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PubMed2006

Detecting functional modules in the yeast protein-protein interaction network.

MOTIVATION: Identification of functional modules in protein interaction networks is a first step in understanding the organization and dynamics of cell functions. To ensure that the identified modules are biologically meaningful, network-partitioning algorithms should take into account not only topological features but also functional relationships, and identified modules should be rigorously validated. RESULTS: In this study we first integrate proteomics and microarray datasets and represent the yeast protein-protein interaction network as a weighted graph. We then extend a betweenness-based partition algorithm, and use it to identify 266 functional modules in the yeast proteome network. For validation we show that the functional modules are indeed densely connected subgraphs. In addition, genes in the same functional module confer a similar phenotype. Furthermore, known protein complexes are largely contained in the functional modules in their entirety. We also analyze an example of a functional module and show that functional modules can be useful for gene annotation. CONTACT: yuan.33@osu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗

PubMed1999

Impaired modulation of quadriceps tendon jerk reflex during spastic gait: differences between spinal and cerebral lesions.

In healthy subjects, functionally appropriate modulation of short latency leg muscle reflexes occurs during gait. This modulation has been ascribed, in part, to changes in presynaptic inhibition of Ia afferents. The changes in modulation of quadriceps tendon jerk reflexes during gait of healthy subjects were compared with those of hemi- or paraparetic spastic patients. The spasticity was due to unilateral cerebral infarction or traumatic spinal cord injury, respectively. The modulation of the quadriceps femoris tendon jerk reflex at 16 phases of the step cycle was studied. The reflex responses obtained during treadmill walking were compared with control values obtained during gait-mimicking standing postures with corresponding levels of voluntary muscle contraction and knee angles. In healthy subjects the size of the reflexes was profoundly modulated and was generally depressed throughout the step cycle. In patients with spinal lesion the reflex depression during gait was almost removed and was associated with weak or no modulation during the step cycle. In patients with cerebral lesion there was less depression of the reflex size associated with a reduced reflex modulation on the affected side compared with healthy subjects. On the 'unaffected' side of these patients reflex modulation was similar to that of healthy subjects, but the reflex size during gait was not significantly different from standing control values. These observations suggest that the mechanisms responsible for the depression of reflex size and the modulation normally seen during gait in healthy subjects are impaired to different extents in spasticity of spinal or cerebral origin, possibly due to the unilateral preservation of fibre tracts in hemiparesis.

Adolescent↗

PubMed1999

A mini-protein designed by removing a module from barnase: molecular modeling and NMR measurements of the conformation.

A globular domain can be decomposed into compact modules consisting of contiguous 10-30 amino acid residues. The correlation between modules and exons observed in different proteins suggests that each module was encoded by an ancestral exon and that modules were combined into globular domains by exon fusion. Barnase is a single domain RNase consisting of 110 amino acid residues and was decomposed into six modules. We designed a mini-protein by removing the second module, M2, from barnase in order to gain an insight into the structural and functional roles of the module. In the molecular modeling of the mini-protein, we evaluated thermodynamic stability and aqueous solubility together with mechanical stability of the model. We chemically synthesized a mini-barnase with (15)N-labeling at 10 residues, whose corresponding residues in barnase are all found in the region around the hydrophobic core. Circular dichroism and NMR measurements revealed that mini-barnase takes a non-random specific conformation that has a similar hydrophobic core structure to that of barnase. This result, that a module could be deleted without altering the structure of core region of barnase, supports the view that modules act as the building blocks of protein design.

Bacterial Proteins↗

PubMed1991

The structure and function of protein modules.

Analysis of protein sequences shows that many proteins in multicellular organisms have evolved by a process of exon shuffling, deletion and duplication. These exons often correspond to autonomously folding protein modules. Many extracellular enzymes have this modular structure; for example, serine proteases involved in blood-clotting, fibrinolysis and complement. The main role of these modules is to confer specificity by protein-protein interactions. Lack of structural information about such proteins has required a new strategy for studying the structure and function of protein modules. The strategy involves the production of individual modules by protein expression techniques, determination of their structure by high resolution nuclear magnetic resonance and definition of functional patches on the modules by site-directed mutagenesis and biological assays. The structures of the growth factor module, the fibronectin type 1 module and the complement module are briefly described. The possible functional roles of modules in various proteins, including the enzymes factor IX and tissue plasminogen activator, are discussed.

Amino Acid Sequence↗

PubMed1992

Modulation discrimination interference and auditory grouping.

The detection of a change in the modulation pattern of a (target) carrier frequency, fc (for example a change in the depth of amplitude or frequency modulation, AM or FM) can be adversely affected by the presence of other modulated sounds (maskers) at frequencies remote from fc, an effect called modulation discrimination interference (MDI). MDI cannot be explained in terms of interaction of the sounds in the peripheral auditory system. It may result partly from a tendency for sounds which are modulated in a similar way to be perceptually 'grouped', i.e. heard as a single sound. To test this idea, MDI for the detection of a change in AM depth was measured as a function of stimulus variables known to affect perceptual grouping, namely overall duration and onset and offset asynchrony between the masking and target sounds. In parallel experiments, subjects were presented with a series of pairs of sounds, the target alone and the target with maskers, and were asked to rate how clearly the modulation of the target could be heard in the complex mixture. The results suggest that two factors contribute to MDI. One factor is difficulty in hearing a pitch corresponding to the target frequency. This factor appears to be strongly affected by perceptual grouping. Its effects can be reduced or abolished by asynchronous gating of the target and masker. The second factor is a specific difficulty in hearing the modulation of the target, or in distinguishing that modulation from the modulation of other sounds that are present. This factor has effects even under conditions promoting perceptual segregation of the target and masker.

Acoustic Stimulation↗

PubMed2004

Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces.

The regulators of complement activation (RCA) are critical to health and disease because their role is to ensure that a complement-mediated immune response to infection is proportionate and targeted. Each protein contains an uninterrupted array of from four to 30 examples of the very widely occurring complement control protein (CCP, or sushi) module. The CCP modules mediate specific protein-protein and protein-carbohydrate interactions that are key to the biological function of the RCA and, paradoxically, provide binding sites for numerous pathogens. Although structural and mutagenesis studies of CCP modules have addressed some aspects of molecular recognition, there have been no studies of the role of molecular dynamics in the interaction of CCP modules with their binding partners. NMR has now been used in the first full characterization of the backbone dynamics of CCP modules. The dynamics of two individual modules-the 16th of the 30 modules of complement receptor type 1 (CD35), and the N-terminal module of membrane cofactor protein (CD46)-as well as their solution structures, are compared. Although both examples share broadly similar three-dimensional structures, many structurally equivalent residues exhibit different amplitudes and timescales of local backbone motion. In each case, however, regions of the module-surface implicated by mutagenesis as sites of interactions with other proteins include several mobile residues. This observation suggests further experiments to explore binding mechanisms and identify new binding sites.

Amino Acid Sequence↗

PubMed1995

Temporal coding of amplitude and frequency modulation in the rat auditory cortex.

The rat primary auditory cortex was explored for neuronal responses to pure tones and sinusoidally amplitude-modulated (SAM) and frequency-modulated (SFM) stimuli. Units showed phase-locked responses to SAM stimulation (55%) and SFM stimulation (80%), with modulation frequencies up to 18 Hz. Tuning characteristics to the modulation frequency were mainly band-pass with best modulation frequencies (BMFs) between 4 and 15 Hz. Units with synchronized activity to SFM stimulation showed three response types with respect to the direction of the frequency modulation: 52% were selective to the upward direction, 30% to the downward direction, and 18% had no preference. Triangular frequency modulations were used to test if units were tuned to specific modulation frequencies or to specific rates of frequency change. In the vast majority of units tested the response characteristics were strongly influenced by varying the modulation frequency, whereas varying the rate of frequency change had little effect in the stimulus range used. Units that showed phase-locked responses to SAM and SFM stimulation had similar activity patterns in response to both types of stimuli. BMFs for SAM and SFM stimulation were significantly correlated. Intrinsic oscillations of up to 20 Hz could be seen in the spontaneous activity and after the stimuli independent of the stimulus type. Oscillation frequencies were significantly correlated with the BMFs of the respective units. The results are discussed in terms of a mechanism for periodicity detection based on a temporal code. This could be important for the recognition of complex acoustic signals.

Acoustic Stimulation↗

PubMed2000

Monaural and binaural detection of sinusoidal phase modulation of a 500-Hz tone.

The detectability of phase modulation was measured for three subjects in two-alternative temporal forced-choice experiments. In experiment 1, the detectability of sinusoidal phase modulation in a 1500-ms burst of an 80-dB (SPL), 500-Hz sinusoidal carrier presented to the left ear (monaural condition) was measured. The experiment was repeated with an 80-dB, 500-Hz static (unmodulated) tone at the right ear (dichotic condition). At a modulation rate of 1 Hz, subjects were an order of magnitude more sensitive to phase modulation in the dichotic condition than in the monaural condition. The dichotic advantage decreased monotonically with increasing modulation rate. Subjects ceased to detect movement in the dichotic stimulus above 10 Hz, but a dichotic advantage remained up to a modulation rate of 40 Hz. Thus, although sound movement detection is sluggish, detection of internal phase modulation is not. In experiment 2, thresholds for detecting 2-Hz phase modulation were measured in the dichotic condition as a function of the level of the pure tone in the right ear. The dichotic advantage persisted even when the level of the pure tone was reduced by 50 dB or more. The findings demonstrate a large dichotic advantage which persists to high modulation rates and which depends very little on interaural level differences.

Adult↗

PubMed2001

Effects of temporal envelope modulation on acoustic signal recognition in a vocal fish, the plainfin midshipman.

Amplitude modulation is an important parameter defining vertebrate acoustic communication signals. Nesting male plainfin midshipman fish, Porichthys notatus, emit simple, long duration hums in which modulation is strikingly absent. Envelope modulation is, however, introduced when the hums of adjacent males overlap to produce acoustic beats. Hums attract gravid females and can be mimicked with continuous tones at the fundamental frequency. While individual hums have flat envelopes, other midshipman signals are amplitude modulated. This study used one-choice playback tests with gravid females to examine the role of envelope modulation in hum recognition. Various pulse train and two-tone beat stimuli resembling natural communication signals were presented individually, and the responses compared to those for continuous pure tones. The effectiveness of pulse trains was graded and depended upon both pulse duration and the ratio of pulse to gap length. Midshipman were sensitive to beat modulations from 0.5 to 10 Hz, with fewer fish approaching the beat than the pure tone. Reducing the degree of modulation increased the effectiveness of beat stimuli. Hence, the lack of modulation in the midshipman's advertisement call corresponds to the importance of envelope modulation for the categorization of communication signals even in this relatively simple system.

Acoustics↗

PubMed2001

Temporal modulation transfer functions obtained using sinusoidal carriers with normally hearing and hearing-impaired listeners.

Temporal modulation transfer functions were obtained using sinusoidal carriers for four normally hearing subjects and three subjects with mild to moderate cochlear hearing loss. Carrier frequencies were 1000, 2000 and 5000 Hz, and modulation frequencies ranged from 10 to 640 Hz in one-octave steps. The normally hearing subjects were tested using levels of 30 and 80 dB SPL. For the higher level, modulation detection thresholds varied only slightly with modulation frequency for frequencies up to 80 Hz, but decreased for high modulation frequencies. The decrease can be attributed to the detection of spectral sidebands. For the lower level, thresholds varied little with modulation frequency for all three carrier frequencies. The absence of a decrease in the threshold for large modulation frequencies can be explained by the low sensation level of the spectral sidebands. The hearing-impaired subjects were tested at 80 dB SPL, except for two cases where the absolute threshold at the carrier frequency was greater than 70 dB SPL; in these cases a level of 90 dB was used. The results were consistent with the idea that spectral sidebands were less detectable for the hearing-impaired than for the normally hearing subjects. For the two lower carrier frequencies, there were no large decreases in threshold with increasing modulation frequency, and where decreases did occur, this happened only between 320 and 640 Hz. For the 5000-Hz carrier, thresholds were roughly constant for modulation frequencies from 10 to 80 or 160 Hz, and then increased monotonically, becoming unmeasurable at 640 Hz. The results for this carrier may reflect "pure" effects of temporal resolution, without any influence from the detection of spectral sidebands. The results suggest that temporal resolution for deterministic stimuli is similar for normally hearing and hearing-impaired listeners.

Adult↗

PubMed2003

Modulation masking in cochlear implant listeners: envelope versus tonotopic components.

It is hypothesized that channel-interaction in cochlear implant listeners as measured in a modulation-masking experiment would be influenced by both the tonotopic overlap between masker and signal as well as an interaction between their envelopes. Two experiments were conducted to measure the effects of maskers with noisy and steady-state envelopes on modulation detection by four adult Nucleus-22 cochlear implant listeners, as a function of tonotopic distance between the masker and the signal. In the first experiment, we measured detection thresholds for a 50-Hz modulation in the envelope of a 500-Hz carrier pulse train, in the presence of a masker stimulating regions basal and apical to, as well as overlapping with, the signal. The maskers had two kinds of envelopes: (i) amplitude-modulated by flat-spectrum noise (NAM) and (ii) steady-state (SS(peak)) at a level corresponding to the maximum of the noise fluctuation range. In general, modulation thresholds obtained in the presence of the NAM maskers significantly exceeded thresholds obtained with the corresponding SS(peak) maskers. The ratio p of the threshold modulation depth m obtained with the NAM masker to that obtained with the SS(peak) masker was defined as a conservative index of "envelope masking." In the second experiment, p was determined for two different tasks: the detection of modulation at 20 Hz and steady-state intensity increment detection. Compared to the 50-Hz modulation detection results, the ratio p was reduced for the 20-Hz modulation detection task and even more so for the steady-state increment detection task. It is concluded that channel-interaction can be significantly increased in cochlear implant listeners when dynamic stimuli are used in place of steady-state stimuli.

Adult↗

PubMed2003

Modulation spectra of natural sounds and ethological theories of auditory processing.

The modulation statistics of natural sound ensembles were analyzed by calculating the probability distributions of the amplitude envelope of the sounds and their time-frequency correlations given by the modulation spectra. These modulation spectra were obtained by calculating the two-dimensional Fourier transform of the autocorrelation matrix of the sound stimulus in its spectrographic representation. Since temporal bandwidth and spectral bandwidth are conjugate variables, it is shown that the joint modulation spectrum of sound occupies a restricted space: sounds cannot have rapid temporal and spectral modulations simultaneously. Within this restricted space, it is shown that natural sounds have a characteristic signature. Natural sounds, in general, are low-passed, showing most of their modulation energy for low temporal and spectral modulations. Animal vocalizations and human speech are further characterized by the fact that most of the spectral modulation power is found only for low temporal modulation. Similarly, the distribution of the amplitude envelopes also exhibits characteristic shapes for natural sounds, reflecting the high probability of epochs with no sound, systematic differences across frequencies, and a relatively uniform distribution for the log of the amplitudes for vocalizations. It is postulated that the auditory system as well as engineering applications may exploit these statistical properties to obtain an efficient representation of behaviorally relevant sounds. To test such a hypothesis we show how to create synthetic sounds with first and second order envelope statistics identical to those found in natural sounds.

Animals↗

PubMed1982

Detection of sinusoidally amplitude modulated noise by the chinchilla.

Amplitude modulation thresholds for sinusoidally amplitude modulated noise were obtained from four monaural chinchillas using shock-avoidance conditioning procedures. The noise was band limited at either 10 or 20 kHz, amplitude modulated at frequencies between 2 and 4096 Hz and presented at levels between 52 and 73 dB SPL. The modulation thresholds of the chinchilla were approximately 9% (-- 2 dB) at modulation frequencies below 32 Hz. At higher modulation frequencies, thresholds increased at the rate of 1.9 dB/octave. Modulation thresholds were also measured in human listeners using the same experimental apparatus. Amplitude modulation functions for both subject groups exhibited low-pass characteristics; however, the thresholds for humans were better than those of the chinchilla at modulation frequencies below 64 Hz.

Acoustic Stimulation↗

PubMed1987

Potentials evoked by the sinusoidal modulation of the amplitude or frequency of a tone.

Steady state responses to the sinusoidal modulation of the amplitude or frequency of a tone were recorded from the human scalp. For both amplitude modulation (AM) and frequency modulation (FM), the responses were most consistent at modulation frequencies between 30 and 50 Hz. However, reliable responses could also be recorded at lower frequencies, particularly at 2-5 Hz for AM and at 3-7 Hz for FM. With increasing modulation depth at 40 Hz, both the AM and FM response increased in amplitude, but the AM response tended to saturate at large modulation depths. Neither response showed any significant change in phase with changes in modulation depth. Both responses increased in amplitude and decreased in phase delay with increasing intensity of the carrier tone, the FM response showing some saturation of amplitude at high intensities. Both responses could be recorded at modulation depths close to the subjective threshold for detecting the modulation and at intensities close to the subjective threshold for hearing the stimulus. The responses were variable but did not consistently adapt over periods of 10 min. The 40-Hz AM and FM responses appear to originate in the same generator, this generator being activated by separate auditory systems that detect changes in either amplitude or frequency.

Acoustic Stimulation↗

PubMed1990

Detection of frequency modulation (FM) in the presence of a second FM tone.

A series of three experiments was undertaken to investigate detection of sinusoidal frequency modulation (FM) in the presence of FM at a separate frequency. The first experiment measured detection of modulation for an FM tone with a modulation frequency (fm) of 6 Hz as a function of carrier frequency (fc) under three conditions: (1) in quiet, (2) in the presence of a 2500-Hz pure tone, and (3) in the presence of a 2500-Hz FM tone with fm = 6 Hz, modulating in phase with the signal. Detection of FM in the presence of the second FM tone was worse than for either the signal presented in quiet or in the presence of the unmodulated tone. Threshold varied as an inverse function of frequency separation between the signal and the masker. In the second experiment, FM detection for a signal with fc = 1900 Hz and fm = 6 Hz was measured as a function of the modulation frequency (fm = 2-18 Hz) of the 2500-Hz masker tone. FM detection improved significantly with increasing difference between the modulation frequencies of the signal and the masker. The final experiment measured detection of FM for a signal (fc = 1900 Hz, fm = 6 Hz) in the presence of a second FM tone (fc = 2500 Hz, fm = 6 Hz) as a function of the relative phase of the 6-Hz modulators. Detection of FM improved monotonically as a function of increasing phase difference between the two modulators. The results are discussed in terms of modulation detection interference and perceptual grouping.

Adult↗

PubMed1991

Discriminating between coherent and incoherent frequency modulation of complex tones.

A series of experiments measured the discrimination by human listeners of frequency-modulated complex tones which differed only in the coherence of frequency modulation (FM). For the coherently modulated tones all components were modulated by the same 5-Hz sinusoid, and by the same percentage of their starting frequencies, whereas for the incoherently modulated tones the modulation of one (target) component differed from that of the rest. When the 400-ms complex was composed of consecutive harmonics of a common fundamental, performance improved monotonically with increases in modulator delay, and was nearly perfect at the longest delays. When the complex was inharmonic, performance was near chance at all modular delays, both for component frequencies between 1500 and 2500 Hz, and for component frequencies between 400 and 800 Hz. It is argued that listeners detected incoherence in harmonic complexes by detecting the resulting mistuning of the target component. This conclusion was supported by the finding that listeners were usually at least as good at detecting a fixed mistuning of the center component of a harmonic complex as they were at detecting a modulator phase delay imposed on it. A final experiment, with a stimulus duration of 1 s and slower modulation rates, showed that listeners could detect incoherence for some inharmonic complexes. However, detection was worse than for harmonic complexes and was, it is argued, based on weak harmonicity cues. The results of all experiments point to the absence of an across-frequency mechanism specific to the detection of FM incoherence.

Attention↗

PubMed1992

Fringe effects in modulation masking.

Modulation detection thresholds (20 log ms) for a sinusoidally amplitude-modulated (SAM) noise were measured in the presence of a SAM noise masker with a modulation depth (mm) of 1.0 and a modulation frequency of 16 or 64 Hz. The signal and masker carriers were presented continuously, and the signal was modulated during one of the two 500-ms observation intervals. The masker was modulated during both observation intervals and, in some conditions, for a certain amount of time before and after signal modulation. The duration of this "fringe" ranged from 62.5 ms to continuous (masker modulated throughout the thresholds estimate). The first experiment showed that a 500-ms fringe could reduce masked thresholds by 4-6 dB, but only at low signal modulation frequencies (2-8 Hz). In the second and third experiments, it was found that the fringe had to have a duration of 500 ms and a depth of about 0.75 to be maximally effective. A final, supplementary experiment indicated that the fringe effect is not due solely to the fringe that occurs prior to the observation intervals. The results are discussed in terms of both peripheral and central auditory processing.

Adult↗

PubMed1993

Modulation detection interference under conditions favoring within- or across-channel processing.

A series of experiments was conducted to examine modulation detection interference (MDI) under two general conditions: one where the processing was likely to be across channel (2.0-kHz signal, 4.0-kHz masker), and the other where the possibility of within-channel processing was much more likely (2.0-kHz signal, 1.8-kHz masker). In the first experiment, MDI was measured as the modulation frequency of the signal and masker was increased from 5 to 100 Hz. The amount of MDI decreased as modulation frequency increased from 5 to 20 Hz, beyond which it remained approximately constant. This effect of common modulation frequency was somewhat smaller for the 1.8-kHz masker. The second experiment examined the effects of relative modulator phase between the masker and signal for modulation frequencies of 10 or 100 Hz. In general, there was not a consistent effect of phase. However, when the signal and masker modulators were in-phase, there was a tendency, on average, for the amount of MDI to be at a maximum when the masker frequency was 1.8 kHz and at a minimum when it was 4.0 kHz. In the third experiment, increases in masker modulation depth usually resulted in nearly proportional increases in signal modulation depth at threshold; this was true for both masker carriers, although the increase was slightly greater for the 1.8-kHz masker. The final experiment examined the effects of level for conditions where the signal and masker carriers were either equal or unequal in level. When they were equal in level, the amount of MDI increased somewhat with increases in level for both masker carriers. Comparing the amount of MDI in these conditions with those where the carriers were unequal in level revealed that the amount of MDI was considerably less when the signal was more intense than the masker. This occurred almost exclusively for the 1.8-kHz masker, however, suggesting that it may reflect a within-channel effect. Taken together, the results from the four experiments suggest that the processing underlying MDI was generally the same in the presence of both the 1.8- and 4.0-kHz masker carriers, although within-channel processing via spread of excitation probably influenced some of the results with the 1.8-kHz masker.

Acoustic Stimulation↗