Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy.

METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras.

CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway.

Imaging and radiation effects of gold nanoparticles in tumour cells

Gold nanoparticle radiosensitization represents a novel technique in enhancement of ionising radiation dose and its effect on biological systems. Variation between theoretical predictions and experimental measurement is significant enough that the mechanism leading to an increase in cell killing and DNA damage is still not clear. We present the first experimental results that take into account both the measured biodistribution of gold nanoparticles at the cellular level and the range of the product electrons responsible for energy deposition. Combining synchrotron-generated monoenergetic X-rays, intracellular gold particle imaging and DNA damage assays, has enabled a DNA damage model to be generated that includes the production of intermediate electrons. We can therefore show for the first time good agreement between the prediction of biological outcomes from both the Local Effect Model and a DNA damage model with experimentally observed cell killing and DNA damage induction via the combination of X-rays and GNPs. However, the requirement of two distinct models as indicated by this mechanistic study, one for short-term DNA damage and another for cell survival, indicates that, at least for nanoparticle enhancement, it is not safe to equate the lethal lesions invoked in the local effect model with DNA damage events.

Casa(l) em construção : uma base teórico-empírica para o desenvolvimento de uma intervenção na transição para a conjugalidade

Tese de doutoramento, Psicologia (Psicologia da Família e Intervenção Familiar), Universidade de Lisboa, Faculdade de Psicologia, 2014

Churchill as Chancellor of the Exchequer (1924–9) and the return to the gold standard

The general election of 29 October 1924 saw Winston Churchill return to Parliament as Constitutionalist MP for Epping after two years in the political wilderness. It also saw Stanley Baldwin swept back to Number 10 on a Conservative landslide. Speculation about whether Baldwin would cement Churchill’s drift from the Liberal fold by offering him office surfaced during the election campaign. Churchill nevertheless thought ‘it very unlikely that I shall be invited to join the Government, as owing to the size of the majority it will probably be composed only of impeccable Conservatives’. [ 1 ] Because of his anti-socialist credentials, his ability to reassure wavering Liberals through his opposition to protectionism – dropped by Baldwin after its rejection in the 1923 general election – and concern he could prove a rallying point for backbench malcontents, there was however much to commend giving Churchill a post. To his surprise, Baldwin offered Churchill the long-coveted office of Chancellor of the Exchequer, briefly held by his father before his ill-conceived resignation in 1887. Having arranged a meeting with his Labour predecessor, Philip Snowden, about outstanding business the new Chancellor set to work. Marking his political transition, a few days later Churchill resigned from the National Liberal Club.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1928/08 (A62,N8,T95).

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1922/06/15 (A56,T89,N12)-1922/06/30.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1921/06/01 (A55,T88,N11)-1921/06/14.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1925/08/01 (A59,T92,N15).

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1868/01 (A3)-1868/06.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1928/09 (A62,N9,T95).

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1900/07 (A34,NOUV SER,T50)-1900/12.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1926/07/01 (A60,T93,N13).

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1882/01 (A16,NOUV SER,T13)-1882/06.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1932/04/01 (N4,A66,T99)-1932/04/30.

Revue critique d'histoire et de littérature / publiée sous la direction de MM. P. Meyer, Ch. Morel, G. Paris, H. Zotenberg

1922/05/15 (A56,T89,N10)-1922/05/31.