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  • 1
    Electronic Resource
    Electronic Resource
    Quaternary Ammonium Salts from Halogenated Alkyl Dimethylamines. III. Omega-Bromo-Heptyl-, -Octyl-, -Nonyl- and -Decyl-dimethylamines (1933)
    s.l. : American Chemical Society
    Journal of the American Chemical Society 55 (1933), S. 1977-1981 
    Details
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/ja01332a030
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    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Rearrangements of Polyynes. VII.1 Formation of Allenes (1935)
    s.l. : American Chemical Society
    Journal of the American Chemical Society 57 (1935), S. 2619-2623 
    Details
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/ja01315a090
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Global wire routing in two-dimensional arrays (1987)
    Springer
    Algorithmica 2 (1987), S. 113-129 
    Details
    ISSN: 1432-0541
    Keywords: Global routing ; Gate arrays ; Integer programming ; Linear programming ; Computer-aided design for integrated circuits
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Mathematics
    Notes: Abstract We examine the problem of routing wires of a VLSI chip, where the pins to be connected are arranged in a regular rectangular array. We obtain tight bounds for the worst-case “channel-width” needed to route ann×n array, and develop provably good heuristics for the general case. Single-turn routings are proved to be near-optimal in the worst-case. A central result of our paper is a “rounding algorithm” for obtaining integral approximations to solutions of linear equations. Given a matrix A and a real vector x, then we can find an integral x such that for alli, ¦x i -x i ¦ 〈1 and (Ax) i -(Ax) i 〈Δ. Our error bound Δ is defined in terms of sign-segregated column sums of A: $$\Delta = \mathop {\max }\limits_j \left( {\max \left\{ {\sum\limits_{i:a_{ij} 〉 0} {a_{ij} ,} \sum\limits_{i:a_{ij}〈 0} { - a_{ij} } } \right\}} \right).$$
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01840353
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  • 4
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    Magnitude of the Magnetic Exchange Interaction in the Heavy-Fermion Antiferromagnet CeRhIn_{5} (2014)
    American Physical Society (APS)
    Details
    Publication Date: 2014-12-10
    Description: Author(s): Pinaki Das, S.-Z. Lin, N. J. Ghimire, K. Huang, F. Ronning, E. D. Bauer, J. D. Thompson, C. D. Batista, G. Ehlers, and M. Janoschek We have used high-resolution neutron spectroscopy experiments to determine the complete spin wave spectrum of the heavy-fermion antiferromagnet CeRhIn 5 . The spin wave dispersion can be quantitatively reproduced with a simple frustrated J 1 -J 2 model that also naturally explains the magnetic spin-spira... [Phys. Rev. Lett. 113, 246403] Published Mon Dec 08, 2014
    Keywords: Condensed Matter: Electronic Properties, etc.
    Print ISSN: 0031-9007
    Electronic ISSN: 1079-7114
    Topics: Physics
    Published by American Physical Society (APS)
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  • 5
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    Metabolites of PPI-2458, a Selective, Irreversible Inhibitor of Methionine Aminopeptidase-2: Structure Determination and In Vivo Activity [Articles] (2013)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2013-03-14
    Description: The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N -[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ~ 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ([(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N -(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 6
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    Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization [Genome Replication and Regulation of Viral Gene Expression] (2013)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2013-11-20
    Description: Full-length genomic DNA of the recently identified laboratory mouse papillomavirus 1 (MusPV1) was synthesized in vitro and was used to establish and characterize a mouse model of papillomavirus pathobiology. MusPV1 DNA, whether naked or encapsidated by MusPV1 or human papillomavirus 16 (HPV 16) capsids, efficiently induced the outgrowth of papillomas as early as 3 weeks after application to abraded skin on the muzzles and tails of athymic NCr nude mice. High concentrations of virions were extracted from homogenized papillomatous tissues and were serially passaged for 〉10 generations. Neutralization by L1 antisera confirmed that infectious transmission was capsid mediated. Unexpectedly, the skin of the murine back was much less susceptible to virion-induced papillomas than the muzzle or tail. Although reporter pseudovirions readily transduced the skin of the back, infection with native MusPV1 resulted in less viral genome amplification and gene expression on the back, including reduced expression of the L1 protein and very low expression of the L2 protein, results that imply skin region-specific control of postentry aspects of the viral life cycle. Unexpectedly, L1 protein on the back was predominantly cytoplasmic, while on the tail the abundant L1 was cytoplasmic in the lower epithelial layers and nuclear in the upper layers. Nuclear localization of L1 occurred only in cells that coexpressed the minor capsid protein, L2. The pattern of L1 protein staining in the infected epithelium suggests that L1 expression occurs earlier in the MusPV1 life cycle than in the life cycle of high-risk HPV and that virion assembly is regulated by a previously undescribed mechanism.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 7
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    Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+ T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge [Vaccines and Antivi (2014)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2014-12-17
    Description: No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8 + T cells that were able to secrete gamma interferon (IFN-) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8 + T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. IMPORTANCE Genital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 8
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    A Cell-Free Assembly System for Generating Infectious Human Papillomavirus 16 Capsids Implicates a Size Discrimination Mechanism for Preferential Viral Genome Packaging [Structure and Assembly] (2015)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2015-12-31
    Description: We have established a cell-free in vitro system to study human papillomavirus type 16 (HPV16) assembly, a poorly understood process. L1/L2 capsomers, obtained from the disassembly of virus-like particles (VLPs), were incubated with nuclear extracts to provide access to the range of cellular proteins that would be available during assembly within the host cell. Incorporation of a reporter plasmid "pseudogenome" was dependent on the presence of both nuclear extract and ATP. Unexpectedly, L1/L2 VLPs that were not disassembled prior to incubation with a reassembly mixture containing nuclear extract also encapsidated a reporter plasmid. As with HPV pseudoviruses (PsV) generated intracellularly, infection by cell-free particles assembled in vitro required the presence of L2 and was susceptible to the same biochemical inhibitors, implying the cell-free assembled particles use the infectious pathway previously described for HPV16 produced in cell culture. Using biochemical and electron microscopy analyses, we observed that, in the presence of nuclear extract, intact VLPs partially disassemble, providing a mechanistic explanation to how the exogenous plasmid was packaged by these particles. Further, we provide evidence that capsids containing an 〈8-kb pseudogenome are resistant to the disassembly/reassembly reaction. Our results suggest a novel size discrimination mechanism for papillomavirus genome packaging in which particles undergo iterative rounds of disassembly/reassembly, seemingly sampling DNA until a suitably sized DNA is encountered, resulting in the formation of a stable virion structure. IMPORTANCE Little is known about papillomavirus assembly biology due to the difficulties in propagating virus in vitro . The cell-free assembly method established in this paper reveals a new mechanism for viral genome packaging and will provide a tractable system for further dissecting papillomavirus assembly. The knowledge gained will increase our understanding of virus-host interactions, help to identify new targets for antiviral therapy, and allow for the development of new gene delivery systems based on in vitro -generated papillomavirus vectors.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 9
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    Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism [Virus-Cell Interactions] (2017)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2017-04-29
    Description: In this study, we report that gamma interferon (IFN-) treatment, but not IFN-α, -β, or - treatment, dramatically decreased infection of human papillomavirus 16 (HPV16) pseudovirus (PsV). In a survey of 20 additional HPV and animal papillomavirus types, we found that many, but not all, PsV types were also inhibited by IFN-. Microscopic and biochemical analyses of HPV16 PsV determined that the antiviral effect was exerted at the level of endosomal processing of the incoming capsid and depended on the JAK2/STAT1 pathway. In contrast to infection in the absence of IFN-, where L1 proteolytic products are produced during endosomal capsid processing and L2/DNA complexes segregate from L1 in the late endosome and travel to the nucleus, IFN- treatment led to decreased L1 proteolysis and retention of L2 and the viral genome in the late endosome/lysosome. PsV sensitivity or resistance to IFN- treatment was mapped to the L2 protein, as determined with infectious hybrid PsV, in which the L1 protein was derived from an IFN--sensitive HPV type and the L2 protein from an IFN--insensitive type or vice versa. IMPORTANCE A subset of HPV are the causative agents of many human cancers, most notably cervical cancer. This work describes the inhibition of infection of multiple HPV types, including oncogenic types, by treatment with IFN-, an antiviral cytokine that is released from stimulated immune cells. Exposure of cells to IFN- has been shown to trigger the expression of proteins with broad antiviral effector functions, most of which act to prevent viral transcription or translation. Interestingly, in this study, we show that infection is blocked at the early step of virus entry into the host cell by retention of the minor capsid protein, L2, and the viral genome instead of trafficking into the nucleus. Thus, a novel antiviral mechanism for IFN- has been revealed.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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  • 10
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    Identification of a Role for the trans-Golgi Network in Human Papillomavirus 16 Pseudovirus Infection [Virus-Cell Interactions] (2013)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2013-03-09
    Description: Human papillomavirus 16 (HPV16) enters its host cells by a process that most closely resembles macropinocytosis. Uncoating occurs during passage through the endosomal compartment, and the low pH encountered in this environment is essential for infection. Furin cleavage of the minor capsid protein, L2, and cyclophilin B-mediated separation of L2 and the viral genome from the major capsid protein, L1, are necessary for escape from the late endosome (LE). Following this exodus, L2 and the genome are found colocalized at the ND10 nuclear subdomain, which is essential for efficient pseudogenome expression. However, the route by which L2 and the genome traverse the intervening cytoplasm between these two subcellular compartments has not been determined. This study extends our understanding of this phase in PV entry in demonstrating the involvement of the Golgi complex. With confocal microscopic analyses involving 5-ethynyl-2'-deoxyuridine (EdU)-labeled pseudogenomes and antibodies to virion and cellular proteins, we found that the viral pseudogenome and L2 travel to the trans -Golgi network (TGN) following exit from the LE, while L1 is retained. This transit is dependent upon furin cleavage of L2 and can be prevented pharmacologically with either brefeldin A or golgicide A, inhibitors of anterograde and retrograde Golgi trafficking. Additionally, Rab9a and Rab7b were determined to be mediators of this transit, as expression of dominant negative versions of these proteins, but not Rab7a, significantly inhibited HPV16 pseudovirus infection.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
    Published by The American Society for Microbiology (ASM)
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