bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic/Pharmacodynamic Analysis of the Influence of Inoculum Size on the Selection of Resistance in
Escherichia coli
by a Quinolone in a Mouse Thigh Bacterial Infection Model
Authors: Ferran Aude A. , Kesteman Anne-Sylvie , Toutain Pierre-Louis , Bousquet-Mélou Alain 
Published: June 2009

ABSTRACT

Maintaining quinolone concentrations outside the mutant selection window (MSW) between the MIC and mutant prevention concentration (MPC) was suggested by in vitro and in vivo studies to prevent the selection of resistant mutants. However, selection also may depend on the presence of resistant bacterial mutants at the start of treatment, which is highly dependent on the initial inoculum size. In this study, a mouse thigh bacterial infection model was used to test the influence of different exposures to marbofloxacin on the selection of resistant bacteria after infection with a low (10
5
CFU) or high (10
8
CFU) initial inoculum of
Escherichia coli
. The inoculum size was shown to influence the exposure to marbofloxacin and the values of pharmacokinetic/pharmacodynamic indices. When the abilities of the indices time within the MSW (
T
MSW
), area under the concentration-time curve of 0 to 24 h divided by the MIC, and the maximum concentration of drug in plasma divided by the MIC to predict the selection of resistant bacteria were compared, only
T
MSW
appeared to be a good predictor of the prevention of resistance for values less than 30%. When the T
MSW
was higher than 34%, the selection of resistant bacteria occurred less often in thighs initially infected with the low inoculum (11/24; 46%) than in those infected with the high inoculum (30/36; 80%), suggesting that the selection of resistant mutants depends on both the
T
MSW
and inoculum size. The relevance of these results merits further investigation to test different strategies of antibiotic therapy depending on the expected bacterial burden at the infectious site.
Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization
Authors: Dolan Kristy , Montgomery Sara , Buchheit Bradley , DiDone Louis , Wellington Melanie , Krysan Damian J. 
Published: June 2009

ABSTRACTTamoxifen (TAM), an estrogen receptor antagonist used primarily to treat breast cancer, has well-recognized antifungal properties, but the activity of TAM has not been fully characterized using standardized (i.e., CLSI) in vitro susceptibility testing, nor has it been demonstrated in an in vivo model of fungal infection. In addition, its mechanism of action remains to be clearly defined at the molecular level. Here, we report that TAM displays in vitro activity (MIC, 8 to 64 μg/ml) against pathogenic yeasts (Candida albicans, otherCandidaspp., andCryptococcus neoformans). In vivo, 200 mg/kg of body weight per day TAM reduced kidney fungal burden (−1.5 log10CFU per g tissue;P= 0.008) in a murine model of disseminated candidiasis. TAM is a known inhibitor of mammalian calmodulin, and TAM-treated yeast show phenotypes consistent with decreased calmodulin function, including lysis, decreased new bud formation, disrupted actin polarization, and decreased germ tube formation. The overexpression of calmodulin suppresses TAM toxicity, hypofunctional calmodulin mutants are hypersensitive to TAM, and TAM interferes with the interaction between Myo2p and calmodulin, suggesting that TAM targets calmodulin as part of its mechanism of action. Taken together, these experiments indicate that the further study of compounds related to TAM as antifungal agents is warranted.
Viral Booster Vaccines Improve
Mycobacterium bovis
BCG-Induced Protection against Bovine Tuberculosis
Authors: Vordermeier H. Martin , Villarreal-Ramos Bernardo , Cockle Paul J. , McAulay Martin , Rhodes Shelley G. , Thacker Tyler , Gilbert Sarah C. , McShane Helen , Hill Adrian V. S. , Xing Zhou , Hewinson R. Glyn 
Published: June 2009

ABSTRACT

Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using
Mycobacterium bovis
bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after
M. bovis
challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.
Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during
Pneumocystis
Pneumonia
Authors: Lasbury Mark E. , Durant Pamela J. , Liao Chung-Ping , Lee Chao-Hung 
Published: June 2009

ABSTRACT

Pneumocystis
infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during
Pneumocystis
pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.
Chlamydia trachomatis-Infected Patients Display Variable Antibody Profiles against the Nine-Member Polymorphic Membrane Protein Family
Authors: Tan Chun , Hsia Ru-ching , Shou Huizhong , Haggerty Catherine L. , Ness Roberta B. , Gaydos Charlotte A. , Dean Deborah , Scurlock Amy M. , Wilson David P. , Bavoil Patrik M. 
Published: June 2009

ABSTRACTGenomic analysis of theChlamydiaceaehas revealed a multigene family encoding large, putatively autotransported polymorphic membrane proteins (Pmps) with nine members in the sexually transmitted pathogen Chlamydia trachomatis. While various pathogenesis-related functions are emerging for the Pmps, observed genotypic and phenotypic variation among several chlamydial Pmps in variousChlamydiaspecies has led us to hypothesize that thepmpgene repertoire is the basis of a previously undetected mechanism of antigenic variation. To test this hypothesis, we chose to examine the serologic response ofC. trachomatis-infected patients to each Pmp subtype. Immune serum samples were collected from four populations of patients with confirmedC. trachomatisgenital infection: 40 women with pelvic inflammatory disease from Pittsburgh, PA; 27 and 34 adolescent/young females from Oakland, CA, and Little Rock, AR, respectively; and 58 adult male patients from Baltimore, MD. The Pmp-specific antibody response was obtained using immunoblot analysis against each of the nine recombinantly expressed Pmps and quantified by densitometry. Our results show that nearly allC. trachomatis-infected patients mount a strong serologic response against individual or multiple Pmp subtypes and that the antibody specificity profile varies between patients. Moreover, our analysis reveals differences in the strengths and specificities of the Pmp subtype-specific antibody reactivity relating to gender and clinical outcome. Overall, our results indicate that the Pmps elicit various serologic responses inC. trachomatis-infected patients and are consistent with thepmpgene family being the basis of a mechanism of antigenic variation.
The Role of Biomacromolecular Crowding, Ionic Strength, and Physicochemical Gradients in the Complexities of Life's Emergence
Authors: Spitzer Jan , Poolman Bert 
Published: June 2009

SUMMARY
We have developed a general scenario of prebiotic physicochemical evolution during the Earth's Hadean eon and reviewed the relevant literature. We suggest that prebiotic chemical evolution started in microspaces with membranous walls, where external temperature and osmotic gradients were coupled to free-energy gradients of potential chemical reactions. The key feature of this scenario is the onset of an emergent evolutionary transition within the microspaces that is described by the model of complex vectorial chemistry. This transition occurs at average macromolecular crowding of 20 to 30% of the cell volume, when the ranges of action of stabilizing colloidal forces (screened electrostatic forces, hydration, and excluded volume forces) become commensurate. Under these conditions, the macromolecules divide the interior of microspaces into dynamically crowded macromolecular regions and topologically complementary electrolyte pools. Small ions and ionic metabolites are transported vectorially between the electrolyte pools and through the (semiconducting) electrolyte pathways of the crowded macromolecular regions from their high electrochemical potential (where they are biochemically produced) to their lower electrochemical potential (where they are consumed). We suggest a sequence of tentative transitions between major evolutionary periods during the Hadean eon as follows: (i) the early water world, (ii) the appearance of land masses, (iii) the pre-RNA world, (iv) the onset of complex vectorial chemistry, and (v) the RNA world and evolution toward Darwinian thresholds. We stress the importance of high ionic strength of the Hadean ocean (short Debye's lengths) and screened electrostatic interactions that enabled the onset of the vectorial structure of the cytoplasm and the possibility of life's emergence.
ACTIVE CIRCULATOR CIRCUITS USING OA, CCII, CFOA AND DVCC
Authors: SOLIMAN AHMED M. 
Published: June 2009

A review of the two types of circulators using Operational Amplifiers (OA) with detailed comparison is given. Novel active circulator circuits using Current Conveyors (CCII) and Current Feedback Operational Amplifiers (CFOA) and Differential Voltage Current Conveyor (DVCC) are introduced. The proposed CCII circulator circuit uses six CCIIs and three floating resistors. Two different circulator types using the CFOA are given. A circulator circuit which uses three DVCCs and has the advantage of using three grounded resistors is also introduced. Spice simulation results using 0.5 μm CMOS transistors are included to support the theoretical analysis and demonstrate comparisons among the different types of circulators.
MOS-C KHN FILTER USING VOLTAGE OP AMP, CFOA, OTRA AND DCVC
Authors: SOLIMAN AHMED M. , MADIAN AHMED H. 
Published: June 2009

MOS-C realizations of the Kerwin–Huelsman–Newcomb (KHN) circuit using the commercially available Voltage Operational Amplifier (VOA) and the Current Feedback Operational Amplifier (CFOA) are reviewed in this paper. Additional MOS-C KHN realizations using the Operational Transresistance Amplifier (OTRA) and the Differential Current Voltage Conveyor (DCVC) are also included. MOS-C realizations of the KHN circuit using CMOS operational amplifier, CMOS current feedback operational amplifier and CMOS operational transresistance amplifier are also given.Spice simulation results using 0.18 CMOS technology model from MOSIS are included together with detailed comparison tables to demonstrate the differences between MOS-C KHN circuits using both of the commercially available active building blocks and CMOS integrated building blocks. A comparison with the Gm-C KHN circuit is also included.
A New Extension Theorem for Concave Operators
Authors: Peng Jian-wen , Rong Wei-dong , Yao Jen-Chih 
Published: May 2009

AbstractWe present a new and interesting extension theorem for concave operators as follows. Let "Equation missing" be a real linear space, and let "Equation missing" be a real order complete PL space. Let the set "Equation missing" be convex. Let "Equation missing" be a real linear proper subspace of "Equation missing", with "Equation missing", where "Equation missing" for some "Equation missing". Let "Equation missing" be a concave operator such that "Equation missing" whenever "Equation missing" and "Equation missing". Then there exists a concave operator "Equation missing" such that (i) "Equation missing" is an extension of "Equation missing", that is, "Equation missing" for all "Equation missing", and (ii) "Equation missing" whenever "Equation missing".
Expression of the K303R Estrogen Receptor-α Breast Cancer Mutation Induces Resistance to an Aromatase Inhibitor via Addiction to the PI3K/Akt Kinase Pathway
Authors: Barone Ines , Cui Yukun , Herynk Matthew H. , Corona-Rodriguez Arnoldo , Giordano Cinzia , Selever Jennifer , Beyer Amanda , Andò Sebastiano , Fuqua Suzanne A.W. 
Published: June 2009

Abstract
Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor-α (ERα)–positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERα in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERα mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective “addiction” to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERα mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy. [Cancer Res 2009;69(11):4724–32]
Changes in Sensory Evoked Responses Coincide with Rapid Improvement in Speech Identification Performance
Authors: Alain Claude , Campeanu Sandra , Tremblay Kelly 
Published: June 2009

Abstract
Perceptual learning is sometimes characterized by rapid improvements in performance within the first hour of training (fast perceptual learning), which may be accompanied by changes in sensory and/or response pathways. Here, we report rapid physiological changes in the human auditory system that coincide with learning during a 1-hour test session in which participants learned to identify two consonant vowel syllables that differed in voice onset time. Within each block of trials, listeners were also presented with a broadband noise control stimulus to determine whether changes in auditory evoked potentials were specific to the trained speech cue. The ability to identify the speech sounds improved from the first to the fourth block of trials and remained relatively constant thereafter. This behavioral improvement coincided with a decrease in N1 and P2 amplitude, and these learning-related changes differed from those observed for the noise stimulus. These training-induced changes in sensory evoked responses were followed by an increased negative peak (between 275 and 330 msec) over fronto-central sites and by an increase in sustained activity over the parietal regions. Although the former was also observed for the noise stimulus, the latter was specific to the speech sounds. The results are consistent with a top–down nonspecific attention effect on neural activity during learning as well as a more learning-specific modulation, which is coincident with behavioral improvements in speech identification.
A Global Climatology of Temperature and Water Vapor Variance Scaling from the Atmospheric Infrared Sounder
Authors: Kahn Brian H. , Teixeira João 
Published: June 2009

AbstractA global climatology of height-resolved variance scaling within the troposphere is presented using derived temperature (T) and water vapor (q) profiles from the Atmospheric Infrared Sounder (AIRS). The power-law exponent of T variance scaling approaches 1.0 outside of the tropics at scales &gt;500–800 km, but it is closer to 0.3 at scales &lt;500 km, similar to exponents obtained from aircraft campaigns, numerical modeling, and theoretical studies. The T exponents in the tropics at all scales become less than 0.3, with a similar pattern observed within the boundary layer in some extratropical regions. For q, the variance scaling differs substantially from T with exponents near 0.5–0.6 in parts of the tropics and subtropics with little to no scale break, showing some consistency with a very limited set of aircraft and satellite studies. Scaling differences as a function of land and ocean, altitude, and cloudy- and clear-sky scenes are quantified. Both T and q exponents indicate peak magnitudes in the midtroposphere and reductions are observed near the boundary layer and upper troposphere. Seasonal variations of T and q scaling reveal a stronger seasonal cycle over land than ocean, especially for T at large length scales. While the zonal variations of T and q exponents vary significantly for scales &lt;500 km, the seasonal variations are much smaller in magnitude. The exponents derived from AIRS could eventually be extrapolated to smaller scales in the absence of additional scale breaks &lt;150 km to provide useful information for constraining subgrid-scale cloud parameterizations.
LMODEL: A Satellite Precipitation Methodology Using Cloud Development Modeling. Part II: Validation
Authors: Hsu Kuo-lin , Bellerby Tim , Sorooshian S. 
Published: June 2009

Abstract
A new satellite-based rainfall monitoring algorithm that integrates the strengths of both low Earth-orbiting (LEO) and geostationary Earth-orbiting (GEO) satellite information has been developed. The Lagrangian Model (LMODEL) algorithm combines a 2D cloud-advection tracking system and a GEO data–driven cloud development and rainfall generation model with procedures to update model parameters and state variables in near–real time. The details of the LMODEL algorithm were presented in Part I. This paper describes a comparative validation against ground radar rainfall measurements of 1- and 3-h LMODEL accumulated rainfall outputs. LMODEL rainfall estimates consistently outperform accumulated 3-h microwave (MW)-only rainfall estimates, even before the more restricted spatial coverage provided by the latter is taken into account. In addition, the performance of LMODEL products remains effective and consistent between MW overpasses. Case studies demonstrate that the LMODEL provides the potential to synergize available satellite data to generate useful precipitation measurements at an hourly scale.
Cyclic hydrostatic pressure and cotton particles stimulate synthesis by human lung macrophages of cytokines in vitro
Authors: Lewis Sarah , Singh Dave , Evans Carol E 
Published: June 2009

Abstract

Background
Inhalation of particulates is a leading cause of the development of lung diseases and current understanding of the complex relationship between lung metabolism and airborne particulates is incomplete. It is well established that mechanical load is important in the development of the lung and in lung cell differentiation. The interaction between particle exposure and physical forces on alveolar macrophages is a physiologically relevant issue, but as yet understudied. This study examines the effect of cyclic hydrostatic pressure and cotton particles on synthesis of cytokines by human alveolar macrophages.

Methods
Alveolar macrophages were obtained from patients with lung disease, either from lavage samples or from lung tissue resection. The commonly used cell line THP-1 was included in the experiments. Cell cultures were exposed to cotton particles and/cyclic hydrostatic pressure (3 or 5 psi); control cultures were exposed to medium only. TNFα, IL-1β and IL-6 were assayed in the culture media using specific ELISAs. Cells were characterized using morphology and markers specific for macrophages (Jenner/Giemsa staining, CD14 and CD68).

Results
Exposure to cotton particles stimulated cytokine synthesis by macrophages from all three sources; exposure to cyclic hydrostatic pressure alone did not stimulate cytokine synthesis significantly. However, the combination of both particles and cyclic hydrostatic pressure increased the simulation of cytokine synthesis still further. Cell characterization demonstrated that the large majority of cells had a macrophage morphology and were positive for CD14 and CD68.

Conclusion
These data suggest an interaction between cyclic hydrostatic pressure and particulate exposure, which increases alveolar macrophage cytokine production. This interaction was only observed at the higher cyclic hydrostatic pressure. However, in patient samples, there was considerable variation in the amount by which secretion of an individual cytokine increased and there was also variation in the mechanosensitivity of cells from the three different sources. Cyclic hydrostatic pressure, therefore, may be an important modulator of the response of alveolar macrophages to cotton particles, but the source of the cells may be a confounding factor which demands further investigation.