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PubMed1992

Oxidation-induced persistent activation of protein kinase C in hippocampal homogenates.

Incubation of purified protein kinase C with H2O2 results in the generation of a persistently activated form of the enzyme which is no longer dependent on Ca2+ or lipid cofactors. This oxidative activation of purified protein kinase C requires added Fe2+ in the incubation medium. Treatment of the soluble fraction of hippocampal homogenates with H2O2 also leads to persistent activation of protein kinase C; however, oxidative activation of protein kinase C under these conditions does not require the addition of Fe2+. The persistently activated form of protein kinase C appears as a novel peak of activity on DE52 anion exchange columns, suggesting a modification of the charge character of the enzyme. Thus, oxidative modification of protein kinase C can result in its persistent activation, and this mechanism may constitute a pathway for physiological activation of the enzyme in the hippocampus.

Animals↗
PubMed1989

Persistent intracellular binding of mitoxantrone in a human colon carcinoma cell line.

Incubation of human carcinoma cells with mitoxantrone resulted in an intracellular distribution of the drug into cytoplasmic, nuclear and cytoskeletal compartments occurring within 1 min of drug treatment. Incubation of the cells in drug-free medium resulted in an efflux of the drug such that 80% of the intracellular drug was eliminated from the cells by 72 hr. Approximately 20% of the initial intracellular drug concentration remained in the cells after the drug had been removed from the medium. The majority of the persistent intracellular drug was associated with soluble cytoplasmic proteins and fractions enriched in nucleic acid. Approximately 10% of the persistent drug binding was associated with cellular structures that had been depleted of soluble cytoplasmic protein and nucleic acid. During the persistent drug binding, the cells enlarged at least 2-fold as determined by microscopic examination. An increasing percentage of the cells was also observed to contain a DNA content consistent with a G2 cell cycle arrest. Taken together, these data suggest that the persistent intracellular binding of mitoxantrone results in a G2 cell cycle arrest and cellular damage.

Cell Cycle↗
PubMed1989

Phosphoproteins localized to presynaptic terminal linked to persistence of long-term potentiation (LTP): quantitative analysis of two-dimensional gels.

Previous findings suggest: (1) that altering protein kinase C (PKC) activity alters the persistence of long-term potentiation (LTP) in the intact hippocampal formation; and (2) that PKC activity is directly correlated with persistence of LTP in vivo as measured by the in vitro phosphorylation of two major PKC substrates in adult hippocampus, protein F1 and 80k. Using quantitative analysis of two-dimensional gels, we report here two additional phosphoproteins of 72 and 55 kDa which were directly correlated to persistence of LTP induced in the intact dorsal hippocampal formation. The phosphorylation of both proteins in response to addition of different kinase stimulators was distinct from that of protein F1 and 80k. Moreover, neither protein was a substrate for exogenous PKC. The physicochemical properties of these phosphoproteins suggest they are identical to the previously described synaptic vesicle proteins IIIa and IIIb, and as such are immunologically indistinguishable. Because proteins IIIa and IIIb are known to be phosphorylated by a Ca2+/calmodulin (CaM)-stimulated kinase, and protein F1 is known to be a plasma membrane-associated protein (P-57) which releases bound CaM in response to phosphorylation by PKC, the present findings suggest a potential mechanism in which PKC-mediated changes in plasma membrane proteins produce CaM kinase-mediated changes in synaptic vesicle proteins through a phosphorylation cascade. These membrane/vesicle alterations are postulated to underlie the increased synaptic efficacy which marks persistent LTP.

Adaptation, Physiological↗
PubMed1993

32P-postlabeling analysis of DNA adduct formation and persistence in English sole (Pleuronectes vetulus) exposed to benzo[a]pyrene and 7H-dibenzo[c,g]carbazole.

The formation and persistence of benzo[a]pyrene (BaP)- and 7H-dibenzo[c,g]-carbazole (DBC)-DNA adducts in liver of English sole (Pleuronectes vetulus) were investigated. BaP is a putative hepatocarcinogen in English sole based on its ability to induce formation of preneoplastic foci, while DBC is a hepatocarcinogen in mammals but whose carcinogenicity in fish is not known. English sole liver was sampled from 2 h through 84 days after a single intermuscular injection of a BaP and DBC mixture (100 mumol of each/kg body wt.), and DNA adduct levels were measured by the nuclease P1 version of the 32P-postlabeling assay. The major BaP adducts detected were from binding of BaP-7,8-diol-9,10-epoxide to DNA, whereas multiple uncharacterized DBC-DNA adducts were detected. Total adduct levels for both BaP and DBC reached a maximum at 2 days post exposure. The levels of DBC-DNA adducts were greater than the levels of BaP adducts at all time points and increased more rapidly than did the levels of BaP-DNA adducts. The DBC to BaP adduct ratio was 33 +/- 8.8 at 2 h and declined to 4.2 +/- 0.48 by 12 h post exposure. From 2 to 28 days, the levels of both BaP and DBC adducts declined with apparent half-lives of 11 and 13 days, respectively. There was no apparent decline from 28 to 84 days in the levels of the remaining BaP or DBC adducts; these persistent adducts represented 32 and 36% of maximum levels, respectively. These results provide the first data on the kinetics of adduct formation and removal of a carcinogenic nitrogen-containing polycyclic aromatic compound in fish. The results showing greater binding and similar persistence of DBC-DNA adducts compared to BaP-DNA adducts suggest that DBC may be hepatotoxic and potentially carcinogenic in English sole. In a separate experiment, the effect of multiple doses of BaP (30 mumol/kg body wt.) on the levels of hepatic BaP-DNA adducts showed that adduct levels increased linearly (r = 0.815, P = 0.0007) with 5 successive doses administered at 2 day-intervals and sampled 2 days after the last dose. The persistence of both BaP-DNA and DBC-DNA adducts in liver, together with the increase in BaP-DNA adducts in English sole exposed to successive doses of BaP, suggest that hepatic xenobiotic-DNA adducts in English sole are molecular dosimeters of relatively longterm environmental exposure to genotoxic polycyclic aromatic compounds.

Animals↗
PubMed1987

Effect of cysteine on the persistent depletion of brain monoamines by amphetamine, p-chloroamphetamine and MPTP.

The administration of L-cysteine (500 mg/kg i.p.) 30 min before and 5 h after the administration of (+)-amphetamine sulfate markedly attenuated the persistent decreases in striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rats one week after the administration of a single dose of amphetamine (9.2 mg/kg i.p.) to iprindole-treated animals and in mice one week after the last of four daily injections of amphetamine (30 mg/kg i.p.). Cysteine prevented the persistent decreases in striatal serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) one week after the administration of p-chloroamphetamine to rats, but failed to alter the persistent decreases in striatal DA, DOPAC and HVA in mice one week after the last of four daily doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 30 mg/kg s.c.). The results suggest that the mechanisms by which amphetamine and p-chloroamphetamine, but not MPTP, produce persistent depletions of striatal monoamines involve the generation of neurotoxic electrophilic intermediates which can be inactivated by the administration of cysteine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Immunoglobulin A antibody against hepatitis B core antigen in the acute and persistent infection with hepatitis B virus.

Antibody to hepatitis B core antigen of immunoglobulin A class was determined in the serum of patients infected with hepatitis B virus by a sandwich-type solid-phase radioimmunoassay with monoclonal antibodies. The antibody, as defined by a sample to normal ratio greater than 2.1, was detected in all of 39 patients with acute hepatitis, with titers varying widely depending on the time of blood sampling. In persons with persistent infection, the antibody was detected in only 2 (4%) of 46 asymptomatic carriers of the virus, contrasting with the positivity in as many as 15 (41%) of 37 patients with chronic persistent hepatitis, in 45 (94%) of 48 patients with chronic active hepatitis, and in 40 (87%) of 46 patients with liver cirrhosis with or without hepatocellular carcinoma. The mean +/- SE titer of antibody in chronic persistent hepatitis (3.8 +/- 0.9) was significantly lower than those in chronic active hepatitis (13.8 +/- 3.2) and cirrhosis with or without carcinoma (25.6 +/- 6.1) (p less than 0.001). Based on the results obtained, the antibody may reflect hepatic injury in the persistent hepatitis B virus infection.

Antibodies, Monoclonal↗
PubMed1995

Crohn's disease: pathogenesis and persistent measles virus infection.

The Inflammatory Bowel Disease Study Group at the Royal Free Hospital School of Medicine has tested the hypothesis that the primary pathological abnormality in Crohn's disease is in the mesenteric blood supply. Early morphological studies involved arterial perfusion-fixation and either resin casting and scanning electron microscopy or vascular immunostaining of resected intestine affected by Crohn's disease. Granulomatous and lymphocytic damage to intramural blood vessels, even in macroscopically normal areas, was observed. We put forward possible mechanisms by which a chronic ischemic process might account for many of the idiosyncracies of Crohn's disease. It was proposed that persistent viral infection of the mesenteric microvascular endothelium might underly this vasculitic process; based on certain behavioral characteristics of measles virus, including its tropism for the submucosal endothelium of the intestine, this agent was investigated further. This report reviews the preliminary evidence from both epidemiological and basic scientific data for persistent measles virus in the intestine of patients with Crohn's disease. Possible mechanisms for virus persistence and subsequent reactivation are discussed. In conclusion, we believe that Crohn's disease may be a chronic granulomatous vasculitis in reaction to a persistent infection with measles virus within the vascular endothelium. This granulomatous inflammation, perhaps aggravated by either a hypercoagulable state or mechanical stress, results in the clinical features of Crohn's disease.

Colon↗
PubMed1993

Clinical diagnosis of caliber-persistent labial artery of the lower lip.

Only 14 cases of caliber-persistent labial artery of the lower lip have been reported to date. Six of these were misdiagnosed and treated as squamous cell carcinoma, another as a mucocele. The correct diagnosis emerged only after the wedge resections were examined histopathologically. We report the first cases of caliber-persistent labial artery to be diagnosed clinically since the original description of the condition by Howell and Freeman in 1973. Our first case was a nonpulsatile hard, linear, "gooseneck lamp" submucosal nodule of the lower lip. On the basis of an initial misdiagnosis of sclerosing sialadenitis, a biopsy was attempted. Brisk pulsatile bleeding proved the lesion to be an artery, and the superficial location and large diameter of the vessel lead to the clinical diagnosis of caliber-persistent labial artery. The "gooseneck lamp" hardening is typical of Monckeberg's arteriosclerosis. The second case was a pulsatile blue linear submucosal nodule of the lower lip. The clinical diagnosis of caliber-persistent labial artery was confirmed when angiography showed the lesion to be an abnormally dilated labial artery. Both cases were successfully ligated with no complications at 16 and 10 months after surgery.

Adult↗
PubMed1991

Recessive hereditary deafness, assortative mating, and persistence of a sign language.

We model the cultural transmission of sign language when there is one-locus genetic variation for deafness and hearing. Our premises are that the deaf are more motivated to learn sign language than the hearing, and that a vertically transmitted sign language, unlike recessive hereditary deafness, cannot "jump a generation." Conditions are obtained for persistence (i.e. protection from loss) of signers. These conditions are more easily satisfied the greater the fraction of the hearing who also learn sign language and as the frequency of the recessive gene for deafness increases. Persistence is also facilitated by assortative mating for deafness, but not by assortment for signing. With vertical transmission only, it is necessary that one signer parent be able to transmit sign language with greater than one-half the efficiency of two. Under the assumption that the hearing do not learn sign language, the following additional results are obtained. Persistence is more likely with dominant as opposed to recessive inheritance. When recessive hereditary and acquired deafness co-occur, increasing the frequency of the latter has opposite effects depending on the degree of assortment. Opportunities for the deaf to learn sign language outside the family seem not to affect the conditions for persistence.

Deafness↗
PubMed1983

Defective viral RNAs in Aedes albopictus C6/36 cells persistently infected with Semliki Forest virus.

A persistent infection of Semliki Forest virus (SFV) has been established in Aedes albopictus C6/36 cells. Only a small number of cells survived the initial infection with this RNA virus and gave rise to a persistently infected culture which produced continuously small amounts of infectious virus. To investigate whether defective viral RNA was analyzed early and late after infection by blot hybridizations. Several defective viral RNAs were detected with a common sequence corresponding to the 3' end of the viral genome during and after the establishment of the persistent infection. These defective viral RNAs resemble the defective interfering RNAs in vertebrate cells generated during serial undiluted passages of standard SFV. The defective viral RNAs are rarely released from cells as virions. The rapid generation of defective viral RNAs may be important for the establishment of a persistent infection in mosquito cells.

Aedes↗
PubMed1983

Analysis of genetic variation in Theiler's virus during persistent infection in the mouse central nervous system.

The genetic changes occurring in the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) during persistent infection in the mouse central nervous system (CNS) were studied. RNase T1-oligonucleotide fingerprinting of the RNAs of 28 BeAn viruses isolated at various times postinfection (p.i.) demonstrated that mutation occurred throughout the infection. Although plaque-purified BeAn virus was used to inoculate mice intracerebrally, genetically different viruses were recovered from the CNS. One to three oligonucleotide changes were found up to Day 152 p.i., but all three viruses isolated at Day 180 had four to nine oligonucleotide changes. No pattern of oligonucleotide changes occurring in different virus isolates was found, yet three viruses isolated from different animals at Day 180 had the same four new oligonucleotides. Overall, the number of oligonucleotide changes represented a 0.1 to 1.2% change in the virus genome. In addition, the analytical two-dimensional gel technique of P.Z. O'Farrell, H.M. Goodman, and P.H. O'Farrell (Cell 12, 1133-1142, 1977) suggested that mutation occurred in all virus isolates. In nine isolates, one to three proteins were found to have charge changes, and in general, as many nonstructural proteins had charge changes as structural proteins. P20, a nonstructural protein probably equivalent to the protease described for encephalomyocarditis virus, was found to have shifted cathodally in six different viruses. Several virus isolates had doublet patterns, suggesting the possibility that within the CNS, subpopulations existed which had proteins of slightly different charge or that virus-specified proteins had been modified after translation. Finally, antigenic variation of neutralizing site(s) on BeAn virus isolates as a way for virus to evade immune surveillance and thereby maintain the persistent state was studied. The ability of mouse serum to neutralize persisting virus isolates was not significantly different from the ability to neutralize the infecting virus. Therefore, antigenic variation does not appear to be a factor in TMEV persistence.

Animals↗
PubMed1984

Restriction of cell surface expression of Sendai virus hemagglutinin-neuraminidase glycoprotein correlates with its higher instability in persistently and standard plus defective interfering virus infected BHK-21 cells.

To gain an understanding of the mechanism(s) by which Sendai virus generates a persistent infection, the expression of the hemagglutinin-neuraminidase (HN) and fusion (Fo) glycoproteins at the surfaces of BHK-21 cells infected with standard virus, a mixture of standard and defective interfering (DI) particles (mixed virus infection), and during persistent infection was investigated. The expression of HN and Fo was measured on the surfaces of infected cells by the binding of anti-HN and anti-Fo monoclonal antibodies. The results show that HN expression was restricted relative to Fo during mixed virus and persistent infections. The decreased levels of HN were investigated further by pulse-chase experiments which revealed that HN has an increased turnover rate in persistently infected cells and, to a lesser extent, in mixed virus infected cells. In analyzing the [35S]methionine-labeled protein composition of virus particles produced during the pulse-chase experiments, the increased turnover of newly synthesized HN was found to correlate with its decreased incorporation into virus particles. Interestingly, the poor HN incorporation also correlates with less efficient incorporation of the matrix M protein into virus particles.

Animals↗
PubMed1987

A 14K envelope protein of vaccinia virus with an important role in virus-host cell interactions is altered during virus persistence and determines the plaque size phenotype of the virus.

The phenomenon of genetic variability and attenuation or virulence of poxviruses is poorly understood. We have identified mutants of vaccinia virus from untreated and interferon (IFN)-treated persistently infected Friend erythroleukemia (FEL) cells that have major alterations in the size of a virus structural protein. This protein is part of the virus envelope as documented with specific monoclonal antibody (mAbC3). This protein, under reducing conditions, has a molecular weight of about 14,000 (14K) Da in wild-type virus but gained 1.5 K in mutants from untreated, persistently infected cells and about 0.5 K in mutants from IFN-treated persistently infected cells. Under nonreducing conditions, this protein forms covalently linked oligomers which also differ in size between wild-type and mutant viruses. The 14K protein elicits humoral immune response as assessed by immunoblots of two-dimensional SDS-PAGE analysis using rabbit anti-vaccinia serum. Two molecular forms of the 14K protein with different isoelectric points were found only in mutants from untreated, persistently infected cells. Protein modifications were the result of DNA sequence alterations in the virus population since the 15.5 K protein could be reverted to 14K after marker-rescue with the cloned 14K encoding gene. We provide direct evidence that changes in size of the 14K envelope protein are responsible for the small plaque size phenotype of these variants. From our previous studies (J. F. Rodriguez, R. Janeczko, and M. Esteban, 1985, J. Virol. 56, 352-356; J. F. Rodriguez, E. Paez, and M. Esteban, 1987, J. Virol. 61, 395-404) and those described here, we established that the 14K protein plays an important role in virus-host cell interactions. This is because this protein is part of the virus envelope, is highly antigenic, elicits neutralizing antibodies, has a role in virus penetration acting in cell fusion, is involved in the virus plaque size phenotype and is highly conserved among Orthopoxviruses. In addition, because mutants with altered 14K protein that have gained 1.5K in size are attenuated (S. Dallo and M. Esteban, 1987, Virology 159, 408-422), it suggests that a modified form of this protein contributes to the decrease of the virulence of vaccinia virus.

Animals↗
PubMed1988

Virus-lymphocyte interactions. III. Biologic parameters of a virus variant that fails to generate CTL and establishes persistent infection in immunocompetent hosts.

Viruses that cause in vivo persistent infections avoid the host's immunologic surveillance machinery. A major component of that armamentarium is virus-specific MHC-restricted cytotoxic T lymphocyte (CTL) response of the host. Studies with lymphocytic choriomeningitis virus (LCMV) have uncovered a parental virus (CTL+) that in immuno-competent adults induces CTL and terminates acute infection and a variant (CTL-) that fails to elicit CTL responses and establishes a persistent state (R. Ahmed et al. (1984) J. Exp. Med. 160, 521-540). The biologic properties, similarities, and differences between CTL+ and CTL- viruses as regards their interactions with lymphocytes of newborn and adult mice is recorded here. CTL+ and CTL- viruses persist in lymphocytes of newborn inoculated mice, primarily within the T helper subset. Approximately 2% of lymphocytes express viral nucleic acid sequences while only 0.04% score as infectious centers suggesting incomplete viral replication. These levels were maintained over the course of infectious. In contrast, CTL- virus but not CTL+ persists in lymphocytes of mice inoculated when adults. Lymphocytes easily scored as infecting centers but rarely displayed nucleic acid sequences suggesting a different balance of incomplete to complete virion replication. Further, infectious centers decreased by 10-fold from the 3rd to 68th day of infection and the total numbers of T lymphocytes in the circulation decreased suggesting CTL- may replicate in and destroy lymphocytes of adult mice. In the following paper the primary nucleotide structure of the LCMV small RNA segment, the segment responsible for generation of CTL and encoding the proteins recognized by CTL, for CTL+ and CTL- viruses is reported.

Animals↗
PubMed1989

Mutated and hypermutated genes of persistent measles viruses which caused lethal human brain diseases.

Persistent measles viruses (MVs) causing lethal human brain diseases are defective, and the structure of several mutated matrix genes has been elucidated previously. The present study of four persistent MVs revealed a high number of differences from a consensus sequence also in other genes. Amino acid changes accumulated in the carboxyl terminus of the nucleocapsid protein and in the amino terminus of the phosphoprotein, but did not significantly alter these products, which are implicated in viral replication and transcription. The contrary is true for the envelope glycoproteins: In three of four cases, mutations caused partial deletion of the short intracellular domain of the fusion protein, most likely compromising efficient viral budding. Moreover, in the hemagglutinin gene of a strain showing strongly reduced hemadsorption, 20 clustered A to G mutations, resulting in 16 amino acid changes, were detected. This hypermutation might be due to unwinding modification of a part of the MV RNA genome accidentally present in a double-stranded form. Finally, we classified four lytic and seven persistent MV strains on the basis of their sequences. Surprisingly, the four lytic viruses considered belong to the same class. The persistent viruses form more loosely defined groups, which all differ from the vaccine strain Edmonston.

Amino Acid Sequence↗
PubMed1991

Characterization of persistent poliovirus mutants selected in human neuroblastoma cells.

Six Sabin-derived persistent poliovirus mutants were selected in human neuroblastoma IMR-32 cells. The mutants had a titer 30 to 10(5) times lower in nonneural HEp-2c cells than in IMR-32 cells. When the growth cycles of persistent viruses in the two cell lines were compared, the most striking feature was a delay of 2 to 4 hr in virus release from HEp-2c cells. In Hep-2c cells, type 1 mutants could spontaneously establish a persistent infection in the absence of any exogenous viral inhibitor. Mutations at a rate of 1 every 210 nucleotides had accumulated in the genome of the type 1 mutants selected in neuroblastoma cells, modifying cell specificity and conferring the ability to persist in some nonneural cells. These results indicate that mutants of poliovirus with highly modified biological properties can be selected in vitro in cells of neural origin.

Blotting, Northern↗
PubMed1985

Visual cortical correlates of visible persistence.

In order to evaluate their possible role in visible persistence, cortical cells from area 17 of the cat were investigated with a stationary light bar flashed for different durations. Thirteen out of 72 cells with non-overlapping On and Off subregions were able to respond to the briefest On stimulus (12.5 msec) for low and moderate contrasts. The responses of these cells outlasted brief On stimuli and this neural persistence increased as the On duration was shortened, mimicking the inverse duration effect of visible persistence. The 30 cells with overlapping On and Off subregions were all able to respond to brief stimuli but their neural persistence was independent of stimulus duration. At very high contrast levels, the inverse duration effect, observed in cells with non-overlapping subregions, disappeared since the On responses were followed by Off rebound discharges regardless of stimulus duration. It is suggested that the latter responses are a possible cortical equivalent of positive afterimages.

Afterimage↗
PubMed1990

The visible persistence of stimuli in stroboscopic motion.

This paper reports an improved paradigm to measure visible persistence. The stimulus is a pair of lines stroboscopically displayed in successive positions moving in opposite directions. The subjects' judgement of simultaneous appearance of all the presented lines is used to estimate visible persistence. This paradigm permitted independent manipulation of spatial and temporal stimulus separations in linear motion. The resulting estimates of visible persistence increase with spatial separation up to 0.24 deg of visual angle and approaches a maximum value at larger spatial separations. The results are consistent with the existence of a hypothetical visual gain mechanism that operates over small retinal distances to effectively decrease persistence duration with decreasing spatial separation.

Afterimage↗