A tunable, dual mode field-effect or single electron transistor

A dual mode device behaving either as a field-effect transistor or a single electron transistor (SET) has been fabricated using silicon-on-insulator metal oxide semiconductor technology. Depending on the back gate polarisation, an electron island is accumulated under the front gate of the device (SET regime), or a field-effect transistor is obtained by pinching off a bottom channel with a negative front gate voltage. The gradual transition between these two cases is observed. This dual function uses both vertical and horizontal tunable potential gradients in non-overlapped silicon-on-insulator channel

Modelling of the anthropogenic tritium transient and its decay product helium-3 in the Mediterranean Sea using a high-resolution regional model

International audienceThis numerical study provides the first simulation of the anthropogenic tritium invasion and its decay product helium-3 (3 He) in the Mediterranean Sea. The simulation covers the entire tritium (3 H) transient generated by the atmospheric nuclear weapons tests performed in the 1950s and early 1960s and is run till 2011. Tritium, helium-3 and their derived age estimates are particularly suitable for studying intermediate and deep-water ventilation and spreading of water masses at intermediate/deep levels. The simulation is made using a high-resolution regional model NEMO (Nucleus for European Modelling of the Ocean), in a regional configuration for the Mediterranean Sea called MED12, forced at the surface with prescribed tritium evolution derived from observations. The simulation is compared to measurements of tritium and helium-3 performed along large-scale transects in the Mediterranean Sea during the last few decades on cruises of R/V Meteor: M5/6, M31/1, M44/4, M51/2, M84/3, and R/V Poseidon: 234. The results show that the input function used for the tritium generates a realistic distribution of the main hydrographic features of the Mediterranean Sea circulation. In the eastern basin, the results highlight the weak formation of Adriatic Deep Water in the model, which explains its weak contribution to the Eastern Mediterranean Deep Water (EMDW) in the Ionian sub-basin. It produces a realistic representation of the Eastern Mediterranean Transient (EMT) signal, simulating a deep-water formation in the Aegean sub-basin at the beginning of 1993, with a realistic timing of deep-water renewal in the eastern basin

Sources of pro-cyclicality in east Asian financial systems

Procyclicality is a normal feature of economic systems, but financial sector weaknesses can exacerbate it sufficiently to pose a threat to macroeconomic and financial stability. These include shortcomings in bank risk management and governance, in supervision and in terms of dependence on volatile sources of funds. The paper tests econometrically for the importance of such features leading to pro-cyclicality in the financial systems of 11 East Asian countries. This analysis makes it possible to identify specific policy measures for East Asian countries that could limit the extent to which financial systems exacerbate pro-cyclicality

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Docosahexaenoic and eicosapentaenoic acids increase prion formation in neuronal cells

<p>Abstract</p> <p>Background</p> <p>The transmissible spongiform encephalopathies, otherwise known as prion diseases, occur following the conversion of the cellular prion protein (PrP^C) to an alternatively folded, disease-associated isoform (PrP^Sc). Recent studies suggest that this conversion occurs via a cholesterol-sensitive process, as cholesterol synthesis inhibitors reduced the formation of PrP^Scand delayed the clinical phase of scrapie infection. Since polyunsaturated fatty acids also reduced cellular cholesterol levels we tested their effects on PrP^Scformation in three prion-infected neuronal cell lines (ScGT1, ScN2a and SMB cells).</p> <p>Results</p> <p>We report that treatment with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) or the cholesterol synthesis inhibitor simvastatin reduced the amounts of free cholesterol in membrane extracts from prion-infected neuronal cells. Simvastatin reduced cholesterol production while DHA and EPA promoted the conversion of free cholesterol to cholesterol esters. Crucially, while simvastatin reduced PrP^Scformation, both DHA and EPA significantly increased the amounts of PrP^Scin these cells. Unlike simvastatin, the effects of DHA and EPA on PrP^Sccontent were not reversed by stimulation of cholesterol synthesis with mevalonate. Treatment of ScGT1 cells with DHA and EPA also increased activation of cytoplasmic phospholipase A₂and prostaglandin E₂production. Finally, treatment of neuronal cells with DHA and EPA increased the amounts of PrP^Cexpressed at the cell surface and significantly increased the half-life of biotinylated PrP^C.</p> <p>Conclusion</p> <p>We report that although treatment with DHA or EPA significantly reduced the free cholesterol content of prion-infected cells they significantly increased PrP^Scformation in three neuronal cell lines. DHA or EPA treatment of infected cells increased activation of phospholipase A₂, a key enzyme in PrP^Scformation, and altered the trafficking of PrP^C. PrP^Cexpression at the cell surface, a putative site for the PrP^Scformation, was significantly increased, and the rate at which PrP^Cwas degraded was reduced. Cholesterol depletion is seen as a potential therapeutic strategy for prion diseases. However, these results indicate that a greater understanding of the precise relationship between membrane cholesterol distribution, PrP^Ctrafficking, cell activation and PrP^Scformation is required before cholesterol manipulation can be considered as a prion therapeutic.</p

Prion Protein Misfolding Affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress

Prion-related disorders (PrDs) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrPRES. Altered endoplasmic reticulum (ER) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrPRES. Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrPRES and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models

Identification of an Intracellular Site of Prion Conversion

Prion diseases are fatal, neurodegenerative disorders in humans and animals and are characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrPC), denoted PrPSc, which represents the major component of infectious scrapie prions. Characterization of the mechanism of conversion of PrPC into PrPSc and identification of the intracellular site where it occurs are among the most important questions in prion biology. Despite numerous efforts, both of these questions remain unsolved. We have quantitatively analyzed the distribution of PrPC and PrPSc and measured PrPSc levels in different infected neuronal cell lines in which protein trafficking has been selectively impaired. Our data exclude roles for both early and late endosomes and identify the endosomal recycling compartment as the likely site of prion conversion. These findings represent a fundamental step towards understanding the cellular mechanism of prion conversion and will allow the development of new therapeutic approaches for prion diseases

Inhibition of cholesterol recycling impairs cellular PrPSc propagation

The infectious agent in prion diseases consists of an aberrantly folded isoform of the cellular prion protein (PrPc), termed PrPSc, which accumulates in brains of affected individuals. Studies on prion-infected cultured cells indicate that cellular cholesterol homeostasis influences PrPSc propagation. Here, we demonstrate that the cellular PrPSc content decreases upon accumulation of cholesterol in late endosomes, as induced by NPC-1 knock-down or treatment with U18666A. PrPc trafficking, lipid raft association, and membrane turnover are not significantly altered by such treatments. Cellular PrPSc formation is not impaired, suggesting that PrPSc degradation is increased by intracellular cholesterol accumulation. Interestingly, PrPSc propagation in U18666A-treated cells was partially restored by overexpression of rab 9, which causes redistribution of cholesterol and possibly of PrPSc to the trans-Golgi network. Surprisingly, rab 9 overexpression itself reduced cellular PrPSc content, indicating that PrPSc production is highly sensitive to alterations in dynamics of vesicle trafficking