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Berlin Brandenburg

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  • 1
    Language: English
    In: 2014, Vol.9(7), p.e102664
    Description: Transcutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. However, the feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity. ; To overcome these obstacles, we developed an imiquimod-containing emulsion gel (IMI-Gel) and characterized it in comparison to Aldara for rheological properties and mouse skin permeation in a Franz diffusion cell system. Imiquimod was readily released from Aldara, while IMI-Gel showed markedly decreased drug release. Nevertheless, comparing vaccination potency of Aldara or IMI-Gel-based TCI in C57BL/6 mice against the model cytotoxic T-lymphocyte epitope SIINFEKL, we found that IMI-Gel was equally effective in terms of the frequency of peptide-specific T-cells and cytolytic activity. Importantly, transcutaneous delivery of IMI-Gel for vaccination was clearly superior to the subcutaneous or oral route of administration. Finally, IMI-Gel based TCI was at least equally effective compared to Aldara-based TCI in rejection of established SIINFEKL-expressing E.G7 tumors in a therapeutic setup indicated by enhanced tumor rejection and survival. ; In summary, we developed a novel imiquimod formulation with feasible pharmaceutical properties and immunological efficacy that fosters the rational design of a next generation transcutaneous vaccination platform suitable for the treatment of cancer or persistent virus infections.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences ; Physical Sciences ; Research And Analysis Methods
    E-ISSN: 1932-6203
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  • 2
    In: Nature, 2011, Vol.477(7364), p.335
    Description: Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum (1). In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium (2). Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans (3). However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp[8.sup.[DELTA]IEC]]) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp[8.sup.[DELTA]IEC]] mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-a, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-[alpha]-induced necroptotic cell death.
    Keywords: Cysteine Proteinases -- Health Aspects ; Epithelial Cells -- Health Aspects ; Intestinal Diseases -- Causes Of ; Intestinal Diseases -- Care And Treatment ; Tumor Necrosis Factor -- Health Aspects;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Food Chemistry, 01 May 2013, Vol.138(1), pp.263-269
    Description: ► Purification protocol of lipid transfer proteins from wine and grapes. ► Vinification does not cause notable structural changes of lipid transfer protein. ► Resistance of lipid transfer protein to acidic and alcoholic environment of wine. ► LTP may not lose the allergenic potential as experienced for grape LTP. Lipid transfer proteins (LTP) play a major role in plant defence and are of particular interest due to their known ability to cause allergic reactions. These proteins are expressed in grapes and also remain detectable after vinification, especially in red wine. However, it remains unknown whether the protein undergoes any changes during the vinification process. Here, we present a purification method for LTPs from Dornfelder grapes and wine. By liquid-chromatography–mass spectroscopy (LC–MS/MS) we identified LTPs from two different species ( and ). Additionally, the purified LTPs were characterised using spectrometric methods, confirming their high purity and structural stability during vinification. We conclude that LTPs are resistant to the alcohol content (13.5 vol%), acidic milieu of wine and other ingredients present during the vinification process, indicating that the allergenic potential of grape LTP is not diminished by the vinification process.
    Keywords: Lipid Transfer Protein ; Circular Dichroism ; LC–MS/MS ; Red Wine ; Grape ; Chemistry ; Diet & Clinical Nutrition ; Economics
    ISSN: 0308-8146
    E-ISSN: 1873-7072
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  • 4
    In: PLoS ONE, 2017, Vol.12(12)
    Description: Studying folding and assembly of naturally occurring α-helical transmembrane proteins can inspire the design of membrane proteins with defined functions. Thus far, most studies have focused on the role of membrane-integrated protein regions. However, to fully understand folding pathways and stabilization of α–helical membrane proteins, it is vital to also include the role of soluble loops. We have analyzed the impact of interhelical loops on folding, assembly and stability of the heme-containing four-helix bundle transmembrane protein cytochrome b 6 that is involved in charge transfer across biomembranes. Cytochrome b 6 consists of two transmembrane helical hairpins that sandwich two heme molecules. Our analyses strongly suggest that the loop connecting the helical hairpins is not crucial for positioning the two protein “halves” for proper folding and assembly of the holo-protein. Furthermore, proteolytic removal of any of the remaining two loops, which connect the two transmembrane helices of a hairpin structure, appears to also not crucially effect folding and assembly. Overall, the transmembrane four-helix bundle appears to be mainly stabilized via interhelical interactions in the transmembrane regions, while the soluble loop regions guide assembly and stabilize the holo-protein. The results of this study might steer future strategies aiming at designing heme-binding four-helix bundle structures, involved in transmembrane charge transfer reactions.
    Keywords: Research Article ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Physical Sciences ; Biology And Life Sciences ; Biology And Life Sciences
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: 2012, Vol.7(8), p.e43685
    Description: Nicotinic acetylcholine receptors (nAChR) play important neurophysiological roles and are of considerable medical relevance. They have been studied extensively, greatly facilitated by the gastropod acetylcholine-binding proteins (AChBP) which represent soluble structural and functional homologues of the ligand-binding domain of nAChR. All these proteins are ring-like pentamers. Here we report that AChBP exists in the hemolymph of the planorbid snail Biomphalaria glabrata (vector of the schistosomiasis parasite) as a regular pentagonal dodecahedron, 22 nm in diameter (12 pentamers, 60 active sites). We sequenced and recombinantly expressed two ∼25 kDa polypeptides ( Bg AChBP1 and Bg AChBP2) with a specific active site, N-glycan site and disulfide bridge variation. We also provide the exon/intron structures. Recombinant Bg AChBP1 formed pentamers and dodecahedra, recombinant Bg AChBP2 formed pentamers and probably disulfide-bridged di-pentamers, but not dodecahedra. Three-dimensional electron cryo-microscopy (3D-EM) yielded a 3D reconstruction of the dodecahedron with a resolution of 6 Å. Homology models of the pentamers docked to the 6 Å structure revealed opportunities for chemical bonding at the inter-pentamer interfaces. Definition of the ligand-binding pocket and the gating C-loop in the 6 Å structure suggests that 3D-EM might lead to the identification of functional states in the Bg AChBP dodecahedron.
    Keywords: Research Article ; Biology ; Computational Biology ; Physiology ; Biophysics ; Biochemistry
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: PLoS ONE, July 15, 2014, Vol.9(7)
    Description: Background Transcutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. However, the feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity. Methodology/Principal Findings To overcome these obstacles, we developed an imiquimod-containing emulsion gel (IMI-Gel) and characterized it in comparison to Aldara for rheological properties and in vitro mouse skin permeation in a Franz diffusion cell system. Imiquimod was readily released from Aldara, while IMI-Gel showed markedly decreased drug release. Nevertheless, comparing vaccination potency of Aldara or IMI-Gel-based TCI in C57BL/6 mice against the model cytotoxic T-lymphocyte epitope SIINFEKL, we found that IMI-Gel was equally effective in terms of the frequency of peptide-specific T-cells and in vivo cytolytic activity. Importantly, transcutaneous delivery of IMI-Gel for vaccination was clearly superior to the subcutaneous or oral route of administration. Finally, IMI-Gel based TCI was at least equally effective compared to Aldara-based TCI in rejection of established SIINFEKL-expressing E.G7 tumors in a therapeutic setup indicated by enhanced tumor rejection and survival. Conclusion/Significance In summary, we developed a novel imiquimod formulation with feasible pharmaceutical properties and immunological efficacy that fosters the rational design of a next generation transcutaneous vaccination platform suitable for the treatment of cancer or persistent virus infections.
    Keywords: Peptides – Analysis ; Antigenic Determinants – Analysis ; T Cells – Analysis ; Imiquimod – Analysis ; House Mouse – Analysis ; Hostages – Analysis ; Vaccination – Analysis
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: Food Chemistry, 15 September 2015, Vol.183, pp.49-57
    Description: Polyphenoloxidases (PPO) of the type-3 copper protein family are considered to be catecholoxidases catalyzing the oxidation of -diphenols to their corresponding quinones. PPO from Grenache grapes has recently been reported to display only diphenolase activity. In contrast, we have characterized PPOs from Dornfelder and Riesling grapes which display both monophenolase and diphenolase activity. Ultracentrifugation and size exclusion chromatography indicated that both PPOs occur as monomers with of about 38 kDa. Non-reducing SDS–PAGE shows two bands of about 38 kDa exhibiting strong activity. Remarkably, three bands up to 60 kDa displayed only very weak PPO activity, supporting the hypothesis that the C-terminal domain covers the entrance to the active site. Molecular dynamic analysis indicated that the hydroxyl group of monophenolic substrates can bind to CuA after the flexible but sterically hindering Phe 259 swings away on a picosecond time scale.
    Keywords: Polyphenoloxidase ; Tyrosinase Activity ; Grapes ; Riesling ; Dornfelder ; Chemistry ; Diet & Clinical Nutrition ; Economics
    ISSN: 0308-8146
    E-ISSN: 1873-7072
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  • 8
    Language: English
    In: Food Chemistry, Sept 15, 2015, Vol.183, p.49(9)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.foodchem.2015.03.016 Byline: Petra Fronk, Hermann Hartmann, Margarita Bauer, Even Solem, Elmar Jaenicke, Stefan Tenzer, Heinz Decker Abstract: * Grape PPOs (Dornfelder and Riesling) exhibit monophenolase and diphenolase activity. * Grape PPOs occur as monomers. * Monophenols can bind to CuA after a conserved phenylalanine residue swings away. Article History: Received 21 October 2014; Revised 6 March 2015; Accepted 7 March 2015 Article Note: (footnote) [star] "The Handling Editor, Dr Melton, allows this manuscript to contain more than 40 references. Please see the note left by the Editorial Office in the Manuscript details. Kindly re-assign the manuscript to the HE."
    Keywords: Wine ; Grapes
    ISSN: 0308-8146
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: Gastroenterology, May 2014, Vol.146(5), pp.S-348-S-349
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
    Source: ScienceDirect Journals (Elsevier)
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  • 10
    Language: English
    In: Analytical chemistry, 18 April 2017, Vol.89(8), pp.4474-4479
    Description: To have confidence in results acquired during biological mass spectrometry experiments, a systematic approach to quality control is of vital importance. Nonetheless, until now, only scattered initiatives have been undertaken to this end, and these individual efforts have often not been complementary. To address this issue, the Human Proteome Organization-Proteomics Standards Initiative has established a new working group on quality control at its meeting in the spring of 2016. The goal of this working group is to provide a unifying framework for quality control data. The initial focus will be on providing a community-driven standardized file format for quality control. For this purpose, the previously proposed qcML format will be adapted to support a variety of use cases for both proteomics and metabolomics applications, and it will be established as an official PSI format. An important consideration is to avoid enforcing restrictive requirements on quality control but instead provide the basic technical necessities required to support extensive quality control for any type of mass spectrometry-based workflow. We want to emphasize that this is an open community effort, and we seek participation from all scientists with an interest in this field.
    Keywords: Qualitätssteuerung Und -Regelung ; Proteomik ; Arbeitsgemeinschaft ; Proteom ; Massenspektrometrie ; Dateiformat ; Engineering ; Chemistry;
    ISSN: 00032700
    E-ISSN: 1520-6882
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