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At least 1,189 records · Page 66Linked to original sources
PubMed2004

The prototypic tissue pentraxin PTX3, in contrast to the short pentraxin serum amyloid P, inhibits phagocytosis of late apoptotic neutrophils by macrophages.

OBJECTIVE: Phagocytosis of apoptotic cells can be facilitated by complement components and short pentraxins, such as serum amyloid P (SAP). In contrast, the long pentraxin PTX3 was shown to inhibit phagocytosis of apoptotic Jurkat cells by dendritic cells and to bind late apoptotic polymorphonuclear leukocytes (PMNs). Recently, levels of the pentraxin PTX3 were shown to parallel disease activity in small-vessel vasculitis, which is often characterized by leukocytoclasia, a persistence of leukocyte remnants in the vessel wall. We undertook this study to test our hypothesis that PTX3 inhibits phagocytosis of late apoptotic PMNs by macrophages, thereby leading to their accumulation in the vessel wall. METHODS: Macrophages were allowed to phagocytose late apoptotic or secondary necrotic PMNs that were incubated with or without PTX3 for 30 minutes prior to phagocytosis. Phagocytosis was allowed to occur in the presence of 30% normal human serum with or without SAP and with or without depletion of complement. To discriminate between an inhibitory effect of PTX3 on binding and the internalization of apoptotic PMNs into macrophages, internalization was blocked by cytochalasin B. RESULTS: SAP and complement were both necessary for effective in vitro phagocytosis. In contrast, PTX3 inhibited phagocytosis in a dose-dependent manner, from 11% inhibition at 6.25 microg/ml to almost complete inhibition at 100 microg/ml. Furthermore, PTX3 partly affected binding of apoptotic PMNs to macrophages. CONCLUSION: PTX3, in contrast to SAP and complement, inhibits phagocytosis of late apoptotic PMNs by monocyte-derived macrophages in a dose-dependent manner. Therefore, PTX3 can play a role in the development of leukocytoclasia by affecting the clearance of apoptotic PMNs, thereby inducing their accumulation in the vessel wall.

Apoptosis↗
PubMed2003

Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 3. Intervention with PK11195.

BACKGROUND: Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp). METHODS: Pregnant CD-1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT-PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure. RESULTS: The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co-treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA. CONCLUSIONS: The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53-dependent mode of action of 2CdA on ocular development.

Animals↗
PubMed1993

The ascidian embryo as a prototype of vertebrate neurogenesis.

Ascidian tadpole larvae, composed of only about 2500 cells, have a primitive nervous system which is derived from the neural plate. The stereotyped cell cleavage pattern and well characterized cell lineage in these animals allow the isolation and culture of identified blastomeres in variable combinations. Ascidian embryos express cell-type-specific markers corresponding to their cell fates, even when cultured under cleavage-arrest by cytochalasin B. This system provides us with a unique opportunity to study the roles of cell lineage and cell contact in early neuronal differentiation in the absence of events associated with complex morphogenesis. In addition, the isolated, cleavage-arrested blastomeres are ideally suited to electrical recording, permitting the use of ionic channels as specific markers for differentiation. In the cleavage-arrested embryos, suppression of one type of K+ channel, and induction of two types of Na+ channels, occur following cell contact with the vegetal blastomere. The combination of molecular and electrophysiological analyses on this simple animal system may provide insights into the nature of the cell interactions important in early neurogenesis, both in ascidians and in vertebrates.

Animals↗
PubMed1986

Mechanosensory appendages and giant interneurons in the firebrat (Thermobia domestica, Thysanura): a prototype system for terrestrial predator evasion.

Aspects of the structure and function of the abdominal cerci and caudal filament sensory systems, and associated giant interneurons of the thysanuran insect Thermobia domestica, the firebrat, extend comparative studies of a widespread predator evasion system. All elements of the cercal system, which is well known from diverse orthopteroid insects, are present in the primitively wingless thysanuran. In addition, a median terminal sensory appendage, the caudal filament, projects to the same general regions of the terminal ganglion but shows limited overlap of synaptic regions with cercal input. A segmental series of giant interneurons appears to be homologous with those of the orthopteroid insects. The cercal system, which may have evolved with the first terrestrial hexapods, reaches its zenith in the orthopteroid insects, but was replaced in holometabolan insects by visual startle mechanisms with descending giant interneurons.

Action Potentials↗
PubMed1995

Organization of somatosensory cortex in monotremes: in search of the prototypical plan.

The present investigation was designed to determine the number and internal organization of somatosensory fields in monotremes. Microelectrode mapping methods were used in conjunction with cytochrome oxidase and myelin staining to reveal subdivisions and topography of somatosensory cortex in the platypus and the short-billed echidna. The neocortices of both monotremes were found to contain four representations of the body surface. A large area that contained neurons predominantly responsive to cutaneous stimulation of the contralateral body surface was identified as the primary somatosensory area (SI). Although the overall organization of SI was similar in both mammals, the platypus had a relatively larger representation of the bill. Furthermore, some of the neurons in the bill representation of SI were also responsive to low amplitude electrical stimulation. These neurons were spatially segregated from neurons responsive to pure mechanosensory stimulation. Another somatosensory field (R) was identified immediately rostral to SI. The topographic organization of R was similar to that found in SI; however, neurons in R responded most often to light pressure and taps to peripheral body parts. Neurons in cortex rostral to R were responsive to manipulation of joints and hard taps to the body. We termed this field the manipulation field (M). The mediolateral sequence of representation in M was similar to that of both SI and R, but was topographically less precise. Another somatosensory field, caudal to SI, was adjacent to SI laterally at the representation of the face, but medially was separated from SI by auditory cortex. Its position relative to SI and auditory cortex, and its topographic organization led us to hypothesize that this caudal field may be homologous to the parietal ventral area (PV) as described in other mammals. The evidence for the existence of four separate representations in somatosensory cortex in the two species of monotremes indicates that cortical organization is more complex in these mammals than was previously thought. Because the two monotreme families have been separate for at least 55 million years (Richardson, B.J. [1987] Aust. Mammal. 11:71-73), the present results suggest either that the original differentiation of fields occurred very early in mammalian evolution or that the potential for differentiation of somatosensory cortex into multiple fields is highly constrained in evolution, so that both species arrived at the same solution independently.

Animals↗
PubMed1989

The transforming prototype of Epstein-Barr virus (B95-8) is also a lytic virus.

The B95-8 isolate of the Epstein-Barr virus (EBV) has been described as a non-lytic transforming virus. We have performed experiments in order to determine if the B95-8 EBV is capable of super-infecting and replicating in EBV-genome-positive non-producer lymphoblastoid cells. Using concentrates of B95-8 EBV, prepared from 6 different B95-8 cell lines treated with 12-O-tetradecanoylphorbol-13-acetate (TPA), we demonstrated that virus concentrates could transform human or cotton-top tamarin B-lymphocytes and also lytically replicate in Raji cells, inducing EBV antigens and infectious virus. While the virus obtained from B95-8 super-infected Raji cells was able to transform cord-blood lymphocytes (CBLs) and super-infect Raji cells, transformation was abortive, with cell cultures only growing for up to 6 weeks. Transformation titers of the B95-8 virus concentrates ranged from 10(5) to greater than 10(8) transforming units/ml; early antigen (EA) induction ranged from 1% to 50% after superinfection of Raji cells, depending on the virus stock used, as determined by immunofluorescence. Southern blot analysis was carried out on the DNA prepared from B95-8 cells and virion DNA. The results were consistent with the published EcoRI restriction pattern for B95-8 EBV. The issue of whether the B95-8 cells produce virions with a dual biological phenotype or, rather, 2 biologically distinct viruses, is addressed.

Cell Line↗
PubMed1993

First structure of a snake venom metalloproteinase: a prototype for matrix metalloproteinases/collagenases.

Adamalysin II, a 24 kDa zinc endopeptidase from the snake venom of Crotalus adamanteus, is a member of a large family of metalloproteinases isolated as small proteinases or proteolytic domains of mosaic haemorrhagic proteins from various snake venoms. Homologous domains have recently been detected in multimodular mammalian reproductive tract proteins. The 2.0 A crystal structure of adamalysin II reveals an ellipsoidal molecule with a shallow active-site cleft separating a relatively irregularly folded subdomain from the calcium-binding main molecular body composed of a five-stranded beta-sheet and four alpha-helices. The folding of the peptide fragment containing the zinc-binding motif HExxHxxGxxH bears only a distant resemblance to thermolysin, but is identical to that found in astacin, with the three histidines and a water molecule (linked to the glutamic acid) likewise constituting the zinc ligand; adamalysin II lacks a fifth (tyrosine) zinc ligand, however, leaving its zinc ion tetrahedrally co-ordinated. Furthermore, adamalysin II and astacin share an identical active-site basement formed by a common Metturn. Due to their virtually identical active-site environment and similar folding topology, the snake venom metalloproteinases (hitherto called adamalysins) and the astacins (and presumably also the matrix metalloproteinases/mammalian collagenases and the Serratia proteinase-like large bacterial proteinases) might be grouped into a common superfamily with distinct differences from the thermolysin family.

Amino Acid Sequence↗
PubMedDate not supplied

Flecainide: a new prototype antiarrhythmic agent.

Flecainide acetate is the first class IC antiarrhythmic agent marketed in the United States. In vitro, animal and human studies have shown that the drug markedly prolongs conduction and has minimal effect on repolarization. Efficacy trials have shown flecainide to be effective in a wide range of ventricular and selected atrial arrhythmias. The drug is generally well tolerated, although minor adverse effects are common. These generally are related to the central nervous system and respond to a reduction in dosage. Like other antiarrhythmic agents, flecainide may demonstrate proarrhythmic effects. It is excreted in the urine as the parent compound and inactive metabolites. The elimination half-life ranges from 12-27 hours in patients with normal renal function, allowing convenient dosing regimens of 100-200 mg twice daily in most patients. Flecainide has the potential for widespread use.

Administration, Oral↗
PubMed2006

Application of standard DFT theory for nonbonded interactions in soft matter: prototype study of poly-para-phenylene.

We present a detailed analysis of the application of density functional theory (DFT) methods to the study of structural properties of molecular and supramolecular systems, using as a paradigmatic example three para-phenylene-based systems: isolated biphenyl, single chain poly-para-phenylene, and crystalline biphenyl. We use different functionals for the exchange correlation potential, the local density (LDA), and generalized gradient approximations (GGA), and also different basis sets expansions, localized, plane waves (PW), and mixed (localized plus PW), within the reciprocal space formulation for the hamiltonian. We find that regardless of the choice of basis functions, the GGA calculations yield larger interring distances and torsion angles than LDA. For the same XC approximation, the agreement between calculations with different basis functions lies within 1% (LDA) or 0.5% (GGA) for distances, and while PW and mixed basis calculations agree within 1 degrees for torsion angles, the localized basis results show larger angles by approximately 8 degrees and a nonmonotonic dependence on basis size, with differences within 6 degrees. The most prominent features, namely the torsion between rings for isolated molecule and infinite chain, and planarity for the molecule in crystalline environment, are well reproduced by all DFT calculations.

Biphenyl Compounds↗
PubMed2001

The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair?

PC3(TIS21/BTG2) is the founding member of a family of genes endowed with antiproliferative properties, namely BTG1, ANA/BTG3, PC3B, TOB, and TOB2. PC3 was originally isolated as a gene induced by nerve growth factor during neuronal differentiation of rat PC12 cells, or by TPA in NIH3T3 cells (named TIS21), and is a marker for neuronal birth in vivo. This and other findings suggested its implication in the process of neurogenesis as mediator of the growth arrest before differentiation. Remarkably, its human homolog, named BTG2, was shown to be p53-inducible, in conditions of genotoxic damage. PC3(TIS21/BTG2) impairs G(1)-S progression, either by a Rb-dependent pathway through inhibition of cyclin D1 transcription, or in a Rb-independent fashion by cyclin E downregulation. PC3(TIS21/BTG2) might also control the G(2) checkpoint. Furthermore, PC3(TIS21/BTG2) interacts with carbon catabolite repressor protein-associated factor 1 (CAF-1), a molecule that associates to the yeast transcriptional complex CCR4 and might influence cell cycle, with the transcription factor Hoxb9, and with the protein-arginine methyltransferase 1, that might control transcription through histone methylation. Current evidence suggests a physiological role of PC3(TIS21/BTG2) in the control of cell cycle arrest following DNA damage and other types of cellular stress, or before differentiation of the neuron and other cell types. The molecular function of PC3(TIS21/BTG2) is still unknown, but its ability to modulate cyclin D1 transcription, or to synergize with the transcription factor Hoxb9, suggests that it behaves as a transcriptional co-regulator.

Amino Acid Sequence↗
PubMedDate not supplied

Prototype system for an MR simulation of intracavitary brachytherapy for cervical cancer: preliminary results in six cases.

We report a newly developed MR simulation system for intracavitary brachytherapy for cervical cancer and subsequent treatment results. MR simulation was performed on six patients. The spatial relationship of the tumor to the bladder, rectum, bowel, applicators, etc. was depicted well. Doses to the tumor and surrounding normal tissues were read from isodose curves superimposed on the T2-weighted sagittal image. This system promises to be useful in customizing the dose distribution.

Aged↗
PubMed1994

Infectivity titration of a prototype strain of hepatitis E virus in cynomolgus monkeys.

The infectivity titer of a standard stock of the SAR-55 strain of hepatitis E virus (HEV) was determined in cynomolgus macaques (Macaca fascicularis) and the effect of dose on the course of the infection was examined by weekly monitoring of alanine aminotransferase (ALT) and anti-HEV levels. Antibody to HEV (anti-HEV) was measured with ELISAs based on ORF-2 recombinant antigens consisting of either a 55 kDa region expressed in insect cells or shorter regions expressed as fusion proteins in bacteria. The ELISA based on the 55 kDa antigen was generally more sensitive. The infectivity titer of SAR-55 was 10(6) cynomolgus 50% infectious doses per gram of feces. The infectivity titer corresponded to the HEV genome titer of the inoculum as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Anti-HEV IgM was detected in only a portion of the animals that had an anti-HEV IgG response. Biochemical evidence of hepatitis was most prominent in animals that were inoculated with the higher concentrations of virus and the incubation period to seroconversion was prolonged in animals that received the lower doses.

Alanine Transaminase↗
PubMed2005

Biophysical signatures of noncovalent aggregates formed by a glucagonlike peptide-1 analog: a prototypical example of biopharmaceutical aggregation.

LY307161 is a 31 amino acid analog of glucagonlike peptide-1(7-37)OH susceptible to physical instability associated with pharmaceutical processing. Orthogonal biophysical studies were conducted to explore the origins of this physical instability and to distinguish pharmaceutically desirable states of this aggregating peptide from undesirable ones. Equilibrium sedimentation analysis established that LY307161 exists as a monomer at pH 3, and reversibly self-associates in the pH range 7.5-10.5. Causative factors for physical instability related to lyophilization conditions were investigated. Solution pH, acetonitrile content, and concentration of the peptide prior to lyophilization each impacted physicochemical properties of the resultant powders. A comparative study of two powder samples exhibiting physicochemically disparate properties established that LY307161 forms soluble noncovalent aggregates. FT-IR analyses in the solid and solution states identified a prominent band at 1657-1659 cm(-1) attributed to alpha-helix structure. Noncovalent soluble aggregate exhibited characteristic bands at 1615 and 1698 cm(-1) indicative of intermolecular beta-sheet structure. An agitation-induced, precipitated solid form of LY307161 exhibited a different FT-IR signature indicative of a conformationally distinct species. Circular dichroism and fluorescence spectroscopy, together with dynamic light scattering measurements and dye-aggregate complexation, provided additional insights into the distinctions between aggregated and native LY307161.

Biophysical Phenomena↗
PubMed1985

Simultaneous liquid chromatographic determination of glutaric acid, phenylephrine, and benzyl alcohol in a prototype nasal spray with application to di- and tricarboxylic acids.

A rapid reversed-phase high-performance liquid chromatographic method for the simultaneous determination of glutaric acid, phenylephrine, and benzyl alcohol in nasal spray has been developed. UV detection was utilized at 210 nm for the assay of glutaric acid and phenylephrine with an adjustment to 254 nm for the measurement of benzyl alcohol. Linearity and recovery data were obtained for each component in spiked placebo studies. An investigation of the retention mechanisms of the three components showed that phenylephrine was retained by ion-pairing with octanesulfonate anion while glutaric acid and benzyl alcohol partitioned as a suppressed ion and a neutral molecule, respectively. The method has been further extended to the reversed-phase separation of di- and tricarboxylic acids using a totally aqueous 0.0074 M phosphoric acid mobile phase. The retention of these acids was related to their octanol-water partition coefficients and structural variation.

Aerosols↗
PubMed1983

Prototype of a multipurpose trilaser unit in a teaching hospital surgical department.

We describe our experience and the problems we encountered organizing an autonomous surgical unit in which the equipment and organization enable three lasers to be used in may different applications in medicine and surgery. The three lasers--CO2, Nd:YAG, and argon--may now be used by all the departments concerned within our teaching hospital. As our unit goes into operation, we have determined that we must now begin an evaluation 1) To assess the clinical value of laser usage via the careful selection of cases for laser treatment, the storage of data for future reference on card and computer records, and the assessment of the vital role of the laser within a range of modern therapeutic aids; 2) to achieve technical improvements, by the optimum use of laser sources and related optical equipment; and 3) to assess the economics of the unit, the profitability of bringing together the three types of laser, and the total cost involved.

France↗