bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the Anti-Influenza Virus Activity of RWJ-270201 with Those of Oseltamivir and Zanamivir
Authors: Bantia S. , Parker C. D. , Ananth S. L. , Horn L. L. , Andries K. , Chand P. , Kotian P. L. , Dehghani A. , El-Kattan Y. , Lin T. , Hutchison T. L. , Montgomery J. A. , Kellog D. L. , Babu Y. S. 
Published: July 2002

ABSTRACT

We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (
P
< 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.
Antiviral Activity of Lovastatin against Respiratory Syncytial Virus In Vivo and In Vitro
Authors: Gower Tara L. , Graham Barney S. 
Published: July 2002

ABSTRACT
Respiratory syncytial virus (RSV) is an important human pathogen that can cause severe and life-threatening respiratory infections in infants and immunocompromised adults. We have recently shown that the RSV F glycoprotein, which mediates viral fusion, binds to RhoA. One of the steps in RhoA activation involves isoprenylation at the carboxy terminus of the protein by geranylgeranyltransferase. This modification allows RhoA to be attached to phosphatidyl serine on the inner leaflet of the plasma membrane. Treatment of mice with lovastatin, a drug that inhibits prenylation pathways in the cell by directly inhibiting hydroxymethylglutaryl coenzyme A reductase, diminishes RSV but not vaccinia virus replication when administered up to 24 h after RSV infection and decreases virus-induced weight loss and illness in mice. The inhibition of replication is not likely due to the inhibition of cholesterol biosynthesis, since gemfibrozil, another cholesterol-lowering agent, did not affect virus replication and serum cholesterol levels were not significantly lowered by lovastatin within the time frame of the experiment. Lovastatin also reduces cell-to-cell fusion in cell culture and eliminates RSV replication in HEp-2 cells. These data indicate that lovastatin, more specific isoprenylation inhibitors, or other pharmacological approaches for preventing RhoA membrane localization should be considered for evaluation as a preventive antiviral therapy for selected groups of patients at high risk for severe RSV disease, such as the institutionalized elderly and bone marrow or lung transplant recipients.
Short-Term Measures of Relative Efficacy Predict Longer-Term Reductions in Human Immunodeficiency Virus Type 1 RNA Levels following Nelfinavir Monotherapy
Authors: Mittler John , Essunger Paulina , Yuen Geoffrey J. , Clendeninn Neil , Markowitz Martin , Perelson Alan S. 
Published: July 2002

ABSTRACT
We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir. Relative efficacies based on the rate of decline of HIV-1 RNA levels in plasma over the first 14 to 21 days correlated with drug dose and viral load reduction by day 56. Calculation of relative treatment efficacies over the first 2 to 3 weeks of treatment can allow rapid assessment of new antiretroviral agents and dosing regimens, reducing the need to keep subjects in clinical trials on monotherapy for prolonged periods of time. Relative efficacy may also serve as a measure of treatment efficacy in patients in initiating established therapies.
In Vitro Antifungal Activity of KP-103, a Novel Triazole Derivative, and Its Therapeutic Efficacy against Experimental Plantar Tinea Pedis and Cutaneous Candidiasis in Guinea Pigs
Authors: Tatsumi Yoshiyuki , Yokoo Mamoru , Arika Tadashi , Yamaguchi Hideyo 
Published: July 2002

ABSTRACT

The in vitro activity of KP-103, a novel triazole derivative, against pathogenic fungi that cause dermatomycoses and its therapeutic efficacy against plantar tinea pedis and cutaneous candidiasis in guinea pigs were investigated. MICs were determined by a broth microdilution method with morpholinepropanesulfonic acid-buffered RPMI 1640 medium for
Candida
species and with Sabouraud dextrose broth for dermatophytes and by an agar dilution method with medium C for
Malassezia furfur
. KP-103 was the most active of all the drugs tested against
Candida albicans
(geometric mean [GM] MIC, 0.002 μg/ml), other
Candida
species including
Candida parapsilosis
and
Candida glabrata
(GM MICs, 0.0039 to 0.0442 μg/ml), and
M. furfur
(GM MIC, 0.025 μg/ml). KP-103 (1% solution) was highly effective as a treatment for guinea pigs with cutaneous candidiasis and achieved mycological eradication in 8 of the 10 infected animals, whereas none of the imidazoles tested (1% solutions) was effective in even reducing the levels of the infecting fungi. KP-103 was as active as clotrimazole and neticonazole but was less active than lanoconazole and butenafine against
Trichophyton rubrum
(MIC at which 80% of isolates are inhibited [MIC
80
], 0.125 μg/ml) and
Trichophyton mentagrophytes
(MIC
80
, 0.25 μg/ml). However, KP-103 (1% solution) exerted therapeutic efficacy superior to that of neticonazole and comparable to those of lanoconazole and butenafine, yielding negative cultures for all samples from guinea pigs with plantar tinea pedis tested. This suggests that KP-103 has better pharmacokinetic properties in skin tissue than the reference drugs. Because the in vitro activity of KP-103, unlike those of the reference drugs, against
T. mentagrophytes
was not affected by hair as a keratinic substance, its excellent therapeutic efficacy seems to be attributable to good retention of its antifungal activity in skin tissue, in addition to its potency.
All Detectable High-Molecular-Mass Penicillin-Binding Proteins Are Modified in a High-Level β-Lactam-Resistant Clinical Isolate of
Streptococcus mitis
Authors: Amoroso Ana , Demares Diego , Mollerach Marta , Gutkind Gabriel , Coyette Jacques 
Published: July 2002

ABSTRACT

All detectable high-molecular-mass penicillin-binding proteins (HMM PBPs) are altered in a clinical isolate of
Streptococcus mitis
for which the β-lactam MICs are increased from those previously reported in our region (cefotaxime MIC, 64 μg/ml). These proteins were hardly detected at concentrations that saturate all PBPs in clinical isolates and showed, after densitometric analysis, 50-fold-lower radiotracer binding. Resistance was related to mosaic structure in all HMM PBP-coding genes, where critical region replacement was complemented not only by substitutions already reported for the closely related
Streptococcus pneumoniae
but also by other specific replacements that are presumably close to the active-site serine. Mosaic structure was also presumed in a
pbp1a
-sensitive strain used for comparison, confirming that these structures do not unambiguously imply, by themselves, detectable critical changes in the kinetic properties of these proteins.
Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series
Authors: Kelly Jane Xu , Winter Rolf , Peyton David H. , Hinrichs David J. , Riscoe Michael 
Published: July 2002

ABSTRACT

Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-ω-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (
R
2
= 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC
50
) values against strains of chloroquine-susceptible and multidrug-resistant
Plasmodium falciparum
in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 × 10
5
and 9.02 × 10
5
M
−1
, respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.
Pharmacokinetics and Safety of an Antirhinoviral Agent, Ruprintrivir, in Healthy Volunteers
Authors: Hsyu Poe-Hirr , Pithavala Yazdi K. , Gersten Merril , Penning Carol A. , Kerr Bradley M. 
Published: July 2002

ABSTRACT
A single-dose study and a multiple-dose study of the safety and pharmacokinetics of ruprintrivir, a new selective irreversible inhibitor of human rhinovirus 3C protease, were conducted with healthy adult volunteers. Both studies were double-blind, randomized, placebo-controlled, parallel-group investigations of ruprintrivir administered intranasally at two dose levels. The parent drug and its acid metabolite, AG7185, were measured in plasma samples and nasal washings, and the safety of the treatments was monitored. Intranasal ruprintrivir, administered as single doses of 4 and 8 mg or every 3 h, six times per day, for 7 days was safe and well tolerated. Adverse events were mild, short-lived, and confined to the upper respiratory tract (i.e., nose and throat, taste and smell perceptions). Adverse events were similar after placebo and after single or multiple doses of active drug. Systemic exposure to ruprintrivir was rarely detectable with the highest measured concentration of ≤0.52 ng/ml; the assay had a lower limit of quantification of 0.2 ng/ml. Systemic exposure to the metabolite was also low, with a highest measured concentration of 3.25 ng/ml. Concentrations of AG7185 observed during multiple dosing were higher than those observed after the first dose but were no more than predicted from the single-dose study. Substantial amounts of ruprintrivir were observed intranasally for at least 9 h after multiple doses of ruprintrivir.
Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Authors: Meyer Peter R. , Matsuura Suzanne E. , Tolun Adviye A. , Pfeifer Ingrid , So Antero G. , Mellors John W. , Scott Walter A. 
Published: July 2002

ABSTRACT
Nucleotide-dependent unblocking of chain-terminated DNA by human immunodeficiency virus type 1 reverse transcriptase (RT) is enhanced by the presence of mutations associated with 3′-azido-3′-deoxythymidine (AZT) resistance. The increase in unblocking activity was greater for mutant combinations associated with higher levels of in vivo AZT resistance. The difference between mutant and wild-type activity was further enhanced by introduction of a methyl group into the nucleotide substrate and was decreased for a nonaromatic substrate, suggesting that π-π interactions between RT and an aromatic structure may be facilitated by these mutations.
Comparison of Methods for Quantification of Cytochrome
cd
1
-Denitrifying Bacteria in Environmental Marine Samples
Authors: Michotey Valérie , Méjean Vincent , Bonin Patricia 
Published: July 2002

ABSTRACT

Two PCR primer sets were developed for the detection and quantification of cytochrome
cd
1
-denitrifying bacteria in environmental marine samples. The specificity and sensitivity of these primers were tested. Both primer sets were suitable for detection, but only one set, cd3F–cd4R, was suitable for the quantification and enumeration of the functional community using most-probable-number PCR and competitive PCR techniques. Quantification of cytochrome
cd
1
denitrifiers taken from marine sediment and water samples was achieved using two different molecular techniques which target the
nirS
gene, and the results were compared to those obtained by using the classical cultivation method. Enumerations using both molecular techniques yielded similar results in seawater and sediment samples. However, both molecular techniques showed 1,000 or 10 times more cytochrome
cd
1
denitrifiers in the sediment or water samples, respectively, than were found by use of the conventional cultivation method for counting.
Gene Cloning, Sequencing, and Inactivation of the Branched-Chain Aminotransferase of
Lactococcus lactis
LM0230
Authors: Atiles Myrta W. , Dudley Edward G. , Steele James L. 
Published: July 2002

ABSTRACT

A branched-chain aminotransferase gene (
ilvE
) from
Lactococcus lactis
LM0230 was identified on a 9-kb chromosomal insert by complementation in
Escherichia coli
DL39. Sequencing of a 2.0-kbp fragment resulted in the identification of a 1,023-bp open reading frame that could encode a 340-amino-acid protein. Sequence analysis of the deduced amino acid sequence revealed 62% identity to IlvE of
Haemophilus influenzae
and high similarity to IlvEs from a variety of organisms found in GenBank classified as class IV aminotransferases. Under logarithmic growth in complex medium,
ilvE
is transcribed monocistronically as a 1.1-kb transcript. Hydrophobicity plot analysis of the deduced amino acid sequence and the lack of a signal peptide sequence suggest IlvE is a cytosolic protein. A derivative of LM0230 lacking IlvE activity was constructed by gene replacement. Comparison of the IlvE-deficient strain's ability to grow in defined media lacking an amino acid but containing its α-keto acid biosynthetic precursor to that of the wild-type strain indicated that IlvE is the only enzyme capable of synthesis of Ile and Val from their biosynthetic precursors. Comparison of the aminotransferase activity of the IlvE mutant to LM0230 revealed that the mutant retained <2, 4.5, 43, 40, and 76% of its aminotransferase activity with Ile, Val, Leu, Met, and Phe, respectively. No difference in growth or acidification rate between LM0230 and the IlvE-deficient strain was observed in milk.
Effect of Electron Donor and Solution Chemistry on Products of Dissimilatory Reduction of Technetium by
Shewanella putrefaciens
Authors: Wildung R. E. , Gorby Y. A. , Krupka K. M. , Hess N. J. , Li S. W. , Plymale A. E. , McKinley J. P. , Fredrickson J. K. 
Published: July 2002

ABSTRACT

To help provide a fundamental basis for use of microbial dissimilatory reduction processes in separating or immobilizing
99
Tc in waste or groundwaters, the effects of electron donor and the presence of the bicarbonate ion on the rate and extent of pertechnetate ion [Tc(VII)O
4
−
] enzymatic reduction by the subsurface metal-reducing bacterium
Shewanella putrefaciens
CN32 were determined, and the forms of aqueous and solid-phase reduction products were evaluated through a combination of high-resolution transmission electron microscopy, X-ray absorption spectroscopy, and thermodynamic calculations. When H
2
served as the electron donor, dissolved Tc(VII) was rapidly reduced to amorphous Tc(IV) hydrous oxide, which was largely associated with the cell in unbuffered 0.85% NaCl and with extracellular particulates (0.2 to 0.001 μm) in bicarbonate buffer. Cell-associated Tc was present principally in the periplasm and outside the outer membrane. The reduction rate was much lower when lactate was the electron donor, with extracellular Tc(IV) hydrous oxide the dominant solid-phase reduction product, but in bicarbonate systems much less Tc(IV) was associated directly with the cell and solid-phase Tc(IV) carbonate may have been present. In the presence of carbonate, soluble (<0.001 μm) electronegative, Tc(IV) carbonate complexes were also formed that exceeded Tc(VII)O
4
−
in electrophoretic mobility. Thermodynamic calculations indicate that the dominant reduced Tc species identified in the experiments would be stable over a range of E
h
and pH conditions typical of natural waters. Thus, carbonate complexes may represent an important pathway for Tc transport in anaerobic subsurface environments, where it has generally been assumed that Tc mobility is controlled by low-solubility Tc(IV) hydrous oxide and adsorptive, aqueous Tc(IV) hydrolysis products.
Rhamnolipid-Induced Removal of Lipopolysaccharide from
Pseudomonas aeruginosa
: Effect on Cell Surface Properties and Interaction with Hydrophobic Substrates
Authors: Al-Tahhan Ragheb A. , Sandrin Todd R. , Bodour Adria A. , Maier Raina M. 
Published: July 2002

ABSTRACT

Little is known about the interaction of biosurfactants with bacterial cells. Recent work in the area of biodegradation suggests that there are two mechanisms by which biosurfactants enhance the biodegradation of slightly soluble organic compounds. First, biosurfactants can solubilize hydrophobic compounds within micelle structures, effectively increasing the apparent aqueous solubility of the organic compound and its availability for uptake by a cell. Second, biosurfactants can cause the cell surface to become more hydrophobic, thereby increasing the association of the cell with the slightly soluble substrate. Since the second mechanism requires very low levels of added biosurfactant, it is the more intriguing of the two mechanisms from the perspective of enhancing the biodegradation process. This is because, in practical terms, addition of low levels of biosurfactants will be more cost-effective for bioremediation. To successfully optimize the use of biosurfactants in the bioremediation process, their effect on cell surfaces must be understood. We report here that rhamnolipid biosurfactant causes the cell surface of
Pseudomonas
spp. to become hydrophobic through release of lipopolysaccharide (LPS). In this study, two
Pseudomonas aeruginosa
strains were grown on glucose and hexadecane to investigate the chemical and structural changes that occur in the presence of a rhamnolipid biosurfactant. Results showed that rhamnolipids caused an overall loss in cellular fatty acid content. Loss of fatty acids was due to release of LPS from the outer membrane, as demonstrated by 2-keto-3-deoxyoctonic acid and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and further confirmed by scanning electron microscopy. The amount of LPS loss was found to be dependent on rhamnolipid concentration, but significant loss occurred even at concentrations less than the critical micelle concentration. We conclude that rhamnolipid-induced LPS release is the probable mechanism of enhanced cell surface hydrophobicity.
An Antifungal Exo-α-1,3-Glucanase (AGN13.1) from the Biocontrol FungusTrichoderma harzianum
Authors: Ait-Lahsen Hassane , Soler Andrés , Rey Manuel , de la Cruz Jesús , Monte Enrique , Llobell Antonio 
Published: July 2002

ABSTRACTTrichoderma harzianumsecretes α-1,3-glucanases when it is grown on polysaccharides, fungal cell walls, or autoclaved mycelium as a carbon source (simulated antagonistic conditions). We have purified and characterized one of these enzymes, named AGN13.1. The enzyme was monomeric and slightly basic. AGN13.1 was an exo-type α-1,3-glucanase and showed lytic and antifungal activity against fungal plant pathogens. Northern and Western analyses indicated that AGN13.1 is induced by conditions that simulated antagonism. We propose that AGN13.1 contributes to the antagonistic response ofT. harzianum.
Evidence for Extensive Resistance Gene Transfer among
Bacteroides
spp. and among
Bacteroides
and Other Genera in the Human Colon
Authors: Shoemaker N. B. , Vlamakis H. , Hayes K. , Salyers A. A. 
Published: July 2002

ABSTRACT

Transfer of antibiotic resistance genes by conjugation is thought to play an important role in the spread of resistance. Yet virtually no information is available about the extent to which such horizontal transfers occur in natural settings. In this paper, we show that conjugal gene transfer has made a major contribution to increased antibiotic resistance in
Bacteroides
species, a numerically predominant group of human colonic bacteria. Over the past 3 decades, carriage of the tetracycline resistance gene,
tetQ
, has increased from about 30% to more than 80% of strains. Alleles of
tetQ
in different
Bacteroides
species, with one exception, were 96 to 100% identical at the DNA sequence level, as expected if horizontal gene transfer was responsible for their spread. Southern blot analyses showed further that transfer of
tetQ
was mediated by a conjugative transposon (CTn) of the CTnDOT type. Carriage of two erythromycin resistance genes,
ermF
and
ermG
, rose from <2 to 23% and accounted for about 70% of the total erythromycin resistances observed. Carriage of
tetQ
and the
erm
genes was the same in isolates taken from healthy people with no recent history of antibiotic use as in isolates obtained from patients with
Bacteroides
infections. This finding indicates that resistance transfer is occurring in the community and not just in clinical environments. The high percentage of strains that are carrying these resistance genes in people who are not taking antibiotics is consistent with the hypothesis that once acquired, these resistance genes are stably maintained in the absence of antibiotic selection. Six recently isolated strains carried
ermB
genes. Two were identical to
erm
(B)-P from
Clostridium perfringens
, and the other four had only one to three mismatches. The nine strains with
ermG
genes had DNA sequences that were more than 99% identical to the
ermG
of
Bacillus sphaericus
. Evidently, there is a genetic conduit open between gram-positive bacteria, including bacteria that only pass through the human colon, and the gram-negative
Bacteroides
species. Our results support the hypothesis that extensive gene transfer occurs among bacteria in the human colon, both within the genus
Bacteroides
and among
Bacteroides
species and gram-positive bacteria.
Twelve-Hour PCR-Based Method for Detection of
Salmonella
spp. in Food
Authors: Ferretti R. , Mannazzu I. , Cocolin L. , Comi G. , Clementi F. 
Published: July 2002

ABSTRACT

A PCR-based method for the detection of
Salmonella
spp. in food was developed. The method, set up on typical salami from the Italian region of Marche, is sensitive and specific and shows excellent correlation with the conventional method of reference when naturally contaminated foods are analyzed. Moreover, it can be easily performed within a maximum of 12 h from food sampling, thus allowing prompt detection of
Salmonella
spp. in the food stocks analyzed.