Analysis of the hippocampal proteome in ME7 prion disease reveals a predominant astrocytic signature and highlights the brain-restricted production of clusterin in chronic neurodegeneration

Prion diseases are characterized by accumulation of misfolded protein, gliosis, synaptic dysfunction, and ultimately neuronal loss. This sequence, mirroring key features of Alzheimer disease, is modeled well in ME7 prion disease. We used iTRAQ(TM)/mass spectrometry to compare the hippocampal proteome in control and late-stage ME7 animals. The observed changes associated with reactive glia highlighted some specific proteins that dominate the proteome in late-stage disease. Four of the up-regulated proteins (GFAP, high affinity glutamate transporter (EAAT-2), apo-J (Clusterin), and peroxiredoxin-6) are selectively expressed in astrocytes, but astrocyte proliferation does not contribute to their up-regulation. The known functional role of these proteins suggests this response acts against protein misfolding, excitotoxicity, and neurotoxic reactive oxygen species. A recent convergence of genome-wide association studies and the peripheral measurement of circulating levels of acute phase proteins have focused attention on Clusterin as a modifier of late-stage Alzheimer disease and a biomarker for advanced neurodegeneration. Since ME7 animals allow independent measurement of acute phase proteins in the brain and circulation, we extended our investigation to address whether changes in the brain proteome are detectable in blood. We found no difference in the circulating levels of Clusterin in late-stage prion disease when animals will show behavioral decline, accumulation of misfolded protein, and dramatic synaptic and neuronal loss. This does not preclude an important role of Clusterin in late-stage disease, but it cautions against the assumption that brain levels provide a surrogate peripheral measure for the progression of brain degeneration

Loess origin, transport, and deposition over the past 10,000 years, Wrangell-St. Elias National Park, Alaska

Contemporary glaciogenic dust has not received much attention, because most research has been on glaciogenic dust of the last glacial period or non-glaciogenic dust of the present interglacial period. Nevertheless, dust from modern glaciogenic sources may be important for Fe inputs to primary producers in the ocean. Adjacent to the subarctic Pacific Ocean, we studied a loess section near Chitina, Alaska along the Copper River in Wrangell-St. Elias National Park, where dust has been accumulating over the past ~10,000 years. Mass accumulation rates for the fine-grained (\u3c20 \u3eµm) fraction of this loess section are among the highest reported for the Holocene of high-latitude regions of the Northern Hemisphere. Based on mineralogy and geochemistry, loess at Chitina is derived from glacial sources in the Wrangell Mountains, the Chugach Mountains, and probably the Alaska Range. Concentrations of Fe in the silt-plus-clay fraction of the loess at Chitina are much higher than in all other loess bodies in North America and higher than most loess bodies on other continents. The very fine-grained (\u3c2 \u3eµm) portion of this sediment, capable of long-range transport, is dominated by Fe-rich chlorite, which can yield Fe readily to primary producers in the ocean. Examination of satellite imagery shows that dust from the Copper River is transported by wind on a regular basis to the North Pacific Ocean. This Alaskan example shows that high-latitude glaciogenic dust needs to be considered as a significant Fe source to primary producers in the open ocean

Creative Futures: Act, Sing, Play. Evaluation report and executive summary

Act, Sing, Play (ASP) offered music and drama tuition to Year 2 pupils. The aim of the programme was to evaluate whether music workshops had a bigger impact than drama workshops in terms of pupils’ maths and literacy attainment. The evaluation was based on the hypothesis that participation in high-quality music instruction promotes educational attainment over and above instruction in other artistic pursuits. The ASP programme was developed specifically for this trial and ran from September 2013 to June 2014: 909 pupils participated in 19 schools across London, Essex, Sussex and Coventry. In each participating Year 2 class, pupils were randomly allocated to one of three groups: violin or cello workshops (ASPstrings), singing lessons (ASP-singing), or drama workshops (ASP-drama). The two music groups (strings and singing) represented the treatment arms of the trial. Students in the ASP-drama workshops represented the control. Each workshop had around 10 students. Workshops were held once a week over 32 weeks. This evaluation provides no evidence that ASP-music workshops had a greater impact on maths or literacy attainment than ASP-drama workshops. Analysis of students receiving free school meals similarly found no evidence that ASP-music workshops had a greater impact on maths or literacy than ASP-drama workshops

Durham Shared Maths Project. Evaluation report and executive summary

Published in July 2015, this report details the findings of the Durham University Shared Maths intervention project on pupils from 82 primary schools across four local authorities. The intervention was a cross-age peer tutoring, developed at Durham University, where older pupils (Year 5/Year 6) work with younger pupils (Year 3/Year 4) to discuss and work through maths problems using a structured approach. The intervention was delivered by teachers, with training and support from a Local Co-ordinator and participating pupils spent 20 minutes each week using the approach, for two blocks of 16 weeks over consecutive years

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects