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  • 1
    Keywords: Forschungsbericht
    Type of Medium: Online Resource
    Pages: 1 Online-Ressource (50 Seiten, 3,42 MB) , Illustrationen, Diagramme
    Language: German
    Note: Förderkennzeichen BMBF 03MAI03F. - Verbund-Nummer 01120126 , Unterschiede zwischen dem gedruckten Dokument und der elektronischen Ressource können nicht ausgeschlossen werden , Mit deutscher Zusammenfassung
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  • 2
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 18 (1997), S. 723-743 
    ISSN: 0192-8651
    Keywords: Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A Monte Carlo docking procedure that combines random displacements of the substrate and protein side chains with minimization of the enzyme - substrate complex is described and applied to finding the binding mode of the blocked tetrapeptide N-acetyl-Leu-Pro-Phe-methylamide to the FK506 binding protein (FKBP). The tetrapeptide, an analog of the preferred FKBP substrate, and the FKBP binding site are flexible during the docking procedure. The twisted-imide transition-state form of the substrate is used during docking. The enzyme charges are scaled individually to account for solvent screening of specific binding site residues during the Monte Carlo sampling. To evaluate the relative binding free energies of the resulting structures, a rapid method for calculating polar and nonpolar solvation effects is introduced. Accurate electrostatic solute - solvent energies are calculated by solving the finite-difference linearized Poisson - Boltzmann equation; nonpolar contributions to the stability of the different conformers are estimated by the free energy of cavity formation, which is obtained from the molecular surface, and the solute - solvent van der Waals energy, which is calculated with a continuum approach. In the conformation of the enzyme - substrate complex with the lowest free energy, the tetrapeptide is bound as a type VIa proline turn with solvent accessible ends to permit longer polypeptide chains to act as substrates. Except for the imide carbonyl, which is involved in polar interactions with aromatic side chains of the FKBP binding site, all of the seven potential hydrogen bond donors or acceptors of the tetrapeptide are satisfied. The FKBP binding site has a similar conformation in the substrate complex as in the FKBP-FK506 cocrystal structure, except for the predicted reorientation of the Tyr 82 hydroxyl, which plays an important role in substrate binding. The present model for the FKBP - substrate complex is in agreement with the recently determined crystal structure of a cyclic peptide - FK506 hybrid bound to FKBP and supports the structure obtained previously by iterative model building. In addition, it is consistent with the observed effects of FKBP point mutations on the enzyme activity. The approach described here should be useful, in general, for the prediction of the structure of a molecule in solution or as part of a complex. It provides for the effective sampling of conformational space and for the inclusion of solvent effects. © 1997 by John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 3
    Publication Date: 2014-05-14
    Description: Obtaining functional information on the human lung is of tremendous interest in the characterization of lung defects and pathologies. However, pulmonary ventilation and perfusion maps usually require contrast agents and the application of electrocardiogram (ECG) triggering and breath holds to generate datasets free of motion artifacts. This work demonstrates the possibility of obtaining highly resolved perfusion-weighted and ventilation-weighted images of the human lung using proton MRI and the SElf-gated Non-Contrast-Enhanced FUnctional Lung imaging (SENCEFUL) technique. The SENCEFUL technique utilizes a two-dimensional fast low-angle shot (FLASH) sequence with quasi-random sampling of phase-encoding (PE) steps for data acquisition. After every readout, a short additional acquisition of the non-phase-encoded direct current (DC) signal necessary for self-gating was added. By sorting the quasi-randomly acquired data according to respiratory and cardiac phase derived from the DC signal, datasets of representative respiratory and cardiac cycles could be accurately reconstructed. By application of the Fourier transform along the temporal dimension, functional maps (perfusion and ventilation) were obtained. These maps were compared with dynamic contrast-enhanced (DCE, perfusion) as well as standard Fourier decomposition (FD, ventilation) reference datasets. All datasets were additionally scored by two experienced radiologists to quantify image quality. In addition, one initial patient examination using SENCEFUL was performed. Functional images of healthy volunteers and a patient diagnosed with hypoplasia of the left pulmonary artery and left-sided pulmonary fibrosis were successfully obtained. Perfusion-weighted images corresponded well to DCE-MRI data; ventilation-weighted images offered a significantly better depiction of the lung periphery compared with standard FD. Furthermore, the SENCEFUL technique hints at a potential clinical relevance by successfully detecting a perfusion defect in the patient scan. It can be concluded that SENCEFUL enables highly resolved ventilation- and perfusion-weighted maps of the human lung to be obtained using proton MRI, and might be interesting for further clinical evaluation. Copyright © 2014 John Wiley & Sons, Ltd. SElf-gated Non-Contrast-Enhanced FUnctional Lung imaging (SENCEFUL) is a non-contrast-enhanced technique to obtain highly resolved images of lung morphology, ventilation and perfusion. SENCFUL involves the acquisition of the direct current (DC) self-gating signal which was additionally recorded during imaging in free breathing without electrocardiogram (ECG) triggering. The data are retrospectively sorted according to the DC signal, thereby obtaining time-resolved datasets of cardiac and respiratory motion, which allow the calculation of qualitative functional lung maps by applying the Fourier transform, similar to Fourier decomposition.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 4
    Publication Date: 2013-08-07
    Description: Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural IFN-α-producing (NIP) cells. Here, we describe two functionally distinct pDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1 − pDCs are mainly found in the bone marrow, appear first during development, show a higher proliferative activity and represent the more precursor phenotype. Sca-1 + pDCs are mostly located in secondary lymphoid organs and represent a later developmental stage. Sca-1 − pDCs give rise to a Sca-1 + subset upon activation or in response to endogenous type I IFN. Interestingly, in contrast to Sca-1 − pDCs, Sca-1 + pDCs are defective in IFN-α production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin (Opn) is strongly upregulated in Sca-1 − pDCs. These data provide evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of Opn couples TLR9 signaling to IFN-α expression. Taken together, our results indicate that Sca-1 − pDCs are an early developmental stage of pDCs with distinct innate functions representing the true murine NIP cell.
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 5
    Publication Date: 2018-01-25
    Description: In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK + NSCLC) patients with a worse outcome, who might require novel therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2, V3 as detected by next-generation sequencing (NGS) or RT-PCR (n=67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p=0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p=0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p=0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p=0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p=0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK + NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
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  • 6
    Publication Date: 2014-12-19
    Description: Background: Members of the urokinase-type plasminogen activator (uPA) system including uPA, its receptor uPAR and the plasminogen activator inhibitor 1 (PAI-1) play an important role in tumour invasion and progression in a variety of tumour types. Since the majority of clear cell renal cell carcinoma (ccRCC) shows distant metastasis at time of diagnosis or later, the interplay of uPA, uPAR and PAI-1 might be of importance in this process determining the patients' outcome. Methods: Corresponding pairs of malignant and non-malignant renal tissue specimens were obtained from 112 ccRCC patients without distant metastasis who underwent tumour nephrectomy. Tissue extracts prepared from fresh-frozen tissue samples by detergent extraction were used for the determination of antigen levels of uPA, uPAR and PAI-1 by ELISA. Antigen levels were normalised to protein concentrations and expressed as ng per mg of total protein. Results: Antigen levels of uPA, uPAR, and PAI-1 correlated with each other in the malignant tissue specimens (rs=0.51-0.65; all P
    Electronic ISSN: 1471-2407
    Topics: Medicine
    Published by BioMed Central
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  • 7
    Publication Date: 2018-05-31
    Description: Sustainability, Vol. 10, Pages 1800: Morphology Dependent Assessment of Resilience for Urban Areas Sustainability doi: 10.3390/su10061800 Authors: Kai Fischer Stefan Hiermaier Werner Riedel Ivo Häring The formation of new threats and the increasing complexity of urban built infrastructures underline the need for more robust and sustainable systems, which are able to cope with adverse events. Achieving sustainability requires the strengthening of resilience. Currently, a comprehensive approach for the quantification of resilience of urban infrastructure is missing. Within this paper, a new generalized mathematical framework is presented. A clear definition of terms and their interaction builds the basis of this resilience assessment scheme. Classical risk-based as well as additional components are aligned along the timeline before, during and after disruptive events, to quantify the susceptibility, the vulnerability and the response and recovery behavior of complex systems for multiple threat scenarios. The approach allows the evaluation of complete urban surroundings and enables a quantitative comparison with other development plans or cities. A comprehensive resilience framework should cover at least preparation, prevention, protection, response and recovery. The presented approach determines respective indicators and provides decision support, which enhancement measures are more effective. Hence, the framework quantifies for instance, if it is better to avoid a hazardous event or to tolerate an event with an increased robustness. An application example is given to assess different urban forms, i.e., morphologies, with consideration of multiple adverse events, like terrorist attacks or earthquakes, and multiple buildings. Each urban object includes a certain number of attributes, like the object use, the construction type, the time-dependent number of persons and the value, to derive different performance targets. The assessment results in the identification of weak spots with respect to single resilience indicators. Based on the generalized mathematical formulation and suitable combination of indicators, this approach can quantify the resilience of urban morphologies, independent of possible single threat types and threat locations.
    Electronic ISSN: 2071-1050
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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