bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Basic Amino Acids at the N-Terminal End of the Core Protein That Are Crucial for Hepatitis C Virus Infectivity
Authors: Alsaleh Khaled , Delavalle Pierre-Yves , Pillez André , Duverlie Gilles , Descamps Véronique , Rouillé Yves , Dubuisson Jean , Wychowski Czeslaw 
Published: October 2010

ABSTRACT
A major function of the hepatitis C virus (HCV) core protein is the interaction with genomic RNA to form the nucleocapsid, an essential component of the virus particle. Analyses to identify basic amino acid residues of HCV core protein, important for capsid assembly, were initially performed with a cell-free system, which did not indicate the importance of these residues for HCV infectivity. The development of a cell culture system for HCV (HCVcc) allows a more precise analysis of these core protein amino acids during the HCV life cycle. In the present study, we used a mutational analysis in the context of the HCVcc system to determine the role of the basic amino acid residues of the core protein in HCV infectivity. We focused our analysis on basic residues located in two clusters (cluster 1, amino acids [aa]6 to 23; cluster 2, aa 39 to 62) within the N-terminal 62 amino acids of the HCV core protein. Our data indicate that basic residues of the first cluster have little impact on replication and are dispensable for infectivity. Furthermore, only four basic amino acids residues of the second cluster (R50, K51, R59, and R62) were essential for the production of infectious viral particles. Mutation of these residues did not interfere with core protein subcellular localization, core protein-RNA interaction, or core protein oligomerization. Moreover, these mutations had no effect on core protein envelopment by intracellular membranes. Together, these data indicate that R50, K51, R59, and R62 residues play a major role in the formation of infectious viral particles at a post-nucleocapsid assembly step.
Interaction of Poxvirus Intracellular Mature Virion Proteins with the TPR Domain of Kinesin Light Chain in Live Infected Cells Revealed by Two-Photon-Induced Fluorescence Resonance Energy Transfer Fluorescence Lifetime Imaging Microscopy
Authors: Jeshtadi Ananya , Burgos Pierre , Stubbs Christopher D. , Parker Anthony W. , King Linda A. , Skinner Michael A. , Botchway Stanley W. 
Published: October 2010

ABSTRACT
Using two-photon-induced fluorescence lifetime imaging microscopy, we corroborate an interaction (previously demonstrated by yeast two-hybrid domain analysis) of full-length vaccinia virus (VACV; an orthopoxvirus) A36 protein with the cellular microtubule motor protein kinesin. Quenching of enhanced green fluorescent protein (EGFP), fused to the C terminus of VACV A36, by monomeric red fluorescent protein (mDsRed), fused to the tetratricopeptide repeat (TPR) domain of kinesin, was observed in live chicken embryo fibroblasts infected with either modified vaccinia virus Ankara (MVA) or wild-type fowlpox virus (FWPV; an avipoxvirus), and the excited-state fluorescence lifetime of EGFP was reduced from 2.5 ± 0.1 ns to 2.1 ± 0.1 ns due to resonance energy transfer to mDsRed. FWPV does not encode an equivalent of intracellular enveloped virion surface protein A36, yet it is likely that this virus too must interact with kinesin to facilitate intracellular virion transport. To investigate possible interactions between innate FWPV proteins and kinesin, recombinant FWPVs expressing EGFP fused to the N termini of FWPV structural proteins Fpv140, Fpv168, Fpv191, and Fpv198 (equivalent to VACV H3, A4, p4c, and A34, respectively) were generated. EGFP fusions of intracellular mature virion (IMV) surface protein Fpv140 and type II membrane protein Fpv198 were quenched by mDsRed-TPR in recombinant FWPV-infected cells, indicating that these virion proteins are found within 10 nm of mDsRed-TPR. In contrast, and as expected, EGFP fusions of the IMV core protein Fpv168 did not show any quenching. Interestingly, the p4c-like protein Fpv191, which demonstrates late association with preassembled IMV, also did not show any quenching.
MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection
Authors: Seo Sang-Uk , Kwon Hyung-Joon , Song Joo-Hye , Byun Young-Ho , Seong Baik Lin , Kawai Taro , Akira Shizuo , Kweon Mi-Na 
Published: October 2010

ABSTRACTRecent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF−/−, MyD88−/−, MyD88−/−TRIF−/−, TLR3−/−TLR7−/−, and IPS-1−/−). In this study, we found that MyD88 signaling was required for recruitment of CD11b+granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88−/−and MyD88−/−TRIF−/−mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge.
Discovery and Characterization of Mammalian Endogenous Parvoviruses
Authors: Kapoor Amit , Simmonds Peter , Lipkin W. Ian 
Published: October 2010

ABSTRACT

Public databases of nucleotide sequences contain exponentially increasing amounts of sequence data from mammalian genomes. Through the use of large-scale bioinformatic screening for sequences homologous to exogenous mammalian viruses, we found several sequences related to human and animal parvoviruses (PVs) in the
Parvovirus
and
Dependovirus
genera within genomes of several mammals, including rats, wallabies, opossums, guinea pigs, hedgehogs, African elephants, and European rabbits. However, phylogenetic analysis of these endogenous parvovirus (EnPV) sequences demonstrated substantial genetic divergence from exogenous mammalian PVs characterized to date. Entire nonstructural and capsid gene sequences of a novel EnPV were amplified and genetically characterized from rat (
Rattus norvegicus
) genomic DNA. Rat EnPV sequences were most closely related to members of the genus
Parvovirus
, with >70% and 65% amino acid identities to nonstructural and capsid proteins of canine parvovirus, respectively. Integration of EnPV into chromosome 5 of rats was confirmed by PCR cloning and sequence analysis of the viral and chromosomal junctions. Using inverse PCR, we determined that the rat genome contains a single copy of rat EnPV. Considering mammalian phylogeny, we estimate that EnPV integrated into the rat genome less than 30 million years ago. Comparative phylogenetic analysis done using all known representative exogenous parvovirus (ExPV) and EnPV sequences showed two major genetic groups of EnPVs, one genetically more similar to genus
Parvovirus
and the other genetically more similar to the genus
Dependovirus
. The full extent of the genetic diversity of parvoviruses that have undergone endogenization during evolution of mammals and other vertebrates will be recognized only once complete genomic sequences from a wider range of classes, orders, and species of animals become available.
Ultrastructural Analysis of Virion Formation and Intraaxonal Transport of Herpes Simplex Virus Type 1 in Primary Rat Neurons
Authors: Negatsch Alexandra , Granzow Harald , Maresch Christina , Klupp Barbara G. , Fuchs Walter , Teifke Jens P. , Mettenleiter Thomas C. 
Published: October 2010

ABSTRACT

After primary replication at the site of entry into the host, alphaherpesviruses infect and establish latency in neurons. To this end, they are transported within axons retrograde from the periphery to the cell body for replication and in an anterograde direction to synapses for infection of higher-order neurons or back to the periphery. Retrograde transport of incoming nucleocapsids is well documented. In contrast, there is still significant controversy on the mode of anterograde transport. By high-resolution transmission electron microscopy of primary neuronal cultures from embryonic rat superior cervical ganglia infected by pseudorabies virus (PrV), we observed the presence of enveloped virions in axons within vesicles supporting the “married model” of anterograde transport of complete virus particles within vesicles (C. Maresch, H. Granzow, A. Negatsch, B.G. Klupp, W. Fuchs, J.P. Teifke, and T.C. Mettenleiter, J. Virol.
84:
5528-5539, 2010). We have now extended these analyses to the related human herpes simplex virus type 1 (HSV-1). We have demonstrated that in neurons infected by HSV-1 strains HFEM, 17+ or SC16, approximately 75% of virus particles observed intraaxonally or in growth cones late after infection constitute enveloped virions within vesicles, whereas approximately 25% present as naked capsids. In general, the number of HSV-1 particles in the axons was significantly less than that observed after PrV infection.
The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and β2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers
Authors: Chaumont Agnès , De Winter Frédéric , Dumont Xavier , Haufroid Vincent , Bernard Alfred 
Published: October 2010

ObjectiveTo evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking.MethodsWe studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b2-microglobulin (b2-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU<1 μg/g creatinine.ResultsRelationships between urinary proteins and CdU (μg/g creatinine) were influenced by sex, age, diuresis and especially smoking. When considering all workers, odds for abnormal RBPU and b2-mU were significantly increased from CdU of 6-10 and >10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b2-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b2-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5.ConclusionsOn the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 μg/g creatinine.
A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation
Authors: Daniels R D , Schubauer-Berigan M K 
Published: October 2010

ContextMore than 400 000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure.ObjectiveWe conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia.Data sourcesReviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009.Study selectionWe selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case–control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure–response analyses using relative or excess RR per unit exposure.MethodsStudies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods.ResultsWe found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99).ConclusionsProtracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of protracted radiation exposures.
Job stress and the use of antidepressant medicine: a 3.5-year follow-up study among Danish employees
Authors: Thielen Karsten , Nygaard Else , Rugulies Reiner , Diderichsen Finn 
Published: October 2010

ObjectivesTo investigate if exposure to adverse psychological job characteristics predicts incident use of antidepressants, taking into account differential misclassification and residual confounding.MethodsA prospective cohort study with a 3.5-year follow-up of 4661 Danish employees, aged 40 and 50 years, drawn from a 10% random sample of the Danish population was carried out. Job characteristics were the predictor variables and use of antidepressants was the outcome variable. Survey data on psychosocial work environment were linked with register data on dispensing of antidepressant medicine between June 2000 and December 2003. Respondents with major depression at baseline, with antidepressant use in the 5 years preceding baseline, or not employed at baseline were excluded.ResultsAmong men, the OR for antidepressant use was significantly increased for high quantitative demands (OR 2.12, 95% CI 1.29 to 3.48) and low social support from colleagues (OR 2.28, 95% 1.36 to 3.82) after adjustment for lifestyle factors, socio-demographic factors, co-morbidity, other work factors and depressive symptoms at baseline. Both effects were dose dependent. An interaction effect with high demands was found for high anticipated private social support and living with children. Among women, no effect of job characteristics on antidepressant use was found.ConclusionAmong men, but not among women, high quantitative demands and low social support from colleagues were predictive of incident use of antidepressants, indicating incident depressive episodes, even after taking into account differential misclassification and residual confounding. The effects were buffered for those with high anticipated private social support and for those having children.
Temperature and density effects on the absorption maximum of solvated electrons in sub- and super-critical methanol
Authors: Yan Y. , Lin M. , Katsumura Y. , Muroya Y. , Yamashita S. , Hata K. , Meesungnoen J. , Jay-Gerin J.-P. 
Published: October 2010

The optical absorption spectra of the solvated electron ([Formula: see text]) in sub- and super-critical methanol are measured by both electron pulse radiolysis and laser photolysis techniques, at temperatures in the range 220–270 °C. Over the density range studied (~0.45–0.59 g/cm3), the position of the absorption maximum ([Formula: see text]) of [Formula: see text] is found to shift only slightly to the red with decreasing density. In agreement with our previous work in water, at a fixed pressure, [Formula: see text] decreases monotonically with increasing temperature in passing through the phase transition at Tc(239.5 °C). By contrast, at a fixed density, [Formula: see text] exhibits a minimum as the solvent passes above the critical point into the supercritical state. These behaviors are discussed in terms of microscopic arguments based on the changes that occur in the methanol properties and methanol structure in the sub- and super-critical regimes. The effect of the addition of a small amount of water to the alcohol on the optical absorption energy of [Formula: see text] is also investigated.
Blockade of the Ubiquitin Protease UBP43 Destabilizes Transcription Factor PML/RARα and Inhibits the Growth of Acute Promyelocytic Leukemia
Authors: Guo Yongli , Dolinko Andrey V. , Chinyengetere Fadzai , Stanton Bruce , Bomberger Jennifer M. , Demidenko Eugene , Zhou Da-Cheng , Gallagher Robert , Ma Tian , Galimberti Fabrizio , Liu Xi , Sekula David , Freemantle Sarah , Dmitrovsky Ethan 
Published: October 2010

Abstract
More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative–acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment. Cancer Res; 70(23); 9875–85. ©2010 AACR.
Plasma Micronutrients and the Acquisition and Clearance of Anal Human Papillomavirus Infection: The Hawaii HPV Cohort Study
Authors: Shvetsov Yurii B. , Hernandez Brenda Y. , Wilkens Lynne R. , Thompson Pamela J. , Franke Adrian A. , Zhu Xuemei , Goodman Marc T. 
Published: October 2010

Abstract
Anal human papillomavirus (HPV) infection is common among women and the cause of most anal malignancies. The incidence of anal cancer has been increasing among U.S. women, yet few cofactors for the natural history of anal HPV infection have been identified. We examined the hypothesis that plasma carotenoid, retinol, and tocopherol concentrations are associated with the acquisition and clearance of anal HPV infection in a cohort of 279 Hawaiian residents followed at 4-month intervals for a mean duration of 16 months. At each visit, interviews were conducted and biological specimens were obtained, including anal cell specimens for HPV DNA detection and genotyping, and a fasting blood sample to measure 27 micronutrients. Cohort participants acquired 189 anal HPV infections, 113 of which cleared during the study period. The most frequently acquired HPV genotypes were HPV-52, -53, -84, and -16. Women in the highest quartile of trans-zeaxanthin, trans -anhydro-lutein, and trans-, cis-, and total β-carotene had significant 43% to 50% reduction in the risk of acquisition of any HPV infection compared with women in the lowest quartile. Few associations were observed between micronutrient levels and clearance of transient (≤150 days) anal HPV infections. However, clearance of persistent (&gt;150 days) infections was associated with higher levels of β-tocopherol + γ-tocopherol and lower levels of carotenoids and retinol. Our findings suggest that several carotenoids can reduce the risk and clearance of anal HPV infections that contribute to anal cancer. Cancer Res; 70(23); 9787–97. ©2010 AACR.
Definition of an Enhanced Immune Cell Therapy in Mice That Can Target Stem-Like Lymphoma Cells
Authors: Contag Christopher H. , Sikorski Rachel , Negrin Robert S. , Schmidt Tobi , Fan Alice C. , Bachireddy Pavan , Felsher Dean W. , Thorne Steve H. 
Published: October 2010

AbstractCurrent treatments of high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel therapeutics that can target the residual cancer cells whose phenotypes are distinct from the bulk tumor and that are capable of reforming tumors from very few cells. Oncolytic viruses offer an approach to destroy tumors by multiple mechanisms, but they cannot effectively reach residual disease or micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic tumor killing. In this study, we tested this approach against minimal disease states of lymphomas characterized by the persistence of cancer cells that display stem cell–like properties and resistance to conventional therapies. We found that the immune cells were capable of trafficking to and targeting residual cancer cells. The combination biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual biotherapy could be applied before or after conventional therapy. Our approach offers a potentially powerful new way to clear residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state. Cancer Res; 70(23); 9837–45. ©2010 AACR.
Roles of Fibroblast Growth Factor Receptors in Carcinogenesis
Authors: Haugsten Ellen Margrethe , Wiedlocha Antoni , Olsnes Sjur , Wesche Jørgen 
Published: October 2010

Abstract
The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression. Mol Cancer Res; 8(11); 1439–52. ©2010 AACR.