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

Public health, human rights and the harm reduction paradigm: from risk reduction to vulnerability reduction

This paper explores the utility of expanding the harm reduction paradigm to incorporate vulnerability reduction. The thrust of harm reduction interventions to date, particularly in injection drug use, has been risk reduction. Many interventions have been designed to reduce drug-related harm by altering high-risk behaviours. Vulnerability looks behind risk. The notion of vulnerability incorporates the complex of underlying factors that promotes harmful outcomes as a result of drug use, and limits attempts to modify drug use to make harmful outcomes less likely. A conceptual framework will be introduced that looks at harm, risk and vulnerability at the three levels of individual, community and society. This paper uses illicit injection drug use as an example. This conceptual framework will be used to position human rights more centrally in the harm reduction debate. Human rights violations and infringements can contribute to drug-related harm by first creating the preconditions for risky drug use; and second, by limiting access to prevention and care. A human rights framework allows us to better understand vulnerability to drug-related harm, and provides an important advocacy tool for improved interventions. This expanded harm reduction paradigm that incorporates vulnerability and human rights allows for better development of a public health approach in harm reduction, exposes gaps in research, and allows for better development of more effective interventions

Low- and high-order gravitational harmonics of rigidly rotating Jupiter

The Juno Orbiter has provided improved estimates of the even gravitational harmonics J2 to J8 of Jupiter. To compute higher-order moments, new methods such as the Concentric Maclaurin Spheroids (CMS) method have been developed which surpass the so far commonly used Theory of Figures (ToF) method in accuracy. This progress rises the question whether ToF can still provide a useful service for deriving the internal structure of giant planets in the Solar system. In this paper, I apply both the ToF and the CMS method to compare results for polytropic Jupiter and for the physical equation of state H/He-REOS.3 based models. An accuracy in the computed values of J2 and J4 of 0.1% is found to be sufficient in order to obtain the core mass safely within 0.5 Mearth numerical accuracy and the atmospheric metallicity within about 0.0004. ToF to 4th order provides that accuracy, while ToF to 3rd order does not for J4. Furthermore, I find that the assumption of rigid rotation yields J6 and J8 values in agreement with the current Juno estimates, and that higher order terms (J10 to J18) deviate by about 10% from predictions by polytropic models. This work suggests that ToF4 can still be applied to infer the deep internal structure, and that the zonal winds on Jupiter reach less deep than 0.9 RJup.Comment: 8 pages, accepted to A&