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PubMed1987

Frequency modulation detection by normally hearing and profoundly hearing-impaired listeners.

The ability of normally hearing and profoundly hearing-impaired subjects to detect frequency modulations was evaluated under conditions where the amplitudes of the test signals were either constant (CA), sinusoidally modulated (SAM), or randomly modulated (RAM). Results for hearing-impaired listeners showed larger frequency difference limens (DLFM) than those for normally hearing listeners for all test frequencies (100 to 1000 Hz) and for all amplitude conditions. For both normal-hearing and hearing-impaired subjects, the DFLM was smallest for the constant amplitude condition and largest for the randomly modulated condition. Differences in performance between the RAM and CA conditions were generally much larger for impaired listeners than for normally hearing listeners. With random amplitude modulation, DLFMs for the hearing-impaired subjects were approximately 36 times larger than those for normally hearing subjects.

Adult↗
PubMed1994

Modulation Detection Interference (MDI) in listeners with cochlear hearing loss.

This study compared Modulation Detection Interference (MDI) in listeners with cochlear hearing loss and in listeners with normal hearing. The study was motivated by questions of temporal resolution in the listeners with cochlear hearing loss as well as by their general difficulty in monitoring target sounds in the presence of competing background noise. The first experiment was similar to the MDI paradigm of Yost and Sheft (1989) and showed an equivalence in performance between the two groups of listeners: MDI brought about by an interfering tone comodulated with the target tone at 10 Hz was about 11 dB in both groups. There was also no difference in MDI magnitude when the modulation rate of the interferer changed to 25 Hz, indicating a lack of tuning to differential modulation rate in the gated paradigm employed here. The second experiment was analogous in concept to the measurement of a psychophysical tuning curve; the depth of modulation of the interfering carrier was adjusted to just interfere with the detection of a suprathreshold degree of modulation on the target carrier. The listeners with cochlear hearing loss performed quite similarly to the normal group, and the general lack of a frequency effect for the carrier tones suggested that MDI was relatively insensitive to presumed differences in auditory filter bandwidth between listeners. Because the basis of MDI has been hypothesized to be the fusion of the interfering tone with the target tone, the results of this study suggest that the auditory grouping factors presumed to underlie MDI are intact in listeners with hearing loss of cochlear origin.

Acoustic Stimulation↗
PubMed1997

Modulation masking in listeners with sensorineural hearing loss.

This study compares amplitude-modulation (AM) masking in listeners with normal hearing and in listeners with a hearing loss. To address this issue, we measured the detection of sinusoidal AM applied to a white noise carrier, as a function of the frequency of a masking sinusoidal AM applied to the same noise carrier. These input filter patterns were measured for four listeners with normal hearing and three listeners with moderate or mild-to-severe sensorineural hearing losses. Stimuli were presented at 50 dB SL for all listeners with normal hearing and for two of the three listeners with hearing loss. The third listener with hearing loss was tested at 25 dB SL. For the listeners with normal hearing, the input filter patterns obtained for 100-Hz signal modulation had a broad bandpass characteristic. All input filter patterns showed a primary masking peak at 100 Hz. A secondary masking peak was apparent also at 50 Hz. For the listeners with impaired hearing, the unmasked modulation thresholds were similar to those measured in the listeners with normal hearing. One listener with a moderate hearing loss exhibited a broadly tuned input filter pattern with a masking peak at 100 Hz, but no secondary peak. The two other listeners with moderate or mild-to-severe sensorineural hearing loss showed no main masking peak and increased thresholds at low masker modulation frequencies. These results suggest that cochlear damage may affect performance in a modulation masking task.

Adult↗
PubMed2001

Identification by cDNA microarray technology of genes modulated by artificial ultraviolet radiation in normal human melanocytes: relation to melanocarcinogenesis.

Target genes of ultraviolet stress response in cutaneous melanocytes, potentially associated with solar-induced melanocarcinogenesis, were characterized by cDNA microarray technology. In cultured normal human melanocytes, 198 genes out of approximately 9000 arrayed were found modulated > or = 1.9 times following artificial ultraviolet minus sign mainly ultraviolet-B minus sign irradiation (100 mJ per cm(2)). Among them, 159 corresponded to known sequences, the encoded proteins being mostly involved in DNA or RNA binding/synthesis/modification, or ribosomal proteins. The others were transcription factors, receptors, tumor suppressors, and (proto)oncogenes. Members of these families have already been linked to melanoma. In addition, some of the modulated genes were borne by chromosomes harboring candidate melanoma loci. Comparisons with genes modified in melanoma samples reported in previous studies with similar microarray platform showed that 59% of the known genes sensitive to ultraviolet were modulated in the same way. Furthermore, 39 expressed sequence tags were modulated, and preliminary experiments showed that two expressed sequence tags displayed differential expressions both in melanoma cell lines and in melanoma tumors. These results provide a basis for further studies on the role of modulated genes in ultraviolet-induced melanoma. Because some of these genes are potential markers of the disease, they might help for developing new molecular-based strategies for risk prediction in patients.

Chromosomes↗
PubMed2002

Alpha-adrenoreceptor activation modulates swimming via glycinergic and GABAergic inhibitory pathways in Xenopus laevis tadpoles.

This study focuses upon the network pathways underlying the adrenoreceptor-mediated modulation of fictive swimming in the immobilized Xenopus laevis tadpole. As shown recently, noradrenaline (NA) increases cycle periods while simultaneously reducing the rostrocaudal delay in head-to-tail firing and the duration of swimming episodes. Furthermore, both swimming frequency and duration are reduced by selective pharmacological activation of alpha1- and/or alpha2-adrenoreceptors, while alpha1-receptor activation also reduces rostrocaudal delays. We show that NA could still modulate aspects of swimming after blocking either glycine or GABA(A) receptors with strychnine and bicuculline, respectively. Furthermore, after prior application of NA, strychnine could counteract noradrenergic effects on cycle periods and rostrocaudal delays, while bicuculline could counteract effects on cycle periods, suggesting that these two fast inhibitory pathways are both involved in the NA modulation of swimming. In addition, blocking glycine receptors reduced the effects of alpha1-receptors on cycle periods and delays, while blocking GABA(A) receptors had no effect. Blocking either glycine or GABA(A) receptors, however, lessened the reduction in swimming frequency by alpha2-receptors. In addition, pre-application of bicuculline prevented a reduction in episode durations by NA, alpha1- and alpha2-receptors. Our findings suggest that the noradrenergic modulation of Xenopus swimming is mediated via alpha-adrenoreceptors interacting with both glycinergic and GABAergic inhibitory pathways. Both alpha1- and alpha2-receptor activation influences the GABAergic pathway controlling the duration of swimming episodes and is involved in the glycinergic modulation of the swimming rhythm and its longitudinal co-ordination, with alpha2-receptors additionally affecting swimming frequency through GABAergic pathways.

Adrenergic alpha-Agonists↗
PubMed2001

Differential modulation of CD8beta by rat gammadelta and alphabeta T cells after activation.

Major histocompatibility complex (MHC) class I-restricted alphabeta T cells express the CD8alphabeta heterodimer, which acts as a MHC class I-specific co-receptor. Rats are so far the only species with frequent expression of the CD8alphabeta by MHC-unrestricted gammadelta T cells. This study compares CD8alphabeta expression by splenic rat alphabeta and gammadelta T cells and reveals a lineage-specific difference in the control of CD8beta expression. After activation in vitro, many gammadelta T cells, but not alphabeta T cells, persistently down-modulate the expression of CD8beta, but not CD8alpha, at the RNA level. Down-regulation occurred after stimulation with T-cell receptor (TCR)-specific monoclonal antibody (mAb) and interleukin-2 (IL-2) or CD28-mediated costimulation, and after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Functional differences between modulating and non-modulating cells were not found with respect to interferon-gamma (IFN-gamma) production and cytolytic activity. The modulation could be indicative for a fundamental difference between alphabeta and gammadelta T cells and also limits the use of CD8beta as a stable marker of gammadelta T-cell subsets. Possibly, CD8beta modulation provides a mechanism to escape over-stimulation by (auto-)antigens by increasing the threshold of TCR-mediated activation in gammadelta T cells.

Animals↗
PubMed2002

The personal and professional impact of undertaking an educational module on human caring.

AIM OF THE STUDY: To evaluate the personal and professional impact of undertaking a 15-week degree level module on nursing as human caring. BACKGROUND: Little is known about how to teach and enhance caring practices. An innovative module was implemented on a 4-year, postregistration nursing degree course in Wales to develop students' capacity to be caring practitioners. An understanding of its impact was sought to facilitate better future preparation of students. RESEARCH METHODS: A full cohort of 25 part-time students, divided into four groups, participated in audio-taped focus groups before and after undertaking the module. FINDINGS: From a personal perspective, the students experienced increased spiritual awareness characterized by: (1) enhanced connecting relationships with self and others, (2) finding purpose and meaning in life, and (3) clarification of values. Professionally, the module resulted in: (1) an increased knowledge and understanding of caring theory and related concepts, (2) a more holistic approach to care, and (3) enhanced caring practice. CONCLUSIONS: Education may enhance students' capacity to be caring practitioners. Spirituality, in particular, was illuminated for the students as an important means of developing both themselves and their caring practices. They experienced transformative learning, and the focus groups, employed as the research method, served as a useful vehicle in this process. Reflective groups will be used as a teaching method on future modules.

Education, Nursing↗
PubMed2002

Direct modulation of the effective sensitivity of a CCD detector: a new approach to time-resolved fluorescence imaging.

In this paper a novel approach to frequency-domain fluorescence lifetime imaging (FLIM) is described. In a CCD camera a single pixel is defined by a charge pattern on a group of electrodes. By modulation of the pattern of voltages defining the pixel structure it is possible to modulate the sensitivity of the CCD at radio frequency. The modulation enhances the noise performance of the CCD, in contrast to the deterioration in performance seen when an intensifier stage is similarly modulated. The new technology has potential applications to a wide range of assays as well as in conventional FLIM applications. Unlike intensifier-based systems, the directly modulated CCD is physically small, inexpensive, robust and offers superior resolution and noise performance.

Journal Article↗
PubMed1999

Site-directed mutagenesis of serine 158 demonstrates its role in spinach leaf sucrose-phosphate synthase modulation.

Site-directed mutagenesis of spinach sucrose-phosphate synthase (SPS) was performed to investigate the role of Ser158 in the modulation of spinach leaf SPS. Tobacco plants expressing the spinach wild-type (WT), S158A, S158T and S157F/S158E SPS transgenes were produced. Expression of transgenes appeared not to reduce expression of the tobacco host SPS. SPS activity in the WT and the S158T SPS transgenics showed light/dark modulation, whereas the S158A and S157F/S158E mutants were not similarly light/dark modulated: the S158A mutant enzyme was not inactivated in the dark, and the S157F/S158E was not activated in the light. The inability to modulate the activity of the S158A mutant enzyme by protein phosphorylation was demonstrated in vitro. The WT spinach enzyme immunopurified from dark transgenic tobacco leaves had a low initial activation state, and could be activated by PP2A and subsequently inactivated by SPS-kinase plus ATP. Rapid purification of the S158A mutant enzyme from dark leaves of transgenic plants using spinach-specific monoclonal antibodies yielded enzyme that had a high initial activation state, and pre-incubation with leaf PP2A or ATP plus SPS-kinase (the PKIII enzyme) caused little modulation of activity. The results demonstrate the regulatory significance of Ser158 as the major site responsible for dark inactivation of spinach SPS in vivo, and indicate that the significance of phosphorylation is the introduction of a negative charge at the Ser158 position.

Base Sequence↗
PubMed1999

A Dictyostelium protein binds to distinct oligo(dA) x oligo(dT) DNA sequences in the C-module of the retrotransposable element DRE.

The genome of the eukaryotic microbe Dictyostelium discoideum contains some 200 copies of the nonlong-terminal repeat retrotransposon DRE. Among several unique features of this retroelement, DRE is transcribed in both directions leading to the formation of partially overlapping plus strand and minus strand RNAs. The synthesis of minus strand RNAs is controlled by the C-module, a 134-bp DNA sequence located at the 3'-end of DRE. A nuclear protein (CMBF) binds to the C-module via interaction with two almost homopolymeric 24 bp oligo(dA) x oligo(dT) sequences. The DNA-binding drugs distamycin and netropsin, which bind to A x T-rich DNA sequences in the minor groove, competed efficiently for the binding of CMBF to the C-module. The CMBF-encoding gene, cbfA, was isolated and a DNA-binding domain was mapped to a 25-kDa C-terminal region of the protein. A peptide motif involved in the binding of A x T-rich DNA by high mobility group-I proteins ('GRP' box) was identified in the deduced CMBF protein sequence, and exchange of a consensus arginine residue for alanine within the CMBF GRP box abolished the interaction of CMBF with the C-module. The current data support the theory that CMBF binds to the C-module by detecting its long-range DNA conformation and interacting with A x T base pairs in the minor groove of oligo(dA) x oligo(dT) stretches.

Amino Acid Sequence↗
PubMed2001

Adrenoreceptor-mediated modulation of the spinal locomotor pattern during swimming in Xenopus laevis tadpoles.

This study focused on the contribution of different adrenoreceptor subtypes to the modulation of fictive swimming activity in a relatively simple, yet intact, lower vertebrate system, the immobilized Xenopus laevis tadpole and explored their possible role in mediating the noradrenergic modulation of spinal motor networks. In Xenopus embryos, near the time of hatching, activation of alpha(1) adrenoreceptors increased the duration of episodes of fictive swimming, whilst in larvae, 24 h after hatching, they were decreased. Activation of alpha(2) adrenoreceptors, however, markedly reduced episode duration at both developmental stages. Cycle periods in both stages were increased by the activation of alpha(1) and/or alpha(2) receptor subclasses, whereas beta adrenoreceptors were not apparently involved in the modulation of cycle periods or the duration of swim episodes. However, both beta and alpha(1) receptor activation decreased the intersegmental delay in the head-to-tail propagation of swimming activity, while alpha(2) receptors did not influence these rostro-caudal delays. Activation of neither alpha, nor beta, receptor subclasses had any consistent effect on the duration of ventral motor bursts. Our findings suggest that noradrenergic modulation of the swim-pattern generator in Xenopus tadpoles is mediated through the activation of alpha and beta adrenoreceptors. In addition, activation of particular receptor subclasses might enable the selective modulation of either the segmental rhythm generating networks, the intersegmental coordination of those networks or control at both levels simultaneously.

Adrenergic alpha-Agonists↗
PubMed1998

Characterization and modulation of transitional cell carcinoma cell lines with acquired multidrug resistance.

OBJECTIVES: To characterize in vitro drug-induced multidrug resistance (MDR) in transitional cell carcinoma (TCC) cell lines, and to elucidate the possible mechanisms of acquired MDR and their modulation. MATERIALS AND METHODS: Two drug-resistant cell lines, TCC8702/A1000 (adriamycin 1000 ng/mL) and TCC8803/A200 (adriamycin 200 ng/mL), were established after long-term adriamycin treatment for at least 16 months. Their biological characteristics, including growth morphology, doubling time and cell cycle, were analysed. The drug-resistance pattern to various anticancer drugs was measured using a microplate cytotoxicity assay. The modulation of drug sensitivity by calcium-channel blockers and protein kinase C inhibitor was assessed among the different cancer cell lines. RESULTS: Both MDR sublines had lower growth rates, lower saturation densities and higher nuclear/cytoplasmic ratios than the parent cell lines. DNA staining and cell cycle analysis revealed that both TCC8702/A1000 and TCC8803/A200 cells had a decreased S-phase fraction and the TCC8803/A200 cells a changed stem line; both sublines showed increased expression of membranous glycoprotein gp-170. The cytoplasmic content of glutathione and glucose-6-phosphate dehydrogenase were not related to the MDR development in the sublines. The drug-resistance index of TCC8702/A1000 to adriamycin was 121-fold higher than the native cell line and TCC8803/A200 was 189-fold higher. TCC8803/A200 also had a broader MDR to cisplatin, vinblastine and vincristine. Calcium-channel blockers (verapamil, quinidine) and protein kinase C inhibitors (tamoxifen) inhibited gp-170 activity and slowed the drug-efflux pump, with the acquired-MDR cells subsequently accumulating anticancer drugs. A calcium antagonist-based combination of modulators all presented synergistic cytotoxic enhancement of the anticancer drugs. Parent TCC cell lines had a poorer response to modulator treatment than their MDR sublines. CONCLUSION: Different MDR mechanisms and subsequent modulator responses exist between native and acquired drug resistance in TCC cells. Acquired MDR seems strongly related to increased gp-170 expression and responds well to calcium antagonists. This phenomenon may be applicable in clinical conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Calcium/calmodulin-dependent kinase II phosphorylation of the GABAA receptor alpha1 subunit modulates benzodiazepine binding.

gamma-Aminobutyric acid (GABA) is the primary neurotransmitter that is responsible for the fast inhibitory synaptic transmission in the central nervous system. A major post-translational mechanism that can rapidly regulate GABAAR function is receptor phosphorylation. This study was designed to test the effect of endogenous calcium and calmodulin-dependent kinase II (CaM kinase II) activation on both allosteric modulator binding and GABAA receptor subunit phosphorylation. Endogenous CaM kinase II activity was stimulated, and GABAA receptors were subsequently analyzed for bothallosteric modulator binding properties and immunoprecipitated and analyzed for subunit phosphorylation levels. A significant increase in allosteric-modulator binding of the GABAAR was observed under conditions maximal for CaM kinase II activation. In addition, CaM kinase II activation resulted in a direct increase in phosphorylation of the GABAA receptor alpha1 subunit. The data suggest that the CaM kinase II-dependent phosphorylation of the GABAA receptor alpha1 subunit modulated allosteric modulator binding to the GABAA receptor.

Allosteric Regulation↗
PubMed2004

Intracellular calcium modulates the nuclear translocation of calsenilin.

Calsenilin, which was originally identified as a presenilin interacting protein, has since been shown to be involved in the processing of presenilin(s), the modulation of amyloid beta-peptide (Abeta) levels and apoptosis. Subsequent to its original identification, calsenilin was shown to act as a downstream regulatory element antagonist modulator (and termed DREAM), as well as to interact with and modulate A-type potassium channels (and termed KChIP3). Calsenilin is primarily a cytoplasmic protein that must translocate to the nucleus to perform its function as a transcriptional repressor. This study was designed to determine the cellular events that modulate the translocation of calsenilin from the cytoplasm to the nucleus. The nuclear translocation of calsenilin was found to be enhanced following serum deprivation. A similar effect was observed when cells were treated with pharmacological agents that directly manipulate the levels of intracellular calcium (caffeine and the calcium ionophore A23187), suggesting that the increased levels of calsenilin in the nucleus are mediated by changes in intracellular calcium. A calsenilin mutant that was incapable of binding calcium retained the ability to translocate to the nucleus. Taken together, these findings indicate that the level of intracellular calcium can modulate the nuclear translocation of calsenilin and that this process does not involve the direct binding of calcium to calsenilin.

Active Transport, Cell Nucleus↗
PubMed1999

An oral health promotion module for the primary health care nursing course in Acornhoek, South Africa.

The severe personnel shortage in the health professions in most developing communities is well documented. This dearth of health workers and the widespread adoption of the primary health care approach (PHCA), requires that health professionals be trained to understand and effectively utilize the skills offered by other disciplines in the health care field. Nurses are expected to play active roles in the promotion of health including oral health, particularly in the rural under-served communities. There is a paucity of oral health education in nursing curricula. This article describes a 4-day module on oral health promotion developed and delivered to 36 nurses as part of a 12-month primary health care nursing (PHCN) training course. The module utilized a variety of educational methods and materials to facilitate and encourage both individual and group learning. The module was evaluated using both student academic attainment and perceptions as outcome measures. The evaluation and the experience of facilitating this module show that an oral health promotion module of short duration can sensitize nurses to the importance of oral health and increase oral health knowledge and skills.

Curriculum↗
PubMed2005

STAT module can function as a biphasic amplitude filter.

Signal transducer and actuator of transcription (STATs) are a family of transcription factors activated by various cytokines, growth factors and hormones. They are important mediators of immune responses and growth and differentiation of various cell types. The STAT signalling system represents a defined functional module with a pattern of signalling that is conserved from flies to mammals. In order to probe and gain insights into the signalling properties of the STAT module by computational means, we developed a simple non-linear ordinary differential equations model within the 'Virtual Cell' framework. Our results demonstrate that the STAT module can operate as a 'biphasic amplitude filter' with an ability to amplify input signals within a specific intermediate range. We show that dimerisation of phosphorylated STAT is crucial for signal amplification and the amplitude filtering function. We also demonstrate that maximal amplification at intermediate levels of STAT activation is a moderately robust property of STAT module. We propose that these observations can be extrapolated to the analogous SMAD signalling module.

Cell Physiological Phenomena↗
PubMed2001

Biochemical effects of dietary intake of different broccoli samples. II. Multivariate analysis of contributions of specific glucosinolates in modulating cytochrome P-450 and antioxidant defense enzyme activities.

Dietary broccoli exposure modulates various cytochrome P-450 (CYP)-associated activities and antioxidant defense enzyme activities in liver, colon, and kidney of rats. We present an analysis by the partial least-square method (PLS) of the contribution of single glucosinolates in modulating xenobiotic metabolizing and antioxidant defense enzyme activities. Generally, modulation of colonic enzyme activities was well described (58% to 75%) by models consisting of 3 principal components (PCs). The indolyl glucosinolates were not the only major contributors to the regulation of colonic 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) activities, as would be expected from results of previous experiments testing the pure compounds, glucobrassicin (GB), neoglucobrassicin (NeoGB), and 4-methoxyglucobrassicin (4-MeOGB). In hepatic and renal microsomes, the modulation of enzyme activities could be partly described for hepatic and renal 7-pentoxyresorufin O-deethylase (PROD) activities (42% to 44%, 3 to 4 PCs), hepatic superoxide dismutase activity (45%, 2 PCs), and renal glutathione peroxidase (GSH Px) and glutathione reductase (GSSG Red) activities (43%, 3 PCs). These results indicate that substances other than glucosinolates in the complex mixtures modulate hepatic EROD, MROD, GSH Px, and GSSG Red activities or that the active glucosinolate metabolites vary in their systemic disposition.

Animals↗
PubMed2001

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer.

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.

Adult↗