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PubMed2004

A module map showing conditional activity of expression modules in cancer.

DNA microarrays are widely used to study changes in gene expression in tumors, but such studies are typically system-specific and do not address the commonalities and variations between different types of tumor. Here we present an integrated analysis of 1,975 published microarrays spanning 22 tumor types. We describe expression profiles in different tumors in terms of the behavior of modules, sets of genes that act in concert to carry out a specific function. Using a simple unified analysis, we extract modules and characterize gene-expression profiles in tumors as a combination of activated and deactivated modules. Activation of some modules is specific to particular types of tumor; for example, a growth-inhibitory module is specifically repressed in acute lymphoblastic leukemias and may underlie the deregulated proliferation in these cancers. Other modules are shared across a diverse set of clinical conditions, suggestive of common tumor progression mechanisms. For example, the bone osteoblastic module spans a variety of tumor types and includes both secreted growth factors and their receptors. Our findings suggest that there is a single mechanism for both primary tumor proliferation and metastasis to bone. Our analysis presents multiple research directions for diagnostic, prognostic and therapeutic studies.

Databases, Genetic↗
PubMed2002

Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil.

BACKGROUND: Different 5-fluorouracil (5-FU) schedules and/or biochemical modulators may result in different mechanisms of cytotoxicity, potentially affecting the correlation between thymidylate synthase (TS) expression and the clinical response to the fluoropyrimidine. PATIENTS AND METHODS: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 124 patients homogeneously treated in a series of clinical trials at our institutions with: (A) leucovorin (LV)-modulated infusional 5-FU (n = 48); (B) LV-modulated bolus 5-FU (n = 41); (C) methotrexate (MTX)-modulated bolus 5-FU (n = 35). RESULTS: A statistically significant correlation between TS levels and the clinical response was observed with the regimens involving continuous infusion and/or LV modulation (response rate in patients with low and high TS: 66% versus 24%, P = 0.003, and 50% versus 0%, P = 0.0001, in group A and B, respectively). Conversely, TS levels failed to predict the clinical response within the group of patients treated with MTX-modulated bolus 5-FU (response rate 21% versus 13%, P = 0.50, with low and high TS, respectively). Consistently, the median time to progression/overall survival time in patients with low and high TS were 9 versus 6 months/19 versus 14 months (P = 0.009/0.035, group A), 8 versus 2 months/12 versus 6 months (P = 0.002/0.0006, group B) and 3 versus 2 months/12 versus 13 months (P = 0.14/0.74, group C). CONCLUSIONS: The correlation between intratumoral TS levels and the clinical response to 5-FU depends strongly on the schedule of administration/biochemical modulators that are used in different 5-FU regimens. These data strengthen the notion that different 5-FU schedules have different mechanisms of cytotoxicity.

Adult↗
PubMed2000

Module shuffling of a family F/10 xylanase: replacement of modules M4 and M5 of the FXYN of Streptomyces olivaceoviridis E-86 with those of the Cex of Cellulomonas fimi.

To facilitate an understanding of structure-function relationships, chimeric xylanases were constructed by module shuffling between the catalytic domains of the FXYN from Streptomyces olivaceoviridis E-86 and the Cex from Cellulomonas fimi. In the family F/10 xylanases, the modules M4 and M5 relate to substrate binding so that modules M4 and M5 of the FXYN were replaced with those of the Cex and the chimeric enzymes denoted FCF-C4, FCF-C5 and FCF-C4,5 were constructed. The k(cat) value of FCF-C5 for p-nitrophenyl-beta-D-cellobioside was similar to that of the FXYN (2.2 s(-1)); however, the k(cat) value of FCF-C4 for p-nitrophenyl-beta-D-cellobioside was significantly higher (7.0 s(-1)). The loss of the hydrogen bond between E46 and S22 or the presence of the I49W mutation would be expected to change the position of Q88, which plays a pivotal role in discriminating between glucose and xylose, resulting in the increased k(cat) value observed for FCF-C4 acting on p-nitrophenyl-beta-D-cellobioside since module M4 directly interacts with Q88. To investigate the synergistic effects of the different modules, module M10 of the FCF-C4 chimera was replaced with that of the Cex. The effects of replacement of module M4 and M10 were almost additive with regard to the K:(m) and k(cat) values.

Amino Acid Sequence↗
PubMed2005

Modulation masking produced by second-order modulators.

Recent studies suggest that an auditory nonlinearity converts second-order sinusoidal amplitude modulation (SAM) (i.e., modulation of SAM depth) into a first-order SAM component, which contributes to the perception of second-order SAM. However, conversion may also occur in other ways such as cochlear filtering. The present experiments explored the source of the first-order SAM component by investigating the ability to detect a 5-Hz, first-order SAM probe in the presence of a second-order SAM masker beating at the probe frequency. Detection performance was measured as a function of masker-carrier modulation frequency, phase relationship between the probe and masker modulator, and probe modulation depth. In experiment 1, the carrier was a 5-kHz sinusoid presented either alone or within a notched-noise masker in order to restrict off-frequency listening. In experiment 2, the carrier was a white noise. The data obtained in both carrier conditions are consistent with the existence of a modulation distortion component. However, the phase yielding poorest detection performance varied across experimental conditions between 0 degrees and 180 degrees, confirming that, in addition to nonlinear mechanisms, cochlear filtering and off-frequency listening play a role in second-order SAM perception. The estimated magnitude of the modulation distortion component ranges from 5%-12%.

Adolescent↗
PubMed2006

Effect of modulation maskers on the detection of second-order amplitude modulation with and without notched noise.

The mechanisms underlying the detection of second-order amplitude modulation (AM) were explored. The detectability of second-order AM (fixed depth for each subject) was measured for first- and second-order modulation rates of 16 and 2 Hz, respectively (slow-rate pair), and 50 and 10 Hz, respectively (fast-rate pair), with no masker, a low-band modulation masker (centered at 2 or 10 Hz), and a high-band modulation masker (centered at 16 or 50 Hz). This was done in the absence and presence of an audio-frequency notched noise centered at the carrier frequency of 4000 Hz. Both modulation maskers were "low-noise" noises, to prevent overmodulation. In the absence of notched noise, both modulation maskers impaired performance for the slow-rate pair, but only the low-band masker impaired performance for the fast-rate pair. When notched noise was present, the low-band masker had no significant effect for either rate pair and the high-band masker had an effect only for the slow-rate pair. These results suggest that second-order AM detection is mediated both by an envelope distortion component at the second-order rate and by slow fluctuations in the output of a modulation filter tuned to the first-order rate. When notched noise is present, the distortion component plays little role.

Adult↗
PubMed1989

Modulation interference in detection and discrimination of amplitude modulation.

Two experiments were conducted to assess the effect of the rate of sinusoidal amplitude modulation (SAM) of a masker tone on detection of SAM of a probe tone (experiment 1) or on SAM-rate discrimination for the probe tone (experiment 2). When modulated at the same rate as the probe, the masker interfered with both the detection of probe modulation and the discrimination of the rate of probe modulation. The interference was obtained when the masker was either higher or lower in frequency than the probe (the probe and masker were separated by 2 oct). The amount of interference in detecting probe modulation (experiment 1) decreased as the common base rate of modulation was increased from 5 to 200 Hz. For rate discrimination (experiment 2), the amount of interference remained approximately the same for base rates of 2-40 Hz, the range over which rate discrimination was measured. In both experiments, the amount of interference was reduced when the masker was modulated at a different rate than the probe.

Acoustic Stimulation↗
PubMed1990

The effect of modulation coherence on signal threshold in frequency-modulated noise bands.

A series of four experiments was undertaken to ascertain whether signal threshold in frequency-modulated noise bands is dependent upon the coherence of modulation. The specific goal was to determine whether a masking release could be obtained with frequency modulation (FM), analogous to the comodulation masking release (CMR) phenomenon observed with amplitude modulation (AM). It was hypothesized that an across-frequency grouping process might give rise to such an effect. In experiments 1-3, maskers were composed of three noise bands centered on 1600, 2000, and 2400 Hz; these were either comodulated or noncomodulated with respect to both FM and AM. In experiment 1, the modulation was sinusoidal, and the signal was a 2000-Hz pure tone; in experiment 2, the modulation was random, and the signal was an FM noise band centered on 2000 Hz. The results obtained showed that, given sufficient width of modulation, thresholds were lower in a coherent FM masker than in an incoherent FM masker, regardless of the pattern of AM or signal type. However, thresholds in multiband maskers were usually elevated relative to that in a single-band masker centered on the signal. Experiment 3 demonstrated that coherent FM could be discriminated from incoherent FM. Experiment 4 gave similar patterns of results to the respective conditions of experiments 2 and 3, but for an inharmonic masker with bands centered on 1580, 2000, and 2532 Hz. While within-channel processes could not be entirely excluded from contributing to the present results, the experimental conditions were designed to be minimally conducive to such processes.

Adult↗
PubMed1998

The role of excitation-pattern cues and temporal cues in the frequency and modulation-rate discrimination of amplitude-modulated tones.

These experiments examine the influence of excitation-pattern cues and temporal-fine-structure cues on frequency difference limens (FDLs) measured as a function of duration. In the first three conditions, listeners were required to detect a change in carrier frequency from a baseline of 250 or 2000 Hz, for stimuli with half-amplitude durations ranging from 5 to 320 ms. In the "steady" condition, duration was manipulated by increasing the steady-state portion of the envelope between two 5-ms linear onset and offset ramps. This resulted in spectra and excitation patterns that broadened with decreasing duration. In the "modulated" condition, the carrier was amplitude modulated with a triangle function (period 10 ms) and duration was manipulated by varying the number of cycles of the modulator. In this case, the spectral envelope did not vary with duration, but the width of individual spectral lobes broadened with decreasing duration. The "low-peak-constant" condition was similar to the modulated condition, except that an increase in carrier frequency was accompanied by a decrease in the period of the modulator, so as to hold constant the frequency of the spectral lobe located roughly 100 Hz below the carrier frequency. In this condition, changes in carrier frequency resulted in minimal changes in excitation level on the low-frequency side of the excitation pattern, but changes on the high-frequency side were larger than for the first two conditions. Both the values of the FDLs, and their variation with frequency and duration, were similar in these three conditions. The fourth, "modulator varying," condition differed in that the carrier frequency was held constant and listeners were required to detect a change in modulator frequency. Thresholds were expressed as the change in frequency of the spectral side lobes adjacent to the carrier frequency ("equivalent" FDLs). Excitation-pattern cues in this condition were at least as large as in the first three conditions. However, equivalent FDLs were significantly higher than for the other three conditions. The higher FDLs are attributed to the lack of temporal fine-structure cues related to the carrier frequency. Overall, the results suggest that FDLs in the first three conditions were determined by temporal cues rather than by excitation-pattern cues. The increase of the FDLs with decreasing duration did not arise from increasing spectral splatter.

Auditory Perception↗
PubMed2005

Processing of modulated sounds in the zebra finch auditory midbrain: responses to noise, frequency sweeps, and sinusoidal amplitude modulations.

The avian auditory midbrain nucleus, the mesencephalicus lateralis, dorsalis (MLd), is the first auditory processing stage in which multiple parallel inputs converge, and it provides the input to the auditory thalamus. We studied the responses of single MLd neurons to four types of modulated sounds: 1) white noise; 2) band-limited noise; 3) frequency modulated (FM) sweeps, and 4) sinusoidally amplitude-modulated tones (SAM) in adult male zebra finches. Responses were compared with the responses of the same neurons to pure tones in terms of temporal response patterns, thresholds, characteristic frequencies, frequency tuning bandwidths, tuning sharpness, and spike rate/intensity relationships. Most neurons responded well to noise. More than one-half of the neurons responded selectively to particular portions of the noise, suggesting that, unlike forebrain neurons, many MLd neurons can encode specific acoustic components of highly modulated sounds such as noise. Selectivity for FM sweep direction was found in only 13% of cells that responded to sweeps. Those cells also showed asymmetric tuning curves, suggesting that asymmetric inhibition plays a role in FM directional selectivity. Responses to SAM showed that MLd neurons code temporal modulation rates using both spike rate and synchronization. Nearly all cells showed low-pass or band-pass filtering properties for SAM. Best modulation frequencies matched the temporal modulations in zebra finch song. Results suggest that auditory midbrain neurons are well suited for encoding a wide range of complex sounds with a high degree of temporal accuracy rather than selectively responding to only some sounds.

Acoustic Stimulation↗
PubMed1983

The selection of modulation rates for frequency modulated sound field stimuli.

Frequency modulated (FM) tones are used in sound field audiometry in order to avoid problems caused by standing waves. The FM stimuli to be used must be specified in terms of bandwidth (twice the frequency deviation), modulation rate and modulation waveform. This paper deals with selection of the modulation rate. Improved field uniformity obtained with FM tones relies upon the ear averaging the sound intensity as the frequency sweeps. The modulation rate must be less than about 1/3 of the frequency deviation in order to provide sufficient spectral components to ensure reasonable averaging across the frequency band. If the rate is too low threshold will be determined by the peak intensity during the sweep. For normal listeners a modulation rate of 5 Hz is just satisfactory but in the hearing impaired a higher rate is required because of their altered temporal integration characteristics. A suitable value for the modulation rate can be inferred from the literature on temporal integration and the acoustic characteristics of typical test rooms. The optimum rate increases with the stimulus centre frequency, but a constant rate of 20 Hz appears to be acceptable.

Audiometry↗
PubMed2004

Comparisons of predicted genetic modules: identification of co-expressed genes through module gene flow.

A question of fundamental importance is the definition and identification of modules from microarray experiments. A wide variety of techniques have been used to gain insight into the elucidation of such modules. One problem, however, is the inability to directly compare results between the different data sets produced due to the inherent parameterizations of their approaches. We first aim to provide a mechanism by which different approaches to module finding can be directly compared. Moreover, the same approach can be used to internally compare the modules predicted by the same technique, but at different parameterizations. We apply this approach to analyze the flow of genes through modules at different module thresholds of the Barkai Signature method, thereby further resolving the modules into sets of co-expressed genes.

Algorithms↗
PubMed1978

Membrane-bound forms of Ca2+-dependent protein modulator: Ca2+-dependent and independent binding of modulator protein to the particulate fraction from brain.

Ca2+-dependent binding of modulator protein to the particulate fraction was studied. The particulate fraction from one gram of rat brain bound in a Ca2+-dependent fashion 144 microgram of modulator protein, representing more than one third of the total soluble modulator protein in this tissue. The binding site was present in both the mitochondrial and microsomal fractions, the specific activity of the microsomes being the higher. The binding was reversible with a physiological concentration of Ca2+, and was temperature-dependent, and the site can be saturated with modulator protein (4.5 microgram modulator protein per mg of microsomal protein). Tryptic digestion of the membranes caused complete disappearance of the binding activity, but heat-treatment for 5 min at 70 degrees C caused only 40% loss of activity. The binding site may be a known or unknown enzyme(s), the activity of which is regulated by Ca2+ and modulator. Alternatively, this binding site may be a nonenzymic protein that regulates the concentration of free modulator protein in the cell.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Baculovirus-mediated expression of the epidermal growth factor-like modules of human factor IX fused to the factor XIIIa transamidation site in fibronectin. Evidence for a direct interaction between the NH2-terminal epidermal growth factor-like module of factor IXa beta and factor X.

Factor IX is a vitamin K-dependent procoagulant zymogen of a serine protease. In the presence of Ca2+ the active form of factor IX (factor IXa beta) forms a complex with factor VIIIa on suitable phospholipid surfaces such as aggregated platelets. This macromolecular complex rapidly activates factor X. We have previously provided data that suggest an interaction between the NH2-terminal epidermal growth factor (EGF)-like module of factor IXa beta and the substrate factor X. In an alternative approach to study this protein-protein interaction, we have expressed three recombinant baculovirus constructs encoding the EGF-like modules of human factor IX and a truncated form of fibronectin in a system based on the infection of insect cells (Spodoptera frugiperda 21). This strategy allows a simple one-step purification of the recombinant proteins on a gelatin-Sepharose column, followed by removal of the gelatin-binding part derived from fibronectin by proteolytic cleavage. The fusion proteins were isolated at yields of 20-50 micrograms/ml culture medium. The recombinant EGF-like modules contained 0.2-0.4 mol of erythro-beta-hydroxyaspartic acid/mol of protein, i.e. similar to the amount found in factor IX from human plasma, and appeared to be glycosylated at Ser-53. The NH2-terminal EGF-like module, which contained a transamidation acceptor site derived from fibronectin, was cross-linked by factor XIIIa in solution to intact and Gla-domainless factor X. There was no evidence of cross-linking to activated factor X or to factor X fragments containing only the gamma-carboxyglutamic acid module and the two EGF-like modules. The cross-linking results suggest a specific interaction between the NH2-terminal EGF-like module of factor IXa beta and the heavy chain of unactivated factor X. This interaction, albeit weak as judged by competition experiments, may be important for the targeting of factor X to the factor IXa beta-factor VIIIa complex on biological membranes and for the subsequent dissociation of factor Xa from the complex after activation.

Amino Acid Sequence↗
PubMed1998

Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network.

Tachykinin immunoreactivity is found in a ventromedial spinal plexus in the lamprey. Neurons in this plexus project bilaterally and are thus in a position to modulate locomotor networks on both sides of the spinal cord. We have examined the effects of the tachykinin substance P on NMDA-evoked locomotor activity. Brief (10 min) application of tachykinin neuropeptides results in a prolonged concentration-dependent (>24 hr) modulation of locomotor activity, shown by the increased burst frequency and more regular burst activity. These effects are blocked by the tachykinin antagonist spantide II. There are at least two phases to the burst frequency modulation. An initial phase (approximately 2 hr) is associated with the protein kinase C-dependent potentiation of cellular responses to NMDA. The long-lasting phase (>2 hr) appears to be protein synthesis-dependent, with protein synthesis inhibitors causing the increased burst frequency to recover after washing for 2-3 hr. The modulation of the burst regularity is caused by a separate effect of tachykinins, because unlike the burst frequency modulation it does not require the modulation of NMDA receptors for its induction and is blocked by H8, an inhibitor of cAMP- and cGMP-dependent protein kinases. The effects of substance P were mimicked by the dopamine D2 receptor antagonist eticlopride. The effects of eticlopride were blocked by the tachykinin antagonist spantide II, suggesting that eticlopride may endogenously release tachykinins. Because locomotor activity in vitro corresponds to that during swimming in intact animals, we suggest that endogenously released tachykinins will result in prolonged modulation of locomotor behavior.

Animals↗
PubMed2000

Differential modulation of the GYKI 53784-induced inhibition of AMPA currents by various AMPA-positive modulators in cerebellar Purkinje cells.

The effects of various (S)-alpha-amino-3-hydroxy-5-methyl-4-izoxazole-propionate (AMPA) receptor modulators on AMPA-induced whole-cell currents were compared in isolated rat cerebellar Purkinje cells. The positive modulators, aniracetam, cyclothiazide, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and 1-(quinoxaline-6-ylcarbonyl)-piperidine (BDP-12), dose-dependently potentiated the steady-state component of AMPA currents. The negative modulator, (-)1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI 53784), dose-dependently suppressed AMPA responses. Its concentration-response curve was shifted to the right in a parallel fashion by all positive modulators, indicating a competitive type of interaction. However, the relative potencies of the positive modulators were different with regard to the enhancement of AMPA responses and the reversal of GYKI 53784-induced inhibition, respectively. It is supposed that positive modulators act at multiple allosteric sites and that they interact with GYKI 53784 at only one of these sites.

Animals↗
PubMed1997

N-terminal type I modules required for fibronectin binding to fibroblasts and to fibronectin's III1 module.

Assembly of fibronectin fibrils occurs at the surface of substrate-attached cells and is mediated by the first to the fifth type I modules in the N-terminal 70 kDa portion of the molecule. The first type III module (III1) of fibronectin, not present in the 70 kDa portion, contains a conformation-dependent binding site for the 70 kDa N-terminal region of fibronectin, suggesting that the III1 module on cell-surface fibronectin may serve as a binding site for fibronectin's N-terminus on substrate-attached cells. To explore this possiblility, we compared the ability of mutant recombinant 70 kDa proteins containing deletions of one or several of the first five type I modules to bind to fibroblasts and to III1. Proteins containing the fourth and fiftBiomolecular Chemistry and Medicine, University of Wisconsin, Madison, WI 53706U.S.A. Assembly of fibronectin fibrils occurs at the surface of substrate-attached cells and is mediated by the first to the fifth type I modules in the N-terminal 70 kDa portion of the molecule. The first type III module (III1) of fibronectin, not present in the 70 kDa portion, contains a conh as 70 kDa deletion mutants lacking I4 and I5 also bound to the cell surface, and deletion mutants lacking I1-3 and I4-5 both competed only partially for binding of 125I-labelled fibronectin or 70 kDa protein. These data indicate that the N-terminal part of fibronectin binds to III1 via I4 and I5 and that interactions in addition to that of I4 and I5 with III1 are important for cell-surface-mediated fibronectin polymerization.

Animals↗