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At least 1,711 records · Page 95Linked to original sources
PubMed1983

Characterization of Hantaan virions, the prototype virus of hemorrhagic fever with renal syndrome.

Hantaan virus, strain 76-118, was propagated to high titer in a clone of Vero cells, and infectious virions were successfully concentrated and purified. Infectivity and virus antigenic activity were closely associated with a virus particle that exhibited a sedimentation rate indistinguishable from a representative member of the Bunyaviridae. Purified virions sedimented to a density of 1.16-1.17 in sucrose and 1.20-1.21 in cesium chloride. Detergent disruption of virions resulted in a nucleocapsid structure (density, 1.18 in sucrose and 1.25 in cesium chloride) and soluble protein antigens. Three separate nucleocapsids were resolved by rate-zonal centrifugation and contained a single but common polypeptide of 50,000 daltons. Electrophoresis of radiolabeled RNA extracted from purified virions yielded a profile of three RNA species with apparent molecular weights of 2.7, 1.2, and 0.6 X 10(6). These data support earlier electron microscopy reports which suggested that Hantaan virus has characteristics similar to some members of the virus family Bunyaviridae.

Animals↗
PubMed1993

Endemic human T cell leukemia virus type II infection in southwestern US Indians involves two prototype variants of virus.

Human T cell leukemia virus (HTLV) type II is endemic in certain American Indians, and high rates of infection occur in intravenous drug users (IVDUs). North American IVDUs are infected with two distinct variants, HTLV-IIa and -IIb. If IVDUs became infected as a result of interaction with members of an American Indian population, both viral forms should be demonstrable in such populations. Nucleotide sequence analysis of 630 bases of the env gene encoding the gp21 protein was done on DNA from 12 New Mexico Indians (8 Pueblo, 4 Navajo). All samples were typical subtype a or b viruses. Seven of the 8 Pueblo and 2 of 4 Navajo had subtype b; the rest had subtype a. The results are compatible with an indigenous New World origin for both subtypes of HTLV-II.

Adult↗
PubMed1996

Silver iontophoretic catheter: a prototype of a long-term antiinfective vascular access device.

A silver iontophoretic catheter (SIC) was developed consisting of two electrically charged parallel silver wires helically wrapped around the proximal segment of a vascular catheter. In vitro and in vivo activities of this catheter were compared with those of an aseptic catheter coated with chlorhexidine and silver sulfadiazine (CH/SS). The SIC demonstrated broad-spectrum in vitro inhibitory activity against bacteria and Candida albicans comparable to that of the CH/SS-coated catheter. The durability of activity was determined by incubating catheters in serum at 37 degrees C for various time intervals. After 30 days, the antimicrobial activity of the SIC did not change significantly, while that of the CH/SS-coated catheter was reduced to a suboptimal level. In a rabbit model, the SIC was safe and significantly more efficacious than the CH/SS-coated catheter in preventing colonization with Staphylococcus aureus (P < .05). The SIC has broad-spectrum inhibitory activity of long durability and is highly efficacious in preventing colonization in vivo.

Animals↗
PubMed1996

Development of a purified, inactivated, dengue-2 virus vaccine prototype in Vero cells: immunogenicity and protection in mice and rhesus monkeys.

The feasibility of a purified, inactivated dengue (DEN) vaccine made in Vero cells was explored. A DEN-2 virus candidate was chosen for production of a monotypic, purified, inactivated vaccine (PIV). Virus was harvested from roller bottle culture supernatants, concentrated, and purified on sucrose gradients. The purified virus was inactivated with 0.05% formalin at 22 degrees C. After inactivation, the virus retained its antigenicity and was immunogenic in mice and rhesus monkeys, in which it elicited high titers of DEN-2 virus-neutralizing antibody. Mice were completely protected against challenge with live, virulent virus after receiving two 0.15-microg doses of PIV. Monkeys vaccinated with three doses ranging as low as 0.25 microg demonstrated complete absence or a significant reduction in the number of days of viremia after challenge with homologous virus. These results warrant further testing and development of PIVs for other DEN virus serotypes.

Animals↗
PubMed2001

Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil).

Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)--a nucleoside reverse transcriptase inhibitor--to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose-response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log10. Based on virological outcomes, dose-response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.

Adult↗
PubMedDate not supplied

Electronic clinical trial protocol distribution via the World-Wide Web: a prototype for reducing costs and errors, improving accrual, and saving trees.

Clinical trials today typically are inefficient, paper-based operations. Poor community physician awareness of available trials and difficult referral mechanisms also contribute to poor accrual. The Physicians Research Network (PRN) web was developed for more efficient trial protocol distribution and eligibility inquiries. The Medical University of South Carolina's Hollings Cancer Center trials program and two community oncology practices served as a testbed. In 581 man-hours over 18 months, 147 protocols were loaded into PRN. The trials program eliminated all protocol hardcopies except the masters, reduced photocopier use 59%, and saved 1.0 full-time equivalents (FTE), but 1.0 FTE was needed to manage PRN. There were no known security breaches, downtime, or content-related problems. Therefore, PRN is a paperless, user-preferred, reliable, secure method for distributing protocols and reducing distribution errors and delays because only a single copy of each protocol is maintained. Furthermore, PRN is being extended to serve other aspects of trial operations.

Clinical Trials as Topic↗
PubMed2004

Quantitative structure-activity relationship for the cleavage of C3/C4-substituted catechols by a prototypal extradiol catechol dioxygenase with broad substrate specificity.

Catechol 2,3-dioxygenase [EC 1.13.11.2] from Pseudomonas putida mt-2 (Mpc) catalyzes the extradiol cleavage of catechol to produce 2-hydroxymuconate semialdehyde. The K(m) values for the catecholic substrate (K(mA)) and O(2) (K(mO2)), and catalytic constants (k(cat)) were kinetically determined for eight C3/C4-substituted catechols at 25 degrees C and pH 6.5 or 7.5. The first pK(a) values (pK(1)) were determined for eleven catechols (pK(1) = 7.26-9.47), correlated with Hammett substituent constants, and electron-withdrawing substituents significantly stabilized the monoanionic species of free catechols. Mpc preferred catechols with non-ionic substituents at the C3 or C4 position. 3-Phenylcatechol, a biphenyl, was cleaved, while 4-tert-butylcatechol was not. The logarithm of k(cat)/K(mA) (substrate specificity constant) exhibited a good linear correlation with pK(1), with the exception of those for 4-halocatechols. The logarithm of k(cat)/K(mO2) showed a good linear correlation with pK(1), with the exception of that of 3-phenylcatechol. These results demonstrate that catechol binding to the Mpc active site, the following O(2) binding, and the activation of the bound O(2) are all sensitive to electronic effects of the substituents. However, k(cat) did not correlate significantly with pK(1). The present study distinguishes clearly between the electronic and the steric effects of catecholic substrates in the reactivity of Mpc, and provides important insight into the mechanistic basis for a vast range of substrate specificities of extradiol dioxygenases.

Binding Sites↗
PubMed1992

Purification and properties of the Eco57I restriction endonuclease and methylase--prototypes of a new class (type IV).

The Eco57I restriction endonuclease and methylase were purified to homogeneity from the E.coli RR1 strain carrying the eco57IRM genes on a recombinant plasmid. The molecular weight of the denaturated methylase is 63 kDa. The restriction endonuclease exists in a monomeric form with an apparent molecular weight of 104-108 kDa. R.Eco57I also possesses methylase activity. The methylation activities of both enzymes modify the outer A residue in the target sequence 5'CTGAAG yielding N6-methyladenine. M.Eco57I modifies both strands of the substrate while R.Eco57I modifies only one. Only the methylase enzyme is stimulated by Ca2+. The restriction endonuclease shows an absolute requirement for Mg2+ and is stimulated by AdoMet. ATP has no influence on either activity of the enzymes. The subunit structure and enzymatic properties of the Eco57I enzymes distinguish them from all other restriction-modification enzymes that have been described previously. Therefore, RM.Eco57I may be regarded as a representative of a novel class of restriction-modification systems, and we propose to classify it as type IV.

Base Sequence↗
PubMed1997

Mechanistic analyses of site-specific degradation in DNA-RNA hybrids by prototypic DNA cleavers.

Bleomycin (BLM) binding and chemistry are apparently sensitive to differences in nucleic acid conformation and could conceivably be developed as a probe for sequence-dependent elements of conformation. We report on the development of a new methodology to synthesize heterogeneous DNA-RNA hybrids of defined sequence and present the results of our comparative studies on the cleavage of DNA and DNA-RNA hybrids by four drugs: BLM, neocarzinostatin and esperamicins A1 and C. In the case of BLM with duplex DNA, purine-pyrimidine steps such as GT and GC, are consistently hit, as previously observed. However, in heterogeneous sequence hybrids, not all GC sites are recognized by the drug, although all GT sites are. Suppressed GC sites are consistently flanked by pyrimidines on both the 3' and 5' sides, suggesting that the BLM binding site in hybrids spans at least four bases. Kinetic isotope studies with specifically deuterated substrates (kH/kD = 1.2-4.0) and the effect of oxygen on the product profile are presented in support of a mechanism consistent with 4'-hydrogen abstraction in hybrids. The powerful double-labeled probe technique was extended to study the mechanism of action of other DNA degrading drugs on DNA-RNA hybrids. For neocarzinostatin, the sequence specificity lies in the AT-rich region for hybrids and is similar to that of DNA, however, the overall cleavage pattern for the hybrid is significantly different from that for the same sequence of DNA. In the hybrid, a stretch of AT residues is essential and the A sites are damaged to a greater extent than they are in DNA. However, no kinetic isotope effects are observed and, based on the product profile, the mechanism of degradation of the DNA strand of hybrids seems to be limited to abstraction of the 5'-hydrogen. For esperamicin A1, damage on the DNA strand of hybrids occurs exclusively via 5'-hydrogen abstraction in a non-rate determining step and primarily at A and T sites. Esperamicin C behaves similarly, exhibiting no isotope effects at 1', 4' and 5' positions. Overall, the differences observed in site-specific cleavage between the two substrates is proposed to be a result of conformational differences between the DNA strand of duplex DNA and DNA-RNA hybrids.

Aminoglycosides↗
PubMed1998

PAH Mutation Analysis Consortium Database: 1997. Prototype for relational locus-specific mutation databases.

PAHdb (http://www.mcgill.ca/pahdb ) is a curated relational database (Fig. 1) of nucleotide variation in the human PAH cDNA (GenBank U49897). Among 328 different mutations by state (Fig. 2) the majority are rare mutations causing hyperphenylalaninemia (HPA) (OMIM 261600), the remainder are polymorphic variants without apparent effect on phenotype. PAHdb modules contain mutations, polymorphic haplotypes, genotype-phenotype correlations, expression analysis, sources of information and the reference sequence; the database also contains pages of clinical information and data on three ENU mouse orthologues of human HPA. Only six different mutations account for 60% of human HPA chromosomes worldwide, mutations stratify by population and geographic region, and the Oriental and Caucasian mutation sets are different (Fig. 3). PAHdb provides curated electronic publication and one third of its incoming reports are direct submissions. Each different mutation receives a systematic (nucleotide) name and a unique identifier (UID). Data are accessed both by a Newsletter and a search engine on the website; integrity of the database is ensured by keeping the curated template offline. There have been >6500 online interrogations of the website.

Animals↗
PubMed2000

The homeodomain resource: a prototype database for a large protein family.

The Homeodomain Resource is an annotated collection of non-redundant protein sequences, three-dimensional structures and genomic information for the homeodomain protein family. Release 2.0 contains 765 full-length homeodomain-containing sequences, 29 experimentally derived structures and 116 homeobox loci implicated in human genetic disorders. Entries are fully hyperlinked to facilitate easy retrieval of the original records from source databases. A simple search engine with a graphical user interface is provided to query the component databases and assemble customized data sets. A new feature for this release is the addition of more automated methods for database searching, maintenance and implementation of efficient data management. The Homeodomain Resource is freely available through the WWW at http://genome.nhgri.nih.gov/homeodomain

Amino Acid Sequence↗