bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiangiogenic Arming of an Oncolytic Vaccinia Virus Enhances Antitumor Efficacy in Renal Cell Cancer Models
Authors: Guse Kilian , Sloniecka Marta , Diaconu Iulia , Ottolino-Perry Kathryn , Tang Nan , Ng Calvin , Le Boeuf Fabrice , Bell John C. , McCart J. Andrea , Ristimäki Ari , Pesonen Sari , Cerullo Vincenzo , Hemminki Akseli 
Published: November 2009

ABSTRACTOncolytic vaccinia viruses have shown compelling results in preclinical cancer models and promising preliminary safety and antitumor activity in early clinical trials. However, to facilitate systemic application it would be useful to improve tumor targeting and antitumor efficacy further. Here we report the generation of vvdd-VEGFR-1-Ig, a targeted and armed oncolytic vaccinia virus. Tumor targeting was achieved by deletion of genes for thymidine kinase and vaccinia virus growth factor, which are necessary for replication in normal but not in cancer cells. Given the high vascularization typical of kidney cancers, we armed the virus with the soluble vascular endothelial growth factor (VEGF) receptor 1 protein for an antiangiogenic effect. Systemic application of high doses of vvdd-VEGFR-1-Ig resulted in cytokine induction in an immunocompromised mouse model. Upon histopathological analysis, splenic extramedullary hematopoiesis was seen in all virus-injected mice and was more pronounced in the vvdd-VEGFR-1-Ig group. Analysis of the innate immune response after intravenous virus injection revealed high transient and dose-dependent cytokine elevations. When medium and low doses were used for intratumoral or intravenous injection, vvdd-VEGFR-1-Ig exhibited a stronger antitumor effect than the unarmed control. Furthermore, expression of VEGFR-1-Ig was confirmed, and a concurrent antiangiogenic effect was seen. In an immunocompetent model, systemic vvdd-VEGFR-1-Ig exhibited superior antitumor efficacy compared to the unarmed control virus. In conclusion, the targeted and armed vvdd-VEGFR-1-Ig has promising anticancer activity in renal cell cancer models. Extramedullary hematopoiesis may be a sensitive indicator of vaccinia virus effects in mice.
Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+T Cells Are Important in Control of SARS-CoV Infection
Authors: Chen Jun , Lau Yuk Fai , Lamirande Elaine W. , Paddock Christopher D. , Bartlett Jeanine H. , Zaki Sherif R. , Subbarao Kanta 
Published: November 2009

ABSTRACTWe characterized the cellular immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 12- to 14-month-old BALB/c mice, a model that mimics features of the human disease. Following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. Enhanced production of cytokines (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) correlated with migration of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of cytokines (TNF-α, IL-6, gamma interferon [IFN-γ], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. Depletion of CD8+T cells at the time of infection did not affect viral replication or clearance. However, depletion of CD4+T cells resulted in an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs, which was associated with reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of lymphocytes. Innate defense mechanisms are able to control SARS-CoV infection in the absence of CD4+and CD8+T cells and antibodies. Our findings provide new insights into the pathogenesis of SARS, demonstrating the important role of CD4+but not CD8+T cells in primary SARS-CoV infection in this model.
Wide-Scale Use of Notch Signaling Factor CSL/RBP-Jκ in RTA-Mediated Activation of Kaposi's Sarcoma-Associated Herpesvirus Lytic Genes
Authors: Persson Linda M. , Wilson Angus C. 
Published: November 2009

ABSTRACT

For Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8 [HHV8]), the switch from latency to active lytic replication requires RTA, the product of open reading frame 50 (ORF50). RTA activates transcription from nearly 40 early and delayed-early viral promoters, mainly through interactions with cellular DNA binding proteins, such as CSL/RBP-Jκ, Oct-1, C/EBPα, and c-Jun. Reliance on cellular coregulators may allow KSHV to adjust its lytic program to suit different cellular contexts or interpret signals from the outside. CSL is a key component of the Notch signaling pathway and is targeted by several viruses. A search with known CSL binding sequences from cellular genes found at least 260 matches in the KSHV genome, many from regions containing known or suspected lytic promoters. Analysis of clustered sites located immediately upstream of ORF70 (thymidylate synthase), ORF19 (tegument protein), and ORF47 (glycoprotein L) uncovered RTA-responsive promoters that were validated using mRNAs isolated from KSHV-infected cells undergoing lytic reactivation. Notably, ORF19 behaves as a true late gene, indicating that RTA regulates all three phases of the lytic program. For each new promoter, the response to RTA was dependent on CSL, and 5 of the 10 candidate sites were shown to bind CSL
in vitro
. Analysis of individual sites highlighted the importance of a cytosine residue flanking the core CSL binding sequence. These findings broaden the role for CSL in coordinating the KSHV lytic gene expression program and help to define a signature motif for functional CSL sites within the viral genome.
Recombination, Reservoirs, and the Modular Spike: Mechanisms of Coronavirus Cross-Species Transmission
Authors: Graham Rachel L. , Baric Ralph S. 
Published: November 2009

ABSTRACTOver the past 30 years, several cross-species transmission events, as well as changes in virus tropism, have mediated significant animal and human diseases. Most notable is severe acute respiratory syndrome (SARS), a lower respiratory tract disease of humans that was first reported in late 2002 in Guangdong Province, China. The disease, which quickly spread worldwide over a period of 4 months spanning late 2002 and early 2003, infected over 8,000 individuals and killed nearly 800 before it was successfully contained by aggressive public health intervention strategies. A coronavirus (SARS-CoV) was identified as the etiological agent of SARS, and initial assessments determined that the virus crossed to human hosts from zoonotic reservoirs, including bats, Himalayan palm civets (Paguma larvata), and raccoon dogs (Nyctereutes procyonoides), sold in exotic animal markets in Guangdong Province. In this review, we discuss the molecular mechanisms that govern coronavirus cross-species transmission bothin vitroandin vivo, using the emergence of SARS-CoV as a model. We pay particular attention to how changes in the Spike attachment protein, both within and outside of the receptor binding domain, mediate the emergence of coronaviruses in new host populations.
Mutations in the Ectodomain of Newcastle Disease Virus Fusion Protein Confer a Hemagglutinin-Neuraminidase-Independent Phenotype
Authors: Ayllón Juan , Villar Enrique , Muñoz-Barroso Isabel 
Published: November 2009

ABSTRACT
The entry of enveloped viruses into host cells is preceded by membrane fusion, which in paramyxoviruses is triggered by the fusion (F) protein. Refolding of the F protein from a metastable conformation to a highly stable postfusion form is critical for the promotion of fusion, although the mechanism is still not well understood. Here we examined the effects of mutations of individual residues of the F protein of Newcastle disease virus, located at critical regions of the protein, such as the C terminus of the N-terminal heptad repeat (HRA) and the N terminus of the C-terminal heptad repeat (HRB). Seven of the mutants were expressed at the cell surface, showing differences in antibody reactivity in comparison with the F wild type. The N211A, L461A, I463A, and I463F mutants showed a hyperfusogenic phenotype both in syncytium and in dye transfer assays. The four mutants promoted fusion more efficiently at lower temperatures than the wild type did, meaning they probably had lower energy requirements for activation. Moreover, the N211A, I463A, and I463F mutants exhibited hemagglutinin-neuraminidase (HN)-independent activity when influenza virus hemagglutinin (HA) was coexpressed as an attachment protein. The data are discussed in terms of alterations of the refolding pathway and/or the stability of the prefusion and fusion conformations.
Temperature Protects Insect Cells from Infection by Cricket Paralysis Virus
Authors: Cevallos Randal C. , Sarnow Peter 
Published: November 2009

ABSTRACT

Heat shock is a well-known stress response characterized by a rapid synthesis of a set of proteins which are responsible for protection against stress. We examined the role of temperature on the growth of cricket paralysis virus, a member of the family
Dicistroviridae
, in insect cells. Heat shock caused an induction of heat shock protein-encoding mRNAs in uninfected cells but not in infected cells. While viral RNA and protein were abundant during heat shock, virion formation was inhibited at higher temperatures. The different susceptibility to pathogens at different temperatures is likely a crucial feature of host-pathogen interaction in cold-blooded animals.
Some Attenuated Variants of Vesicular Stomatitis Virus Show Enhanced Oncolytic Activity against Human Glioblastoma Cells relative to Normal Brain Cells
Authors: Wollmann Guido , Rogulin Vitaliy , Simon Ian , Rose John K. , van den Pol Anthony N. 
Published: November 2009

ABSTRACT

Vesicular stomatitis virus (VSV) has been shown in laboratory studies to be effective against a variety of tumors, including malignant brain tumors. However, attenuation of VSV may be necessary to balance the potential toxicity toward normal cells, particularly when targeting brain tumors. Here we compared 10 recombinant VSV variants resulting from different attenuation strategies. Attenuations included gene shifting (VSV-p1-GFP/RFP), M protein mutation (VSV-M51), G protein cytoplasmic tail truncations (VSV-CT1/CT9), G protein deletions (VSV-dG-GFP/RFP), and combinations thereof (VSV-CT9-M51). Using
in vitro
viability and replication assays, the VSV variants were grouped into three categories, based on their antitumor activity and non-tumor-cell attenuation. In the first group, wild-type-based VSV-G/GFP, tumor-adapted VSV-rp30, and VSV-CT9 showed a strong antitumor profile but also retained some toxicity toward noncancer control cells. The second group, VSV-CT1, VSV-dG-GFP, and VSV-dG-RFP, had significantly diminished toxicity toward normal cells but showed little oncolytic action. The third group displayed a desired combination of diminished general toxicity and effective antitumor action; this group included VSV-M51, VSV-CT9-M51, VSV-p1-GFP, and VSV-p1-RFP. A member of the last group, VSV-p1-GFP, was then compared
in vivo
against wild-type-based VSV-G/GFP. Intranasal inoculation of young, postnatal day 16 mice with VSV-p1-GFP showed no adverse neurological effects, whereas VSV-G/GFP was associated with high lethality (80%). Using an intracranial tumor xenograft model, we further demonstrated that attenuated VSV-p1-GFP targets and kills human U87 glioblastoma cells after systemic application. We concluded that some, but not all, attenuated VSV mutants display a favorable oncolytic profile and merit further investigation.
Immune Evasion Proteins of Murine Cytomegalovirus Preferentially Affect Cell Surface Display of Recently Generated Peptide Presentation Complexes
Authors: Lemmermann Niels A. W. , Gergely Kerstin , Böhm Verena , Deegen Petra , Däubner Torsten , Reddehase Matthias J. 
Published: November 2009

ABSTRACTFor recognition of infected cells by CD8 T cells, antigenic peptides are presented at the cell surface, bound to major histocompatibility complex class I (MHC-I) molecules. Downmodulation of cell surface MHC-I molecules is regarded as a hallmark function of cytomegalovirus-encoded immunoevasins. The molecular mechanisms by which immunoevasins interfere with the MHC-I pathway suggest, however, that this downmodulation may be secondary to an interruption of turnover replenishment and that hindrance of the vesicular transport of recently generated peptide-MHC (pMHC) complexes to the cell surface is the actual function of immunoevasins. Here we have used the model of murine cytomegalovirus (mCMV) infection to provide experimental evidence for this hypothesis. To quantitate pMHC complexes at the cell surface after infection in the presence and absence of immunoevasins, we generated the recombinant viruses mCMV-SIINFEKL and mCMV-Δm06m152-SIINFEKL, respectively, expressing the Kb-presented peptide SIINFEKL with early-phase kinetics in place of an immunodominant peptide of the viral carrier protein gp36.5/m164. The data revealed ∼10,000 Kbmolecules presenting SIINFEKL in the absence of immunoevasins, which is an occupancy of ∼10% of all cell surface Kbmolecules, whereas immunoevasins reduced this number to almost the detection limit. To selectively evaluate their effect on preexisting pMHC complexes, cells were exogenously loaded with SIINFEKL peptide shortly after infection with mCMV-SIINFEKA, in which endogenous presentation is prevented by an L174A mutation of the C-terminal MHC-I anchor residue. The data suggest that pMHC complexes present at the cell surface in advance of immunoevasin gene expression are downmodulated due to constitutive turnover in the absence of resupply.
Interactions between Lipids and Human Anti-HIV Antibody 4E10 Can Be Reduced without Ablating Neutralizing Activity
Authors: Xu Hengyu , Song Likai , Kim Mikyung , Holmes Margaret A. , Kraft Zane , Sellhorn George , Reinherz Ellis L. , Stamatatos Leonidas , Strong Roland K. 
Published: November 2009

ABSTRACT
Human 4E10 is one of the broadest-specificity, HIV-1-neutralizing monoclonal antibodies known, recognizing a membrane-proximal linear epitope on gp41. The lipid cross-reactivity of 4E10 has been alternately suggested either to contribute to the apparent rarity of 4E10-like antibody responses in HIV infections, through elimination by B-cell tolerance mechanisms to self-antigens, or to contribute to neutralization potency by virus-specific membrane binding outside of the membrane-proximal external region (MPER). To investigate how 4E10 interacts with membrane and protein components, and whether such interactions contribute to neutralization mechanisms, we introduced two mutations into 4E10 Fv constructs, Trp to Ala at position 100 in the heavy chain [W(H100)A] and Gly to Glu at position 50 in the light chain [G(L50)E], selected to disrupt potential lipid interactions via different mechanisms. Wild-type and mutant Fvs all bound with the same affinity to peptides and monomeric and trimeric gp140s, but the affinities for gp140s were uniformly 10-fold weaker than to peptides. 4E10 Fv binding responses to liposomes in the presence or absence of MPER peptides were weak in absolute terms, consistent with prior observations, and both mutations attenuated interactions even further, as predicted. The W(H100)A mutation reduced neutralization efficiency against four HIV-1 isolates, but the G(L50)E mutation increased potency across the same panel. Electron paramagnetic resonance experiments showed that the W(H100)A mutation, but not the G(L50)E mutation, reduced the ability of 4E10 to extract MPER peptides from membranes. These results show that 4E10 nonspecific membrane binding is separable from neutralization, which is achieved through specific peptide/lipid orientation changes.
LINEAR TWO-DIMENSIONAL MHD OF ACCRETION DISKS: CRYSTALLINE STRUCTURE AND NERNST COEFFICIENT
Authors: MONTANI GIOVANNI , BENINI RICCARDO 
Published: November 2009

We analyse the two-dimensional MHD configurations characterising the steady state of the accretion disk on a highly magnetised neutron star. The model we describe has a local character and represents the extension of the crystalline structure outlined in Ref. 1, dealing with a local model too, when a specific accretion rate is taken into account. We limit our attention to the linearised MHD formulation of the electromagnetic back-reaction characterising the equilibrium, by fixing the structure of the radial, vertical and azimuthal profiles. Since we deal with toroidal currents only, the consistency of the model is ensured by the presence of a small collisional effect, phenomenologically described by a nonzero constant Nernst coefficient (thermal power of the plasma). Such an effect provides a proper balance of the electron force equation via nonzero temperature gradients, related directly to the radial and vertical velocity components. We show that the obtained profile has the typical oscillating feature of the crystalline structure, reconciled with the presence of viscosity, associated to the differential rotation of the disk, and with a net accretion rate. In fact, we provide a direct relation between the electromagnetic reaction of the disk and the (no longer zero) increasing of its mass per unit time. The radial accretion component of the velocity results to be few orders of magnitude below the equatorial sound velocity. Its oscillating-like character does not allow a real matter in-fall to the central object (an effect to be searched into nonlinear MHD corrections), but it accounts for the outgoing of steady fluxes, favourable to the ring-like morphology of the disk.
On the Tropospheric Ozone Variations in a Coastal Area of Southwestern Europe under a Mesoscale Circulation
Authors: Adame J. A. , Serrano E. , Bolívar J. P. , de la Morena B. A. 
Published: November 2009

Abstract
It is well established that surface ozone levels are greatly affected by orography, solar radiation intensity, meteorological conditions, and the levels of their precursors. In this work, the authors study the sea–land breeze circulation in its relation with the behavior of ozone in a coastal area, located in southwestern Europe, with high levels of solar radiation and an important industrial complex emitting air pollutants. Hourly mean data over a 7-yr period (1999–2005) have been used in the study. Two patterns of sea–land breeze have been identified after analyzing 2298 days of measurements: a “pure” breeze (179 cases) and another one, called a “nonpure” breeze (284 cases), which is the resulting flow of the former and northwesterlies synoptic forcing. Among other results, the highest levels of surface ozone were observed under pure sea–land breeze, with hourly values up to 100 μg m−3 in the mean daily evolution. In contrast, for a nonpure breeze, the 24-h average daily value was lower than the corresponding one under a pure breeze by a factor of 1.16 and could reach 1.60 in representative real cases. These findings give evidence that the formation and accumulation of ozone are favored by the conditions under a pure sea–land breeze: that is, perpendicular wind directions toward the coastline, effective recirculation of air masses, and formation of ozone residual layers above the sea. Because these atmospheric conditions occur in other coastal regions in the world, the conclusions of this study could be extended to them.
Performance Assessment of New Land Surface and Planetary Boundary Layer Physics in the WRF-ARW
Authors: Gilliam Robert C. , Pleim Jonathan E. 
Published: November 2009

Abstract
The Pleim–Xiu land surface model, Pleim surface layer scheme, and Asymmetric Convective Model (version 2) are now options in version 3.0 of the Weather Research and Forecasting model (WRF) Advanced Research WRF (ARW) core. These physics parameterizations were developed for the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5) and have been used extensively by the air quality modeling community, so there was a need based on several factors to extend these parameterizations to WRF. Simulations executed with the new WRF physics are compared with simulations produced with the MM5 and another WRF configuration with a focus on the replication of near-surface meteorological conditions and key planetary boundary layer features. The new physics in WRF is recommended for retrospective simulations, in particular, those used to drive air quality simulations. In the summer, the error of all variables analyzed was slightly lower across the domain in the WRF simulation that used the new physics than in the similar MM5 configuration. This simulation had an even lower error than the other more common WRF configuration. For the cold season case, the model simulation was not as accurate as the other simulations overall, but did well in terms of lower 2-m temperature error in the western part of the model domain (plains and Rocky Mountains) and most of the Northeast. Both MM5 and the other WRF configuration had lower errors across much of the southern and eastern United States in the winter. The 2-m water vapor mixing ratio and 10-m wind were generally well simulated by the new physics suite in WRF when contrasted with the other simulations and modeling studies. Simulated planetary boundary layer features were compared with both wind profiler and aircraft observations, and the new WRF physics results in a more precise wind and temperature structure not only in the stable boundary layer, but also within most of the convective boundary layer. These results suggest that the WRF performance is now at or above the level of MM5. It is thus recommended to drive future air quality applications.
Investigating Time-Scale Effects on Reference Evapotranspiration from Epan Data in North China
Authors: Li Yi , Horton Robert , Ren Tusheng , Chen Chunyan 
Published: November 2009

Abstract
Reference evapotranspiration (ETo) and pan evaporation (Epan) are key parameters in hydrological and meteorological studies. The authors’ objectives were to evaluate the ratio of ETo to Epan (kp) at daily and monthly scales and to predict average ETo in the following years using calibrated kp and observed Epan at the two time scales. Using 50 yr of data obtained at six typical sites in north China, daily and monthly ETo were calculated using the Food and Agriculture Organization estimation method (FAO-56) Penman–Monteith equation, and kp values were determined at the two time scales. Values of kp varied from 0.457 to 0.589 daily and from 0.392 to 0.528 monthly for the six sites. Both daily and monthly kp could be fitted as multilinear functions of longitude, latitude, elevation, and relative humidity. Relatively accurate predictions of daily mean ETo for the subsequent years following the calibration years at all six sites were obtained when the year number L used for calibrating daily mean kp was sufficient (&gt;38). In cases when large deviations occurred between average kp for the L calibration years and the actual kp of the following (L + 1)th year, relatively large prediction errors resulted. For the monthly scale, soil heat flux G fluctuated periodically. When variations of G were included, the calculated monthly ETo values were smaller than the monthly ETo cumulated from daily ETo. Thus, monthly kp values were smaller than daily kp values. Predictions of monthly ETo in 2001 for the six sites were relatively accurate with relative errors ranging from −11.9% to 12.1%. In conclusion, this method is simple and accurate with a small demand for weather data.