Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Search for vector-like T quarks decaying to top quarks and Higgs bosons in the all-hadronic channel using jet substructure

Peer reviewe

YeTFaSCo: a database of evaluated yeast transcription factor sequence specificities

The yeast Saccharomyces cerevisiae is a prevalent system for the analysis of transcriptional networks. As a result, multiple DNA-binding sequence specificities (motifs) have been derived for most yeast transcription factors (TFs). However, motifs from different studies are often inconsistent with each other, making subsequent analyses complicated and confusing. Here, we have created YeTFaSCo (The Yeast Transcription Factor Specificity Compendium, http://yetfasco.ccbr.utoronto.ca/), an extensive collection of S. cerevisiae TF specificities. YeTFaSCo differs from related databases by being more comprehensive (including 1709 motifs for 256 proteins or protein complexes), and by evaluating the motifs using multiple objective quality metrics. The metrics include correlation between motif matches and ChIP-chip data, gene expression patterns, and GO terms, as well as motif agreement between different studies. YeTFaSCo also features an index of ‘expert-curated’ motifs, each associated with a confidence assessment. In addition, the database website features tools for motif analysis, including a sequence scanning function and precomputed genome-browser tracks of motif occurrences across the entire yeast genome. Users can also search the database for motifs that are similar to a query motif

Integration of Global Signaling Pathways, cAMP-PKA, MAPK and TOR in the Regulation of FLO11

The budding yeast, Saccharomyces cerevisiae, responds to various environmental cues by invoking specific adaptive mechanisms for their survival. Under nitrogen limitation, S. cerevisiae undergoes a dimorphic filamentous transition called pseudohyphae, which helps the cell to forage for nutrients and reach an environment conducive for growth. This transition is governed by a complex network of signaling pathways, namely cAMP-PKA, MAPK and TOR, which controls the transcriptional activation of FLO11, a flocculin gene that encodes a cell wall protein. However, little is known about how these pathways co-ordinate to govern the conversion of nutritional availability into gene expression. Here, we have analyzed an integrative network comprised of cAMP-PKA, MAPK and TOR pathways with respect to the availability of nitrogen source using experimental and steady state modeling approach. Our experiments demonstrate that the steady state expression of FLO11 was bistable over a range of inducing ammonium sulphate concentration based on the preculturing condition. We also show that yeast switched from FLO11 expression to accumulation of trehalose, a STRE response controlled by a transcriptional activator Msn2/4, with decrease in the inducing concentration to complete starvation. Steady state analysis of the integrative network revealed the relationship between the environment, signaling cascades and the expression of FLO11. We demonstrate that the double negative feedback loop in TOR pathway can elicit a bistable response, to differentiate between vegetative growth, filamentous growth and STRE response. Negative feedback on TOR pathway function to restrict the expression of FLO11 under nitrogen starved condition and also with re-addition of nitrogen to starved cells. In general, we show that these global signaling pathways respond with specific sensitivity to regulate the expression of FLO11 under nitrogen limitation. The holistic steady state modeling approach of the integrative network revealed how the global signaling pathways could differentiate between multiple phenotypes

Global Transcriptome and Deletome Profiles of Yeast Exposed to Transition Metals

A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to non-essential metals and metalloids. The molecular mechanisms linking metal exposure to human pathologies have not been clearly defined. To address these gaps in our understanding of the molecular biology of transition metals, the genomic effects of exposure to Group IB (copper, silver), IIB (zinc, cadmium, mercury), VIA (chromium), and VB (arsenic) elements on the yeast Saccharomyces cerevisiae were examined. Two comprehensive sets of metal-responsive genomic profiles were generated following exposure to equi-toxic concentrations of metal: one that provides information on the transcriptional changes associated with metal exposure (transcriptome), and a second that provides information on the relationship between the expression of ∼4,700 non-essential genes and sensitivity to metal exposure (deletome). Approximately 22% of the genome was affected by exposure to at least one metal. Principal component and cluster analyses suggest that the chemical properties of the metal are major determinants in defining the expression profile. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. The transcriptome and deletome had 22 genes in common, however, comparison between Gene Ontology biological processes for the two gene sets revealed that metal stress adaptation and detoxification categories were commonly enriched. Analysis of the transcriptome and deletome identified several evolutionarily conserved, signal transduction pathways that may be involved in regulating the responses to metal exposure. In this study, we identified genes and cognate signaling pathways that respond to exposure to essential and non-essential metals. In addition, genes that are essential for survival in the presence of these metals were identified. This information will contribute to our understanding of the molecular mechanism by which organisms respond to metal stress, and could lead to an understanding of the connection between environmental stress and signal transduction pathways

Gis1 and Rph1 Regulate Glycerol and Acetate Metabolism in Glucose Depleted Yeast Cells

Aging in organisms as diverse as yeast, nematodes, and mammals is delayed by caloric restriction, an effect mediated by the nutrient sensing TOR, RAS/cAMP, and AKT/Sch9 pathways. The transcription factor Gis1 functions downstream of these pathways in extending the lifespan of nutrient restricted yeast cells, but the mechanisms involved are still poorly understood. We have used gene expression microarrays to study the targets of Gis1 and the related protein Rph1 in different growth phases. Our results show that Gis1 and Rph1 act both as repressors and activators, on overlapping sets of genes as well as on distinct targets. Interestingly, both the activities and the target specificities of Gis1 and Rph1 depend on the growth phase. Thus, both proteins are associated with repression during exponential growth, targeting genes with STRE or PDS motifs in their promoters. After the diauxic shift, both become involved in activation, with Gis1 acting primarily on genes with PDS motifs, and Rph1 on genes with STRE motifs. Significantly, Gis1 and Rph1 control a number of genes involved in acetate and glycerol formation, metabolites that have been implicated in aging. Furthermore, several genes involved in acetyl-CoA metabolism are downregulated by Gis1

Searches for Higgs bosons in pp collisions at root s=7 and 8 TeV in the context of four-generation and fermiophobic models

Searches are reported for Higgs bosons in the context of either the standard model extended to include a fourth generation of fermions (SM4) with masses of up to 600 GeV or fermiophobic models. For the former, results from three decay modes (tau tau, WW, and ZZ) are combined, whilst for the latter the diphoton decay is exploited. The analysed proton-proton collision data correspond to integrated luminosities of up to 5.1 fb(-1) at 7 TeV and up to 5.3 fb(-1) at 8 TeV. The observed results exclude the SM4 Higgs boson in the mass range 110-600 GeV at 99% confidence level (CL), and in the mass range 110-560 GeV at 99.9% CL. A fermiophobic Higgs boson is excluded in the mass range 110-147 GeV at 95% CL, and in the range 110-133 GeV at 99% CL. The recently observed boson with a mass near 125 GeV is not consistent with either an SM4 or a fermiophobic Higgs boson. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved

Search for new physics in final states with a lepton and missing transverse energy in pp collisions at the LHC

This Letter describes the search for an enhanced production rate of events with a charged lepton and a neutrino in high-energy pp collisions at the LHC. The analysis uses data collected with the CMS detector, with an integrated luminosity of 5.0 fb(-1) at root s = 7 TeV, and a further 3.7 fb(-1) at root s = 8 TeV. No evidence is found for an excess. The results are interpreted in terms of limits on a heavy charged gauge boson (W') in the sequential standard model, a split universal extra dimension model, and contact interactions in the helicity-nonconserving model. For the last, values of the binding energy below 10.5 (8.8) TeV in the electron (muon) channel are excluded at a 95% confidence level. Interpreting the l(nu) final state in terms of a heavy W' with standard model couplings, masses below 2.90 TeV are excluded. DOI: 10.1103/PhysRevD.87.07200

Measurement of the elliptic anisotropy of charged particles produced in PbPb collisions at root s(NN)=2.76 TeV

The anisotropy of the azimuthal distributions of charged particles produced in root s(NN) = 2.76 TeV PbPb collisions is studied with the CMS experiment at the LHC. The elliptic anisotropy parameter, upsilon(2), defined as the second coefficient in a Fourier expansion of the particle invariant yields, is extracted using the event-plane method, two- and four-particle cumulants, and Lee-Yang zeros. The anisotropy is presented as a function of transverse momentum (p(T)), pseudorapidity (eta) over a broad kinematic range, 0.3 < p(T) < 20 GeV/c, vertical bar eta vertical bar < 2.4, and in 12 classes of collision centrality from 0 to 80%. The results are compared to those obtained at lower center-of-mass energies, and various scaling behaviors are examined. When scaled by the geometric eccentricity of the collision zone, the elliptic anisotropy is found to obey a universal scaling with the transverse particle density for different collision systems and center-of-mass energies. DOI: 10.1103/PhysRevC.87.01490

Search for a non-standard-model Higgs boson decaying to a pair of new light bosons in four-muon final states

Results are reported from a search for non-standard-model Higgs boson decays to pairs of new light bosons, each of which decays into the mu(+)mu(-) final state. The new bosons may be produced either promptly or via a decay chain. The data set corresponds to an integrated luminosity of 5.3 fb(-1) of proton-proton collisions at root s = 7 TeV, recorded by the CMS experiment at the LHC in 2011. Such Higgs boson decays are predicted in several scenarios of new physics, including supersymmetric models with extended Higgs sectors or hidden valleys. Thus, the results of the search are relevant for establishing whether the new particle observed in Higgs boson searches at the LHC has the properties expected for a standard model Higgs boson. No excess of events is observed with respect to the yields expected from standard model processes. A model-independent upper limit of 0.86 +/- 0.06 fb on the product of the cross section times branching fraction times acceptance is obtained. The results, which are applicable to a broad spectrum of new physics scenarios, are compared with the predictions of two benchmark models as functions of a Higgs boson mass larger than 86 GeV/c(2) and of a new light boson mass within the range 0.25-3.55 GeV/c(2). (C) 2013 CERN. Published by Elsevier B.V. All rights reserved