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Biomedical subjects

I Winkler

Publications and source records attributed to I Winkler.

At least 55 records · Page 3Linked to original sources
PubMed1997

Characterization of the genome of feline foamy virus and its proteins shows distinct features different from those of primate spumaviruses.

The genome of the feline foamy virus (FeFV) isolate FUV was characterized by molecular cloning and nucleotide sequence analysis of subgenomic proviral DNA. The overall genetic organization of FeFV and protein sequence comparisons of different FeFV genes with their counterparts from other known foamy viruses confirm that FeFV is a complex foamy virus. However, significant differences exist when FeFV is compared with primate foamy viruses. The FeFV Gag protein is smaller than that of the primate spumaviruses, mainly due to additional MA/CA sequences characteristic of the primate viruses only. Gag protein sequence motifs of the NC domain of primate foamy viruses assumed to be involved in genome encapsidation are not conserved in FeFV. FeFV Gag and Pol proteins were detected with monospecific antisera directed against Gag and Pol domains of the human foamy virus and with antisera from naturally infected cats. Proteolytic processing of the FeFV Gag precursor was incomplete, whereas more efficient proteolytic cleavage of the pre125Pro-Pol protein was observed. The active center of the FeFV protease contains a Gln that replaces an invariant Gly residue at this position in other retroviral proteases. Functional studies on FeFV gene expression directed by the promoter of the long terminal repeat showed that FeFV gene expression was strongly activated by the Bell/Tas transactivator protein. The FeFV Bell/Tas transactivator is about one-third smaller than its counterpart of primate spumaviruses. This difference is also reflected by a limited sequence similarity and only a moderate conservation of structural motifs of the different foamy virus transactivators analyzed.

Amino Acid Sequence↗
PubMed1996

Adaptive modeling of the unattended acoustic environment reflected in the mismatch negativity event-related potential.

The mismatch negativity (MMN) event-related potential is elicited by changes in repetitive auditory stimuli. The present paper suggests that: (1) an acoustic model of the auditory environment is maintained even in the absence of attention focussed on auditory stimuli, preattentively detecting repetitive features of the acoustic stimulation; and (2) the MMN reflects modifications to existing parts of this model during incorporation of a new stimulus into the model. MMN responses were investigated during the period when a repetitive stimulus (standard) was replaced by a new standard sound. It was found that whereas the new standard stimulus stopped eliciting an MMN after its third presentation with respect to the old standard, a probe stimulus, differing from both standards, elicited an MMN with respect to the old standard, even when following four presentations of the new standard. The probe stimulus also elicited an MMN with respect to the new standard after four or more presentations of this new standard stimulus, thus eliciting two consecutive MMNs. The comparison (conducted on the basis of the present and some previous findings) of the present hypothesis with alternative explanations of MMN based on the presence and strength of auditory transient memory traces supported the model adjustment hypothesis.

Acoustic Stimulation↗
PubMed1996

Preattentive auditory change detection relies on unitary sensory memory representations.

Event-Related potentials (ERPs) were recorded to series of frequent (standard) and three types of rare (deviant) tones differing from the standard in frequency, duration, or in both features. All deviants elicited the mismatch negativity (MMN) ERP component, indexing the deviation of a sound from the transient auditory memory trace of the standard. Duration deviance could be detected only after the offset of the duration deviant delaying the MMN to this deviant by 70 ms compared with the MMN of the frequency deviant. The MMN to the double deviant extended only to the latency range of the frequency MMN, revealing that feature-MMNs were coordinated by a memory trace integrating the outcome of the various feature analysers.

Acoustic Stimulation↗
PubMed1996

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4- dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTI-binding pocket, and five of six strains displayed the RT G190-->E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190-->Q) most likely evolved from preexisting G190-->E mutants. The negative charge introduced by the G190-->E substitution was maintained at that site of the pocket by simultaneous selection for V179-->D together with G190-->Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74-->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNA-binding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of HIV-1 infection has yet to be determined.

Antiviral Agents↗
PubMed1996

Characterization of the spliced pol transcript of feline foamy virus: the splice acceptor site of the pol transcript is located in gag of foamy viruses.

Foamy viruses, or spumaviruses, are distinct members of the Retroviridae. Here we have characterized the long terminal repeat of the feline, or cat, foamy virus by determining the locations of the transcriptional start site and the poly(A) addition site. The splice donor and splice acceptor sites of the subgenomic mRNA responsible for Pro-Pol protein expression were identified by nucleotide sequencing of the corresponding cDNAs. The leader exon of the feline foamy virus is 57 nucleotides long. The splice acceptor of the subgenomic pol mRNA was found to be located in gag. The location of the splice acceptor of the human foamy virus pol mRNA was confirmed to map in gag. The pol splice acceptor site in gag of the cat foamy virus is located further downstream than that of human foamy virus.

Animals↗
PubMed1995

From objective to subjective: pitch representation in the human auditory cortex.

Magnetic brain responses to infrequent changes in the pitch of complex sounds were recorded. The composition of the test sounds required that pitch-deviant stimuli elicited the mismatch response only if perceived pitch was represented in auditory sensory memory. Results revealed that subjective features, such as pitch, are formed from objective stimulus parameters (i.e. the spectral contents of a sound) before storing acoustic information in memory. The origin of the magnetic response to pitch change showed that pitch deviation was detected in the auditory cortex. Pitch memory might also be located in the auditory cortex, as previous evidence suggests that storage for an auditory feature lies in the vicinity of the neuronal elements activated by deviations in that feature.

Acoustic Stimulation↗
PubMed1995

Presentation rate and magnitude of stimulus deviance effects on human pre-attentive change detection.

The present study investigated the effects of the inter-stimulus interval (ISI) and the magnitude of deviance on the mismatch negativity (MMN), an event-related potential index of pre-attentive change detection. The latency of the MMN to infrequent changes in intensity and duration was prolonged by increasing the ISI from 400 ms to 4 s. Results indicate that these features are preserved in sensory memory for several seconds. By increasing the ISI the sharpness of the neural traces decreases, thus prolonging the change detection process.

Acoustic Stimulation↗
PubMed1995

Neural representation for the temporal structure of sound patterns.

Responses to infrequently exchanging two segments of a complex tonal pattern were tested for the presence of the mismatch negativity event-related brain potential component. This component is elicited when an auditory stimulus differs from the sensory memory trace of the previously presented repetitive sound. Because the segments exchanged in the tonal pattern differed from each other only in their durations, the elicitation of the mismatch response revealed that the temporal structure of sound patterns is encoded in the traces underlying the mismatch process. Results showing that the mismatch response was elicited even when the tonal patterns were presented continuously (i.e. without silent intervals separating successive patterns) demonstrate the automatic detection of periodicity in the acoustic stream.

Adult↗
PubMed1995

Correlation dimension changes accompanying the occurrence of the mismatch negativity and the P3 event-related potential component.

The aim of this study was to apply recently developed mathematical tools of chaos theory to the analysis of event-related potentials (ERPs) recorded in paradigms in which the mismatch negativity (MMN) and the P3 component appeared. A new method, the point correlation dimension (PD2i), was used for data analysis, which is more accurate than other algorithms for the calculation of the correlation dimension (D2), which latter is a measure of the complexity of the generator(s) responsible for producing the analyzed time series, i.e., the EEG. ERPs were recorded from Fz, Cz and Pz in 6 subjects. With respect to baseline, the PD2i decreased significantly both during the event-related potentials in which the MMN and also in which the P3 was present, but the pattern and magnitude of this decrease was different between these two situations. The pattern of PD2i changes during the occurrence of deviant stimuli eliciting the MMN suggests the presence of a frontal MMN generator. The conspicuous PD2i decrease during the occurrence of the P3 wave may support the "context closure" hypothesis concerning its functional significance.

Acoustic Stimulation↗
PubMed1995

In vivo antiherpesvirus activity of N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.

The efficacy of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) was evaluated in several animal models for herpesvirus infections. Compound S2242 was more effective than acyclovir (i) when administered subcutaneously in a model for herpes simplex virus type 1 (HSV-1)-induced mortality in immunocompetent mice and (ii) when applied topically to hairless (hr/hr) mice that had been infected intracutaneously with HSV-2. In SCID (severe combined immune deficient) mice that had been infected with a thymidine kinase-deficient HSV-1 strain, S2242 (administered subcutaneously at a dosage of 50 mg/kg/day) completely protected against virus-induced mortality whereas foscarnet was less effective and acyclovir had no or little protective effect. Compound S2242 was far more effective than ganciclovir in preventing or delaying murine cytomegalovirus-induced mortality in immunocompetent and SCID mice. The compound was more effective when a given dose was fractionated and administered on subsequent days than when this dose was administered in one single injection. A 5-day treatment course with S2242 (10 and 50 mg/kg/day) for newborn mice that had been infected with a lethal dose of murine cytomegalovirus suppressed virus-induced mortality. Compound S2242 had no inhibitory effect on the growth of weanling (at 50 mg/kg for 5 days) and 3- to 4-week-old mice (at doses of 50 to 200 mg/kg for 6 weeks). However, akin to ganciclovir, compound S2242 significantly reduced testicle weight, testicle morphology, and spermatogenesis.

Acyclovir↗
PubMed1995

Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.

Compound 2242, also known as 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, is the first known antivirally active nucleoside analog with the side chain substituted at the N-7 position of the purine ring system. Our purpose was to evaluate its retinal toxicity and assess the efficacy of its highest nontoxic concentration in a rabbit model of herpes simplex retinitis. Concentrations of the drug from 0.5 to 2,000 microM were injected intravitreally in twelve New Zealand White rabbits. Fundoscopic, histologic, and electrophysiologic data revealed no evidence of toxicity even at the highest dose of the compound. Dutch pigmented rabbits (n = 34) had their left eyes injected with herpes simplex virus type 1 3 days after, concurrently, or 3 days before intravitreal injection of either 2,000 microM compound 2242 or 480 microM ganciclovir (final concentration in the eye). Both compound 2242 and ganciclovir were equally effective compared with saline when administered simultaneously with the virus (P < 0.0001). In the 3-day pretreatment paradigm, compound 2242 was superior to ganciclovir (P < 0.04), but there was no clear difference between the two with regard to their effects on an established infection. The pharmacokinetics of compound 2242 in 10 rabbits injected intravitreally with 30 microM showed an intravitreal half-life of 8 h. This compound, which may be orally active in its pro form, has a very high therapeutic index in the eye and is more efficient than ganciclovir in this animal model of herpes retinitis.

Administration, Oral↗
PubMed1994

The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication.

2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 microgram/ml), varicella-zoster virus (EC50, 0.01 to 0.02 microgram/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 microgram/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 microgram/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 microgram/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 microgram/ml), and human herpesvirus 6 (EC50, 0.0005 microgram/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 micrograms/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM degrees. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK. Compound S2242 inhibited (i) the expression of late HCHV antigens at an EC50 of 0.07 microgram/ml (0.6 microgram/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 microgram/ml (0.32 microgram/ml for ganciclovir), i.e., values that are close to the EC50S for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.

Animals↗
PubMed1993

Memory prerequisites of mismatch negativity in the auditory event-related potential (ERP).

The mismatch negativity (MMN) is a component of the auditory event-related brain potential that occurs in response to infrequent changes in the physical properties of homogeneous series of sounds, even when subjects are instructed to ignore the auditory channel of stimulation. It has been proposed (e.g., Näätänen, 1990) that the MMN is generated by an automatic process in which a difference between the deviant sound and the previous, standard sound is detected by the brain. However, it is unclear how the form of memory involved is related to the rest of the memory system. The present study indicates that, for an MMN to be elicited in response to a change in tone frequency, the representation of the standard tone must be both (a) well-established as a standard in memory, and (b) in a currently active state. The relation between physiological and psychological aspects of memory representation is discussed.

Acoustic Stimulation↗
PubMed1993

Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication.

S-2720 [6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4- dihydroquinoxalin-2(1H)-thione], a quinoxaline derivative, was found to be a very potent inhibitor of both human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) activity and HIV-1 replication in tissue culture. Like other nonnucleoside RT inhibitors, S-2720 does not affect the HIV-2 RT. A S-2720-resistant virus was selected and shown to possess a mutation within the RT-coding region that has not previously been described. Notably, this mutation gives rise to a dramatic decrease in enzyme activity. S-2720, therefore, belongs to a new class of RT inhibitors that bind differently to the RT than other known nonnucleoside RT inhibitors. As no toxic effects were observed with S-2720 in mice, these quinoxaline derivatives deserve further evaluation to prove their potency as possible therapeutic agents for HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Event-related brain potentials reflect traces of echoic memory in humans.

In sequences of identical auditory stimuli, infrequent deviant stimuli elicit an event-related brain potential component called mismatch negativity (MMN). MMN is presumed to reflect the existence of a memory trace of the frequent stimulus at the moment of presentation of the infrequent stimulus. This hypothesis was tested by applying the recognition-masking paradigm of cognitive psychology. In this paradigm, a masking sound presented shortly before or after a test stimulus diminishes the recognition memory of this stimulus, the more so the shorter the interval between the test and masking stimuli. This interval was varied in the present study. It was found that the MMN amplitude strongly correlated with the subject's ability to discriminate between frequent and infrequent stimuli. This result strongly suggests that MMN provides a measure for a trace of sensory memory, and further, that with MMN, this memory can be studied without performance-related distortions.

Adolescent↗
PubMed1992

Event-related potentials in auditory backward recognition masking: a new way to study the neurophysiological basis of sensory memory in humans.

Task-irrelevant pairs of short tones were presented to healthy human subjects while electric potentials were recorded from their scalp ('event-related brain potential', ERP). Infrequent increments in the frequency of the first tone of the repetitive tone-pair elicited an extra ERP component termed 'mismatch negativity' (MMN) when the silent interval between the first and second tone of the pair ('inter-tone interval') was long (150, 300, or 400 ms) but not when this interval was short (20 or 50 ms). This effect did not depend on whether the two tones of the tone-pair were presented to the same or to different ears. The present inter-tone interval effect is consistent with the effects of backward-masking on recognition performance in audition, suggesting that the MMN reflects the neurophysiological basis of echoic memory.

Adult↗
PubMed1992

Secondary metabolites by chemical screening. 17. Nigericinol derivatives: synthesis, biological activities, and modeling studies.

The synthesis and the biological activity of C-1-reduced nigericin derivatives (nigericinols) are described and discussed. The dichloronigericinol 7 impressively demonstrated that the C-1 carboxylic acid moiety was not required for a distinct activity against bacteria and viruses. Based on the correlation between K+/H+ antiport activities and antibacterial activities it was deduced that the mode of action of the described nigericinols are related to their ionophoric properties. Molecular modeling studies showed that the efficiency of the nigericinols as ionophores correlates, qualitatively, with the probability of forming a cyclic structure, with the exception of 7.

Anti-Bacterial Agents↗