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Artikel ; Online: Sequence determinants of GLUT1-mediated accelerated-exchange transport: analysis by homology-scanning mutagenesis.

Vollers, Sabrina S / Carruthers, Anthony

2012 Band 287, Heft 51, Seite(n) 42533–42544

Abstract: The class 1 equilibrative glucose transporters GLUT1 and GLUT4 are structurally similar but catalyze distinct modes of transport. GLUT1 exhibits trans-acceleration, in which the presence of intracellular sugar stimulates the rate of unidirectional sugar ... ...

Abstract	The class 1 equilibrative glucose transporters GLUT1 and GLUT4 are structurally similar but catalyze distinct modes of transport. GLUT1 exhibits trans-acceleration, in which the presence of intracellular sugar stimulates the rate of unidirectional sugar uptake. GLUT4-mediated uptake is unaffected by intracellular sugar. Using homology-scanning mutagenesis in which domains of GLUT1 are substituted with equivalent domains from GLUT4 and vice versa, we show that GLUT1 transmembrane domain 6 is both necessary and sufficient for trans-acceleration. This region is not directly involved in GLUT1 binding of substrate or inhibitors. Rather, transmembrane domain 6 is part of two putative scaffold domains, which coordinate membrane-spanning amphipathic helices that form the sugar translocation pore. We propose that GLUT1 transmembrane domain 6 restrains import when intracellular sugar is absent by slowing transport-associated conformational changes.
Mesh-Begriff(e)	Amino Acid Sequence ; Biocatalysis ; Biological Transport ; Carbohydrate Metabolism ; Cell Membrane/metabolism ; Deoxyglucose/metabolism ; Glucose Transporter Type 1/chemistry ; Glucose Transporter Type 1/metabolism ; Glucose Transporter Type 4/chemistry ; Glucose Transporter Type 4/metabolism ; HEK293 Cells ; Humans ; Kinetics ; Models, Biological ; Molecular Sequence Data ; Mutagenesis/genetics ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Protein Structure, Tertiary ; Sequence Alignment ; Sequence Homology, Amino Acid ; Structure-Activity Relationship
Chemische Substanzen	Glucose Transporter Type 1 ; Glucose Transporter Type 4 ; Mutant Proteins ; Deoxyglucose (9G2MP84A8W)
Sprache	Englisch
Erscheinungsdatum	2012-10-23
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.369587
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Class II major histocompatibility complex tetramer staining: progress, problems, and prospects.

Vollers, Sabrina S / Stern, Lawrence J

Immunology

2008 Band 123, Heft 3, Seite(n) 305–313

Abstract: The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4+ T cells ...

Abstract	The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4+ T cells centred around difficulties in the expression of various class II MHC allelic variants and the detection of low-frequency T cells in mixed populations. As many of the technical obstacles to class II MHC tetramer staining have been overcome, the focus has returned to uncertainties concerning how oligomer valency and T-cell receptor/MHC affinity affect tetramer binding. Such issues have become more important with an increase in the number of studies relying on direct ex vivo analysis of antigen-specific CD4+ T cells. In this review we discuss which problems in class II MHC tetramer staining have been solved to date, and which matters remain to be considered.
Mesh-Begriff(e)	Antibody Affinity ; CD4-Positive T-Lymphocytes/immunology ; Flow Cytometry/methods ; Histocompatibility Antigens Class II/analysis ; Histocompatibility Antigens Class II/immunology ; Humans ; Staining and Labeling/methods
Chemische Substanzen	Histocompatibility Antigens Class II
Sprache	Englisch
Erscheinungsdatum	2008-02-05
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2007.02801.x
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Class II major histocompatibility complex tetramer staining: progress, problems, and prospects

Vollers, Sabrina S / Stern, Lawrence J

Immunology. 2008 Mar., v. 123, no. 3

2008

Abstract	The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4⁺ T cells centred around difficulties in the expression of various class II MHC allelic variants and the detection of low-frequency T cells in mixed populations. As many of the technical obstacles to class II MHC tetramer staining have been overcome, the focus has returned to uncertainties concerning how oligomer valency and T-cell receptor/MHC affinity affect tetramer binding. Such issues have become more important with an increase in the number of studies relying on direct ex vivo analysis of antigen-specific CD4⁺ T cells. In this review we discuss which problems in class II MHC tetramer staining have been solved to date, and which matters remain to be considered.
Schlagwörter	flow cytometry
Sprache	Englisch
Erscheinungsverlauf	2008-03
Umfang	p. 305-313.
Verlag	Blackwell Publishing Ltd
Erscheinungsort	Oxford, UK
Dokumenttyp	Artikel
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2007.02801.x
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen.

Sesterhenn, Fabian / Galloux, Marie / Vollers, Sabrina S / Csepregi, Lucia / Yang, Che / Descamps, Delphyne / Bonet, Jaume / Friedensohn, Simon / Gainza, Pablo / Corthésy, Patricia / Chen, Man / Rosset, Stéphane / Rameix-Welti, Marie-Anne / Éléouët, Jean-François / Reddy, Sai T / Graham, Barney S / Riffault, Sabine / Correia, Bruno E

PLoS biology

2019 Band 17, Heft 2, Seite(n) e3000164

Abstract: Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, ... ...

Abstract	Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.
Mesh-Begriff(e)	Animals ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Neutralizing/genetics ; Antibodies, Viral/biosynthesis ; Antibodies, Viral/genetics ; Cloning, Molecular ; Computer-Aided Design ; Epitopes/chemistry ; Epitopes/immunology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Female ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Immunization/methods ; Immunogenicity, Vaccine ; Mice ; Mice, Inbred BALB C ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Palivizumab/chemistry ; Palivizumab/immunology ; Receptors, Antigen, B-Cell/chemistry ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/immunology ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Respiratory Syncytial Virus Vaccines/administration & dosage ; Respiratory Syncytial Virus Vaccines/biosynthesis ; Respiratory Syncytial Virus Vaccines/genetics ; Respiratory Syncytial Viruses/immunology ; Structural Homology, Protein ; Viral Fusion Proteins/administration & dosage ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/genetics ; Viral Fusion Proteins/immunology
Chemische Substanzen	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Receptors, Antigen, B-Cell ; Recombinant Fusion Proteins ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins ; motavizumab (50Y163LK8Q) ; Palivizumab (DQ448MW7KS)
Sprache	Englisch
Erscheinungsdatum	2019-02-21
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000164
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Determination of Peptide oligomerization state using rapid photochemical crosslinking.

Vollers, Sabrina S / Teplow, David B / Bitan, Gal

Methods in molecular biology (Clifton, N.J.)

2005 Band 299, Seite(n) 11–18

Abstract: The assembly of the amyloid beta-protein (Abeta) into neurotoxic oligomers and fibrils is a seminal pathogenic process in Alzheimer's disease (AD). Understanding the mechanisms of Abeta assembly could prove useful in the identification of therapeutic ... ...

Abstract	The assembly of the amyloid beta-protein (Abeta) into neurotoxic oligomers and fibrils is a seminal pathogenic process in Alzheimer's disease (AD). Understanding the mechanisms of Abeta assembly could prove useful in the identification of therapeutic targets. Owing to the metastable nature of Abeta oligomers, it is difficult to obtain interpretable data through application of classical methods, such as electrophoresis, chromatography, fluorescence, and light scattering. Here, we apply the method Photo-Induced Crosslinking of Unmodified Proteins (PICUP) to the study of Abeta oligomerization. This method directly produces covalent bonds among unmodified polypeptide chains through in situ generation of peptide free radicals. PICUP provides a snapshot of the native oligomerization state of proteins and can be used for assembly state analysis of a wide variety of peptides and proteins.
Mesh-Begriff(e)	Amyloid beta-Peptides/analysis ; Amyloid beta-Peptides/chemistry ; Organometallic Compounds ; Photochemistry/instrumentation ; Photochemistry/methods ; Photolysis
Chemische Substanzen	Amyloid beta-Peptides ; Organometallic Compounds ; tris(2,2'-bipyridyl)ruthenium(II)
Sprache	Englisch
Erscheinungsdatum	2005-09-01
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1385/1-59259-874-9:011
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Author Correction: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Giordano-Attianese, Greta / Gainza, Pablo / Gray-Gaillard, Elise / Cribioli, Elisabetta / Shui, Sailan / Kim, Seonghoon / Kwak, Mi-Jeong / Vollers, Sabrina / Corria Osorio, Angel De Jesus / Reichenbach, Patrick / Bonet, Jaume / Oh, Byung-Ha / Irving, Melita / Coukos, George / Correia, Bruno E

Nature biotechnology

2020 Band 38, Heft 4, Seite(n) 503

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Sprache	Englisch
Erscheinungsdatum	2020-03-04
Erscheinungsland	United States
Dokumenttyp	Published Erratum
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-020-0461-z
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Nature biotechnology

2020 Band 38, Heft 4, Seite(n) 426–432

Abstract: Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically ... ...

Abstract	Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
Mesh-Begriff(e)	Cell Engineering ; Cells, Cultured ; Humans ; Immunotherapy, Adoptive ; Jurkat Cells ; Lymphocyte Activation/drug effects ; PC-3 Cells ; Protein Binding ; Protein Engineering ; Protein Multimerization ; Receptors, Antigen, T-Cell/antagonists & inhibitors ; Receptors, Antigen, T-Cell/chemistry ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/antagonists & inhibitors ; Receptors, Chimeric Antigen/chemistry ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Signal Transduction ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemische Substanzen	Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Small Molecule Libraries
Sprache	Englisch
Erscheinungsdatum	2020-02-03
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-019-0403-9
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: De novo protein design enables the precise induction of RSV-neutralizing antibodies.

Sesterhenn, Fabian / Yang, Che / Bonet, Jaume / Cramer, Johannes T / Wen, Xiaolin / Wang, Yimeng / Chiang, Chi-I / Abriata, Luciano A / Kucharska, Iga / Castoro, Giacomo / Vollers, Sabrina S / Galloux, Marie / Dheilly, Elie / Rosset, Stéphane / Corthésy, Patricia / Georgeon, Sandrine / Villard, Mélanie / Richard, Charles-Adrien / Descamps, Delphyne /

Delgado, Teresa / Oricchio, Elisa / Rameix-Welti, Marie-Anne / Más, Vicente / Ervin, Sean / Eléouët, Jean-François / Riffault, Sabine / Bates, John T / Julien, Jean-Philippe / Li, Yuxing / Jardetzky, Theodore / Krey, Thomas / Correia, Bruno E

Science (New York, N.Y.)

2020 Band 368, Heft 6492

Abstract: De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses ... ...

Abstract	De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.
Mesh-Begriff(e)	Amino Acid Motifs ; Antibodies, Neutralizing/biosynthesis ; Computational Biology/methods ; Humans ; Immunodominant Epitopes/chemistry ; Immunodominant Epitopes/immunology ; Protein Conformation ; Protein Engineering/methods ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/immunology ; Respiratory Syncytial Virus Vaccines/chemistry ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/immunology ; Single-Domain Antibodies/chemistry ; Single-Domain Antibodies/immunology
Chemische Substanzen	Antibodies, Neutralizing ; Immunodominant Epitopes ; Recombinant Fusion Proteins ; Respiratory Syncytial Virus Vaccines ; Single-Domain Antibodies
Sprache	Englisch
Erscheinungsdatum	2020-06-24
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aay5051
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization.

Bitan, Gal / Vollers, Sabrina S / Teplow, David B

The Journal of biological chemistry

2003 Band 278, Heft 37, Seite(n) 34882–34889

Abstract: Assembly of monomeric amyloid beta-protein (A beta) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight A beta 40 and A beta 42 can be assessed ... ...

Abstract	Assembly of monomeric amyloid beta-protein (A beta) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight A beta 40 and A beta 42 can be assessed quantitatively using the technique of photo-induced cross-linking of unmodified proteins. This approach revealed that low molecular weight A beta 40 is a mixture of monomer, dimer, trimer, and tetramer, in rapid equilibrium, whereas low molecular weight A beta 42 preferentially exists as pentamer/hexamer units (paranuclei), which self-associate to form larger oligomers. Here, photo-induced cross-linking of unmodified proteins was used to evaluate systematically the oligomerization of 34 physiologically relevant A beta alloforms, including those containing familial Alzheimer's disease-linked amino acid substitutions, naturally occurring N-terminal truncations, and modifications altering the charge, the hydrophobicity, or the conformation of the peptide. The most important structural feature controlling early oligomerization was the length of the C terminus. Specifically, the side-chain of residue 41 in A beta 42 was important both for effective formation of paranuclei and for self-association of paranuclei into larger oligomers. The side-chain of residue 42, and the C-terminal carboxyl group, affected paranucleus self-association. A beta 40 oligomerization was particularly sensitive to substitutions of Glu22 or Asp23 and to truncation of the N terminus, but not to substitutions of Phe19 or Ala21. A beta 42 oligomerization, in contrast, was largely unaffected by substitutions at positions 22 or 23 or by N-terminal truncations, but was affected significantly by substitutions of Phe19 or Ala21. These results reveal how specific regions and residues control A beta oligomerization and show that these controlling elements differ between A beta 40 and A beta 42.
Mesh-Begriff(e)	Alzheimer Disease/pathology ; Amino Acid Sequence ; Amyloid beta-Peptides/chemistry ; Dimerization ; Humans ; Molecular Weight
Chemische Substanzen	Amyloid beta-Peptides
Sprache	Englisch
Erscheinungsdatum	2003-07-02
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M300825200
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen.

Fabian Sesterhenn / Marie Galloux / Sabrina S Vollers / Lucia Csepregi / Che Yang / Delphyne Descamps / Jaume Bonet / Simon Friedensohn / Pablo Gainza / Patricia Corthésy / Man Chen / Stéphane Rosset / Marie-Anne Rameix-Welti / Jean-François Éléouët / Sai T Reddy / Barney S Graham / Sabine Riffault / Bruno E Correia

PLoS Biology, Vol 17, Iss 2, p e

2019 Band 3000164

Abstract	Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.
Schlagwörter	Biology (General) ; QH301-705.5
Thema/Rubrik (Code)	570
Sprache	Englisch
Erscheinungsdatum	2019-02-01T00:00:00Z
Verlag	Public Library of Science (PLoS)
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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