The phenomenological MSSM in view of the 125 GeV Higgs data

The parameter space of the phenomenological MSSM (pMSSM) is explored by means of Markov Chain Monte Charlo (MCMC) methods, taking into account the latest LHC results on the Higgs signal at 125 GeV in addition to relevant low-energy observables and LEP constraints. We use a Bayesian approach to derive posterior densities for the parameters and observables of interests. We find in particular that the Higgs measurements have a significant impact on the parameters mu and tan beta due to radiative corrections to the bottom Yukawa coupling. We show moreover the impact of the most recent dark matter measurements on the probability distributions, and we discuss prospects for the next run of the LHC at 13-14 TeV.Comment: 28 pages, 13 figures; v2: matches version accepted for publication in PR

Constraints on and future prospects for Two-Higgs-Doublet Models in light of the LHC Higgs signal

We analyze the Two-Higgs-Doublet Models (2HDMs) of Type I and II for consistency with the latest measurements of the ~125.5 GeV Higgs-like signal at the LHC. To this end, we perform scans of the 2HDM parameter space taking into account all relevant pre-LHC constraints as well as the most recent limits coming from searches for heavy Higgs-like states at the LHC. The current status of the 2HDMs of Type I and II is discussed assuming that the observed 125.5 GeV state is one of the two CP-even Higgs bosons, either the lighter h or the heavier H. Implications for future experiments, including expectations regarding other lighter or heavier Higgs bosons are given. The possible importance of heavier Higgs bosons feeding the signals for the 125.5 GeV state is also evaluated.Comment: 52 pages, 32 figures, match to the published versio

Differentiation of Human Adipose-Derived Stem Cells into “Brite” (Brown-in-White) Adipocytes

It is well established now that adult humans possess active brown adipose tissue (BAT) which represents a potential pharmacological target to combat obesity and associated diseases. Moreover thermogenic brown-like adipocytes (“brite adipocytes”) appear also in mouse white adipose tissue (WAT) upon β3-adrenergic stimulation. We had previously shown that human multipotent adipose-derived stem cells (hMADS) are able to differentiate into cells which exhibit the key properties of human white adipocytes, and then to convert into functional brown adipocytes upon PPARγ activation. In light of a wealth of data indicating that thermogenic adipocytes from BAT and WAT have a distinct cellular origin, we have characterized at the molecular level UCP1 positive hMADS adipocytes from both sexes as brite adipocytes. Conversion of white to brown hMADS adipocytes is dependent on PPARγ activation with rosiglitazone as the most potent agonist and is inhibited by a PPARγ antagonist. In contrast to mouse cellular models, hMADS cells conversion into brown adipocytes is weakly induced by BMP7 treatment and not modulated by activation of the Hedgehog pathway. So far no primary or clonal precursor cells of human brown adipocytes have been obtained that can be used as a tool to develop therapeutic drugs and to gain further insights into the molecular mechanisms of brown adipogenesis in humans. Thus hMADS cells represent a suitable human cell model to delineate the formation and/or the uncoupling capacity of brown/brite adipocytes that could help to dissipate caloric excess intake among individuals

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

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

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

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

Yeast Two-Hybrid: State of the Art

Genome projects are approaching completion and are saturating sequence databases. This paper discusses the role of the two-hybrid system as a generator of hypotheses. Apart from this rather exhaustive, financially and labour intensive procedure, more refined functional studies can be undertaken. Indeed, by making hybrids of two-hybrid systems, customised approaches can be developed in order to attack specific function-related problems. For example, one could set-up a "differential" screen by combining a forward and a reverse approach in a three-hybrid set-up. Another very interesting project is the use of peptide libraries in two-hybrid approaches. This could enable the identification of peptides with very high specificity comparable to "real" antibodies. With the technology available, the only limitation is imagination

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