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PubMedDate not supplied

Microprocessor controlled particle counter system.

Operation of an optical particle counter with microprocessor control of particle size calibration and data recording is described. Sensors are available to measure particles 0.1 micron and larger. A system with a range from 2 microns to 125 microns will be described. Calibration data based on response to monosized particles are stored in the system memory, along with sensor resolution information and system changes since the last calibration. The instrument adjusts the particle size channels internally for the selected calibration base particles. Once calibrated, the instrument can be set to report data in operator selectable sizes or any of four default particle size groups. Three default groups are based on pharmaceutical and hydraulic fluid power industry standards and one is set in a logarithmic spread of 16 particle sizes that covers the system dynamic range. A front-panel keyboard and CRT display allow selection and control of all operating parameters. These include reported size ranges, liquid sample size, number of sample replications (including suspect sample rejection), data averaging, and comparison of data from two sensors. Differential or cumulative data can be reported in tabular or histogram format. Data can be sent to an internal thermal printer or to an RS-232C output.

Calibration↗
PubMed2006

The molecular receptive range of an olfactory receptor in vivo (Drosophila melanogaster Or22a).

Understanding how odors are coded within an olfactory system requires knowledge about its input. This is constituted by the molecular receptive ranges (MRR) of olfactory sensory neurons that converge in the glomeruli of the olfactory bulb (vertebrates) or the antennal lobe (AL, insects). Aiming at a comprehensive characterization of MRRs in Drosophila melanogaster we measured odor-evoked calcium responses in olfactory sensory neurons that express the olfactory receptor Or22a. We used an automated stimulus application system to screen [Ca(2+)] responses to 104 odors both in the antenna (sensory transduction) and in the AL (neuronal transmission). At 10(-2) (vol/vol) dilution, 39 odors elicited at least a half-maximal response. For these odorants we established dose-response relationships over their entire dynamic range. We tested 15 additional chemicals that are structurally related to the most efficient odors. Ethyl hexanoate and methyl hexanoate were the best stimuli, eliciting consistent responses at dilutions as low as 10(-9). Two substances led to calcium decrease, suggesting that Or22a might be constitutively active, and that these substances might act as inverse agonists, reminiscent of G-protein coupled receptors. There was no difference between the antennal and the AL MRR. Furthermore we show that Or22a has a broad yet selective MRR, and must be functionally described both as a specialist and a generalist. Both these descriptions are ecologically relevant. Given that adult Drosophila use approximately 43 ORs, a complete description of all MRRs appears now in reach.

Animals↗
PubMed1995

Extracochlear electrically evoked otoacoustic emissions: a model for in vivo assessment of outer hair cell electromotility.

Cochlear outer hair cell (OHC) motion in response to changes in membrane potential (electromotility) has been extensively studied in vitro. Electromotility is thought to actively control the micromechanical properties of the sensory epithelium. In order to understand how OHC electromotility contributes to normal cochlear responses, its role must be assessed in vivo. We have developed a novel animal model for the study of electromotility in vivo. Alternating current is delivered by an electrode to the round window (RW) of gerbil cochlea and the electrically evoked otoacoustic emission (EEOE) is measured from the external ear canal. As much as 45 dB SPL sound could be generated by about 200 micro A RMS extracochlear current delivered to the RW. Except for the fine structure of EEOE transfer function curves, the magnitude of the EEOE has a bandpass appearance ranging from about 4 to 32 kHz and shows a positive linear relationship to the current intensity. The phase has a linear relationship with frequency and shows no significant change with current intensity. Local intracochlear perfusion of 4% paraformaldehyde caused EEOE to decrease by approximately 20 dB. These results indicate that the EEOE is probably generated by OHCs near the electrode location and propagates to the external ear canal. In addition, the force generated by OHCs in vivo is a linear function of the electrical stimulus. The major advantages of our model include: (1) non-invasive procedure and normal cochlea; (2) wide dynamic range of the measurement; (3) simple and easy preparation. With these features this model has potential applications in basic hearing research and in the diagnosis and treatment of otological patients.

Animals↗
PubMed2005

Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins.

Quantitative LC-MS/MS assays were designed for tryptic peptides representing 53 high and medium abundance proteins in human plasma using a multiplexed multiple reaction monitoring (MRM) approach. Of these, 47 produced acceptable quantitative data, demonstrating within-run coefficients of variation (CVs) (n = 10) of 2-22% (78% of assays had CV <10%). A number of peptides gave CVs in the range 2-7% in five experiments (10 replicate runs each) continuously measuring 137 MRMs, demonstrating the precision achievable in complex digests. Depletion of six high abundance proteins by immunosubtraction significantly improved CVs compared with whole plasma, but analytes could be detected in both sample types. Replicate digest and depletion/digest runs yielded correlation coefficients (R(2)) of 0.995 and 0.989, respectively. Absolute analyte specificity for each peptide was demonstrated using MRM-triggered MS/MS scans. Reliable detection of L-selectin (measured at 0.67 microg/ml) indicates that proteins down to the microg/ml level can be quantitated in plasma with minimal sample preparation, yielding a dynamic range of 4.5 orders of magnitude in a single experiment. Peptide MRM measurements in plasma digests thus provide a rapid and specific assay platform for biomarker validation, one that can be extended to lower abundance proteins by enrichment of specific target peptides (stable isotope standards and capture by anti-peptide antibodies (SISCAPA)).

Amino Acid Sequence↗
PubMed2004

Quantitation of canine coronavirus RNA in the faeces of dogs by TaqMan RT-PCR.

A TaqMan fluorogenic reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed for the detection and quantitation of canine coronavirus (CCoV) RNA in the faeces of naturally or experimentally infected dogs. The CCoV fluorogenic RT-PCR assay, which targeted the ORF5 (M gene), was more sensitive than a conventional RT-PCR assay targeting the same gene, showing a detection limit of 10 copies of CCoV standard RNA, and was linear from 10 to 10(8) copies, allowing quantitation of samples with a wide range of CCoV RNA loads. A total of 78 faecal samples of diarrhoeic dogs were tested simultaneously by conventional and fluorogenic RT-PCR: 29 were negative by both techniques, whereas 27 tested positive by conventional RT-PCR and 48 by the established CCoV fluorogenic assay. One sample, which was positive by conventional RT-PCR, gave no signal in the fluorogenic assay. In addition, by the fluorogenic assay CCoV shedding in the faecal samples of an experimentally infected dog was monitored for 28 days. The high sensitivity, simplicity and reproducibility of the CCoV fluorogenic RT-PCR assay, combined with its wide dynamic range and high throughput, make this method especially suitable for efficacy trials on CCoV vaccines.

Animals↗
PubMed2001

RANTES and MIP-1beta mRNA expression in human peripheral blood mononuclear cells: transcript quantification using NASBA technology.

The importance of chemokines in the immune response, as well as in a range of specific disease states, is becoming increasingly apparent. The role of CC- (or beta-) chemokines and their receptors in the pathology and mechanisms of HIV-1 infection has served to intensify interest in these factors. Although the functionality of these factors resides in their protein forms, assays for the detection and quantification of these protein factors in clinical samples are not readily available. Consequently, we designed NASBA-based assays for the quantification of the mRNA encoding two members of the CC-chemokine family: RANTES and MIP-1beta. The NASBA-based assays are extremely sensitive, accurate, and reproducible across a dynamic range of at least four orders of magnitude. Inter-assay performance is comparable to intra-assay performance. We applied these methods to the analysis of normal human PBMC and PBMC from HIV-1 infected individuals. Although MIP-1beta mRNA levels are higher than RANTES levels in both populations, RANTES levels in HIV-1+ patients are higher than in normal individuals. The utility of these assays in longitudinal studies of specific subpopulations of cells, as well as their potential use in clinical diagnostics, is discussed.

Blood Circulation↗
PubMed2002

Enhancement of calcium signalling dynamics and stability by delayed modulation of the plasma-membrane calcium-ATPase in human T cells.

In addition to its homeostatic role of maintaining low resting levels of intracellular calcium ([Ca2+](i)), the plasma-membrane calcium-ATPase (PMCA) may actively contribute to the generation of complex Ca2+ signals. We have investigated the role of the PMCA in shaping Ca2+ signals in Jurkat human leukaemic T cells using single-cell voltage-clamp and calcium-imaging techniques. Crosslinking the T-cell receptor with the monoclonal antibody OKT3 induces a biphasic elevation in [Ca2+](i) consisting of a rapid overshoot to a level > 1 microM, followed by a slow decay to a plateau of approximately 0.5 microM. A similar overshoot was triggered by a constant level of Ca2+ influx through calcium-release-activated Ca2+ (CRAC) channels in thapsigargin-treated cells, due to a delayed increase in the rate of Ca2+ clearance by the PMCA. Following a rise in [Ca2+](i), PMCA activity increased in two phases: a rapid increase followed by a further calcium-dependent increase of up to approximately fivefold over 10-60 s, termed modulation. After the return of [Ca2+](i) to baseline levels, the PMCA recovered slowly from modulation (tau approximately 4 min), effectively retaining a 'memory' of the previous [Ca2+](i) elevation. Using a Michaelis-Menten model with appropriate corrections for cytoplasmic Ca2+ buffering, we found that modulation extended the dynamic range of PMCA activity by increasing both the maximal pump rate and Ca2+ sensitivity (reduction of K(M)). A simple flux model shows how pump modulation and its reversal produce the initial overshoot of the biphasic [Ca2+](i) response. The modulation of PMCA activity enhanced the stability of Ca2+ signalling by adjusting the efflux rate to match influx through CRAC channels, even at high [Ca2+](i) levels that saturate the transport sites and would otherwise render the cell defenceless against additional Ca2+ influx. At the same time, the delay in modulation enables small Ca2+ fluxes to transiently elevate [Ca2+](i), thus enhancing Ca2+ signalling dynamics.

Adenosine Triphosphate↗
PubMed2005

Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase.

OBJECTIVE: Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. METHODS: This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. RESULTS: After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion (<10 degrees ) and in the time taken to stand, walk, and turn starting from a seated position (Expanded Timed Get-Up and Go test). Improvement in pulmonary function based on forced vital capacity and forced expiratory volume at 1 minute in the absence of growth was observed in 3 of 6 patients, and the observed gains occurred in the 24- to 48-week treatment interval. A mean decrease of 76% in urinary excretion of glycosaminoglycans indicated that a satisfactory biochemical response was achieved and the ERT was well tolerated. CONCLUSIONS: The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.

Adolescent↗
PubMedDate not supplied

Computer simulation of rapidly responding forced exponential systems.

Two common problems in computer simulations are the decisions to ignore or include a particular element of a system under study in a model and the choice of an appropriate integration algorithm. To examine aspects of these problems, a simple exponential system is considered in which a large simulation error is induced by a rather small truncation error. The effect of computational precision, step size and hardware selection on this error is examined at standard and extended precisions over a range of step sizes and on a variety of computers. For this model, simulation accuracy is an exponential function of the number of bits in the mantissa of the computer word. Optimal step size is a function of accuracy required and precision used; a trade-off between truncation and round-off errors becomes important as accuracy requirements increase. Machine selection is important primarily in economic terms if the required precision is available. We conclude that the effect on a simulation of small terms such as truncation errors can be unexpectedly large, that solutions should always be checked, and that high precision and wide dynamic range are important to the successful computer simulation of models such as that examined.

Computers↗
PubMed1975

Neurophysiological characterization of the anterolateral quadrant neurons subserving pain in M. mulatta.

An electrophysiological analysis has been made of 82 L7 dorsal horn neurons antidromically activated from the contralateral C1 anterolateral quadrant (ALQ) of unanesthetized rhesus monkeys (bilateral carotid ligation). This analysis was made to compare refractory periods and antidromic activation thresholds with these same parameters of ALQ stimulation required to produce pain in conscious humans. Refractory periods of laminae IV-VI cells that were optimally but not exclusively responsive to noxious skin stimulation ranged from 0.8 to 2.8 msec (m = 1.5) and were briefer than those of lamina I cells. The latter ranged from 1.1 to 10 msec (m = 4.7 msec). Electrical thresholds of laminae IV-VI cells were, in general, much lower than those of lamina I cells. Unlike lamina I cells, refractory periods and electrical thresholds of laminae IV-VI nociceptive neurons closely parallel those of ALQ-evoked pain in man. However, both lamina I and laminae IV-VI neurons usually responded to nociceptive skin temperatures (greater than 43 degrees C). This analysis indicates that pain may be signaled by the combined output of dorsal horn laminae I and IV-VI but that activation of only laminae IV-VI wide dynamic range neurons is sufficient to produce pain.

Action Potentials↗
PubMed1974

Inhibition within the trigeminal nucleus induced by afferent inputs and its influence on stimulus coding by mechanosensitive neurones.

1. In decerebrate, unanaesthetized cats two thirds of slowly adapting mechanosensitive neurones sampled in the trigeminal nucleus oralis exhibited inhibition in response to conditioning mechanical stimulation applied beyond their excitatory receptive fields. The influence of this inhibition was examined over the response range of these neurones using controlled, reproducible natural stimulation procedures.2. The extent of the inhibition was graded according to the intensity of the conditioning stimulus. It was evoked most strongly by vibratory skin indentation which very effectively excites rapidly adapting afferent fibres. Tonic conditioning inputs associated with steady skin indentation were less effective.3. The slope of stimulus-response relationships constructed from responses to inputs from the excitatory receptive field was reduced in 42% of trigeminal nuclear cells in the presence of afferent-induced inhibition. In the remainder the slope was unchanged.4. There was no evidence, in the neurones subject to inhibition, of an expansion of their dynamic range defined as the range of stimulus intensities over which a neurone exhibited a graded responsiveness.5. The variability in responses of an individual neurone at a given stimulus intensity was unchanged by this inhibition.6. Analysis of the stimulus-response data using information theory statistics revealed that neurones which underwent a reduction in the slope of their stimulus-response relationship in the presence of inhibition displayed a reduced capacity for defining the intensity of skin indentation. This capacity was not modified in those neurones where the slope was unchanged by the peripherally evoked inhibition.

Action Potentials↗
PubMed2000

Efficacy of 3 commonly used hearing aid circuits: A crossover trial. NIDCD/VA Hearing Aid Clinical Trial Group.

CONTEXT: Numerous studies have demonstrated that hearing aids provide significant benefit for a wide range of sensorineural hearing loss, but no carefully controlled, multicenter clinical trials comparing hearing aid efficacy have been conducted. OBJECTIVE: To compare the benefits provided to patients with sensorineural hearing loss by 3 commonly used hearing aid circuits. DESIGN: Double-blind, 3-period, 3-treatment crossover trial conducted from May 1996 to February 1998. SETTING: Eight audiology laboratories at Department of Veterans Affairs medical centers across the United States. PATIENTS: A sample of 360 patients with bilateral sensorineural hearing loss (mean age, 67.2 years; 57% male; 78.6% white). INTERVENTION: Patients were randomly assigned to 1 of 6 sequences of linear peak clipper (PC), compression limiter (CL), and wide dynamic range compressor (WDRC) hearing aid circuits. All patients wore each of the 3 hearing aids, which were installed in identical casements, for 3 months. MAIN OUTCOME MEASURES: Results of tests of speech recognition, sound quality, and subjective hearing aid benefit, administered at baseline and after each 3-month intervention with and without a hearing aid. At the end of the experiment, patients ranked the 3 hearing aid circuits. RESULTS: Each circuit markedly improved speech recognition, with greater improvement observed for soft and conversationally loud speech (all 52-dB and 62-dB conditions, P</=.001). All 3 circuits significantly reduced the frequency of problems encountered in verbal communication. Some test results suggested that CL and WDRC circuits provided a significantly better listening experience than PC circuits in word recognition (P =.002), loudness (P =.003), overall liking (P =.001), aversiveness of environmental sounds (P =.02), and distortion (P =.02). In the rank-order ratings, patients preferred the CL hearing aid circuits more frequently (41.6%) than the WDRC (29.8%) and the PC (28.6%) (P =.001 for CL vs both WDRC and PC). CONCLUSIONS: Each circuit provided significant benefit in quiet and noisy listening situations. The CL and WDRC circuits appeared to provide superior benefits compared with the PC, although the differences between them were much less than the differences between the aided vs unaided conditions. JAMA. 2000;284:1806-1813.

Adult↗
PubMed2001

Changes in dorsal horn neuronal responses in an experimental wrist contracture model.

Joint contracture, a major complication after casting, usually makes the therapeutic outcome worse by causing a limited range of motion and related pain. We developed rat models of wrist contracture with fracture of the radius (group A) and wrist contracture without fracture (group B), and investigated whether contracture and fracture changed the characteristics of cervical dorsal horn neuronal responses and the behavior of the animals. After 4 weeks of immobilization, both groups showed wrist contracture and disuse tendencies in the treated forelimb. In an electrophysiological study, the responses of 403 cervical dorsal horn neurons to mechanical stimuli were examined. In normal (control) animals, the neurons had the following distribution: 63% were low-threshold (LT); 15% were high-threshold (HT); and 22% were wide-dynamic-range (WDR). In group A, the distribution of the neurons changed to 51% LT, 16% HT, and 33% WDR. Similar changes were observed for group B. Responses during wrist movement were also examined. Forty-one percent of cells in the control group were responsive to the movements, whereas the number of neurons responding to motion stimulus in both groups A and B was increased, to 77%. The changed population of WDR and LT neurons responding to wrist movement suggests that the characteristics of dorsal horn neurons may undergo plastic changes after contracture.

Animals↗
PubMed2003

An investigation of input level range for the nucleus 24 cochlear implant system: speech perception performance, program preference, and loudness comfort ratings.

OBJECTIVE: Cochlear implant recipients often have limited access to lower level speech sounds. In this study we evaluated the effects of varying the input range characteristics of the Nucleus 24 cochlear implant system on recognition of vowels, consonants, and sentences in noise and on listening in everyday life. DESIGN: Twelve subjects participated in the study that was divided into two parts. In Part 1 subjects used speech processor (Nucleus 24 SPrint trade mark ) programs adjusted for three input sensitivity settings: a standard or default microphone sensitivity setting (MS 8), a setting that increased the input sensitivity by 10.5 dB (MS 15), and the same setting that increased input sensitivity but also incorporated the automatic sensitivity control (ASC; i.e., MS 15A) that is designed to reduce the loudness of noise. The default instantaneous input dynamic range (IIDR) of 30 dB was used in these programs (i.e., base level of 4; BL 4). Subjects were tested using each sensitivity program with vowels and consonants presented at very low to casual conversational levels of 40 dB SPL and 55 dB SPL, respectively. They were also tested with sentences presented at a raised level of 65 dB SPL in multi-talker babble at individually determined signal to noise ratios. In addition, subjects were given experience outside of the laboratory for several weeks. They were asked to complete a questionnaire where they compared the programs in different listening situations as well as the loudness of environmental sounds, and state the setting they preferred overall. In Part 2 of the study, subjects used two programs. The first program was their preferred sensitivity program from Part 1 that had an IIDR of 30 dB (BL 4). Seven subjects used MS 8 and four used MS 15, and one used the noise reduction program MS 15A. The second program used the same microphone sensitivity but had the IIDR extended by an additional 8 to 10 dB (BL 1/0). These two programs were evaluated similarly in the speech laboratory and with take-home experience as in Part 1. RESULTS PART 1: Increasing the microphone input sensitivity by 10.5 dB (from MS 8 to MS 15) significantly improved the perception of vowels and consonants at 40 and 55 dB SPL. The group mean improvement in vowel scores was 25 percentage points at 40 dB SPL and 4 percentage points at 55 dB SPL. The group mean improvement for consonants was 23 percentage points at 40 dB SPL and 11 percentage points at 55 dB SPL. Increased input sensitivity did not significantly reduce the perception of sentences presented at 65 dB SPL in babble despite the fact that speech peaks were then within the compressed range above the SPrint processor's automatic gain control (AGC) knee-point. Although there was a demonstrable advantage for perception of low-level speech with the higher input sensitivity (MS 15 and 15A), seven of the 12 subjects preferred MS 8, four preferred MS 15 or 15A, and one had no preference overall. Approximately half the subjects preferred MS 8 across the 18 listening situations, whereas an average of two subjects preferred MS 15 or 15A. The increased microphone sensitivity of MS 15 substantially increased the loudness of environmental sounds. However, use of the ASC noise reduction setting with MS 15 reduced the loudness of environmental sounds to equal or below that for MS 8. RESULTS PART 2: The increased instantaneous input range gave some improvement (8 to 9 percentage points for the 40 dB SPL presentation level) in the perception of consonants. There was no statistically significant increase in vowel scores. Mean scores for sentences presented at 65 dB SPL in babble were significantly lower (5 percentage points) for the increased IIDR setting. Subjects had no preference for the increased IIDR over the default. The IIDR setting had no effect on the loudness of environmental sounds. CONCLUSIONS: Given the fact that individuals differ in threshold (T) and comfort (C) levels for electrical stimulation, and preferred microphone sensitivity, volume control, and noise-reduction settings, it is essential for the clinicid recipient to determine what combination is best for the individual over several sessions. The results of this study clearly show the advantage of using higher microphone sensitivity settings than the default MS 8 to provide better speech recognition for low-level stimuli. However, it was also necessary to adjust other parameters such as map C levels, automatic sensitivity control and base level, to optimize loudness comfort in the diversity of listening situations an individual encounters in everyday life.

Auditory Threshold↗
PubMed2004

A PFG NMR experiment for translational diffusion measurements in low-viscosity solvents containing multiple resonances.

Pulsed gradient simulated-echo (PGSE) NMR diffusion measurements provide a facile and accurate means for determining the self-diffusion coefficients for molecules over a wide range of sizes and conditions. The measurement of diffusion in solvents of low intrinsic viscosity is particularly challenging, due to the persistent presence of convection. Although convection can occur in most solvent systems at elevated temperatures, in lower viscosity solvents (e.g., short chain alkanes), convection may manifest itself even at ambient laboratory temperatures. In most circumstances, solvent suppression will also be required, and for solvents that have multiple resonances, effective suppression can likewise represent a substantial challenge. In this article, we report an NMR experiment that combines a double-stimulated echo PFG approach with a WET-based solvent suppression scheme that effectively and simultaneously address the issues of dynamic range and the deleterious effects of convection. The experiment described will be of general benefit to studies aimed at the characterization of diffusion of single molecules directly dissolved in low-viscosity solvents, and should also be of substantial utility in studies of supramolecular assemblies such as reverse-micelles dissolved in apolar solvents.

Alkanes↗
PubMed1996

Temporal mapping of gene expression levels during the differentiation of individual primary hematopoietic cells.

A hierarchical order of gene expression has been proposed to control developmental events in hematopoiesis, but direct demonstration of the temporal relationships between regulatory gene expression and differentiation has been difficult to achieve. We modified a single-cell PCR method to detect 2-fold changes in mRNA copies per cell (dynamic range, 250-250,000 copies/cell) and used it to sequentially quantitate gene expression levels as single primitive (CD34+,CD38-) progenitor cells underwent differentiation to become erythrocytes, granulocytes, or monocyte/macrophages. Markers of differentiation such as CD34 or cytokine receptor mRNAs and transcription factors associated with their regulation were assessed. All transcription factors tested were expressed in multipotent progenitors. During lineage-specific differentiation, however, distinct patterns of expression emerged. SCL, GATA-2, and GATA-1 expression sequentially extinguished during erythroid differentiation. PU.1, AML1B, and C/EBP alpha expression profiles and their relationship to cytokine receptor expression in maturing granulocytes could be distinguished from similar profiles in monocytic cells. These data characterize the dynamics of gene expression accompanying blood cell development and define a signature gene expression pattern for specific stages of hematopoietic differentiation.

Adult↗
PubMed2005

Effects of inhibitory feedback in a network model of avian brain stem.

The avian auditory brain stem consists of a network of specialized nuclei, including nucleus laminaris (NL) and superior olivary nucleus (SON). NL cells show sensitivity to interaural time difference (ITD), a critical cue that underlies spatial hearing. SON cells provide inhibitory feedback to the rest of the network. Empirical data suggest that feedback inhibition from SON could increase the ITD sensitivity of NL across sound level. Using a bilateral network model, we assess the effects of SON feedback inhibition. Individual cells are specified as modified leaky-integrate-and-fire neurons with time constants and thresholds that vary with inhibitory input. Acoustic sound level is reflected in the discharge rates of the model auditory-nerve fibers, which innervate the network. Simulations show that with SON inhibitory feedback, ITD sensitivity is maintained in model NL cells over a threefold range in auditory-nerve discharge rate. In contrast, without SON feedback inhibition, ITD sensitivity is significantly reduced as input rates are increased. Feedback inhibition is most beneficial in maintaining ITD sensitivity at high-input rates (simulating high sound levels). With SON inhibition, ITD sensitivity is maintained for both interaurally balanced inputs (simulating an on-center sound source) and interaurally imbalanced inputs (simulating a lateralized source). Further, the empirically observed temporal build-up of SON inhibition and the presence of reciprocal inhibitory connections between the ipsi- and contralateral SON both improve ITD sensitivity. In sum, our network model shows that inhibitory feedback can substantially increase the sensitivity and dynamic range of ITD coding in the avian auditory brain stem.

Action Potentials↗
PubMedDate not supplied

A beam intensity monitor for the Loma Linda cancer therapy proton accelerator.

A beam intensity monitor was tested in a 230-MeV proton beam at the Loma Linda Proton Therapy Accelerator during its commissioning at Fermi National Accelerator Laboratory. The intensity monitor was designed to regulate the beam intensity extracted from the proton synchrotron. The proton beam is tunable between 70 and 250 MeV with an adjustable intensity between 10(10) and 10(11) protons per spill. A beam spill is typically 1 s long with a 2-s repetition period. The intensity monitor must be radiation hard, expose minimum mass to the beam, and measure intensity to 1% in 1-ms time intervals. To this end, a 5-cm-thick xenon gas scintillator optically coupled to a photomultiplier tube (PMT) was tested to measure its response to the proton beam. The gas cell was operated at 1.2 atm of pressure and has 12.7-microns-thick titanium entrance and exit foils. The total mass exposed to the beam is 0.14 g/cm2 and is dominated by the titanium windows. This mass corresponds to a range attenuation equal to 1.4 mm of water. The energy lost to the xenon gas is about 70 keV per proton. Each passing proton will produce approximately 2000 photons. With a detection efficiency on the order of 0.05% for this UV light, one would anticipate over 10(10) photoelectrons per second. In a 1-ms time bin there will be approximately 10(7) photoelectrons. This yields a resolution limited by systematics. For unregulated 0.4-s proton spills, we observe a response bandwidth in excess of 10(4) Hz. While signal-to-noise and linearity were not easily measured, we estimate as few as 10(3) protons can be observed suggesting a dynamic range in excess of 10(5) is available.

Humans↗