bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of Retapamulin against
Streptococcus pyogenes
and
Staphylococcus aureus
Evaluated by Agar Dilution, Microdilution, E-Test, and Disk Diffusion Methodologies
Authors: Pankuch Glenn A. , Lin Gengrong , Hoellman Dianne B. , Good Caryn E. , Jacobs Michael R. , Appelbaum Peter C.
Published: April 2006

The in vitro activity of retapamulin against 106
Staphylococcus aureus
isolates and 109
Streptococcus pyogenes
isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for
S. aureus
yielded similar MICs, in the range of 0.03 to 0.25 μg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-μg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for
S. aureus
were within ±1 dilution of the microdilution results. For
S. pyogenes
, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 μg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 μg/ml. For
S. pyogenes
, 100% of the agar dilution MIC results were within ±1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within ±1 and ±2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for
S. pyogenes
strains in CO
2
were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO
2
, due to the adverse effect of CO
2
on the activity of this compound. Diffusion zones (with incubation in CO
2
) for
S. pyogenes
were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were ≤0.25 μg/ml. These results demonstrate that
S. pyogenes
(including macrolide-resistant strains) and
S. aureus
(including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.
Antimalarial Activity of Allicin, a Biologically Active Compound from Garlic Cloves
Authors: Coppi Alida , Cabinian Melissa , Mirelman David , Sinnis Photini
Published: April 2006

The incidence of malaria is increasing, and there is an urgent need to identify new drug targets for both prophylaxis and chemotherapy. Potential new drug targets includePlasmodiumproteases that play critical roles in the parasite life cycle. We have previously shown that the major surface protein ofPlasmodiumsporozoites, the circumsporozoite protein (CSP), is proteolytically processed by a parasite-derived cysteine protease, and this processing event is temporally associated with sporozoite invasion of host cells. E-64, a cysteine protease inhibitor, inhibits CSP processing and prevents invasion of host cells in vitro and in vivo. Here we tested allicin, a cysteine protease inhibitor found in garlic extracts, for its ability to inhibit malaria infection. At low concentrations, allicin was not toxic to either sporozoites or mammalian cells. At these concentrations, allicin inhibited CSP processing and prevented sporozoite invasion of host cells in vitro. In vivo, mice injected with allicin had decreasedPlasmodiuminfections compared to controls. When sporozoites were treated with allicin before injection into mice, malaria infection was completely prevented. We also tested allicin on erythrocytic stages and found that a 4-day regimen of allicin administered either orally or intravenously significantly decreased parasitemias and increased the survival of infected mice by 10 days. Together, these experiments demonstrate that the same cysteine protease inhibitor can target two different life cycle stages in the vertebrate host.
Clarithromycin Delays Progression of Bronchial Epithelial Cells from G
1
Phase to S Phase and Delays Cell Growth via Extracellular Signal-Regulated Protein Kinase Suppression
Authors: Shinkai Masaharu , Tamaoki Jun , Kobayashi Hideo , Kanoh Soichiro , Motoyoshi Kazuo , Kute Tim , Rubin Bruce K.
Published: April 2006

The nonsteroidal anti-inflammatory drugs have been shown to support cytoprotection of cells by shifting cells toward a quiescent state (G
0
/G
1
). Extracellular signal-regulated kinase (ERK) is required for cells to pass from G
1
phase into S phase, and macrolide antibiotics can inhibit ERK1/2 phosphorylation. However, previous reports suggest that macrolide antibiotics do not affect cell growth in bronchial epithelial cells. Therefore, we studied normal human bronchial epithelial (NHBE) cells to determine whether clarithromycin (CAM) suppresses ERK, delays bronchial epithelial cells from progressing to S phase, and delays cell growth. Exposure to CAM at 10 μg/ml daily over 4 days irreversibly decreased the cell proliferation with and without growth supplements (
P
< 0.0001). CAM also inhibited ERK1/2 phosphorylation over the first 90 min of exposure (
P
 < 0.05 for 30 min,
P
< 0.0001 for 60 min, and
P
< 0.01 for 90 min) and decreased the ratio of phosphorylated ERK1/2 (pERK1/2) to total ERK1/2 (tERK1/2) (
P
< 0.0001). Incubation with CAM for 48 h increased the proportion of cells in G
1
phase (means ± standard deviations) from 63.5% ± 0.9% to 79.1% ± 1.4% (
P
< 0.0001), decreased that in S phase from 19.8% ± 1.2% to 10.0% ± 2.1% (
P
< 0.01), and decreased that in G
2
/M phase from 16.7% ± 0.4% to 11.0% ± 0.8% (
P
< 0.001). In contrast, the ratio of pMEK1/2 to tMEK1/2 was not altered after exposure to CAM. These results suggest that macrolide antibiotics can delay the progression of NHBE cells from G
1
phase to S phase and can slow cell growth, probably through the suppression of ERK1/2.
Complex Genetic Structures with Repeated Elements, a
sul
-Type Class 1 Integron, and the
bla
VEB
Extended-Spectrum β-Lactamase Gene
Authors: Naas Thierry , Aubert Daniel , Lambert Thierry , Nordmann Patrice
Published: April 2006

Two clinical isolates of
Pseudomonas aeruginosa
, TL-1 and TL-2, were isolated from a patient transferred from Bangladesh and hospitalized for osteomyelitis in Paris, France.
P. aeruginosa
TL-1 expressed the extended-spectrum β-lactamase VEB-1a and was susceptible only to imipenem and colistin, while
P. aeruginosa
TL-2 expressed only the naturally occurring
bla
AmpC
gene at a basal level and exhibited a wild-type β-lactam resistance phenotype. In TL-1, the typical 5′-end conserved sequence (5′-CS) region of class 1 integrons usually present upstream of the
bla
VEB-1a
gene was replaced by a truncated 3′-CS and a 135-bp repeated element (Re). Downstream of the
bla
VEB-1a
gene, an insertion sequence, IS
Pa31
disrupted by IS
Pa30
, and an
orf513
sequence, belonging to a common region (conserved region 1 [CR1]) immediately upstream of the
aphA-6
gene, were present. Further downstream, a second truncated 3′-CS region in direct repeat belonged to In51, an integron containing two gene cassettes (
aadA6
and the OrfD cassette). Thus, the overall structure corresponded to a
sul
-type class 1 integron termed In121. Genetic analyses revealed that both isolates were clonally related and differed by a ca. 100-kb fragment that contained In121. Both isolates contained another integron, In122, that carried three gene cassettes:
aadB
,
dfrA1
, and the OrfX cassette. This work identifies for the first time the spread of Re-associated
bla
VEB
genes located on a
sul
-type integron. It also reports for the first time a CR1 element in
P. aeruginosa
that is associated with an aminoglycoside resistance
aphA-6
gene that is expressed from a composite promoter.
Poly(I)-Poly(C
12
U) but Not Ribavirin Prevents Death in a Hamster Model of Nipah Virus Infection
Authors: Georges-Courbot M. C. , Contamin H. , Faure C. , Loth P. , Baize S. , Leyssen P. , Neyts J. , Deubel V.
Published: April 2006

Clinical nonrandomized trials demonstrate some efficacy for ribavirin in the treatment of patients with severe Nipah virus-induced encephalitis. We report here that EICAR, the 5-ethynyl analogue of ribavirin, and the OMP-decarboxylase inhibitors 6-aza-uridine and pyrazofurin have strong antiviral activity against Nipah virus replication in vitro. Ribavirin and 6-aza-uridine were tested further in hamsters infected with a lethal dose of Nipah virus. The activity of these small-molecule inhibitors was compared with that of the interferon inducer poly(I)-poly(C
12
U). Both ribavirin and 6-aza-uridine were able to delay but not prevent Nipah virus-induced mortality. Poly(I)-poly(C
12
U), at 3 mg/kg of body weight daily from the day of infection to 10 days postinfection, prevented mortality in 5 of 6 infected animals.
Stepwise Upregulation of thePseudomonas aeruginosaChromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD Homologues
Authors: Juan Carlos , Moyá Bartolomé , Pérez José L. , Oliver Antonio
Published: April 2006

Development of resistance to the antipseudomonal penicillins and cephalosporins mediated by hyperproduction of the chromosomal cephalosporinase AmpC is a major threat to the successful treatment ofPseudomonas aeruginosainfections. AlthoughampDinactivation has been previously found to lead to a partially derepressed phenotype characterized by increased AmpC production but retaining further inducibility, the regulation ofampCinP. aeruginosais far from well understood. We demonstrate thatampCexpression is coordinately repressed by three AmpD homologues, including the previously described protein AmpD plus two additional proteins, designated AmpDh2 and AmpDh3. The three AmpD homologues are responsible for a stepwiseampCupregulation mechanism ultimately leading to constitutive hyperexpression of the chromosomal cephalosporinase and high-level antipseudomonal β-lactam resistance, as shown by analysis of the three singleampDmutants, the three doubleampDmutants, and the tripleampDmutant. This is achieved by a three-step escalating mechanism rendering four relevant expression states: basal-level inducible expression (wild type), moderate-level hyperinducible expression with increased antipseudomonal β-lactam resistance (ampDmutant), high-level hyperinducible expression with high-level β-lactam resistance (ampD ampDh3double mutant), and very high-level (more than 1,000-fold compared to the wild type) derepressed expression (triple mutant). Although one-step inducible-derepressed expression models are frequent in natural resistance mechanisms, this is the first characterized example in which expression of a resistance gene can be sequentially amplified through multiple steps of derepression.
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

Pentavalent 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

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

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

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

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

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

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

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

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

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.
STUDY OF THE SU(3)c⊗SU(3)L⊗U(1)X MODEL WITH THE MINIMAL SCALAR SECTOR
Authors: GUTIÉRREZ DIEGO A. , PONCE WILLIAM A. , SÁNCHEZ LUIS A.
Published: April 2006

A study of the three-family local gauge group SU (3)c⊗ SU (3)L⊗ U (1)X with right-handed neutrinos is carried out. We use the minimal scalar sector able to break the symmetry in a proper way and produce, at the same time, masses for the fermion fields. We embed the structure into a simple gauge group and, by using experimental results from the CERN LEP, SLAC linear collider and atomic parity violation data, we also constrain relevant parameters for the new neutral and charged currents. We discuss the mass spectrum for the gauge boson sector and for the spin 1/2 particles. With the use of discrete symmetries and the introduction of extra scalar fields, a consistent mass spectrum could be constructed.
ARE NEUTRON-RICH ELEMENTS PRODUCED IN THE COLLAPSE OF STRANGE DWARFS?
Authors: MARRANGHELLO G. F. , DE FREITAS PACHECO J. A.
Published: April 2006

The structure of strange dwarfs and that of hybrid stars with the same baryonic number is compared. There is a critical mass (M ≈ 0.24M⊙) in the strange dwarf branch, below which configurations with the same baryonic number in the hybrid star branch are more stable. If a transition occurs between both branches, the collapse releases an energy of about of 3 × 1050 erg , mostly in the form of neutrinos resulting from the conversion of hadronic matter onto strange quark matter. Only a fraction (~ 4%) is required to expel the outer neutron-rich layers. These events may contribute significantly to the chemical yield of nuclides with A ≥ 80 in the Galaxy, if their frequency is of about one per 1,500 years.
Themahoganoidmutation (Mgrn1md)improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independently of effects on adiposity
Authors: Phan Loan K. , Chung Wendy K. , Leibel Rudolph L.
Published: April 2006

Mahoganoid ( Mgrn1md) is a mutation of the mahogunin ( Mgrn1) gene. The hypomorphic allele suppresses the yellow pigmentation and obesity of the Aymouse that ubiquitously overexpresses agouti signaling protein (ASP). To assess the physiological effects of MGRN1 on energy and glucose homeostasis, we generated animals doubly mutant for Mgrn1mdand Ay, Lepob, or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1md. Mgrn1mdsuppressed the obesity, hyperglycemia, and hyperinsulinemia of Aymice. Mgrn1mdsuppressed Ay-induced obesity by reducing food intake, and reduced adiposity in Lepob/Lepobfemales, but did not alter the body weight or body composition of mice fed a high-fat diet. There was no effect of Mgrn1mdon weight gain, body composition, energy intake, or energy expenditure in Mc4r-null animals. Mgrn1mdreduced circulating insulin concentrations in DIO, Ay, and Mc4r-null but not Lepob/Lepobmice. The effect of Mgrn1mdon circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1mdmice segregating for either Ayor Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with Ayand Mc4r mice, respectively. The effect of Mgrn1mdon insulin sensitivity of Mc4r-null mice suggests that Mgrn1mdmay be increasing insulin sensitivity via the hypothalamic melanocortin-3 receptor pathway.
Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1
Authors: Park So-Young , Cho You-Ree , Kim Hyo-Jeong , Hong Eun-Gyoung , Higashimori Takamasa , Lee Sang Jun , Goldberg Ira J. , Shulman Gerald I. , Najjar Sonia M. , Kim Jason K.
Published: April 2006

Mice with liver-specific overexpression of dominant negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-h hyperinsulinemic euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl-CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by 1H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.
On the Decay of Tropical Cyclone Winds Crossing Narrow Landmasses
Authors: DeMaria Mark , Knaff John A. , Kaplan John
Published: April 2006

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

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

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.
Optimization of a Sea Ice Model Using Basinwide Observations of Arctic Sea Ice Thickness, Extent, and Velocity
Authors: Miller Paul A. , Laxon Seymour W. , Feltham Daniel L. , Cresswell Douglas J.
Published: April 2006

A stand-alone sea ice model is tuned and validated using satellite-derived, basinwide observations of sea ice thickness, extent, and velocity from the years 1993 to 2001. This is the first time that basin-scale measurements of sea ice thickness have been used for this purpose. The model is based on the CICE sea ice model code developed at the Los Alamos National Laboratory, with some minor modifications, and forcing consists of 40-yr ECMWF Re-Analysis (ERA-40) and Polar Exchange at the Sea Surface (POLES) data. Three parameters are varied in the tuning process: Ca, the air–ice drag coefficient; P*, the ice strength parameter; and α, the broadband albedo of cold bare ice, with the aim being to determine the subset of this three-dimensional parameter space that gives the best simultaneous agreement with observations with this forcing set. It is found that observations of sea ice extent and velocity alone are not sufficient to unambiguously tune the model, and that sea ice thickness measurements are necessary to locate a unique subset of parameter space in which simultaneous agreement is achieved with all three observational datasets.
Interannual to Decadal Climate Predictability in the North Atlantic: A Multimodel-Ensemble Study
Authors: Collins M. , Botzet M. , Carril A. F. , Drange H. , Jouzeau A. , Latif M. , Masina S. , Otteraa O. H. , Pohlmann H. , Sorteberg A. , Sutton R. , Terray L.
Published: April 2006

Ensemble experiments are performed with five coupled atmosphere–ocean models to investigate the potential for initial-value climate forecasts on interannual to decadal time scales. Experiments are started from similar model-generated initial states, and common diagnostics of predictability are used. We find that variations in the ocean meridional overturning circulation (MOC) are potentially predictable on interannual to decadal time scales, a more consistent picture of the surface temperature impact of decadal variations in the MOC is now apparent, and variations of surface air temperatures in the North Atlantic Ocean are also potentially predictable on interannual to decadal time scales, albeit with potential skill levels that are less than those seen for MOC variations. This intercomparison represents a step forward in assessing the robustness of model estimates of potential skill and is a prerequisite for the development of any operational forecasting system.
Changes in Low Cloudiness over China between 1971 and 1996
Authors: Endo Nobuhiko , Yasunari Tetsuzo
Published: April 2006

The climatology and long-term trends of low-cloud conditions over China were examined using the Extended Edited Cloud Report Archive data from 1971 to 1996. Linear regression analysis was applied to time series of clear-sky frequencies and low-cloud frequencies, and low-cloud amounts when present. Over the 26-yr study period, the clear-sky frequency increased over northern China. During summer, the frequency of cumuliform clouds decreased over almost all of China. A significant decrease characterized the trend in cumulonimbus (Cb) frequency; however, the Cb cloud amount when present increased over the Yangtze River basin and southern China. Increasing trends in stratocumulus (Sc) cloud amount when present were also observed over much of China.
Gas Leakage Evaluation of CFRP Cross-ply Laminates under Biaxial Loadings
Authors: Kumazawa Hisashi , Susuki Ippei , Aoki Takahira
Published: April 2006

In this study, leak characteristics of CFRP (carbon fiber reinforced plastic) cross-ply laminates are experimentally investigated under biaxial loadings using a specially prepared in-plane biaxial testing system. Permeability through the damaged laminate under biaxial stresses was measured with a leak detection system. In order to evaluate the effect of damage on leakage, ultrasonic C-scan was used to inspect the matrix cracking in the specimens. Experimental results reveal that leakage through the damaged laminate is in correlation with the amount of damage and depends not only on load level but also on biaxial load ratio. Leak analysis, which had been previously developed, was employed and calculations of permeability were in good agreement with the experimental data. The results indicate the validity of the assumption of domination of crack openings on permeability, and the dependency of constants of leak conductance on damage susceptibility in the leak analysis.
Calorimetric and Rheological Measurements of Three Commercial Thermosetting Prepreg Epoxies
Authors: Hargis Mitch , Grady Brian P. , Aktas Levent , Bomireddy Krishnasumanth R. , Howsman Steve , Altan M. Cengiz , Rose Tom , Rose Hans
Published: April 2006

The cure kinetics of three different thermosetting resins are investigated using differential scanning calorimetry and oscillatory shear rheometry. For the latter, two different types of plates are used, smooth plates and grooved plates; the latter are used to improve sample–plate contact. In addition, oscillatory compression rheology is used; however, machine compliance prevents accurate measurements at high conversions. A fractional conversion is defined based on the maximum storage modulus achieved at a given temperature, and is compared to the fractional conversion calculated from enthalpy measurements. As expected, the rates of reaction derived from these fractional conversions are very different for calorimetry and rheometry. However, the rates of reaction using the two types of plates are identical, although the grooved plates give much more reproducible storage moduli. A number of previously used mathematical expressions are employed to fit the calorimetric and rheological data, and the activation energies calculated from these fits are compared.
Strain Rate Effect on Mechanical Behaviors of Nylon 6–Clay Nanocomposites
Authors: Tsai Jia-Lin , Huang Jen-Chieh
Published: April 2006

This study aims to investigate strain rate effect on the mechanical behaviors of nylon 6–clay nanocomposites. Both dry and wet nylon 6–clay nanocomposites are examined in this study. To determine the strain rate effect, the nylon 6 nanocomposites with 5 wt% loading of the organoclay are tested in compression at different strain rates. For strain rates less than 1/s, the experiments are conducted using a hydraulic MTS machine. However, the high strain rate tests are performed using a split Hopkinson pressure bar (SHPB). To establish reliable dynamic stress and strain curves for the nanocomposites, a pulse-shaper technology is employed in the SHPB tests. Experimental observations reveal that for dry nanocomposites, the linear portions of the stress and strain curves are not affected substantially by the strain rates, but the yielding stresses increase with the increment of the strain rates. On the other hand, for the wet nanocomposites, the stress and strain curves are almost nonlinear demonstrating significant stiffening behaviors as the strain rates increase. This stiffening behavior is continuous until the stress and strain curves are almost linear at the strain rate of 500/s. Comparison of nylon 6–clay nanocomposites and unfilled nylon 6 indicates that the supplement of 5 wt% organoclay in the dry nylon 6 can enhance the Young's modulus to 32% within the tested strain rate ranges. Moreover, for the wet nylon reinforced with organoclay, the increment of Young's modulus can be achieved up to 43%.
The Effect of Topic of Discussion on Gendered Language in Computer-Mediated Communication Discussion
Authors: Thomson Rob
Published: April 2006

Gendered language in computer-mediated communication (CMC) is more than just a function of the gender of the participants because people are very flexible in the language style they use. In these studies, the use of gender-preferential language was examined in postings on public discussions where the topic was gender-stereotypical or gender-neutral. It was found that both men and women in discussions about gender-stereotypical topics were more likely to adhere to gender-based group norms and hence would use more gender-preferential language than in discussions about non-gender-stereotypical topics. The results of these two studies indicate that gendered language in CMC discussion is more a function of the context or topic of discussion than the gender of the participants.
Sustainability and Water Quality
Authors: Kraft Michael E.
Published: April 2006

This article examines efforts to improve water quality in the Fox-Wolf River basin in northeastern Wisconsin. It places the history of these efforts within the context of sustainability-based environmental policy, including reliance on broadly inclusive stakeholder involvement and collaborative decision making. Water quality in the area has improved significantly over time, but further improvement will require intensive actions focused on nonpoint sources of pollution and remediation of contaminated sediments. The barriers to such actions require consideration of new policy approaches that can complement conventional regulation. A review of the promise and limitations of collaborative decision making indicates what can be done both in this case and in comparable locations around the nation.