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  • 1
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    Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells [Vaccines and Antiviral Agents] (2015)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2015-05-06
    Description: Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen. Human vaccine recipients responded to the peptide sequences identified by LC-MS/MS. Peptides derived from the conserved HIV-1 regions were readily detected as early as 1.5 h after MVA.HIVconsv infection. Four of the seven conserved peptides were monitored between 0 and 3.5 h of infection by using quantitative mass spectrometry (Q-MS), and their abundance in HLA class I associations reflected levels of the whole HIVconsv protein in the cell. While immunopeptides delivered by the incoming MVA vector proteins could be detected, all early HIVconsv-derived immunopeptides were likely synthesized de novo . MVA.HIVconsv infection generally altered the composition of HLA class I-associated human (self) peptides, but these changes corresponded only partially to changes in the whole cell host protein abundance. IMPORTANCE The vast changes in cellular antigen presentation after infection of cells with a vectored vaccine, as shown here for MVA.HIVconsv, highlight the complexity of factors that need to be considered for efficient antigen delivery and presentation. Identification and quantitation of HLA class I-associated peptides by Q-MS will not only find broad application in T-cell epitope discovery but also inform vaccine design and allow evaluation of efficient epitope presentation using different delivery strategies.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 2
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    Ecto-5'-Nucleotidase (CD73) Deficiency in Mycobacterium tuberculosis-Infected Mice Enhances Neutrophil Recruitment [Host Response and Inflammation] (2015)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2015-08-13
    Description: The immune system needs safeguards that prevent collateral tissue damage mediated by the immune system while enabling an effective response against a pathogen. The purinergic pathway is one such mechanism and finely modulates inflammation by sensing nucleotides in the environment. Extracellular ATP is considered to be a danger signal leading to a proinflammatory response, whereas adenosine is immunosuppressive. CD73, also called ecto-5'-nucleotidase, occupies a strategic position in this pathway, as it is the main enzyme responsible for the generation of adenosine from ATP. Here, we explore the role of CD73 during tuberculosis, a disease characterized by an immune response that is harmful to the host and unable to eradicate Mycobacterium tuberculosis . Using CD73 knockout (KO) mice, we found that CD73 regulates the response to M. tuberculosis infection in vitro and in vivo . Mycobacterium-infected murine macrophages derived from CD73 KO mice secrete more keratinocyte chemoattractant (KC), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) and release less vascular endothelial growth factor (VEGF) upon ATP stimulation than do those derived from wild-type (WT) mice. In vivo , CD73 limits the early influx of neutrophils to the lungs without affecting bacterial growth and dissemination. Collectively, our results support the view that CD73 fine-tunes antimycobacterial immune responses.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 3
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    In Vivo Efficacy of Ceftaroline Fosamil in a Methicillin-Resistant Panton-Valentine Leukocidin-Producing Staphylococcus aureus Rabbit Pneumonia Model [Experimental Therapeutics] (2014)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2014-03-19
    Description: Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
    Published by The American Society for Microbiology (ASM)
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  • 4
    Electronic Resource
    Electronic Resource
    MYOGENIC REGULATORY FACTORS AND THE SPECIFICATION OF MUSCLE PROGENITORS IN VERTEBRATE EMBRYOS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 747-783 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Embryological and genetic studies of mouse, bird, zebrafish, and frog embryos are providing new insights into the regulatory functions of the myogenic regulatory factors, MyoD, Myf5, Myogenin, and MRF4, and the transcriptional and signaling mechanisms that control their expression during the specification and differentiation of muscle progenitors. Myf5 and MyoD genes have genetically redundant, but developmentally distinct regulatory functions in the specification and the differentiation of somite and head muscle progenitor lineages. Myogenin and MRF4 have later functions in muscle differentiation, and Pax and Hox genes coordinate the migration and specification of somite progenitors at sites of hypaxial and limb muscle formation in the embryo body. Transcription enhancers that control Myf5 and MyoD activation in muscle progenitors and maintain their expression during muscle differentiation have been identified by transgenic analysis. In epaxial, hypaxial, limb, and head muscle progenitors, Myf5 is controlled by lineage-specific transcription enhancers, providing evidence that multiple mechanisms control progenitor specification at different sites of myogenesis in the embryo. Developmental signaling ligands and their signal transduction effectors function both interactively and independently to control Myf5 and MyoD activation in muscle progenitor lineages, likely through direct regulation of their transcription enhancers. Future investigations of the signaling and transcriptional mechanisms that control Myf5 and MyoD in the muscle progenitor lineages of different vertebrate embryos can be expected to provide a detailed understanding of the developmental and evolutionary mechanisms for anatomical muscles formation in vertebrates. This knowledge will be a foundation for development of stem cell therapies to repair diseased and damaged muscles.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105758
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  • 5
    Electronic Resource
    Electronic Resource
    BIODIVERSITY OF STREAM INSECTS:Variation at Local, Basin, and Regional Scales1 (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Entomology 43 (1998), S. 271-293 
    Details
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Abstract We review the major conceptual developments that have occurred over the last 50 years concerning the factors that influence insect biodiversity in streams and examine how well empirical descriptions and theory match. Stream insects appear to respond to both spatial and temporal variation in physical heterogeneity. At all spatial scales, the data largely support the idea that physical complexity promotes biological richness, although exceptions to this relationship were found. These exceptions may be related to how we measure habitat complexity at finer spatial scales and to factors that influence regional richness, such as biogeographic history, at broader spatial scales. However, the degree to which local stream insect assemblages are influenced by regional processes is largely unknown.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.ento.43.1.271
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    Paper (German National Licenses)
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  • 6
    Electronic Resource
    Electronic Resource
    NALTREXONE IN THE TREATMENT OF ALCOHOLISM (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 48 (1997), S. 477-487 
    Details
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Abstract Alcoholism affects nearly 12.5 million Americans and is responsible for annual costs of over $130 billion from loss of job productivity, deleterious health effects, and direct treatment expenses. Research on treating alcoholism from the standpoint of relapse prevention using psychosocial interventions alone has produced only modest results. Studies on the efficacy of adjunctive medications using multiple medications in placebo-controlled and open trials combined with psychosocial interventions have shown mixed results. Recently, a safe and well-tolerated opiate antagonist, naltrexone, was approved by the Food and Drug Administration (FDA) for the adjunctive treatment of alcoholism. This review describes the pertinent preclinical and clinical research that led to the FDA's approval. Details are provided describing the subjects, methods, and results of the two pivotal human studies that led to the FDA review for this indication. Clinical therapeutic guidelines, appropriate patient selection, and future directions are also elucidated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.med.48.1.477
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