a reduced risk of recurrences in patients with NTM lymphadenitis or SSTI requires further confirmation in prospective trials. 相似文献30.
Violetta R. Beklemisheva Polina L. Perelman Natalya A. Lemskaya Anastasia I. Kulemzina Anastasia A. Proskuryakova Vladimir N. Burkanov Alexander S. Graphodatsky 《PloS one》2016,11(1)
Karyotype evolution in Carnivora is thoroughly studied by classical and molecular cytogenetics and supplemented by reconstructions of Ancestral Carnivora Karyotype (ACK). However chromosome painting information from two pinniped families (Odobenidae and Otariidae) is noticeably missing. We report on the construction of the comparative chromosome map for species from each of the three pinniped families: the walrus (Odobenus rosmarus, Odobenidae–monotypic family), near threatened Steller sea lion (Eumetopias jubatus, Otariidae) and the endemic Baikal seal (Pusa sibirica, Phocidae) using combination of human, domestic dog and stone marten whole-chromosome painting probes. The earliest karyological studies of Pinnipedia showed that pinnipeds were characterized by a pronounced karyological conservatism that is confirmed here with species from Phocidae, Otariidae and Odobenidae sharing same low number of conserved human autosomal segments (32). Chromosome painting in Pinnipedia and comparison with non-pinniped carnivore karyotypes provide strong support for refined structure of ACK with 2n = 38. Constructed comparative chromosome maps show that pinniped karyotype evolution was characterized by few tandem fusions, seemingly absent inversions and slow rate of genome rearrangements (less then one rearrangement per 10 million years). Integrative comparative analyses with published chromosome painting of Phoca vitulina revealed common cytogenetic signature for Phoca/Pusa branch and supports Phocidae and Otaroidea (Otariidae/Odobenidae) as sister groups. We revealed rearrangements specific for walrus karyotype and found the chromosomal signature linking together families Otariidae and Odobenidae. The Steller sea lion karyotype is the most conserved among three studied species and differs from the ACK by single fusion. The study underlined the strikingly slow karyotype evolution of the Pinnipedia in general and the Otariidae in particular. 相似文献