bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sodium Antimony Gluconate Induces Generation of Reactive Oxygen Species and Nitric Oxide via Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Activation inLeishmania donovani-Infected Macrophages
Authors: Mookerjee Basu Jayati , Mookerjee Ananda , Sen Prosenjit , Bhaumik Suniti , Sen Pradip , Banerjee Subha , Naskar Ksudiram , Choudhuri Soumitra K. , Saha Bhaskar , Raha Sanghamitra , Roy Syamal 
Published: April 2006

ABSTRACTPentavalent antimony complexes, such as sodium stibogluconate and sodium antimony gluconate (SAG), are still the first choice for chemotherapy against various forms of leishmaniasis, including visceral leishmaniasis, or kala-azar. Although the requirement of a somewhat functional immune system for the antileishmanial action of antimony was reported previously, the cellular and molecular mechanism of action of SAG was not clear. Herein, we show that SAG induces extracellular signal-regulated kinase 1 (ERK-1) and ERK-2 phosphorylation through phosphoinositide 3-kinase (PI3K), protein kinase C, and Ras activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation through PI3K and Akt activation. ERK-1 and ERK-2 activation results in an increase in the production of reactive oxygen species (ROS) 3 to 6 h after SAG treatment, while p38 MAPK activation and subsequent tumor necrosis factor alpha release result in the production of nitric oxide (NO) 24 h after SAG treatment. Thus, this study has provided the first evidence that SAG treatment induces activation of some important components of the intracellular signaling pathway, which results in an early wave of ROS-dependent parasite killing and a stronger late wave of NO-dependent parasite killing. This opens up the possibility of this metalloid chelate being used in the treatment of various diseases either alone or in combination with other drugs and vaccines.
Effect of a Nutritional Supplement on Posaconazole Pharmacokinetics following Oral Administration to Healthy Volunteers
Authors: Sansone-Parsons Angela , Krishna Gopal , Calzetta Angela , Wexler David , Kantesaria Bhavna , Rosenberg Mitchell A. , Saltzman Marc A. 
Published: April 2006

ABSTRACT
We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics. In this study, coadministration of posaconazole with Boost Plus increased the maximum concentration of posaconazole in serum and area under the concentration-time curve from 0 to 72 h values 3.4- and 2.6-fold, respectively, compared to those for the fasted state.
Identification of Human Papillomavirus Type 16 L1 Surface Loops Required for Neutralization by Human Sera
Authors: Carter Joseph J. , Wipf Greg C. , Madeleine Margaret M. , Schwartz Stephen M. , Koutsky Laura A. , Galloway Denise A. 
Published: April 2006

ABSTRACT
The variable surface loops on human papillomavirus (HPV) virions required for type-specific neutralization by human sera remain poorly defined. To determine which loops are required for neutralization, a series of hybrid virus-like particles (VLPs) were used to adsorb neutralizing activity from HPV type 16 (HPV16)-reactive human sera before being tested in an HPV16 pseudovirion neutralization assay. The hybrid VLPs used were composed of L1 sequences of either HPV16 or HPV31, on which one or two regions were replaced with homologous sequences from the other type. The regions chosen for substitution were the five known loops that form surface epitopes recognized by monoclonal antibodies and two additional variable regions between residues 400 and 450. Pretreatment of human sera, previously found to react to HPV16 VLPs in enzyme-linked immunosorbent assays, with wild-type HPV16 VLPs and hybrid VLPs that retained the neutralizing epitopes reduced or eliminated the ability of sera to inhibit pseudovirus infection in vitro. Surprisingly, substitution of a single loop often ablated the ability of VLPs to adsorb neutralizing antibodies from human sera. However, for all sera tested, multiple surface loops were found to be important for neutralizing activity. Three regions, defined by loops DE, FG, and HI, were most frequently identified as being essential for binding by neutralizing antibodies. These observations are consistent with the existence of multiple neutralizing epitopes on the HPV virion surface.
Monomeric APOBEC3G Is Catalytically Active and Has Antiviral Activity
Authors: Opi Sandrine , Takeuchi Hiroaki , Kao Sandra , Khan Mohammad A. , Miyagi Eri , Goila-Gaur Ritu , Iwatani Yasumasa , Levin Judith G. , Strebel Klaus 
Published: April 2006

ABSTRACT

APOBEC3G (APO3G) is a cytidine deaminase that restricts replication of
vif
-defective human immunodeficiency virus type 1 (HIV-1). Like other members of the cellular deaminase family, APO3G has the propensity to form homo-multimers. In the current study, we investigated the functional determinants for multimerization of human APO3G and studied the role of APO3G multimerization for catalytic activity, virus encapsidation, and antiviral activity. We found that human APO3G is capable of forming multimeric complexes in transfected HeLa cells. Interestingly, multimerization of APO3G was exquisitely sensitive to RNase treatment, suggesting that interaction of APO3G subunits is facilitated or stabilized by an RNA bridge. Mutation of a conserved cysteine residue (C97) that is part of an N-terminal zinc-finger motif in APO3G abolished multimerization of APO3G; however, the C97 mutation inhibited neither in vitro deaminase activity nor antiviral function of APO3G. These results suggest that monomeric APO3G is both catalytically active and has antiviral activity. Interference studies employing either catalytically inactive or packaging-incompetent APO3G variants suggest that wild-type APO3G is packaged into HIV-1 particles in monomeric form. These results provide novel insights into the catalytic function and antiviral property of APO3G and demonstrate an important role for C97 in the RNA-dependent multimerization of this protein.
Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model
Authors: Crawford Sue E. , Patel Dinesh G. , Cheng Elly , Berkova Zuzana , Hyser Joseph M. , Ciarlet Max , Finegold Milton J. , Conner Margaret E. , Estes Mary K. 
Published: April 2006

ABSTRACT

Rotaviruses infect mature, differentiated enterocytes of the small intestine and, by an unknown mechanism, escape the gastrointestinal tract and cause viremia. The neonatal rat model of rotavirus infection was used to determine the kinetics of viremia, spread, and pathology of rotavirus in extraintestinal organs. Five-day-old rat pups were inoculated intragastrically with an animal (RRV) or human (HAL1166) rotavirus or phosphate-buffered saline. Blood was collected from a subset of rat pups, and following perfusion to remove residual blood, organs were removed and homogenized to analyze rotavirus-specific antigen by enzyme-linked immunosorbent assay and infectious rotavirus by fluorescent focus assay or fixed in formalin for histology and immunohistochemistry. Viremia was detected following rotavirus infection with RRV and HAL1166. The RRV 50% antigenemia dose was 1.8 × 10
3
PFU, and the 50% diarrhea dose was 7.7 × 10
5
PFU, indicating that infection and viremia occurred in the absence of diarrhea and that detecting rotavirus antigen in the blood was a more sensitive measure of infection than diarrhea. Rotavirus antigens and infectious virus were detected in multiple organs (stomach, intestines, liver, lungs, spleen, kidneys, pancreas, thymus, and bladder). Histopathological changes due to rotavirus infection included acute inflammation of the portal tract and bile duct, microsteatosis, necrosis, and inflammatory cell infiltrates in the parenchymas of the liver and lungs. Colocalization of structural and nonstructural proteins with histopathology in the liver and lungs indicated that the histological changes observed were due to rotavirus infection and replication. Replicating rotavirus was also detected in macrophages in the lungs and blood vessels, indicating a possible mechanism of rotavirus dissemination. Extraintestinal infectious rotavirus, but not diarrhea, was observed in the presence of passively or actively acquired rotavirus-specific antibody. These findings alter the previously accepted concept of rotavirus pathogenesis to include not only gastroenteritis but also viremia, and they indicate that rotavirus could cause a broad array of systemic diseases in a number of different organs.
Cottontail Rabbit Papillomavirus E8 Protein Is Essential for Wart Formation and Provides New Insights into Viral Pathogenesis
Authors: Nonnenmacher Mathieu , Salmon Jérôme , Jacob Yves , Orth Gérard , Breitburd Françoise 
Published: April 2006

ABSTRACT
The cottontail rabbit papillomavirus (CRPV) a and b subtypes display a conserved E8 open reading frame encoding a 50-amino-acid hydrophobic protein, with structural similarities to the E5 transmembrane oncoprotein of genital human PVs (HPVs). CRPV E8 has been reported to play a role in papilloma growth but not to be essential in papilloma formation. Here we report that the knockout of E8 start codon almost prevented wart induction upon biobalistic inoculation of viral DNA onto rabbit skin. The scarce warts induced showed very slow growth, despite sustained expression of E6 and E7 oncogenes. This points to an essential role of E8 in disturbing epidermal homeostasis. Using a yeast two-hybrid screen, we found that E8 interacted with the zinc transporter ZnT1, protocadherin 1 (PCDH1), and AHNAK/desmoyokin, three proteins as yet unrelated to viral pathogenesis or cell transformation. HPV16 E5 also interacted with these proteins in two-hybrid assay. CRPV E8 mainly localized to the Golgi apparatus and the early endosomes of transfected keratinocytes and colocalized with ZnT1, PCDH1, and AHNAK. We showed that ZnT1 and PCDH1 formed a complex and that E8 disrupted this complex. CRPV E8, like HPV16 E5, increased epidermal growth factor (EGF)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and both the EGF-dependent and the EGF-independent activity of activating protein-1 (AP-1). Competition experiments with a nonfunctional truncated ZnT1 protein showed that E8-ZnT1 interaction was required for AP-1 activation. Our data identify CRPV E8 as a key player in papilloma induction and unravel novel cellular targets for inducing the proliferation of keratinocytes.
Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir
Authors: Westby Mike , Lewis Marilyn , Whitcomb Jeannette , Youle Mike , Pozniak Anton L. , James Ian T. , Jenkins Tim M. , Perros Manos , van der Ryst Elna 
Published: April 2006

ABSTRACT

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log
10
copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (
Env
) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on
Env
clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.
Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic
Escherichia coli
Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers
Authors: Stephenson Iain , Zambon Maria C. , Rudin Anna , Colegate Anthony , Podda Audino , Bugarini Roberto , del Giudice Giusseppe , Minutello Ada , Bonnington Susan , Holmgren Jan , Mills Kingston H. G. , Nicholson Karl G. 
Published: April 2006

ABSTRACT

Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-μg doses of hemagglutinin from each virus strain with either 3, 10, or 30 μg of heat-labile
Escherichia coli
enterotoxin (LTK63) and 990 μg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-μg doses of hemagglutinin with 30 μg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 μg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 μg LTK63 with the biovector, occurring in 7/15 (47%;
P
= 0.0103), 8/15 (53%;
P
= 0.0362), and 14/15 (93%;
P
= 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 μg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (
P
= 0.0491) and B/Guandong (
P
= 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.
The ORF3 Protein of Porcine Circovirus Type 2 Is Involved in Viral Pathogenesis In Vivo
Authors: Liu Jue , Chen Isabelle , Du Qingyun , Chua Huikheng , Kwang Jimmy 
Published: April 2006

ABSTRACT

Porcine circovirus type 2 (PCV2) is the primary causative agent of an emerging swine disease, postweaning multisystemic wasting syndrome. We previously showed that a novel identified protein, ORF3, was not essential for PCV2 replication in cultured PK15 cells and played a major role in virus-induced apoptosis. To evaluate the role of the ORF3 protein in viral pathogenesis in vivo, we inoculated 8-week-old BALB/c mice that have been developed for PCV2 replication with ORF3-deficient mutant PCV2 (mPCV2). By 42 days postinoculation, all of the mice inoculated with the mPCV2, as well as with wild-type PCV2 (wPCV2), had seroconverted to PCV2 capsid antibody, and the mutant induced levels of PCV2 antibodies that were higher than those of the wPCV2. The PCV2 genomic copy numbers in serum were significantly higher (
P
< 0.05) in the wPCV2-inoculated mice than in mice inoculated with the mPCV2. Also, the wPCV2 caused microscopic lesions characterized by lymphocyte depletion with histiocytic infiltration of lymphoid organs, but the mutant virus failed to induce any obvious pathological lesions. In situ hybridization and immunohistochemical analyses also showed that larger amounts of viral DNA and antigens were detected in the lymph nodes of the wPCV2-inoculated than mPCV2-inoculated mice. Furthermore, animals of the wPCV2-inoculated group showed significant downshifts of CD8
+
T-cell subsets of peripheral blood lymphocytes compared to the control mice (
P
< 0.05) at various time points postinoculation. Also, the proportions of the CD4
+
and CD4
+
CD8
+
cells were significantly reduced in wPCV2-inoculated mice at some time points postinoculation. In contrast, there are some reductions in the proportions of these subsets in the mutant virus-inoculated mice, but the proportions do not decrease significantly. Taken together, these results demonstrate that the ORF3 protein is also dispensable for viral replication in vivo and that it plays an important role in viral pathogenesis.
Chaperone-Mediated In Vitro Disassembly of Polyoma- and Papillomaviruses
Authors: Chromy Laura R. , Oltman Amy , Estes Patricia A. , Garcea Robert L. 
Published: April 2006

ABSTRACT
Hsp70 chaperones play a role in polyoma- and papillomavirus assembly, as evidenced by their interaction in vivo with polyomavirus capsid proteins at late times after virus infection and by their ability to assemble viral capsomeres into capsids in vitro. We studied whether Hsp70 chaperones might also participate in the uncoating reaction. In vivo, Hsp70 coimmunoprecipitated with polyomavirus virion VP1 at 3 h after infection of mouse cells. In vitro, prokaryotic and eukaryotic Hsp70 chaperones efficiently disassembled polyoma- and papillomavirus-like particles and virions in energy-dependent reactions. These observations support a role for cell chaperones in the disassembly of these viruses.
On the Decay of Tropical Cyclone Winds Crossing Narrow Landmasses
Authors: DeMaria Mark , Knaff John A. , Kaplan John 
Published: April 2006

Abstract
A method is developed to adjust the Kaplan and DeMaria tropical cyclone inland wind decay model for storms that move over narrow landmasses. The basic assumption that the wind speed decay rate after landfall is proportional to the wind speed is modified to include a factor equal to the fraction of the storm circulation that is over land. The storm circulation is defined as a circular area with a fixed radius. Application of the modified model to Atlantic Ocean cases from 1967 to 2003 showed that a circulation radius of 110 km minimizes the bias in the total sample of landfalling cases and reduces the mean absolute error of the predicted maximum winds by about 12%. This radius is about 2 times the radius of maximum wind of a typical Atlantic tropical cyclone. The modified decay model was applied to the Statistical Hurricane Intensity Prediction Scheme (SHIPS), which uses the Kaplan and DeMaria decay model to adjust the intensity for the portion of the predicted track that is over land. The modified decay model reduced the intensity forecast errors by up to 8% relative to the original decay model for cases from 2001 to 2004 in which the storm was within 500 km from land.
Tropical Cyclone Wind Retrievals from the Advanced Microwave Sounding Unit: Application to Surface Wind Analysis
Authors: Bessho Kotaro , DeMaria Mark , Knaff John A. 
Published: April 2006

Abstract
Horizontal winds at 850 hPa from tropical cyclones retrieved using the nonlinear balance equation, where the mass field was determined from Advanced Microwave Sounding Unit (AMSU) temperature soundings, are compared with the surface wind fields derived from NASA's Quick Scatterometer (QuikSCAT) and Hurricane Research Division H*Wind analyses. It was found that the AMSU-derived wind speeds at 850 hPa have linear relations with the surface wind speeds from QuikSCAT or H*Wind. There are also characteristic biases of wind direction between AMSU and QuikSCAT or H*Wind. Using this information to adjust the speed and correct for the directional bias, a new algorithm was developed for estimation of the tropical cyclone surface wind field from the AMSU-derived 850-hPa winds. The algorithm was evaluated in two independent cases from Hurricanes Floyd (1999) and Michelle (2001), which were observed simultaneously by AMSU, QuikSCAT, and H*Wind. In this evaluation the AMSU adjustment algorithm for wind speed worked well. Results also showed that the bias correction algorithm for wind direction has room for improvement.
The Physical Properties of the Atmosphere in the New Hadley Centre Global Environmental Model (HadGEM1). Part I: Model Description and Global Climatology
Authors: Martin G. M. , Ringer M. A. , Pope V. D. , Jones A. , Dearden C. , Hinton T. J. 
Published: April 2006

Abstract
The atmospheric component of the new Hadley Centre Global Environmental Model (HadGEM1) is described and an assessment of its mean climatology presented. HadGEM1 includes substantially improved representations of physical processes, increased functionality, and higher resolution than its predecessor, the Third Hadley Centre Coupled Ocean–Atmosphere General Circulation Model (HadCM3). Major developments are the use of semi-Lagrangian instead of Eulerian advection for both dynamical and tracer fields; new boundary layer, gravity wave drag, microphysics, and sea ice schemes; and major changes to the convection, land surface (including tiled surface characteristics), and cloud schemes. There is better coupling between the atmosphere, land, ocean, and sea ice subcomponents and the model includes an interactive aerosol scheme, representing both the first and second indirect effects. Particular focus has been placed on improving the processes (such as clouds and aerosol) that are most uncertain in projections of climate change.
These developments lead to a significantly more realistic simulation of the processes represented, the most notable improvements being in the hydrological cycle, cloud radiative properties, the boundary layer, the tropopause structure, and the representation of tracers.