Induction of tetraploidy through loss of p53 and upregulation of Plk1 by Human Papillomavirus type-16 E6

Cancer cells are insensitive to many signals that inhibit growth of untransformed cells. Here, we show that primary human epithelial cells expressing human papillomavirus (HPV) type-16 E6/E7 bypass arrest caused by the DNA-damaging drug adriamycin and become tetraploid. To determine the contribution of E6 in the context of E7 to the resistance of arrest and induction of tetraploidy, we used an E6 mutant unable to degrade p53 or RNAi targeting p53 for knockdown. The E6 mutant fails to generate tetraploidy; however, the presence of E7 is sufficient to bypass arrest while the p53 RNAi permits both arrest insensitivity and tetraploidy. We published previously that polo-like kinase 1 (Plk1) is upregulated in E6/E7-expressing cells. We observe here that abnormal expression of Plk1 protein correlates with tetraploidy. Using the p53 binding-defective mutant of E6 and p53 RNAi, we show that p53 represses Plk1, suggesting that loss of p53 results in tetraploidy through upregulation of Plk1. Consistent with this hypothesis, overexpression of Plk1 in cells generates tetraploidy but does not confer resistance to arrest. These results support a model for transformation caused by HPV-16 where bypass of arrest and tetraploidy are separable consequences of p53 loss with Plk1 required only for the latter effect.

Antagonistic effects of two novel GIP analogs, (Hyp(3))GIP and (Hyp(3)) GIPLys(16)PAL, on the biological actions of GIP and longer-term effects in diabetic ob/ob mice

This study examines the actions of the novel enzyme- resistant, NH2- terminally modified GIP analog ( Hyp(3)) GIP and its fatty acid- derivatized analog ( Hyp(3)) GIPLys(16)PAL. Acute effects are compared with the established GIP receptor antagonist ( Pro(3)) GIP. All three peptides exhibited DPP IV resistance, and significantly inhibited GIP stimulated cAMP formation and insulin secretion in GIP receptor- transfected fibroblasts and in clonal pancreatic BRIN- BD11 cells, respectively. Likewise, in obese diabetic ob/ob mice, intraperitoneal administration of GIP analogs significantly inhibited the acute antihyperglycemic and insulinreleasing effects of native GIP. Administration of once daily injections of ( Hyp(3)) GIP or ( Hyp(3)) GIPLys(16)PAL for 14 days resulted in significantly lower plasma glucose levels ( P <0.05) after ( Hyp3) GIP on days 12 and 14 and enhanced glucose tolerance ( P <0.05) and insulin sensitivity ( P <0.05 to P <0.001) in both groups by day 14. Both ( Hyp(3)) GIP and ( Hyp(3)) GIPLys(16)PAL treatment also reduced pancreatic insulin ( P <0.05 to P <0.01) without affecting islet number. These data indicate that ( Hyp3) GIP and ( Hyp(3)) GIPLys(16)PAL function as GIP receptor antagonists with potential for ameliorating obesity- related diabetes. Acylation of ( Hyp(3)) GIP to extend bioactivity does not appear to be of any additional benefit.

Paul Karl Feyerabend Las proyecciones de la proliferación teórica en la relación ciencia-metafísica

La doctrina de la Proliferación teórica de Paul Karl Feyerabend ha sido interpretada por sus especialistas como un intento de salvaguardar el ideal del progreso científico. Aunque tales estudios hacen justicia, en parte, a la intencionalidad de nuestro filósofo no explicitan la crítica fundamental que implica para Feyerabend el pluralismo teórico. La proliferación teórica constituye en sí misma una reductio ad absurdum de los distintos intentos del positivismo lógico y del racionalismo crítico por definir la ciencia a expensas de lo metafísico. Este artículo presenta la proliferación teórica como una reivindicación del papel positivo que ocupa la metafísica en el quehacer científico. Se consigna la defensa que hace Feyerabend de la metafísica en cuanto que ésta constituye la posibilidad de superar el conservadurismo conceptual, aumentar de contenido empírico de la ciencia y recuperar el valor descriptivo de las teorías científicas.

La ciudad de Rávena y los paisajes de la abstracción en "Deserto Rosso" de Michelangelo Antonioni

La presente investigación trata de poner énfasis en la importancia del paisaje en Deserto Rosso de Michelangelo Antonioni, erigiéndose este como elemento fundamental de la trama argumental del filme. Partiendo de esta premisa, se analiza el significado de dicho paisaje en el contexto socioartístico de los años 60. La interacción del hombre con su entorno parece ser el punto de partida para una reflexión más profunda sobre el devenir humano. Las nuevas conquistas estéticas alcanzadas y el análisis históricoartístico de los precedentes más inmediatos del filme, sitúan a Deserto Rosso como obra cumbre de la neovanguardia posmoderna europea.

Rapid ecosystem response to abrupt climate changes during the last glacial period in western Europe, 40-16 ka

We present a high-resolution and independently dated multiproxy lake sediment record from the paleolake at Les Echets in southeastern France that displays synchronous changes in independent limnic and terrestrial ecosystem proxies, in concert with millennial-scale climate oscillations during the last glacial period. Distinct lake-level fluctuations, low lake organic productivity, and open, treeless vegetation indicate cold and dry conditions in response to Heinrich events. Alternating phases of higher and low lake organic productivity, stratified surface waters and long-lasting lake ice cover, decreased or increased catchment erosion, and tree-dominated or herb-dominated vegetation resemble Dansgaard-Oeschger interstadial-stadial variability. Transitions between different ecological states occurred in as little as 40-230 yr and seem to have been controlled by the position of the Polar Front. Ecosystem response after 30 ka suggests that local climate conditions became more important. Our results demonstrate that all parts of the terrestrial system responded to the abrupt and dramatic climatic changes associated with Dansgaard-Oeschger and Heinrich events, and that regional factors modulated ecosystem response.

The persistence of the HgCl2 molecule in five new compounds in the system (NH4)(w)HgxCly(H2O)(z) with w : x : y : z=1 : 5 : 11 : 0, 2 : 3 : 8 : 1, 4 : 3 : 10 : 2, 2 : 1 : 4 : 1, and 10 : 3 : 16 : 0

Five new compounds in the system (NH4)Cl/HgCl2/H2O have been obtained as colourless single crystals, (NH4)Hg5Cl11, (NH4)(2)Hg3Cl8(H2O), (NH4)(4)Hg3Cl10(H2O)(2), (NH4)(2)HgCl4(H2O), and (NH4)(10)Hg3Cl16. In all of these, as in HgCl2 itself, (almost) linear HgCl2 molecules persist with Hg-Cl distances varying from 229 to 236 pm. In (NH4)(10)Hg3Cl16 there are also tetrahedra [HgCl4] with d(Hg-Cl) = 247 pm present. If larger Hg-Cl distances (of up to 340 pm) are considered as belonging to the coordination sphere of Hg-II, the structures may be described as consisting of isolated octahedra and tetrahedra as in (NH4)(10)Hg3Cl16, edge-connected chains as in (NH4)(2)HgCl4(H2O), edge-connected chains and layers of octahedra as in (NH4)(4)Hg3Cl10(H2O)(2), corrugated layers of edge-connected octahedra as in (NH4)(2)Hg3Cl8(H2O), and, finally, a three-dimensional network of connected six- and seven-coordinate Hg-Cl polyhedra as in (NH4)Hg5Cl11. The water molecules are never attached to Hg-II. The (NH4)(+) cations, and sometimes Cl- anions, play a role for electroneutrality only.

Cardiac rehabilitation uptake following myocardial infarction: cross-sectional study in primary care

Background Policies suggest that primary care should be more involved in delivering cardiac rehabilitation. However, there is a lack of information about what is known in primary care regarding patients' invitation or attendance. Aim To determine, within primary care, how many patients are invited to and attend rehabilitation after myocardial infarction (MI), examine sociodemographic factors related to invitation, and compare quality of life between those who do and do not attend. Design of study Review of primary care paper and computer records; cross-sectional questionnaire. Setting Northern Ireland general practices (38); stratified sample, based on practice size and health board area. Method Patients, identified from primary care records, 12-16?weeks after a confirmed diagnosis of MI, were posted questionnaires, including a validated MacNew post-MI quality-of-life questionnaire. Practices returned anonymised data for non-responders. Results Information about rehabilitation was available for 332 of the 432 patients identified (76.9%): 162 (37.5%) returned questionnaires. Of the total sample, 54.4% (235/432) were invited and 37.0% (160/432) attended; of those invited, 68.1% (160/235) attended. Invited patients were younger than those not invited (mean age 63?years [standard deviation SD 16] versus 68.5?years [SD 16]); mean difference 5.5?years (95% confidence interval [CI] = 1.7 to 9.3). Among questionnaire responders, those who attended were younger and reported better emotional, physical, and social functioning than non-attenders (P = 0.01; mean differences 0.44 (95% CI = 0.11 to 0.77), 0.48 (95% CI = 0.10 to 0.85) and 0.54 (95% CI = 0.15 to 0.94) respectively). Conclusion Innovative strategies are needed to improve cardiac rehabilitation uptake, integration of hospital and primary care services, and healthcare professionals' awareness of patients' potential for health gain after MI.