RESUMEN
We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu's southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu's history.
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The shapes of asteroids reflect interplay between their interior properties and the processes responsible for their formation and evolution as they journey through the Solar System. Prior to the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) mission, Earth-based radar imaging gave an overview of (101955) Bennu's shape. Here, we construct a high-resolution shape model from OSIRIS-REx images. We find that Bennu's top-like shape, considerable macroporosity, and prominent surface boulders suggest that it is a rubble pile. High-standing, north-south ridges that extend from pole to pole, many long grooves, and surface mass wasting indicate some low levels of internal friction and/or cohesion. Our shape model indicates that, similar to other top-shaped asteroids, Bennu formed by reaccumulation and underwent past periods of fast spin leading to its current shape. Today, Bennu might follow a different evolutionary pathway, with interior stiffness permitting surface cracking and mass wasting.
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The sizes of Saturn's ring particles range from meters (boulders) to nanometers (dust). Determination of the rings' ages depends on loss processes, including the transport of dust into Saturn's atmosphere. During the Grand Finale orbits of the Cassini spacecraft, its instruments measured tiny dust grains that compose the innermost D-ring of Saturn. The nanometer-sized dust experiences collisions with exospheric (upper atmosphere) hydrogen and molecular hydrogen, which forces it to fall from the ring into the ionosphere and lower atmosphere. We used the Magnetospheric Imaging Instrument to detect and characterize this dust transport and also found that diffusion dominates above and near the altitude of peak ionospheric density. This mechanism results in a mass deposition into the equatorial atmosphere of ~5 kilograms per second, constraining the age of the D-ring.
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The Pioneer and Voyager spacecraft made close-up measurements of Saturn's ionosphere and upper atmosphere in the 1970s and 1980s that suggested a chemical interaction between the rings and atmosphere. Exploring this interaction provides information on ring composition and the influence on Saturn's atmosphere from infalling material. The Cassini Ion Neutral Mass Spectrometer sampled in situ the region between the D ring and Saturn during the spacecraft's Grand Finale phase. We used these measurements to characterize the atmospheric structure and material influx from the rings. The atmospheric He/H2 ratio is 10 to 16%. Volatile compounds from the rings (methane; carbon monoxide and/or molecular nitrogen), as well as larger organic-bearing grains, are flowing inward at a rate of 4800 to 45,000 kilograms per second.
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OBJECTIVES: The aim of the study was to identify differences in infant outcomes, virological efficacy, and preterm delivery (PTD) outcome between women exposed to lopinavir/ritonavir (LPV/r) and those exposed to atazanavir/ritonavir (ATV/r). METHODS: A retrospective case note review was carried out. The case notes of 493 women who conceived while on LPV/r or ATV/r or initiated LPV/r or ATV/r during pregnancy and who delivered between 1 September 2007 and 30 August 2012 were reviewed. Data collected included demographics, antiretroviral use, HIV markers, and pregnancy and infant outcomes. Infant outcomes, virological efficacies and PTD rates for LPV/r and ATV/r were compared. RESULTS: A total of 306 women received LPV/r (82 conceiving while on the drug and 224 commencing it post-conception) and 187 received ATV/r (96 conceiving while on the drug and 91 commencing it post-conception). Comparing the two protease inhibitors (PIs), viral suppression rates were similar and, in women starting antiretroviral therapy (ART) post-conception, the median times to first undetectable HIV viral load were not significantly different (P = 0.64). PTD rates did not differ by therapy overall (ATV/r, 13%; LPV/r, 14%) or when considering the timing of first exposure (conceiving on ART, P = 0.81; commencing ART in pregnancy, P = 0.08). Poor fetal outcomes were very uncommon. There were two transmissions, giving a mother-to-child transmission (MTCT) rate of 0.4% (95% confidence interval 0.05-1.5%). CONCLUSIONS: Both ART regimens were well tolerated and successful in preventing MTCT. No significant differences in tolerability or in pregnancy or infant outcomes were observed, which supports the provision of a choice of PI in pregnancy.
Asunto(s)
Sulfato de Atazanavir/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Lopinavir/administración & dosificación , Nacimiento Prematuro/epidemiología , Ritonavir/administración & dosificación , Carga Viral/efectos de los fármacos , Adolescente , Adulto , Sulfato de Atazanavir/farmacología , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Lactante , Recién Nacido , Lopinavir/farmacología , Persona de Mediana Edad , Embarazo , Resultado del Embarazo/epidemiología , Nacimiento Prematuro/etiología , Estudios Retrospectivos , Ritonavir/farmacología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Infecciones por Chlamydia/epidemiología , Chlamydia trachomatis , Gonorrea/epidemiología , Homosexualidad Masculina/estadística & datos numéricos , Neisseria gonorrhoeae , Infecciones por Chlamydia/diagnóstico , Chlamydia trachomatis/genética , Chlamydia trachomatis/aislamiento & purificación , Gonorrea/diagnóstico , Humanos , Masculino , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
OBJECTIVES: Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR(2) expression on rheumatoid arthritis (RA)-derived leucocyte subsets. METHODS: Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR(2) on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. RESULTS: Patients with RA had elevated but variable surface expression of PAR(2) on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86-4.10%) vs 0.06% (0.03-0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR(2) expression in patients with RA compared with controls (3.05% (0.36-11.82%) vs 0.08% (0.02-0.28%), p<0.0001). For both subsets, PAR(2) expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR(2) expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR(2) expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR(2) expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR(2) agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). CONCLUSIONS: These findings are consistent with a pathogenic role for PAR(2) in RA.
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Artritis Reumatoide/inmunología , Monocitos/inmunología , Receptor PAR-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/metabolismo , Complejo CD3/metabolismo , Células Cultivadas , Estudios Transversales , Femenino , Citometría de Flujo , Expresión Génica/inmunología , Humanos , Interleucina-6/inmunología , Interleucina-6/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Osteoartritis/inmunología , Osteoartritis/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismoRESUMEN
We assessed changes in serum amyloid A protein (SAA) levels during treatment with etanercept in AA amyloidosis complicating inflammatory arthritis. Five women and four men with AA amyloidosis and inflammatory arthritis received etanercept. SAA levels were recorded before and after commencement of treatment. Previous immunosuppressive drugs included cyclophosphamide (four patients), azathioprine (three patients), methotrexate (two patients) and chlorambucil (in one patient). Two patients received no disease modifying drugs between the time of diagnosis of AA amyloidosis and commencement of etanercept. In seven out of nine patients the median SAA level during etanercept treatment was lower than levels before anti-tumour necrosis factor therapy. In five out of nine patients, the median post treatment level was <11 mg/l. There were no significant changes in serum creatinine or proteinuria during periods (median, 23 months; range, 1-24 months) of etanercept therapy. The etanercept was stopped in four patients because of: acute bacterial endocarditis, psoriasiform rash, psychosis and leukopenia. In two of these patients alternative biologics were commenced (adalimumab or anakinra) and one was restarted on etanercept. One patient died of cerebral haemorrhage during the study. Etanercept therapy was associated with a fall in SAA levels in seven of nine patients, five of whom achieved levels which might be expected to be associated with stable or regressing amyloid deposits. Etanercept represents a useful alternative to immunosuppressant therapy such as cyclophosphamide or chlorambucil. Further work is needed to establish whether organ damage related to AA amyloidosis is slowed by etanercept.
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Amiloidosis/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Proteína Amiloide A Sérica/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Amiloidosis/sangre , Estudios de Cohortes , Etanercept , Femenino , Humanos , Masculino , Estudios RetrospectivosAsunto(s)
Crioglobulinemia/diagnóstico , Úlcera de la Pierna/etiología , Síndrome de Sjögren/complicaciones , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , Crioglobulinemia/complicaciones , Crioglobulinas/análisis , Progresión de la Enfermedad , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Úlcera de la Pierna/patología , Persona de Mediana Edad , Factor Reumatoide/sangre , Síndrome de Sjögren/patologíaRESUMEN
Ultraviolet (UV) irradiation transiently stabilizes p53 through a mechanism that may require a decrease in the activity of the ubiquitin ligase, p90(MDM2). Conversely, the recovery of low levels of p53 following UV exposure may depend on an increase in p90(MDM2). The level of p90(MDM2) is increased by UV light following the p53-dependent induction of an internal mdm2 promoter, P2. If this induction of mdm2 were critical for the recovery of low levels of p53 following UV exposure, defects in mdm2's transcription would result in a prolonged increase in p53. Cells defective in transcription coupled repair (TCR) maintain high levels of p53 for a prolonged period following UV exposure. Such cells also have defects in general transcription after UV irradiation. We investigated whether TCR-deficient cells express diminished levels of mdm2 mRNA and p90(MDM2) following UV exposure. We found that transcription of mdm2 was reduced in TCR-deficient cells. The uninducible mdm2 promoter, P1, was more sensitive to the inhibitory effects of UV irradiation than the P2 promoter. The decrease in transcription from the P1 promoter was sufficient to reduce the level of p90(MDM2) and correlated with a prolonged increase in p53. Thus, p53-independent transcription of mdm2 appears critical to p53's regulation.
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Reparación del ADN/efectos de la radiación , Proteínas Nucleares , Proteínas Proto-Oncogénicas/efectos de la radiación , Transcripción Genética/efectos de la radiación , Proteína p53 Supresora de Tumor/efectos de la radiación , Daño del ADN , Reparación del ADN/fisiología , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Genes p53/efectos de la radiación , Humanos , Regiones Promotoras Genéticas/efectos de la radiación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero/metabolismo , ARN Mensajero/efectos de la radiación , Factores de Tiempo , Transcripción Genética/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Rayos UltravioletaRESUMEN
The damage caused by thermal trauma is augmented by the subsequent inflammatory response in a similar fashion to reperfusion injury. Animal studies have demonstrated a significant role for neutrophils in this delayed damage, but little is known about the numbers of neutrophils or other leucocytes that enter human skin following burns. We have longitudinally examined profiles of leucocyte migration into five cases of human partial thickness burns in relation to continued dermal microvascular destruction during the acute post-burn period. All burn wounds had a rapid influx of neutrophils that was followed by a delayed influx of macrophages. Compared to the controls, the two superficial burns also had rapid and sustained influx of CD4 and CD8 lymphocytes via patent post capillary venules in the dermal superficial vascular plexus, whilst in the three deeper burns, in which this superficial vascular plexus was occluded, the number of lymphocytes decreased. These results suggest that the patterns of leucocyte extravasation were dependent on the initial level of vascular occlusion, indicating that the dermal microvascular anatomy plays a pivotal role in determining the composition of the extravascular inflammatory cell infiltrates. The potential importance of this finding is highlighted by the differences in wound behaviour associated with the different leucocyte profiles.
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Quemaduras/inmunología , Quemaduras/patología , Mediadores de Inflamación/análisis , Piel/irrigación sanguínea , Piel/patología , Adulto , Biopsia con Aguja , Quemaduras/diagnóstico por imagen , Movimiento Celular/fisiología , Estructuras Celulares/metabolismo , Intervalos de Confianza , Femenino , Humanos , Inmunidad Celular/fisiología , Puntaje de Gravedad del Traumatismo , Flujometría por Láser-Doppler , Linfocitos/fisiología , Masculino , Microcirculación , Persona de Mediana Edad , Neutrófilos/fisiología , Valores de Referencia , Piel/diagnóstico por imagen , Piel/inmunología , Estadísticas no Paramétricas , Ultrasonografía , Cicatrización de Heridas/fisiologíaRESUMEN
The murine double minute 2 (mdm2) gene is essential for embryogenesis in mice that express the p53 tumor suppressor protein. Mdm2 levels must be regulated tightly because overexpression of mdm2 contributes to tumorigenesis. We investigated whether the 5' and 3' untranslated regions (UTRs) of murine mdm2 affect the expression of MDM2 proteins. Induction of mdm2 expression by p53 results in synthesis of an mdm2 mRNA with a short 5' UTR. The long 5' UTR increases internal initiation of translation of a minor MDM2 protein, p76(MDM2), without affecting the efficiency of translation of the full-length p90(MDM2). We discovered two alternative 3' untranslated regions in murine mdm2 mRNA expressed in the testis. The longer 3' UTR contains a consensus instability element, but mdm2 mRNAs containing the long and short 3' UTRs have comparable half-lives. The 3' UTRs do not affect either initiation codon use or translation efficiency. Thus, the murine 5' UTR, but not the 3'UTR, influences the ratio of the two MDM2 proteins but neither UTR affects MDM2 abundance significantly.
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Regiones no Traducidas 3'/genética , Regiones no Traducidas 5'/genética , Proteínas Nucleares , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , Empalme Alternativo , Animales , Secuencia de Bases , Northern Blotting , Células COS , Línea Celular , ADN/química , ADN/genética , Repeticiones de Dinucleótido/genética , Exones/genética , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Datos de Secuencia Molecular , Muridae , Poli A/genética , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero/metabolismo , ARN Mensajero/efectos de la radiación , Análisis de Secuencia de ADN , Especificidad de la Especie , Distribución TisularRESUMEN
A histidine-tagged, carboxy-terminal fragment of the murine double minute 2 gene product, p90(MDM2), was purified by Ni--NTA chromatography and preparative gel electrophoresis. The purified MDM2 fragment was used to generate polyclonal antisera that recognize multiple species of MDM2 proteins, including the inhibitor of p53, p90(MDM2), as well as the activator of p53, p76(MDM2). The antibodies are useful for Western analysis, immunoprecipitation, and immunofluorescence.
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Histidina , Sueros Inmunes/inmunología , Proteínas Nucleares , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas/aislamiento & purificación , Animales , Especificidad de Anticuerpos , Western Blotting , Cromatografía de Afinidad , Escherichia coli , Técnica del Anticuerpo Fluorescente , Sueros Inmunes/biosíntesis , Ratones , Níquel/metabolismo , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/aislamiento & purificación , Fragmentos de Péptidos/metabolismo , Péptidos/metabolismo , Pruebas de Precipitina , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Conejos , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
This paper describes a new technique for burn depth measurement, based on the histological assessment of dermal microvascular occlusion in burn biopsies. The technique was validated in a preliminary study of acute progressive microvascular damage in five adults with partial thickness burns. Burn depth was calculated at three time points post burn from the mean histological measurement of the most superficial patent and the deepest blocked vessels in five separate sections from each biopsy. The results were expressed as a percentage of the total dermal thickness and correlated well with the laser Doppler measurement of dermal blood flow and clinical estimation of burn depth. The reproducibility of the technique was tested by the repeated blind analysis of five randomly chosen biopsies on a separate occasion. Altman-Bland plot analysis demonstrated a median variation of 0.1% (95% confidence interval -1 to 2%). A second independent observer (MPHT), who carried out a blind analysis of the same randomly chosen biopsies, tested the precision of the technique. The median variation was 2% (95% confidence interval -5 to 8.5%).
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Quemaduras/patología , Dermis/irrigación sanguínea , Dermis/patología , Flujometría por Láser-Doppler/métodos , Adulto , Biopsia con Aguja , Quemaduras/diagnóstico , Intervalos de Confianza , Femenino , Humanos , Inmunohistoquímica , Puntaje de Gravedad del Traumatismo , Masculino , Microcirculación , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Piel/irrigación sanguíneaRESUMEN
Standard immunohistochemical methods were used to detect the presence of vimentin, cytokeratin 8, cytokeratin 18, macrophages and Langerhans cells in the human tonsillar epithelium in formalin-fixed and frozen tissue specimens. Vimentin detection was restricted to infiltrating cells of the lymphoid series, dendritic and vascular endothelial cells. All epithelial cells were negative. Cytokeratin 8 and 18 were readily detected in a large proportion of epithelial cells lining the crypt, but these cells bore no resemblance to the intestinal M-cells. Langerhans cells and macrophages were seen in both the oropharyngeal and crypt epithelium and were more common in the latter. This study confirms the presence of antigen-presenting cells, macrophages and Langerhans cells in the tonsillar epithelium and shows that intermediate filament proteins, vimentin, cytokeratin 8 and 18 are unreliable markers for human tonsillar M-cells, if indeed such cells exist in human tonsils.
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Células Epiteliales/citología , Queratinas/análisis , Tonsila Palatina/citología , Vimentina/análisis , Anticuerpos Monoclonales , Células Presentadoras de Antígenos/citología , Biomarcadores/análisis , Células Epiteliales/química , Humanos , Técnicas para Inmunoenzimas , Células de Langerhans/citología , Macrófagos/citología , Orofaringe/química , Tonsila Palatina/química , Coloración y Etiquetado/métodosRESUMEN
The mdm2 oncogene encodes p90(MDM2), which binds to and inactivates the p53 tumor suppressor protein. p90(MDM2) inhibits p53 by blocking the transcriptional activation domain of p53 as well as by stimulating its degradation. Recently, we showed that another product of the wild-type mdm2 gene, p76(MDM2), lacks the first 49 amino acids of p90(MDM2) and cannot bind p53. Here, we report that, like p90(MDM2), p76(MDM2) is expressed in both the nuclear and cytoplasmic compartments. Overexpression of p76(MDM2) antagonizes the ability of p90(MDM2) to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76(MDM2) but not p90(MDM2), as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90(MDM2) is much more abundant than p76(MDM2) in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to gamma-irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.
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Proteínas Nucleares , Proteínas Proto-Oncogénicas/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Células 3T3 , Empalme Alternativo , Animales , Fosfatos de Calcio/metabolismo , Fibroblastos , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testículo/metabolismo , Distribución Tisular , Activación Transcripcional , Células Tumorales CultivadasRESUMEN
MDM2 is an important regulator of the p53 tumor suppressor protein. MDM2 inhibits p53 by binding to it, physically blocking its ability to transactivate gene expression, and stimulating its degradation. In cultured cells, mdm2 expression can be regulated by p53. Hence, mdm2 and p53 can interact to form an autoregulatory loop in which p53 activates expression of its own inhibitor. The p53/MDM2 autoregulatory loop has been elucidated within cultured cells; however, regulation of mdm2 expression by p53 has not been demonstrated within intact tissues. Here, we examine the role of p53 in regulating mdm2 expression in vivo in order to test the hypothesis that the p53/MDM2 autoregulatory loop is the mechanism by which low levels of p53 are maintained. We demonstrate that basal expression of mdm2 in murine tissues is p53 independent, even in tissues that express functional p53. Transcription of mdm2 is induced in a p53-dependent manner following gamma irradiation, indicating that p53 regulates mdm2 expression in vivo following a stimulus. The requirement for a stimulus to activate p53-dependent regulation of mdm2 expression in vivo appeared to differ from the situation in early-passage mouse embryo fibroblasts, where mdm2 expression is enhanced by the presence of p53. Analysis of mdm2 expression in intact and dispersed embryos revealed that establishment of mouse embryo fibroblasts in culture induces p53-dependent mdm2 expression, suggesting that an unknown stimulus activates p53 function in cultured cells. Together, these results indicate that p53 does not regulate expression of its own inhibitor, except in response to stimuli.
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Fibroblastos/fisiología , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Animales , Células Cultivadas , Genes Supresores de Tumor , Ratones , Ratones Endogámicos C57BL , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor/metabolismo , Irradiación Corporal TotalRESUMEN
High-risk human papillomaviruses are causally associated with cervical cancer. Two viral oncogenes, E6 and E7, are expressed in most cervical cancers, and these genes cause cancer when expressed in experimental animals. The E6 protein targets the p53 tumor suppressor for degradation, while the E7 protein inactivates the retinoblastoma susceptibility protein (pRb), in part by stimulating its degradation. In contrast, expression of E7 in the absence of E6 leads to stabilization of p53. Here we show that E7 stabilizes p53 in mouse embryo fibroblasts lacking p19(ARF). The stable p53 is active as a transcriptional activator, as evidenced by the increased expression of the p53-responsive mdm2 gene. Normally, MDM2 protein inhibits p53 function in an autoregulatory loop. Regulation of p53 by MDM2 is required for murine development as well as for proliferation of cultured human fibroblasts. However, E7-expressing human fibroblasts continue to divide even though E7 abrogates the ability of MDM2 and p53 to bind. Furthermore, E7-expressing cells are not more sensitive to UV light, an agent that has been reported to induce apoptosis mediated by p53. These results indicate that in addition to inhibiting the ability of MDM2 to regulate p53, E7 must block signaling steps downstream of p53 to allow cell division.
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Proteínas Nucleares , Proteínas Oncogénicas Virales/metabolismo , Papillomaviridae/metabolismo , Proteínas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Fibroblastos/citología , Humanos , Ratones , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p14ARF Supresora de Tumor , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The aim of this study was to find the most suitable manual measurements to estimate the age of preserved fetuses. A new technique was used to make successful ultrasonic measurements on 86 out of 100 preserved fetuses under conditions simulating the intrauterine environment. The ultrasonographic images of the preserved specimens were very similar to those of live fetuses. Ultrasonic measurements of standard parameters, and the ages derived from them, were computed directly by the ultrasound scanning machine. Manual measurements were made of the same parameters using established techniques and standard tables for estimating fetal age. The measurements and the ages obtained for each parameter by the two techniques were statistically compared using the limits of agreement (Bland and Altman, 1986). Of the manual measurements used in the estimation of fetal age, foot length was found to be the most suitable parameter for practical use. Biparietal diameter was equally good, but the head circumference was the most precise, especially when used in conjunction with the formulae developed for ultrasonic measurements. Crown-rump length was found to be unsuitable to age fetuses beyond the first trimester due to distortion of the spine caused by compression in storage.