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PubMed1982

The influence of antigen density and a comparison of IgG and IgM antibodies in the anti-complementary modulation of lymphocytic surface immunoglobulin.

Experiments were carried out to determine the influence of antigen density on anti-complementary modulation, defined here as the conferring by anti-immunoglobulin (Ig) of resistance to lysis of guinea pig L2C leukaemic cells varied widely in their quantitative expression of surface membrane Ig as judged by the binding to cells of 125I-labelled Fab' fragments from anti-Ig, and a good correlation between the bulk antigen density and the percentage of cells lysed by anti-Ig plus C was obtained (P=0.02). In the presence of 10 mM sodium azide, which has been shown to diminish the modulation occurring during simultaneous incubations with anti-Ig and C, this correlation was even stronger (P less than 0.001). No zone could be defined in which the level of surface Ig expression was sufficient to serve complement lysis but too low for modulation. Furthermore, both the degrees and rates of modulation occurring on incubation with antibody at 37 degrees C, either before C addition or in the presence of lytic C, were similar for populations of high, low, or intermediate antigen density. Separation of cells by their size or density failed to yield populations differing in either their susceptibility to humoral killing through anti-Ig or their modulating capacity. IgG and IgM antibodies to the L2C cell surface Ig evoked similar levels of killing with syngeneic C, and when compared for their ability to promote anti-complementary modulation, no difference was revealed in either the rate or degree of modulation occurring during incubations at 37 degrees C with the two isotopes. The findings are discussed with particular reference to observations on the modulation of mouse thymus leukaemia (TL) antigens.

Animals↗
PubMed1997

Chemical synthesis and characterization of the epidermal growth factor-like module of human complement protease C1r.

C1r is one of the two serine proteases of C1, the first component of complement, in which it is associated in a calcium-dependent manner to the homologous serine protease C1s. This interaction is mediated by the N-terminal region of C1r, which comprises a single epidermal growth factor (EGF)-like module containing the consensus sequence required for calcium binding, surrounded by two CUB modules. With a view to determine the structure of the EGF-like module of C1r and evaluate its contribution to calcium binding, this module [C1r(123-175)] was synthesized by automated solid-phase methodology using the Boc strategy. A first synthesis using the Boc-His(Z) derivative gave very low yield, due to partial deprotection of His residues leading to chain termination by acetylation, and to insertion of glycine residues. This could be circumvented by using the Boc-His(DNP) derivative and by condensation of appropriate glycine-containing segments. The synthetic peptide was efficiently folded under redox conditions to the species with three correct disulfide bridges, as determined by mass spectrometry and N-terminal sequence analyses of thermolytic fragments. The homogeneity of the synthetic peptide was assessed by reversed-phase HPLC and electrospray mass spectrometry. One-dimensional 1H NMR spectroscopic analysis provided evidence that the EGF-like module had a well defined structure, and was able to bind calcium with an apparent Kd of 10 mM. This value, comparable to that found for the isolated EGF-like modules of coagulation factors IX and X, is much higher than that measured for native C1r. As already proposed for factors IX and X, it is suggested that neighbouring module(s), most probably the N-terminal CUB module, contribute(s) to the calcium binding site.

Amino Acid Sequence↗
PubMed2003

Modulation of gene expression induced in human epidermis by environmental stress in vivo.

Environmental insults on the skin induce biologic responses through the modulation of expression of genes implicated in different cell functions. The aim of this study was to investigate the modulation of gene expression profile in human epidermis in vivo following different stresses. We determined the modulations of gene expression using cDNA macroarray in the epidermis of 28 healthy volunteers, following mild and physiologic insults, including: (1), tape stripping; (2) application of 10% sodium dodecyl sulfate; (3) daily application of vaseline; and (4), exposure to one minimal erythema dose of solar-simulated radiation. The analysis was performed 19 h after treatment. The reverse transcription-polymerase chain reaction method was used to confirm our results. We showed that: (1) the intensity of gene modulation was variable among the volunteers following the same skin stress; (2) the nature and intensity of skin treatment modified the pattern of gene expression; and (3) some genes were modulated only by specific stress, some others are modulated irrespective of the stress. GADD45, Bax, SAS, and granulocyte chemotactic protein-2 were overexpressed exclusively following solar-simulated radiation, whereas tape stripping led to the modulation of genes implicated in different pathways (inflammation, cell proliferation, cell differentiation, detoxification, etc.). Concerning common gene modulation, MRP8 and MRP14 were highly upregulated in human skin epidermis after solar-simulated radiation, vaseline application or tape stripping, and to a lower extent after sodium dodecyl sulfate. Such upregulation of the MRP 8/14 genes was confirmed at the protein level in an ex-vivo skin culture model following tape stripping and solar-simulated radiation. Together, these results suggest that MRP8 and MRP14 may be general, yet highly sensitive, markers for a great variety of skin stresses and that they are implicated in several epidermal repair pathways.

Adult↗
PubMed1998

Incorporation of a "Coping with the Death of a Child" module into the pediatric advanced life support (PALS) curriculum.

OBJECTIVE: To develop an educational module for health professionals (HPs) addressing the clinical reality of death as an outcome of pediatric resuscitation efforts. Module goals were to: 1) reduce HPs' discomfort with situations involving patient death and survivor grief, 2) assist HPs coping with their own emotions surrounding a patient death, and 3) provide specific strategies useful in clinical management. The module was designed to be presented as part of the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) Pediatric Advanced Life Support (PALS) provider course. METHODS: A multidisciplinary team created a module addressing both survivors' and HPs' needs regarding a PALS course "Coping with the Death of a Child" module. The module was presented to 964 PALS course participants. Content was revised after analysis of survey data collected from these participants. RESULTS: The revised module was presented to 601 PALS course participants; evaluations were obtained from 590 participants. On a 4-point Likert scale, ratings were: 79% "excellent," 18% "good," 2% "fair," and <1% "poor." CONCLUSION: The PALS course offers an opportunity to target HPs likely to encounter pediatric deaths for special education. While this is a challenging and potentially controversial topic to present to a diverse audience, incorporation of a "Coping with the Death of a Child" module into the PALS provider curriculum appears to be both feasible and useful.

Adaptation, Psychological↗
PubMed1990

Facilitatory and inhibitory transmitters modulate spontaneous transmitter release at cultured Aplysia sensorimotor synapses.

1. The monoamine transmitter 5-hydroxytryptamine (5-HT) and the peptide Phe-Met-Arg-Phe-amide (FMRFa), which appear to contribute to presynaptic facilitation and inhibition of the sensorimotor synapse in the abdominal ganglion of Aplysia, can modulate the frequency of spontaneous transmitter release at synapses formed between dissociated Aplysia sensory neurones and motoneurones in vitro. 2. 5-HT caused a decrease in the mean time interval between consecutive miniature EPSPs (mEPSPs), while FMRFa, applied either by itself or together with 5-HT, caused an increase in the mean time interval between consecutive mEPSPs. 3. Depolarization of the presynaptic neurone caused a decrease in the mean time interval between consecutive mEPSPs. This modulation required external Ca2+. 4. 5-HT and FMRFa were able to modulate spontaneous release when applied in saline solutions lacking Ca2+ and containing Ca2(+)-chelating agents, suggesting that the modulation of spontaneous release by 5-HT and FMRFa did not require a Ca2+ influx. Similarly, spontaneous release could still be modulated by 5-HT and FMRFa in saline solutions containing 1 mM-Cd2+, which blocked both the voltage-gated Ca2+ channels and the evoked transmitter release. 5. To prevent a rise in intracellular Ca2+, we buffered the concentration of Ca2+ in the presynaptic terminals by injecting into the sensory neurone the Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The injection of BAPTA blocked evoked transmitter release, suggesting that it acted as an effective buffer of Ca2+ in the terminals. However, spontaneous release could still be observed and was still modulated by 5-HT and FMRFa. This suggests that the modulation of spontaneous release does not require an elevation of intracellular Ca2+. 6. We propose that 5-HT and FMRFa can modulate the rate of spontaneous release directly by mechanisms that do not require changes in the intracellular concentration of Ca2+. These mechanisms might contribute an additional component to the presynaptic inhibition and facilitation of evoked transmitter release.

Action Potentials↗
PubMed1993

Modulation of respiratory activity of neonatal rat phrenic motoneurones by serotonin.

1. The effects of serotonin on phrenic motoneurones were studied in an in vitro preparation of the isolated brainstem and spinal cord from neonatal rats. 2. Serotonin (5-HT; > or = 5-10 microM) increased inspiratory-modulated phrenic nerve activity and produced a small amount of tonic activity during expiration. Inspiratory-modulated activity of the fourth cervical ventral root also increased, but was accompanied by robust tonic activity, which often obscured the rhythmic activity. 3. Serotonin, in both normal and tetrodotoxin-containing medium, depolarized phrenic motoneurones and increased cell input resistance. Serotonin also increased inspriatory-modulated firing as well as the response of phrenic motoneurones to injected current. The y-intercept of the relationship between firing frequency and injected current (f-I) was increased, but the slope was not affected. There was no bistable firing behaviour. 4. Under voltage clamp conditions, 5-HT produced a tonic inward current of 0.07-0.37 nA. This current increased with less negative holding potentials and decreased with more negative holding potentials (-75 to -90 mV) but did not reverse. 5. In addition, 5-HT decreased inspiratory-modulated synaptic current by 23 +/- 6%. The degree of attenuation was not affected by holding potential. The time course of the decrease in inspiratory-modulated synaptic current was similar to the changes seen in tonic inward current and input resistance. 6. Depolarization, tonic inward current, and shift in the f-I relationship produced by 5-HT were antagonized by the 5-HT2/1C receptor antagonist ketanserin and mimicked by the 5-HT2/1C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). However, the 5-HT induced decrease in inspiratory-modulated synaptic current was not reduced by ketanserin nor mimicked by DOI. 7. We conclude that exogenously applied 5-HT simultaneously increases cell excitability and decreases inspiratory-modulated synaptic current in phrenic motoneurones via different types of receptors. When these responses occurred simultaneously, the increase in excitability predominated and the net effect was an augmentation of inspiratory-modulated phrenic motoneurone activity.

Animals↗
PubMed2006

Optimization of current modulation function for proton spread-out Bragg peak fields.

Proton treatments with spread-out Bragg peak (SOBP) fields often use a rotating modulation wheel of varying thickness to modulate the pristine Bragg peak in depth and intensity. The technique of modulating also the beam current independently over the wheel rotation provides an additional control over the intensities of the pulled-back Bragg peaks. As a result, a single wheel can be used over a large range of energies and SOBP parameters and field-specific wheels are no longer necessary. An essential task in commissioning a particular treatment depth is the determination of this current modulation function. We have developed a method for the optimization of the current modulation function. The basic idea is to treat the entire beam nozzle, housing the various beam scattering and modulating components, as a whole and to characterize its effect as a transformation from a modulating beam current to a depth-dose distribution. While this transformation is difficult to calculate theoretically due to the complex scattering paths in the nozzle and the phantom, it can, however, be determined by time-resolved dose measurements. Using this transformation, we can calculate SOBP depth-dose distributions for any current modulation function and optimize it by a simple numerical optimization. We have applied the new method to a number of proton beams with satisfactory results.

Computer Simulation↗
PubMedDate not supplied

Evaluation of fixed- versus variable-modulation treatment modes for charged-particle irradiation of the gastrointestinal tract.

The clinical usefulness of variable-modulation dose delivery of neon ion and proton beams over fixed-modulation beams is evaluated for several patients with tumors in the gastrointestinal tract by comparing dose distributions, dose volume histograms, and predictions of normal tissue complication probabilities calculated with the two methods. Both techniques provide excellent coverage of the target volume with neon ion and proton beams. The advantage of variable modulation is that less dose is delivered proximal to the target volume. For tumors in the gastrointestinal tract, this implies that less dose is given to the liver, gut, kidneys, and lungs. For the ten patients considered in this study, variable-modulation reduced the total integral dose by an average of 17% for neon ion beams and by 18% for protons as compared to fixed-modulation. If the tumor volume is excluded, the reduction in the integral dose to normal tissues ranged from 15% to 32% for neon ions and from 18% to 34% for proton beams. These gains are larger than those anticipated on the basis of an analytic study by Goitein and Chen [Med. Phys. 10, 831-840 (1983)], which predicted integral dose reductions of the order of 10% for protons and 14% for neon ions. They are also larger than those reported in a similar study by Urie and Goitein [Med. Phys. 16, 593-601 (1989)] for proton irradiation of skull-base tumors. This is probably because the tumors in the GI tract considered in this study were more irregularly shaped than Goitein and Chen's analytic model assumes. The results of this study also suggest that due to increased sparing of normal tissues, the number of different portal directions required to achieve a satisfactory treatment plan will be reduced for variable-modulation beam delivery systems. This implies that variable-modulation treatment plans will be easier to execute than current fixed-modulation plans.

Adenocarcinoma↗
PubMed1999

Dose reduction in CT by anatomically adapted tube current modulation. II. Phantom measurements.

Theoretical considerations and simulation studies have led to the expectation that patient dose in CT (computed tomography) can be reduced significantly without a concomitant loss in image quality if tube current is modulated according to rotation angle-dependent x-ray attenuation. In this study, the simulation results presented in Part I were validated with phantoms. We used one cylindrical, two oval, and one elliptical phantom, available both as mathematical descriptions and in physical form, to mimic different parts of the human anatomy. Prototype hardware was available to control tube current on a commercial clinical CT scanner. The potential for dose reduction was evaluated for sinusoidal and attenuation-based current modulation for variable modulation amplitudes. Agreement between simulations and measured results was better than within 10%. Dose reduction values of 8%-56% were found depending on the phantom geometry and tube current modulation function. Attenuation-based tube current modulation consistently yielded higher reduction than fixed-shape sinusoidal modulation functions. For the shoulder phantom and 70% modulation amplitude, 44.6% dose reduction was measured as compared to 34.1% for sinusoidal modulation. A maximum of 56% was measured for the shoulder phantom including inserts. Specifying mAs reduction as an estimate for dose reduction proved to be a valid and conservative estimate; measured dose is reduced more strongly than the total mAs product both centrally and on average. First patient studies confirm the results of simulation and phantom studies. We conclude that attenuation-based online tube current control has great potential for reducing patient dose in CT and that it should be made generally available for clinical use.

Air Pollutants, Radioactive↗
PubMed2001

Modulation detection interference: effects of concurrent and sequential streaming.

The presence of amplitude fluctuations in one frequency region can interfere with our ability to detect similar fluctuations in another (remote) frequency region. This effect is known as modulation detection interference (MDI). Gating the interfering and target sounds asynchronously is known to lead to a reduction in MDI, presumably because the two sounds become perceptually segregated. The first experiment examined the relative effects of carrier and modulator gating asynchrony in producing a release from MDI. The target carrier was a 900-ms, 4.3-kHz sinusoid, modulated in amplitude by a 500-ms, 16-Hz sinusoid, with 200-ms unmodulated fringes preceding and following the modulation. The interferer (masker) was a 1-kHz sinusoid, modulated by a narrowband noise with a 16-Hz bandwidth, centered around 16 Hz. Extending the masker carrier for 200 ms before and after the signal carrier reduced MDI, regardless of whether the target and masker modulators were gated synchronously or were gated with onset and offset asynchronies of 200 ms. Similarly, when the carriers were gated synchronously, asynchronous gating of the modulators did not produce a release from MDI. The second experiment measured MDI with a synchronous target and masker and investigated the effect of adding a series of precursor tones, which were designed to promote the forming of a perceptual stream with the masker, thereby leaving the target perceptually isolated. Four modulated or unmodulated precursor tones presented at the masker frequency were sufficient to completely eliminate MDI. The results support the idea that MDI is due to a perceptual grouping of the masker and target, and show that conditions promoting sufficient perceptual segregation of the masker and target can lead to a total elimination of MDI.

Adult↗
PubMed2005

Beating frequency and amplitude modulation of the piano tone due to coupling of tones.

The influence on a piano tone from weak coexcitation of damped adjacent tones due to coupling via the bridge is studied. The frequency and amplitude modulation of the sound resulting from coexcitation of one strong and one or two weak tones is analyzed. One weak tone causes frequency and amplitude modulation of the sound, and two weak tones produce beating frequency and amplitude modulation, where the beatings of the two modulations are of opposite phase. By digital recording of the sound of piano tones, the appearance of these phenomena is verified. The audibility of the observed frequency and amplitude modulation is discussed in terms of previously determined detection thresholds. The beating character of both frequency and amplitude modulations, however, distinguishes the phenomena from those previously studied and prompts further psychoacoustic investigations. It is shown that detuning of unison strings may significantly increase the frequency deviation of the frequency modulation in conjunction with affected amplitude modulation. The modulatory effects of coupling to adjacent tones therefore may possibly be utilized in the tuning process. A coupling of tones analogous to the situation in a piano may arise in other stringed musical instruments transferring string vibrations to a soundboard via a bridge.

Journal Article↗
PubMed1985

Temporal interactions between pure tones and amplitude-modulated noise.

An auditory interaction between the temporal fine structure of a low-frequency tone and the envelope of a high-frequency waveform was observed at very large frequency separations. Thresholds for detection of sinusoidal amplitude modulation of a high-frequency, narrow-band noise were measured as a function of the relative phase between the modulator and a pure tone with the same frequency as the modulator. These "phase functions" were determined at various intensities of the noise and tone for three different modulation frequencies. In general, the phase functions show that low-frequency stimulation has a cyclic effect on the sensitivity to amplitude modulation; over a limited range of relative phases, the modulation threshold is lower than that measured without low-frequency stimulation whereas over a broader range of relative phases, the modulation threshold is much higher. The difference between minimum and maximum modulation thresholds was observed to be as great as 23 dB. Despite this substantial degree of temporal interaction, little, if any, masking by the low-frequency tone of the high-frequency noise was observed.

Acoustic Stimulation↗
PubMed1994

Pitch percepts associated with amplitude-modulated current pulse trains in cochlear implantees.

The percepts elicited by electrical stimulation of auditory neurons by trains of amplitude-modulated current pulses were studied in a group of six cochlear implant users. Modulation frequencies of 100, 150, and 200 Hz were studied, with a range of carrier rates up to 1200 Hz. It was found that all but one subject could consistently rank 150- and 200-Hz modulated stimuli by modulation frequency when the carrier rate was more than 800 Hz, but for lower carrier rates the ranking was greatly affected by the harmonic relationship between carrier and modulation frequency. Pitch matching experiments showed that the subjects generally considered the modulated stimuli to be equal in pitch to unmodulated stimuli with rates the same as, or somewhat higher than, the modulation frequency. The results showed that the "pitch" of pulsatile electrical stimulation resulting from periodicities in the time structure of the electrical stimulus has similarities to the "pitch" observed for temporal patterns in acoustic stimulation such as amplitude-modulated noise. There were some differences, however, which may be attributable at least in part to the physiological response differences for electric and acoustic stimulation.

Adult↗
PubMed1995

Effects of combining maskers in modulation detection interference.

The threshold for detecting 10-Hz amplitude modulation of a 2000-Hz carrier was measured in quiet, in the presence of an unmodulated masker, and in the presence of an amplitude-modulated masker. Two experiments were run; in each, the masker consisted of one or two sinusoidal carriers (chosen from among the frequencies of 800, 1600, 2400, and 3200 Hz). In experiment 1, the modulation rate of the masker ranged from 2 to 80 Hz. The "tuning" in the modulation domain was not affected much by the masker carrier frequency or the increase from one to two carriers. The amount of interference, however, was sometimes greater in the two-carrier condition, although this resulted primarily from the presence of the carriers and not from their modulation. In experiment 2, the modulation rate of each single-carrier masker ranged from 2 to 80 Hz (as in experiment 1), but for the two-carrier conditions, all possible combinations of two carriers (2400 and 3200 Hz) and three masker rates (5, 10, and 20 Hz) were evaluated. In general, the combination of two modulated carriers did not produce more interference than that produced by the more interfering carrier presented alone. Thus the results from both experiments provide little evidence for an additivity of modulation detection interference.

Adult↗
PubMed1996

Vowel identification based on amplitude modulation.

This study investigated the extent to which flat-spectrum harmonic complexes could be identified as one of six vowels when three pairs of successive harmonics, located at the first, second, and third formant frequency values, were amplitude modulated. In experiment 1, the amplitude modulation (AM) rate was at or close to 10 Hz. In condition 1, all components were added in cosine phase, and the 10-Hz AM was in phase for all "formants." Performance improved monotonically with increasing modulation index, m. In condition 2, m was fixed at 0.5 and the level of each background harmonic was varied randomly (roved) from stimulus to stimulus. Even a rove range of only +/- 2 dB reduced scores considerably. Condition 3 was like condition 1, but with components added in random phase. Performance was very poor for all modulation indices. This suggests that subjects were unable to use momentary differences in level between formant and background harmonics, and supports the idea that, for cosine-phase stimuli, they were using information from the low-amplitude portions ("valleys") of the cochlea-filtered waveforms. In further conditions, the components were added in cosine phase and the AM had a different phase and/or different rate (10, 16, and 24 Hz) on the different formants. Scores were very similar to those obtained when the AM was identical for all formants. In experiment 2, the AM rate was at or close to 2 Hz. When all formants were modulated in phase at 2 Hz, very good performance was found for components added in cosine phase, and performance was essentially unaffected by making the AM different in rate and/or phase across formants. When the components were added in random phase, performance was well above chance when the formants were modulated in-phase at 2-Hz, but worsened markedly when the modulation differed in rate and/or phase across formants. Randomizing the level of each background harmonic caused performance to deteriorate and to become similar for cosine-phase and random-phase stimuli. Performance deteriorated further when the AM differed in phase across formants. The results suggest that, for a 2-Hz modulation rate, and when information from the valleys is not available, performance depends on momentary increases in level of the formant harmonics relative to the background.

Humans↗
PubMed2000

The influence of carrier level and frequency on modulation and beat-detection thresholds for sinusoidal carriers

This paper is concerned with modulation and beat detection for sinusoidal carriers. In the first experiment, temporal modulation transfer functions (TMTFs) were measured for carrier frequencies between 1 and 10 kHz. Modulation rates covered the range from 10 Hz to about the rate equaling the critical bandwidth at the carrier frequency. In experiment 2, TMTFs for three carrier frequencies were obtained as a function of the carrier level. In the final experiment, thresholds for the detection of either the lower or the upper modulation sideband (beat detection) were measured for "carrier" frequencies of 5 and 10 kHz, using the same range of modulation rates as in experiment 1. The TMTFs for carrier frequencies of 2 kHz and higher remained flat up to a modulation rate of about 100-130 Hz and had similar values across carrier frequencies. For higher rates, modulation thresholds initially increased and then decreased rapidly, reflecting the subjects' ability to resolve the sidebands spectrally. Detection thresholds generally improved with increasing carrier level, but large variations in the exact level dependence were observed, across subjects as well as across carrier frequencies. For beat rates up to about 70 Hz (at 5 kHz) and 100 Hz (at 10 kHz), beat detection thresholds were the same for the upper and the lower sidebands and were about 6 dB higher than the level per sideband at the modulation-detection threshold. At higher rates the threshold for both sidebands increased, but the increase was larger for the lower sideband. This reflects an asymmetry in masking with more masking towards lower frequencies. Only at rates well beyond the maximum of the TMTF did detection for the lower sideband start to be better than that for the upper sideband. The asymmetry at intermediate frequency separations can be explained by assuming that detection always takes place in filters centered above the stimulus spectrum. The shape of the TMTF and the beat-detection data reflects a limitation in resolving fast amplitude variations, which must occur central to the inner-ear filtering. Its characteristic resembles that of a first-order low-pass filter with a cutoff frequency of about 150 Hz.

Journal Article↗
PubMed2004

Agonist-induced internalization of leukotriene B(4) receptor 1 requires G-protein-coupled receptor kinase 2 but not arrestins.

The leukotriene B(4) (LTB(4)) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB(4) stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB(4), BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail-truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB(4), suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type-specific signaling in response to LTB(4), depending on GRK expression levels.

Animals↗
PubMed2006

Modulation of motor unit firing rates during a complex sinusoidal force task in young and older adults.

This study compared motor unit rate coding and muscular force control in the first dorsal interosseous muscle of older (n = 11, mean 72.3 yr) and young (n = 12, mean 18.7 yr) adults. Rate coding during a sinusoidal isometric force-matching task was evaluated using spectral analysis of the time-varying changes in firing rate. The task required force modulations to match a trajectory comprising the sum of 0.15- and 0.45-Hz sine waves. Based on the amplitude of spectral peaks at 0.15 and 0.45 Hz, the amplitude of force modulation was similar in young and older adults at both frequencies (F = 1.9, P = 0.17). Force modulation gain (FMG) was computed as the ratio of the amplitude of force modulation to the amplitude of firing rate modulation. To account for rate coding differences related to the properties of the motoneuron, recruitment threshold force was used as a covariate in age-group comparisons. At both task frequencies, firing rate was modulated with less amplitude (F = 0 14, P < 0.001) and FMG was greater (F = 0 27, P < 0.001) in the older adults. In its transformation of neural input to mechanical output, muscle is known to act as a low-pass filter. Compared with modulation at 0.15 Hz, less change in force per change in firing rate at 0.45 Hz (lower FMG; F = 0 67, P < 0.001), independent of age group, is consistent with this filtering effect. Our conclusion is that there is a reduced amplitude of firing rate modulation in older adults.

Action Potentials↗