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S Buus

Publications and source records attributed to S Buus.

At least 91 records · Page 5Linked to original sources
PubMed1991

Psychometric functions for level discrimination.

To determine the form of psychometric functions for 2I,2AFC level discrimination (commonly called intensity discrimination), ten increment levels were presented in random order within blocks of 100 trials. Stimuli were chosen to encompass a wide range of conditions and difference limens: eight 10-ms tones had frequencies of 0.25, 1, 8, or 14 kHz and levels of 30, 60, or 90 dB SPL; two 500-ms stimuli also were tested: a 1-kHz tone at 90 dB SPL and broadband noise at 63 dB SPL. For each condition, at least 20 blocks were presented in mixed order. Results for five normal listeners show that the sensitivity, d', is nearly proportional to delta L (= 20 log [(p + delta p)/p], where p is sound pressure) over the entire range of difference limens. When d' is plotted against Weber fractions for sound pressure, delta p/p, or intensity, delta I/I, exponents of the best-fitting power functions decrease with increasing difference limens and are less than unity for large difference limens. The approximately proportional relation between d' and delta L agrees with modern multichannel models of level discrimination and with psychometric functions derived for single auditory-nerve fibers. The results also support the notion that the difference limen, expressed as delta LDL and plotted on a logarithmic scale, is an appropriate representation of performance in level-discrimination experiments.

Adult↗
PubMed1990

MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation.

Seven synthetic peptides corresponding to the polymorphic regions of the alpha and beta chains of the I-Ak molecule were examined for their ability to inhibit the presentation of foreign antigens to antigen-specific, I-A-restricted T cell hybridomas. Two of the peptides, representing the sequences found in the first and third polymorphic regions (PMR) of the A alpha k chain (alpha k-1 and alpha k-3) were capable of inhibiting the presentation of three different HEL-derived peptide antigens to their appropriate T cells. In addition, the alpha k-1 peptide inhibited the presentation of the OVA(323-339) immunodominant peptide to the I-Ad-restricted T cell hybridomas specific for it. Prepulsing experiments demonstrated that the PMR peptides were interacting with the APC and not with the T cell hybridomas. These observations were confirmed and extended by the demonstration that the alpha k-1 and alpha k-3 peptides blocked the direct binding of HEL(46-61) to purified I-Ak and that the alpha k-1 peptide blocked the binding of OVA(323-339) to I-Ad. The binding competition experiments suggest that the alpha k-1 peptide binds to the I-Ak molecule from which it was derived with a Kd approximately 10(-5) M, while the alpha k-3 peptide binds slightly less well. These combined data, suggesting that class II-derived peptides can bind to MHC class II molecules, including the autologous molecule from which they are derived, have important implications for the molecular basis of alloreactivity and autoreactivity. Further, they suggest a possible mechanism by which selecting elements, involving only MHC molecules, may be generated in the thymus.

Amino Acid Sequence↗
PubMed1990

Structural requirements for the interaction between class II MHC molecules and peptide antigens.

Previous work from our and other laboratories indicates that T cells recognize a complex between the MHC restriction element and peptide antigen fragments. This paper reviews the structural characteristics of the formation of such a complex. By analyzing in detail the interactions between purified IA(d) and IE(d) molecules and their peptide ligands, we found that some structural characteristics apply to both antigen-MHC interactions. In particular, we found: 1) each MHC molecule is capable of binding many unrelated peptides through the same peptide-binding site; 2) despite this permissiveness of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity (IA(d) or IE(d)); 3) IA(d) and IE(d) molecules recognize different and independent structures on the antigen molecule; 4) only about 10% of the single amino acid substitutions tested on two IA(d)- and IE(d)-binding peptides had significant effect on their MHC-binding capacities, while over 80% of these substitutions significantly impaired T cell recognition of the Ia-peptide complex; 5) based on the segregation between residues that are crucial for T cell activation and Ia binding, the easiest model for the antigen-Ia-T-cell-receptor complex pictures the antigen molecule sandwiched in a planar conformation between the MHC and the T cell.

Amino Acid Sequence↗
PubMed1990

Level discrimination of frozen and random noise.

This paper examines how the difference limen for level, delta L, is affected by stimulus bandwidth and variability. The delta L's were measured in three normal listeners using an adaptive two-interval, forced-choice procedure. The 30-ms stimuli were a 3-kHz tone and nine noise bands with half-power bandwidths ranging from 50 Hz-12 kHz. Except for the 12-kHz bandwidth, which was a low-pass noise, the noise bands were centered at 3 kHz. The delta L's were measured for both frozen and random noises presented at 30, 60, or 90 dB SPL overall. For frozen noises, the same sample of noise was presented throughout a block of 50 trials; for the random noises, different samples of noise were used in each interval of the trials. Results show that the delta L's are higher for random than for frozen noises at narrow bandwidths, but not at wide bandwidths. The delta L's for frozen narrow-band noises decrease with increasing level and are similar to those for the pure tone, whereas the delta L's for wideband noises are only slightly smaller at 90 than at 30 dB SPL. An unexpected finding is that the delta L's are larger at 60 than at 30 dB SPL for both frozen and random noises with bandwidths greater than one critical band. The effect of bandwidth varies with level: The delta L's decrease with increasing bandwidth at low levels, but are nearly independent of bandwidth at 90 dB SPL. The interaction of bandwidth and level is consistent with the multiband excitation-pattern model, but the nonmonotonic behavior of delta L as a function of level suggests modifications to the model.

Acoustic Stimulation↗
PubMed1990

Temporal integration of trains of tone pulses by normal and by cochlearly impaired listeners.

Two experiments investigated the temporal integration of trains of tone pulses by normal and by cochlearly impaired listeners. In the first experiment, thresholds were measured for a single 5-ms, 4-kHz tone pulse, and for ten such tone pulses as a function of interpulse interval (delta t). For normal listeners, temporal integration, defined as the threshold difference between one and ten pulses, was about 8 dB for delta t less than 20 ms, and about 5 dB at longer delta t's. For impaired listeners, temporal integration was only about 2-3 dB across the range of delta t's (5-160 ms) studied. A second experiment measured psychometric functions (log d' versus log signal power) for a single pulse and for ten pulses with delta t's of 5 ms and 80 ms. The normal listeners' functions had slopes close to unity in all three conditions, with a few exceptions. The impaired listeners' functions had slopes close to unity for ten pulses with delta t = 5 ms, but had slopes significantly greater than unity for delta t = 80 ms, and for a single pulse. At delta t = 80 ms, the increase in d' relative to the condition with a single tone was similar (a factor of square root of 10) for both impaired and normal listeners, but the threshold difference was smaller for the impaired listeners due to their steeper psychometric functions. For impaired listeners, then, temporal integration at delta t = 80 ms was normal in terms of a change in d' but abnormal when measured as a threshold difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1989

Structural requirements for the interaction between peptide antigens and I-Ed molecules.

We have analyzed the structural characteristics of the interaction between I-Ed molecules and their peptide ligands. It was found that unrelated good I-Ed binders share structurally similar "core" regions that were experimentally demonstrated to be crucial for binding to I-Ed molecules. Single amino acid substitution analogues of one good I-Ed binder, hen egg lysozyme 107-116, were analyzed for their capacity to bind to I-Ed molecules and to activate two different I-Ed-restricted T cell hybridomas. The results illustrate the great permissiveness of I-Ed-peptide interaction and the great specificity of T cell recognition. It was concluded from these analyses that basic residues on the peptide molecule play a crucial role in binding to I-Ed. This contrasts with the structural requirements for binding to the other Iad isotype, I-Ad, the crucial hydrophobic residues. Thus, different class II molecules of the same MHC haplotype may have rather distinct peptide binding specificities, thereby expanding the repertoire of possible immunogenic peptides presented for T cell recognition.

Amino Acid Sequence↗
PubMed1989

Capacity of intact proteins to bind to MHC class II molecules.

Here we have demonstrated that denatured, but not native protein antigens can interact with Ia molecules. Thus, the failure of native antigens to be recognized as such by T cells appears to be at least in part due to a deficient antigen/Ia interaction. These results also support previous observations that some T cells can recognize denatured antigens without a further processing requirement. Moreover, a striking correlation was observed between the in vitro binding pattern of denatured proteins and the pattern of restriction of T cell responses elicited by immunization with the native antigen, raising the possibility that an unfolding step may actually occur early during in vivo processing and influence the final outcome of Ia-restricted T cell responses.

Animals↗
PubMed1989

Effect of conformational propensity of peptide antigens in their interaction with MHC class II molecules. Failure to document the importance of regular secondary structures.

In an attempt to define some of the conformational requirements for binding of the antigenic peptide OVA 323-336 to purified IAd molecules, three distinct experimental approaches were applied. First, the effect of introducing proline or glycine residues within the region of OVA 323-336 crucial for its IAd binding capacity was analyzed. In most instances these substitutions had little or no effect, suggesting that neither alpha-helical nor beta-sheet regular structures may be strictly required for productive interaction with MHC molecules. Some of the same substitutions were also found to have no effect on the capacity of the peptide to stimulate OVA 323-336 specific T cell hybridomas, suggesting that regular structures such as alpha-helices or beta-sheets may not be strictly required for T cell stimulation, either. Second, we introduced, within the OVA 323-336 molecule, structural modifications predicted to alter its dipole characteristics and stabilize helical structures. No improvement of the IAd binding capacity was detected following these structural alterations. Surprisingly, some but not others of these analogs displayed increased antigenicity for OVA 323-336 specific T cell hybridomas. Third, a panel of analogs of OVA 323-336 were synthesized in which the crucial IAd binding core region was linked to non-native sequences of differing conformational propensities. When 22 such analogs were tested for IAd binding, it was found that these non-native sequences could drastically influence the binding capacity, but no correlation was found between their effect and their alpha-helical, beta-sheet, or beta-turn conformational propensity as calculated by the Chou and Fasman algorithm. In summary, all the data presented herein suggest that, at least in the case of OVA 323-336 and IAd, the propensity of the antigen molecule to form secondary structures such as alpha-helices, beta-sheets, or beta-turns does not correlate with its capacity to bind MHC molecules.

Amino Acid Sequence↗
PubMed1989

Structural requirements and biological significance of interactions between peptides and the major histocompatibility complex.

Previous studies indicate that T cells recognize a complex between the major histocompatibility complex (MHC) restriction-element and peptide-antigen fragments. Two aspects of this complex formation are considered in this paper: (1) what is the nature of the specificity of the interactions that allows a few MHC molecules to serve as restriction elements for a large universe of antigens; and (2) what is the relative contribution of determinant selection (i.e. antigen-MHC complex formation) and T-cell repertoire in determining the capacity of an individual to respond to an antigen? By analysing single amino acid substitution analogues of a peptide antigen (Ova 325-335) as well as by analysing the structural similarities between unrelated peptides capable of binding to the same MHC molecule, we have been able to document the very permissive nature of the antigen-MHC interaction. Despite this permissiveness of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity. With respect to the question of the relative role of 'determinant selection' and 'holes in the T-cell repertoire' in determining immune responsiveness, we present data that suggest both mechanisms operate in concert with one another. Thus only about 30% of a collection of peptides that in sum represent the sequence of a protein molecule were found to bind to Ia. Although immunogenicity was restricted to those peptides that were capable of binding to Ia (i.e. determinant selection was operative), we found that about 40% of Ia-binding peptides were not immunogenic (i.e. there were also 'holes in the T-cell repertoire').

Amino Acid Sequence↗
PubMed1989

Structural analysis of peptides capable of binding to more than one Ia antigen.

The Ia binding regions were analyzed for three unrelated peptide Ag (sperm whale myoglobin 106-118, influenza hemagglutinin 130-142, and lambda repressor protein 12-26) for which binding to more than one Ia molecule has previously been demonstrated. By determining the binding profile of three separate series of truncated synthetic peptides, it was found that in all three cases the different Ia reactivities mapped to largely overlapping regions of the peptides; although, for two of the peptides, the regions involved in binding the different Ia specificities were distinct. Moreover, subtle differences were found to dramatically influence some, but not other, Ia reactivities. Using a large panel of synthetic peptides it was found that a significant correlation exists between the capacity of peptides to interact with different alleles of the same molecule (i.e., IAd and IAk), but no correlation was found with the capacity of peptides to interact with different isotypes within the same haplotype (i.e., IAd and IEd). These data suggest that different alleles of the same MHC molecule may actually recognize closely related structures, whereas different isotypes may recognize unrelated, albeit non-mutually exclusive, structures on an Ag molecule.

Amino Acid Sequence↗
PubMed1989

Comodulation masking release for three types of modulator as a function of modulation rate.

To investigate the dependence of 'Comodulation Masking Release' (CMR) on the type and frequency of modulator, thresholds were measured for a 4-kHz tone masked by modulated and unmodulated noises. The maskers were a 400-Hz wide band of noise centered on 4 kHz (NOCUE), the same noise with a 2700-Hz lowpass noise added (LPCUE), and a wideband noise with a passband between 3 and 6 kHz (WBCUE). In each condition three types of modulator were used: a square wave, a sinewave, and a lowpass noise. Several frequencies of each type of modulator were used, allowing measurement of the interaction between envelope frequency (fe) and modulator type. Thresholds were lower in the presence than in the absence of modulation for all modulator types, except when fe was high (e.g. 100 Hz). The 'Modulated-Unmodulated Difference' (MUD) decreased monotonically with increasing fe in all conditions. For any given fe, MUDs generally were greater for square-wave and lowpass-noise modulation than for sinusoidal modulation. As significant MUDs were sometimes obtained even in the NOCUE condition, the MUD was not an accurate measure of CMR. Therefore, CMR was defined as the difference between the MUD obtained in the NOCUE condition and that obtained in each cue condition, for each combination of fe and modulator type. Measured this way, the CMR for our 4-kHz signals did not vary systemically with fc over the range studied. When a CMR was obtained it was smaller for sinusoidal modulation than for either square-wave or lowpass-noise modulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1989

Relative contribution of "determinant selection" and "holes in the T-cell repertoire" to T-cell responses.

Using BALB/c and CBA/J mice, the I-region associated (Ia) binding capacity and T-cell immunogenicity of a panel of 14 overlapping peptides that span the entire sequence of the protein staphylococcal nuclease (Nase) was examined to evaluate major histocompatibility gene complex (MHC) control of T-cell responses. Ia binding and Ia-restricted T-cell immunogenicity could be determined for a total of 54 peptide-MHC combinations. Only 30% of the 54 instances examined involved detectable Ia binding, but they represented almost all (12 of 13) of the immune responses found. However, binding to Ia was not sufficient to ensure T-cell immunogenicity, since only 70% of the binding events were productive--i.e., were associated with an immune response. Thus, Ia molecules have the expected characteristics of a highly permissive capacity for antigen interaction that allows them to function as restriction elements for a large universe of antigens. On the other hand, since the Ia molecules cannot distinguish between self and non-self, not all antigen-Ia interactions would be permitted to elicit a T-cell response. It appears that both Ia binding ("determinant selection") and T-cell repertoire act in concert to define the immune response status of an individual toward any particular T-cell epitope.

Animals↗
PubMed1989

Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis.

We have previously experimentally analyzed the structural requirements for interaction between peptide antigens and mouse major histocompatibility complex (MHC) molecules of the d haplotype. We describe here two procedures devised to predict specifically the capacity of peptide molecules to interact with these MHC class II molecules (IAd and IEd). The accuracy of these procedures has been tested on a large panel of synthetic peptides of eukaryotic, prokaryotic, and viral origin, and also on a set of overlapping peptides encompassing the entire staphylococcal nuclease molecule. For both sets of peptides, IAd and IEd binding was successfully predicted in approximately 75% of the cases. This suggests that definition of such sequence "motifs" could be of general use in predicting potentially immunogenic peptide regions within proteins.

Amino Acid Sequence↗
PubMed1988

Autologous peptides constitutively occupy the antigen binding site on Ia.

Low molecular weight material associated with affinity-purified class II major histocompatibility complex (MHC) molecules of mouse (Ia) had the expected properties of peptides bound to the antigen binding site of Ia. Thus, the low molecular weight material derived from the I-Ad isotype was efficient in inhibiting the binding of 125I-labeled I-Ad-specific peptide to I-Ad, but did not significantly inhibit the binding of an I-Ed-specific peptide to I-Ed; the reciprocal isotype-specific inhibition was demonstrated with low molecular weight material derived from I-Ed. The inhibitory material was predominantly peptide in nature, as shown by its susceptibility to protease digestion. It was heterogeneous as measured by gel filtration (mean molecular weight approximately 3000), and when characterized by high-performance liquid chromatography, it eluted over a wide concentration of solvent. Such self peptide-MHC complexes may have broad significance in the biology of T cell responses, including generation of the T cell repertoire, the specificity of mixed lymphocyte responses, and the immune surveillance of self and nonself antigens in peripheral lymphoid tissues.

Animals↗
PubMed1988

I-Ad-binding peptides derived from unrelated protein antigens share a common structural motif.

Purified Ia molecules can specifically bind many unrelated peptide Ag, and such binding appears to be a necessary, albeit not sufficient, prerequisite for the immunogenicity of the proteins from which such peptides are derived. We have recently analyzed the affect of single amino acid substitutions on the I-Ad binding of the immunogenic peptide OVA 323-339. The results obtained demonstrated the very permissive nature of Ag-Ia interaction. We also showed that unrelated peptides that are good I-Ad binders share a common structural motif and speculated that recognition of such motifs could represent a mechanism to achieve a very permissive type of interaction that yet retained some degree of specificity. In the present set of experiments we analyzed the I-Ad binding pattern of a series of overlapping peptides derived from sperm whale myoglobin (residues 102-125) and influenza hemagglutinin (residues 121-146) to determine whether the peptide regions predicted on the basis of structural similarity to be involved in I-Ad binding were in fact involved. In both cases, the I-Ad-interacting determinants were found to contain the sequence motif postulated to be important for I-Ad binding. These data support the hypothesis that I-Ad molecules recognize a large library of Ag by virtue of common structural motifs present in peptides derived from phylogenetically unrelated proteins.

Amino Acid Sequence↗
PubMed1988

Interaction of an immunodominant epitope with Ia molecules in T-cell activation.

The amino acid sequence corresponding to residues 107-116 of hen egg-white lysozyme (HEL) has been identified as containing an immunodominant T-cell epitope recognized in association with the I-Ed molecule. The immunodominance of this epitope in HEL-primed H-2d mice was demonstrated by analysis of the T-cell proliferative response induced by synthetic peptides covering almost the entire HEL sequence. All the T-cell hybridomas from H-2d mice analyzed recognize the HEL sequence 107-116 in association with the I-Ed molecule. Correlating with the restriction of T-cell recognition, HEL-(105-120)-peptide binds to I-Ed but not to I-Ad molecules. Conservative or semiconservative substitutions at positions 113 (Asn----Lys), 114 (Arg----His), or 115 (Cys----Ala) abrogate the ability of HEL-(105-120) to activate T cells. Substitutions at residues 113 and 115 affect T-cell recognition but not the binding to I-Ed molecules, whereas, as shown by binding data and competition experiments, an Arg----His substitution at position 114 profoundly impairs the capacity of the peptide to interact with I-Ed molecules. In agreement with these results, [Lys113]HEL-(105-120)-peptide but not [His114]HEL-(105-120)-peptide was found to be immunogenic in H-2d mice. Thus, a single semiconservative substitution drastically reduces binding capacity and abolishes immunogenicity, suggesting that a strict correlation exists between binding of a peptide to Ia molecules and its immunogenicity.

Amino Acid Sequence↗