22 research outputs found
The cyclin B2 promoter depends on NF-Y, a trimer whose CCAAT-binding activity is cell-cycle regulated
No full textCyclin B2 is a regulator of p34cdc2 kinase, involved in G2/M progression of the cell cycle, whose gene is strictly regulated at the transcriptional level in cycling cells. The mouse promoter was cloned and three conserved CCAAT boxes were found. In this study, we analysed the mechanisms leading to activation of the cyclin B2 CCAAT boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) EMSAs with nuclear extracts, antibodies and NF-Y recombinant proteins and (iv) transfections with an NF-YA dominant negative mutant established the positive role of the three CCAAT sequences and proved that NF-Y plays a crucial role in their activation. NF-Y, an ubiquitous trimer containing histone fold subunits, activates several other promoters regulated during the cell cycle. To analyse the levels of NF-Y subunits in the different phases of the cycle we separated MEL cells by elutriation, obtaining fractions > 80% pure. The mRNA and protein levels of the histone-fold containing NF-YB and NF-YC were invariant, whereas the NF-YA protein, but not its mRNA, was maximal in mid-S and decreased in G2/M. EMSA confirmed that the CCAAT-binding activity followed the amount of NF-YA, indicating that this subunit is limiting within the NF-Y complex, and suggesting that post-transcriptional mechanisms regulate NF-YA levels. Our results support a model whereby fine tuning of this activator is important for phase-specific transcription of CCAAT-containing promoters
Gene expression profile analysis of pituitary adenomas developed by HMGA transgenic mice
No full textThe High Mobility Group A (HMGA) nonhistone chromatin proteins alter chromatin structure and, thereby, regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumors. Conversely, unrearranged HMGA overexpression is a feature of malignant tumors and is also causally related to neoplastic cell transformation. Recently, we have generated transgenic mice carrying wild type or truncated HMGA genes under transcriptional control of the cytomegalovirus promoter. These mice developed pituitary adenomas secreting prolactin and growth hormone. We have recently
demonstrated that the mechanism of the HMGA2 induced-pituitary tumorigenesis is based on the increased E2F1 activity. To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 and HMGA1 genes, we have analysed here the gene expression profile
of HMGA2- and HMGA1-induced pituitary adenomas in comparison with a pool of ten normal pituitary glands from control mice using the Affymetrix MG MU11K oligonucleotide array representing ~ 13,000 unique genes. We have identified 82 transcripts increased and 72 transcripts decreased of at least 4-fold in all mice pituitary adenomas analyzed compared to normal pituitary gland. The microarray
results have been confirmed by semi-quantitative RT-PCR on RNA extracted from different HMGA2- and HMGA1-induced mouse pituitary adenomas. Then, we focused our attention on the Mia/Cd-rap and Cyclin B2 gene, the first down-regulated and the second up-regulated in all pituitary adenomas tested by the microarray. We demonstrated that the HMGA proteins directly bind and regulate their promoters
When the heart kills the liver: acute liver failure in congestive heart failure
No full textAbstract Congestive heart failure as a cause of acute liver failure is rarely documented with only a few cases. Although the pathophysiology is poorly understood, there is rising evidence, that low cardiac output with consecutive reduction in hepatic blood flow is a main causing factor, rather than hypotension. In the setting of acute liver failure due to congestive heart failure, clinical signs of the latter can be absent, which requires an appropriate diagnostic approach. As a reference center for acute liver failure and liver transplantation we recorded from May 2003 to December 2007 202 admissions with the primary diagnoses acute liver failure. 13/202 was due to congestive heart failure, which was associated with a mortality rate of 54%. Leading cause of death was the underlying heart failure. Asparagine transaminase (AST), bilirubin, and international normalized ratio (INR) did not differ significantly in surviving and deceased patients at admission. Despite both groups had signs of cardiogenic shock, the cardiac index (CI) was significantly higher in the survival group on admission as compared with non-survivors (2.1 L/min/m2 vs. 1.6 L/min/m2, p = 0.04). Central venous - and pulmonary wedge pressure did not differ significantly. Remarkable improvement of liver function was recorded in the group, who recovered from cardiogenic shock. In conclusion, patients with acute liver failure require an appropriate diagnostic approach. Congestive heart failure should always be considered as a possible cause of acute liver failure.</p
Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2
No full textAcute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE
Continuous-wave Doppler velocities and gradients across fixed tunnel obstructions: studies in vitro and in vivo.
No full textThe simplified Bernoulli relationship appears to be quite accurate for predicting gradients across discrete valvular obstructions. Controversy exists about how accurately it predicts the severity of disease in longer segment obstructions. In this study we constructed a pulsatile model of subvalvular pulmonary stensosis in vitro to study nine custom-made subvalvular tunnels 2, 4, and 7 mm in length with flow cross sections of 0.5 to 1.5 cm2 and with the stenotic segment proximal to a nonstenotic bioprosthetic valve, and a pulsatile model in vitro of a 16 mm long tunnel-like ventricular septal defect (VSD) of varying cross-sectional area (0.20 to 0.64 cm2). We also compared the observations in vitro with those in an open-chest dog preparation with a tunnel-like interventricular communication. In the subpulmonic stenosis model, for each individual tunnel, 10 instantaneous peak gradients between 15 to 105 mm Hg were available. The pressure gradients across the tunnel alone, measured in the subvalvular area, were consistently higher than the measured gradients across the tunnel plus valve, suggesting some relaminarization of flow (i.e., a decrease in velocity) and pressure recovery (i.e., an increase in pressure) distal to the obstruction. Continuous-wave Doppler velocities across the 4 and 7 mm tunnels for the highest gradients were slightly lower than for the 2 mm tunnel at the same gradients, and it was only for the 0.5 cm2 cross section, 4 and 7 mm tunnels that there was a suggestion of minor viscous energy loss. For all the subvalvular tunnels studied, the Bernoulli relationship accurately predicted the results of the pressure drop across the tunnel only, while the gradient across tunnel plus valve was consistently lower. For the VSD tunnel model in vitro, the Doppler-derived gradients were approximately 40% higher than the measured gradients. The findings for the subvalvular and VSD tunnels in vitro and similar findings in the open-chest dogs with VSD suggest that relaminarization of flow and recovery of pressure occurred distal to the tunnel orifice, whereas continuous-wave Doppler findings correlate with the highest instantaneous gradients measured in the lowest pressure areas at the vena contracta of the tunnel.</jats:p
Sobre o projeto kantiano de uma Filosofia Transcendental
No full text*Doutor em Filosofia pela Universidade Federal do Rio de Janeiro, com bolsa de doutorado Sanduíche na Albert Ludwigs-Universität Freiburg (CNPq/1996). Professor Titular do Departamento de Filosofia da Universidade Federal de Pernambuco e do Programa Integrado de Doutorado em Filosofia (UFRN/UFPB/UFPE).Sobre o projeto kantiano de uma filosofia transcendentalResumo:Â É sabido que a Crítica da razão pura apresenta uma estrutura arquitetônica bastante peculiar. No entanto, o que nem sempre é notado é que essa estrutura está intrinsecamente ligada à sua estratégia argumentativa. Na verdade, para justificar a idéia de Filosofia Transcendental como a melhor solução disponível para o problema do conhecimento metafísico levantado por uma crítica da razão pura, Kant defende que é preciso encontrar um lugar específico e justificável para um conhecimento a priori na metafísica. Mas isso só pode ser feito ao abandonarmos a pretensão ao conhecimento de objetos a priori e abraçarmos a noção de conhecimento a priori da forma de objetos empíricos. Nesse sentido, o artigo reconstrói a idéia geral, a estratégia argumentativa e do quadro metodológico da primeira Crítica como um programa para a metafísica como filosofia transcendental. Também sugere-se que a crítica funciona como uma teoria geral de um conhecimento a priori, a saber, como uma metateoria do conhecimento racional que dá conta das condições não-empíricas mais gerais dos objetos e da experiência.Palavras-chave: Kant. Filosofia transcendental. Metafísica. Metateoria. Conhecimento a priori. Sobre o projeto kantiano de uma filosofia transcendentalAbstract: It is well known that the Critique of pure reason presents quite a peculiar architectural structure. Yet, it is not always noticed that this is intrinsically connected to its argumentative strategy. Indeed, to justify the very idea of Transcendental Philosophy as the best available solution to the problem of metaphysical knowledge, Kant argues that one needs to find a specific and justifiable place for a priori knowledge in metaphysics. This can only be accomplished by abandoning the claim to knowledge of pure entities beyond experience and embracing the notion of a priori knowledge of the form of empirical objects. Accordingly, the paper reconstructs the general idea, the argumentative strategy and the methodological framework of the first Critique as a program for metaphysics as transcendental philosophy. It also suggests that the Critique operates as a general theory of a priori cognition, viz. as a meta-theory of rational knowledge that gives account for the most general and fundamental non-empirical conditions of objects and experience.Keywords: Kant. Transcendental Philosophy. Metaphysics. Meta-theory. A priori knowledge.Data de registro:27/05/2013Data de aceite: 08/07/2013Referências:ALCOFORADO, P. Roteiro para o estudo do Órganon, Educação e Filosofia, Uberlândia, v. 7, n. 13, p. 9-31. 1993.BIRD, G. The Revolutionary Kant.La Salle: Open Court, 2006.BONACCINI, J. A. Anotações sobre a Metafísica Dohna. Philosophica, Lisboa, n. 30, p. 225-243. 2007.______. Kant e o problema da coisa em si no Idealismo Alemão,Rio de Janeiro: Relume Dumará, 2003.______. A Dialética em Kant e Hegel. Natal: EDUFRN, 2000.CAIMI, M. Leçons sur Kant. La déduction transcendantale dans la deuxiène édition de la Critique de la raison pure. Paris: Publications de la Sorbonne, 2007.CHENET, F. X. L\u27assise de l\u27ontologie critique: L\u27Esthétique transcendantale. Lille: Presses Universitaires de Lille, 1994.FALKENSTEIN,L. Kant\u27s Intuitionism, A Commentary on the Transcendental Aesthetic. University of Toronto Press: Toronto, 1995.KANT . I. Kants Gesammelte Schriften. Herausgegeben von der Königlichen Preussischen Akademie der Wissenschaften (Berlin: G. Reimer. 1902-ff.); Königlichen Preussischen u. Deutschen Akademie der Wissenschaften. Berlin: W. De Gruyter. 1922-ff. (29 vols.)______. Kritik der reinen Vernunft. Nach der ersten und zweiten Original-Ausgabe neu herausgegeben von Raymund Schmidt. Hamburg: F. Meiner, 1956 (Durchgesehener Nachdruck von 1976.)KITCHER, P. Kant Ìs Transcendental Psychology. Oxford: Oxford University Press, 1990.LANDIM FILHO, R. Descartes: "idealista empírico e realista transcendental"?, Síntese-Nova Fase, v. 23, n. 74, p. 313-343. 1993.LOPARIC, Z. A Semântica Transcendental de Kant. Campinas, Brazil: UNICAMP, Centro de Lógica, Epistemologia e História da Ciência, 2000.PARSONS, C. The Transcendental Aesthetic, In: GUYER, P. (Ed.). The Cambridge Companion to Kant, Cambridge: Cambridge University Press, 1992.PATON, H. J.Kant Ìs metaphysic of experience. A commentary on the first half of the Kritik der reinen Vernunft. London: N. York; Allen & Unwin, 1936, 2vols.PORTELA, L. C. Yanzer, Por que a Crítica da razão pura é uma Metafísica?Ensaio de uma defesa. 2001. Dissertação (Mestrado em Filosofia) - Faculdade de Filosofia, Universidade Federal da Paraíba, João Pessoa, 2001.POZZO, R. Kant on Five Intellectual Virtues, In: POZZO, R. (Ed.). The Impact of Aristotelianism on Modern Philosophy, Studies in Philosophy and the History of Philosophy, v. 39, Catholic University of America Press, 2004. p. 173-192.PRAUSS, G. Kant und das Problem der Dinge an sich.Bonn: Bouvier, 1989 [1973].REINHOLD, C. L. Versuch einer neuen Theorie des menschlichen Vorstellungsvermögens.Prag u. Jena: C. Widtmann & J.M. Mauke,1789.RIBEIRO, dos Santos, L.A Razão Sensível, Estudos Kantianos. Lisboa: Colibri, 1994.SHABEL, L. The Transcendental Aesthetic. In: GUYER, P. (Ed.). The Cambridge Companion to Kant Ìs Critique of pure Reason. Cambridge: CambridgeUniversity Press, 2010.SCHöNRICH, G. Kategorien und transzendentale Argumentation: Kant und die Idee einer transzendentalen Semiotik, Frankfurt a/M: Suhrkamp, 1981.STRAWSON, P. F. The Bounds of Sense: An Essay on Kant Ìs Critique of Pure Reason, London: Methuen & Co, 1966.TONELLI, G. Der historische Ursprung der Kantischen Termini, "Analytik" und "Dialektik", In: Rothaker, E. (Hrsg.). Archiv für Begriffsgeschichte. Bausteine zu einem Historischen Wörterbuch der Philosophie. Hrsg. im Auftrage der Kommission für Philosophie der Akademie der Wissenschaften und der Literatur zu Mainz, v. 7. Bonn: Bouvier, 1962.______. Kant\u27s Critique of Pure Reason Within the Tradition of Modern Logic (Ed. by David H. Chandler), Studien und Materialien zur Geschichte der Philosophie, Olms: Hildesheim, 1994.VAIHINGER, H. Kommentarzu Kants Kritik der reinen Vernunft [I, 1881; II, 1892], hrsg. von R. Schmidt, Scientia: AAlen, 1970 (Neudruck der 2. Aufl. Stuttgart: Union Deutsche Verlagsgesellschaft)
EUROSMART: European spinal muscular atrophy randomised placebo-controlled trial of acetyl-L-carnitine in spinal muscular atrophy
No full textArchitektur von 1750 - 1850, Serie 2
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Modeling disease vector occurrence when detection is imperfect: infestation of Amazonian palm trees by triatomine bugs at three spatial scales.
No full textBACKGROUND: Failure to detect a disease agent or vector where it actually occurs constitutes a serious drawback in epidemiology. In the pervasive situation where no sampling technique is perfect, the explicit analytical treatment of detection failure becomes a key step in the estimation of epidemiological parameters. We illustrate this approach with a study of Attalea palm tree infestation by Rhodnius spp. (Triatominae), the most important vectors of Chagas disease (CD) in northern South America. METHODOLOGY/PRINCIPAL FINDINGS: The probability of detecting triatomines in infested palms is estimated by repeatedly sampling each palm. This knowledge is used to derive an unbiased estimate of the biologically relevant probability of palm infestation. We combine maximum-likelihood analysis and information-theoretic model selection to test the relationships between environmental covariates and infestation of 298 Amazonian palm trees over three spatial scales: region within Amazonia, landscape, and individual palm. Palm infestation estimates are high (40-60%) across regions, and well above the observed infestation rate (24%). Detection probability is higher ( approximately 0.55 on average) in the richest-soil region than elsewhere ( approximately 0.08). Infestation estimates are similar in forest and rural areas, but lower in urban landscapes. Finally, individual palm covariates (accumulated organic matter and stem height) explain most of infestation rate variation. CONCLUSIONS/SIGNIFICANCE: Individual palm attributes appear as key drivers of infestation, suggesting that CD surveillance must incorporate local-scale knowledge and that peridomestic palm tree management might help lower transmission risk. Vector populations are probably denser in rich-soil sub-regions, where CD prevalence tends to be higher; this suggests a target for research on broad-scale risk mapping. Landscape-scale effects indicate that palm triatomine populations can endure deforestation in rural areas, but become rarer in heavily disturbed urban settings. Our methodological approach has wide application in infectious disease research; by improving eco-epidemiological parameter estimation, it can also significantly strengthen vector surveillance-control strategies
