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  • 1
    Online Resource
    Online Resource
    Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
    American Society for Microbiology ; 2017
    In:  Antimicrobial Agents and Chemotherapy Vol. 61, No. 9 ( 2017-09)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 61, No. 9 ( 2017-09)
    Abstract: Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC 50 ], 〈 0.09 to 0.71 nM) and RSV-B (IC 50 , 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro . In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC 50 , 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00737-17
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    The Immunologically Distinct O Antigens from Francisella tularensis Subspecies tularensis and Francisella novicida Are both Virulence Determinants and Protective Antigens
    American Society for Microbiology ; 2007
    In:  Infection and Immunity Vol. 75, No. 1 ( 2007-01), p. 371-378
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 75, No. 1 ( 2007-01), p. 371-378
    Abstract: We have determined the sequence of the gene cluster encoding the O antigen in Francisella novicida and compared it to the previously reported O-antigen cluster in Francisella tularensis subsp. tularensis . Immunization with purified lipopolysaccharide (LPS) from F. tularensis subsp. tularensis or F. novicida protected against challenge with Francisella tularensis subsp. holarctica and F. novicida , respectively. The LPS from F. tularensis subsp. tularensis did not confer protection against challenge with F. novicida , and the LPS from F. novicida did not confer protection against challenge with F. tularensis subsp. holarctica . Allelic replacement mutants of F. tularensis subsp. tularensis or F. novicida which failed to produce O antigen were attenuated, but exposure to these mutants did not induce a protective immune response. The O antigen of F. tularensis subsp. tularensis appeared to be important for intracellular survival whereas the O antigen of F. novicida appeared to be critical for serum resistance and less important for intracellular survival.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.01241-06
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2007
    detail.hit.zdb_id: 1483247-1
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  • 3
    Online Resource
    Online Resource
    One-Year Duration of Immunity Induced by Vaccination with a Canine Lyme Disease Bacterin
    American Society for Microbiology ; 2010
    In:  Clinical and Vaccine Immunology Vol. 17, No. 5 ( 2010-05), p. 870-874
    Details
    In: Clinical and Vaccine Immunology, American Society for Microbiology, Vol. 17, No. 5 ( 2010-05), p. 870-874
    Abstract: Laboratory-reared beagles were vaccinated with a placebo or a bacterin comprised of Borrelia burgdorferi S-1-10 and ospA -negative/ ospB -negative B. burgdorferi 50772 and challenged after 1 year with B. burgdorferi -infected Ixodes scapularis ticks. For the placebo recipients, spirochetes were recovered from 9 (60%) skin biopsy specimens collected after 1 month, and the organisms persisted in the skin thereafter. Ten (67%) dogs also developed joint infection (3 dogs), lameness or synovitis (7 dogs), or B. burgdorferi -specific antibodies (8 dogs). For the vaccine recipients, spirochetes were recovered from 6 (40%) skin biopsy specimens collected after 1 month. However, subsequent biopsy specimens were negative, and the dogs failed to develop joint infection ( P = 0.224), lameness/synovitis ( P = 0.006), or Lyme disease-specific antibody responses ( P = 0.002). The bacterin provided a high level of protection for 1 year after immunization, and the addition of the OspC-producing B. burgdorferi 50772 provided enhanced protection.
    Type of Medium: Online Resource
    ISSN: 1556-6811 , 1556-679X
    URL: Article
    DOI: 10.1128/CVI.00524-09
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2010
    detail.hit.zdb_id: 1496863-0
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  • 4
    Online Resource
    Online Resource
    Histone Modifications in Papillomavirus Virion Minichromosomes
    American Society for Microbiology ; 2021
    In:  mBio Vol. 12, No. 1 ( 2021-02-23)
    Details
    In: mBio, American Society for Microbiology, Vol. 12, No. 1 ( 2021-02-23)
    Abstract: An unusual feature of papillomaviruses is that their genomes are packaged into virions along with host histones. Viral minichromosomes were visualized as “beads on a string” by electron microscopy in the 1970s but, to date, little is known about the posttranslational modifications of these histones. To investigate this, we analyzed the histone modifications in HPV16/18 quasivirions, wart-derived bovine papillomavirus (BPV1), and wart-derived human papillomavirus type 1 (HPV1) using quantitative mass spectrometry. The chromatin from all three virion samples had abundant posttranslational modifications (acetylation, methylation, and phosphorylation). These histone modifications were verified by acid urea polyacrylamide electrophoresis and immunoblot analysis. Compared to matched host cell controls, the virion minichromosome was enriched in histone modifications associated with active chromatin and depleted for those commonly found in repressed chromatin. We propose that the viral minichromosome acquires specific histone modifications late in infection that are coupled to the mechanisms of viral replication, late gene expression, and encapsidation. We predict that, in turn, these same modifications benefit early stages of infection by helping to evade detection, promoting localization of the viral chromosome to beneficial regions of the nucleus, and promoting early transcription and replication. IMPORTANCE A relatively unique feature of papillomaviruses is that the viral genome is associated with host histones inside the virion. However, little is known about the nature of the epigenome within papillomavirions or its biological relevance to the infectious viral cycle. Here, we define the epigenetic signature of the H3 and H4 histones from HPV16 virions generated in cell culture and native human papillomavirus type 1 (HPV1) and bovine papillomavirus 1 (BPV1) virions isolated from bovine and human wart tissue. We show that native virions are enriched in posttranslational modifications associated with active chromatin and depleted with those associated with repressed chromatin compared to cellular chromatin. Native virions were also enriched in the histone variant H3.3 compared to the canonical histone H3.1. We propose that the composition of virion-packaged chromatin reflects the late stages of the viral life cycle and promotes the early stages of infection by being primed for viral transcription.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.03274-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2021
    detail.hit.zdb_id: 2557172-2
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  • 5
    Online Resource
    Online Resource
    Bacterin That Induces Anti-OspA and Anti-OspC Borreliacidal Antibodies Provides a High Level of Protection against Canine Lyme Disease
    American Society for Microbiology ; 2009
    In:  Clinical and Vaccine Immunology Vol. 16, No. 2 ( 2009-02), p. 253-259
    Details
    In: Clinical and Vaccine Immunology, American Society for Microbiology, Vol. 16, No. 2 ( 2009-02), p. 253-259
    Abstract: Groups of 15 laboratory-bred beagles were vaccinated and boosted with either a placebo or adjuvanted bivalent bacterin comprised of a traditional Borrelia burgdorferi strain and a unique ospA - and ospB -negative B. burgdorferi strain that expressed high levels of OspC and then challenged with B. burgdorferi -infected Ixodes scapularis ticks. The vaccinated dogs produced high titers of anti-OspA and anti-OspC borreliacidal antibodies, including borreliacidal antibodies specific for an epitope within the last seven amino acids at the OspC carboxy terminus (termed OspC7) that was conserved among pathogenic Borrelia genospecies. In addition, spirochetes were eliminated from the infected ticks that fed on the bacterin recipients, B. burgdorferi was not isolated from the skin or joints, and antibody responses associated specifically with canine infection with B. burgdorferi were not produced. In contrast, B. burgdorferi was recovered from engorged ticks that fed on 13 (87%) placebo-vaccinated dogs ( P 〈 0.0001), skin biopsy specimens from 14 (93%) dogs ( P 〈 0.0001), and joint tissue specimens from 8 (53%) dogs ( P = 0.0022). In addition, 14 (93%) dogs developed specific antibody responses against B. burgdorferi proteins, including 11 (73%) with C6 peptide antibodies ( P 〈 0.0001). Moreover, 10 (67%) dogs developed Lyme disease-associated joint abnormalities ( P 〈 0.0001), including 4 (27%) dogs that developed joint stiffness or lameness and 6 (40%) that developed chronic joint inflammation (synovitis). The results therefore confirmed that the bacterin provided a high level of protection against Lyme disease shortly after immunization.
    Type of Medium: Online Resource
    ISSN: 1556-6811 , 1556-679X
    URL: Article
    DOI: 10.1128/CVI.00373-08
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
    detail.hit.zdb_id: 1496863-0
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  • 6
    Online Resource
    Online Resource
    Student Attitudes Contribute to the Effectiveness of a Genomics CURE
    American Society for Microbiology ; 2022
    In:  Journal of Microbiology & Biology Education Vol. 23, No. 2 ( 2022-08-31)
    Details
    In: Journal of Microbiology & Biology Education, American Society for Microbiology, Vol. 23, No. 2 ( 2022-08-31)
    Abstract: The Genomics Education Partnership (GEP) engages students in a course-based undergraduate research experience (CURE). To better understand the student attributes that support success in this CURE, we asked students about their attitudes using previously published scales that measure epistemic beliefs about work and science, interest in science, and grit. We found, in general, that the attitudes students bring with them into the classroom contribute to two outcome measures, namely, learning as assessed by a pre- and postquiz and perceived self-reported benefits. While the GEP CURE produces positive outcomes overall, the students with more positive attitudes toward science, particularly with respect to epistemic beliefs, showed greater gains. The findings indicate the importance of a student’s epistemic beliefs to achieving positive learning outcomes.
    Type of Medium: Online Resource
    ISSN: 1935-7877 , 1935-7885
    URL: Article
    DOI: 10.1128/jmbe.00208-21
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2560245-7
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  • 7
    Online Resource
    Online Resource
    Facilitating Growth through Frustration: Using Genomics Research in a Course-Based Undergraduate Research Experience
    American Society for Microbiology ; 2020
    In:  Journal of Microbiology & Biology Education Vol. 21, No. 1 ( 2020-01)
    Details
    In: Journal of Microbiology & Biology Education, American Society for Microbiology, Vol. 21, No. 1 ( 2020-01)
    Abstract: A hallmark of the research experience is encountering difficulty and working through those challenges to achieve success. This ability is essential to being a successful scientist, but replicating such challenges in a teaching setting can be difficult. The Genomics Education Partnership (GEP) is a consortium of faculty who engage their students in a genomics Course-Based Undergraduate Research Experience (CURE). Students participate in genome annotation, generating gene models using multiple lines of experimental evidence. Our observations suggested that the students’ learning experience is continuous and recursive, frequently beginning with frustration but eventually leading to success as they come up with defendable gene models. In order to explore our “formative frustration” hypothesis, we gathered data from faculty via a survey, and from students via both a general survey and a set of student focus groups. Upon analyzing these data, we found that all three datasets mentioned frustration and struggle, as well as learning and better understanding of the scientific process. Bioinformatics projects are particularly well suited to the process of iteration and refinement because iterations can be performed quickly and are inexpensive in both time and money. Based on these findings, we suggest that a dynamic of “formative frustration” is an important aspect for a successful CURE.
    Type of Medium: Online Resource
    ISSN: 1935-7877 , 1935-7885
    URL: Article
    DOI: 10.1128/jmbe.v21i1.2005
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2560245-7
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  • 8
    Online Resource
    Online Resource
    Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum
    American Society for Microbiology ; 2013
    In:  Eukaryotic Cell Vol. 12, No. 9 ( 2013-09), p. 1171-1178
    Details
    In: Eukaryotic Cell, American Society for Microbiology, Vol. 12, No. 9 ( 2013-09), p. 1171-1178
    Abstract: Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen-activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression in P. falciparum .
    Type of Medium: Online Resource
    ISSN: 1535-9778 , 1535-9786
    URL: Article
    DOI: 10.1128/EC.00028-13
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2013
    detail.hit.zdb_id: 2071564-X
    SSG: 12
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  • 9
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    Online Resource
    Highly Pathological Influenza A Virus Infection Is Associated with Augmented Expression of PD-1 by Functionally Compromised Virus-Specific CD8 + T Cells
    American Society for Microbiology ; 2014
    In:  Journal of Virology Vol. 88, No. 3 ( 2014-02), p. 1636-1651
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 88, No. 3 ( 2014-02), p. 1636-1651
    Abstract: One question that continues to challenge influenza A research is why some strains of virus are so devastating compared to their more mild counterparts. We approached this question from an immunological perspective, investigating the CD8 + T cell response in a mouse model system comparing high- and low-pathological influenza virus infections. Our findings reveal that the early (day 0 to 5) viral titer was not the determining factor in the outcome of disease. Instead, increased numbers of antigen-specific CD8 + T cells and elevated effector function on a per-cell basis were found in the low-pathological infection and correlated with reduced illness and later-time-point (day 6 to 10) viral titer. High-pathological infection was associated with increased PD-1 expression on influenza virus-specific CD8 + T cells, and blockade of PD-L1 in vivo led to reduced virus titers and increased CD8 + T cell numbers in high- but not low-pathological infection, though T cell functionality was not restored. These data show that high-pathological acute influenza virus infection is associated with a dysregulated CD8 + T cell response, which is likely caused by the more highly inflamed airway microenvironment during the early days of infection. Therapeutic approaches specifically aimed at modulating innate airway inflammation may therefore promote efficient CD8 + T cell activity. IMPORTANCE We show that during a severe influenza virus infection, one type of immune cell, the CD8 T cell, is less abundant and less functional than in a more mild infection. This dysregulated T cell phenotype correlates with a lower rate of virus clearance in the severe infection and is partially regulated by the expression of a suppressive coreceptor called PD-1. Treatment with an antibody that blocks PD-1 improves T cell functionality and increases virus clearance.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02851-13
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
    detail.hit.zdb_id: 1495529-5
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  • 10
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    Online Resource
    Validation of a Novel Murine Wound Model of Acinetobacter baumannii Infection
    American Society for Microbiology ; 2014
    In:  Antimicrobial Agents and Chemotherapy Vol. 58, No. 3 ( 2014-03), p. 1332-1342
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 3 ( 2014-03), p. 1332-1342
    Abstract: Patients recovering from traumatic injuries or surgery often require weeks to months of hospitalization, increasing the risk for wound and surgical site infections caused by ESKAPE pathogens, which include A. baumannii (the ESKAPE pathogens are Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species). As new therapies are being developed to counter A. baumannii infections, animal models are also needed to evaluate potential treatments. Here, we present an excisional, murine wound model in which a diminutive inoculum of a clinically relevant, multidrug-resistant A. baumannii isolate can proliferate, form biofilms, and be effectively treated with antibiotics. The model requires a temporary, cyclophosphamide-induced neutropenia to establish an infection that can persist. A 6-mm-diameter, full-thickness wound was created in the skin overlying the thoracic spine, and after the wound bed was inoculated, it was covered with a dressing for 7 days. Uninoculated control wounds healed within 13 days, whereas infected, placebo-treated wounds remained unclosed beyond 21 days. Treated and untreated wounds were assessed with multiple quantitative and qualitative techniques that included gross pathology, weight loss and recovery, wound closure, bacterial burden, 16S rRNA community profiling, histopathology, peptide nucleic acid-fluorescence in situ hybridization, and scanning electron microscopy assessment of biofilms. The range of differences that we are able to identify with these measures in antibiotic- versus placebo-treated animals provides a clear window within which novel antimicrobial therapies can be assessed. The model can be used to evaluate antimicrobials for their ability to reduce specific pathogen loads in wounded tissues and clear biofilms. Ultimately, the mouse model approach allows for highly powered studies and serves as an initial multifaceted in vivo assessment prior to testing in larger animals.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01944-13
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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