bluuebunny/crossref_metadata_2025_split huggingface dataset:
Curiosity, Contingency, and Cultural Diversity: Montaigne's Readings at the Vatican Library*
Authors: Rigolot François 
Published: September 2011

AbstractOne of the key episodes of Michel de Montaigne's trip to Rome (1580–81) was his visit to the Vatican Library, which he comments upon in hisJournal de voyage,posthumously published. Strangely enough, few scholars have paid close attention to what Montaigne says about the selection of manuscripts and printed material he consulted there on 6 March 1581. He claims that he was given free access to thatWunderkammer,and scholarly research shows that his wish list indeed reflected his taste for irony, humor, and cultural diversity, ranging from Greco-Roman manuscripts to Egyptian papyrus and a Chinese booklet. At the same time, a case could be made for interpreting the selection, not as Montaigne's, but as the library custodian's, with Aquinas's sermons, anti-Lutheran material, and documents used at the Council of Trent. This paper tries to sort out to what extent the selection of books and items that Montaigne saw at the Vatican Library can be considered as the meeting ground between the interests of Montaigne himself as skeptic and the agenda of the Counter-Reformation.
Type-Specific Human Papillomavirus E6/E7 mRNA Detection by Real-Time PCR Improves Identification of Cervical Neoplasia
Authors: Andersson Elin , Kärrberg Cecilia , Rådberg Thomas , Blomqvist Lennart , Zetterqvist Britt-Marie , Ryd Walter , Lindh Magnus , Horal Peter 
Published: September 2011

ABSTRACT
DNA-based human papillomavirus (HPV) assays show high sensitivity but poor specificity in detecting high-grade cervical lesions. Assays detecting mRNA of the oncoproteins E6 and E7 show higher specificity but lack either detection of all high-risk HPV genotypes or the capacity to specify the detected genotypes. Therefore, a real-time PCR assay detecting type-specific E6/E7 mRNA was developed and the clinical performance evaluated. A total of 210 cervical LBC (liquid-based cytology) samples from 204 women were analyzed for HPV DNA and mRNA with the in-house real-time PCR as well as PreTect HPV-Proofer. The sensitivity of real-time PCR mRNA detection to identify histologically confirmed CIN2+ (cervical intraepithelial neoplasia, grade 2 or higher) was 0.91, compared to 0.95 for DNA analysis. The specificity was 0.68 compared to 0.38, and the positive predictive value (PPV) was higher for mRNA (0.67 versus 0.52) without any loss in negative predictive value (NPV). The sensitivity of the real-time PCR mRNA test was somewhat higher than that for PreTect HPV-Proofer (0.83 versus 0.75) in analyses for the same genotypes. The specificities were similar (0.76 versus 0.77). In analyses for mRNA of the eight most common genotypes in cervical cancer (HPV16, -18, -31, -33, -35, -45, -52, and -58), the sensitivity of detection of CIN2+ lesions was 0.87 and the specificity 0.74, with a PPV of 0.70. In conclusion, real-time PCR for detection of HPV E6/E7 mRNA transcripts can be a sensitive and specific tool in screening and investigation of cervical neoplasia. The composition of HPV types in mRNA testing needs to be further investigated to optimize sensitivity and specificity.
Evaluation of Aspergillus PCR Protocols for Testing Serum Specimens
Authors: White P. Lewis , Mengoli Carlo , Bretagne Stéphane , Cuenca-Estrella Manuel , Finnstrom Niklas , Klingspor Lena , Melchers Willem J. G. , McCulloch Elaine , Barnes Rosemary A. , Donnelly J. Peter , Loeffler Juergen 
Published: September 2011

ABSTRACT

A panel of human serum samples spiked with various amounts of
Aspergillus fumigatus
genomic DNA was distributed to 23 centers within the European
Aspergillus
PCR Initiative to determine analytical performance of PCR. Information regarding specific methodological components and PCR performance was requested. The information provided was made anonymous, and meta-regression analysis was performed to determine any procedural factors that significantly altered PCR performance. Ninety-seven percent of protocols were able to detect a threshold of 10 genomes/ml on at least one occasion, with 83% of protocols reproducibly detecting this concentration. Sensitivity and specificity were 86.1% and 93.6%, respectively. Positive associations between sensitivity and the use of larger sample volumes, an internal control PCR, and PCR targeting the internal transcribed spacer (ITS) region were shown. Negative associations between sensitivity and the use of larger elution volumes (≥100 μl) and PCR targeting the mitochondrial genes were demonstrated. Most
Aspergillus
PCR protocols used to test serum generate satisfactory analytical performance. Testing serum requires less standardization, and the specific recommendations shown in this article will only improve performance.
Epidemic Methicillin-Susceptible Staphylococcus aureus Lineages Are the Main Cause of Infections at an Iranian University Hospital
Authors: Havaei Seyed Asghar , Vidovic Sinisa , Tahmineh Narimani , Mohammad Kazemi , Mohsen Karbalaei , Starnino Stefania , Dillon Jo-Anne R. 
Published: September 2011

ABSTRACT

The majority of
Staphylococcus aureus
infections from Isfahan, Iran, were caused by epidemic methicillin-susceptible
S. aureus
(MSSA) lineages, sequence type 8 (ST8), ST22, ST30, and ST6. The predominant methicillin-resistant
S. aureus
strain was ST239. We observed a high prevalence of Panton-Valentine leukocidin-positive MSSA strains (19.7%), which is a matter of considerable concern, since these strains have the ability to cause severe infections.
A Novel Pancreatropic Coxsackievirus Vector Expressing Glucagon-Like Peptide 1 Reduces Hyperglycemia in Streptozotocin-Treated Mice
Authors: Dan Meixia , Chantler Janet K. 
Published: September 2011

ABSTRACTA coxsackievirus vector, vCVB(dm) (v stands for vector, CVB stands for group B coxsackievirus, and dm stands for double mutant), has been produced from a unique strain of coxsackievirus B3 (CVB3) containing 2 mutations that confer the property of highly selective pancreatropism. This vector has been tested as a delivery vehicle for glucagon-like peptide 1 (GLP-1), a peptide that enhances pancreatic regeneration following tissue damage. vCVB(dm) is a live vector comprising the entire plus-strand RNA genome with a multiple cloning site (MCS) inserted between the P1 and P2 gene regions. The MCS is flanked by sequences encoding the cleavage site for viral protease 2Apro that processes the polyprotein to release the incorporated gene. Our studies show that this vector selectively delivers GLP-1 to the pancreas where it is expressed in foci scattered throughout the acinar tissue for 4 or 5 days. Moreover, expression is associated with new beta cell clusters in juxtaposition to vector-infected cells. Inoculation of streptozotocin (STZ)-treated mice with vCVB(dm)GLP-1 was found to suppress development of hyperglycemia and increase insulin production relative to mice treated with STZ alone or with empty vector. This vector has the advantage of exclusively targeting pancreas and has potential use for short-term gene delivery to this tissue. The lack of viral integration provides a significant safety feature, making this vector a possible option for use as a therapeutic tool for pancreas-related diseases, including type 1 and 2 diabetes, pancreatitis, and pancreatic cancer.
DNA Damage Response Signaling Triggers Nuclear Localization of the Chicken Anemia Virus Protein Apoptin
Authors: Kucharski Thomas J. , Gamache Isabelle , Gjoerup Ole , Teodoro Jose G. 
Published: September 2011

ABSTRACT

The chicken anemia virus (CAV) protein Apoptin is a small, 13.6-kDa protein that has the intriguing activity of inducing G
2
/M arrest and apoptosis specifically in cancer cells by a mechanism that is independent of p53. The activity of Apoptin is regulated at the level of localization. Whereas Apoptin is cytoplasmic in primary cells and does not affect cell growth, in transformed cells it localizes to the nucleus, where it induces apoptosis. The properties of cancer cells that are responsible for activating the proapoptotic activities of Apoptin remain unclear. In the current study, we show that DNA damage response (DDR) signaling is required to induce Apoptin nuclear localization in primary cells. Induction of DNA damage in combination with Apoptin expression was able to induce apoptosis in primary cells. Conversely, chemical or RNA interference (RNAi) inhibition of DDR signaling by ATM and DNA-dependent protein kinase (DNA-PK) was sufficient to cause Apoptin to localize in the cytoplasm of transformed cells. Furthermore, the nucleocytoplasmic shuttling activity of Apoptin is required for DDR-induced changes in localization. Interestingly, nuclear localization of Apoptin in primary cells was able to inhibit the formation of DNA damage foci containing 53BP1. Apoptin has been shown to bind and inhibit the anaphase-promoting complex/cyclosome (APC/C). We observe that Apoptin is able to inhibit formation of DNA damage foci by targeting the APC/C-associated factor MDC1 for degradation. We suggest that these results may point to a novel mechanism of DDR inhibition during viral infection.
Hepatocytes Traffic and Export Hepatitis B Virus Basolaterally by Polarity-Dependent Mechanisms
Authors: Bhat Purnima , Snooks Michelle J. , Anderson David A. 
Published: September 2011

ABSTRACTViruses commonly utilize the cellular trafficking machinery of polarized cells to effect viral export. Hepatocytes are polarizedin vivo, but mostin vitrohepatocyte models are either nonpolarized or have morphology unsuitable for the study of viral export. Here, we investigate the mechanisms of trafficking and export for the hepadnaviruses hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) in polarized hepatocyte-derived cell lines and primary duck hepatocytes. DHBV export, but not replication, was dependent on the development of hepatocyte polarity, with export significantly abrogated over time as primary hepatocytes lost polarity. Using Transwell cultures of polarized N6 cells and adenovirus-based transduction, we observed that export of both HBV and DHBV was vectorially regulated and predominantly basolateral. Monitoring of polarized N6 cells and nonpolarized C11 cells during persistent, long-term DHBV infection demonstrated that newly synthesized sphingolipid and virus displayed significant colocalization and fluorescence resonance energy transfer, implying cotransportation from the Golgi complex to the plasma membrane. Notably, 15% of virus was released apically from polarized cells, corresponding to secretion into the bile ductin vivo, also in association with sphingolipids. We conclude that DHBV and, probably, HBV are reliant upon hepatocyte polarity to be efficiently exported and this export is in association with sphingolipid structures, possibly lipid rafts. This study provides novel insights regarding the mechanisms of hepadnavirus trafficking in hepatocytes, with potential relevance to pathogenesis and immune tolerance.
Localization of Sequences in a Protein (ORF2) Encoded by the Latency-Related Gene of Bovine Herpesvirus 1 That Inhibits Apoptosis and Interferes with Notch1-Mediated
trans
-Activation of the bICP0 Promoter
Authors: Sinani Devis , Jones Clinton 
Published: September 2011

ABSTRACT

Bovine herpesvirus 1 (BHV-1) infection induces clinical symptoms in the upper respiratory tract, inhibits immune responses, and can result in life-threatening secondary bacterial infections. Following acute infection, BHV-1 establishes latency in sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs, resulting in virus transmission. The latency-related (LR) RNA is abundantly expressed in latently infected sensory neurons, suggesting that LR gene products regulate the latency-reactivation cycle. An LR mutant virus with stop codons at the amino terminus of the first open reading frame (ORF) in the LR gene (ORF2) does not reactivate from latency, in part because it induces higher levels of apoptosis in infected neurons. ORF2 inhibits apoptosis in transiently transfected cells, suggesting that it plays an important role in the latency-reactivation cycle. ORF2 also interacts with Notch1 or Notch3 and consequently inhibits their ability to
trans
-activate the bICP0 early and glycoprotein C promoters. In this study, we identified ORF2 sequences that were necessary for inhibiting cold shock-induced apoptosis or Notch1-mediated
trans
-activation of the bICP0 early promoter and stimulation of productive infection. Relative to ORF2 sequences necessary for inhibiting apoptosis, distinct domains in ORF2 were important for interfering with Notch1-mediated
trans
-activation. Five consensus protein kinase A and/or protein kinase C phosphorylation sites within ORF2 regulate the steady-state levels of ORF2 in transfected cells. A nuclear localization signal in ORF2 was necessary for inhibiting Notch1-mediated
trans
-activation but not apoptosis. In summary, ORF2 has more than one functional domain that regulates its stability and functional properties.
Nonconsensus West Nile Virus Genomes Arising during Mosquito Infection Suppress Pathogenesis and Modulate Virus Fitness
In Vivo
Authors: Ebel Gregory D. , Fitzpatrick Kelly A. , Lim Pei-Yin , Bennett Corey J. , Deardorff Eleanor R. , Jerzak Greta V. S. , Kramer Laura D. , Zhou Yangsheng , Shi Pei-Yong , Bernard Kristen A. 
Published: September 2011

ABSTRACT

West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an
in vivo
fitness assay in
Culex quinquefasciatus
mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.
Herpes Simplex Virus 1 ICP0 Phosphorylation Site Mutants Are Attenuated for Viral Replication and Impaired for Explant-Induced Reactivation
Authors: Mostafa Heba H. , Thompson Thornton W. , Kushnir Anna S. , Haenchen Steve D. , Bayless Adam M. , Hilliard Joshua G. , Link Malen A. , Pitcher Lisa A. , Loveday Emma , Schaffer Priscilla A. , Davido David J. 
Published: September 2011

ABSTRACT

In cell culture experiments, phosphorylation appears to be a critical regulator of the herpes simplex virus 1 (HSV-1) immediate-early (IE) protein, ICP0, which is an E3 ubiquitin ligase that transactivates viral gene expression. Three major regions of phosphorylation in ICP0 (amino acids 224 to 232, 365 to 371, and 508 to 518) have been identified, and mutant viruses that block phosphorylation sites within each region (termed Phos 1, 2, and 3, respectively) have been constructed. Previous studies indicated that replication of Phos 1 is significantly reduced compared to that of wild-type virus in cell culture (C. Boutell, et al., J. Virol. 82:10647–10656, 2008). To determine the effects these phosphorylation site mutations have on the viral life cycle
in vivo
, mice were ocularly infected with wild-type HSV-1, the Phos mutants, or their marker rescue counterparts. Subsequently, viral replication, establishment of latency, and viral explant-induced reactivation of these viruses were examined. Relative to wild-type virus, Phos 1 eye titers were reduced as much as 7- and 18-fold on days 1 and 5 postinfection, respectively. Phos 2 eye titers showed a decrease of 6-fold on day 1 postinfection. Titers of Phos 1 and 2 trigeminal ganglia were reduced as much as 16- and 20-fold, respectively, on day 5 postinfection. Additionally, the reactivation efficiencies of Phos 1 and 2 were impaired relative to wild-type HSV-1, although both viruses established wild-type levels of latency
in vivo
. The acute replication, latency, and reactivation phenotypes of Phos 3 were similar to those of wild-type HSV-1. We conclude from these studies that phosphorylation is likely a key modulator of ICP0's biological activities in a mouse ocular model of HSV-1 infection.
Cooperative Roles of Fish Protein Kinase Containing Z-DNA Binding Domains and Double-Stranded RNA-Dependent Protein Kinase in Interferon-Mediated Antiviral Response
Authors: Liu Ting-Kai , Zhang Yi-Bing , Liu Ying , Sun Fan , Gui Jian-Fang 
Published: September 2011

ABSTRACT

The double-stranded RNA (dsRNA)-dependent protein kinase (PKR) inhibits protein synthesis by phosphorylating eukaryotic translation initiation factor 2α (eIF2α). In fish species, in addition to PKR, there exists a PKR-like protein kinase containing Z-DNA binding domains (PKZ). However, the antiviral role of fish PKZ and the functional relationship between fish PKZ and PKR remain unknown. Here we confirmed the coexpression of fish PKZ and PKR proteins in
Carassius auratus
blastula embryonic (CAB) cells and identified them as two typical interferon (IFN)-inducible eIF2α kinases, both of which displayed an ability to inhibit virus replication. Strikingly, fish IFN or all kinds of IFN stimuli activated PKZ and PKR to phosphorylated eIF2α. Overexpression of both fish kinases together conferred much more significant inhibition of virus replication than overexpression of either protein, whereas morpholino knockdown of both made fish cells more vulnerable to virus infection than knockdown of either. The antiviral ability of fish PKZ was weaker than fish PKR, which correlated with its lower ability to phosphorylate eIF2α than PKR. Moreover, the independent association of fish PKZ or PKR reveals that each of them formed homodimers and that fish PKZ phosphorylated eIF2α independently on fish PKR and vice versa. These results suggest that fish PKZ and PKR play a nonredundant but cooperative role in IFN antiviral response.
The Interaction of Alphavirus E1 Protein with Exogenous Domain III Defines Stages in Virus-Membrane Fusion
Authors: Roman-Sosa Gleyder , Kielian Margaret 
Published: September 2011

ABSTRACT
Alphaviruses such as Semliki Forest virus (SFV) are enveloped viruses that infect cells through a low-pH-triggered membrane fusion reaction mediated by the transmembrane fusion protein E1. E1 drives fusion by insertion of its hydrophobic fusion loop into the cell membrane and refolding to a stable trimeric hairpin. In this postfusion conformation, the immunoglobulin-like domain III (DIII) and the stem region pack against the central core of the trimer. Membrane fusion and infection can be specifically inhibited by exogenous DIII, which binds to an intermediate in the E1 refolding pathway. Here we characterized the properties of the E1 target for interaction with exogenous DIII. The earliest target for DIII binding was an extended membrane-inserted E1 trimer, which was not detectable by assays for the stable postfusion hairpin. DIII binding provided a tool to detect this extended trimer and to define a series of SFV fusion-block mutants. DIII binding studies showed that the mutants were blocked in distinct steps in fusion protein refolding. Our results suggested that formation of the initial extended trimer was reversible and that it was stabilized by the progressive fold-back of the DIII and stem regions.
A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge
Authors: Bolles Meagan , Deming Damon , Long Kristin , Agnihothram Sudhakar , Whitmore Alan , Ferris Martin , Funkhouser William , Gralinski Lisa , Totura Allison , Heise Mark , Baric Ralph S. 
Published: September 2011

ABSTRACTSevere acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.
Src Activation Plays an Important Key Role in Lymphomagenesis Induced by FGFR1 Fusion Kinases
Authors: Ren Mingqiang , Qin Haiyan , Ren Ruizhe , Tidwell Josephine , Cowell John K. 
Published: September 2011

Abstract
Chromosomal translocations and activation of the fibroblast growth factor (FGF) receptor 1 (FGFR1) are a feature of stem cell leukemia–lymphoma syndrome (SCLL), an aggressive malignancy characterized by rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. It has been suggested that FGFR1 proteins lose their ability to recruit Src kinase, an important mediator of FGFR1 signaling, as a result of the translocations that delete the extended FGFR substrate-2 (FRS2) interacting domain that Src binds. In this study, we report evidence that refutes this hypothesis and reinforces the notion that Src is a critical mediator of signaling from the FGFR1 chimeric fusion genes generated by translocation in SCLL. Src was constitutively active in BaF3 cells expressing exogenous FGFR1 chimeric kinases cultured in vitro as well as in T-cell or B-cell lymphomas they induced in vivo. Residual components of the FRS2-binding site retained in chimeric kinases that were generated by translocation were sufficient to interact with FRS2 and activate Src. The Src kinase inhibitor dasatinib killed transformed BaF3 cells and other established murine leukemia cell lines expressing chimeric FGFR1 kinases, significantly extending the survival of mice with SCLL syndrome. Our results indicated that Src kinase is pathogenically activated in lymphomagenesis induced by FGFR1 fusion genes, implying that Src kinase inhibitors may offer a useful option to treatment of FGFR1-associated myeloproliferative/lymphoma disorders. Cancer Res; 71(23); 7312–22. ©2011 AACR.