bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal Dynamics of Cytomegalovirus Chromatin Assembly in Productively Infected Human Cells
Authors: Nitzsche Alexandra , Paulus Christina , Nevels Michael 
Published: September 2008

ABSTRACT
The genomes of herpesviruses, including human cytomegalovirus (CMV), are double-stranded DNA molecules maintained as episomes during infection. The viral DNA lacks histones when encapsidated in the virion. However, it has been found histone associated inside infected cells, implying unidentified chromatin assembly mechanisms. Our results indicate that components of the host cell nucleosome deposition machinery target intranuclear CMV DNA, resulting in stepwise viral-chromatin assembly. CMV genomes undergo limited histone association and nucleosome assembly as early as 30 min after infection via DNA replication-independent mechanisms. Low average viral-genome chromatinization is maintained throughout the early stages of infection. The late phase of infection is characterized by a striking increase in average histone occupancy coupled with the process of viral-DNA replication. While the initial chromatinization affected all analyzed parts of the CMV chromosome, a subset of viral genomic regions, including the major immediate-early promoter, proved to be largely resistant to replication-dependent histone deposition. Finally, our results predict the likely requirement for an unanticipated chromatin disassembly process that enables packaging of histone-free DNA into progeny capsids.
Internal Deletions of IE2 86 and Loss of the Late IE2 60 and IE2 40 Proteins Encoded by Human Cytomegalovirus Affect the Levels of UL84 Protein but Not the Amount of UL84 mRNA or the Loading and Distribution of the mRNA on Polysomes
Authors: Sanders Rebecca L. , Del Rosario Christia J. , White Elizabeth A. , Spector Deborah H. 
Published: September 2008

ABSTRACT
The major immediate-early (IE) region of human cytomegalovirus encodes two IE proteins, IE1 72 and IE2 86, that are translated from alternatively spliced transcripts that differ in their 3′ ends. Two other proteins that correspond to the C-terminal region of IE2 86, IE2 60 and IE2 40, are expressed at late times. In this study, we used IE2 mutant viruses to examine the mechanism by which IE2 86, IE2 60, and IE2 40 affect the expression of a viral DNA replication factor, UL84. Deletion of amino acids (aa) 136 to 290 of IE2 86 results in a significant decrease in UL84 protein during the infection. This loss of UL84 is both proteasome and calpain independent, and the stability of the protein in the context of infection with the mutant remains unaffected. The RNA for UL84 is expressed to normal levels in the mutant virus-infected cells, as are the RNAs for two other proteins encoded by this region, UL85 and UL86. Moreover, nuclear-to-cytoplasmic transport and the distribution of the UL84 mRNA on polysomes are unaffected. A region between aa 290 and 369 of IE2 86 contributes to the UL84-IE2 86 interaction in vivo and in vitro. IE2 86, IE2 60, and IE2 40 are each able to interact with UL84 in the mutant-infected cells, suggesting that these interactions may be important for the roles of UL84 and the IE2 proteins. Thus, these data have defined the contribution of IE2 86, IE2 60, and IE2 40 to the efficient expression of UL84 throughout the infection.
Group A Human Rotavirus Genomics: Evidence that Gene Constellations Are Influenced by Viral Protein Interactions
Authors: Heiman Erica M. , McDonald Sarah M. , Barro Mario , Taraporewala Zenobia F. , Bar-Magen Tamara , Patton John T. 
Published: September 2008

ABSTRACT
Group A human rotaviruses (HRVs) are the major cause of severe viral gastroenteritis in infants and young children. To gain insight into the level of genetic variation among HRVs, we determined the genome sequences for 10 strains belonging to different VP7 serotypes (G types). The HRVs chosen for this study, D, DS-1, P, ST3, IAL28, Se584, 69M, WI61, A64, and L26, were isolated from infected persons and adapted to cell culture to use as serotype references. Our sequencing results revealed that most of the individual proteins from each HRV belong to one of three genotypes (1, 2, or 3) based on their similarities to proteins of genogroup strains (Wa, DS-1, or AU-1, respectively). Strains D, P, ST3, IAL28, and WI61 encode genotype 1 (Wa-like) proteins, whereas strains DS-1 and 69M encode genotype 2 (DS-1-like) proteins. Of the 10 HRVs sequenced, 3 of them (Se584, A64, and L26) encode proteins belonging to more than one genotype, indicating that they are intergenogroup reassortants. We used amino acid sequence alignments to identify residues that distinguish proteins belonging to HRV genotype 1, 2, or 3. These genotype-specific changes cluster in definitive regions within each viral protein, many of which are sites of known protein-protein interactions. For the intermediate viral capsid protein (VP6), the changes map onto the atomic structure at the VP2-VP6, VP4-VP6, and VP7-VP6 interfaces. The results of this study provide evidence that group A HRV gene constellations exist and may be influenced by interactions among viral proteins during replication.
Early B-Cell Activation after West Nile Virus Infection Requires Alpha/Beta Interferon but Not Antigen Receptor Signaling
Authors: Purtha Whitney E. , Chachu Karen A. , Virgin Herbert W. , Diamond Michael S. 
Published: September 2008

ABSTRACTThe B-cell response against West Nile virus (WNV), an encephaliticFlavivirusof global concern, is critical to controlling central nervous system dissemination and neurological sequelae, including death. Here, using a well-characterized mouse model of WNV infection, we examine the factors that govern early B-cell activation. Subcutaneous inoculation with a low dose of replicating WNV results in extensive B-cell activation in the draining lymph node (LN) within days of infection as judged by upregulation of the surface markers CD69, class II major histocompatibility complex, and CD86 on CD19+cells. B-cell activation in the LN but not the spleen was dependent on signals through the type I alpha/beta interferon (IFN-α/β) receptor. Despite significant activation in the draining LN at day 3 after infection, WNV-specific B cells were not detected by immunoglobulin M enzyme-linked immunospot analysis until day 7. Liposome depletion experiments demonstrate that B-cell activation after WNV infection was not affected by the loss of F4/80+or CD169+subcapsular macrophages. Nonetheless, LN myeloid cells were essential for control of viral replication and survival from infection. Overall, our data suggest that the massive, early polyclonal B-cell activation occurring in the draining LN after WNV infection is immunoglobulin receptor and macrophage independent but requires sustained signals through the type I IFN-α/β receptor.
An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats
Authors: Mok Hoyin , Tollefson Sharon J. , Podsiad Amy B. , Shepherd Bryan E. , Polosukhin Vasiliy V. , Johnston Robert E. , Williams John V. , Crowe James E. 
Published: September 2008

ABSTRACTHuman metapneumovirus (hMPV) is a recently discovered paramyxovirus that causes upper and lower respiratory tract infections in infants, the elderly, and immunocompromised individuals worldwide. Here, we developed Venezuelan equine encephalitis virus replicon particles (VRPs) encoding hMPV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and protective efficacy of these vaccine candidates in mice and cotton rats. VRPs encoding hMPV F protein, when administered intranasally, induced F-specific virus-neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. Challenge virus replication was reduced significantly in both the upper and lower respiratory tracts following intranasal hMPV challenge in these animals. However, vaccination with hMPV G protein VRPs did not induce neutralizing antibodies or protect animals from hMPV challenge. Close examination of the histopathology of the lungs of VRP-MPV F-vaccinated animals following hMPV challenge revealed no enhancement of inflammation or mucus production. Aberrant cytokine gene expression was not detected in these animals. Together, these results represent an important first step toward the use of VRPs encoding hMPV F proteins as a prophylactic vaccine for hMPV.
Structural Evolution of
Reoviridae
Revealed by
Oryzavirus
in Acquiring the Second Capsid Shell
Authors: Miyazaki Naoyuki , Uehara-Ichiki Tamaki , Xing Li , Bergman Leif , Higashiura Akifumi , Nakagawa Atsushi , Omura Toshihiro , Cheng R. Holland 
Published: September 2008

ABSTRACT

The conservation of the core structure and diversification of the external features among the turreted reoviruses appear to be relevant to structural evolution in facilitating the infection of diverse host species. The structure of
Rice ragged stunt virus
(RRSV), in the genus
Oryzavirus
of the family
Reoviridae
, is determined to show a core composed of capsid shell, clamps, and long turrets. The RRSV core structure is equivalent to the core structure of
Orthoreovirus
and the virion structure of
Cytoplasmic polyhedrosis virus
(CPV). In RRSV, five peripheral trimers surround each long turret and sit at the Q trimer position in the T=13
l
icosahedral symmetry, a structural feature unique to turreted reoviruses. That is, the core of RRSV is partially covered by 60 copies of the peripheral trimer. In contrast, the core of
Orthoreovirus
is covered by 200 copies of the trimer that sit at the Q, R, S, and T trimer positions. Our results suggest that among the three viruses, RRSV has a structure intermediate between that of
Orthoreovirus
and the CPV virion. This conclusion coincides with the results of the phylogenetic analysis of amino acid sequences of RNA-dependent RNA polymerases.
Dome-building eruptions: insights from analogue experiments
Authors: Lane S. J. , Phillips J. C. , Ryan G. A. 
Published: September 2008

Abstract
Laboratory flows, self-capped by high-viscosity fluid, exhibit vertical pressure gradients similar to those postulated within conduits feeding dome-building eruptions. Overpressure and pressure cycles exhibited at laboratory scale provide insight into the mechanism of tilt cycles at volcanic scale. Experimental pressure cycles correlated with the rate of gas escape, with pressure rise being controlled by diffusion of volatile into bubbles during times when gas escape from the flow was negligible. The increase in pressure continued until margin decrepitation created preferential pathways for rapid gas escape from permeable foam, thereby reducing pressure within the flow. As pressure reduced, the gas escape pathways sealed and diffusion repressurized the system. This implies that tilt cycles, such as those exhibited by the Soufrière Hills Volcano, Montserrat, result from a diffusively pumped process that oscillates around the viscous-elastic transition within the outer regions of the flow. Phases of open- and closed-system degassing result, with gas escaping through fractures created and maintained by the flow process itself. Fluid-dynamically, this mechanism generates an oscillation between Poiseuille flow and plug flow, with a 1-D model of plug motion giving a reasonable representation of observation in both experimental and volcanic cases.
Modelling the rapid near-surface expansion of gas slugs in low-viscosity magmas
Authors: James M. R. , Lane S. J. , Corder S. B. 
Published: September 2008

Abstract

The ascent of large gas bubbles (slugs) in vertical cylindrical conduits and low-viscosity magmas is simulated using 1D mathematical and 3D computational fluid dynamic (CFD) models. Following laboratory evidence, the 1D model defines a constant rise velocity for the slug base and allows gas expansion to accelerate the slug nose through the overlying fluid during ascent. The evolution of rapidly expanding gas slugs observed in laboratory experiments is reproduced well and, at volcano scales, predicts at-surface overpressures of several atmospheres without requiring any initial overpressure at depth. The near-surface dynamics increase slug nose velocities through the overlying magma by a factor of
c
. 2.5 and the gas expansion results in pre-burst magma surface velocities of
c
. 35 m s
−1
. To examine pressure distributions and the forces exerted on a conduit, 3D CFD simulations were carried out. At volcano scales, the vertical single forces during final slug ascent to the surface are
c
. 10
6
N, two orders of magnitude smaller than those associated with very-long-period seismic events at Stromboli. This supports a previous interpretation of these events in which they are generated by gas slugs flowing through changes in conduit geometry, rather than being the direct result of slug eruption processes.
Discovery of a novel class of AKT pleckstrin homology domain inhibitors
Authors: Mahadevan Daruka , Powis Garth , Mash Eugene A. , George Benjamin , Gokhale Vijay M. , Zhang Shuxing , Shakalya Kishore , Du-Cuny Lei , Berggren Margareta , Ali M. Ahad , Jana Umasish , Ihle Nathan , Moses Sylvestor , Franklin Chloe , Narayan Satya , Shirahatti Nikhil , Meuillet Emmanuelle J. 
Published: September 2008

Abstract
AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non–lipid-based compounds that bind selectively to the PH domain of AKT, with “in silico” calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide–dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain–binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide–dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. [Mol Cancer Ther 2008;7(9):2621–32]
Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-κB-dependent mechanism
Authors: Rettig Matthew B. , Heber David , An Jiabin , Seeram Navindra P. , Rao Jian Y. , Liu Huiren , Klatte Tobias , Belldegrun Arie , Moro Aune , Henning Susanne M. , Mo Deqiong , Aronson William J. , Pantuck Allan 
Published: September 2008

Abstract
Constitutive nuclear factor-κB (NF-κB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-κB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-κB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-κB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-κB activity. [Mol Cancer Ther 2008;7(9):2662–71]
Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901
Authors: Leyton Julius , Smith Graham , Lees Mark , Perumal Meg , Nguyen Quang-de , Aigbirhio Franklin I. , Golovko Oksana , He Quimin , Workman Paul , Aboagye Eric O. 
Published: September 2008

Abstract
The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [18F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [18F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUVmax) after 1 day of vehicle or PD0325901 therapy was 1.81 ± 0.18 versus 1.23 ± 0.10, respectively (P = 0.03). In this model, NUVmax after 10 days was 2.07 ± 0.40 versus 1.08 ± 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 ± 0.84 versus 1.88 ± 0.36 (P = 0.045) after 1 day, and 1.97 ± 0.13 versus 1.00 ± 0.03 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [18F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r ≥ 0.6; P ≥ 0.003). In summary, [18F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901. [Mol Cancer Ther 2008;7(9):3112–21]
16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development
Authors: Ducès Aurélie , Karaky Racha , Martel-Renoir Dominique , Mir Lluis , Hamma-Kourbali Yamina , Biéche Ivan , Opolon Paule , Delbé Jean , Courty José , Perricaudet Michel , Griscelli Frank 
Published: September 2008

Abstract
Pleiotrophin (PTN) is a 136-amino acid secreted heparin-binding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTNΔ111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTNΔ111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTNΔ111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1α mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTNΔ111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTNΔ111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer. [Mol Cancer Ther 2008;7(9):2817–27]
A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells
Authors: Kim Byung Hak , Yin Chang-Hong , Guo Qianxu , Bach Erika A. , Lee Haeryun , Sandoval Claudio , Jayabose Somasundaram , Ulaczyk-Lesanko Agnieszka , Hall Dennis G. , Baeg Gyeong-Hun 
Published: September 2008

Abstract
Inappropriate activation of JAK/STAT signaling occurs with high frequency in human cancers and is associated with cancer cell survival and proliferation. Therefore, the development of pharmacologic STAT signaling inhibitors has therapeutic potential in the treatment of human cancers. Here, we report 2-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-1-(4-nitro-phenylamino)-6-phenyl-1,2,4a,7a-tetrahydro-pyrrolo[3,4-b]-pyridine-5,7-dione (AUH-6-96) as a novel small-molecule inhibitor of JAK/STAT signaling that we initially identified through a cell-based high-throughput screening using cultured Drosophila cells. Treatment of Drosophila cells with AUH-6-96 resulted in a reduction of Unpaired-induced transcriptional activity and tyrosine phosphorylation of STAT92E, the sole Drosophila STAT homologue. In human cancer cell lines, AUH-6-96 inhibited both constitutive and interleukin-6-induced STAT3 phosphorylation. Specifically, in Hodgkin lymphoma L540 cells, treatment with AUH-6-96 resulted in reduced levels of tyrosine phosphorylated STAT3 and of the STAT3 downstream target gene SOCS3 in a dose- and time-dependent manner. In addition, AUH-6-96-treated L540 cells showed decreased expression of persistently activated JAK3, suggesting that AUH-6-96 inhibits the JAK/STAT pathway signaling in L540 cells by affecting JAK3 activity and subsequently blocking STAT3 signaling. Importantly, AUH-6-96 selectively affected cell viability only of cancer cells harboring aberrant JAK/STAT signaling. In support of the specificity of AUH-6-96 for inhibition of JAK/STAT signaling, treatment with AUH-6-96 decreased cancer cell survival by inducing programmed cell death by down-regulating the expression of STAT3 downstream target antiapoptotic genes, such as Bcl-xL. In summary, this study shows that AUH-6-96 is a novel small-molecule inhibitor of JAK/STAT signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK/STAT signaling. [Mol Cancer Ther 2008;7(9):2672–80]