bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytotoxicological Analysis of a gp120 Binding Aptamer with Cross-Clade Human Immunodeficiency Virus Type 1 Entry Inhibition Properties: Comparison to Conventional Antiretrovirals
Authors: de Campos Walter Rangel Lopes , Coopusamy Dayaneethie , Morris Lynn , Mayosi Bongani M. , Khati Makobetsa 
Published: April 2009

ABSTRACT

The long-term cumulative cytotoxicity of antiretrovirals (ARVs) is among the major causes of treatment failure in patients infected with human immunodeficiency virus (HIV) and patients with AIDS. This calls for the development of novel ARVs with less or no cytotoxicity. In the present study, we compared the cytotoxic effects of a cross-clade HIV type 1-neutralizing aptamer called B40 with those of a panel of nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and the entry inhibitor (EI) T20 in human cardiomyocytes and peripheral blood mononuclear cells. An initial screen in which cell death was used as the end-point measurement revealed that the B40 aptamer and T20 were the only test molecules that had insignificant (0.61 <
P
< 0.92) effects on the viability of both cell types at the maximum concentration used. PIs were the most toxic class (0.001 <
P
< 0.00001), followed by NNRTIs and NRTIs (0.1 <
P
< 0.00001). Further studies revealed that B40 and T20 did not interfere with the cellular activity of the cytochrome P450 3A4 enzyme (0.78 <
P
< 0.24) or monoamine oxidases A and B (0.83 <
P
< 0.56) when the activities of the enzymes were compared to those in untreated controls of both cell types. Mitochondrion-initiated cellular toxicity is closely associated with the use of ARVs. Therefore, we used real-time PCR to quantify the relative ratio of mitochondrial DNA to nuclear DNA as a marker of toxicity. The levels of mitochondrial DNA remained unchanged in cells exposed to the B40 aptamer compared to the levels in untreated control cells (0.5 >
P
> 0.06). These data support the development of B40 and related EI aptamers as new ARVs with no cytotoxicity at the estimated potential therapeutic dose.
Gene Context and DNA Rearrangements in the Carbapenemase Locus of Division II Strains of
Bacteroides fragilis
Authors: García Nuria , Gutiérrez Gloria , Lorenzo María , Vadillo Santiago , Píriz Segundo , Quesada Alberto 
Published: April 2009

ABSTRACT

The
cfiA
gene is clustered in a bicistronic operon encoding an
N
-acetyltransferase and an
O
-acetyltransferase related to resistance markers. This genetic context, exclusively found in strains of
Bacteroides fragilis
division II, has been highly rearranged by the successive integration of two new mobile sequences, a miniature element and IS
Bf9
. Besides that, among the DNA polymorphisms detected in the
cfiA
locus, only the integration of IS
942
at its promoter was a determinant for expression of carbapenemase activity.
Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity
Authors: Holloway Georgina A. , Charman William N. , Fairlamb Alan H. , Brun Reto , Kaiser Marcel , Kostewicz Edmund , Novello Patrizia M. , Parisot John P. , Richardson John , Street Ian P. , Watson Keith G. , Baell Jonathan B. 
Published: April 2009

ABSTRACT
High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.
Comparison of Tigecycline and Vancomycin for Treatment of Experimental Foreign-Body Infection Due to Methicillin-Resistant
Staphylococcus aureus
Authors: Vaudaux Pierre , Fleury Bénédicte , Gjinovci Asllan , Huggler Elzbieta , Tangomo-Bento Manuela , Lew Daniel P. 
Published: April 2009

ABSTRACT

Twice-daily 7-day regimens of tigecycline (7 mg/kg) and vancomycin (50 mg/kg) were compared in a rat tissue cage model of chronic foreign-body infection due to methicillin (meticillin)-resistant
Staphylococcus aureus
strain MRGR3. Subcutaneously administered tigecycline reached levels in tissue cage fluid that were nearly equivalent or slightly superior to the antibiotic MIC (0.5 μg/ml) for strain MRGR3. After 7 days, equivalent, significant reductions in bacterial counts were recorded for tigecycline-treated and vancomycin-treated rats, compared with those for untreated animals.
R964C Mutation of DNA Polymerase γ Imparts Increased Stavudine Toxicity by Decreasing Nucleoside Analog Discrimination and Impairing Polymerase Activity
Authors: Bailey Christopher M. , Kasiviswanathan Rajesh , Copeland William C. , Anderson Karen S. 
Published: April 2009

ABSTRACT
The R964C mutation of human DNA polymerase γ was recently linked to stavudine (d4T)-mediated mitochondrial toxicity. We utilized pre-steady-state kinetics to determine the effect of this mutation on incorporation of natural substrate dTTP and the active metabolite of d4T (d4TTP). The R964C polymerase γ holoenzyme demonstrated a 33% decrease in dTTP incorporation efficiency and a threefold-lower d4TTP discrimination relative to that of the wild-type polymerase γ, providing a mechanistic basis for genetic predisposition to nucleoside reverse transcriptase inhibitor toxicity.
Crystal Structure of
Bacillus anthracis
Dihydrofolate Reductase with the Dihydrophthalazine-Based Trimethoprim Derivative RAB1 Provides a Structural Explanation of Potency and Selectivity
Authors: Bourne Christina R. , Bunce Richard A. , Bourne Philip C. , Berlin K. Darrell , Barrow Esther W. , Barrow William W. 
Published: April 2009

ABSTRACT

Bacillus anthracis
possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in
B. anthracis
. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (≤12.8 μg/ml) values. RAB1 was cocrystallized with the
B. anthracis
DHFR in the space group P2
1
2
1
2
1
, and X-ray diffraction data were collected to a 2.3-Å resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against
B. anthracis
.
HLA and Infectious Diseases
Authors: Blackwell Jenefer M. , Jamieson Sarra E. , Burgner David 
Published: April 2009

SUMMARYFollowing their discovery in the early 1970s, classical human leukocyte antigen (HLA) loci have been the prototypical candidates for genetic susceptibility to infectious disease. Indeed, the original hypothesis for the extreme variability observed at HLA loci (H-2 in mice) was the major selective pressure from infectious diseases. Now that both the human genome and the molecular basis of innate and acquired immunity are understood in greater detail, do the classical HLA loci still stand out as major genes that determine susceptibility to infectious disease? This review looks afresh at the evidence supporting a role for classical HLA loci in susceptibility to infectious disease, examines the limitations of data reported to date, and discusses current advances in methodology and technology that will potentially lead to greater understanding of their role in infectious diseases in the future.
Endothelial Nitric Oxide Synthase Gene Polymorphisms and
Plasmodium falciparum
Infection in Indian Adults
Authors: Dhangadamajhi Gunanidhi , Mohapatra Biranchi N. , Kar Shantanu K. , Ranjit Manoranjan 
Published: April 2009

ABSTRACT

To explore the hypothesis that susceptibility to cerebral malaria is influenced by genetic variation in endothelial nitric oxide synthase (eNOS), we genotyped three commonly defined polymorphic loci of eNOS, Glu
298
→Asp, intron 4 variable number of tandem repeat region, and T-786→C, in 244 patients (mean age, 36.2 years) with mild malaria and 194 patients (mean age, 35.6 years) with severe malaria belonging to same ethnic group in Orissa, an eastern Indian state. We found that there was an association of the Glu
298
→Asp substitution (
P
= 0.0037; odds ratio, 1.95; 95% confidence interval, 1.2 to 3.0) and a single unique haplotype defined by “C-b-Asp” (
P
corrected
= 0.0024) for protection against cerebral malaria. Further, the median plasma level of nitrite-nitrate was found to be increased in individuals with the Glu
298
→Asp substitution and was significantly higher in the mild malaria group (
P
≤ 0.0001), but the increase was not significant in the severe malaria group (
P
= 0.0528). These findings suggest that the Glu
298
→Asp substitution and the “C-b-Asp” haplotype may enhance eNOS expression and NO production, which leads to protection against cerebral malaria. These findings may increase our understanding of the pathogenesis of malaria.
Expression of B-Cell Activating Factor Enhances Protective Immunity of a Vaccine againstPseudomonas aeruginosa
Authors: Tertilt Christine , Joh Ju , Krause Anja , Chou Paigee , Schneeweiss Kristin , Crystal Ronald G. , Worgall Stefan 
Published: April 2009

ABSTRACTB-cell activating factor (BAFF), a member of the TNF family, is a potent cytokine with stimulatory effects on B and T cells. To evaluate the potential of transient overexpression of BAFF to enhance vaccine immunogenicity, a replication-deficient adenovirus expressing full-length murine BAFF (AdBAFF) was tested in a mouse vaccine model againstPseudomonas aeruginosa. When coadministered with heat-killedP. aeruginosa, AdBAFF mediated a significant increase in anti-P. aeruginosa-specific serum and lung mucosal antibodies and resulted in improved protection against a lethal respiratory challenge withP. aeruginosa. This effect was independent of the site of administration of AdBAFF and was observed both when AdBAFF was given simultaneously with heat-killedP. aeruginosaas well as when AdBAFF was administered 4 weeks after immunization with heat-killedP. aeruginosa. These data demonstrate that a temporal increase in systemic BAFF levels is able to augment aP. aeruginosa-specific immune response upon immunization with heat-killedP. aeruginosa, suggesting that the immune-stimulatory effects of BAFF may be exploited as a molecular adjuvant for genetic vaccines.
O-Antigen-NegativeSalmonella entericaSerovar Typhimurium Is Attenuated in Intestinal Colonization but Elicits Colitis in Streptomycin-Treated Mice
Authors: Ilg Karin , Endt Kathrin , Misselwitz Benjamin , Stecher Bärbel , Aebi Markus , Hardt Wolf-Dietrich 
Published: April 2009

ABSTRACTLipopolysaccharide (LPS) is a major constituent of the outer membrane and an important virulence factor ofSalmonella entericasubspecies 1 serovar Typhimurium (serovar Typhimurium). To evaluate the role of LPS in eliciting intestinal inflammation in streptomycin-treated mice, we constructed an O-antigen-deficient serovar Typhimurium strain through deletion of thewbaPgene. The resulting strain was highly susceptible to human complement activity and the antimicrobial peptide mimic polymyxin B. Furthermore, it showed a severe defect in motility and an attenuated phenotype in a competitive mouse infection experiment, where the ΔwbaPstrain (SKI12) was directly compared to wild-typeSalmonella. Nevertheless, the ΔwbaPstrain (SKI12) efficiently invaded HeLa cells in vitro and elicited acute intestinal inflammation in streptomycin-pretreated mice. Our experiments prove that the presence of complete LPS is not essential for in vitro invasion or for triggering acute colitis.
Presence of the neuropeptide Y1 receptor in tenocytes and blood vessel walls in the human Achilles tendon
Authors: Bjur D , Alfredson H , Forsgren S 
Published: April 2009

Background:Questions remain concerning the mechanisms of the development of chronic pain and impaired function of tendons (tendinosis). Aspects known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide Y (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.Objective:To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of humans.Methods:Immunohistochemical methods were used. Examination on NPY was carried out in parallel.Results:The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of tendinosis tendons than in non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in perivascular innervation.Conclusions:This study shows that there is a morphological correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, especially for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel-regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be evaluated further.
Effect of an intervention aimed at reducing the risk of allergic respiratory disease in bakers: change in flour dust and fungal alpha-amylase levels
Authors: Meijster T , Tielemans E , Heederik D 
Published: April 2009

Introduction:We evaluated the effect on exposure of an intervention programme, which focused on risk education and providing information on good work practices. This intervention programme was enrolled as part of a Dutch covenant in the flour processing industry (industrial bakeries, flour mills, ingredient producers).Methods:Data from several measurement surveys collected pre- and post-intervention were used to evaluate changes in exposure over time. All datasets contained personal measurements analysed for flour dust and fungal α-amylase contents, and contextual information was available on process characteristics, work practice, and use of control measures.Results:Changes in exposure over time varied substantially between sectors and jobs. For bakeries a modest downward annual trend of −2% was found for flour dust and −8% for amylase. For flour mills the annual trend for flour dust was −12%; no significant trend was observed for amylase. For ingredient producers results were generally non-significant but indicated a reduction in flour dust exposure and increase in fungal α-amylase exposure. Modest increase in use of control measures and proper work practices were reported in most sectors, especially the use of local exhaust ventilation and decreased use of compressed air.Conclusions:The magnitude of the observed reductions in exposure levels indicates that the sector-wide intervention strategy implemented during the covenant period had a limited overall effect. This indicates that a more rigorous approach is needed to substantially decrease the exposure levels to flour dust and related allergens and, respectively, the prevalence of associated occupational diseases.
Prunus avium: nuclear DNA study in wild populations and sweet cherry cultivars
Authors: Guarino Carmine , Santoro Simona , De Simone Luciana , Cipriani Guido 
Published: April 2009

The PCR–SSR technique was used to detect nuclear DNA diversity in five wild populations of Prunus avium from deciduous forests in Italy, Slovenia, and Croatia and 87 sweet cherry accessions from different geographical areas that have been maintained in the sweet cherry collection in Italy. This sweet cherry collection includes local accessions from the Campania Region as well as accessions from different countries. Twenty-eight microsatellites, previously developed in this species, generated polymorphic amplification products. Between 2 and 14 alleles were revealed for the polymorphic loci studied, with the expected heterozygosity ranging from 0.045 to 0.831. The total probability of identity was 56.94 × 10−18. A model-based Bayesian clustering analysis identified nine distinct gene pools in cultivated P. avium. The probability that wild populations were assigned to cultivated gene pools indicated that three gene pools accounted for the genomic origin of 53% of P. avium sampled. A dendrogram was generated using UPGMA (unweighted pair group method with arithmetic averages) based on Nei genetic distance analysis. This dendrogram classified most of the genotypes into one major group with an additional group of five accessions. The results indicate that this set of SSRs is highly informative, and they are discussed in terms of the implications for sweet cherry characterization.
Predictors of cardiovascular fitness in sedentary men
Authors: Riou Marie-Ève , Pigeon Étienne , St-Onge Josée , Tremblay Angelo , Marette André , Weisnagel S. John , Joanisse Denis R. 
Published: April 2009

The relative contribution of anthropometric and skeletal muscle characteristics to cardiorespiratory fitness was studied in sedentary men. Cardiorespiratory fitness (maximal oxygen consumption) was assessed using an incremental bicycle ergometer protocol in 37 men aged 34–53 years. Vastus lateralis muscle biopsy samples were used to assess fiber type composition (I, IIA, IIX) and areas, capillary density, and activities of glycolytic and oxidative energy metabolic pathway enzymes. Correlations (all p < 0.05) were observed between maximal oxygen consumption (L·min–1) and body mass (r = 0.53), body mass index (r = 0.39), waist circumference (r = 0.34), fat free mass (FFM; r = 0.68), fat mass (r = 0.33), the enzyme activity of cytochrome c oxidase (COX; r = 0.39), muscle type IIA (r = 0.40) and IIX (r = 0.50) fiber area, and the number of capillaries per type IIA (r = 0.39) and IIX (r = 0.37) fiber. When adjusted for FFM in partial correlations, all correlations were lost, with the exception of COX (r = 0.48). Stepwise multiple regression revealed that maximal oxygen consumption was independently predicted by FFM, COX activity, mean capillary number per fiber, waist circumference, and, to a lesser extent, muscle capillary supply. In the absence of regular physical activity, cardiorespiratory fitness is strongly predicted by the potential for aerobic metabolism of skeletal muscle and negatively correlated with abdominal fat deposition.
Impact of wall filter selection on the detection of vasomotor changes in the brachial artery: a pilot study
Authors: Johnson Michel J. , Shoemaker J. Kevin 
Published: April 2009

During Doppler ultrasound assessment of blood flow, a wall filter is used to reduce or eliminate high-amplitude, low-velocity signals from the vessel wall and the surrounding tissue. This study investigated the impact of a range of wall filters (22 Hz, 75 Hz, 128 Hz, and 252 Hz) on the accuracy of forearm blood flow monitoring during the sympathoexcitatory application of lower body negative pressure, when peripheral blood flow may decrease substantially. The 252 Hz filter eliminated diastolic flow in 4 of 10 participants. In the remaining participants, the 252 Hz filter minimized the sensitivity of the pulsatility index. The interpretation of physiological responses could ultimately be compromised by using filters beyond 128 Hz.
Effect of the transition from high school to university on anthropometric and lifestyle variables in malesPresented in part at the Canadian Society for Nutritional Sciences, Canadian Nutrition Congress, held in Winnipeg, Manitoba, from 18–21 June 2007.
Authors: Pullman Allison W. , Masters Rachel C. , Zalot Lindsay C. , Carde Lauren E. , Saraiva Michelle M. , Dam Yian Yian , Randall Simpson Janis A. , Duncan Alison M. 
Published: April 2009

The obesity epidemic in North America has focused attention on the health risks of excess weight gain. The transition from high school to university is a critical period for weight gain, commonly referred to as the Freshman 15. The purpose of this study was to investigate the effect of the transition from high school to university on anthropometrics and physical and sedentary activities in males. A total of 108 males completed 3 study visits: the summer prior to first year university, and the ends of the first and second semesters. Outcome measures were body mass, height, body mass index (BMI), body fat, waist circumference, hip circumference, waist:hip ratio, dietary intake, and participation in physical and sedentary activities. Between the summer prior to and the end of first year university, male students experienced a significant weight gain, of 3.0 kg, with significant increases in BMI, body fat, waist circumference, hip circumference, and waist:hip ratio. Energy and nutrient intake did not change. Final body mass was significantly predicted by intention for body mass to stay the same, relative to weight loss intention. Fast aerobic physical activity significantly decreased between the summer prior to and the end of first year university, while slow aerobic physical activity, strength training, and flexibility training did not change. Computer and studying time significantly increased, while television time and hours of nightly sleep significantly decreased between the summer prior to and the end of first year university. Weekly alcoholic drinks and binge drinking frequency significantly increased over this time period. In conclusion, between the summer prior to and the end of first year university, male students gained an average of 3.0 kg, with increases in related anthropometrics. These changes may be due to body mass change intention and (or) the observed decreased physical and increased sedentary activities, but appear to be unrelated to dietary intake.