bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of Resistance in Nontyphoidal
Salmonella enterica
Strains Exhibiting a Nonclassical Quinolone Resistance Phenotype
Authors: Gunell Marianne , Webber Mark A. , Kotilainen Pirkko , Lilly Andrew J. , Caddick Jonathan M. , Jalava Jari , Huovinen Pentti , Siitonen Anja , Hakanen Antti J. , Piddock Laura J. V. 
Published: July 2009

ABSTRACT

Nontyphoidal
Salmonella enterica
strains with a nonclassical quinolone resistance phenotype were isolated from patients returning from Thailand or Malaysia to Finland. A total of 10 isolates of seven serovars were studied in detail, all of which had reduced susceptibility (MIC ≥ 0.125 μg/ml) to ciprofloxacin but were either susceptible or showed only low-level resistance (MIC ≤ 32 μg/ml) to nalidixic acid. Phenotypic characterization included susceptibility testing by the agar dilution method and investigation of efflux activity. Genotypic characterization included the screening of mutations in the quinolone resistance-determining regions (QRDR) of
gyrA
,
gyrB
,
parC
, and
parE
by PCR and denaturing high-pressure liquid chromatography and the amplification of plasmid-mediated quinolone resistance (PMQR) genes
qnrA
,
qnrB
,
qnrS
,
qnrD
,
aac(6
′
)-Ib-cr
, and
qepA
by PCR. PMQR was confirmed by plasmid analysis, Southern hybridization, and plasmid transfer. No mutations in the QRDRs of
gyrA
,
gyrB
,
parC
, or
parE
were detected with the exception of a Thr57-Ser substitution within ParC seen in all but the
S. enterica
serovar Typhimurium strains. The
qnrA
and
qnrS
genes were the only PMQR determinants detected. Plasmids carrying
qnr
alleles were transferable in vitro, and the resistance phenotype was reproducible in
Escherichia coli
DH5α transformants. These data demonstrate the emergence of a highly mobile
qnr
genotype that, in the absence of mutation within topoisomerase genes, confers the nontypical quinolone resistance phenotype in
S. enterica
isolates. The
qnr
resistance mechanism enables bacteria to survive elevated quinolone concentrations, and therefore, strains carrying
qnr
alleles may be able to expand during fluoroquinolone treatment. This is of concern since nonclassical quinolone resistance is plasmid mediated and therefore mobilizable.
Comparative Efficacy and Safety of Vancomycin versus Teicoplanin: Systematic Review and Meta-Analysis
Authors: Svetitsky Shuli , Leibovici Leonard , Paul Mical 
Published: July 2009

ABSTRACT
Vancomycin and teicoplanin are the glycopeptides currently in use for the treatment of infections caused by invasive beta-lactam-resistant gram-positive organisms. We conducted a systematic review and meta-analysis of randomized controlled trials that have compared vancomycin and teicoplanin administered systemically for the treatment of suspected or proven infections. A comprehensive search of trials without year, language, or publication status restrictions was performed. The primary outcome was all-cause mortality. Two reviewers independently extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled by using the fixed-effect model (RRs of >1 favor vancomycin). Twenty-four trials were included. All-cause mortality was similar overall (RR, 0.95; 95% CI, 0.74 to 1.21), and there was no significant heterogeneity. In trials that used adequate allocation concealment, the results favored teicoplanin (RR, 0.82; 95% CI, 0.63 to 1.06), while in trials with unknown methods or inadequate concealment, the results favored vancomycin (RR, 3.61; 95% CI, 1.27 to 10.30). The latter trials might have recruited more severely ill patients. No other variable affected the RRs for mortality, including the assessment of glycopeptides administered empirically or for proven infections, neutropenia, the participant's age, and drug dosing. There were no significant differences between teicoplanin and vancomycin with regard to clinical failure (RR, 0.92; 95% CI, 0.81 to 1.05), microbiological failure (RR, 1.24; 95% CI, 0.93 to 1.65), and other efficacy outcomes. Lower RRs (in favor of teicoplanin) for clinical failure were observed with a lower risk of bias and when treatment was initiated for infections caused by gram-positive organisms rather than empirically. Total adverse events (RR, 0.61; 95% CI, 0.50 to 0.74), nephrotoxicity (RR, 0.44; 95% CI, 0.32 to 0.61), and red man syndrome were significantly less frequent with teicoplanin. Teicoplanin is not inferior to vancomycin with regard to efficacy and is associated with a lower adverse event rate than vancomycin.
DAS181 Inhibits H5N1 Influenza Virus Infection of Human Lung Tissues
Authors: Chan Renee W. Y. , Chan Michael C. W. , Wong Adam C. N. , Karamanska Rositsa , Dell Anne , Haslam Stuart M. , Sihoe Alan D. L. , Chui W. H. , Triana-Baltzer Gallen , Li Qixiang , Peiris J. S. Malik , Fang Fang , Nicholls John M. 
Published: July 2009

ABSTRACT
DAS181 is a novel candidate therapeutic agent against influenza virus which functions via the mechanism of removing the virus receptor, sialic acid (Sia), from the adjacent glycan structures. DAS181 and its analogues have previously been shown to be potently active against multiple strains of seasonal and avian influenza virus strains in several experimental models, including cell lines, mice, and ferrets. Here we demonstrate that DAS181 treatment leads to desialylation of both α2-6-linked and α2-3-linked Sia in ex vivo human lung tissue culture and primary pneumocytes. DAS181 treatment also effectively protects human lung tissue and pneumocytes against the highly pathogenic avian influenza virus H5N1 (A/Vietnam/3046/2004). Two doses of DAS181 treatment given 12 h apart were sufficient to block H5N1 infection in the ex vivo lung tissue culture. These findings support the potential value of DAS181 as a broad-spectrum therapeutic agent against influenza viruses, especially H5N1.
High-Throughput Screening Identifies Three Inhibitor Classes of the Telomere Resolvase from the Lyme Disease Spirochete
Authors: Lefas Georgia , Chaconas George 
Published: July 2009

ABSTRACT

Lyme disease, the most common vector-borne zoonosis in North America, is caused by the spirochetal pathogen
Borrelia burgdorferi
. The telomere resolvase encoded by this organism (ResT) promotes the formation of covalently closed hairpin ends on the linear DNA molecules of
B. burgdorferi
through a two-step transesterification. ResT is essential for survival and is therefore an attractive target for the development of highly specific antiborrelial drugs. To identify ResT inhibitors, a novel fluorescence-based high-throughput assay was developed and used to screen a library of 27,520 small-molecule drug-like compounds. Six confirmed inhibitors of ResT, with 50% inhibitory concentrations between 2 and 10 μM, were identified. The inhibitors were characterized further and were grouped into three distinct classes based on their inhibitory features. The high-throughput screening assay developed in this paper, along with the six inhibitory compounds identified, provides a starting point for the future development of novel antiborrelial drugs as well as small-molecule inhibitors that will be helpful for the further dissection of the reaction mechanism.
AI-2/LuxS Is Involved in Increased Biofilm Formation by
Streptococcus intermedius
in the Presence of Antibiotics
Authors: Ahmed Nibras A. , Petersen Fernanda C. , Scheie Anne A. 
Published: July 2009

ABSTRACT

Bacteria utilize quorum-sensing communication to organize their behavior by monitoring the concentration of bacterial signals, referred to as autoinducers (AIs). The widespread detection of AI-2 signals and its enzymatic synthase (LuxS) in bacteria suggests that AI-2 is an inter- and intraspecies communication signal. We have previously shown that antibiotic susceptibility is affected by AI-2 signaling in
Streptococcus anginosus
. Since chronic infections involve persistent biofilms resilient to antibiotic treatment, we explored the role of AI-2/LuxS in
Streptococcus intermedius
biofilm formation and cell viability when the organism was exposed to sub-MICs of ampicillin, ciprofloxacin, or tetracycline. The
S. intermedius
wild type (WT) and its isogenic
luxS
mutant, strain SI006, were exposed to sub-MICs of ampicillin, ciprofloxacin, or tetracycline. Biofilms were formed on polystyrene discs in microtiter plates. To assess planktonic cell viability, the ATP microbial viability assay was performed and the numbers of CFU were determined. For complementation assays, the AI-2 precursor dihydroxy pentanedione (DPD) was used as a supplement for SI006. Relative
luxS
expression was quantified by real-time PCR. The sub-MICs of all three antibiotics increased biofilm formation in
S. intermedius
WT. However, biofilm formation by SI006 was either unaffected or reduced (
P
≤ 0.05). Bacterial viability tests of biofilm and planktonic cell cultures indicated that SI006 was more susceptible to antibiotics than the WT. DPD complemented the
luxS
mutant phenotype. Real-time PCR revealed modest yet significant changes in
luxS
expression in the presence of antibiotic concentrations that increased biofilm formation. In conclusion, in
S. intermedius
, AI-2/LuxS was involved in antibiotic susceptibility and increased biofilm formation at sub-MICs of antibiotic.
Exploring the Mode of Action of Antimicrobial Peptide MUC7 12-Mer by Fitness Profiling of
Saccharomyces cerevisiae
Genomewide Mutant Collection
Authors: Lis Maciej , Fuss Jason R. , Bobek Libuse A. 
Published: July 2009

ABSTRACT

The MUC7 12-mer (RKSYKCLHKRCR) is a cationic antimicrobial peptide derived from the human salivary mucin MUC7. To study its effect/mechanism of action on fungi, we performed a fitness screen of a tagged, diploid, homozygous gene deletion mutant pool of the yeast
Saccharomyces cerevisiae
grown in the presence of the MUC7 peptide. Forty-five strains exhibiting reduced fitness and 13 strains exhibiting increased fitness (sensitivity or resistance, respectively) were identified by hybridization intensities to tag arrays. The strongest fitness defects were observed with deletions in genes encoding elements of the RIM101 signaling pathway (regulating response to alkaline and neutral pH and other environmental conditions) and of the endosomal sorting complex required for transport (ESCRT; functioning mainly in protein sorting for degradation, but also required for activation of the RIM101 pathway). Other deletions identified as conferring fitness defect or gain are in genes associated with a variety of functions, including transcription regulation, protein trafficking, transport, metabolism, and others. The results of the pool fitness screen were validated by a set of mutant strains tested individually in the presence of the MUC7 12-mer. All tested RIM101-related deletion strains showing fitness defects confirmed their sensitivities. Taken together, the results led us to conclude that deletions of genes associated with the RIM101 pathway confer sensitivity to the peptide by preventing activation of this pathway and that this stress response plays a major role in the protection of
S. cerevisiae
against damage inflicted by the MUC7 12-mer peptide.
Genetic Context of Plasmid-CarriedblaCMY-2-Like Genes inEnterobacteriaceae
Authors: Verdet C. , Gautier V. , Chachaty E. , Ronco E. , Hidri N. , Decré D. , Arlet G. 
Published: July 2009

ABSTRACTAnalysis of 15 European clinicalEnterobacteriaceaeisolates showed that differences in the genetic context ofblaCMY-2-like genes reflected the replicon type, usually IncA/C or IncI1. TheseblaCMY-2loci may originate from the same ISEcp1-mediated mobilization from theCitrobacter freundiichromosome as structures described in earlier studies.
Staphylococcus aureusInduces Microglial Inflammation via a Glycogen Synthase Kinase 3β-Regulated Pathway
Authors: Cheng Yi-Lin , Wang Chi-Yun , Huang Wei-Ching , Tsai Cheng-Chieh , Chen Chia-Ling , Shen Ching-Fen , Chi Chia-Yu , Lin Chiou-Feng 
Published: July 2009

ABSTRACTA proinflammatory role for glycogen synthase kinase 3β (GSK-3β) has been demonstrated. Here, we addressed its roles on heat-inactivatedStaphylococcus aureus-induced microglial inflammation. Heat-inactivatedS. aureusinduced tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) production, at least in part, via a Toll-like receptor 2-regulated pathway. Neutralization of TNF-α largely blocked heat-inactivatedS. aureus-induced NO. Heat-inactivatedS. aureusactivated GSK-3β, and inhibiting GSK-3β reduced TNF-α production as well as inducible NO synthase (iNOS)/NO biosynthesis. While activation of NF-κB was essential for heat-inactivatedS. aureus-induced TNF-α and NO, inhibiting GSK-3β blocked heat-inactivatedS. aureus-induced NF-κB p65 nuclear translocation. Additionally, inhibiting GSK-3β enhanced heat-inactivatedS. aureus-induced interleukin-10 (IL-10) production (IL-10 is an anti-inflammatory cytokine which inhibits TNF-α production). Neutralization of IL-10 reduced TNF-α downregulation caused by GSK-3β inhibition. These results suggest that GSK-3β regulates heat-inactivatedS. aureus-induced TNF-α and NO production in microglia mainly by activating NF-κB and probably by inhibiting IL-10.
Genomic Analysis of an AttenuatedChlamydia abortusLive Vaccine Strain Reveals Defects in Central Metabolism and Surface Proteins
Authors: Burall L. S. , Rodolakis A. , Rekiki A. , Myers G. S. A. , Bavoil P. M. 
Published: July 2009

ABSTRACTComparative genomic analysis of a wild-type strain of the ovine pathogenChlamydia abortusand its nitrosoguanidine-induced, temperature-sensitive, virulence-attenuated live vaccine derivative identified 22 single nucleotide polymorphisms unique to the mutant, including nine nonsynonymous mutations, one leading to a truncation ofpmpG, which encodes a polymorphic membrane protein, and two intergenic mutations potentially affecting promoter sequences. Other nonsynonymous mutations mapped to apmpGpseudogene and to predicted coding sequences encoding a putative lipoprotein, a sigma-54-dependent response regulator, a PhoH-like protein, a putative export protein, two tRNA synthetases, and a putative serine hydroxymethyltransferase. One of the intergenic mutations putatively affects transcription of two divergent genes encoding pyruvate kinase and a putative SOS response nuclease, respectively. These observations suggest that the temperature-sensitive phenotype and associated virulence attenuation of the vaccine strain result from disrupted metabolic activity due to altered pyruvate kinase expression and/or alteration in the function of one or more membrane proteins, most notably PmpG and a putative lipoprotein.
BAR Domain Proteins Rvs161 and Rvs167 Contribute to
Candida albicans
Endocytosis, Morphogenesis, and Virulence
Authors: Douglas Lois M. , Martin Stephen W. , Konopka James B. 
Published: July 2009

ABSTRACT

The
Candida albicans
plasma membrane plays critical roles in growth and virulence and as a target for antifungal drugs. Three
C. albicans
genes that encode Bin-Amphiphysin-Rvs homology domain proteins were mutated to define their roles in plasma membrane function. The deletion of
RVS161
and
RVS167
, but not
RVS162
, caused strong defects. The
rvs161
Δ mutant was more defective in endocytosis and morphogenesis than
rvs167
Δ, but both were strongly defective in polarizing actin patches. Other plasma membrane constituents were still properly localized, including a filipin-stained domain at the hyphal tips. An analysis of growth under different in vitro conditions showed that the
rvs161
Δ and
rvs167
Δ mutants grew less invasively in agar and also suggested that they have defects in cell wall synthesis and Rim101 pathway signaling. These mutants were also more resistant to the antimicrobial peptide histatin 5 but showed essentially normal responses to the drugs caspofungin and amphotericin. Surprisingly, the
rvs161
Δ mutant was more sensitive to fluconazole, whereas the
rvs167
Δ mutant was more resistant, indicating that these mutations cause overlapping but distinct effects on cells. The
rvs161
Δ and
rvs167
Δ mutants both showed greatly reduced virulence in mice. However, the mutants were capable of growing to high levels in kidneys. Histological analyses of infected kidneys revealed that these
rvs
Δ mutants grew in a large fungal mass that was walled off by leukocytes, rather than forming disseminated microabscesses as seen for the wild type. The diminished virulence is likely due to a combination of the morphogenesis defects that reduce invasive growth and altered cell wall construction that exposes proinflammatory components to the host immune system.
A Characteristic Estimation of Bio-Signals for Electro-Acupuncture Stimulations in Human Subjects
Authors: Kim Min Soo , Cho Young Chang , Moon Joo Hyun , Pak Sok Cheon 
Published: July 2009

This research evaluates the effect of physiological responses during electrical acupuncture (EA) stimulation on specific acupuncture points (APs: PC5 and PC6). A variety of special responses in the human body were determined by electroencephalogram (EEG), heart rate (HR) in an electrocardiogram (ECG), and skin impedance test for 2 groups, sham group as a control and a group under acupuncture stimulation. The total stimulation time in this study was set for 5 min since the effect of EA on all recorded parameters became stable within this period. According to the experiments, during EA stimulation of PC5 and PC6, the power spectrum of EEG showed that the number of low frequency waves was increased in all lobes. Heart rate variability measures of 10 subjects stimulation trials at PC6 and PC5 were compared to 10 subjects who received no stimulation treatment. In both the AP and the sham groups, the mean R-R interval increased significantly during EA stimulation. A comparison between the AP and non-AP group in terms of skin resistance measurement experiments revealed no difference in skin resistance. The results of this study verified that EA stimulation of APs (PC5, PC6) causes EEG changes, and ECG heart rate changes. However, from human skin impedance measurements, the beneficial effects were not sustained. These results may be helpful in the understanding of the mechanism underlying the effect of electrical acupuncture on PC6 and PC5.
Unanswered Questions in the Electroweak Theory
Authors: Quigg Chris 
Published: July 2009

This article is devoted to the status of the electroweak theory on the eve of experimentation at CERN's Large Hadron Collider (LHC). A compact summary of the logic and structure of the electroweak theory precedes an examination of what experimental tests have established so far. The outstanding unconfirmed prediction is the existence of the Higgs boson, a weakly interacting spin-zero agent of electroweak symmetry breaking and the giver of mass to the weak gauge bosons, the quarks, and the leptons. General arguments imply that the Higgs boson or other new physics is required on the 1-TeV energy scale.Even if a “standard” Higgs boson is found, new physics will be implicated by many questions about the physical world that the Standard Model cannot answer. Some puzzles and possible resolutions are recalled. The LHC moves experiments squarely into the 1-TeV scale, where answers to important outstanding questions will be found.
AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts
Authors: Byth Kate F. , Thomas Andrew , Hughes Gareth , Forder Cheryl , McGregor Alexandra , Geh Catherine , Oakes Sandra , Green Clive , Walker Mike , Newcombe Nicholas , Green Stephen , Growcott Jim , Barker Andy , Wilkinson Robert W. 
Published: July 2009

AbstractDeregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC50, 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2–1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38–153; P &lt; 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (&gt;40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer249/Thr252, for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise. [Mol Cancer Ther 2009;8(7):1856–66]
Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine
Authors: Jian Weiguo , Yamashita Hideyuki , Levitt Jonathan M. , Lerner Seth P. , Sonpavde Guru 
Published: July 2009

Abstract
Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathways. We preclinically evaluated enzastaurin alone and in combination with gemcitabine for transitional cell cancer (TCC). Immunohistochemistry (IHC) was done on 105 human samples from a microarray to show the expression of PKC-β. The preclinical antitumor activity of enzastaurin and gemcitabine as single agents and in combination against aggressive human -lines (-SUP and 5637) and murine subcutaneous xenografts bearing 5637 cells was determined. Western Blot was done on tumor cells in vitro to detect signaling through PKC-β, GSK-3β, and AKT. The effect on cell migration was determined in vitro. Modulation of proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (CD31) in vivo was determined by IHC. IHC done on human TCC samples from a microarray showed the expression of PKC-β in 33% of tumors. Enzastaurin induced significant apoptosis and inhibited proliferation in vitro at low micromolar concentrations. The in vitro inhibitory activity of combination enzastaurin and gemcitabine by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay seemed synergistic. Western Blotting revealed down-regulation of Akt, PKC-β, and GSK-3 β phosphorylation. Enzastaurin inhibited migration at an earlier time point independent of antiproliferative activity. Combination therapy had significantly superior antitumor activity in murine xenografts compared with untreated controls, whereas single agents did not. IHC showed reduced Ki-67 and CD31 and increased cleaved caspase-3 with combination therapy compared with controls. Enzastaurin showed preclinical antitumor activity against human TCC and enhanced the activity of gemcitabine. [Mol Cancer Ther 2009;8(7):1772–8]