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Biomedical subjects

R Ratcliff

Publications and source records attributed to R Ratcliff.

At least 19 recordsLinked to original sources
PubMed2003

Expression and regulation of the Na+-K+-2Cl- cotransporter NKCC1 in the normal and CFTR-deficient murine colon.

Defective regulation and/or reduced expression of the Na+-K+-2Cl- cotransporter NKCC1 may contribute to the severe secretory defect that is observed in cystic fibrosis, but data concerning the expression and function of NKCC1 in cystic fibrosis transmembrane conductance regulator (CFTR)-deficient cells are equivocal. We therefore investigated NKCC1 mRNA expression, Na+-K+-2Cl- cotransport activity and regulation by cAMP in crypts isolated from the proximal colon of CFTR-containing (CFTR (+/+)) and CFTR-deficient (CFTR (-/-)) mice. mRNA expression levels were determined by semiquantitative PCR, transport rates were measured fluorometrically in 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetomethylester (BCECF)-loaded crypts, cytoplasmic volume changes were assessed by confocal microscopy, and [Cl-]i changes were examined by N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) quenching. NKCC1 mRNA expression levels were not significantly reduced in CFTR (-/-) crypts compared to controls. Azosemide-sensitive NH4+ influx (used as a measure of Na+-K+-2Cl- cotransport) was 2.23 +/- 0.72 vs. 1.56 +/- 0.16 mM min-1, and increased by 63.6 % in (+/+) and 87.3 % in (-/-) crypts upon stimulation for 5 min with forskolin. After 20 min of stimulation with forskolin, the Na+-K+-2Cl- cotransport rates in (-/-) and (+/+) crypts were identical. Crypt cross-sectional area and [Cl-]i decreased only in (+/+) crypts upon stimulation. In conclusion, normal NKCC1 expression levels, somewhat reduced Na+-K+-2Cl- cotransport rates, but preserved activation by cAMP were found in colonic crypts from CFTR (-/-) mice, ruling out a severe dysfunction of the Na+-K+-2Cl- cotransporter in the CF intestine. Furthermore, these studies establish the existence of a direct, cell-volume- and [Cl-]i-independent activation of colonic NKCC1 by an increase in intracellular cAMP.

Animals↗
PubMed2002

cAMP-mediated regulation of murine intestinal/pancreatic Na+/HCO3- cotransporter subtype pNBC1.

Basolateral Na(+)-HCO(3)(-) cotransport is essential for intestinal anion secretion, and indirect evidence suggests that it may be stimulated by a rise of intracellular cAMP. We therefore investigated the expression, activity, and regulation by cAMP of the Na(+)-HCO(3)(-) cotransporter isoforms NBC1 and NBCn1 in isolated murine colonic crypts. Na(+)-HCO(3)(-) transport rates were measured fluorometrically in BCECF-loaded crypts, and mRNA expression levels and localization were determined by semiquantitative PCR and in situ hybridization. Acid-activated Na(+)-HCO(3)(-) cotransport rates were 5.07 +/- 0.7 mM/min and increased by 62% after forskolin stimulation. NBC1 mRNA was more abundant in colonic crypts than in surface cells, and crypts expressed far more NBC1 than NBCn1. To investigate whether the cAMP-induced Na(+)-HCO(3)(-) cotransport activation was secondary to secretion-associated changes in HCO(3)(-) or cell volume, we measured potential forskolin-induced changes in intracellular pH and assessed Na(+)-HCO(3)(-) transport activity in CFTR -/- crypts (in which no forskolin-induced cell shrinkage occurs). We found 30% reduced Na(+)-HCO(3)(-) transport rates in CFTR -/- compared with CFTR +/+ crypts but similar Na(+)-HCO(3)(-) cotransport activation by forskolin. These studies establish the existence of an intracellular HCO(3)(-) concentration- and cell volume-independent activation of colonic NBC by an increase in intracellular cAMP.

Animals↗
PubMed2002

A novel approach to pathogen reduction in biosolids: the enzymic hydrolyser.

Revision of the Sludge (Use in Agriculture) Regulations in the UK has resulted in the requirement of a final product standard in terms of E. coli per gram of dry solids. Conventional mesophilic digestion including 14-day secondary storage should normally provide adequate treatment to meet the Treated Sludge Standard. Any process capable of greater pathogen reduction would ensure more process security and compliance comfort. Such a process would be a welcome alternative to extra secondary storage where an existing works does not have sufficient capacity, particularly if the differences in costs between the options are small. Enzymic hydrolysis was found to be up to ten-fold more effective in E. coli reduction than conventional secondary digestion. A two-stage digestion process based on this technique has been developed by United Utilities and Montgomery Watson Harza (termed the enzymic hydrolyser, patent pending). Studies showed that the mean numbers of E. coli were significantly lower in the enzymic hydrolyser systems (P > 0.05; t = 13.19) compared to conventional digesters. Increased stability was a secondary benefit of the system (foam was eliminated or greatly reduced in the enzymic hydrolyser units). Another benefit of the system for retrofit to existing assets is the decreased tankage volumes required compared to secondary digestion to achieve more than twice the log kill of pathogens.

Bioreactors↗
PubMed2001

Counter model for word identification: reply to Bowers (1999).

The counter model (R. Ratcliff & G. McKoon, 1997) was designed to explain the normal processes of word identification and how they are influenced by a prior encounter with a word. The model accounts for the findings of word identification experiments in which words are flashed briefly. A crucial finding is that prior encounters with words typically lead to biases such that a previously encountered word is more likely to be given as a response. However, for low-frequency words, a prior encounter can improve overall performance (J. S. Bowers, 1999; E. M. Wagenmakers, R. Zeelenberg, & J. G. W. Raaijmakers, 2000). The authors show how the model can explain this result. Also, J. S. Bowers (1999) has claimed that some earlier data concerning dissimilar alternatives in forced-choice experiments that support the counter model are spurious, but the authors show that his claims are incorrect. In sum, the authors argue for a theoretical approach that offers a detailed description of the cognitive processes of word identification and explains performance across tasks, measures, and independent variables.

Bias↗
PubMed2001

A multinomial model for short-term priming in word identification.

A simple multinomial model for short-term priming in perceptual word identification is presented. In the experiments to which the model is applied, prime words are presented just prior to a flashed target word, and subjects must decide which of 2 alternative words matches the target. The model assumes that on some proportion of trials, confusion among the words leads to the decision being based on 1 of the prime words instead of the target. In addition, it is assumed that subjects sometimes discount a prime that matches 1 of the test alternatives and so choose the alternative that does not match. With these assumptions, the model fits the data from 5 experiments (including 4 used to develop the model known as ROUSE [responding optimally with unknown sources of evidence]; D. E. Huber, R. Shiffrin, K. Lyle, & K. Ruys, 2001). The multinomial model fits the data about as well as the ROUSE model and so should lead to further development and critical testing of both models.

Adult↗
PubMed2001

A comparison of four methods for simulating the diffusion process.

Four methods for the simulation of the Wiener process with constant drift and variance are described. These four methods are (1) approximating the diffusion process by a random walk with very small time steps; (2) drawing directly from the joint density of responses and reaction time by means of a (possibly) repeated application of a rejection algorithm; (3) using a discrete approximation to the stochastic differential equation describing the diffusion process; and (4) a probability integral transform method approximating the inverse of the cumulative distribution function of the diffusion process. The four methods for simulating response probabilities and response times are compared on two criteria: simulation speed and accuracy of the simulation. It is concluded that the rejection-based and probability integral transform method perform best on both criteria, and that the stochastic differential approximation is worst. An important drawback of the rejection method is that it is applicable only to the Wiener process, whereas the probability integral transform method is more general.

Algorithms↗
PubMed2001

The effects of aging on reaction time in a signal detection task.

The effects of aging on response time are examined in 2 simple signal detection tasks with young and older subjects (age 60 years and older). Older subjects were generally slower than young subjects, and standard Brinley plot analyses of response times showed typical results: slopes greater than 1 and (mostly) negative intercepts. R. Ratcliff, D. Spieler, and G. McKoon (2000) showed that the slopes of Brinley plots measure the relative standard deviations of the distributions of response times for older versus young subjects. Applying R. Ratcliff's (1978) diffusion model to fit the response times, their distributions, and response accuracy, it was found that the larger spread in older subjects' response times and their slowness relative to young subjects comes from a 50-ms slowing of the nondecision components of response time and more from conservative settings of response criteria.

Adolescent↗
PubMed2000

A diffusion model account of masking in two-choice letter identification.

The diffusion model developed by R. Ratcliff (1978, 1981, 1985, 1988) for 2-choice decisions was applied to data from 2 letter identification experiments. In the experiments, stimulus letters were displayed and then masked, and the stimulus onset asynchrony between letter and mask was manipulated to vary accuracy from near chance to near ceiling. A standard reaction time procedure was used in one experiment and a deadline procedure in the other. Two hypotheses about the effect of masking on the information provided to the decision process were contrasted: (a) The output of perception to the decision process varies with time, so that the information used by the decision process rises and falls, reflecting the stimulus onset and mask onset. (b) The output of perception to the decision is constant over time, reflecting information integrated over the time between the stimulus and mask onsets. The data were well fit by the diffusion model only with the assumption of constant information over time.

Adult↗
PubMed2000

A neural network model of implicit memory for object recognition.

People name well-known objects shown in pictures more quickly if they have studied them previously. The most common interpretation of this priming effect is that processing is facilitated by an implicit memory trace in a perceptual representation system. We show that object priming can be explained instead as a bias in information processing, without recourse to an implicit memory system. Assumptions about psychological decision-making processes and bias were added to a neural network model for object identification, and the model accounted for performance both qualitatively and quantitatively in four object identification experiments.

Adult↗
PubMed2000

Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice.

Sodium channel inhibitors block the enhanced Na+ reabsorption in cystic fibrosis (CF). Extracellular nucleotides facilitate Cl- secretion via Ca2+ gated Cl- channels. A combination of these effects may produce less viscid secretions in CF which are easier to expectorate. This study examined the effects of combining sodium channel blockers with uridine triphosphate (UTP) on nasal membrane potential difference (PD) in CF insertional null mutant mice (cftr(tm1HGU)), deltaF508 homozygous mice (cftr(tm1Cam)) and matched control animals. Median basal PD in the insertional CF mice and deltaF508 CF mice were -28 and -34 mV respectively. These values were significantly different to the control animals (-20 mV). Amiloride and loperamide reduced the PD in cftr(tm1HGU) CF mice (deltaPD 13 mV & 15 mV respectively) suggesting Na+ blockade. The subsequent addition of UTP in a chloride-free vehicle increased the PD (deltaPD -8- -12.5 mV). DeltaF508 mice showed significantly greater responses compared with CF insertional null mutant mice (p<0.05). The action of UTP was brief and not prolonged by the addition alpha-beta-methylene-adenosine 5' diphosphate. Suramin, a competitive antagonist of P2 purinoceptors blocked the action of UTP. In conclusion, this study demonstrated dose dependant nasal membrane potential changes in differences mice with uridine triphosphate in the presence of sodium channel blockers suggestive of chloride secretion. More stable analogues of uridine triphosphate in combination with long acting sodium channel blockers such as loperamide may have therapeutic potential in cystic fibrosis.

Amiloride↗
PubMed2000

Explicitly modeling the effects of aging on response time.

Research into the effects of aging on response time has focused on Brinley plots. Brinley plots are constructed by plotting mean response times for older subjects against those for young subjects for a set of experimental conditions. The typical result is a straight line with a slope greater than 1 and a negative intercept. This linear function has been interpreted as showing that aging leads to a general slowing of cognitive processes. In this article, we show that the slope of the Brinley plot is actually a measure of the relative standard deviations of older versus young subjects' response times; it is not a measure of general slowing. We examine current models of the effects of aging on mean response time and show how they might be reinterpreted. We also show how a more comprehensive model, Ratcliff's diffusion model (1978), can account for Brinley plot regularities and, at the same time, provide an account of accuracy rates, the shapes of response time distributions, and the relative speeds of error and correct response times, aspects of the data about which models designed to account for Brinley plots are mute. We conclude by endorsing a research approach that applies explicit models to response time data in aging in order to use the parameters of the model to interpret the effects of aging.

Aging↗
PubMed2000

Modeling the effects of repetition and word frequency in perceptual identification.

The counter model for word identification (Ratcliff & McKoon, 1997) has been challenged by recent empirical findings that performance on low-frequency words improves as the result of repetition of the words. We show that the model can accommodate this learning effect, and that it can do so without jeopardizing its explanations of the effects on word identification of a large number of other variables.

Cues↗
PubMed1999

Connectionist and diffusion models of reaction time.

Two connectionist frameworks, GRAIN (J. L. McClelland, 1993) and brain-state-in-a-box (J. A. Anderson, 1991), and R. Ratcliff's (1978) diffusion model were evaluated using data from a signal detection task. Dependent variables included response probabilities, reaction times for correct and error responses, and shapes of reaction-time distributions. The diffusion model accounted for all aspects of the data, including error reaction times that had previously been a problem for all response-time models. The connectionist models accounted for many aspects of the data adequately, but each failed to a greater or lesser degree in important ways except for one model that was similar to the diffusion model. The findings advance the development of the diffusion model and show that the long tradition of reaction-time research and theory is a fertile domain for development and testing of connectionist assumptions about how decisions are generated over time.

Adult↗
PubMed1998

Salmonella typhi uses CFTR to enter intestinal epithelial cells.

Homozygous mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF). In the heterozygous state, increased resistance to infectious diseases may maintain mutant CFTR alleles at high levels in selected populations. Here we investigate whether typhoid fever could be one such disease. The disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. We found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wild-type CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, a phenylalanine deleted at residue 508 (delta508). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous deltaF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than wild-type Cftr mice; no translocation occurred in deltaF508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound to S. typhi in the submucosa of Cftr wild-type mice than in deltaF508 heterozygous mice. We conclude that diminished levels of CFTR in heterozygotes may decrease susceptibility to typhoid fever.

Animals↗
PubMed1998

Memory-based language processing: psycholinguistic research in the 1990s.

There are two main domains of research in psycholinguistics: sentence processing, concerned with how the syntactic structures of sentences are computed, and text processing, concerned with how the meanings of larger units of text are understood. In recent sentence processing research, a new and controversial theme is that syntactic computations may rely heavily on statistical information about the relative frequencies with which different syntactic structures occur in the language. In text processing, recent research has focused on what information the words and ideas of a text evoke from long-term memory quickly, passively, and at low processing cost. Research in both domains has begun to use the information that can be obtained from large corpora of naturally occurring texts.

Humans↗
PubMed1998

Basal chloride currents in murine airway epithelial cells: modulation by CFTR.

We have isolated ciliated respiratory cells from the nasal epithelium of wild-type and cystic fibrosis (CF) null mice and used the patch-clamp technique to investigate their basal conductances. Current-clamp experiments on unstimulated cells indicated the presence of K+ and Cl- conductances and, under certain conditions, a small Na+ conductance. Voltage-clamp experiments revealed three distinct Cl- conductances. Itv-indep was time and voltage independent with a linear current-voltage (I-V) plot; Iv-act exhibited activation at potentials greater than +/- 50 mV, giving an S-shaped I-V plot; and Ihyp-act was activated by hyperpolarizing potentials and had an inwardly rectified I-V plot. The current density sequence was Ihyp-act = Iv-act >> Itv-indep. These conductances had Cl(-)-to-N-methyl-D-glucamine cation permeability ratios of between 2.8 and 10.3 and were unaffected by tamoxifen, flufenamate, glibenclamide, DIDS, and 5-nitro-2-(3-phenylpropylamino) benzoic acid but were inhibited by Zn2+ and Gd3+. Itv-indep and Iv-act were present in wild-type and CF cells at equal density and frequency. However, Ihyp-act was detected in only 3% of CF cells compared with 26% of wild-type cells, suggesting that this conductance may be modulated by cystic fibrosis transmembrane conductance regulator (CFTR).

Animals↗
PubMed1997

A functional CFTR protein is required for mouse intestinal cAMP-, cGMP- and Ca(2+)-dependent HCO3- secretion.

1. Most segments of the gastrointestinal tract secrete HCO3-, but the molecular nature of the secretory mechanisms has not been identified. We had previously speculated that the regulator for intestinal electrogenic HCO3- secretion is the cystic fibrosis transmembrane regulator (CFTR) channel. To prove this hypothesis, we have now measured HCO3- secretion by pH-stat titration, and recorded the electrical parameters of in vitro duodenum, jejunum and ileum of mice deficient in the gene for the CFTR protein ('CF-mice') and their normal littermates. 2. Basal HCO3- secretory rates were reduced in all small intestinal segments of CF mice. Forskolin, PGE2, 8-bromo-cAMP and VIP (cAMP-dependent agonists), heat-stable enterotoxin of Escherichia coli (STa), guanylin and 8-bromo-cGMP (cGMP-dependent agonists) and carbachol (Ca2+ dependent) stimulated both the short-circuit current (Isc) and the HCO3- secretory rate (JHCO3-) in all intestinal segments in normal mice, whereas none of these agonists had any effect on JHCO3- in the intestine of CF mice. 3. To investigate whether Cl(-)-HCO3- exchangers, which have been implicated in mediating the response to some of these agonists in the intestine, were similarly active in the small intestine of normal and CF mice, we studied Cl- gradient-driven 36Cl- uptake into brush-border membrane (BBM) vesicles isolated from normal and CF mouse small intestine. Both the time course and the peak value for 4,4'-diisothiocyanostilbene-2',2-disulphonic acid (DIDS)-inhibited 36Cl- uptake was similar in normal and CF mice BBM vesicles. 4. In summary, the results demonstrate that the presence of the CFTR channel is necessary for agonist-induced stimulation of electrogenic HCO3- secretion in all segments of the small intestine, and all three intracellular signal transduction pathways stimulate HCO3- secretion exclusively via activation of the CFTR channel.

8-Bromo Cyclic Adenosine Monophosphate↗