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  • 1
    Publication Date: 2015-07-09
    Print ISSN: 1045-2249
    Electronic ISSN: 1465-7279
    Topics: Biology
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  • 2
    Publication Date: 2013-01-03
    Description: The spectra of several high-redshift ( z 〉 6) quasars have shown indications for a Gunn–Peterson (GP) damping wing, suggesting a substantial mean neutral hydrogen fraction ( $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\gtrsim 0.03$ ) in the z 6 intergalactic medium (IGM). However, previous analyses assumed that the IGM was uniformly ionized outside of the quasar’s H  ii region. Here we relax this assumption and model patchy reionization scenarios for a range of IGM and quasar parameters. Compared to uniform reionization, patchy reionization imprints a different average damping wing profile with an associated sightline-to-sightline scatter. We quantify the impact of these differences on the inferred $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}$ , by fitting the spectra of three quasars: SDSS J1148+5251 ( z = 6.4189), J1030+0524 ( z = 6.308) and J1623+3112 ( z = 6.247). We find that the best-fitting values of $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}$ in the patchy models agree well with the uniform case. More importantly, we confirm that the observed spectra favour the presence of a GP damping wing, with peak likelihoods decreasing by factors of few–10 when the spectra are modelled without a damping wing. We also find that the Lyα absorption spectra, by themselves, cannot distinguish the damping wing in a relatively neutral IGM from a damping wing in a highly ionized IGM, caused either by an isolated neutral patch or by a damped Lyα absorber (DLA). However, neutral patches in a highly ionized universe ( $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\lesssim 10^{-2}$ ) and DLAs with the large required column densities ( $N_{\rm H\,{\small I}}\gtrsim {\rm { few}}\times 10^{20}{\rm { cm}^{-2}}$ ) are both rare. As a result, when we include reasonable prior probabilities for the line of sight (LOS) to intercept either a neutral patch or a DLA at the required distance of ~ 40-60 comoving Mpc away from the quasar, we find strong lower limits on the neutral fraction in the IGM, $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\gtrsim 0.1$ (at 95 per cent confidence). This supports earlier claims that a substantial global fraction of hydrogen in the z 6 IGM is in neutral form.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 3
    Publication Date: 2012-09-06
    Description: Nonpigmented Yersinia pestis ( pgm ) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout ( Hjv –/– ) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis . Unlike wild-type mice, Hjv –/– mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv –/– mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
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  • 4
    Publication Date: 2016-03-11
    Description: Evidence shows that factor VIII (FVIII) ectopically expressed in platelets (2bF8) is therapeutic in FVIII null mice even with anti-FVIII inhibitory antibodies (inhibitors). If current efforts to generate platelets in vitro succeed, genetically manipulated platelets containing FVIII may be used therapeutically in hemophilia A patients with inhibitors. One important concern is the immunogenicity of platelet-derived FVIII. To address this concern, we infused 2bF8 transgenic (2bF8 Tg ) platelets into naïve FVIII null mice weekly for 8 weeks. No anti-FVIII antibodies were detected in the infused animals during the study course. We then explored whether platelet-derived FVIII is immunogenic in FVIII null mice with inhibitors. The 2bF8 Tg platelets were transfused into rhF8-primed FVIII null mice, resulting in no augmentation of anti-FVIII antibodies. To investigate whether preconditioning affects the immune response, animals were sublethally irradiated and subsequently transfused with 2bF8 Tg platelets. No anti-FVIII antibodies were detected in the recipients after platelet infusions. Following further challenge with rhF8, the inhibitor titer in this group was significantly lower than in naïve FVIII null mice utilizing the same immunization protocol. Thus, our data demonstrate that infusion of platelets containing FVIII triggers neither primary nor memory anti-FVIII immune response in FVIII null mice and that sublethal irradiation plus 2bF8 Tg platelet infusion suppresses anti-FVIII immune response in FVIII null mice.
    Keywords: Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2016-02-16
    Description: We employed a semi-Markov multistate model for the simultaneous analysis of various endpoints describing the course of breast cancer. Results were compared with those from standard analyses using a Cox proportional hazards model. We included 3,012 patients with invasive breast cancer newly diagnosed between 2001 and 2005 who were recruited in Germany for a population-based study, the Mamma Carcinoma Risk Factor Investigation (MARIE Study), and prospectively followed up until the end of 2009. Locoregional recurrence and distant metastasis were included as intermediate states, and deaths from breast cancer, secondary cancer, and other causes were included as competing absorbing states. Tumor characteristics were significantly associated with all breast cancer–related endpoints. Nodal involvement was significantly related to local recurrence but more strongly related to distant metastases. Smoking was significantly associated with mortality from second cancers and other causes, whereas menopausal hormone use was significantly associated with reduced distant metastasis and death from causes other than cancer. The presence of cardiovascular disease at diagnosis was solely associated with mortality from other causes. Compared with separate Cox models, multistate models allow for dissection of prognostic factors and intermediate events in the analysis of cause-specific mortality and can yield new insights into disease progression and associated pathways.
    Print ISSN: 0002-9262
    Electronic ISSN: 1476-6256
    Topics: Medicine
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  • 6
    Publication Date: 2012-08-15
    Description: Aims Dynamic three-dimensional-cardiac magnetic resonance (3D-CMR) perfusion proved highly diagnostic for the detection of angiographically defined coronary artery disease (CAD) and has been used to assess the efficacy of coronary stenting procedures. The present study aimed to relate significant coronary lesions as assessed by fractional flow reserve (FFR) to the volume of myocardial hypoenhancement on 3D-CMR adenosine stress perfusion imaging and to define the inter-study reproducibility of stress inducible 3D-CMR hypoperfusion. Methods and results A total of 120 patients with known or suspected CAD were examined in two CMR centres using 1.5 T systems. The protocol included cine imaging, 3D-CMR perfusion during adenosine infusion, and at rest followed by delayed enhancement (DE) imaging. Fractional flow reserve was recorded in epicardial coronary arteries and side branches with ≥2 mm luminal diameter and 〉40% severity stenosis (pathologic FFR 〈 0.75). Twenty-five patients underwent an identical repeat CMR examination for the determination of inter-study reproducibility of 3D-CMR perfusion deficits induced by adenosine. Three-dimensional CMR perfusion scans were visually classified as pathologic if one or more segments showed an inducible perfusion deficit in the absence of DE. Myocardial ischaemic burden (MIB) was measured by segmentation of the area of inducible hypoenhancement and normalized to left ventricular myocardial volume (MIB, %). Three-dimensional CMR perfusion resulted in a sensitivity, specificity, and diagnostic accuracy of 90, 82, and 87%, respectively. Substantial concordance was found for inter-study reproducibility [Lin's correlation coefficient: 0.98 (95% confidence interval: 0.96–0.99)]. Conclusion Three-dimensional CMR stress perfusion provided high diagnostic accuracy for the detection of functionally significant CAD. Myocardial ischaemic burden measurements were highly reproducible and allowed the assessment of CAD severity.
    Print ISSN: 0195-668X
    Electronic ISSN: 1522-9645
    Topics: Medicine
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  • 7
    Publication Date: 2014-01-17
    Description: Our previous studies have demonstrated that platelet FVIII (2bF8) gene therapy can improve hemostasis in hemophilia A mice, even in the presence of inhibitory antibodies, but none of our studies has targeted human cells. Here, we evaluated the feasibility for lentivirus (LV)-mediated human platelet gene therapy of hemophilia A. Human platelet FVIII expression was introduced by 2bF8LV-mediated transduction of human cord blood (hCB) CD34 + cells followed by xenotransplantation into immunocompromised NSG mice or NSG mice in an FVIII null background (NSGF8KO). Platelet FVIII was detected in all recipients that received 2bF8LV-transduced hCB cells as long as human platelet chimerism persisted. All NSGF8KO recipients (n = 7) that received 2bF8LV-transduced hCB cells survived tail clipping if animals had greater than 2% of platelets derived from 2bF8LV-transduced hCB cells, whereas 5 of 7 survived when human platelets were 0.3% to 2%. Whole blood clotting time analysis confirmed that hemostasis was improved in NSGF8KO mice that received 2bF8LV-transduced hCB cells. We demonstrate, for the first time, the feasibility of 2bF8LV gene delivery to human hematopoietic stem cells to introduce FVIII expression in human platelets and that human platelet–derived FVIII can improve hemostasis in hemophilia A.
    Keywords: Thrombosis and Hemostasis, Gene Therapy
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2014-04-29
    Description: Potassium (K + )-uptake transport proteins present in prokaryote and eukaryote cells are categorized into two classes; Trk/Ktr/HKT, K + channel, and Kdp belong to the same superfamily, whereas the remaining K + -uptake family, Kup/HAK/KT has no homology to the others, and neither its membrane topology nor crucial residues for K + uptake have been identified. We examined the topology of Kup from Escherichia coli . Results from the reporter fusion and cysteine labeling assays support a model with 12 membrane-spanning domains. A model for proton-coupled K + uptake mediated by Kup has been proposed. However, this study did not show any stimulation of Kup activity at low pH and any evidence of involvement of the three His in Kup-mediated K + uptake. Moreover, replacement of all four cysteines of Kup with serine did not abolish K + transport activity. To gain insight on crucial residues of Kup-mediated K + uptake activity, we focused on acidic residues in the predicted external and transmembrane regions, and identified four residues in the membrane regions required for K + uptake activity. This is different from no membrane-localized acidic residues essential for Trk/Ktr/HKTs, K + channels and Kdp. Taken together, these results demonstrate that Kup belongs to a distinct type of K + transport system.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
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