bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis
Authors: Llano-Sotelo Beatriz , Dunkle Jack , Klepacki Dorota , Zhang Wen , Fernandes Prabhavathi , Cate Jamie H. D. , Mankin Alexander S. 
Published: September 2010

ABSTRACT

We characterized the mechanism of action and the drug-binding site of a novel ketolide, CEM-101, which belongs to the latest class of macrolide antibiotics. CEM-101 shows high affinity for the ribosomes of Gram-negative (
Escherichia coli
) and Gram-positive (
Staphylococcus aureus
) bacteria. The ketolide shows high selectivity in its inhibitory action and readily interferes with synthesis of a reporter protein in the bacterial but not eukaryotic cell-free translation system. Binding of CEM-101 to its ribosomal target site was characterized biochemically and by X-ray crystallography. The X-ray structure of CEM-101 in complex with the
E. coli
ribosome shows that the drug binds in the major macrolide site in the upper part of the ribosomal exit tunnel. The lactone ring of the drug forms hydrophobic interactions with the walls of the tunnel, the desosamine sugar projects toward the peptidyl transferase center and interacts with the A2058/A2509 cleft, and the extended alkyl-aryl arm of the drug is oriented down the tunnel and makes contact with a base pair formed by A752 and U2609 of the 23S rRNA. The position of the CEM-101 alkyl-aryl extended arm differs from that reported for the side chain of the ketolide telithromycin complexed with either bacterial (
Deinococcus radiodurans
) or archaeal (
Haloarcula marismortui
) large ribosomal subunits but closely matches the position of the side chain of telithromycin complexed to the
E. coli
ribosome. A difference in the chemical structure of the side chain of CEM-101 in comparison with the side chain of telithromycin and the presence of the fluorine atom at position 2 of the lactone ring likely account for the superior activity of CEM-101. The results of chemical probing suggest that the orientation of the CEM-101 extended side chain observed in the
E. coli
ribosome closely resembles its placement in
Staphylococcus aureus
ribosomes and thus likely accurately reflects interaction of CEM-101 with the ribosomes of the pathogenic bacterial targets of the drug. Chemical probing further demonstrated weak binding of CEM-101, but not of erythromycin, to the ribosome dimethylated at A2058 by the action of Erm methyltransferase.
Ethidium Bromide MIC Screening for Enhanced Efflux Pump Gene Expression or Efflux Activity in
Staphylococcus aureus
Authors: Patel Diixa , Kosmidis Christos , Seo Susan M. , Kaatz Glenn W. 
Published: September 2010

ABSTRACT

Multidrug resistance efflux pumps contribute to antimicrobial and biocide resistance in
Staphylococcus aureus
. The detection of strains capable of efflux is time-consuming and labor-intensive using currently available techniques. A simple and inexpensive method to identify such strains is needed. Ethidium bromide is a substrate for all but one of the characterized
S. aureus
multidrug-resistant (MDR) efflux pumps (NorC), leading us to examine the utility of simple broth microtiter MIC determinations using this compound in identifying efflux-proficient strains. Quantitative reverse transcription-PCR identified the increased expression of one or more MDR efflux pump genes in 151/309 clinical strains (49%). Ethidium bromide MIC testing was insensitive (48%) but specific (92%) in identifying strains with gene overexpression, but it was highly sensitive (95%) and specific (99%) in identifying strains capable of ethidium efflux. The increased expression of
norA
with or without other genes was most commonly associated with efflux, and in the majority of cases that efflux was inhibited by reserpine. Ethidium bromide MIC testing is a simple and straightforward method to identify effluxing strains and can provide accurate predictions of efflux prevalence in large strain sets in a short period of time.
Cadaverine Suppresses Persistence to Carboxypenicillins in
Pseudomonas aeruginosa
PAO1
Authors: Manuel Jerrylynn , Zhanel George G. , de Kievit Teresa 
Published: September 2010

ABSTRACT

The refractory nature of
Pseudomonas aeruginosa
infections is due in part to the presence of specialized cells, termed persisters, within the population. To identify genes involved in
P. aeruginosa
persister formation, a PAO1 transposon (Tn) library was challenged
en masse
with 1,000 μg/ml of carbenicillin and was enriched for mutants that were able to survive in the presence of this antibiotic. For one mutant that was further characterized, the carbenicillin MIC was equal to that of PAO1, but persister formation exhibited a 20-fold increase after exposure to the antibiotic. Sequence analysis revealed that the Tn had inserted into PA4115, a gene encoding a putative lysine decarboxylase. A PA4115 mutant that produced 48-fold and 20-fold more survivors than PAO1 after 10-h exposures to carbenicillin and ticarcillin, respectively, was generated by allelic exchange. Furthermore, the rate of carboxypenicillin-induced lysis was reduced in the PA4115 mutant. Under certain pH conditions, lysine decarboxylase converts lysine to cadaverine. By measuring cadaverine production, we discovered that the PA4115 mutant had significantly reduced lysine decarboxylase activity. To determine if reduced cadaverine levels are responsible for the increase in carbenicillin and ticarcillin persistence, viability and lysis assays were performed in the presence of exogenous cadaverine. Cadaverine increased the rate of killing and lysis of the PA4115 mutant in the presence of both antibiotics. These findings suggest that cadaverine may be able to enhance the effectiveness of carboxypenicillins against
P. aeruginosa
by reducing persister formation.
Interleukin-17-Mediated Control of Parasitemia in ExperimentalTrypanosoma congolenseInfection in Mice
Authors: Mou Zhirong , Jia Ping , Kuriakose Shiby , Khadem Forough , Uzonna Jude E. 
Published: September 2010

ABSTRACTBALB/c mice are highly susceptible to experimentalTrypanosoma congolenseinfections, whereas C57BL/6 mice are relatively resistant. Infected highly susceptible BALB/c mice die of systemic inflammatory response syndrome. Because interleukin-17 (IL-17) and Th17 cells regulate inflammatory responses, we investigated their role in the pathogenesis of experimental African trypanosomiasis in mice. We show that the production of IL-17 by spleen and liver cells and the serum IL-17 level increased afterT. congolenseinfection in mice. Interestingly, infected highly susceptible BALB/c mice produced more IL-17 and had more Th17 cells than infected relatively resistant C57BL/6 mice. Paradoxically, neutralization of IL-17 with anti-IL-17 monoclonal antibodyin vivoinduced higher parasitemia in both the susceptible and the relatively resistant mice. Interestingly, anti-IL-17 antibody-treated mice had higher serum levels of alanine aminotransferase and aspartate aminotransferase, and the production of IL-10 and nitric oxide by liver cells was markedly decreased. Moreover, recombinant IL-17-treated mice exhibited significantly faster parasite control and lower peak parasitemia compared to control mice. Collectively, these results suggest that the IL-17/Th17 axis plays a protective role in murine experimental African trypanosomiasis.
Constitutive MEK1 Activation Rescues Anthrax Lethal Toxin-Induced Vascular Effects
In Vivo
Authors: Bolcome Robert E. , Chan Joanne 
Published: September 2010

ABSTRACT

Anthrax lethal toxin (LT) increases vascular leakage in a number of mammalian models and in human anthrax disease. Using a zebrafish model, we determined that vascular delivery of LT increased permeability, which was phenocopied by treatment with a selective chemical inhibitor of MEK1 and MEK2 (also known as mitogen-activated protein kinase [MAPK] kinase, MEK, or MKK). Here we investigate further the role of MEK1/phospho-ERK (pERK) in the action of LT. Overexpression of wild-type zebrafish MEK1 at high levels did not induce detrimental effects. However, a constitutively activated version, MEK1
S219D,S223D
(MEK1DD), induced early defects in embryonic development that correlated with increased ERK/MAPK phosphorylation. To bypass these early developmental defects and to provide a genetic tool for examining the action of lethal factor (LF), we generated inducible transgenic zebrafish lines expressing either wild-type or activated MEK1 under the control of a heat shock promoter. Remarkably, induction of MEK1DD transgene expression prior to LT delivery prevented vascular damage, while the wild-type MEK1 line did not. In the presence of both LT and MEK1DD transgene expression, cardiovascular development and function proceeded normally in most embryos. The resistance to microsphere leakage in transgenic animals demonstrated a protective role against LT-induced vascular permeability. A consistent increase in ERK phosphorylation among LT-resistant MEK1DD transgenic animals provided additional confirmation of transgene activation. These findings provide a novel genetic approach to examine mechanism of action of LT
in vivo
through one of its known targets. This approach may be generally applied to investigate additional pathogen-host interactions and to provide mechanistic insights into host signaling pathways affected by pathogen entry.
Entamoeba histolytica
Infection and Secreted Proteins Proteolytically Damage Enteric Neurons
Authors: Lourenssen Sandra , Houpt Eric R. , Chadee Kris , Blennerhassett Michael G. 
Published: September 2010

ABSTRACT

The enteric protozoan parasite
Entamoeba histolytica
causes amebic colitis through disruption of the mucus layer, followed by binding to and destruction of epithelial cells. However, it is not known whether ameba infections or ameba components can directly affect the enteric nervous system. Analysis of mucosal innervations in the mouse model of cecal amebiasis showed that axon density was diminished to less than 25% of control. To determine whether amebas directly contributed to axon loss, we tested the effect of either
E. histolytica
secreted products (Eh-SEC) or soluble components (Eh-SOL) to an established coculture model of myenteric neurons, glia, and smooth muscle cells. Neuronal survival and axonal degeneration were measured after 48 h of exposure to graded doses of Eh-SEC or Eh-SOL (10 to 80 μg/ml). The addition of 80 μg of either component/ml decreased the neuron number by 30%, whereas the axon number was decreased by 50%. Cytotoxicity was specific to the neuronal population, since the glial and smooth muscle cell number remained similar to that of the control, and was completely abrogated by prior heat denaturation. Neuronal damage was partially prevented by the cysteine protease inhibitor E-64, showing that a heat-labile protease was involved.
E. histolytica
lysates derived from amebas deficient in the major secreted protease
EhCP5
caused a neurotoxicity similar to that of wild-type amebas. We conclude that
E. histolytica
infection and ameba protease activity can cause selective damage to enteric neurons.
The Capsular Serotype ofStreptococcus pneumoniaeIs More Important than the Genetic Background for Resistance to Complement
Authors: Melin Merit , Trzciński Krzysztof , Meri Seppo , Käyhty Helena , Väkeväinen Merja 
Published: September 2010

ABSTRACTThe polysaccharide capsule ofStreptococcus pneumoniaeinhibits phagocytic killing by innate immune mechanisms. Certain serotypes are associated with invasive disease while others with a nasopharyngeal carriage. The invasiveness of serotypes may partly be explained by ability to resist deposition of complement (C3) on the bacterial surface and consequent opsonophagocytic killing. In our previous studies, we observed that clinical isolates of serotypes 1 and 5, which are rarely detected in asymptomatic carriage, were resistant to complement deposition and opsonophagocytosis, whereas serotypes 6B and 23F, both common in carriage, were more sensitive to deposition of C3 and opsonophagocytic killing. However, presence of significant variation in C3 deposition between isolates of the same serotype indicated that factors other than the capsule also affect complement resistance. To distinguish the relative effect of the capsular serotype and other virulence factors on C3 deposition, we compared capsule-switched mutants prepared in genetic backgrounds of pneumococcal strains TIGR4, 603, and 618. Clinical isolates which had the same multilocus sequence type but expressed different serotypes were also compared. We found that the serotype had a significant impact on complement resistance and that the more resistant the strain was to complement, the higher was the concentration of polysaccharide-specific antibodies required for opsonophagocytic killing. Comparison of strains expressing the same capsular polysaccharides in the different genetic backgrounds and various capsular mutants of the same strain suggests that while the genotype affects complement resistance, the serotype is the most important determinant. Differences between serotypes were more significant than the differences between strains.
Mortality in Vermont granite workers and its association with silica exposure
Authors: Vacek Pamela M , Verma Dave K , Graham William G , Callas Peter W , Gibbs Graham W 
Published: September 2010

ObjectivesTo assess mortality in Vermont granite workers and examine relationships between silica exposure and mortality from lung cancer, kidney cancer, non-malignant kidney disease, silicosis and other non-malignant respiratory disease.MethodsWorkers employed between 1947 and 1998 were identified. Exposures were estimated using a job–exposure matrix. Mortality was assessed through 2004 and standardised mortality ratios (SMRs) were computed. Associations between mortality and exposure to silica were assessed by nested case–control analyses using conditional logistic regression.Results7052 workers had sufficient data for statistical analysis. SMRs were significantly elevated for lung cancer (SMR 1.37, 95% CI 1.23 to 1.52), silicosis (SMR 59.13, 95% CI 44.55 to 76.97), tuberculosis (SMR 21.74, 95% CI 18.37 to 25.56) and other non-malignant respiratory disease (SMR 1.74, 95% CI 1.50 to 2.02) but not for kidney cancer or non-malignant kidney disease. In nested case–control analyses, significant associations with cumulative exposure to respirable free silica were observed for silicosis (OR 1.13, 95% CI 1.05 to 1.21 for each 1 mg/m3-year increase in cumulative exposure) and other non-malignant respiratory disease (OR 1.10, 95% CI 1.03 to 1.16) but not for lung cancer (OR 0.99, 95% CI 0.94 to 1.03), kidney cancer (OR 0.96, 95% CI 0.84 to 1.09) or non-malignant kidney disease (OR 0.95, 95% CI 0.84 to 1.08).ConclusionsExposure to crystalline silica in Vermont granite workers was associated with increased mortality from silicosis and other non-malignant respiratory disease, but there was no evidence that increased lung cancer mortality in the cohort was due to exposure. Mortality from malignant and non-malignant kidney disease was not significantly increased or associated with exposure.
COST ESTIMATION OF ADVANCE RESERVATIONS OVER QUEUED JOBS: A QUANTITATIVE STUDY
Authors: ZHAO CHUNJIANG , CAO JUNWEI , WU HUARUI , ZHANG FAN 
Published: September 2010

A grid is a geographically distributed resource sharing environment across multiple organizations. The most typical grid resources are clusters with high performance/cost ratio. In general, these clusters are shared as non-dedicated grid resources since local users may run their jobs simultaneously. Local jobs are usually queued and processed in a batch mode with uncertain waiting time, while grid jobs always require advance reservations with guaranteed resource allocation. In this paper, we provide quantitative analysis on the impact of advance reservations over queued jobs, in terms of job waiting time and resource utilization, respectively. It is observed that advance reservations will lead to longer job waiting time and lower resource utilization. That is to say, advance reservations should cost more than queued jobs. In this work, based on quantitative experimental results, an empirical formula for cost estimation of advance reservations over queued jobs is presented. It is suggested that compared with queued jobs, advance reservations should be doubly charged to compensate resource utilization loss. If the notice time of an advance reservation is short below a threshold, additional cost should be applied further since queue waiting time is increased.
Microwave Dielectric Properties of CaTiO3–(LiNd)TiO3–(BiNa)TiO3 Ceramics
Authors: Moon Sang Hwan , Kim Jeong Seog , Cheon Chae Il , Kim Eung Soo , Ohsato Hitoshi 
Published: September 2010

The microwave dielectric properties of the CaTiO3–(Li1/2Nd1/2)TiO3–(Bi1/2Na1/2)TiO3 (CT–LNT–BNT) ternary ceramics were studied on the basis of their crystal structure. The microwave dielectric constant improved from 139 to 432, and Qf decreased continuously from 3249 to 124 GHz with an increase in BNT content in the 0.4CT–(0.6-x)LNT–xBNT ternary compositions. The crystal structures of 0.4CT–(0.6-x)LNT–xBNT (x=0–0.6) ceramics were confirmed to be perovskite with an orthorhombic crystal system P
c
m
n (No. 62) and the lattice parameter differences between the a- and c-axes became small with increasing BNT content (x). The increase in the dielectric constant with the increase in BNT content could be explained by not only the large polarizability of a Bi ion but also the crystal structure change: increases in bond lengths, volumes of octahedra and cuboctaheda, and the tilt angle of an octahedron. The tendency of the crystal structure to change from paraelectric orthorhombic to ferroelectric trigonal or tetragonal perovskite structure resulted in a decrease in Qf value with increasing BNT content.
Late Jurassic-early Cretaceous reef trends on the continental margin SW of the British Isles
Authors: Masson D.G. , Roberts D.G. 
Published: September 2010

Abstract:
SUMMARY: Multichannel seismic reflection data has been used to outline the distribution of reefs or carbonate banks on the continental margin SW of the British Isles. This distribution is discussed in terms of regional structure and stratigraphy. All the reefal bodies are pre-Aptian in age, with evidence for both late Jurassic and early Cretaceous phases of reef development. Reef growth was contemporaneous with rifting prior to the occurrence of sea-floor spreading in the Bay of Biscay. The distribution of reefs suggests that shallow marine conditions persisted in the Goban Spur area until middle Cretaceous time, while a deeper embayment may have occupied the Bay of Biscay as early as the late Jurassic.
Strain factorizations from lapilli tuff, English Lake District
Authors: Bell A.M. 
Published: September 2010

Abstract:
SUMMARY: Two existing and two new methods of strain analysis have been used on samples of accretionary lapilli tuff from the English Lake District. Results from each method are presented for comparison. Factors responsible for lapilli shape are itemized and discussed. Regional studies indicate that lapilli ellipsoids contain initial, compaction and tectonic components. The most reliable results indicate that compaction of 66% of original thickness normal to bedding during diagenesis was followed by tectonic strains due to folding and cleavage formation. The effects of folding on lapilli shape are thought to be small. Slaty cleavage was produced by strains close to plane strain, indicating a shortening of SO-70% normal to the cleavage plane. It is concluded that slaty cleavage does not form perpendicular to the maximum total shortening of the rock, but perpendicular to the short axis of a strain ellipsoid associated solely with cleavage formation and computation of three-dimensional progressive deformations.
Primary bedding-parallel fabrics in structural geology
Authors: Maltman A.J. 
Published: September 2010

Abstract:
SUMMARY: Many phyllosilicate minerals gain greatest mechanical stability on sedimentation by orienting themselves parallel to bedding. Loss of water during the initial stages of compaction also promotes or enhances such a preferred alignment. If the mineral is then buried in the absence of tectonic stress, static mimetic recrystallization will be prompted, so that the fabric becomes metamorphic in appearance while retaining its bedding-parallel orientation.
Such a fabric, in its various stages of evolution, appears not to have received due attention in structural geology. Examples are given where problems associated with microstructures in slump sheets, the early stages of cleavage generation, the development of early schistosities and the interpretation of structural sequence, can be alleviated by the recognition of a primary fabric.
Farletuzumab, a Humanized Monoclonal Antibody against Folate Receptor α, in Epithelial Ovarian Cancer: a Phase I Study
Authors: Konner Jason A. , Bell-McGuinn Katherine M. , Sabbatini Paul , Hensley Martee L. , Tew William P. , Pandit-Taskar Neeta , Els Nicholas Vander , Phillips Martin D. , Schweizer Charles , Weil Susan C. , Larson Steven M. , Old Lloyd J. 
Published: September 2010

Abstract
Purpose: Folate receptor α expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. Farletuzumab, a humanized monoclonal antibody against folate receptor α, has shown antitumor activity and favorable toxicity in preclinical evaluation. This phase I, dose-escalation study was conducted to determine the safety of weekly i.v. farletuzumab and establish the maximum tolerated dose (MTD).
Experimental Design: Patients with platinum-refractory or platinum-resistant epithelial ovarian cancer received farletuzumab (12.5-400 mg/m2) on days 1, 8, 15, and 22 of a 5-week cycle. Intrapatient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related adverse event of grade 3 or higher, and the MTD was the highest dose at which one or none of six patients experienced a DLT. Disease progression was recorded using Response Evaluation Criteria in Solid Tumors criteria and serum CA-125.
Results: Twenty-five heavily pretreated patients were included in the safety, efficacy, and pharmacokinetic analyses. No DLTs or MTDs were encountered, and dose escalation was continued to farletuzumab 400 mg/m2. Cmax and AUC0-24 (area under the serum concentration-time curve) increased in an approximately dose-proportional manner, and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. Stable disease by Response Evaluation Criteria in Solid Tumors was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles.
Conclusions: In this phase I study, farletuzumab administered as an i.v. infusion at doses of 12.5 to 400 mg/m2 was generally safe and well tolerated in the management of heavily pretreated patients with epithelial ovarian cancer. Clin Cancer Res; 16(21); 5288–95. ©2010 AACR.