Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques — glucose clamps and in vivo microdialysis — as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (K(ATP)) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K(ATP) channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that K(ATP) channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels

(Invited) intrinsic reliability assessment of 650V rated AlGaN/GaN based power devices:an industry perspective

Although astounding performance is already proven by many research papers, the widespread adoption of GaN power devices in the market is still hampered by (1) yield and reproducibility ; (2) cost ; (3) reliability. All three factors are to be considered, but to convince customers to adopt GaN power devices, proven device and product reliability is a must. Cost is kept acceptably low by growing the GaN epi stack on 6 inch and 8inch Si substrates, and by processing the GaN power device technology in standard CMOS production lines. This paper will focus on the most important intrinsic reliability mechanisms for GaN power devices. It will cover gate dielectric reliability, Ohmic contact reliability, accelerated drain stress testing (high temperature reverse bias--HTRB) and high voltage device wear-out testing (high voltage off-state stress--HVOS). Acceleration models are discussed A measurement strategy to extract valuable information about the physical properties of the buffer layers (e.g. activation energies of the traps, conduction mechanisms, \u2026) based on simple transmission line structures, is outlined

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Reading and Ownership

First paragraph: ‘It is as easy to make sweeping statements about reading tastes as to indict a nation, and as pointless.’ This jocular remark by a librarian made in the Times in 1952 sums up the dangers and difficulties of writing the history of reading. As a field of study in the humanities it is still in its infancy and encompasses a range of different methodologies and theoretical approaches. Historians of reading are not solely interested in what people read, but also turn their attention to the why, where and how of the reading experience. Reading can be solitary, silent, secret, surreptitious; it can be oral, educative, enforced, or assertive of a collective identity. For what purposes are individuals reading? How do they actually use books and other textual material? What are the physical environments and spaces of reading? What social, educational, technological, commercial, legal, or ideological contexts underpin reading practices? Finding answers to these questions is compounded by the difficulty of locating and interpreting evidence. As Mary Hammond points out, ‘most reading acts in history remain unrecorded, unmarked or forgotten’. Available sources are wide but inchoate: diaries, letters and autobiographies; personal and oral testimonies; marginalia; and records of societies and reading groups all lend themselves more to the case-study approach than the historical survey. Statistics offer analysable data but have the effect of producing identikits rather than actual human beings. The twenty-first century affords further possibilities, and challenges, with its traces of digital reader activity, but the map is ever-changing

Schoolbooks and textbook publishing.

In this chapter the author looks at the history of schoolbooks and textbook publishing. The nineteenth century saw a rise in the school book market in Britain due to the rise of formal schooling and public examinations. Although the 1870 Education and 1872 (Scotland) Education Acts made elementary education compulsory for childern between 5-13 years old, it was not until the end of the First World War that some sort form of secondary education became compulsory for all children

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding

International audienceThe nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic RORα by generating mice with liver-specific RORα deletion to elucidate the role of this nuclear receptor on host metabolism