Gene regulation and epigenotype in Friedreich's ataxia

Friedreich??????s ataxia (FRDA) is known to be provoked by an abnormal GAA-repeat expansion located in the first intron of the FXN gene. As a result of the GAA expansion, patients exhibit low levels of FXN mRNA, leading to FRDA. Here, via chromatin immunoprecipitation (ChIP), the presence of a RNA pol II transcriptional pausing site at exon 1 of the FXN gene was demonstrated. At this site, FRDA EBVcell lines exhibited elevated levels of the negative elongation factor NELF-E depending on the presence of a GAA repeat expansion compared to controls. This site may represent a rate-limiting step for FXN transcription and consequently provide a means to modify transcription levels in FRDA. Moreover, RNA pol II pausing site binding factors, such as NELF-E, were influenced by Nicotinamide treatment, a HDAC class III inhibitor. Therefore, factors sensitive to chromatin changes may influence the regulation of RNA pol II pausing and also balance otherwise positive chromatin changes. This new finding could explain the relatively minor effects of different drug approaches to up-regulate this gene. Furthermore, CTCF and the histone demethylase LSD1 were also found to be located at the FXN pausing site. Results suggest a function for LSD1 in demethylating H3K4me2 at the pausing site and potentially also in demethylating H3K9me3 in the case of frequently transcribed expanded GAA repeats. Therefore, LSD1 might play a crucial role in preventing heterochromatinisation of a euchromatic gene. Using primary transcript RNA-FISH, a delay in RNA pol II release from the pausing site and furthermore a dramatic loss of RNA pol II elongation in the presence of expanded GAA repeats was seen. The identified and characterised transcriptional pausing site at FXN is likely to play a repressive role and participates in the pathogenesis of FRDA.Imperial Users onl

The axial anomaly in lattice QED. A universal point of view

We give a perturbative proof that U(1) lattice gauge theories generate the axial anomaly in the continuum limit under very general conditions on the lattice Dirac operator. These conditions are locality, gauge covariance and the absense of species doubling. They hold for Wilson fermions as well as for realizations of the Dirac operator that satisfy the Ginsparg-Wilson relation. The proof is based on the lattice power counting theorem.Comment: 7 pages, Latex2e, some misprints removed, reference inserte

Immunity and Simplicity for Exact Counting and Other Counting Classes

Ko [RAIRO 24, 1990] and Bruschi [TCS 102, 1992] showed that in some relativized world, PSPACE (in fact, ParityP) contains a set that is immune to the polynomial hierarchy (PH). In this paper, we study and settle the question of (relativized) separations with immunity for PH and the counting classes PP, C_{=}P, and ParityP in all possible pairwise combinations. Our main result is that there is an oracle A relative to which C_{=}P contains a set that is immune to BPP^{ParityP}. In particular, this C_{=}P^A set is immune to PH^{A} and ParityP^{A}. Strengthening results of Tor\'{a}n [J.ACM 38, 1991] and Green [IPL 37, 1991], we also show that, in suitable relativizations, NP contains a C_{=}P-immune set, and ParityP contains a PP^{PH}-immune set. This implies the existence of a C_{=}P^{B}-simple set for some oracle B, which extends results of Balc\'{a}zar et al. [SIAM J.Comp. 14, 1985; RAIRO 22, 1988] and provides the first example of a simple set in a class not known to be contained in PH. Our proof technique requires a circuit lower bound for ``exact counting'' that is derived from Razborov's [Mat. Zametki 41, 1987] lower bound for majority.Comment: 20 page

Uncertainty aversion and equilibrium in extensive games.

This paper formulates a rationality concept for extensive games in which deviations from rational play are interpreted as evidence of irrationality. Instead of confirming some prior belief about the nature of nonrational play, we assume that such a deviation leads to genuine uncertainty. Assuming complete ignorance about the nature of non-rational play and extreme uncertainty aversion of the rational players, we formulate an equilibrium concept on the basis of Choquet expected utility theory. Equilibrium reasoning is thus only applied on the equilibrium path, maximin reasoning applies off the equilibrium path. The equilibrium path itself is endogenously determined. In general this leads to strategy profiles differ qualitatively from sequential equilibria, but still satisfy equilibrium and perfection requirements. In the centipede game and the finitely repeated prisoners’ dilemma this approach can also resolve the backward induction paradox.