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  • 1
    Publication Date: 2015-03-07
    Description: IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-B has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-B, IB NS , in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IB NS is crucial for murine Th17 cell generation. IB NS is highly expressed in Th17 cells; in the absence of IB NS , the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IB NS –/– Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IB NS –/– mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IB NS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 2
    Publication Date: 2015-10-09
    Description: Objective Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited. Design Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network. Results We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments. Conclusions In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 3
    Publication Date: 2016-01-05
    Description: In this issue, Paul and colleagues' meta-analysis examines the risk for HBV reactivation with and without antiviral prophylaxis and its effectiveness in adults with solid tumors and chronic or resolved HBV infection. The editorialists discuss the findings and their implications for pretreatment HBV screening and prophylaxis.
    Print ISSN: 0003-4819
    Electronic ISSN: 1539-3704
    Topics: Medicine
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  • 4
    Publication Date: 2015-08-26
    Description: Lakes are major depositional systems for which the related depositional processes have long been considered relatively simple. Breaking this statement, this study presents a detailed analysis of deposits in Lake Saint-Jean, the third largest natural lake in Québec. In addition to postglacial deltaic and coastal depositional systems fringing the lake, current-controlled features such as a large subaqueous prograding wedge and three sediment drifts have been identified in its central portion based on two-dimensional (2-D) acoustic high-resolution subbottom profiles. The large subaqueous prograding wedge is a 4-km-long and up to 15-m-thick heterolithic shelf-like construction in the southeastern part of the lake. The three sediment drifts are 0.1–0.5-km-long and 2–5-m-thick mud mounds distributed on the lake floor in the central portion of the lake. Diatom analyses and radiocarbon dating show that the development of these current-controlled features occurred during the lacustrine phase, after the disconnection with the postglacial marine Laflamme Gulf at 8.5 cal. k.y. B.P. Depositional facies show evidence of recurrent bottom-current activity. Related deposits alternate with pelagic sedimentation stages characterized by the settling of mud and biogenic accumulations. We investigated the origin of bottom currents using a numerical simulation (SYMPHONIE, an oceanographic model), with the aim of modeling wind-induced lake-scale water circulation. Simulations suggest that the subaqueous prograding wedge and the three sediment drifts result from wind-induced bottom currents generated by storm events having wind speed greater than 10 m s –1 . Such strong winds are able to significantly affect sedimentation in the central portion of Lake Saint-Jean. The resulting wind-induced sedimentary features were integrated into a refined lacustrine depositional model that summarizes the evolution of a group of water bodies referred to as "wind-driven water bodies." This study applies a new tool for lake strata characterization and highlights the potential difficulty in differentiating them from marine deposits in the geological record.
    Print ISSN: 0016-7606
    Electronic ISSN: 1943-2674
    Topics: Geosciences
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  • 5
    Publication Date: 2016-04-07
    Description: The multifaceted functions of C/EBPα in normal and malignant haematopoiesis Leukemia 30, 767 (April 2016). doi:10.1038/leu.2015.324 Authors: E Ohlsson, M B Schuster, M Hasemann & B T Porse
    Print ISSN: 0887-6924
    Electronic ISSN: 1476-5551
    Topics: Medicine
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  • 6
    Publication Date: 2018-06-05
    Description: Electrifying model catalysts for understanding electrocatalytic reactions in liquid electrolytes Electrifying model catalysts for understanding electrocatalytic reactions in liquid electrolytes, Published online: 04 June 2018; doi:10.1038/s41563-018-0088-3 Fundamental understanding of electrocatalysis is key to a transition to renewable energy systems. A strategy to ‘electrify’ complex oxide-based model catalysts is now proposed to explore electrocatalytic reactions in liquid electrolytes.
    Print ISSN: 1476-1122
    Electronic ISSN: 1476-4660
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 7
    Publication Date: 2017-07-25
    Description: Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IB NS are important regulators of Foxp3 induction in Treg precursors upon -chain cytokine stimulation. In c-REL/IB NS double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IB NS are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IB NS are required for T cell effector function as well. Analyzing Treg development in more detail, we identified a CD122 + subset within the CD25 – Foxp3 – precursor population, which gave rise to classical CD25 + Foxp3 – Treg precursors. Importantly, c-REL, but not IB NS , controlled the generation of classical CD25 + Foxp3 – precursors via direct binding to the Cd25 locus. Thus, we propose that CD4 + GITR + CD122 + CD25 – Foxp3 – cells represent a Treg pre-precursor population, whose transition into Treg precursors is mediated via c-REL.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2015-01-06
    Description: About two thirds of laryngeal cancers originate at the vocal cords. Early-stage detection of malignant vocal fold alterations, including a discrimination of premalignant lesions, represents a major challenge in laryngology as precancerous vocal fold lesions and small carcinomas are difficult to distinguish by means of regular endoscopy only. We report a procedure to discriminate between malignant and precancerous lesions by measuring the characteristics of vocal fold dynamics by means of a computerized analysis of laryngeal high-speed videos. Ten patients with squamous cell T1a carcinoma, ten with precancerous lesions with hyperkeratosis, and ten subjects without laryngeal disease underwent high-speed laryngoscopy yielding 4,000 images per second. By means of wavelet-based phonovibrographic analysis, a set of three clinically meaningful vibratory measures was extracted from the videos comprising a total number of 15,000 video frames. Statistical analysis (ANOVA with post hoc two-sided t tests, P 〈 0.05) revealed that vocal fold dynamics is significantly affected in the presence of precancerous lesions and T1a carcinoma. On the basis of the three measures, a discriminating pattern was extracted using a support vector machine-learning algorithm performing an individual classification in respect to the different clinical groups. By applying a leave-one-out cross-validation strategy, we could show that the proposed measures discriminate with a very high performance between precancerous lesions and T1a carcinoma (sensitivity, 100%; specificity, 100%). Although a large-scale study will be necessary to confirm clinical significance, the set of vibratory measures derived in this study may be applicable to improve the accuracy and reliability of noninvasive diagnostics of vocal fold lesions. Cancer Res; 75(1); 31–39. ©2014 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 9
    Publication Date: 2016-01-22
    Description: Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2 -V617F in 〉90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL -S204P, a germline MPL -V285E mutation, and a germline JAK2 -G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2 -V625F and JAK2 -F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders.
    Keywords: Free Research Articles, Myeloid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2015-07-12
    Description: Key components of the translational apparatus, i.e. ribosomes, elongation factor EF-Tu and most aminoacyl-tRNA synthetases, are stereoselective and prevent incorporation of d -amino acids ( d -aa) into polypeptides. The rare appearance of d -aa in natural polypeptides arises from post-translational modifications or non-ribosomal synthesis. We introduce an in vitro translation system that enables single incorporation of 17 out of 18 tested d -aa into a polypeptide; incorporation of two or three successive d -aa was also observed in several cases. The system consists of wild-type components and d -aa are introduced via artificially charged, unmodified tRNA Gly that was selected according to the rules of ‘thermodynamic compensation’. The results reveal an unexpected plasticity of the ribosomal peptidyltransferase center and thus shed new light on the mechanism of chiral discrimination during translation. Furthermore, ribosomal incorporation of d -aa into polypeptides may greatly expand the armamentarium of in vitro translation towards the identification of peptides and proteins with new properties and functions.
    Keywords: Synthetic Biology and Assembly Cloning, Ribosomes and Protein Translation
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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