Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

The Effect of Transposable Element Insertions on Gene Expression Evolution in Rodents

Background:Many genomes contain a substantial number of transposable elements (TEs), a few of which are known to be involved in regulating gene expression. However, recent observations suggest that TEs may have played a very important role in the evolution of gene expression because many conserved non-genic sequences, some of which are know to be involved in gene regulation, resemble TEs. Results:Here we investigate whether new TE insertions affect gene expression profiles by testing whether gene expression divergence between mouse and rat is correlated to the numbers of new transposable elements inserted near genes. We show that expression divergence is significantly correlated to the number of new LTR and SINE elements, but not to the numbers of LINEs. We also show that expression divergence is not significantly correlated to the numbers of ancestral TEs in most cases, which suggests that the correlations between expression divergence and the numbers of new TEs are causal in nature. We quantify the effect and estimate that TE insertion has accounted for ~20% (95% confidence interval: 12% to 26%) of all expression profile divergence in rodents. Conclusions:We conclude that TE insertions may have had a major impact on the evolution of gene expression levels in rodents

Search for heavy neutrinos mixing with tau neutrinos

We report on a search for heavy neutrinos (\nus) produced in the decay D_s\to \tau \nus at the SPS proton target followed by the decay \nudecay in the NOMAD detector. Both decays are expected to occur if \nus is a component of $\nu_{\tau}$.\ From the analysis of the data collected during the 1996-1998 runs with $4.1\times10^{19}$ protons on target, a single candidate event consistent with background expectations was found. This allows to derive an upper limit on the mixing strength between the heavy neutrino and the tau neutrino in the \nus mass range from 10 to 190 $\rm MeV$. Windows between the SN1987a and Big Bang Nucleosynthesis lower limits and our result are still open for future experimental searches. The results obtained are used to constrain an interpretation of the time anomaly observed in the KARMEN1 detector.\Comment: 20 pages, 7 figures, a few comments adde

Search for the exotic Θ+\Theta^+ resonance in the NOMAD experiment

A search for exotic Theta baryon via Theta -> proton +Ks decay mode in the NOMAD muon neutrino DIS data is reported. The special background generation procedure was developed. The proton identification criteria are tuned to maximize the sensitivity to the Theta signal as a function of xF which allows to study the Theta production mechanism. We do not observe any evidence for the Theta state in the NOMAD data. We provide an upper limit on Theta production rate at 90% CL as 2.13 per 1000 of neutrino interactions.Comment: Accepted to European Physics Journal

Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type

Purpose : A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. Methods : After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. Results : VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. Conclusions : VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65549/1/j.1528-1157.2000.tb00293.x.pd

Final NOMAD results on nu_mu->nu_tau and nu_e->nu_tau oscillations including a new search for nu_tau appearance using hadronic tau decays

Results from the nu_tau appearance search in a neutrino beam using the full NOMAD data sample are reported. A new analysis unifies all the hadronic tau decays, significantly improving the overall sensitivity of the experiment to oscillations. The "blind analysis" of all topologies yields no evidence for an oscillation signal. In the two-family oscillation scenario, this sets a 90% C.L. allowed region in the sin^2(2theta)-Delta m^2 plane which includes sin^2(2theta)<3.3 x 10^{-4} at large Delta m^2 and Delta m^2 < 0.7 eV^2/c^4 at sin^2(2theta)=1. The corresponding contour in the nu_e->nu_tau oscillation hypothesis results in sin^2(2theta)<1.5 x 10^{-2} at large Delta m^2 and Delta m^2 < 5.9 eV^2/c^4 at sin^2(2theta)=1. We also derive limits on effective couplings of the tau lepton to nu_mu or nu_e.Comment: 46 pages, 16 figures, Latex, to appear on Nucl. Phys.

Production properties of K*(892) vector mesons and their spin alignment as measured in the NOMAD experiment

First measurements of K*(892) mesons production properties and their spin alignment in nu_mu charged current (CC) and neutral current (NC) interactions are presented. The analysis of the full data sample of the NOMAD experiment is performed in different kinematic regions. For K*+ and K*- mesons produced in nu_mu CC interactions and decaying into K0 pi+/- we have found the following yields per event: (2.6 +/- 0.2 (stat.) +/- 0.2 (syst.))% and (1.6 +/- 0.1 (stat.) +/- 0.1 (syst.))% respectively, while for the K*+ and K*- mesons produced in nu NC interactions the corresponding yields per event are: (2.5 +/- 0.3 (stat.) +/- 0.3 (syst.))% and (1.0 +/- 0.3 (stat.) +/- 0.2 (syst.))%. The results obtained for the rho00 parameter, 0.40 +/- 0.06 (stat) +/- 0.03 (syst) and 0.28 +/- 0.07 (stat) +/- 0.03 (syst) for K*+ and K*- produced in nu_mu CC interactions, are compared to theoretical predictions tuned on LEP measurements in e+e- annihilation at the Z0 pole. For K*+ mesons produced in nu NC interactions the measured rho00 parameter is 0.66 +/- 0.10 (stat) +/- 0.05 (syst).Comment: 20 p

Prediction of Neutrino Fluxes in the NOMAD Experiment

The method developed for the calculation of the flux and composition of the West Area Neutrino Beam used by NOMAD in its search for neutrino oscillations is described. The calculation is based on particle production rates computed using a recent version of FLUKA and modified to take into account the cross sections measured by the SPY and NA20 experiments. These particles are propagated through the beam line taking into account the material and magnetic fields they traverse. The neutrinos produced through their decays are tracked to the NOMAD detector. The fluxes of the four neutrino flavours at NOMAD are predicted with an uncertainty of about 8% for nu(mu) and nu(e), 10% for antinu(mu), and 12% for antinu(e). The energy-dependent uncertainty achieved on the R(e, mu) prediction needed for a nu(mu)->nu(e) oscillation search ranges from 4% to 7%, whereas the overall normalization uncertainty on this ratio is 4.2%.Comment: 43 pages, 20 figures. Submitted to Nucl. Phys.

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

Cell Cycle- and Cancer-Associated Gene Networks Activated by Dsg2: Evidence of Cystatin A Deregulation and a Potential Role in Cell-Cell Adhesion

This work was supported by grants from the National Institutes of Health (Mahoney, R01AR056067; Riobo, RO1 GM088256). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript