Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

To understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1Plstc which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4+8+ (DP) thymocytes from young pre-leukemic Ikzf1Plstc heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded thymic lymphoma or leukemia and was closely correlated with the first detectable differentiation abnormalities loss of heterozygosity (LOH) eliminating wild-type Ikzf1, and multiple missense and truncating Notch1 mutations. These findings illuminate the early stages of leukemogenesis by demonstrating progressive exaggeration of Notch1 responsiveness at the DP thymocyte stage brought about by multiple mutations acting in concert upon the Notch1 pathwa

Renaissance of the ~1 TeV Fixed-Target Program

This document describes the physics potential of a new fixed-target program based on a {approx} TeV proton source. Two proton sources are potentially available in the future: the existing Tevatron at Fermilab, which can provide 800 GeV protons for fixed-target physics, and a possible upgrade to the SPS at CERN, called SPS+, which would produce 1 TeV protons on target. In this paper we use an example Tevatron fixed-target program to illustrate the high discovery potential possible in the charm and neutrino sectors. We highlight examples which are either unique to the program or difficult to accomplish at other venues

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Louis Bertrand : autopsie d’une déroute

Deux séries de textes du Lorrain Louis Bertrand (1866-1941) apportent un éclairage unique sur l’impact des événements de 1870-1871. Ses « romans africains » (1899-1904) sont le fruit d’une décennie passée en Algérie, entre 1891 et 1900, au cours de laquelle Louis Bertrand joue un rôle majeur dans le lancement d’une littérature algérienne de langue française et dans le processus de légitimation de la colonisation française à travers les notions d’« Afrique latine » et de « peuple néo-français ». Cette perspective non hexagonale, qui voit dans le musulman algérien un ennemi irréductible, vient étayer un rapport ambigu vis-à-vis de l’Allemagne qui est au coeur des oeuvres de la période 1925-1939, dans lesquelles il attire l’attention, en premier lieu, sur le fait que sa génération est « fille de la défaite » de 1870 et que son héros « comme tous ceux de son pays et de sa génération […] avait été élevé dans l’idée de la revanche ». En auscultant une période clé de sa formation, son autobiographie (Une destinée) analyse des tendances intellectuelles et culturelles collectives des années 1870-1914 pour démontrer que le véritable danger vient non pas de ces ennemis héréditaires « du dehors », mais de la France républicaine elle-même, de sa décadence et du manque du « sens de l’ennemi » (titre d’un ouvrage clé, paru en 1917). Nous analysons comment Louis Bertrand, en « romancier et archéologue », voit chez les néo-Français de l’Algérie (perçus comme des Latins et donc des catholiques) « une école d’énergie et quelquefois d’héroïsme, de régénération physique, intellectuelle, nationale et sociale » qui pourrait stopper le déclin d’une France anémiée et défaitiste.Two series of texts by the author from Lorraine Louis Bertrand (1866-1941) throw a unique light on the impact of 1870-1871 events. His ‘African novels’ (1899-1904), arising from a decade spent in Algeria between 1891 and 1900 during which he was to play a key role both in the launch of a French-language Algerian literature and in the legitimization process of French colonisation by means of the concepts of ‘Latin Africa’ and a ‘neo-French’ nation. This non-metropolitan perspective, which treated the Algerian Muslim as an implacable enemy, reinforced the ambiguous view of Germany revealed by the works of the period 1925-1939. The primary stress in these works is on the claim that his generation is the ‘fruit of the defeat’ of 1870, and that his hero ‘like all those of his age […] had been raised with the idea of revenge’. Through a detailed diagnosis of a key moment in his upbringing, his autobiography (Une destinée) analyses the collective intellectual and cultural currents of the years 1870-1914 to show that the real danger faced by the country came less from these hereditary ‘external’ enemies than from Republican France itself, its decadence and lack of any ‘awareness of the enemy’ (title of a collection published in 1917, Le sens de l’ennemi). We investigate how, in his role as ‘novelist and archaeologist’, Bertrand perceived the neo-French of Algeria (seen as Latin, hence Catholic) as a model of ‘energy and sometimes heroism, of physical, intellectual, national and social regeneration’ that could halt the decline of a post-1870 France seen as weakened and defeatist