bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenovirus IVa2 Protein Binds ATP
Authors: Ostapchuk Philomena , Hearing Patrick 
Published: July 2008

ABSTRACT

IVa2 is an essential, multifunctional protein of adenovirus (Ad) supporting packaging of the viral genome into the capsid, assisting in assembly of the capsid, and activating Ad late transcription. A comparison of IVa2 protein sequences from different species of
Adenoviridae
shows conserved motifs associated with binding and hydrolysis of ATP (Walker A and B motifs). ATPases are essential proteins of bacteriophage packaging motors, and such activity may be required for Ad packaging. Results presented here show that the Ad2 IVa2 protein binds ATP in vitro and that sequences in the Walker A and B motifs are necessary for this activity.
PPEY Motif within the Rabies Virus (RV) Matrix Protein Is Essential for Efficient Virion Release and RV Pathogenicity
Authors: Wirblich Christoph , Tan Gene S. , Papaneri Amy , Godlewski Peter J. , Orenstein Jan Marc , Harty Ronald N. , Schnell Matthias J. 
Published: July 2008

ABSTRACT

Late (L) domains containing the highly conserved sequence PPXY were first described for retroviruses, and later research confirmed their conservation and importance for efficient budding of several negative-stranded RNA viruses.
Rabies virus
(RV), a member of the
Rhabdoviridae
family, contains the sequence PPEY (amino acids 35 to 38) within the N terminus of the matrix (M) protein, but the functions of this potential L-domain in the viral life cycle, viral pathogenicity, and immunogenicity have not been established. Here we constructed a series of recombinant RVs containing mutations within the PPEY motif and analyzed their effects on viral replication and RV pathogenicity. Our results indicate that the first proline at position 35 is the most important for viral replication, whereas P36 and Y38 have a lesser but still noticeable impact. The reduction in viral replication was most likely due to inhibition of virion release, because initially no major impact on RV RNA synthesis was observed. In addition, results from electron microscopy demonstrated that the M4A mutant virus (PPEY→SAEA) displayed a more cell-associated phenotype than that of wild-type RV. Furthermore, all mutations within the PPEY motif resulted in reduced spread of the recombinant RVs as indicated by a reduction in focus size. Importantly, recombinant PPEY L-domain mutants were highly attenuated in mice yet still elicited potent antibody responses against RV G protein that were as high as those observed after infection with wild-type virus. Our data indicate that the RV PPEY motif has L-domain activity essential for efficient virus production and pathogenicity but is not essential for immunogenicity and thus can be targeted to increase the safety of rabies vaccine vectors.
Structure of Flexible Filamentous Plant Viruses
Authors: Kendall Amy , McDonald Michele , Bian Wen , Bowles Timothy , Baumgarten Sarah C. , Shi Jian , Stewart Phoebe L. , Bullitt Esther , Gore David , Irving Thomas C. , Havens Wendy M. , Ghabrial Said A. , Wall Joseph S. , Stubbs Gerald 
Published: July 2008

ABSTRACT
Flexible filamentous viruses make up a large fraction of the known plant viruses, but in comparison with those of other viruses, very little is known about their structures. We have used fiber diffraction, cryo-electron microscopy, and scanning transmission electron microscopy to determine the symmetry of a potyvirus, soybean mosaic virus; to confirm the symmetry of a potexvirus, potato virus X; and to determine the low-resolution structures of both viruses. We conclude that these viruses and, by implication, most or all flexible filamentous plant viruses share a common coat protein fold and helical symmetry, with slightly less than 9 subunits per helical turn.
A Hyperfusogenic F Protein Enhances the Oncolytic Potency of a Paramyxovirus Simian Virus 5 P/V Mutant without Compromising Sensitivity to Type I Interferon
Authors: Gainey Maria D. , Manuse Mary J. , Parks Griffith D. 
Published: July 2008

ABSTRACT

Viral fusogenic membrane proteins have been proposed as tools to increase the potency of oncolytic viruses, but there is a need for mechanisms to control the spread of fusogenic viruses in normal versus tumor cells. We have previously shown that a mutant of the paramyxovirus simian virus 5 (SV5) that harbors mutations in the P/V gene from the canine parainfluenza virus (P/V-CPI
−
) is a potent inducer of type I interferon (IFN) and apoptosis and is restricted for spread through normal but not tumor cells in vitro. Here, we have used the cytopathic P/V-CPI
−
as a backbone vector to test the hypothesis that a virus expressing a hyperfusogenic glycoprotein will be a more effective oncolytic vector but will retain sensitivity to IFN. A P/V mutant virus expressing an F protein with a glycine-to-alanine substitution in the fusion peptide (P/V-CPI
−
-G3A) was more fusogenic than the parental P/V-CPI
−
mutant. In two model prostate tumor cell lines which are defective in IFN production (LNCaP and DU145), the hyperfusogenic P/V-CPI
−
-G3A mutant had normal growth properties at low multiplicities of infection and was more effective than the parental P/V-CPI
−
mutant at cell killing in vitro. However, in PC3 cells which produce and respond to IFN, the hyperfusogenic P/V-CPI
−
-G3A mutant was attenuated for growth and spread. Killing of PC3 cells was equivalent between the parental P/V-CPI
−
mutant and the hyperfusogenic P/V-CPI
−
-G3A mutant. In a nude mouse model using LNCaP cells, the hyperfusogenic P/V-CPI
−
-G3A mutant was more effective than P/V-CPI
−
at reducing tumor burden. In the case of DU145 tumors, the two vectors based on P/V-CPI
−
were equally effective at limiting tumor growth. Together, our results provide proof of principle that a cytopathic SV5 P/V mutant can serve as an oncolytic virus and that the oncolytic effectiveness of P/V mutants can be enhanced by a fusogenic membrane protein without compromising sensitivity to IFN. The potential advantages of SV5-based oncolytic vectors are discussed.
Gag-Specific Cytotoxic T-Lymphocyte-Based Control of Primary Simian Immunodeficiency Virus Replication in a Vaccine Trial
Authors: Kawada Miki , Tsukamoto Tetsuo , Yamamoto Hiroyuki , Iwamoto Nami , Kurihara Kyoko , Takeda Akiko , Moriya Chikaya , Takeuchi Hiroaki , Akari Hirofumi , Matano Tetsuro 
Published: July 2008

ABSTRACT

Gag-specific cytotoxic T lymphocytes (CTLs) exert strong suppressive pressure on human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. However, it has remained unclear whether they can actually contain primary viral replication. Recent trials of prophylactic vaccines inducing virus-specific T-cell responses have indicated their potential to confer resistance against primary SIV replication in rhesus macaques, while the immunological determinant for this vaccine-based viral control has not been elucidated thus far. Here we present evidence implicating Gag-specific CTLs as responsible for the vaccine-based primary SIV control. Prophylactic vaccination using a Gag-expressing Sendai virus vector resulted in containment of SIVmac239 challenge in all rhesus macaques possessing the major histocompatibility complex (MHC) haplotype
90-120-Ia
. In contrast,
90-120-Ia
-positive vaccinees failed to contain SIVs carrying multiple
gag
CTL escape mutations that had been selected, at the cost of viral fitness, in SIVmac239-infected
90-120-Ia
-positive macaques. These results show that Gag-specific CTL responses do play a crucial role in the control of wild-type SIVmac239 replication in vaccinees. This study implies the possibility of Gag-specific CTL-based primary HIV containment by prophylactic vaccination, although it also suggests that CTL-based AIDS vaccine efficacy may be abrogated in viral transmission between MHC-matched individuals.
Association of the Cellular Coactivator HCF-1 with the Golgi Apparatus in Sensory Neurons
Authors: Kolb Gaelle , Kristie Thomas M. 
Published: July 2008

ABSTRACT
HCF-1 is a cellular transcriptional coactivator that is critical for mediating the regulated expression of the immediate-early genes of the alphaherpesviruses herpes simplex virus type 1 and varicella-zoster virus. HCF-1 functions, at least in part, by modulating the modification of nucleosomes at these viral promoters to reverse cell-mediated repressive marks and promote activating marks. Strikingly, HCF-1 is specifically sequestered in the cytoplasm of sensory neurons where these viruses establish latency and is rapidly relocalized to the nucleus upon stimuli that result in viral reactivation. However, the analysis of HCF-1 in latently infected neurons and the protein's specific subcellular location have not been determined. Therefore, in this study, the localization of HCF-1 in unstimulated and induced latently infected sensory neurons was investigated and was found to be similar to that observed in uninfected mice, with a time course of induced nuclear accumulation that correlated with viral reactivation. Using a primary neuronal cell culture system, HCF-1 was localized to the Golgi apparatus in unstimulated neurons, a unique location for a transcriptional coactivator. Upon disruption of the Golgi body, HCF-1 was rapidly relocalized to the nucleus in contrast to other Golgi apparatus-associated proteins. The location of HCF-1 is distinct from that of CREB3, an endoplasmic reticulum-resident HCF-1 interaction partner that has been proposed to sequester HCF-1. The results support the model that HCF-1 is an important component of the viral latency-reactivation cycle and that it is regulated by association with a component that is distinct from the identified HCF-1 interaction factors.
Murine Coronavirus Mouse Hepatitis Virus Is Recognized by MDA5 and Induces Type I Interferon in Brain Macrophages/Microglia
Authors: Roth-Cross Jessica K. , Bender Susan J. , Weiss Susan R. 
Published: July 2008

ABSTRACTThe coronavirus mouse hepatitis virus (MHV) induces a minimal type I interferon (IFN) response in several cell types in vitro despite the fact that the type I IFN response is important in protecting the mouse from infection in vivo. When infected with MHV, mice deficient in IFN-associated receptor expression (IFNAR−/−) became moribund by 48 h postinfection. MHV also replicated to higher titers and exhibited a more broad tissue tropism in these mice, which lack a type I IFN response. Interestingly, MHV induced IFN-β in the brains and livers, two main targets of MHV replication, of infected wild-type mice. MHV infection of primary cell cultures indicates that hepatocytes are not responsible for the IFN-β production in the liver during MHV infection. Furthermore, macrophages and microglia, but not neurons or astrocytes, are responsible for IFN-β production in the brain. To determine the pathway by which MHV is recognized in macrophages, IFN-β mRNA expression was quantified following MHV infection of a panel of primary bone marrow-derived macrophages generated from mice lacking different pattern recognition receptors (PRRs). Interestingly, MDA5, a PRR thought to recognize primarily picornaviruses, was required for recognition of MHV. Thus, MHV induces type I IFN in macrophages and microglia in the brains of infected animals and is recognized by an MDA5-dependent pathway in macrophages. These findings suggest that secretion of IFN-β by macrophages and microglia plays a role in protecting the host from MHV infection of the central nervous system.
Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G
1
and G
2
Arrest in Murine Cytomegalovirus-Infected Cells
Authors: Wiebusch Lüder , Neuwirth Anke , Grabenhenrich Linus , Voigt Sebastian , Hagemeier Christian 
Published: July 2008

ABSTRACT

The infectious cycle of human cytomegalovirus (HCMV) is intricately linked to the host's cell cycle. Viral gene expression can be initiated only in G
0
/G
1
phase. Once expressed, the immediate-early gene product IE2 prevents cellular DNA synthesis, arresting infected cells with a G
1
DNA content. This function is required for efficient viral replication in vitro. A prerequisite for addressing its in vivo relevance is the characterization of cell cycle-regulatory activities of CMV species for which animal models have been established. Here, we show that murine CMV (MCMV), like HCMV, has a strong antiproliferative capacity and arrests cells in G
1
. Unexpectedly, and in contrast to HCMV, MCMV can also block cells that have passed through S phase by arresting them in G
2
. Moreover, MCMV can also replicate in G
2
cells. This is made possible by the cell cycle-independent expression of MCMV immediate-early genes. Transfection experiments show that of several MCMV candidate genes, only immediate-early gene 3 (ie3), the homologue of HCMV IE2, exhibits cell cycle arrest activity. Accordingly, an MCMV ie3 deletion mutant has lost the ability to arrest cells in either G
1
or G
2
. Thus, despite interspecies variations in the cell cycle dependence of viral gene expression, the central theme of HCMV IE2-induced cell cycle arrest is conserved in the murine counterpart, raising the possibility of studying its physiological relevance at the level of the whole organism.
The Quality of Chimpanzee T-Cell Activation and Simian Immunodeficiency Virus/Human Immunodeficiency Virus Susceptibility Achieved via Antibody-Mediated T-Cell Receptor/CD3 Stimulation Is a Function of the Anti-CD3 Antibody Isotype
Authors: Bibollet-Ruche Frederic , McKinney Brett A. , Duverger Alexandra , Wagner Frederic H. , Ansari Aftab A. , Kutsch Olaf 
Published: July 2008

ABSTRACTWhile human immunodeficiency virus type 1 (HIV-1) infection is associated with hyperimmune activation and systemic depletion of CD4+T cells, simian immunodeficiency virus (SIV) infection in sooty mangabeys or chimpanzees does not exhibit these hallmarks. Control of immune activation is thought to be one of the major components that govern species-dependent differences in the disease pathogenesis. A previous study introduced the idea that the resistance of chimpanzees to SIVcpz infection-induced hyperimmune activation could be the result of the expression of select sialic acid-recognizing immunoglobulin (Ig)-like lectin (Siglec) superfamily members by chimpanzee T cells. Siglecs, which are absent on human T cells, were thought to control levels of T-cell activation in chimpanzees and were thus suggested as a cause for the pathogenic differences in the course of SIVcpz or HIV-1 infection. As in human models of T-cell activation, stimulation had been attempted using an anti-CD3 monoclonal antibody (MAb) (UCHT1; isotype IgG1), but despite efficient binding, UCHT1 failed to activate chimpanzee T cells, an activation block that could be partially overcome by MAb-induced Siglec-5 internalization. We herein demonstrate that anti-CD3 MAb-mediated chimpanzee T-cell activation is a function of the anti-CD3 MAb isotype and is not governed by Siglec expression. While IgG1 anti-CD3 MAbs fail to stimulate chimpanzee T cells, IgG2a anti-CD3 MAbs activate chimpanzee T cells in the absence of Siglec manipulations. Our results thus imply that prior to studying possible differences between human and chimpanzee T-cell activation, a relevant model of chimpanzee T cell activation needs to be established.
Two Regions within the Amino-Terminal Half of APOBEC3G Cooperate To Determine Cytoplasmic Localization
Authors: Stenglein Mark D. , Matsuo Hiroshi , Harris Reuben S. 
Published: July 2008

ABSTRACT
APOBEC3G limits the replication of human immunodeficiency virus type 1, other retroviruses, and retrotransposons. It localizes predominantly to the cytoplasm of cells, which is consistent with a model wherein cytosolic APOBEC3G packages into assembling virions, where it exerts its antiviral effect by deaminating viral cDNA cytosines during reverse transcription. To define the domains of APOBEC3G that determine cytoplasmic localization, comparisons were made with APOBEC3B, which is predominantly nuclear. APOBEC3G/APOBEC3B chimeric proteins mapped a primary subcellular localization determinant to a region within the first 60 residues of each protein. A panel of 25 APOBEC3G mutants, each with a residue replaced by the corresponding amino acid of APOBEC3B, revealed that several positions within this region were particularly important, with Y19D showing the largest effect. The mislocalization phenotype of these mutants was only apparent in the context of the amino-terminal half of APOBEC3G and not the full-length protein, suggesting the existence of an additional localization determinant. Indeed, a panel of five single amino acid substitutions within the region from amino acids 113 to 128 had little effect by themselves but, in combination with Y19D, two substitutions—F126S and W127A—caused full-length APOBEC3G to redistribute throughout the cell. The critical localization-determining residues were predicted to cluster on a common solvent-exposed surface, suggesting a model in which these two regions of APOBEC3G combine to mediate an intermolecular interaction that controls subcellular localization.
Double-angle shear connections with short outstanding legs
Authors: Gong Yanglin , Gillies Antony 
Published: July 2008

This paper describes an experimental study on double-angle shear connections with a narrow outstanding leg width from 31 to 37 mm. When connection angles are welded to a supporting column with a face width less than 152 mm, a common practice is either to weld the angles to the column by flare bevel groove welds or shorten the outstanding legs to accommodate fillet welds. This practice reduces the rotational capacity of the connections; and therefore confirmation of this practice is required. Three groups, comprising 12 full-scale connection specimens, were tested. Each group consisted of four specimens having three, four, five, and six bolts, respectively. Group A used 9.5 mm thick angles and fillet welds, group B used 6.4 mm thick angles and fillet welds, and group C used 9.5 mm thick angles and flare bevel groove welds. The test results demonstrated that both rotational and shear capacities of the connections are satisfactory when either of the two details are used.
Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells
Authors: Doudican Nicole , Rodriguez Adrianna , Osman Iman , Orlow Seth J. 
Published: July 2008

Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 μmol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC50 of 0.32 μmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308–15)
Exploiting Semantic Role Resources for Preposition Disambiguation
Authors: O'Hara Tom , Wiebe Janyce 
Published: July 2008

This article describes how semantic role resources can be exploited for preposition disambiguation. The main resources include the semantic role annotations provided by the Penn Treebank and FrameNet tagged corpora. The resources also include the assertions contained in the Factotum knowledge base, as well as information from Cyc and Conceptual Graphs. A common inventory is derived from these in support of definition analysis, which is the motivation for this work. The disambiguation concentrates on relations indicated by prepositional phrases, and is framed as word-sense disambiguation for the preposition in question. A new type of feature for word-sense disambiguation is introduced, using WordNet hypernyms as collocations rather than just words. Various experiments over the Penn Treebank and FrameNet data are presented, including prepositions classified separately versus together, and illustrating the effects of filtering. Similar experimentation is done over the Factotum data, including a method for inferring likely preposition usage from corpora, as knowledge bases do not generally indicate how relationships are expressed in English (in contrast to the explicit annotations on this in the Penn Treebank and FrameNet). Other experiments are included with the FrameNet data mapped into the common relation inventory developed for definition analysis, illustrating how preposition disambiguation might be applied in lexical acquisition.
First Steps in Writing Arabic Narrative Fiction: The Case of Hadīqat al-Akhbār
Authors: Bawardi Basiliyus 
Published: July 2008

AbstractThis study tracks the significant literary activity of the Beirut newspaper Hadīqat al-Akhbār (1858-1911) in its first ten years. A textual examination of the newspaper reveals that Khalīl al-Khūrī (1836-1907), a central figure of the nahda and the owner of Hadīqat al-Akhbār, believed that an adoption of a new Western literary genre into the traditional Arabic literary tradition would provide the Arab culture with tools for reviving the Arabic language and create new styles of expression. The textual analysis of numerous narrative fictions that were published in the newspaper demonstrates two significant matters: first, Hadīqat al-Akhbār was the first Arabic newspaper to publish translations from Western narrative fiction, especially from the French Romance stories. Secondly, it will be shown how Khalīl al-Khūrī constructed a fetal model of Arabic narrative fiction by publishing a fictional narrative of his own, Wayy, idhan lastu bi-ifranjī (Alas, I'm not a foreigner), in 1859-1861. The literary activity in Hadīqat al-Akhbār, as the following study illustrates, played a substantial role in changing the aesthetic literary taste, and paved the way for the birth of an authentic Arabic narrative fiction.
The Myth of “The Triumph of Fanaticism” in the Seventeenth-Century Ottoman Empire
Authors: El-Rouayheb Khaled 
Published: July 2008

AbstractSince Halil İnalcık's classic The Ottoman Empire: The Classical Age (1973), the received view amongst historians has been that Ottoman scholars lost interest in the rational sciences after around 1600, largely as an effect of the rise of the puritanical Kādīzādeli movement. In the present article, I argue that there was in fact no decline of interest in the rational sciences amongst seventeenth century Ottoman scholars. On the contrary, interest in logic, dialectic, philosophy and rational theology seems to have been on the rise. Sunni Persian, Azeri and Kurdish scholars fleeing Safavid Iran brought with them new scholarly works in the rational sciences and gained a reputation as accomplished teachers. The number of Ottoman colleges in which works on the rational sciences were studied and taught also seems to have risen dramatically in the course of the 17th century.