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PubMed1990

Delay-dependent impairment of reversal learning in rats treated with trimethyltin.

Recent theories of hippocampal function focus on its role in the formation of associations in the temporal domain. A reversal learning paradigm based on leverpress automaintenance was developed to vary the CS-US relationship along two independent dimensions, one temporal and one not: CS(+)-US delay and the probability of reinforcement [P(RFT)] following the CS+. Eight male hooded Long-Evans rats were trained to reverse these automaintained discriminations repeatedly, until stable performance was achieved. The neurotoxicant trimethyltin (TMT) was used to induce lesions in the CNS, including the CA3-4 region of Ammon's Horn in dorsal hippocampus. Following iv injection of 7 mg/kg TMT to half the rats, reversal learning was assessed under varying conditions of delay and P(RFT). After recovery from the acute effects of TMT (1-2 weeks), treated rats reversed normally when no delay separated the CS+ and US; with delays of 2 to 4 s, they reversed less completely within a session than did controls. Changing P(RFT) did not affect reversal learning in either group, but reduced response rates similarly in both groups. Morphological damage was quantified by measuring the length of the remaining pyramidal cell line in sections of dorsal hippocampus. The degree of behavioral impairment correlated significantly with hippocampal damage only at nonzero CS(+)-US delays. These results indicate that TMT impaired ability of rats to integrate temporal relationships between stimulus events, and are consistent with theories of hippocampal mediation of temporal associations.

Animals↗
PubMed2004

NMDA lesions in the medial prefrontal cortex impair the ability to inhibit responses during reversal of a simple spatial discrimination.

Although lesion studies suggest that the rat medial prefrontal cortex (mPFc) is involved in the process necessary for reversal of a particular set of contingencies, the nature of lesion-induced deficits is unclear. The involvement of rat mPFc in reversal of a simple spatial discrimination was examined in the present study. Our hypothesis was that lesion-induced deficits may reflect a failure to inhibit a learned instrumental response. Lister Hooded rats were trained on a spatial discrimination task (SD), which required a correct barpress matching the cue location, then they were trained on reversal of SD (SDR), which required a correct barpress opposite to the cue location. Rats with mPFc lesions showed a slower learning rate compared to the controls. However, behavior of the lesioned rats during early and later reversal differed. During the initial SDR, the lesioned rats showed a greater number of barpresses during the intertrial interval and a slightly higher percent correct responses than that of the controls. Our data suggest that damage to mPFc may produce a lack of response inhibition, leading to an increase in nondiscriminated bapresses, thereby yielding a 'facilitation' during early reversal. mPFc lesion did not affect either open field activity or prepulse inhibition (PPI), a frequently used measure of sensorimotor gating. Disruption of reversal learning following damage to mPFc is partly due to a failure to inhibit instrumental responses, rather than to disruption of other processes involved in sensorimotor gating or general activity.

Analysis of Variance↗
PubMed2006

Reversal learning in Parkinson's disease depends on medication status and outcome valence.

We investigated the role of dopamine in distinct forms of reversal shifting by comparing two groups of patients with mild Parkinson's disease (PD), one ON and one OFF their normal dopaminergic medication. In accordance with our previous work, patients ON medication exhibited impaired reversal shifting relative to patients OFF medication. The present results extend previous studies by showing that the medication-induced deficit on reversal shifting was restricted to conditions where reversals were signaled by unexpected punishment. By contrast, patients ON medication performed as well as patients OFF medication and controls when the reversal was signaled by unexpected reward. The medication-induced deficit was particularly pronounced in patients on the dopamine D3 receptor agonist pramipexole. These data indicate that dopaminergic medication in PD impairs reversal shifting depending on the motivational valence of unexpected outcomes.

Aged↗
PubMed1984

Characteristics of women requesting reversal of sterilization.

For a definition of the characteristics of women who request reversal of sterilization, 180 such women were compared with 180 women apparently satisfied with sterilization. Women who requested tubal reversal were younger at the time of sterilization, began and completed their families at an earlier age, and were of lower socioeconomic status than those who did not request reversal of sterilization. Women requesting reversal of sterilization had a significantly higher incidence of gynecologic clinic visits after and mental health clinic visits before and after sterilization. Thirty-five women requesting reversal of sterilization were compared with 35 control women by administration of the Minnesota Multiphasic Personality Inventory (MMPI). Higher MMPI scores on the hysteria and psychasthenia scales were noted in women requesting tubal reversal.

Adult↗
PubMed1997

A report on 387 cases of microsurgical tubal reversals.

OBJECTIVE: To survey what factors influence the pregnancy outcome in an effort to improve the pregnancy rate (PR) after microsurgical reversal of tubal sterilization. DESIGN: Retrospective clinical study. PATIENT(S): Three hundred eighty-seven patients who had microsurgical tubal reversal between March 1982 and January 1994. INTERVENTION(S): Postoperative pregnancy outcomes were determined by telephone, letters, and direct interviews. RESULT(S): Pregnancy outcomes were identified in 94.1% of the total patients. The overall PR was 91.6%, of which 3.9% spontaneously aborted and 1.7% were ectopic. The probability that pregnancy occurred within the first 12 months was 0.80. The median interval from the tubal reversal to pregnancy was 5.34 months. The pregnancy success rate after reversal of Falope ring sterilization was statistically significantly higher than in the other groups. Patients with reversed tubal length > or = 7 cm had a statistically significantly higher PR than those with < 7 cm. CONCLUSION(S): The overall probability of pregnancy was 0.89. The tubal length reconstructed after tubal reversal and the type of sterilization performed previously were the important factors affecting the PR.

Adult↗
PubMed2001

Inhibition of human immunodeficiency virus type 1 reverse transcriptase, protease and integrase by bovine milk proteins.

Different proteins have been isolated from bovine milk including lactoferrin, lactoperoxidase, glycolactin, angiogenin-1, lactogenin, alpha-lactalbumin, lactoglobulin and casein. These proteins have been assayed for inhibitory activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, protease and integrase, enzymes crucial to the HIV-1 life cycle. It was found that different milk proteins inhibited the three aforementioned HIV enzymes to different extents. Lactoferrin strongly inhibited HIV-1 reverse transcriptase but only slightly inhibited HIV-1 protease and integrase. On the other hand, alpha-lactalbumin, beta-lactoglobulin and casein inhibited HIV-1 protease and integrase to an appreciable extent but did not inhibit HIV-1 reverse transcriptase. Glycolactin and angiogenin-1 suppressed the activity of HIV-1 reverse transcriptase by a moderate extent but more powerfully inhibited HIV-1 protease and integrase. In comparison with the other milk proteins glycolactin was a strong inhibitor of HIV-1 protease and integrase and a moderate inhibitor of HIV-1 reverse transcriptase. Lactogenin was a strong inhibitor of HIV-1 integrase, a moderate inhibitor of HIV-1 reverse transcriptase and a weak inhibitor of HIV-1 protease.

Animals↗
PubMed2000

Probabilistic learning and reversal deficits in patients with Parkinson's disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication.

Three groups of patients with Parkinson's disease (PD) - mild, unmedicated (UPD), mild, medicated (MPD) and severe, medicated (SPD) - and patients with lesions of the frontal lobe (FLL) or temporal lobe (TLL) were compared with matched controls on the learning and reversal of probabilistic and two-pair concurrent colour discriminations. Both of the cortical lesion groups showed reversal deficits, with no increase in perseverative responding. The UPD group, although impaired on a spatial recognition task, showed intact discrimination learning and reversal; the MPD and SPD patients showed non-perseverative reversal impairments on both reversal tasks. Two hypotheses - based on disease severity and possible deleterious effects of medication - are offered to explain the reversal impairments of the PD patients and the results are discussed in terms of the role of dopamine in reward-based learning.

Adult↗
PubMed2000

Reversal learning deficit in a spatial task but not in a cued one after telencephalic ablation in goldfish.

The fish telencephalon seems to be involved in spatial learning and memory in a similar manner to the hippocampus of the land vertebrates. For instance, telencephalon ablated goldfish are impaired in the post-operative retention of a 'spatial constancy' task, which requires the use of mapping strategies, but not in a directly cued task in which responses are based in a guidance strategy. In this regard, previous experiments showed that intact goldfish trained in the spatial constancy task presented considerable behavioral flexibility, as they showed fast reversal learning, that is, they required less training compared with animals trained in the directly cued task and made a lower number of errors to master the reversal than in acquisition. The purpose of the present work was to investigate if the goldfish telencephalon is involved in the faster reversal learning of the animals trained in the spatial constancy task. Goldfish with bilateral telencephalic ablation, sham operated or intact, were trained in the spatial constancy task or in the directly cued task. Telencephalic ablation selectively impaired reversal learning in the animals trained in the spatial constancy procedure. Ablated animals in this procedure reversed more slowly than control animals. By contrast, telencephalic ablation did not produce any significant deficit during reversal in the animals trained in the directly cued task. These results provide additional evidence that the fish telencephalon, as the land vertebrate hippocampus, plays a crucial role in the use of flexible spatial representations.

Animals↗
PubMed1999

The effect of template RNA structure on elongation by HIV-1 reverse transcriptase.

Reverse transcription of the RNA genome of retroviruses has to proceed through some highly structured regions of the template. The RNA genome of the human immunodeficiency virus type 1 (HIV-1) contains two hairpin structures within the repeat (R) region at the 5' end of the viral RNA (Fig. 1Fig. 1Template RNA structure of the HIV-1 R region and the position of reverse transcription pause sites. The HIV-1 R region (nucleotides +1/97) encodes two stable RNA structures, the TAR and polyA hairpins [5]. The latter hairpin contains the AAUAAA hexamer motif (marked by a box) that is involved in polyadenylation. The lower panel shows the predicted structures of the wild-type and two mutant forms of the polyA hairpin that were used in this study. Nucleotide substitutions are boxed, deletions are indicated by black triangle. The thermodynamic stability (free energy or DeltaG, in kcal/mol) was calculated according to the Zucker algorithm [71]. The TAR hairpin has a DeltaG of -24.8 kcal/mol. Minus-strand DNA synthesis on these templates was initiated by a DNA primer annealed to the downstream PBS. The position of reverse transcription pause sites observed in this study are summarized. All numbers refer to nucleotide positions on the wild-type HIV-1 transcript. Filled arrows represent stops observed on the wild-type template, and open arrows mark the pause sites that are specific for the structured A-mutant template. The sizes of the arrows correspond to the relative frequency of pausing. Little pausing was observed on the B-mutant template with the destabilized polyA hairpin.). These structures, the TAR and polyA hairpins, fulfil important functions in the viral life cycle. We analyzed the in vitro elongation properties of the HIV-1 reverse transcriptase (RT) enzyme on the wild-type RNA template and mutants thereof with either a stabilized or a destabilized polyA hairpin. Stable RNA structure was found to interfere with efficient elongation of the RT enzyme, as judged by the appearance of pause cDNA products. A direct relation was measured between the stability of template RNA structure and the extent of RT pausing. However, the position of structure-induced pause sites is rather diverse, with significant stops at a position approximately 6 nt ahead of the basepaired stem of the TAR and polyA hairpins. This suggests that the RT enzyme is stalled when its most forward domain contacts the RNA duplex. Addition of the viral nucleocapsid protein (NC) to the in vitro assay was found to overcome such structure-induced RT stops. These results indicate that the RT polymerase has problems penetrating regions of the template with stable RNA structure. This effect was more pronounced at high Mg2+ concentrations, which is known to stabilize RNA secondary structure. Such a structure-induced defect was not apparent in reverse transcription assays performed in virus-infected cells, which is either caused by the NC protein or other components of the virion particle. Thus, retroviruses can use relatively stable RNA structures to control different steps in the viral life cycle without interfering with the process of reverse transcription.

Base Sequence↗
PubMed2003

Replication at the level of reverse transcription of HIV-1SF2 strain in Th1 and Th2 cells.

It has been reported that Th2 cells better support replication of T-tropic HIV-1 strain than Th1 cells. We investigated at the level of reverse transcription the replication of T-tropic HIV-1SF2 strain in Th1 and Th2 cells. To determine the presence of the early (RU5), intermediate (gag) and full-length (LTR/gag) product of reverse transcription of virus RNA in Th1 and Th2 cells, we employed the PCR technique. Our results revealed that the early (RU5) product of reverse transcription was detectable 30 min after infection in Th2 cells and 1 h after infection in Th1 cells. The product of reverse transcription corresponding to the gag region of HIV-1 was detected in Th2 cells 2 h after infection, whereas the same fragment of viral DNA in Th1 cells was observed 4 h later. The full-length viral DNA was seen in Th2 cells 6 h after infection but the same time course was not detected in the Th1 cells. We also observed that higher efficiency of reverse transcription of viral RNA correlated with better replication of HIV-1SF2 in Th2 than Th1 cells. The higher concentration of p24 HIV-1 antigen in culture medium than cytoplasm of Th1 and Th2 cells confirmed the lack of restriction at the budding step of HIV-1SF2 replication in Th1 and Th2 cells. Our observation may confirm the suggestion that Th0/Th2 cell orientation supports at the reverse transcriptional level the replication of T-tropic HIV-1 strains, which accelerates the onset of AIDS symptoms.

Adult↗
PubMed1990

Differential inhibitory effects of some catechin derivatives on the activities of human immunodeficiency virus reverse transcriptase and cellular deoxyribonucleic and ribonucleic acid polymerases.

The two components of Camellia sinensis (tea plant) [i.e., (-)-epicatechin gallate and (-)-epigallocatechin gallate] were found to differentially inhibit the activities of reverse transcriptase and cellular DNA and RNA polymerases. Under the assay conditions optimized for each enzyme species, the strongest inhibition by these compounds was observed with reverse transcriptase. The concentrations of (-)-epicatechin gallate and (-)-epigallocatechin gallate required for 50% inhibition of the activity of human immunodeficiency virus (HIV) reverse transcriptase were in the range of 0.01-0.02 microgram/mL. On the other hand, neither (-)-epicatechin, (-)-epigallocatechin, nor gallic acid, the constituents of (-)-epicatechin gallate and (-)-epigallocatechin gallate, was inhibitory to the activity of HIV reverse transcriptase at concentrations up to 1 microgram/mL. The mode of inhibition of reverse transcriptase and other DNA polymerases by these compounds was competitive with respect to the template-primer, whereas the mode of inhibition of RNA polymerase was competitive with respect to the nucleotide substrate. The Ki values of HIV reverse transcriptase for (-)-epicatechin gallate and (-)-epigallocatechin gallate were determined to be 7.2 and 2.8 nM, respectively, which are smaller by 1-2 orders of magnitude than the Ki's of other DNA and RNA polymerases for these compounds.

Animals↗
PubMed2005

Insight into the mechanism of a peptide inhibitor of HIV reverse transcriptase dimerization.

The biologically active forms of human immunodeficiency viruses type 1 and 2 reverse transcriptase (RT) found in infectious virions are heterodimers. We have previously shown that the dimeric nature of reverse transcriptase represents an important target for the design of a new class of antiviral agents and have designed a short peptide (Pep-7) derived from the tryptophan-rich motif of the connection subdomain that blocks dimerization of reverse transcriptase in vitro and abolishes viral infection. In the present work, we have investigated the mechanism through which this peptide inhibits RT dimerization and consequently viral propagation. We demonstrate that Pep-7 interacts preferentially with the p51 subunit within the heterodimeric reverse transcriptase, which destabilizes reverse transcriptase dimer conformation, thereby triggering dissociation. We have identified two residues Trp(24) and Phe(61), located on the fingers subdomain of p51, required for Pep-7 binding. Selective mutation of these residues on p51 to a glycine dramatically alters the stability of the RT-heterodimer suggesting that the fingers subdomain of p51 is also involved in stabilization of reverse transcriptase. We propose that the binding site of Pep-7 is located in a cleft between the fingers and the connection subdomains of p51 that contains the two highly conserved residues Phe(61) and Trp(24).

Amino Acid Motifs↗
PubMed2001

Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations.

The structure and the conformational behavior of the HIV-1 reverse transcriptase inhibitor, 11-cyclopropyl-5,11dihydro-4-methyl-6H-dipyrido[3,2-b2',3'-e][1,4]diazepin-6-one (nevirapine), is investigated by semiempirical (MNDO, AMI and PM3) method, ab initio at the HF/3-21G and HF/6-31G** levels and density functional theory at the B3LYP/6-31G** level. The fully optimized structure and rotational potential of the nitrogen and carbon bond in the cyclopropyl ring were examined in detail. A similar geometrical minimum is obtained from all methods which shows an almost identical structure to the geometry of the molecule in the complex structure with HIV-1 reverse transcriptase. To get some information on the structure in solution, NMR chemical shift calculations were also performed by a density functional theory at the B3LYP/6-31G** level, using GIAO approximation. The calculated 1H-NMR and 13C-NMR spectra for the energy minimum geometry agree well with the experimental results, which indicated that the geometry of nevirapine in solution is very similar to that of the molecule in the inhibition complex. Furthermore, the obtained results are compared to the conformational studies of other non-nucleoside reverse transcriptase inhibitors and reveal a common agreement of the non-nucleoside reverse transcriptase inhibitors. The specific butterfly-like shape and conformational flexibility within the side chain of the non-nucleoside reverse transcriptase inhibitors play an important role inducing conformational change of HIV-1 reverse transcriptase structure and are essential for the association at the inhibition pocket.

Anti-HIV Agents↗
PubMed1983

Attenuation of reversal deficits of mice with septal lesions by shifts in the motivational context.

Response perseveration following septal lesions, demonstrated on tasks that require change of a learned pattern of responding, depends in part on a relatively constant motivational context. The present experiment examined the effects of concurrent changes in the temperature of the water in a water-escape maze and the reversal of a spatial discrimination in mice that had received either septal lesions or control surgery. Control and experimental mice were trained on a spatial discrimination in either 17 or 34 degrees C water. Following acquisition, reversal training was conducted in the maze filled with the same-temperature water used during acquisition or water temperature as well as spatial reinforcement contingencies were reversed. When the water temperature remained constant across acquisition and reversal, the mice with septal lesions showed persistence during reversal training. Changing the water temperature concurrently with the institution of reversal training attenuated the perseverative deficits of mice with lesions, in contrast to the relative lack of effect in control animals. These results are discussed within the framework of the role that the septal region plays in attention.

Animals↗
PubMed1980

Cingulate cortical and anterior thalamic neuronal correlates of reversal learning in rabbits.

Unit activity of the cingulate cortex and the anteroventral (AV) nucleus of the thalamus in rabbits was recorded during reversal training following differential conditioning of a locomotory (wheel rotation) avoidance response. The positive and negative conditional stimuli (CS+ and CS-) were pure tones (1 kHz and 8 kHz), and the unconditional stimulus was footshock (1.5 mA). During the first session, activity appropriate to the original task (i.e., a greater neuronal response to the CS- than to the CS+) occurred in the deep cortical laminae (V and VI), but the superficial laminae (I-IV) manifested the original discrimination in certain records and the reverse discrimination in others. All discriminative effects diminished during subsequent sessions except the short-latency (25-msec) deep laminar original discrimination, which persisted throughout reversal training. Activity of the AV nucleus underwent gradual transition, in parallel with the behavior, from the original to the reverse discrimination. Arousal-producing footshocks given after behavioral reversal educed the original and reverse discriminations in the deep and superficial laminae, respectively. These data are interpreted to indicate the role of cingulate cortex and anterior thalamus for encoding the associative significance of the conditional stimuli.

Animals↗
PubMed2001

Examination of lectins, polysaccharopeptide, polysaccharide, alkaloid, coumarin and trypsin inhibitors for inhibitory activity against human immunodeficiency virus reverse transcriptase and glycohydrolases.

A variety of lectins were tested in vitro for inhibitory action against the activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the N-glycohydrolases (alpha-glucosidase, beta-glucosidase and beta-glucuronidase). Lectins from Phaseolus vulgaris, Momordica charantia, Ricinus communis and its constituent chains, and Agaricus bisporus were able to inhibit HIV-1 reverse transcriptase. P. vulgaris lectin and A. bisporus lectin were the most potent. The aforementioned lectins had only weak or no inhibitory effects on the glycohydrolases. The inhibitory effect of polysaccharopeptide from the mushroom Coriolus versicolor on HIV-1 reverse transcriptase and alpha-glucosidase was enhanced after chemical modification with chlorosulfonic acid. However, the inhibitory effect of the algal polysaccharide fucoidan on HIV-1 reverse transcriptase and alpha-glucosidase was not augmented by sulfation. Trypsin inhibitors from Phaseolus lunatus and Glycine max, gossypol and alkaloids from Corydalis yanhusuo were able to inhibit HIV-1 reverse transcriptase. Dicoumarol was capable of inhibiting HIV-1 reverse transcriptase, alpha-glucosidase, beta-glucosidase and beta-glucuronidase.

Alkaloids↗
PubMed2000

In vitro studies on tRNA annealing and reverse transcription with mutant HIV-1 RNA templates.

The human immunodeficiency virus type 1 (HIV-1) RNA genome encodes a semistable stem-loop structure, the U5-PBS hairpin, which occludes part of the tRNA primer binding site (PBS). In previous studies, we demonstrated that mutations that alter the stability of the U5-PBS hairpin inhibit virus replication. A reverse transcription defect was measured in assays with the virion-extracted RNA-tRNA complexes. We now extend these studies with in vitro synthesized wild-type and mutant RNA templates that were tested in primer annealing and reverse transcription assays. The effect of annealing temperature and the presence of the viral nucleocapsid protein on reverse transcription was analyzed for the templates with a stabilized or destabilized U5-PBS hairpin, and in reactions initiated by tRNA or DNA primers. The results of this in vitro assay are consistent with the in vivo findings, in that both tRNA annealing and initiation of reverse transcription are sensitive to stable template RNA structure. Reverse transcription initiated by a DNA primer is less hindered by secondary structure in the RNA template than tRNA primed reactions. The inhibitory effect of template structure on tRNA-primed reverse transcription is more pronounced in this in vitro assay compared with the in vivo material, indicating that the heat-annealed RNA-tRNA complex differs from the virion-extracted viral RNA-tRNA complex.

Base Sequence↗
PubMed2000

Inhibition of the initiation of HIV-1 reverse transcription by 3'-azido-3'-deoxythymidine. Comparison with elongation.

Initiation of human immunodeficiency virus-1 reverse transcription requires formation of a complex containing the viral RNA, primer tRNA(3)(Lys), and reverse transcriptase. Initiation, corresponding to addition of the first six nucleotides to tRNA(3)(Lys), is distinguished from elongation by its high specificity and low efficiency (processivity). Here, we compared the inhibition of initiation and elongation of reverse transcription by 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP), the active form of 3'-azido-3'-deoxythymidine. We report the first detailed study of nucleotide binding, discrimination, and pyrophosphorolysis by the authentic initiation complex. We showed that the initiation and elongation complexes bound AZTTP and dTTP with the same affinity, while the polymerization rates were reduced by 148-160-fold during initiation. The pyrophosphorolysis rate of dTTP was reduced by the same extent, indicating that the polymerization equilibrium is the same in the two phases. The efficient unblocking of the 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP)-terminated primer by pyrophosphorolysis significantly relieved inhibition of DNA synthesis during elongation in the presence of physiological pyrophosphate concentrations. Remarkably, although pyrophosphorolysis of dTMP and AZTMP were equally efficient during elongation, reverse transcriptase was almost totally unable to unblock the AZTMP-terminated primer during initiation. As a result, inhibition of reverse transcription by AZTTP was more efficient during initiation than elongation of reverse transcription, despite a reduced selectivity of incorporation.

Base Sequence↗