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PubMed1996

Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice.

In this study, we investigated the carcinogenic response of transgenic mice carrying the human prototype c-Ha-ras gene, namely Tg rasH2/CB6F1 mice, to various genotoxic carcinogens and compared it with that of control non-transgenic CB6F1 mice (non-Tg mice). The present studies were conducted as the first step in the evaluation of the Tg rasH2/CB6F1 mouse as a model for the rapid carcinogenicity testing system. Short-term (< or = 6 months) rapid carcinogenicity tests of various genotoxic carcinogens, 4-nitroquinoline-1-oxide, cyclophosphamide, N,N-diethylnitrosamine, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine and methylazoxymethanol, revealed that Tg rasH2/CB6F1 mice are more susceptible to these genotoxic carcinogens than control non-Tg mice. Tg rasH2/CB6F1 mice developed tumors more rapidly compared with non-Tg mice. Malignant tumors were observed only in the carcinogen-treated Tg rasH2/CB6F1 mice, but not in non-Tg mice treated with the same carcinogens. Each carcinogen induced tumors in corresponding target tissues of the Tg rasH2/CB6F1 mice. Only a very few lung adenomas but no other tumors were seen as spontaneous tumors during the 6 months of carcinogenicity tests. These results demonstrate that more rapid onset and higher incidence of more malignant tumors can be expected with high probability after treatment with various genotoxic carcinogens in the Tg rasH2/CB6F1 mice than in control non-Tg mice. The Tg rasH2/CB6F1 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

4-Nitroquinoline-1-oxide↗
PubMed2005

PLCbeta2-independent behavioral avoidance of prototypical bitter-tasting ligands.

Using a brief-access taste assay, we show in the present report that although phospholipase C beta2 knockout (PLCbeta2 KO) mice are unresponsive to low- and midrange concentrations of quinine and denatonium, they do significantly avoid licking higher concentrations of these aversive compounds. PLCbeta2 KO mice displayed no concentration-dependent licking of the prototypical sweetener sucrose but were similar to wild-type mice in their responses to citric acid and NaCl, notwithstanding some interesting exceptions. Although these findings confirm an essential role for PLCbeta2 in taste responsiveness to sucrose and to low- to midrange concentrations of quinine and denatonium in mice as previously reported, they importantly suggest that higher concentrations of the latter two compounds, which are bitter to humans, can engage a PLCbeta2-independent taste transduction pathway.

Animals↗
PubMed1993

Acadesine: the prototype adenosine regulating agent for reducing myocardial ischaemic injury.

Acadesine is the prototype of a new class of therapeutic compounds termed adenosine regulating agents. Acadesine is pharmacologically silent in normal circumstances, but its activity becomes operative during situations of net ATP catabolism, when it increases local adenosine levels. Thus acadesine is able to harness the beneficial effects of this protective autacoid without the limiting side effects associated with using adenosine itself or an adenosine mimetic or transport inhibitor. The demonstrated efficacy of acadesine in various models of myocardial ischaemia and the preliminary clinical results 48 indicate that acadesine and other ARAs could represent important new additions to the cardiologist's armamentarium to combat myocardial ischaemia and its sequelae.

Adenosine↗
PubMed1999

Crystal structure of avian carboxypeptidase D domain II: a prototype for the regulatory metallocarboxypeptidase subfamily.

The crystal structure of domain II of duck carboxypeptidase D, a prohormone/propeptide processing enzyme integrated in a three repeat tandem in the natural system, has been solved, constituting a prototype for members of the regulatory metallocarboxypeptidase subfamily. It displays a 300 residue N-terminal alpha/beta-hydrolase subdomain with overall topological similarity to and general coincidence of the key catalytic residues with the archetypal pancreatic carboxypeptidase A. However, numerous significant insertions/deletions in segments forming the funnel-like access to the active site explain differences in specificity towards larger protein substrates or inhibitors. This alpha/beta-hydrolase subdomain is followed by a C-terminal 80 residue beta-sandwich subdomain, unique for these regulatory metalloenzymes and topologically related to transthyretin and sugar-binding proteins. The structure described here establishes the fundamentals for a better understanding of the mechanism ruling events such as prohormone processing and will enable modelling of regulatory carboxypeptidases as well as a more rational design of inhibitors of carboxypeptidase D.

Amino Acid Sequence↗
PubMed2000

Description of a monomeric prototype galectin from the lizard Podarcis hispanica.

Galectins are a continuously expanding family of beta-galactoside-binding lectins present in a variety of evolutionarily divergent animal species. Here we report, for the first time, that expression of galectins extends to the reptilia lineage of lizards. Up to five lactose-binding proteins were isolated from the lizard Podarcis hispanica by affinity chromatography on asialofetuin-Sepharose. The main component, which is most abundantly expressed in skin, was purified from this tissue and further characterized. Under native conditions the protein behaved as a monomer with a molecular mass of 14,500 Da and an isoelectric point of 6.3. Based on sequence homology of the 58 N-terminal amino acid residues with galectins, and on its demonstrated galactoside-binding activity, this lectin we named LG-14 (from Lizard Galectin and 14 kDa) is classified as a new member of the galectin family. LG-14 falls into and strengthen the still thinly populated category of monomeric prototype galectins.

Amino Acid Sequence↗
PubMed2003

Biochemical and molecular characterization of galectins from zebrafish (Danio rerio): notochord-specific expression of a prototype galectin during early embryogenesis.

Galectins are a family of beta-galactoside-binding lectins that on synthesis are either translocated into the nucleus or released to the extracellular space. Their developmentally regulated expression, extracellular location, and affinity for extracellular components (such as laminin and fibronectin) suggest a role in embryonic development, but so far this has not been unequivocally established. Zebrafish constitute an ideal model for developmental studies because of their external fertilization, transparent embryos, rapid growth, and availability of a large collection of mutants. As a first step in addressing the biological roles in zebrafish embryogenesis, we identified and characterized members of the three galectin types: three protogalectins (Drgal1-L1, Drgal1-L2, Drgal1-L3), one chimera galectin (Drgal3), and one tandem-repeat galectin (Drgal9-L1). Like mammalian prototype galectin-1, Drgal1-L2 preferentially binds to N-acetyllactosamine. Genomic structure of Drgal1-L2 revealed four exons, with the exon-intron boundaries conserved with the mammalian galectin-1. Interestingly, this gene also encodes an alternatively spliced form of Drgal1-L2 that lacks eight amino acids near the carbohydrate-binding domain. Zebrafish galectins exhibited distinct patterns of temporal expression during embryo development. Drgal1-L2 is expressed postbud stage, and its expression is strikingly specific to the notochord. In contrast, Drgal1-L1 is expressed maternally in the oocytes. Drgal1-L3, Drgal3, and Drgal9-L1 are expressed both maternally and zygotically, ubiquitously in the adult tissues. The distinct temporal and spatial patterns of expression of members of the zebrafish galectin repertoire suggest that each may play distinct biological roles during early embryogenesis.

Amino Acid Sequence↗
PubMed2006

The Geodia cydonium galectin exhibits prototype and chimera-type characteristics and a unique sequence polymorphism within its carbohydrate recognition domain.

The ancestral galectin from the sponge Geodia cydonium (GCG) is classified on a structural basis to the prototype subfamily, whereas its carbohydrate-binding specificity is related to that of the mammalian chimera-type galectin-3. This dual coordination reveals GCG as a potential precursor of the later evolved galectin subfamilies, which is reflected in the primary structure of the protein. This study provides evidence that GCG is the LECT1 gene product, while neither a previously described LECT2 gene nor a functional LECT2 gene product was found in the specimen under investigation. The electrophoretically separated protein isomers with apparent molecular masses of 13, 15, and 16 kDa correspond to variants of the LECT1 protein-exhibiting peptide sequence polymorphisms that concern critical positions of the carbohydrate recognition domain (13 kDa: Leu51, Asn55, His130, Gly137; 15 kDa: Ser51, Asn55, Asn130, Gly137; 16 kDa: Ser51, Tyr55, Asn130, Glu137). Four residues, highly conserved in the galectin family, are substituted. None of the residues claimed to be involved in interactions with GalNAcalpha1-3 moieties at an extended binding subsite of galectin-3 was identified in the corresponding positions of GCG. Apparently, the substitutions do not confer distinct binding characteristics to the GCG variants as evidenced by binding studies with a recombinantly expressed 15-kDa isoform. The natural isoforms as well as the recombinant 15-kDa isoform oligomerize by the formation of non-covalent heteromeric or homomeric complexes. A phosphorylation of the galectin was confirmed neither by mass spectrometry nor by alkaline phosphatase treatment combined with isoelectric focusing.

Amino Acid Sequence↗
PubMed1986

Preparation of a prototype inactivated hepatitis A virus vaccine from infected cell cultures.

Studies were conducted on the preparation, inactivation, safety, and immunogenicity of a prototype hepatitis A virus vaccine prepared from infected cell cultures. BS-C-1 cells maintained in medium 199 without serum were infected with the HM175 strain of hepatitis A virus and harvested after 21-28 days. The harvested virus preparation contained 6.8-7.4 (log 10) cell culture infectious doses/ml. After exposure to 1:4,000 formalin at 35 C, the infectivity titer decreased 10(6)-fold in 30 hr at an exponential rate, although virus was detected in 5.0-ml vaccine samples for up to three days. Three separate vaccine lots elicited antibody in all the guinea pigs given three doses. Owl monkeys given three doses of vaccine did not have any evidence of HAV infection but developed antibodies identifiable by radioimmunoassay and serum neutralization tests. After either oral or intravenous challenge with at least 10(6) monkey infectious doses of a virulent field strain of hepatitis A virus, none of the vaccinated monkeys shed virus in their feces or had elevated serum levels of alanine aminotransferase. The findings suggest that an effective inactivated whole virus hepatitis A vaccine can be prepared from cell culture.

Animals↗
PubMed1988

Studies of prototype live hepatitis A virus vaccines in primate models.

We have prepared two prototype live hepatitis A virus (HAV) vaccines by serial passage of the HM-175 strain of HAV in African green monkey kidney cells. Passage 21 (P-21) HM-175 virus shows evidence of attenuation for chimpanzees but not for marmosets; passage 32 (P-32) HM-175 virus shows evidence of attenuation for both species. Animals that received P-32 HAV had fewer elevations in levels of liver enzyme activity and evidence of less virus replication in the liver and excretion of virus in stool than did those that received wild-type virus. The P-21 and P-32 viruses were highly immunogenic in both species. The information provided by this study will aid in the development of a live HAV vaccine.

Alanine Transaminase↗
PubMed1994

Emergence of a new cholera pandemic: molecular analysis of virulence determinants in Vibrio cholerae O139 and development of a live vaccine prototype.

In October 1992, a non-O1 strain of Vibrio cholerae emerged as a cause of epidemic cholera in India and Bangladesh. This antigenically novel clone has been designated serogroup O139 synonym Bengal. Since its emergence, V. cholerae O139 has caused a massive cholera epidemic throughout and beyond the Indian subcontinent. Molecular analysis of virulence determinants in clinical isolates suggests that O139 strains are highly related to El Tor O1 strains. Unlike other non-O1 strains, O139 strains carry multiple copies of the cholera toxin genetic element and also genes for the toxin-coregulated pilus. These results guided construction of a live V. cholerae O139 vaccine prototype through deletion of genes for at least four specific virulence determinants (ctxA, ace, zot, and cep) as well as other factors involved in site-specific and homologous recombination (RS1, attRS1, and recA). It is hoped that this attenuated live vaccine will help control the pandemic spread of V. cholerae O139.

Cholera↗
PubMed1995

Mapping of the linear site on the Fas/APO-1 molecule targeted by the prototypic anti-Fas mAb.

Fas/APO-1 is a member of the nerve growth factor/tumor necrosis factor (TNF) family of receptors and has been shown to mediate apoptotic cell death upon binding of specific mAb. We report here that the prototypic anti-human Fas mAb (clone CH-11) induces apoptosis by binding to a linear epitope present on the extracellular domain of the Fas/APO-1 protein. Synthetic peptides corresponding to this epitope blocked the apoptotic effect of the antibody in a susceptible Jurkat T cell line. Based upon the similarity between the Fas/APO-1 protein and the recently crystallized soluble TNF receptor type I, we generated a molecular model of Fas/APO-1, Our computer modeling indicates that the antibody binding region forms a hairpin loop on the surface of the Fas/ APO-1 protein. These findings further our understanding of the Fas/APO-1-mediated apoptotic signal and may provide a useful tool in future investigations of programmed cell death.

Amino Acid Sequence↗
PubMed2002

In vitro studies of core peptide-bearing immunopotentiating reconstituted influenza virosomes as a non-live prototype vaccine against hepatitis C virus.

Evidence from both animal and human viral diseases indicate that cytotoxic T lymphocytes (CTL) are crucial in antiviral defense. However, a major problem to generate cytotoxic immunity is that in vivo exogenous antigens are usually presented via MHC class II pathway and normally fail to induce CTL. The aim of this study is to describe a novel non-live prototype vaccine based on immunopotentiating reconstituted influenza virosomes (IRIV) as vehicles to deliver HLA-A*0201-restricted hepatitis C virus (HCV) peptides (core 35-44 and 131-140) into the cytoplasm of at least three different target cell types [including T2, a transporter associated with antigen processing (TAP)-deficient cell line] resulting in MHC class I peptide presentation and lysis by peptide-specific CTL lines. Comparison of kinetics and analysis of the influence of peptide-stripping and Brefeldin A (BFA) reveal that there exists an endogenous, TAP-independent and BFA-sensitive pathway for virosomally delivered peptides. Moreover, virosomes containing influenza matrix peptide 58-66 can efficiently re-stimulate in vivo primed CTL and, importantly, IRIV containing HCV core peptides can even prime CTL from peripheral blood mononuclear cells of HCV(-) healthy blood donors in vitro. The fact that in vitro primed CTL are also able to specifically lyse target cells infected with recombinant vaccinia virus encoding the HCV core protein is of great importance for future studies based on in vivo mouse models. One of the most evident advantages of the virosomes in vivo will be their capability to protect the incorporated peptide from a large variety of degrading proteases.

Amino Acid Sequence↗
PubMed1999

EpoDB: a prototype database for the analysis of genes expressed during vertebrate erythropoiesis.

EpoDB is a database of genes expressed in vertebrate red blood cells. It is also a prototype for the creation of cell and tissue-specific databases from multiple external sources. The information in EpoDB obtained from GenBank, SWISS-PROT, Transfac, TRRD and GERD is curated to provide high quality data for sequence analysis aimed at understanding gene regulation during erythropoiesis. New protocols have been developed for data integration and updating entries. Using a BLAST-based algorithm, we have grouped GenBank entries representing the same gene together. This sequence similarity protocol was also used to identify new entries to be included in EpoDB. We have recently implemented our database in Sybase (relational tables) in addition to SICStus Prolog to provide us with greater flexibility in asking complex queries that utilize information from multiple sources. New additions to the public web site (http://www.cbil.upenn.edu/epodb) for accessing EpoDB are the ability to retrieve groups of entries representing different variants of the same gene and to retrieve gene expression data. The BLAST query has been enhanced by incorporating BLASTView, an interactive and graphical display of BLAST results. We have also enhanced the queries for retrieving sequence from specified genes by the addition of MEME, a motif discovery tool, to the integrated analysis tools which include CLUSTALW and TESS.

Animals↗
PubMed2006

PrrC-anticodon nuclease: functional organization of a prototypical bacterial restriction RNase.

The tRNA(Lys) anticodon nuclease PrrC is associated in latent form with the type Ic DNA restriction endonuclease EcoprrI and activated by a phage T4-encoded inhibitor of EcoprrI. The activation also requires the hydrolysis of GTP and presence of dTTP and is inhibited by ATP. The N-proximal NTPase domain of PrrC has been implicated in relaying the activating signal to a C-proximal anticodon nuclease site by interacting with the requisite nucleotide cofactors [Amitsur et al. (2003) Mol. Microbiol., 50, 129-143]. Means described here to bypass PrrC's self-limiting translation and thermal instability allowed purifying an active mutant form of the protein, demonstrating its oligomeric structure and confirming its anticipated interactions with the nucleotide cofactors of the activation reaction. Mutagenesis and chemical rescue data shown implicate the C-proximal Arg320, Glu324 and, possibly, His356 in anticodon nuclease catalysis. This triad exists in all the known PrrC homologs but only some of them feature residues needed for tRNA(Lys) recognition by the Escherichia coli prototype. The differential conservation and consistent genetic linkage of the PrrC proteins with EcoprrI homologs portray them as a family of restriction RNases of diverse substrate specificities that are mobilized when an associated DNA restriction nuclease is compromised.

Amino Acid Sequence↗
PubMed2004

KpnBI is the prototype of a new family (IE) of bacterial type I restriction-modification system.

KpnBI is a restriction-modification (R-M) system recognized in the GM236 strain of Klebsiella pneumoniae. Here, the KpnBI modification genes were cloned into a plasmid using a modification expression screening method. The modification genes that consist of both hsdM (2631 bp) and hsdS (1344 bp) genes were identified on an 8.2 kb EcoRI chromosomal fragment. These two genes overlap by one base and share the same promoter located upstream of the hsdM gene. Using recently developed plasmid R-M tests and a computer program RM Search, the DNA recognition sequence for the KpnBI enzymes was identified as a new 8 nt sequence containing one degenerate base with a 6 nt spacer, CAAANNNNNNRTCA. From Dam methylation and HindIII sensitivity tests, the methylation loci were predicted to be the italicized third adenine in the 5' specific region and the adenine opposite the italicized thymine in the 3' specific region. Combined with previous sequence data for hsdR, we concluded that the KpnBI system is a typical type I R-M system. The deduced amino acid sequences of the three subunits of the KpnBI system show only limited homologies (25 to 33% identity) at best, to the four previously categorized type I families (IA, IB, IC, and ID). Furthermore, their identity scores to other uncharacterized putative genome type I sequences were 53% at maximum. Therefore, we propose that KpnBI is the prototype of a new 'type IE' family.

Amino Acid Sequence↗
PubMed1992

Excimer laser coronary angioplasty: experience with a prototype multifibre catheter in patients with stable angina pectoris.

Percutaneous excimer laser coronary angioplasty (ELCA) was performed in a first group of 20 patients with stable angina pectoris caused by significant coronary stenosis, and long-term follow-up was evaluated. Prototype 4 to 5.5 French multifibre catheters with 18-20 quartz fibres of 100 microns diameter, concentrically arranged around a central lumen for taking up a guide wire, were coupled to a commercial XeCl excimer laser. Energy was delivered at a wavelength of 308 nm with a pulse duration of 60 or 120 ns. Operating at a repetition rate of 20 Hz, mean energy transmission was 13.4 +/- 6.8 mJ per pulse. In all but one patient the lesion could be passed by the catheter. Percent diameter stenosis decreased from 77.1 +/- 10.8% to 53.1 +/- 11.8% after ELCA. Complications were frequently observed, intracoronary thrombus formation in eight instances, dissection in six patients and spasm in five cases, causing total vessel occlusion in five procedures. All complications could be managed efficaciously by thrombolytic and vasodilating drugs and/or balloon angioplasty. Subsequent PTCA was performed in case of complication or insufficient stenosis reduction after ELCA in 18 patients with adequate results (residual stenosis, 28.5 +/- 10.2%). Long-term follow-up angiography, which could be performed in 16 of 19 laser treatments, demonstrated significant restenosis in only three patients. Our preliminary results suggest that, using ELCA, ablation of atherosclerotic lesions is feasible in most cases. However, compared with PTCA, stenosis reduction is significantly less, and the acute complication rate is much higher. Thus, further improvements of the catheter system are necessary in order to realize the advantages of excimer laser ablation, which can be demonstrated by experimental studies.

Adult↗
PubMedDate not supplied

Effects of hemodynamics on thromboembolism in coronary stents and prototype flow cells in vitro.

Thromboembolism was studied as heparinized (3 U/ml) bovine blood was gravity fed through a conduit with a deployed coronary stent or a prototype flow cell. The initial flow rate was established with a pinch valve, and monitored with a clamp-on ultrasonic probe. Emboli production was continuously monitored using a light scattering microemboli detector. Accumulated thrombus at the end of the experiment was assessed gravimetrically in stents or by magnetic resonance imaging in flow cells. Hemodynamic parameters were varied to assess their effects on thromboembolism. With the flow cells, the hemodynamics were controlled by varying the geometry of the stagnation zones. With the stents, the flow characteristics were altered by placing 75% stenoses upstream and/or downstream of the stent. The average values of the shear stress and residence time around the stent were modeled using the commercial fluid dynamics software FLUENT. Combining the computed hemodynamic parameters with the experimental results showed that 1) thrombus accumulation decreased with increasing shear stress and increased with increasing residence time; 2) embolization was promoted by high shear, and did not correlate with the amount of thrombus accumulated at the end of the experiment; and 3) a reconfiguration of the magnetic resonance imaging system is necessary to monitor thrombus accumulation continuously.

Animals↗
PubMed1990

Prototype volume-controlled resuscitator for neonates and infants.

Twenty-five infants receiving assisted ventilation in an ICU were manually ventilated for 5-min periods using either a new prototype volume-controlled resuscitator (VCR) or a standard self-inflating resuscitator (SIR). Variables monitored during these 5-min periods included heart rate, respiratory rate, mean arterial pressure, mean airway pressure (Paw), end-tidal CO2 (PetCO2), pulse oximetry oxygen saturation, PaO2, and PaCO2. Significant differences in posttrial values for the following variables were: a) PetCO2 (31.2 +/- 9.1 vs. 25.6 +/- 8.2 torr, p less than .001); b) PaCO2 (38.0 +/- 4.9 vs. 33.2 +/- 6.7 torr, p less than .01); and c) pH (7.4 +/- 0.6 vs. 7.5 +/- 0.1, p less than .04) at comparable Paw (9.5 +/- 7.6 vs. 8.0 +/- 6.0, NS). Eighty-four percent (21/25) of infants in the VCR group had normal PaCO2 values (35 to 45 torr) while only 44% (11/25) in the SIR group achieved normocarbia (p less than .001). Measurements of the highest (Pmax) and lowest (Pmin) inspiratory pressure (cm H2O) in 15 patients demonstrated marked variation in Pmax with the SIR. Differences in Pmax (SIR minus VCR) were significant (10.8 +/- 3.7, p less than .02) but not in Pmin (0.5 +/- 3.5, NS). Our study demonstrates that ventilation with the VCR resulted in less hyperventilation with minimal pressure variability as compared with the SIR. Further studies in the neonate are warranted.

Equipment Design↗