Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer

The epigenetic regulator BMI1 is upregulated progressively in a wide variety of human tumors including colorectal cancer. In this study, we assessed the requirement for Bmi1 in intestinal tumorigenesis using an autochthonous mouse model in which Apc was conditionally ablated in the intestinal epithelium. Germline mutation of Bmi1 significantly reduced both the number and size of small intestinal adenomas arising in this model, and it acted in a dose-dependent manner. Moreover, in contrast to wild-type controls, Bmi1[superscript −/−] mice showed no increase in median tumor size, and a dramatic decrease in tumor number, between 3 and 4 months of age. Thus, Bmi1 is required for both progression and maintenance of small intestinal adenomas. Importantly, Bmi1 deficiency did not disrupt oncogenic events arising from Apc inactivation. Instead, the Arf tumor suppressor, a known target of Bmi1 epigenetic silencing, was upregulated in Bmi1 mutant tumors. This was accompanied by significant upregulation of p53, which was confirmed by sequencing to be wild-type, and also elevated apoptosis within the smallest Bmi1[superscript −/−] adenomas. By crossing Arf into this cancer model, we showed that Arf is required for the induction of both p53 and apoptosis, and it is a key determinant of the ability of Bmi1 deficiency to suppress intestinal tumorigenesis. Finally, a conditional Bmi1 mutant strain was generated and used to determine the consequences of deleting Bmi1 specifically within the intestinal epithelium. Strikingly, intestinal-specific Bmi1 deletion suppressed small intestinal adenomas in a manner that was indistinguishable from germline Bmi1 deletion. Thus, we conclude that Bmi1 deficiency impairs the progression and maintenance of small intestinal tumors in a cell autonomous and highly Arf-dependent manner.Virginia and D.K. Ludwig Fund for Cancer ResearchNational Science Foundation (U.S.)National Cancer Institute (U.S.

The representation of conflict in the discourse of Italian melodrama

This paper is part of an extensive study of cinematic dialogue in a variety of film genres in Italian, which aims to address the disregard for the verbal plane that characterises film theory and, particularly, genre theory. Assuming a pragmatic and functional semantic perspective, it analyses the scripted dialogues in films against the backdrop of the literature on real life discourse. The focus of the paper is confrontational talk in Italian melodramas from early 1960s to the present. Conflict in such films is, to an extent, comparable to the cooperative sequential rebuttal of speakers' turns that typically occurs in comedies. However, melodramas are also marked by more incisive and subtle patterns of confrontation that can be summarised as 'disaffiliative dysfluency'. The forms of such break in the conversational flow are discussed and illustrated with selected scenes from a number of films

EXPERIÊNCIA PILOTO EM ARBORIZAÇÃO PARTICIPATIVA EM DUAS CIDADES DE PEQUENO PORTE DO SEMI-ÁRIDO BRASILEIRO

As árvores urbanas desempenham funções ecológicas, econômicas e sociais no espaço em que se inserem proporcionando vários benefícios à população. Submetidas a um clima quente e seco, as cidades do semi-árido brasileiro necessitam da presença de uma massa arbórea que lhes proporcionem melhorias no padrão ambiental, garantindo-lhes, melhoria de vida das populações nelas inseridas. Este trabalho objetivou a aplicação do planejamento participativo na arborização urbana em cidades de pequeno porte do semi-árido paraibano. Foi avaliada a Arborização Participativa nas cidades de São Mamede e São José do Bonfim, ambas situadas no Território do Médio Sertão Paraibano, que poderão servir de modelo para as demais cidades similares da região. Neste trabalho realizaram-se a sensibilização da população, levantamentos preliminares (diagnóstico da arborização) e elaboração e execução do plano de arborização. Os resultados evidenciaram que em São Mamede há um déficit de 54% de árvores a serem implantadas nas ruas, enquanto em São José do Bonfim este déficit é de 69,7%. Constatou-se que em cidades de pequeno porte o planejamento participativo é tecnicamente viável, apesar do grau de complexidade operacional

Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus.

Secreted protein Sonic hedgehog (Shh) ventralizes the neural tube by modulating the crucial balance between activating and repressing functions (GliA, GliR) of transcription factors Gli2 and Gli3. This balance—the Shh-Gli code—is species- and context-dependent and has been elucidated for the mouse spinal cord. The hypothalamus, a forebrain region regulating vital functions like homeostasis and hormone secretion, shows dynamic and intricate Shh expression as well as complex regional differentiation. Here we asked if particular combinations of Gli2 and Gli3 and of GliA and GliR functions contribute to the variety of hypothalamic regions, i.e. we wanted to clarify the hypothalamic version of the Shh-Gli code. Based on mouse mutant analysis, we show that: 1) hypothalamic regional heterogeneity is based in part on differentially stringent requirements for Gli2 or Gli3; 2) another source of diversity are differential requirements for Shh of neural vs non-neural origin; 3) Gli2 is indispensable for the specification of a medial progenitor domain generating several essential hypothalamic nuclei plus the pituitary and median eminence; 4) the suppression of Gli3R by neural and non-neural Shh is essential for hypothalamic specification. Finally, we have mapped our results on a recent model which considers the hypothalamus as a transverse region with alar and basal portions. Our data confirm the model and are explained by it

The tetracycline resistance gene tet(M) exhibits mosaic structure.

Tetracycline resistance genes of the M class, tet(M), are typically found on mobile genetic elements as the conjugative transposons of gram-positive bacteria. By comparing the sequences of eight different tet(M) genes (from Enterococcus faecalis, Streptococcus pneumoniae, Staphylococcus aureus, Ureaplasma urealyticum, and Neisseria), a mosaic structure was detected which could be traced to two distinct alleles. The two alleles displayed a divergence of 8% and a different G/C content. The block structure of these genes provides evidence for the contribution of homologous recombination to the evolution and the heterogeneity of the tet(M) locus. Unlike described cases of chromosomally located mosaic loci, tet(M) is a relatively recently acquired determinant in the species examined and it would appear that mosaic structure within tet(M) has evolved after acquisition of the gene by the mobile genetic elements upon which it is located

State: Final Distribution: Public Knowledge Web Consortium

Abstract. The deliverable D1.2.3 analyses and evaluates existing methods for ontology content evaluation according requirements from an industrial point of view. EU-IST Network of Excellence (NoE) IST-2004-507482 KWE