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At least 253 records · Page 14Linked to original sources

Genome-wide strategies for detecting multiple loci that influence complex diseases.

After nearly 10 years of intense academic and commercial research effort, large genome-wide association studies for common complex diseases are now imminent. Although these conditions involve a complex relationship between genotype and phenotype, including interactions between unlinked loci, the prevailing strategies for analysis of such studies focus on the locus-by-locus paradigm. Here we consider analytical methods that explicitly look for statistical interactions between loci. We show first that they are computationally feasible, even for studies of hundreds of thousands of loci, and second that even with a conservative correction for multiple testing, they can be more powerful than traditional analyses under a range of models for interlocus interactions. We also show that plausible variations across populations in allele frequencies among interacting loci can markedly affect the power to detect their marginal effects, which may account in part for the well-known difficulties in replicating association results. These results suggest that searching for interactions among genetic loci can be fruitfully incorporated into analysis strategies for genome-wide association studies.

Alleles↗

Interactions of organic calcium channel antagonists with calcium channels in single frog atrial cells.

Inhibition of whole-cell calcium currents in enzymatically dispersed frog atrial myocytes by D-600, diltiazem, and nifedipine was studied using a single-micropipette voltage-clamp technique. The objective of these experiments was to test the applicability of a modulated-receptor hypothesis similar to that proposed for local anesthetic interactions with sodium channels to account for the tonic and frequency-dependent interactions of these organic compounds with myocardial calcium channels. Data consistent with such a hypothesis include: (a) prominent use-dependent block of iCa by D-600 and diltiazem, which are predominantly charged at physiological pH; (b) iCa block by an externally applied, permanently charged dihydropyridine derivative is greatly attenuated; (c) all three antagonists produce large negative shifts in the voltage dependence of iCa availability; (d) block of iCa by these compounds is state-dependent; (e) reactivation of iCa in the presence of all three antagonists is biexponential, which suggests that drug-free channels recover with a normal time course and drug-bound channels recover more slowly; and (f) the kinetics of the drug-induced slow iCa recovery process may be determined largely by factors such as size and molecular weight, in addition to lipid solubility of the compounds. Experiments in which the pH was modified, however, reveal some important differences for the interaction of organic calcium antagonists with myocardial calcium channels. Acidification, in addition to changing the proportion of charged and neutral antagonist in solution, was found to selectively antagonize tonic inhibition of iCa by diltiazem and nifedipine, without changing the kinetics of the drug-induced slow iCa reactivation process. It is concluded that two distinct receptor sites may be involved in block of iCa by some of these compounds: a proton-accessible site and a proton-inaccessible site.

Animals↗

In silico predicted robustness of viroid RNA secondary structures. II. Interaction between mutation pairs.

Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as highly branched structures. In a previous study, we used RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. Here we used the same approach to explore the sign and strength of epistasis among pairs of random mutations. We found that antagonistic interactions were more abundant than synergistic ones. However, despite their lower frequency, synergistic interactions tended to be more intense. Mutational robustness and the intensity of epistasis were correlated such that viroid species with large average mutational effects showed stronger antagonistic epistasis, whereas viroids with mild average mutational effects showed weaker antagonistic interactions. The strength of antagonistic epistasis decreased with genome complexity as a consequence of the gained robustness of duplicated genomes. In good agreement with our previous finding of an evolutionary trend toward increased robustness, we now found a trend toward reduced antagonistic epistasis.

Base Pairing↗

Effects of filler type in naming: change in time criterion or attentional control of pathways?

We report two naming experiments examining the effects of filler type on the size of regularity and frequency effects. Low-frequency exception words were used as one filler type in both experiments. Their effects were contrasted with the effects of nonword fillers (Experiment 1) and low-frequency regular word fillers (Experiment 2). In both experiments, the size of the regularity effect was unaffected by the filler type manipulation. In contrast, the frequency effect interacted with filler type such that relative to the low-frequency exception filler environment, the size of the frequency effect was reduced in the environment of low frequency regular word fillers, but not in the environment of nonword fillers. These results appear to be better explained in terms of Lupker, Brown, and Colombo's (1997) flexible time-criterion framework than in terms of a pathway control hypothesis (e.g., Zevin & Balota, 2000).

Analysis of Variance↗

Foveal contrast thresholds exhibit spatial-frequency- and polarity-specific contour interactions.

Traditionally, contour interaction has been investigated at the visual acuity limit using a Landolt C and flanking bars, performance being quantified in terms of a percent correct measure. More recently, it has been shown that the properties of the contour interaction are different when larger stimuli are used: Contour interaction is not polarity specific, and spatial frequency tuning for an unflanked C is broader. Here we quantify contour interaction for stimuli 5x larger than the resolution limit in terms of contrast thresholds. We show that polarity of bars has little effect on unfiltered stimuli but does show very different effects on the spatial-frequency-tuning curves for discrimination of the Landolt C. This explains the polarity dependence of crowding at the visual acuity limit and its independence for larger unfiltered targets. Thus the underlying filtering function is composed of more than one mechanism, affected differently depending on the relative polarity of the test and flank contours.

Contrast Sensitivity↗

Low-frequency activity in the binaural interaction component of the auditory brain stem response.

The purpose of this study were to determine (1) the contribution of low-frequency activity in the auditory brain stem response (ABR) to the binaural interaction component, and (2) an optimal set of parameters for recording the binaural interaction component. ABRs were recorded from 12 adult subjects with normal hearing using 1000 Hz tone pips at three stimulation rates (10, 25, and 50/sec) and two physiological filters (150-3000 and 30-3000 Hz). The latencies of wave V in the sum of the left and right monaural responses [V(L + R)] were shorter with the 150 to 3000 Hz filter than with the 30 to 3000 Hz filter, whereas the amplitudes of V(L + R) and peak A of the binaural interaction component were similar. The amplitudes of V(L + R) and A were larger for 50/sec than for 10 or 25/sec, but the amplitude ratio of peak A to wave V(L + R) was not different. In conclusion, (1) the activity between 30 to 150 Hz did not enhance the binaural interaction component, and (2) the largest and most reliable binaural interaction component was recorded with a rate of 50/sec and a filter setting of 150 to 3000 Hz.

Acoustic Stimulation↗

Measuring fundamental frequencies in local field potentials.

Neural processes display rhythmic oscillations in local field potentials; identification of their characteristic frequencies is complicated due to their highly non-stationary nature. A simple technique, combining Fourier transforms and correlation coefficients yields unambiguous determinations of the frequencies without a priori filtering. This procedure also provides quantitative information concerning interactions between frequencies. Fundamental frequencies in local field potential data acquired from the hippocampus, cortex, and striatum from awake, behaving rats were calculated using this technique. Characteristic frequencies identified using this technique from hippocampus and cortex agreed with known oscillations. Application to dorsal striatal local field potentials identified a low-frequency theta component as well as a narrow gamma band oscillation at 50-55 Hz.

Action Potentials↗

Evaluation of different measures of functional connectivity using a neural mass model.

We use a neural mass model to address some important issues in characterising functional integration among remote cortical areas using magnetoencephalography or electroencephalography (MEG or EEG). In a previous paper [Neuroimage (in press)], we showed how the coupling among cortical areas can modulate the MEG or EEG spectrum and synchronise oscillatory dynamics. In this work, we exploit the model further by evaluating different measures of statistical dependencies (i.e., functional connectivity) among MEG or EEG signals that are mediated by neuronal coupling. We have examined linear and nonlinear methods, including phase synchronisation. Our results show that each method can detect coupling but with different sensitivity profiles that depended on (i) the frequency specificity of the interaction (broad vs. narrow band) and (ii) the nature of the coupling (linear vs. nonlinear). Our analyses suggest that methods based on the concept of generalised synchronisation are the most sensitive when interactions encompass different frequencies (broadband analyses). In the context of narrow-band analyses, mutual information was found to be the most sensitive way to disclose frequency-specific couplings. Measures based on generalised synchronisation and phase synchronisation are the most sensitive to nonlinear coupling. These different sensitivity profiles mean that the choice of coupling measures can have dramatic effects on the cortical networks identified. We illustrate this using a single-subject MEG study of binocular rivalry and highlight the greater recovery of statistical dependencies among cortical areas in the beta band when mutual information is used.

Beta Rhythm↗

Social interaction and life satisfaction: an empirical assessment of late-life patterns.

Problems of social and psychological adjustment in later life have been examined by numerous investigators. Some have found positive relationships between social interaction and personal adjustment, while others have found interaction and adjustment to be unrelated. The purpose of the research reported here was to examine how different ways of measuring interaction may affect its relationship with personal adjustment. Data were obtained in interviews with 218 noninstitutionalized persons aged 70 and older. Findings indicate that both the number of persons interacted with, and the frequency of this interaction, are of little importance for the adjustment of older people. We suggest that the quality, rather than quantity, of social interaction is crucial to understanding adaptations to old age.

Aged↗

Relationships among prescription payment methods and interactions between community pharmacists and prescribers.

OBJECTIVE: This research was performed to examine community pharmacists' interactions with prescribers and to determine if these interactions are related to payment method. DESIGN: Randomly selected pharmacists (47 in chain pharmacies and 26 in independent pharmacies) collected data concerning prescriber interactions for a 40-hour period. These interactions were analyzed in terms of payment methods, prescriber acceptance, and types of information discussed. RESULTS: Information concerning 730 interactions by 72 pharmacists was obtained. Payment methods were related to the frequency of interactions per pharmacist (p less than 0.01). There were higher percentages of interactions for self-pay (median 2.2 percent) and Medicaid (median 1.8 percent) prescriptions than for third-party fee-for-service (mode 0 percent) or capitation prescriptions (mode 0 percent). Type of information discussed was related to payment method. The vast majority of information provided by pharmacists (91 percent) was accepted by prescribers. The rate of acceptance was 97 percent for prescriber-initiated interactions versus 88 percent for pharmacist- or patient-initiated interactions (p less than 0.01). CONCLUSIONS: Relationships between payment method and interactions were identified. These findings may be attributable to prescribing policies and reimbursement policies. Prescribing policies that restrict prescribers to a formulary may help make them become more adept at using those products; thus, they will make fewer prescribing errors. Reimbursement policies that require patients to consistently use a specific pharmacy (i.e., capitation) may help pharmacists become more familiar with the patient's prescription history. Therefore, interactions with prescribers are needed less frequently for these patients' prescriptions.

Capitation Fee↗

Frequency of defective sperm-zona pellucida interaction in severely teratozoospermic infertile men.

BACKGROUND: The frequency of defective sperm-zona pellucida (ZP) interaction in teratozoospermic infertile men was investigated. METHODS: Sperm-ZP binding and the ZP-induced acrosome reaction (ZPIAR) were performed in 125 infertile men with <5% of their sperm with normal morphology (strict criteria), but with a sperm count > or =20x10(6)/ml and total motility >30% in semen. Oocytes that failed to fertilize in clinical IVF were used for the tests. Four oocytes were incubated for 2 h with 2x10(6)/ml motile sperm selected by swim-up. The number of sperm bound per ZP and ZPIAR were assessed. Under these conditions, an average < or sperm bound per ZP was defined as poor sperm-ZP binding, and a ZPIAR < or = was defined as low ZPIAR. RESULTS: Among 125 teratozoospermic men, 31% (39/125) had poor sperm-ZP binding. Of those without poor ZP binding, 48% (41/86) had low ZPIAR. Some 64% (28/44) with sperm counts between 20 and 60x10(6)/ml had low ZPIAR. Only 36% (45/125) had normal sperm-ZP binding and ZPIAR. CONCLUSIONS: Defective sperm-ZP interaction was present in 64% of teratozoospermic infertile men: 31% had defective sperm-ZP binding, and 33% low ZPIAR. The frequency of low ZPIAR was higher in men with sperm counts between 20-60x10(6)/ml.

Acrosome Reaction↗

Ephaptic interactions contribute to paired pulse and frequency potentiation of hippocampal field potentials.

The contribution of ephaptic interactions to potentiation of the hippocampal CA1 extracellular population spike during paired pulse or frequency stimulation of stratum radiatum (SR) inputs was investigated using the in vitro hippocampal slice preparation. Records of the transmembrane potential revealed a depolarizing wave with an amplitude and latency that varied directly with that of the extracellular population spike. Paired pulse or repetitive stimulation of SR resulted in a potentiation of the population spike amplitude and a corresponding increase in the amplitude of the TMP depolarizing wave. Action potentials generated during the stimulus train consistently arose from the peak of the depolarizing wave. It is proposed that ephaptic interactions contribute to potentiation of the extracellular population spike through recruitment of subthreshold neurons within the population during repetitive afferent stimulation.

Animals↗

[Density-dependent behavior of the shrews (Sorex araneus, S. caecutiens, and S.minutus) in natural and experimental conditions].

The behavior of three common shrew species was compared in a test of pairwise placement in a neutral territory (10 min) for various population densities in natural habitats and for animals kept isolated or in groups in open-air cage conditions. The behavior of the animals captured in nature was considered as the norm. We considered total number of social contacts (as an index of social activity), as well as the proportions of direct and ritualized aggressive interactions, contact avoidances, and friendly interactions (as a description of the interaction structure). Isolation of the shrews proved to decrease their social activity. Top frequency of interactions was observed in the animals kept in groups in open-air cages. The level of "sociality" and the changes in behavior related to different population density can be more significant in the three shrew species than the species-specific differences in their behavior.

Animal Husbandry↗

Comparison of text and video cases in a postgraduate problem-based learning format.

OBJECTIVE: To investigate whether adding a brief video case instead of an equivalent written text improves the cognitive and metacognitive processes (data exploration, theory building, theory evaluation and metareasoning) of residents in problem-based learning. SUBJECTS: Paediatric residents. SETTING: Department of Paediatrics, Arhus University Hospital, Skejby, Denmark. METHODS: Eleven residents were each assigned to 1 of 2 groups. Both groups analysed an identical vignette of a patient case. Immediately after this, 1 group watched a 2.5-minute video recording and the other group read a description of the same video recording. The groups then reanalysed the case. Thinking processes were tapped by recording and analysing the verbal group interaction. The frequencies of clause categories were calculated and compared using chi-square tests. RESULTS: The verbal interaction showed statistically significant improvements in data exploration, theory building and theory evaluation after the video case. CONCLUSIONS: The greater improvement in clause frequency after the video case compared with the equivalent text suggests an improvement in data exploration, theory building and theory evaluation. The use of patient video recordings may be a valuable supplement to postgraduate paediatric training, particularly pertaining to movement disorders.

Denmark↗

Contribution of click frequency bands to the human binaural interaction components.

The purpose of this study was to determine the contribution of click frequency bands (broad-band, >2000 Hz, <2000 Hz and <1000 Hz) to binaural interaction components (BICs) of the human auditory brainstem evoked potentials (ABEPs). The human BICs were studied by subtracting the potentials to binaural clicks from the algebraic sum of monaurally evoked potentials to either ear. Effective frequency bands were derived using clicks alone or clicks with ipsilateral or binaural masking noise, high- or low-pass filtered at different cut-off frequencies. Analysis included single-channel vertex-cervical spinous process VII derivation of BIC and ABEP, as well as estimating the single, centrally located dipole equivalent of the surface activity from three orthogonally positioned electrode pairs, using the three-channel Lissajous' trajectory (3-CLT) analysis. All BIC 3-CLTs included three major components (labeled BdII, BeI, and BeII) approximately corresponding in latency to IIIn, V and VI ABEP peaks. All apex latencies of BIC 3-CLT, except BeI, were longer in response to <2000 Hz and <1000 Hz (low-frequency) effective clicks. Apex amplitude of components BeI and BeII of BIC 3-CLT were smaller with low-frequency effective clicks than with broad-band or high-frequency (>2000 Hz) clicks. We suggest that binaural interaction component BeI is mainly tuned to high frequencies, showing no frequency effect on latency, and decreasing in amplitude with decreasing click high frequency content. In contrast, BdII and BeII of the human BICs are evoked more synchronously by high-frequency binaural inputs, but are also sensitive to low frequencies, increasing in latency according to the cochleotopic activation pattern. These differences between BIC components may reflect their roles in sound localization.

Acoustic Stimulation↗

Factors governing the flow cytometric analysis and sorting of large biological particles.

We have investigated the suitability of large flow cell tips for the flow cytometric analysis and sorting of large biological particles, including plant cells (pollen) and protoplasts. Using flow tips ranging in diameter from 79-204 micron, we have optimized conditions for the establishment of a stable hydrodynamic flow leading to accurate droplet production. We describe instrument modifications required for large particle sorting and demonstrate the use of these experimental conditions for the sorting to high purity of pollen and viable plant protoplasts possessing diameters as large as 95 micron. Our experiments have revealed a complex interaction among sorting efficiency, particle diameter, flow cell tip diameter and bimorphic crystal drive frequency. This interaction can be satisfactorily explained in terms of interference effects owing to phase differences between the particle-induced disturbance and the undulation driven by the bimorphic crystal.

Cell Separation↗

The Bayesian reader: explaining word recognition as an optimal Bayesian decision process.

This article presents a theory of visual word recognition that assumes that, in the tasks of word identification, lexical decision, and semantic categorization, human readers behave as optimal Bayesian decision makers. This leads to the development of a computational model of word recognition, the Bayesian reader. The Bayesian reader successfully simulates some of the most significant data on human reading. The model accounts for the nature of the function relating word frequency to reaction time and identification threshold, the effects of neighborhood density and its interaction with frequency, and the variation in the pattern of neighborhood density effects seen in different experimental tasks. Both the general behavior of the model and the way the model predicts different patterns of results in different tasks follow entirely from the assumption that human readers approximate optimal Bayesian decision makers.

Attention↗