bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the Nonstructural Protein 3A Confer Resistance to the Novel Enterovirus Replication Inhibitor TTP-8307
Authors: De Palma Armando M. , Thibaut Hendrik Jan , van der Linden Lonneke , Lanke Kjerstin , Heggermont Ward , Ireland Stephen , Andrews Robert , Arimilli Murty , Al-Tel Taleb H. , De Clercq Erik , van Kuppeveld Frank , Neyts Johan 
Published: February 2009

ABSTRACT
A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.
Early Postpartum Pharmacokinetics of Lopinavir Initiated Intrapartum in Thai Women
Authors: Cressey Tim R. , Van Dyke Russell , Jourdain Gonzague , Puthanakit Thanyawee , Roongpisuthipong Anuvat , Achalapong Jullapong , Yuthavisuthi Prapap , Prommas Sinart , Chotivanich Nantasak , Maupin Robert , Smith Elizabeth , Shapiro David E. , Mirochnick Mark 
Published: February 2009

ABSTRACT
Lopinavir (LPV) exposure is reduced during the third trimester of pregnancy. We report the pharmacokinetics of standard LPV-ritonavir dosing (400/100 mg twice daily) in the immediate and early postpartum period when initiated during labor. In 16 human immunodeficiency virus-infected Thai women, the median (range) LPV area under the concentration-time curve and maximum and minimum concentrations in plasma were 99.7 (66.1 to 180.5) μg·h/ml, 11.2 (8.0 to 17.5) μg/ml, and 4.6 (1.7 to 12.5) μg/ml, respectively, at 41 (12 to 74) h after delivery. All of the women attained adequate LPV levels through 30 days postpartum. No serious adverse events were reported.
Cleavage of
Escherichia coli
Cytotoxic Necrotizing Factor 1 Is Required for Full Biologic Activity
Authors: Knust Zeynep , Blumenthal Britta , Aktories Klaus , Schmidt Gudula 
Published: February 2009

ABSTRACT

Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by pathogenic
Escherichia coli
strains. CNF1 constitutively activates small GTPases of the Rho family by deamidation of a glutamine, which is crucial for GTP hydrolysis. The toxin is taken up into mammalian cells by receptor-mediated endocytosis and is delivered from late endosomes into the cytosol. Here, we show that an approximately 55-kDa fragment of CNF1, which contains the catalytic domain and an additional part of the toxin, is present in the cytosol. The processing of this fragment requires an acidic pH and insertion of the toxin into the endosomal membrane. We define the cleavage site region as the region located between amino acids 532 and 544 of CNF1. The data provide insight into the complex mechanism of uptake of bacterial toxins into mammalian cells.
Role of LecA and LecB Lectins in
Pseudomonas aeruginosa
-Induced Lung Injury and Effect of Carbohydrate Ligands
Authors: Chemani Chanez , Imberty Anne , de Bentzmann Sophie , Pierre Maud , Wimmerová Michaela , Guery Benoît P. , Faure Karine 
Published: February 2009

ABSTRACT

Pseudomonas aeruginosa
is a frequently encountered pathogen that is involved in acute and chronic lung infections. Lectin-mediated bacterium-cell recognition and adhesion are critical steps in initiating
P. aeruginosa
pathogenesis. This study was designed to evaluate the contributions of LecA and LecB to the pathogenesis of
P. aeruginosa
-mediated acute lung injury. Using an in vitro model with A549 cells and an experimental in vivo murine model of acute lung injury, we compared the parental strain to
lecA
and
lecB
mutants. The effects of both LecA- and Lec B-specific lectin-inhibiting carbohydrates (α-methyl-galactoside and α-methyl-fucoside, respectively) were evaluated. In vitro, the parental strain was associated with increased cytotoxicity and adhesion on A549 cells compared to the
lecA
and
lecB
mutants. In vivo, the
P. aeruginosa
-induced increase in alveolar barrier permeability was reduced with both mutants. The bacterial burden and dissemination were decreased for both mutants compared with the parental strain. Coadministration of specific lectin inhibitors markedly reduced lung injury and mortality. Our results demonstrate that there is a relationship between lectins and the pathogenicity of
P. aeruginosa
. Inhibition of the lectins by specific carbohydrates may provide new therapeutic perspectives.
Generation of High-Titer Neutralizing Antibodies against Botulinum Toxins A, B, and E by DNA Electrotransfer
Authors: Trollet C. , Pereira Y. , Burgain A. , Litzler E. , Mezrahi M. , Seguin J. , Manich M. , Popoff M. R. , Scherman D. , Bigey P. 
Published: February 2009

ABSTRACT
Botulinum neurotoxins are known to be among the most toxic known substances. They produce severe paralysis by preventing the release of acetylcholine at the neuromuscular junction. Thus, new strategies for efficient production of safe and effective anti-botulinum neurotoxin antisera have been a high priority. Here we describe the use of DNA electrotransfer into the skeletal muscle to enhance antiserum titers against botulinum toxin serotypes A, B, and E in mice. We treated animals with codon-optimized plasmid DNA encoding the nontoxic but highly immunogenic C-terminal heavy chain fragment of the toxin. By employing both codon optimization and the electrotransfer procedure, the immune response and corresponding neutralizing antiserum titers were markedly increased. The cellular localization of the antigen and the immunization regimens were also shown to increase neutralizing titers to >100 IU/ml. This study demonstrates that DNA electrotransfer is an effective procedure for raising neutralizing antiserum titers to remarkably high levels.
Differences in Genome Content among
Helicobacter pylori
Isolates from Patients with Gastritis, Duodenal Ulcer, or Gastric Cancer Reveal Novel Disease-Associated Genes
Authors: Romo-González Carolina , Salama Nina R. , Burgeño-Ferreira Juan , Ponce-Castañeda Veronica , Lazcano-Ponce Eduardo , Camorlinga-Ponce Margarita , Torres Javier 
Published: February 2009

ABSTRACT

Helicobacter pylori
establishes a chronic infection in the human stomach, causing gastritis, peptic ulcer, or gastric cancer, and more severe diseases are associated with virulence genes such as the
cag
pathogenicity island (PAI). The aim of this work was to study gene content differences among
H. pylori
strains isolated from patients with different gastroduodenal diseases in a Mexican-Mestizo patient population.
H. pylori
isolates from 10 patients with nonatrophic gastritis, 10 patients with duodenal ulcer, and 9 patients with gastric cancer were studied. Multiple isolates from the same patient were analyzed by randomly amplified polymorphic DNA analysis, and strains with unique patterns were tested using whole-genome microarray-based comparative genomic hybridization (aCGH). We studied 42 isolates and found 1,319 genes present in all isolates, while 341 (20.5%) were variable genes. Among the variable genes, 127 (37%) were distributed within plasticity zones (PZs). The overall number of variable genes present in a given isolate was significantly lower for gastric cancer isolates. Thirty genes were significantly associated with nonatrophic gastritis, duodenal ulcer, or gastric cancer, 14 (46.6%) of which were within PZs and the
cag
PAI. Two genes (HP0674 and JHP0940) were absent in all gastric cancer isolates. Many of the disease-associated genes outside the PZs formed clusters, and some of these genes are regulated in response to acid or other environmental conditions. Validation of candidate genes identified by aCGH in a second patient cohort allowed the identification of novel
H. pylori
genes associated with gastric cancer or duodenal ulcer. These disease-associated genes may serve as biomarkers of the risk for severe gastroduodenal diseases.
T Cells from Lungs and Livers ofFrancisella tularensis-Immune Mice Control the Growth of Intracellular Bacteria
Authors: Collazo Carmen M. , Meierovics Anda I. , De Pascalis Roberto , Wu Terry H. , Lyons C. Rick , Elkins Karen L. 
Published: February 2009

ABSTRACTParenteral and respiratory vaccinations with the intracellular bacteriumFrancisella tularensishave been studied using the live vaccine strain (LVS) in a mouse model, and spleen cells from immune mice are often used for immunological studies. However, mechanisms of host immunological responses may be different in nonlymphoid organs that are important sites of infection, such as lung and liver. Using parenteral (intradermal) or respiratory (cloud aerosol) vaccination, here we examine the functions of resulting LVS-immune liver or lung cells, respectively. Surprisingly, LVS was considerably more virulent when administered by cloud aerosol than by intranasal instillation, suggesting method-dependent differences in initial localization and/or dissemination patterns. Only low doses were sublethal, and resolution of sublethal cloud aerosol infection was dependent on gamma interferon (IFN-γ), tumor necrosis factor alpha, and inducible nitric oxide synthase. Nonetheless, survival of cloud aerosol or parenteral infection resulted in the development of a protective immune response against lethal LVS intraperitoneal or aerosol challenge, reflecting development of systemic secondary immunity in both cases. Such immunity was further detected by directly examining the functions of LVS-immune lung or liver lymphocytes in vitro. Lung lymphocytes primed by respiratory infection, as well as liver lymphocytes primed by parenteral infection, clearly controlled in vitro intracellular bacterial growth primarily via mechanisms that were not dependent on IFN-γ activity. Thus, our results indicate functional similarities between immune T cells residing in spleens, livers, and lungs of LVS-immune mice.
Contribution of Flagellin Pattern Recognition to Intestinal Inflammation duringSalmonella entericaSerotype Typhimurium Infection
Authors: Winter Sebastian E. , Thiennimitr Parameth , Nuccio Sean-Paul , Haneda Takeshi , Winter Maria G. , Wilson R. Paul , Russell Joseph M. , Henry Thomas , Tran Quynh T. , Lawhon Sara D. , Gomez Gabriel , Bevins Charles L. , Rüssmann Holger , Monack Denise M. , Adams L. Garry , Bäumler Andreas J. 
Published: February 2009

ABSTRACTSalmonella entericaserotype Typhimurium causes acute inflammatory diarrhea in humans. Flagella contribute to intestinal inflammation, but the mechanism remains unclear since most mutations abrogating pattern recognition of flagellin also prevent motility and reduce bacterial invasion. To determine the contribution of flagellin pattern recognition to the generation of innate immune responses, we compared in two animal models a nonmotile, but flagellin-expressing and -secreting serotype Typhimurium strain (flgKmutant) to a nonmotile, non-flagellin-expressing strain (flgK fliC fljBmutant). In vitro, caspase-1 can be activated by cytosolic delivery of flagellin, resulting in release of the interferon gamma inducing factor interleukin-18 (IL-18). Experiments with streptomycin-pretreated caspase-1-deficient mice suggested that induction of gamma interferon expression in the murine cecum early (12 h) after serotype Typhimurium infection was caspase-1 dependent but independent of flagellin pattern recognition. In addition, mRNA levels of the CXC chemokines macrophage inflammatory protein 2 and keratinocyte-derived chemokine were markedly increased early after serotype Typhimurium infection of streptomycin-pretreated wild-type mice regardless of flagellin expression. In contrast, in bovine ligated ileal loops, flagellin pattern recognition contributed to increased mRNA levels of macrophage inflammatory protein 3α and more fluid accumulation at 2 h after infection. Collectively, our data suggest that pattern recognition of flagellin contributes to early innate host responses in the bovine ileal mucosa but not in the murine cecal mucosa.
Stimulation of the Molecule 4-1BB Enhances Host Defense againstListeria monocytogenesInfection in Mice by Inducing Rapid Infiltration and Activation of Neutrophils and Monocytes
Authors: Lee Sang-Chul , Ju Seong-A , Sung Boo-Hee , Heo Sook-Kyoung , Cho Hong Rae , Lee Eun A. , Kim Jung Dae , Lee In Hee , Park Sang-Min , Nguyen Quang Tam , Suh Jae-Hee , Kim Byung-Sam 
Published: February 2009

ABSTRACTThe tumor necrosis factor receptor family molecule 4-1BB (CD137) has diverse roles in adaptive and innate immune responses. However, little is known of its role in bacterial infections. Previously, we showed that 4-1BB-deficient mice have enhanced susceptibility toListeria monocytogenesinfection, and mice pretreated with agonistic anti-4-1BB antibody (3E1) were much more resistant toL. monocytogenesinfection than mice treated with control antibody. In this study, we report that stimulating 4-1BB by administering 3E1 in the early phase ofL. monocytogenesinfection is critical for promoting the survival of mice by inducing rapid infiltration of neutrophils and monocytes intoL. monocytogenes-infected livers. The levels of tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 in the livers of 3E1-treated mice increased as early as 30 min postinfection and peaked by 1 to 2 h, while those in mice treated with control antibody started to increase only at 16 h postinfection. Monocytes and neutrophils from the 3E1-treated mice had higher levels of activation markers, phagocytic activity, and reactive oxygen species than those from control mice. In vitro stimulation of 4-1BB induced the production of the inflammatory cytokines/chemokines of neutrophils, but not those of monocytes. These results suggest that 4-1BB stimulation of neutrophils in the early phase ofL. monocytogenesinfection causes rapid production of inflammatory cytokines/chemokines and that the subsequent infiltration of neutrophils and monocytes is crucial for eliminating the infectingL. monocytogenes.
Immunological Determinants of Clinical Outcome in Peruvian Patients with Tegumentary Leishmaniasis Treated with Pentavalent Antimonials
Authors: Maurer-Cecchini Anne , Decuypere Saskia , Chappuis François , Alexandrenne Coralie , De Doncker Simonne , Boelaert Marleen , Dujardin Jean-Claude , Loutan Louis , Dayer Jean-Michel , Tulliano Gianfranco , Arevalo Jorge , Llanos-Cuentas Alexandro , Chizzolini Carlo 
Published: February 2009

ABSTRACT

The mechanisms linking the immune response to cutaneous and mucosal leishmaniasis (CL and ML, respectively) lesions and the response to treatment are incompletely understood. Our aims were to prospectively assess, by quantitative reverse transcription-PCR, the levels of mRNA for gamma interferon, tumor necrosis factor alpha, interleukin-10 (IL-10), IL-4, and IL-13, as well as the presence of T cells (CD2) and macrophages (CD68), in CL and ML lesions and to follow their changes in response to treatment with pentavalent antimonials. The leishmanin skin test (LST) was performed on all CL and ML patients before treatment. The patient population included individuals living in areas of Peru where the disease is endemic, i.e., 129 with CL and 43 with ML. Compared to CL patients, the LST induration size was larger, the levels of all cytokine mRNAs but IL-10 were higher, T-cell mRNA was similar, and macrophage mRNA was lower in ML patients. The proportion of CL patients with an LST induration size of >8 mm was higher among responders to treatment. In CL, the pretreatment levels of cytokine mRNAs did not discriminate between responders and nonresponders; however, treatment was more often accompanied by a reduction in the levels of T-cell and cytokine mRNAs in responders than in nonresponders. Furthermore, the production of cytokines per T cell and macrophage decreased with treatment but IL-10 production remained high in nonresponders. Overall, these findings point to complex relationships among New World
Leishmania
parasites, skin and mucosal immune responses, and treatment outcome. The persistence of high levels of IL-10 in CL is characteristically associated with a poor response to treatment.
Chronic pelvic pain in women
Authors: Vincent K 
Published: February 2009

AbstractChronic pelvic pain is a major public health problem for women throughout the developed world. The complex innervation of the pelvis and the anatomical proximity of pelvic viscera mean this symptom frequently overlaps traditional medical specialties, leading to diagnostic delay and frequently inadequate treatment. Careful history taking and examination can in itself be therapeutic and will likely identify a number of causal and perpetuating factors which should be managed within the context of a multidisciplinary clinic.
Effects of early growth conditions on body composition, allometry, and survival in the ladybird beetle Harmonia axyridis
Authors: Dmitriew C. , Carroll J. , Rowe L. 
Published: February 2009

During both the larval and adult stages, the ladybird beetles Harmonia axyridis (Pallas, 1773) feed primarily on aphids, populations of which may fluctuate dramatically in time and space. Harmonia axyridis were reared under three resource treatments: high, low, and improving. We predicted that beetles experiencing consistently poor larval conditions would allocate limited resources to dispersal traits (by increasing relative wing surface area and fat storage), whereas larvae facing good or improving conditions were predicted to allocate preferentially to reproductive traits. As predicted, beetles reared at low food had lower wing loading and stored more fat than individuals reared at consistently high food. When conditions were initially poor but improved during development, body size was reduced relative to the high food treatment, though wing area scaled similarly. Allocation of fat and protein was dependent on both sex and treatment. Females in improving conditions stored less fat, and males less protein, relative to low food conditions. This is suggestive of a trade-off between reproduction and dispersal that is resolved differently between the sexes. Unexpectedly, adult survival under starvation was not appreciably affected by larval growth conditions, although males lived about 10 days longer, on average.
Influence of the SST Rise on Baroclinic Instability Wave Activity under an Aquaplanet Condition
Authors: Kodama Chihiro , Iwasaki Toshiki 
Published: February 2009

Abstract
The influence of the sea surface temperature (SST) rise on extratropical baroclinic instability wave activity is investigated using an aquaplanet general circulation model (GCM). Two types of runs were performed: the High+3 run, in which the SST is increased by 3 K only at high latitudes, and the All+3 run, in which the SST is increased uniformly by 3 K all over the globe. These SST rises were intended to reproduce essential changes of the surface air temperature due to global warming. Wave activity changes are analyzed and discussed from the viewpoint of the energetics.
In the High+3 run, midlatitude meridional temperature gradient is decreased in the lower troposphere and the wave energy is suppressed in the extratropics. In the All+3 run, although the large tropical latent heat release greatly enhances the midlatitude meridional temperature gradient in the upper troposphere, global mean wave energy does not change significantly. These results suggest that the low-level baroclinicity is much more important for baroclinic instability wave activity than upper-level baroclinicity. A poleward shift of wave energy, seen in global warming simulations, is evident in the All+3 run. Wave energy generation analysis suggests that the poleward shift of wave activity may be caused by the enhanced and poleward-shifted baroclinicity in the higher latitudes and the increased static stability in the lower latitudes. Poleward expansion of the high-baroclinicity region is still an open question.
Decadal Predictability of the Atlantic Ocean in a Coupled GCM: Forecast Skill and Optimal Perturbations Using Linear Inverse Modeling
Authors: Hawkins Ed , Sutton Rowan 
Published: February 2009

Abstract
The decadal predictability of three-dimensional Atlantic Ocean anomalies is examined in a coupled global climate model [the third climate configuration of the Met Office Unified Model (HadCM3)] using a linear inverse modeling (LIM) approach. It is found that the evolution of temperature and salinity in the Atlantic, and the strength of the meridional overturning circulation (MOC), can be effectively described by a linear dynamical system forced by white noise. The forecasts produced using this linear model are more skillful than other reference forecasts for several decades. Furthermore, significant nonnormal amplification is found under several different norms. The regions from which this growth occurs are found to be fairly shallow and located in the far North Atlantic. Initially, anomalies in the Nordic seas impact the MOC and the anomalies then grow to fill the entire Atlantic basin, especially at depth, over one to three decades. It is found that the structure of the optimal initial condition for amplification is sensitive to the norm employed, but the initial growth seems to be dominated by MOC-related basin-scale changes, irrespective of the choice of norm. The consistent identification of the far North Atlantic as the most sensitive region for small perturbations suggests that additional observations in this region would be optimal for constraining decadal climate predictions.
A Two-Scale Approximation for Efficient Representation of Nonlinear Energy Transfers in a Wind Wave Spectrum. Part II: Application to Observed Wave Spectra
Authors: Perrie William , Resio Donald T. 
Published: February 2009

Abstract
In Part I of this series, a new method for estimating nonlinear transfer rates in wind waves, based on a two-scale approximation (TSA) to the full Boltzmann integral (FBI) for quadruplet wave–wave interactions, was presented, and this new method was tested for idealized spectral data. Here, the focus is on comparisons of the TSA and the discrete interaction approximation (DIA) with the FBI for observed wave spectra from field measurements. Observed wave spectra are taken from a wave gauge array in Currituck Sound and a directional waverider off the coast near the Field Research Facility at Duck, North Carolina. Results show that the TSA compares much more favorably to the FBI than does the DIA, even for cases in which the parametric component of the formulation does not capture the spectral energy distribution very well. These results remain valid for the TSA estimates when the FBI results are significantly affected by the directional distribution of energy. It is also shown that although nonlinear transfers are substantially weaker in swell portions of the spectrum these interactions contribute significantly to the spectral evolution and net energy balance in long-distance swell propagation.