Tyrosine-1 of RNA polymerase II CTD controls global termination of gene transcription in mammals.

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    The carboxy-terminal domain (CTD) of RNA polymerase (Pol) II is composed of a repetition of YSPTSPS heptads and functions as a loading platform for protein complexes that regulate transcription, splicing, and maturation of RNAs. Here, we studied mammalian CTD mutants to analyze the function of tyrosine1 residues in the transcription cycle. Mutation of 3/4 of the tyrosine residues (YFFF mutant) resulted in a massive read-through transcription phenotype in the antisense direction of promoters as well as in the 3' direction several hundred kilobases downstream of genes. The YFFF mutant shows reduced Pol II at promoter-proximal pause sites, a loss of interaction with the Mediator and Integrator complexes, and impaired recruitment of these complexes to chromatin. Consistent with these observations, Pol II loading at enhancers and maturation of snRNAs are altered in the YFFF context genome-wide. We conclude that tyrosine1 residues of the CTD control termination of transcription by Pol II

    Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis?

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    Background: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1b), produced by endotoxin-activated Kupffer cells, play a key role in the pathogenesis of alcoholic liver cirrhosis (ALC). Alleles TNFA-238A, IL1B-31T and variant IL1RN*2 of repeat polymorphism in the gene encoding the IL-1 receptor antagonist increase production of TNF-alpha and IL-1b, respectively. Alleles CD14-159T, TLR4 c.896G and TLR4 c.1196T modify activation of Kupffer cells by endotoxin. We confirmed the published associations between these common variants and genetic predisposition to ALC by means of a large case-control association study conducted on two Central European populations. Methods: The study population comprised a Czech sample of 198 ALC patients and 370 controls (MONICA project), and a German sample of 173 ALC patients and 331 controls (KORA-Augsburg), and 109 heavy drinkers without liver disease. Results: Single locus analysis revealed no significant difference between patients and controls in all tested loci. Diplotype [IL1RN*2/*2; IL1B-31T+] was associated with increased risk of ALC in the pilot study, but not in the validation samples. Conclusions: Although cytokine mediated immune reactions play a role in the pathogenesis of ALC, hereditary susceptibility caused by variants in the corresponding genes is low in Central European populations

    Health-related quality of life in patients with severe COPD hospitalized for exacerbations - comparing EQ-5D, SF-12 and SGRQ.

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    BACKGROUND: The aim of this study was to measure HrQoL during acute exacerbations of COPD using generic and disease-specific instruments, and to assess completeness, proportion with best or worst health state, sensitivity to change and discriminative ability for each instrument. METHODS: EQ-5D, SF-12 and SGRQ were obtained from COPD patients with GOLD stage III and IV hospitalized for an acute exacerbation both at admission and discharge. To assess the instruments' properties, utility values were calculated for EQ-5D and SF-12, and a total score was derived from the SGRQ. RESULTS: Mean utilities ranged from 0.54 (SF-12, stage IV) to 0.62 (EQ-5D, stage III) at admission, and from 0.58 (SF-12, stage IV) to 0.84 (EQ-5D, stage III) at discharge. Completeness was best for EQ-5D and SGRQ, while no utility value for the SF-12 could be calculated for more than 30%. For SGRQ subscales, the minimal score occurred in up to 11% at admission, while full health was observed for the EQ-5D at discharge in 13%. Sensitivity to change was generally good, whereas discrimination between COPD stages was low for the EQ-5D. CONCLUSIONS: Acute exacerbations seriously impair health status and quality of life. The EQ-5D is generally suitable to measure HrQoL in exacerbations of severe COPD, although the high proportion of patients reporting full health at discharge poses a problem. The main issue with the SF-12 is the high proportion of missing values in a self-assessed setting. Properties of the SGRQ were satisfactory. However, since no utility values can be derived from this disease-specific instrument, it is not suitable for cost-utility analyses in health-economic evaluations

    Intercomparison of radiation protection devices in a high-energy stray neutron field, Part II: Bonner sphere spectrometry.

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    The European Commission has funded within its 6th Framework Programme a three-year project (2005-2007) called CONRAD, COordinated Network for RAdiation Dosimetry. A major task of the CONRAD Work Package 'complex mixed radiation fields at workplaces' was to organise a benchmark exercise in a workplace field at a high-energy particle accelerator where neutrons are the dominant radiation component. The CONRAD benchmark exercise took place at the Gesellschaft fur Schwerionenforschung mbH (GSI) in Darmstadt, Germany in July 2006. In this paper, the results of the spectrometry using four extended -range Bonner sphere spectrometers of four different institutes are reported. Outside Cave A the neutron spectra were measured with three spectrometers at six selected positions and ambient dose equivalent values were derived for use in the intercomparison with other area monitors and dose, meters. At a common position all three spectrometers were used to allow a direct comparison of their, results which acts as an internal quality assurance. The comparison of the neutron spectra measured by the different groups shows very good agreement. A detailed analysis presents some differences between the shapes of the spectra and possible sources of these differences are discussed. However, the ability of Bonner sphere spectrometers to provide reliable integral quantities like fluence and ambient dose equivalent is well demonstrated in this exercise. The fluence and dose results derived by the three groups agree very well within the given uncertainties, not only with respect to the total energy region present in this environment but also for selected energy regions which contribute in certain strength to the total values. In addition to the positions outside Cave A one spectrometer was used to measure the neutron spectrum at one position in the entry maze of Cave A. In this case a comparison was possible to, earlier measurements

    In situ mass distribution quotient (iMDQ) - a new factor to compare bioavailability of chemicals in soils?

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    Aim of this work was the development of a new non-biological factor to determine microbial in situ bioavailability of chemicals in soils. Pesticide residues were extracted from ten highly different agricultural soils that had been incubated with the C-14-herbicide isoproturon (IPU) under comparable soil conditions (water tension - 15 kPa; soil density 1.3 g cm(-3)). Two different pesticide extraction approaches were compared: (i) C-14-pesticide residues were measured in the pore water (PW) which was extracted from soil by centrifugation; (ii) C-14-pesticide residues were extracted from soil samples with an excess of water (EEW). We introduce the pesticide's in situ mass distribution quotient (iMDQ) as a measure for pesticide bioavailability, which is calculated as a quotient of adsorbed and dissolved chemical amounts for both approaches (iMDQ(PW), iMDQ(EEW)). Pesticide mineralization in soils served as a reference for real microbial availability. A highly significant correlation between iMDQ(PW) and mineralization showed that PW extraction is adequate to assess IPU bioavailability. In contrast, no correlation exists between IPU mineralization and ist extractability from soil with EEW. Therefore, it can be concluded that soil equilibration at comparable conditions and subsequent PW extraction is vital for a isoproturon bioavailability ranking of soils

    AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome.

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    EBV, a member of the herpes virus family, is a paradigm for human tumor viruses and a model of viral latency amenable for study in vitro. It induces resting human B lymphocytes to proliferate indefinitely in vitro and initially establishes a strictly latent infection in these cells. BZLF1, related to the cellular activating protein 1 (AP-1) family of transcription factors, is the viral master gene essential and sufficient to mediate the switch to induce the EBV lytic phase in latently infected B cells. Enigmatically, after infection BZLF1 is expressed very early in the majority of primary B cells, but its early expression fails to induce the EBV lytic phase. We show that the early expression of BZLF1 has a critical role in driving the proliferation of quiescent naïve and memory B cells but not of activated germinal center B cells. BZLF1's initial failure to induce the EBV lytic phase relies on the viral DNA at first being unmethylated. We have found that the eventual and inevitable methylation of viral DNA is a prerequisite for productive infection in stably, latently infected B cells which then yield progeny virus lacking cytosine-phosphatidyl-guanosine (CpG) methylation. This progeny virus then can repeat EBV's epigenetically regulated, biphasic life cycle. Our data indicate that the viral BZLF1 protein is crucial both to establish latency and to escape from it. Our data also indicate that EBV has evolved to appropriate its host's mode of methylating DNA for its own epigenetic regulation

    Born normalization for fluorescence optical projection tomography for whole heart imaging.

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    Optical projection tomography is a three-dimensional imaging technique that has been recently introduced as an imaging tool primarily in developmental biology and gene expression studies. The technique renders biological sample optically transparent by first dehydrating them and then placing in a mixture of benzyl alcohol and benzyl benzoate in a 2:1 ratio (BABB or Murray s Clear solution). The technique renders biological samples optically transparent by first dehydrating them in graded ethanol solutions then placing them in a mixture of benzyl alcohol and benzyl benzoate in a 2:1 ratio (BABB or Murray s Clear solution) to clear. After the clearing process the scattering contribution in the sample can be greatly reduced and made almost negligible while the absorption contribution cannot be eliminated completely. When trying to reconstruct the fluorescence distribution within the sample under investigation, this contribution affects the reconstructions and leads, inevitably, to image artifacts and quantification errors.. While absorption could be reduced further with a permanence of weeks or months in the clearing media, this will lead to progressive loss of fluorescence and to an unrealistically long sample processing time. This is true when reconstructing both exogenous contrast agents (molecular contrast agents) as well as endogenous contrast (e.g. reconstructions of genetically expressed fluorescent proteins)

    MicroRNAs in brain development and physiology.

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    The crucial role of microRNAs (miRNAs) in brain development is demonstrated by the dramatic apoptotic phenotypes of mouse mutants abolishing all miRNAs synthesis. Recent advances in Caenorhabditis elegans, Drosophila, zebrafish and mouse moved beyond this global understanding by targeting selected miRNAs. They indicate that single miRNAs successively modulate all steps of brain maturation, including patterning, neurogenesis, neuronal differentiation and subtype specification, and neuronal activity. In detail, they reveal an amazing functional complexity: specific miRNAs can either be used reiteratively, such as miR-9 in patterning, neurogenesis and differentiation, or concomitantly target different mRNAs in distinct cellular compartments, such as Pumilio or Limk1 that can be inhibited by miR-134 to control neuritogenesis or spine growth, respectively. Their regulation can be composite, either through multiple loci (miR-9) or in blocks of numerous miRNAs (miR-134). A major step remains to decipher their impact on brain function, in particular in the control of behaviour

    On linear dependence to the initial state for a class of nonstationary cryptodeterministic processes.

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    A one-dimensional version of the Koksma-Hlawka inequality is used to obtain autocovariance bounds for a class of nonstationary stochastic processes generated by the evolution of discrete-time chaotic dynamical systems from a random initial state
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