HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.     

Neurosecretion and hydroelectrolytic regulation in Artemia salina (author's transl)]

The activity of Artemia protocerebral median neurosecretory cells is stimulated when animals are grown in media whose tonicity is lower than that of sea weater. The substance liberated by these cells could regulate the tonicity of the internal medium.     

Preparation of specific antiserum against Rana esculenta pre-alpha lens crystallin.

Specific antiserum against Rana esculenta lens pre-alpha crystallin was prepared in a rabbit by injecting antigen-antibody precipitate of this crystallin obtained from immunoelectrophoresis of esculenta total soluble lens proteins against homologous antiserum.     

Measurements on the electrical resistivity of thin nickel films

Résumé Dans une publication antérieure, nous avions signalé que le coefficient de température de la résistance électrique des films en nickel était négatif en dessous d'une certaine épaisseur critique (40 mµ). Au-dessus de 40 mµ, la courbe «Résistance en fonction de la température» présentait un minimum aux basses températures. A la suite de nouvelles expériences, nous avons constaté que ce phénomène est accompagné d'une déviation de la loi d'Ohm: la résistance diminue quand le courant de mesure augmente. Nous avons pu conclure que ces deux particularités ne sont qu'indirectement provoquées par la minceur des films. La cause principale est leur état de cristallisation imparfaite. En effet, après avoir subi un échauffement à 150° C pendant plusieurs heures, le coefficient de température négatif change de signe (le minimum disparaît) et la loi d'Ohm est respectée.

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Research-fellow of the Belgian «Fonds National de la Recherche Scientifique»     

Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

On the origins and foundations of Laplacian determinism

In this paper I examine the foundations of Laplace’s famous statement of determinism in 1814, and argue that rather than derived from his mechanics, this statement is based on general philosophical principles, namely the principle of sufficient reason and the law of continuity. It is usually supposed that Laplace’s statement is based on the fact that each system in classical mechanics has an equation of motion which has a unique solution. But Laplace never proved this result, and in fact he could not have proven it, since it depends on a theorem about uniqueness of solutions to differential equations that was only developed later on. I show that the idea that is at the basis of Laplace’s determinism was in fact widespread in enlightenment France, and is ultimately based on a re-interpretation of Leibnizian metaphysics, specifically the principle of sufficient reason and the law of continuity. Since the law of continuity also lies at the basis of the application of differential calculus in physics, one can say that Laplace’s determinism and the idea that systems in physics can be described by differential equations with unique solutions have a common foundation.