Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Horizontal and vertical structure of the Eyjafjallajökull ash cloud over the UK: a comparison of airborne lidar observations and simulations

During April and May 2010 the ash cloud from the eruption of the Icelandic volcano Eyjafjallajökull caused widespread disruption to aviation over northern Europe. The location and impact of the eruption led to a wealth of observations of the ash cloud were being obtained which can be used to assess modelling of the long range transport of ash in the troposphere. The UK FAAM (Facility for Airborne Atmospheric Measurements) BAe-146-301 research aircraft overflew the ash cloud on a number of days during May. The aircraft carries a downward looking lidar which detected the ash layer through the backscatter of the laser light. In this study ash concentrations derived from the lidar are compared with simulations of the ash cloud made with NAME (Numerical Atmospheric-dispersion Modelling Environment), a general purpose atmospheric transport and dispersion model. The simulated ash clouds are compared to the lidar data to determine how well NAME simulates the horizontal and vertical structure of the ash clouds. Comparison between the ash concentrations derived from the lidar and those from NAME is used to define the fraction of ash emitted in the eruption that is transported over long distances compared to the total emission of tephra. In making these comparisons possible position errors in the simulated ash clouds are identified and accounted for. The ash layers seen by the lidar considered in this study were thin, with typical depths of 550–750 m. The vertical structure of the ash cloud simulated by NAME was generally consistent with the observed ash layers, although the layers in the simulated ash clouds that are identified with observed ash layers are about twice the depth of the observed layers. The structure of the simulated ash clouds were sensitive to the profile of ash emissions that was assumed. In terms of horizontal and vertical structure the best results were obtained by assuming that the emission occurred at the top of the eruption plume, consistent with the observed structure of eruption plumes. However, early in the period when the intensity of the eruption was low, assuming that the emission of ash was uniform with height gives better guidance on the horizontal and vertical structure of the ash cloud. Comparison of the lidar concentrations with those from NAME show that 2–5% of the total mass erupted by the volcano remained in the ash cloud over the United Kingdom.

Cloud banding and winds in intense European cyclones: results from the DIAMET project

The DIAMET (DIAbatic influences on Mesoscale structures in ExTratropical storms) project aims to improve forecasts of high-impact weather in extratropical cyclones through field measurements, high-resolution numerical modeling, and improved design of ensemble forecasting and data assimilation systems. This article introduces DIAMET and presents some of the first results. Four field campaigns were conducted by the project, one of which, in late 2011, coincided with an exceptionally stormy period marked by an unusually strong, zonal North Atlantic jet stream and a succession of severe windstorms in northwest Europe. As a result, December 2011 had the highest monthly North Atlantic Oscillation index (2.52) of any December in the last 60 years. Detailed observations of several of these storms were gathered using the UK’s BAe146 research aircraft and extensive ground-based measurements. As an example of the results obtained during the campaign, observations are presented of cyclone Friedhelm on 8 December 2011, when surface winds with gusts exceeding 30 m s-1 crossed central Scotland, leading to widespread disruption to transportation and electricity supply. Friedhelm deepened 44 hPa in 24 hours and developed a pronounced bent-back front wrapping around the storm center. The strongest winds at 850 hPa and the surface occurred in the southern quadrant of the storm, and detailed measurements showed these to be most intense in clear air between bands of showers. High-resolution ensemble forecasts from the Met Office showed similar features, with the strongest winds aligned in linear swaths between the bands, suggesting that there is potential for improved skill in forecasts of damaging winds.

Widespread supplementary feeding in domestic gardens explains the return of reintroduced Red Kites Milvus milvus to an urban area

Reintroductions are used worldwide to mitigate biodiversity loss. One prominent case is a charismatic raptor of conservation concern, the Red Kite Milvus milvus. This species has been reintroduced across the UK over the last 25 years following its near extinction after centuries of persecution. The species was not expected to recolonize urban areas; its historical association with human settlements is attributed to scavenging on human waste and refuse, a resource now greatly reduced on the streets of modern Western cities. However, the species has become a common day-time visitor to a large conurbation centred on the town of Reading, southern England, approximately 20 km from the first English reintroduction site. Given a near-absence of breeding and roost sites, we investigated foraging opportunities and habitat associations that might explain use by Red Kites of this urban area. Surveys of discarded human foods and road-kill suggested that these could support at most 13−29 kites/day. Face-to-face surveys of a cross-section of residents revealed that 4.5% (equivalent to 4349 households) provided supplementary food for kites. Using estimates of per-household resource provision from another study, we calculated that this level is potentially sufficient to provision 142−320 kites, a substantial proportion of the total estimated to visit the conurbation each day (between 140 and 440). Road transects found positive associations between Red Kites and residential areas. We therefore suggest that the decision made by thousands of individuals to provide supplementary food for Red Kites is the primary factor explaining their day-time abundance in this urban area.

Development of substorm cross-tail current disruption as seen from the ground

We discuss substorm observations made near 2100 magnetic local time (MLT) on March 7, 1991, in a collaborative study involving data from the European Incoherent Scatter radar, all-sky camera data, and magnetometer data from the Tromsø Auroral Observatory, the U.K. Sub-Auroral Magnetometer Network (SAMNET) and the IMAGE magnetometer chain. We conclude that for the substorm studied a plasmoid was not pinched off until at least 10 min after onset at the local time of the observations (2100 MLT) and that the main substorm electrojet expanded westward over this local time 14 min after onset. In the late growth phase/early expansion phase, we observed southward drifting arcs probably moving faster than the background plasma. Similar southward moving arcs in the recovery phase moved at a speed which does not appear to be significantly different from the measured plasma flow speed. We discuss these data in terms of the “Kiruna conjecture” and classical “near-Earth neutral line” paradigms, since the data show features of both models of substorm development. We suggest that longitudinal variation in behavior may reconcile the differences between the two models in the case of this substorm.

The sexual constitution of political authority: the 'trials' of same sex desire

The Sexual Constitution of Political Authority argues that there are good reasons to suppose that our understandings of state power quiver with erotic undercurrents. Through a series of case studies where a statesman's same sex desire was put on trial (either literally or metaphorically) as a problem for the good exercise of public powers, the book shows the resilience and adaptability of cultural beliefs in the incompatibility between public office and male same-sex desire.

Sexual abuse in childhood and postoperative depression in women with breast cancer who opt for immediate reconstruction after mastectomy

INTRODUCTION Breast reconstruction is routinely offered to women who undergo mastectomy for breast cancer. However, patient-reported outcomes are mixed. Child abuse has enduring effects on adults’ well-being and body image. As part of a study into damaging effects of abuse on adjustment to breast cancer, we examined: (i) whether women with history of abuse would be more likely than other women to opt for reconstruction; and (ii) whether mood problems in women opting for reconstruction can be explained by greater prevalence of abuse. PATIENTS AND METHODS We recruited 355 women within 2-4 days after surgery for primary breast cancer; 104 had mastectomy alone and 29 opted for reconstruction. Using standardised questionnaires, women self-reported emotional distress and recollections of childhood sexual abuse. Self-report of distress was repeated 12 months later. RESULTS Women who had reconstruction were younger than those who did not. Controlling for this, they reported greater prevalence of abuse and more distress than those having mastectomy alone. They were also more depressed postoperatively, and this effect remained significant after controlling for abuse. CONCLUSIONS One interpretation of these findings is that history of abuse influences women's decisions about responding to the threat of mastectomy, but it is premature to draw inferences for practice until the findings are replicated. If they are replicated, it will be important to recognise increased vulnerability of some patients who choose reconstruction. Studying the characteristics and needs of women who opt for immediate reconstruction and examining the implications for women's adjustment should be a priority for research.