bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roscovitine Inhibits EBNA1 Serine 393 Phosphorylation, Nuclear Localization, Transcription, and Episome Maintenance
Authors: Kang Myung-Soo , Lee Eun Kyung , Soni Vishal , Lewis Timothy A. , Koehler Angela N. , Srinivasan Viswanathan , Kieff Elliott 
Published: January 2011

ABSTRACTLatent Epstein-Barr virus (EBV) infection causes human lymphomas and carcinomas. EBV usually persists as an episome in malignant cells. EBV episome persistence, replication, and gene expression are dependent on EBNA1 binding to multiple cognate sites in oriP. To search for inhibitors of EBNA1- and oriP-dependent episome maintenance or transcription, a library of 40,550 small molecules was screened for compounds that inhibit EBNA1- and oriP-dependent transcription and do not inhibit EBNA1- and oriP-independent transcription. This screening identified roscovitine, a selective inhibitor of cyclin-dependent kinase 1 (CDK1), CDK2, CDK5, and CDK7. Based on motif predictions of EBNA1 serine 393 as a CDK phosphorylation site and486RALL489and580KDLVM584as potential cyclin binding domains, we hypothesized that cyclin binding to EBNA1 may enable CDK1, -2, -5, or -7 to phosphorylate serine 393. We found thatEscherichia coli-expressed EBNA1 amino acids 387 to 641 were phosphorylatedin vitroby CDK1-, -2-, -5-, and -7/cyclin complexes and serine 393 phosphorylation was roscovitine inhibited. Further, S393A mutation abrogated phosphorylation. S393A mutant EBNA1 was deficient in supporting EBNA1- and oriP-dependent transcription and episome persistence, and roscovitine had little further effect on the diminished S393A mutant EBNA1-mediated transcription or episome persistence. Immunoprecipitated FLAG-EBNA1 was phosphorylatedin vitro, and roscovitine inhibited this phosphorylation. Moreover, roscovitine decreased nuclear EBNA1 and often increased cytoplasmic EBNA1, whereas S393A mutant EBNA1 was localized equally in the nucleus and cytoplasm and was unaffected by roscovitine treatment. These data indicate that roscovitine effects are serine 393 specific and that serine 393 is important in EBNA1- and oriPCp-dependent transcription and episome persistence.
Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef
Authors: Sloan Richard D. , Kuhl Björn D. , Donahue Daniel A. , Roland André , Bar-Magen Tamara , Wainberg Mark A. 
Published: January 2011

ABSTRACTAlthough transcription from unintegrated human immunodeficiency virus type 1 (HIV-1) DNA can occur inside infected cells, yielding all classes of viral mRNA transcripts, the translation of viral proteins is very limited. One of the proteins made is Nef, but it is unclear whether Nef produced in this way is able to play a role in immune evasion as occurs with integrated virus. We therefore asked whether transcription from preintegrated HIV-1 cDNAs could result in Nef-mediated modulation of cell surface major histocompatibility complex class I (MHC-I) expression. We infected a Rev-CEM green fluorescent protein (GFP) reporter cell line with virus and blocked integration though use of either an inactive integrase or the integrase inhibitor raltegravir. Infected cells were assayed by flow cytometry for cell surface expression of the HLA-A, HLA-B, and HLA-C allotypes (HLA-ABC), HLA-A31, and HLA-E. Viral RNA and DNA products were assayed via quantitative PCR (qPCR). The prevention of integration had no effect, relative to productively infected cells, on levels of expression of multiply spliced viral mRNA transcripts and Nef protein. Downregulation of HLA-ABC and HLA-A31 also occurred at levels similar to those seen in cells in which integration had occurred. Parallel experiments assaying cell surface HLA-ABC expression in infected activated primary CD4+T cells produced a similar pattern of results. Hence, the capacity of HIV-1 to modulate MHC-I is not linked to its ability to integrate. Thus, Nef-mediated evasion of host immune responsiveness might be attributable, in part at least, to transcription from unintegrated viral DNA.
Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza A Virus Replication
Authors: Kumar Naveen , Liang Yuhong , Parslow Tristram G. , Liang Yuying 
Published: January 2011

ABSTRACT
Host signaling pathways play important roles in the replication of influenza virus, but their functional effects remain to be characterized at the molecular level. Here we identify two receptor tyrosine kinase inhibitors (RTKIs) of the tyrphostin class that exhibit robust antiviral activity against influenza A virus replication in cultured cells. One of these (AG879) is a selective inhibitor of the nerve growth factor receptor and human epidermal growth factor receptor 2 (TrkA/HER2) signaling; the other, tyrphostin A9 (A9), inhibits the platelet-derived growth factor receptor (PDGFR) pathway. We find that each inhibits at least three postentry steps of the influenza virus life cycle: AG879 and A9 both strongly inhibit the synthesis of all three influenza virus RNA species, block Crm1-dependent nuclear export, and also prevent the release of viral particles through a pathway that is modulated by the lipid biosynthesis enzyme farnesyl diphosphate synthase (FPPS). Tests of short hairpin RNA (shRNA) knockdown and additional small-molecule inhibitors confirmed that interventions targeting TrkA can suppress influenza virus replication. Our study suggests that host cell receptor tyrosine kinase signaling is required for maximal influenza virus RNA synthesis, viral ribonucleoprotein (vRNP) nuclear export, and virus release and that specific RTKIs hold promise as novel anti-influenza virus therapeutics.
Kaposi's Sarcoma-Associated Herpesvirus ORF57 Promotes Escape of Viral and Human Interleukin-6 from MicroRNA-Mediated Suppression
Authors: Kang Jeong-Gu , Pripuzova Natalia , Majerciak Vladimir , Kruhlak Michael , Le Shu-Yun , Zheng Zhi-Ming 
Published: January 2011

ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) lytic infection increases the expression of viral and human interleukin-6 (vIL-6 and hIL-6, respectively), an important factor for cell growth and pathogenesis. Here, we report genome-wide analysis of viral RNA targets of KSHV ORF57 by a novel UV-cross-linking and immunoprecipitation (CLIP) assay. We identified 11 viral transcripts as putative ORF57 targets and demonstrate that vIL-6 mRNA is an authentic target of ORF57. Disrupting the ORF57 gene in the KSHV genome leads to inefficient expression of vIL-6. With transient transfection, the expression of vIL-6 could be enhanced greatly in the presence of ORF57 in a dose-dependent manner. We found that the open reading frame (ORF) region of vIL-6 RNA contains an MRE (MTA [ORF57]-responsive element) composed of two motifs, MRE-A and MRE-B, and binding of ORF57 to these two motifs stabilizes vIL-6 RNA and promotes vIL-6 translation. We demonstrate that vIL-6 MRE-B bears an miR-1293 binding site and that, mechanistically, ORF57 competes with miR-1293 for the same binding site to interact with vIL-6 RNA, thereby preventing vIL-6 RNA from association with the miR-1293-specified RNA-induced silencing complex (RISC). Consistent with this, ORF57 also interacts with an miR-608 binding site in the hIL-6 ORF and prevents miR-608 repression of hIL-6. Collectively, our results identify a novel function of ORF57 in being responsible for stabilization of viral and human IL-6 RNAs and the corresponding enhancement of RNA translation. In addition, our data provide the first evidence that a tumor virus may use a viral protein to interfere with microRNA (miRNA)-mediated repression of an miRNA target to induce cell proliferation and tumorigenesis during virus infection.
A Comprehensive Structure-Function Comparison of Hepatitis C Virus Strain JFH1 and J6 Polymerases Reveals a Key Residue Stimulating Replication in Cell Culture across Genotypes
Authors: Schmitt Melanie , Scrima Nathalie , Radujkovic Danijela , Caillet-Saguy Célia , Simister Philip C. , Friebe Peter , Wicht Oliver , Klein Rahel , Bartenschlager Ralf , Lohmann Volker , Bressanelli Stéphane 
Published: January 2011

ABSTRACT

The hepatitis C virus (HCV) genotype 2a isolate JFH1 represents the only cloned HCV wild-type sequence capable of efficient replication in cell culture as well as
in vivo
. Previous reports have pointed to NS5B, the viral RNA-dependent RNA polymerase (RdRp), as a major determinant for efficient replication of this isolate. To understand the contribution of the JFH1 NS5B gene at the molecular level, we aimed at conferring JFH1 properties to NS5B from the closely related J6 isolate. We created intragenotypic chimeras in the NS5B regions of JFH1 and J6 and compared replication efficiency in cell culture and RdRp activity of the purified proteins
in vitro
, revealing more than three independent mechanisms conferring the role of JFH1 NS5B in efficient RNA replication. Most critical was residue I405 in the thumb domain of the polymerase, which strongly stimulated replication in cell culture by enhancing overall
de novo
RNA synthesis. A structural comparison of JFH1 and J6 at high resolution indicated a clear correlation of a closed-thumb conformation of the RdRp and the efficiency of the enzyme at
de novo
RNA synthesis, in accordance with the proposal that I405 enhances
de novo
initiation. In addition, we identified several residues enhancing replication independent of RdRp activity
in vitro
. The functional properties of JFH1 NS5B could be restored by a few single-nucleotide substitutions to the J6 isolate. Finally, we were able to enhance the replication efficiency of a genotype 1b isolate with the I405 mutation, indicating that this mechanism of action is conserved across genotypes.
Budding Capability of the Influenza Virus Neuraminidase Can Be Modulated by Tetherin
Authors: Yondola Mark A. , Fernandes Fiona , Belicha-Villanueva Alan , Uccelini Melissa , Gao Qinshan , Carter Carol , Palese Peter 
Published: January 2011

ABSTRACT
We have determined that, in addition to its receptor-destroying activity, the influenza virus neuraminidase is capable of efficiently forming virus-like particles (VLPs) when expressed individually from plasmid DNA. This observation applies to both human subtypes of neuraminidase, N1 and N2. However, it is not found with every strain of influenza virus. Through gain-of-function and loss-of-function analyses, a critical determinant within the neuraminidase ectodomain was identified that contributes to VLP formation but is not sufficient to accomplish release of plasmid-derived VLPs. This sequence lies on the plasma membrane-proximal side of the neuraminidase globular head. Most importantly, we demonstrate that the antiviral restriction factor tetherin plays a role in determining the strain-specific limitations of release competency. If tetherin is counteracted by small interfering RNA knockdown or expression of the HIV anti-tetherin factor vpu, budding and release capability is bestowed upon an otherwise budding-deficient neuraminidase. These data suggest that budding-competent neuraminidase proteins possess an as-yet-unidentified means of counteracting the antiviral restriction factor tetherin and identify a novel way in which the influenza virus neuraminidase can contribute to virus release.
Genetic Elements in the VP Region of Porcine Parvovirus Are Critical to Replication Efficiency in Cell Culture
Authors: Fernandes Sandra , Boisvert Maude , Tijssen Peter 
Published: January 2011

ABSTRACT

Factors controlling porcine parvovirus (PPV) replication efficiency are poorly characterized. Two prototype strains of PPV, NADL-2 and Kresse, differ greatly in pathogenic capacity both
in vivo
and
in vitro
, yet their genomic sequence is nearly identical (13 single-nucleotide substitutions and a 127-nucleotide noncoding repeated sequence). We have created a series of chimeras of these strains to identify the genetic elements involved in replication efficiency in the host porcine cell line. While the capsid proteins ultimately determine viral replication fitness, interaction between the NS1 protein and the
VP
gene occurs and involves interaction with the noncoding repeated sequence.
Functional Genetic and Biophysical Analyses of Membrane Disruption by Human Adenovirus
Authors: Moyer Crystal L. , Wiethoff Christopher M. , Maier Oana , Smith Jason G. , Nemerow Glen R. 
Published: January 2011

ABSTRACT
The identification of the adenovirus (AdV) protein that mediates endosome penetration during infection has remained elusive. Several lines of evidence from previous studies suggest that the membrane lytic factor of AdV is the internal capsid protein VI. While these earlier results imply a role for protein VI in endosome disruption, direct evidence during cell entry has not been demonstrated. To acquire more definitive proof, we engineered random mutations in a critical N-terminal amphipathic α-helix of VI in an attempt to generate AdV mutants that lack efficient membrane penetration and infection. Random mutagenesis within the context of the AdV genome was achieved via the development of a novel technique that incorporates both error-prone PCR and recombineering. Using this system, we identified a single mutation, L40Q, that significantly reduced infectivity and selectively impaired endosome penetration. Furthermore, we obtained biophysical data showing that the lack of efficient endosomalysis is associated with reduced insertion of the L40Q mutation in protein VI (VI-L40Q) into membranes. Our studies indicate that protein VI is the critical membrane lytic factor of AdV during cellular entry and reveal the biochemical basis for its membrane interactions.
Effects of Microtubule Modulators on HIV-1 Infection of Transformed and Resting CD4 T Cells
Authors: Yoder Alyson , Guo Jia , Yu Dongyang , Cui Zongqiang , Zhang Xian-En , Wu Yuntao 
Published: January 2011

ABSTRACTPrevious studies have observed fluorescently labeled HIV particles tracking along microtubule networks for nuclear localization. To provide direct evidence for the involvement of microtubules in early steps of HIV infection of human CD4 T cells, we used multiple microtubule modulators such as paclitaxel (originally called taxol; 1 μM), vinblastine (1 and 10 μM), colchicine (10 and 100 μM), and nocodazole (10 and 100 μM) to disturb microtubule networks in transformed and resting CD4 T cells. Although these drugs disrupted microtubule integrity, almost no inhibition of HIV-1 infection was observed. Our results do not appear to support an essential role for microtubules in the initiation of HIV infection of CD4 T cells.
The nature and origin of the Barrovian metamorphism, Scotland:
40
Ar/
39
Ar apparent age patterns and the duration of metamorphism in the biotite zone
Authors: Viete Daniel R. , Forster Marnie A. , Lister Gordon S. 
Published: January 2011

Abstract:

A geochronological traverse across the Barrovian metamorphic series, Scotland, shows
40
Ar/
39
Ar apparent age spectra that reflect the influence of progressive metamorphism during the Grampian orogenic episode. The lowest-grade units of the Barrovian metamorphic series retain pre-Grampian detrital ages as components of their white mica
40
Ar/
39
Ar apparent age spectra. These relict ages are progressively obliterated in the direction of increasing metamorphic grade, with a Grampian-age
40
Ar/
39
Ar step-heating plateau first occurring in the biotite zone. The microstructure at this point shows only limited recrystallization, suggesting loss of argon mainly by diffusion. Forward modelling of argon diffusion from white mica grains was therefore carried out, for various thermal histories and grain sizes, to match
40
Ar/
39
Ar step-heating apparent age spectra patterns preserved within the biotite zone of the Barrovian metamorphic series. The results imply a thermal duration of between 1 and 10 Ma for Barrovian metamorphism in the biotite zone. Such short time scales for metamorphism place a limit on length scales for the heat sources responsible. Mid-crustal extensional ductile shear zones that crop out in the NE of the Grampian Terrane once focused narrow, Grampian-age heat sources (e.g. magmas, hot fluids, shear heating) that drove a brief thermal episode, resulting in the Barrovian metamorphism.

Supplementary material:

40
Ar/
39
Ar data tables and plots, including (1) data from analyses on flux monitors and plots used for
J
-factor determination, and (2) data from analyses on unknowns and
40
Ar/
39
Ar step-heating spectra and inverse isochron plots for each unknown, are available at
http://www.geolsoc.org.uk/SUP18442
.
Early Cenozoic saucer-shaped sills of the Faroe Islands: an example of intrusive styles in basaltic lava piles
Authors: Hansen J. , Jerram D.A. , McCaffrey K. , Passey S.R. 
Published: January 2011

Abstract:

The Early Cenozoic igneous activity of the North Atlantic Igneous Province that generated widespread sill complexes in sedimentary basins at the NW European margins also generated various intrusive systems in the contemporaneous basaltic lava pile of the Faroe Islands. The Faroe Island Basalt Group comprises seven formations with a total thickness of about 6.5 km, of which four major formations are built up of tholeiitic lava flows, each being several hundred metres thick, and three thinner formations are mostly built up of volcaniclastic lithologies, each being a few metres to a few tens of metres thick. The largest sills are exposed as partly saucer-shaped bodies in the three uppermost formations, where inner gently dipping basal sill sections gradually give way to more steeply inclined discordant outer rims that commonly cut several hundred metres into overlying lava flows. Numerous subvertical and moderately inclined dykes ranging in thickness from
c
. 0.5 to
c
. 4.0 m intersect the areas affected by sill intrusion, but only inclined dykes or sheets have been positively identified as sill feeders. Locally controlled rotations of least principal stress axes σ
3
during initial sill intrusion or propagation may have been an important contributing factor in determining the overall geometry of the investigated intrusions.
Timing of regional deformation and development of the Moine Thrust Zone in the Scottish Caledonides: constraints from the U–Pb geochronology of alkaline intrusions
Authors: Goodenough K.M. , Millar I. , Strachan R.A. , Krabbendam M. , Evans J.A. 
Published: January 2011

Abstract:
The Moine Thrust Zone in the Scottish Highlands developed during the Scandian Event of the Caledonian Orogeny, and now forms the boundary between the Caledonian orogenic belt and the undeformed foreland. The Scandian Event, and the formation of the Moine Thrust Zone, have previously been dated by a range of isotopic methods, and relatively imprecise ages on a suite of alkaline intrusions localized along the thrust zone have provided the best age constraints for deformation. Recent British Geological Survey mapping has improved our understanding of the structural relationships of some of these intrusions, and this work is combined with new U–Pb dates in this paper to provide significantly improved ages for the Moine Thrust Zone. Our work shows that a single early intrusion (the Glen Dessarry Pluton) was emplaced within the orogenic belt to the east of the Moine Thrust Zone at 447.9 ± 2.9 Ma. A more significant pulse of magmatism centred in the Assynt area, which temporally overlapped movement in the thrust zone, occurred at 430.7 ± 0.5 Ma. Movement in the thrust zone had largely ceased by the time of emplacement of the youngest intrusions, the late suite of the Loch Borralan Pluton, at 429.2 ± 0.5 Ma, and the Loch Loyal Syenite Complex.
LISPB DELTA, a lithospheric seismic profile in Britain: analysis and interpretation of the Wales and southern England section
Authors: Maguire Peter , England Richard , Hardwick Anthony 
Published: January 2011

Abstract:
The Lithospheric Seismic Profile in Britain (LISPB), shot in 1974, included a 310 km profile LISPB DELTA, crossing the Palaeozoic Welsh Basin, the western extent of the Midland microcraton and the Cornubian zone of southern England. This first comprehensive analysis of these data has produced a sub-horizontally layered seismic and associated gravity model that correlates well with surface geology. A north–south decrease in crustal velocity and density corresponds to the change from Avalonian crust into the Rheno-Hercynian zone at the south end of the profile. High velocities and densities in the lowest crustal layer beneath north Wales are proposed to result from Cenozoic and possibly Ordovician igneous intrusive rocks, the former derived from an upwelling plume associated with the opening of the North Atlantic. Examination of the load distribution throughout the model shows that it is strongly correlated with the earthquake distribution along LISPB DELTA. Earthquake focal depth also correlates with heat flow. A simple heat-flow profile has been derived, and the seismic velocity model used to constrain crustal heat production values. A long-wavelength excursion from published data can be explained in terms of an increase in mantle heat flow resulting from a previously identified deep thermal anomaly beneath the Irish Sea.

Supplementary material:
normalised, synthetic and true amplitude seismic record sections including picks and modelled phases for shots SP04, SP05, SPS1, SPS2 are available at http://www.geolsoc.org.uk/SUP18450.
Pb-isotopic evidence for rapid trench-parallel mantle flow beneath Vanuatu
Authors: Heyworth Z. , Knesel K.M. , Turner S.P. , Arculus R.J. 
Published: January 2011

Abstract:

Recent geophysical and geochemical studies suggest that some subduction zones have a significant component of trench-parallel flow that is difficult to reconcile with conventional 2D corner-flow models. Mapping of different mantle Pb-isotopic signatures provides an opportunity to assess the role of along-strike flow beneath the Vanuatu region. Young back-arc spreading centres in the southern segment of the subduction zone have high
208
Pb/
204
Pb for a given
206
Pb/
204
Pb, similar to the Indian-type mantle signatures of present-day volcanoes in the central segment of the arc, but distinct from adjacent southern-arc volcanoes with Pacific-like mantle traits. This configuration indicates that convection in the mantle wedge beneath Vanuatu is dominated by southward flow parallel to the trench, rather than pure corner flow induced by viscous drag along the upper surface of the subducting plate. We propose that this southward flow is related to pressure gradients developed during asymmetric rollback of the Australian plate. Trench-parallel flow rates in Vanuatu are estimated at 10–28 cm a
−1
, further highlighting that along-strike flow can exceed the convergence-parallel mantle motions predicted from conventional 2D corner-flow models.
Reconciling deep seismogenic and shallow active faults through analogue modelling: the case of the Messina Straits (southern Italy)
Authors: Bonini Lorenzo , Bucci Daniela Di , Toscani Giovanni , Seno Silvio , Valensise Gianluca 
Published: January 2011

Abstract:

The catastrophic 28 December 1908, M
w
7.1, Messina Straits earthquake was generated by a large, low-angle, SE-dipping, blind normal fault. A number of shallow, high-angle normal faults arranged in a graben-like fashion occur in the same area both on land and offshore, reaching the surface and in some instances affecting recent deposits. These faults are normally interpreted as active and have often been considered potentially seismogenic. We used an analogue modelling approach to simulate the evolution of a large, low-angle normal fault and investigate its relationships with the overlying secondary faults. We find that these faults represent the brittle surface expression of the long-term activity of the underlying master fault, and that all faults mapped by previous workers in the Messina Straits are compatible with sustained slip along the fault responsible for the 1908 earthquake. Our results confirm that analogue modelling provides a useful tool to investigate the evolution and the hierarchical relationships of fault systems, suggesting that this approach is effective in the investigation of complex seismogenic areas.