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PubMed2001

From physical time to the first and second moments of psychological time.

After examination of the status of time in experimental psychology and a review of related major texts, 2 opposite approaches are presented in which time is either unified or fragmented. Unified time perception views, usually guided by Weber's law, are embodied in various models. After a brief review of old models and a description of the major contemporary models of time perception, views on fragmented time perception are presented as challenges for any unified time view. Fragmentation of psychological time emerges from (a) disruptions of the Weber function, which are caused by the types of interval presentation, by extensive practice, and by counting explicitly or not; and (b) modulations of time sensitivity and perceived duration by attention and interval structures. Weber's law is a useful guide for studying psychological time, but it is also reasonable to assume that more than one so-called central timekeeper could contribute to perceiving time.

Attention↗

PubMed2000

T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity.

Given the flexible nature of TCR specificity, deletion or permanent disabling of all T cells with the capacity to recognize self peptides would severely limit the diversity of the repertoire and the capacity to recognize foreign Ags. To address this, we have investigated the patterns of CD8+ CTL reactivity to a naturally H-2Kb-presented self peptide derived from the elongation factor 1alpha (EF1alpha). EF1alpha occurs as two differentially expressed isoforms differing at one position of the relevant peptide. Low avidity CTLs could be raised against both variants of the EF1alpha peptide. These CTLs required 100-fold more peptide-H-2Kb complexes on the target cell compared with CTLs against a viral peptide, and did not recognize the naturally expressed levels of EF1alpha peptides. Thus, low avidity T cells specific for these self peptides escape tolerance by deletion, despite expression of both EF1alpha isoforms in dendritic cells known to mediate negative selection in the thymus. The low avidity in CTL recognition of these peptides correlated with low TCR affinity. However, self peptide-specific CTLs expressed elevated levels of CD8. Furthermore, CTLs generated against altered self peptide variants displayed intermediate avidity, indicating cross-reactivity in induction of tolerance. We interpret these data, together with results previously published by others, in an avidity pit model based on avidity thresholds for maintenance of both maximal diversity and optimal self tolerance in the CD8+ T cell repertoire.

Animals↗

PubMed1997

Band-limited contrast in natural images explains the detectability of changes in the amplitude spectra.

The psychophysical task of discriminating changes in the slopes of the amplitude spectra of complex images has been used in the past to test whether the human visual system might be optimised for coding the spatial structure in natural images (e.g. Knill et al., 1990; Tadmor & Tolhurst, 1994). We have reported that the dependency of these discrimination thresholds on the reference slope has the same overall general form, regardless of the particular digitised photographs that are used for generating the stimuli. The actual discrimination thresholds, however, differ markedly in magnitude for stimuli that are derived from different digitised photographs. Here, we describe a model that aims at explaining this diversity of threshold magnitudes: we suppose that the observer is detecting small changes in image contrast estimated within limited spatial-frequency bands of about 1 octave bandwidth. This local-contrast analysis reveals that contrast changes in only one frequency band are of comparable magnitudes to the changes that observers need for detecting differences in the Michelson contrast of simple sinusoidal gratings. The success of this band-limited contrast model is further shown in experiments where the slopes of the amplitude spectra of stimuli were changed only within restricted frequency bands. We show that when the slope is changed outside the limited frequency band implicated by the contrast model, the observer's thresholds are greatly elevated. Thresholds remain unchanged when slope changes are made within the implicated band. We also find that the exact bandwidth of the contrast operator is not critical, provided that it is in the range of about 0.6-1.5, which is the characteristic bandwidth range of V1 neurons.

Contrast Sensitivity↗

PubMed1996

Excretion of urinary N-telopeptides reflects changes in bone turnover during ovarian suppression and indicates individually variable estradiol threshold for bone loss.

OBJECTIVE: To evaluate the effectiveness of N-telopeptides and E2 in monitoring bone turnover during GnRH agonist- (GnRH-a) or danazol-induced hypoestrogenism. DESIGN: Comparative, nonrandomized prospective study. SETTING: Institute for the Study and Treatment of Endometriosis. PATIENT(S): Premenopausal women undergoing ovarian suppression with GnRH-a (n = 16) or danazol (n = 9). INTERVENTION(S): Serum and urine samples were collected and bone mineral density was measured before, during, and after treatment. MAIN OUTCOME MEASURE(S): N-telopeptide excretion, serum E2, and bone mineral density at L1 to L4 and femoral neck. RESULT(S): During treatment in the GnRH-a group, mean E2 levels were 53% below and N-telopeptides were 38% above the mean baseline. At 1 month post-treatment, L1 to L4 bone mineral density decreased by 3.85%. In the danazol group, E2, N-telopeptides and L1 to L4 bone mineral density changed nonsignificantly in the opposite direction with the mean 1.25% increase in L1 to L4 at 1 month post-treatment. In combined groups, L1 to L4 bone mineral density better correlated with other measures than femoral neck bone mineral density. N-telopeptide excretion was more predictive of L1 to L4 change, with correlation the highest between N-telopeptides at month 4 and bone mineral density at month 1 afterward, while E2 appeared more predictive of the less reliable femoral neck bone mineral density. Individual exceptions to the model of an E2 threshold for bone loss were observed. Also noted were high correlation between on-therapy levels of E2 and N-telopeptides, as well as the presence of a 1-month time lag between E2 and N-telopeptide changes. CONCLUSION(S): Bone density decreases during GnRH-a and may slightly increase during danazol treatment. However, E2 threshold for bone loss varies individually. N-telopeptides predict changes in bone mineral density at L1 to L4 better than E2.

Adult↗

PubMed1999

Threshold of detection of diffuse lung disease.

UNLABELLED: A scintigraphic model of the lungs was used to study the threshold of detection of diffuse disease of the lungs. METHODS: Randomly distributed cold lesions of 4, 8, 12 and 16 mm3 block sizes were created, occupying 0%-50% of lung tissue in steps of 1%. These were submitted for reporting to five observers each with a normal study for comparison. RESULTS: No observer detected lesions of 4-mm3 block size even when up to 50% of the lung was involved. All observers detected lesions of 8-mm3 block size when a mean of 27% of lung tissue was involved with lesions. As lesion size increased to 12 and 16 mm3, observers detected lesions when a mean of 10% and 6% of lung tissue was involved, respectively. Comparison between views for each observer showed that the lateral and anterior oblique views were used more often than the anterior, posterior oblique and posterior views. CONCLUSION: This model suggests that pulmonary scintigraphy has the potential to detect a diffuse disease such as emphysema at an early stage of lung involvement. In general, small anatomic lesions appear to have more profound scintigraphic consequences. However, even scintigraphic lesions of the order of size of the pulmonary acinus are easily detected.

Humans↗

PubMed2003

Comparative microdosimetry of photoelectrons and Compton electrons: an analysis in terms of generalized proximity functions.

A current discussion on mammography screening is focused on claims of high relative biological effectiveness (RBE) of mammography X rays compared to conventional 200 kV X rays. An earlier assessment in terms of the electron spectra of these radiations has led to the conclusion that the RBE is bound to be less than 2, regardless of specific model assumptions and the microdosimetric properties of electrons. The present study extends this result in terms of the microdosimetric proximity function, t(x), for electrons, which is essentially the spatial auto-correlation function of energy within particle tracks. If pairs of DNA lesions, e.g. chromosome breaks or deletions, bring about the observed damage, the value t(x) determines for a specified radiation the relative frequency of pairs of lesions a distance x apart. The effectiveness of the radiation is thus proportional to an average of the values of t(x) over the distances, x, for which lesions can combine. The analysis suggests that 15 keV electrons can have a low-dose relative biological effectiveness (RBE(M)) of 1.6 relative to 40 keV electrons if the interaction distances do not exceed about 1 micro m. An extension of the concept, the reduced proximity function, t(delta)(x), permits the inclusion of models with an energy threshold, such as delta = 100 eV, 500 eV or 2 keV, for the formation of each of the DNA lesions. This makes it possible to assess the potential impact of the Auger electrons which accompany most photoelectrons, but only a minority of the Compton electrons. It is found that the Auger electrons could make photoelectrons substantially more effective than Compton electrons at energies below 10 keV but not at energies above 15 keV. The conclusions obtained for the RBE of 15 keV electrons relative to 40 keV electrons will be roughly representative of the RBE of mammography X rays relative to conventional 200 kV X rays.

Biophysics↗

PubMed1991

The threshold of survival for system of two species in a polluted environment.

The effects of toxicants on naturally stable two-species communities are studied. Persistence-extinction thresholds are given for populations in the toxicant stressed Lotka-Volterra model of two interacting species. The threshold results are expressed in terms of relationships involving the population intrinsic growth rates, dose-response parameters, and interaction rates.

Environmental Pollution↗

PubMed2005

Computer simulation of epilepsy: implications for seizure spread and behavioral dysfunction.

Hippocampal area CA3 has been one of the most intensively studied brain regions for computer models of epileptiform activity. As physiological studies begin to extend outward to other hippocampal and parahippocampal areas, we must extend these models to understand more complex circuitry containing diverse elements. Study of subiculum is of particular interest in this context, as it is a structure of intermediate complexity, with an inchoate columnar and laminar organization. In addition to helping us understand seizures, modeling of these structures will also help us understand the genesis of physiological activity patterns that are below threshold for seizure generation. Such modeling can also serve as a basis for speculation regarding the nonictal behavioral consequences of epilepsy.

Behavior↗

PubMed1991

Combinatorial splicing of exon pairs by two-site binding of U1 small nuclear ribonucleoprotein particle.

A two-site model for the binding of U1 small nuclear ribonucleoprotein particle (U1 snRNP) was tested in order to understand how exon partners are selected in complex pre-mRNAs containing alternative exons. In this model, it is proposed that two U1 snRNPs define a functional unit of splicing by base pairing to the 3' boundary of the downstream exon as well as the 5' boundary of the intron to be spliced. Three-exon substrates contained the alternatively spliced exon 4 (E4) region of the preprotachykinin gene. Combined 5' splice site mutations at neighboring exons demonstrate that weakened binding of U1 snRNP at the downstream site and improved U1 snRNP binding at the upstream site result in the failure to rescue splicing of the intron between the mutations. These results indicate the stringency of the requirement for binding a second U1 snRNP to the downstream 5' splice site for these substrates as opposed to an alternative model in which a certain threshold level of U1 snRNP can be provided at either site. Further support for the two-site model is provided by single-site mutations in the 5' splice site of the third exon, E5, that weaken base complementarity to U1 RNA. These mutations block E5 branchpoint formation and, surprisingly, generate novel branchpoints that are specified chiefly by their proximity to a cryptic 5' splice site located at the 3' terminus of the pre-mRNA. The experiments shown here demonstrate a true stimulation of 3' splice site activity by the downstream binding of U1 snRNP and suggest a possible mechanism by which combinatorial patterns of exon selection are achieved for alternatively spliced pre-mRNAs.

Base Sequence↗

PubMed2006

Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm.

Formation of mesoderm from the pluripotent epiblast depends upon canonical Wnt/beta-catenin signaling, although a precise molecular basis for this requirement has not been established. To develop a robust model of this developmental transition, we examined the role of Wnt signaling during the analogous stage of embryonic stem cell differentiation. We show that the kinetics of Wnt ligand expression and pathway activity in vitro mirror those found in vivo. Furthermore, inhibition of this endogenous Wnt signaling abrogates the functional competence of differentiating ES cells, reflected by their failure to generate Flk1(+) mesodermal precursors and subsequent mature mesodermal lineages. Microarray analysis at various times during early differentiation reveal that mesoderm- and endoderm-associated genes fail to be induced in the absence of Wnt signaling, indicating a lack of germ layer induction that normally occurs during gastrulation in vivo. The earliest genes displaying Wnt-dependent expression, however, were those expressed in vivo in the primitive streak. Using an inducible form of stabilized beta-catenin, we find that Wnt activity, although required, does not autonomously promote primitive streak-associated gene expression in vitro. Our results suggest that Wnt signaling functions in this model system to regulate the thresholds or stability of responses to other effector pathways and demonstrate that differentiating ES cells represent a useful model system for defining complex regulatory interactions underlying primary germ layer induction.

Animals↗

PubMed2001

[A case of permanent pacemaker implantation in small infant using steroid-eluting epicardial pacing lead: changes of the pacing threshold in acute phase].

A 1-year-old infant with complete atrioventricular block was successfully treated with the pacemaker implantation using steroid-eluting epicardial pacing lead by the subxyphoid approach. Pacing threshold after implantation were measured frequently to use the function named "Capture management" of the generator (Medtronic: Kappa, Model 701). The postoperative pacing threshold were kept lower and stabilized after 5 weeks.

Cardiac Pacing, Artificial↗

PubMed1982

Cerebral free amino acids in the amygdaloid kindling model of epilepsy.

A permanent reduction in seizure threshold due to repeated subconvulsive electrical stimulation of the amygdala characterizes the kindling model of epilepsy. Since kindling may involve neurochemical alterations, cerebral amino acids were studied in this induced seizure state. Minimal changes were found in the levels of amino acids in the cerebellum, frontal cortex and brain stem of amygdaloid kindled rats when measured one week after the last seizure. The uptake of taurine into synaptosomes prepared from the cerebellum of kindled rats was significantly elevated, suggesting that alterations in synaptic action of this inhibitory neurotransmitter may play a role in the development of kindling.

Amino Acids↗

PubMed2003

Modeling oscillatory microtubule polymerization.

Polymerization of microtubules is ubiquitous in biological cells and under certain conditions it becomes oscillatory in time. Here, simple reaction models are analyzed that capture such oscillations as well as the length distribution of microtubules. We assume reaction conditions that are stationary over many oscillation periods, and it is a Hopf bifurcation that leads to a persistent oscillatory microtubule polymerization in these models. Analytical expressions are derived for the threshold of the bifurcation and the oscillation frequency in terms of reaction rates, and typical trends of their parameter dependence are presented. Both, a catastrophe rate that depends on the density of guanosine triphosphate liganded tubulin dimers and a delay reaction, such as the depolymerization of shrinking microtubules or the decay of oligomers, support oscillations. For a tubulin dimer concentration below the threshold, oscillatory microtubule polymerization occurs transiently on the route to a stationary state, as shown by numerical solutions of the model equations. Close to threshold, a so-called amplitude equation is derived and it is shown that the bifurcation to microtubule oscillations is supercritical.

Journal Article↗

PubMed2003

Cross section calculations for electron scattering from DNA and RNA bases.

Differential and integral cross sections for elastic electron collisions with uracil, cytosine, guanine, adenine and thymine have been calculated using the independent atom method with a static-polarization model potential for incident energies ranging from 50 to 4000 eV. Total cross sections for single electron-impact ionization of selected DNA and RNA bases have also been calculated with the binary-encounter-Bethe model from the ionization threshold up to 5000 eV. Cross sections within the investigated energy range, can be related to the molecular symmetry, the number of target electrons and molecular size; elastic and ionization processes are most efficient for guanine and adenine molecules, while the lowest cross sections were obtained for the uracil molecule. The ionization cross sections for cytosine, thymine, adenine and guanine are compared with those recently obtained with a semi-classical and binary-encounter-Bethe formalisms. No theoretical and experimental data for elastic electron scattering from DNA and RNA bases are available, but comparisons with calculations for molecules of similar size and geometry allows the validity of the theoretical approach to be verified.

Binding Sites↗

PubMed1985

The relationship between cross-correlation measures and underlying synaptic events.

The relationship between an excitatory postsynaptic potential (EPSP) and the cross-correlation derived from the spike train evoked by a Poisson stimulus train was studied by computer stimulation. The neuron model had a constant threshold and an absolute refractory period. Following a spike, the membrane potential was determined by ongoing activity, i.e., it was not 'reset'. Under all conditions studied, the rise time of the cross-correlation peak accurately reflected EPSP rise time. The agreement between the half-width of the cross-correlation peak and that of the underlying EPSP depended upon the EPSP amplitude, the rate of the driving Poisson input, and the time course of the EPSP. Over a broad range of experimentally relevant conditions, the half-width of the cross-correlation peak deviated from that of the underlying EPSP by less than 30% and bore little resemblance to that of the EPSP's time derivative.

Evoked Potentials↗

PubMed1998

From ideology to logistics: the organizational aspects of syringe exchange in a period of institutional consolidation.

The initial period in the establishment of syringe exchange projects is often characterized by overt conflict: between community AIDS activists, on the one hand, and public officials and political leaders who remain ideologically opposed to the introduction of measures perceived as condoning illicit drug use. In this context, professionals concerned with legitimating the new institutions of syringe exchange may sometimes neglect aspects of their everyday logistics and social organization, obscuring the important choices which have to be made to carry these initiatives forward. In particular, the contrast between formally-constituted institutions-the "storefront" or "community-based" syringe exchange programs (SEPs)-and the model of low-threshold syringe availability through pharmacies, vending machines, and user networks, is here presented not as an either/or choice but rather as a pair of complementary strategies which respond to diverse needs and target different populations. The advantages and disadvantages of each particular approach make it likely that maximum effectiveness will be achieved through a combination of every possible form of needle distribution, each tailored to specific and cultural circumstances. The case is here examined in the light of the experience of the SEPs in New York City, from their clandestine origins in 1990 through their first years of official functioning in 1992-1996.

Attitude of Health Personnel↗

PubMed1983

Spatiotemporal variation of chromatic and achromatic contrast thresholds.

Moving the retinal image of a sinusoidal grating at a constant velocity (compensated for eye movements) provides controlled spatial and temporal frequencies at every point in the stimulus field. Using this controlled-velocity technique, we have measured the detection threshold for isoluminance, red/green gratings as a function of their spatial and temporal frequencies. The chromatic contrast-threshold surface obtained in this way is analogous to the achromatic contrast-threshold surface measured previously, but the results are quite different. For very low temporal frequencies (below 0.2 Hz), the chromatic sensitivity decreases steadily with decreasing temporal frequency. Below 0.01 Hz, chromatic patterns disappear completely even at maximum contrast (although achromatic or homochromatic patterns do not). In the region above 0.2 Hz, both achromatic and chromatic thresholds can be explained by the same receptive-field-like model. When the center and the surround components of this model are additively combined, they form the chromatic threshold surface; when the sign of either component is reversed, they form the achromatic one.

Color Perception↗

PubMed1995

Masking of auditory brainstem responses in young and aged gerbils.

Auditory brainstem responses (ABR) were recorded in the presence of low-pass (1 kHz cutoff) or high-pass (8 kHz cutoff) filtered noise in young (4-8 month) and aged (36 month) gerbils. For low-pass maskers, aged gerbils had higher masked thresholds at 2 and 4 kHz than young subjects. This was true for all aged subjects, including those with quiet thresholds similar to those of young controls. For high-pass masking, the majority of aged subjects had higher masked thresholds at 2 and 4 kHz than young controls; however, aged subjects with relatively normal quiet thresholds had masked thresholds similar to those of young subjects. A modified power-law (MPL) model was used to predict masked thresholds for aged subjects. Thresholds measured in the presence of low-pass noise were higher than predicted in many of the aged subjects, particularly those with near-normal quiet thresholds. In contrast, thresholds measured in the presence of the high-pass masker were similar to the predicted thresholds. These results suggest that: (a) excess masking occurred in aged subjects for low-pass, but not high-pass, maskers; (b) the excess masking occurred independently of quiet thresholds; and (c) excess upward spread of masking was related to the spectrum of the masker and not the 2 and 4 kHz regions of the auditory periphery.

Acoustic Stimulation↗