[Application of the model of 2 classes of tryptophans to the interpretation of data on the ultraviolet fluorescence of x-irradiated cells].
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Animals↗
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Results for “Model interpretability”
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Identification and computationally-based structural interpretation of naturally occurring variants of human protein C.
Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing.
Adolescent↗
A computerized mastitis decision aid using farm-based records: an artificial neural network approach.
A computer module was developed and tested that used field survey and Dairy Herd Improvement Association (DHIA) data to broadly classify bacterial causes of mastitis in dairy herds. Further development of the computer model could aid interpretation of DHIA data by dairy record processing centers and herd consultants. This diagnostic module was developed with an artificial neural network, a technology that processes complex data in a manner similar to human brain function. Information describing herd management practices, quarter milk samples, and monthly DHIA data was collected from Pennsylvania dairy herds with moderate to high somatic cell counts. This information was used to develop or train an artificial neural network model that discriminated among four categories of bacterial organisms (contagious, environmental, no significant growth, and other) associated with clinical and subclinical mastitis. After training the model, new DHIA and management data were presented to the model to assess its ability to classify bacteriological etiology. When the artificial neural network was used, the probabilities of diagnosing the bacteriologic status from three randomly selected cow groups and from new untested herds ranged from 57 to 71%. Performance of the artificial neural network model was best in herds with higher frequency of minor and contagious pathogens. Prediction results for the same test data with linear discriminant analysis were less successful, ranging from 42 to 57%.
Animals↗
Aging of di-isopropyl-phosphorylated human butyrylcholinesterase.
Organophosphate-inhibited cholinesterases can be reactivated by nucleophilic compounds. Sometimes phosphylated (phosphorylated or phosphonylated) cholinesterases become progressively refractory to reactivation; this can result from different reactions. The most frequent process, termed 'aging', involves the dealkylation of an alkoxy group on the phosphyl moiety through a carbocation mechanism. In attempting to determine the amino acid residues involved in the aging of butyrylcholinesterase (BuChE), the human BuChE gene was mutated at several positions corresponding to residues located at the rim of the active site gorge and in the vicinity of the active site. Mutant enzymes were expressed in Chinese hamster ovary cells. Wild-type BuChE and mutants were inhibited by di-isopropylfluorophosphate at pH 8.0 and 25 degrees C. Di-isopropyl-phosphorylated enzymes were incubated with the nucleophilic oxime 2-pyridine aldoxime methiodide and their reactivatability was determined. Reactivatability was expressed by the first-order rate constant of aging and/or the half-life of aging (t12). The t12 was found to be of the order of 60 min for wild-type BuChE. Mutations on Glu-197 increased t12 60-fold. Mutation W82A increased t12 13-fold. Mutation D70G increased t12 8-fold. Mutations in the vicinity of the active site serine residue had either moderate or no effect on aging; t12 was doubled for F329C and F329A, increased only 4-fold for the double mutant A328G+F329S, and no change was observed for the A328G mutant, indicating that the isopropoxy chain to be dealkylated does not directly interact with Ala-328 and Phe-329. These results were interpreted by molecular modelling of di-isopropylphosphorylated wild-type and mutant enzymes. Molecular dynamics simulations indicated that the isopropyl chain that is lost interacted with Trp-82, suggesting that Trp-82 has a role in stabilizing the carbonium ion that is released in the dealkylation step. This study emphasized the important role of the Glu-197 carboxylate in stabilizing the developing carbocation, and the allosteric control of the dealkylation reaction by Asp-70. Indeed, although Asp-70 does not interact with the phosphoryl moiety, mutation D70G affects the rate of aging. This indirect control was interpreted in terms of change in the conformational state of Trp-82 owing to internal motions of the Omega loop (Cys-65-Cys-92) in the mutant enzyme.
Aging↗
A closed lung system study of inert gas absorption.
The demonstration that the rate of rise of the alveolar fraction of nitrous oxide is enhanced when the inspired N2O concentration is high is termed the "concentration effect." A similar effect on a second gas has been termed the "second gas effect". These effects have been observed in open systems and attributed to differential changes between inspired and expired ventilation. The purpose of this investigation is to study these effects in a closed system. A breath-holding maneuver was utilized with a high and a low N2O concentration in argon and oxygen. The results indicate that breath holding with a high N2O concentration "concentrates" both the alveolar fraction of N2O and argon. These results are attributable to alveolar volume shrinkage as a consequence of the large absorption of N2O by the pulmonary blood. A mathematical model verifies this interpretation and suggests that volume shrinkage can be important in breath-holding maneuvers designed for noninvasive measurement of cardiac output and lung tissue volume.
Argon↗
Storage and recall of environmental signals in a plant: modelling by use of a differential (continuous) formulation.
The breaking of the symmetry of bud growth in Bidens seedlings involves a sort of plant 'memory'. An asymmetrical stimulus (e.g., the pricking of one of the seedling cotyledons) stores a 'symmetry-breaking' signal within the plants (function STO). Depending on other stimuli received by the seedlings, the stored signal may remain silent or be recalled (RCL function) and take effect in the seedling morphogenesis (asymmetry of the growth of the cotyledonary buds, with a statistical advantage to the bud at the axil of the non-stimulated cotyledon). We show that this memory mechanism can be interpreted by a model taking into account a genetic control exerted on a non-linear enzymatic system that is able to choose trajectories going to different attractors, depending on the stimulation intensity.
Environment↗
Sodium lactate infusions and panic attacks: a review and critique.
Response to sodium lactate infusions has been proposed as an experimental model and a biologic marker for panic attacks. Several authors have claimed that patients suffering from panic attacks, but not normal controls, "panic" in response to lactate. A careful review of methods and results of 13 studies, however, reveals serious methodologic problems, lack of specificity and sensitivity, and a failure to consider cognitive variables. When baseline differences are ruled out, the responses of patients and controls may not differ. So far, response to lactate cannot be interpreted as a model and marker for panic attacks and does not provide evidence for their underlying biologic distinctness from other types of anxiety. Known biologic mechanisms do not sufficiently explain the effects of lactate. Instead, an interaction of peripheral physiologic changes, past experience, environmental cues, and their appraisal as threatening or dangerous seems to be a more appropriate model.
Anxiety Disorders↗
Epileptogenic effects of status epilepticus.
Determining whether and under what conditions status epilepticus (SE) leads to undesirable long-term sequelae has major clinical ramifications. In addition to structural brain damage and enduring neurological deficits following SE, it has been suggested that SE can establish a chronic condition of active epilepsy. These three residua (epileptic brain damage, neurological deficits, and epilepsy) have been especially linked to protracted SE. The older clinical literature indicates that these sequelae are especially likely if SE occurs in an immature brain, but this point has been challenged in recent studies. Clinical and animal model work that examines the issue of chronic nervous system deficits arising as a consequence of SE is reviewed, with particular attention to the question of the epileptogenic effect of SE. Because of the inherent problem of not being able to exclude occult neurological disease antecedent to SE in brain, animal model work promises to be especially relevant to the issues at hand. Work done on adult rats has shown that a previously normal brain can be "converted" after a bout of SE to an epileptic brain, as manifest both by epileptic brain damage resembling that found in the hippocampus of patients with intractable temporal lobe epilepsy and by spontaneous recurrent seizures registered in the hippocampus. A two-step model is proposed: morphological brain injury takes place first and this change, in turn, promotes seizures. This model is offered as one way in which chronic active epilepsy can be established by a transient episode of SE. Although some findings from work with animal models have been interpreted as not supporting the idea that the immature brain is sensitive to a chronic epileptogenic influence initiated by SE, the majority of such work is consistent with this idea. On the other hand, a considerable amount of animal work indicates that the brains of immature animals are quite resistant to SE-induced brain damage, in contrast to those of adults. Thus, under these circumstances, a different process of epileptogenesis than the two-step model may be operational. It is concluded that, under appropriate conditions, SE does exert an epileptogenic effect that persists.
Animals↗
Communicating probabilistic information to cancer patients: is there 'noise' on the line?
The objective was to examine the way that cancer patients translate verbal descriptors of probability into numerical estimates. A list of words commonly used on consent forms to describe the likelihood for benefits or risks of therapies was provided to 100 cancer patients. Two formats, paper/pencil or computer, were used to provide the list of words. Two methods, magnitude estimation and linear analogue scaling, were used to obtain probability estimates for each word. In addition, two scenarios were developed to study 'context effects' on numerical interpretations of verbal descriptions of probability. All patients provided numerical values for the words on two occasions, separated by one week, and two interviewers collected the data. Regardless of method or format, each word elicited widely variable numerical interpretations. An ANOVA model, including patient, word, interviewer, time, method and format, indicated that patient and interviewer produced major effects on probability estimates. Agreement between methods and across time was good. Paper/pencil and computer formats yielded similar results. Context effects did not appear to influence the numerical probabilities elicited by the 2 scenarios. It was concluded that, within this group of patients, there was no consensus about numerical meaning of a given word, and that interviewers can systematically influence numerical interpretations. There appears to be a great deal of 'noise' in this particular line of communication between patients and health professionals.
Aged↗
Investigating the properties of supported vesicular layers on titanium dioxide by quartz crystal microbalance with dissipation measurements.
Adsorption of phospholipid vesicles on titanium dioxide was studied by a combination of quartz crystal microbalance with dissipation (QCM-D) and atomic force microscopy techniques. Vesicle size, concentration in solution, and bilayer composition were systematically varied. A strong dependence of the QCM-D response (magnitude of the frequency and dissipation factor shifts) on the vesicle concentration in solution was observed. QCM-D data were compared with a linear viscoelastic model based on the Voight element to determine layer thickness, density, elastic modulus, and viscosity. Based on the results of this comparison, it is proposed that (i) layer thickness and density, as sensed by QCM-D, saturate much earlier (in time) than the actual surface coverage of the vesicles (number of vesicles per unit area); (ii) changes in surface coverage that occur after the density and thickness, as sensed by QCM-D, have saturated, are interpreted by the model as changes in the layer's viscoelastic properties. This is caused by the replacement of the viscous media (water) between the vesicles by viscoelastic media of similar density (vesicles); (iii) viscoelastic properties of layers formed at different vesicle concentrations differ significantly, while the vesicle surface coverage in those layers does not. Based on the comparison between the atomic force microscopy images and QCM-D data acquired at various vesicle concentrations it is proposed that QCM-D response is not directly related to the surface coverage of the vesicles.
Journal Article↗
A dynamic model to analyse intravenous glucose and insulin tolerance tests performed on dairy cows.
A dynamic model was developed to assess insulin sensitivity and pancreatic response in lactating dairy cows. The model is based on a simultaneous analysis of insulin and glucose intravenous tolerance tests. It comprises five compartments corresponding to insulin in portal-hepatic plasma, and insulin or glucose in both systemic plasma and in interstitial fluid. Insulin secretion rate is a sigmoidal function of glucose in plasma. Insulin is cleared from hepatic plasma and from the interstitial fluid. The glucose entry rate is constant and glucose utilization rate is a sigmoidal function of insulin in the interstitial fluid. Six parameters were estimated: two for insulin secretion rate, two for insulin clearance, one for glucose entry rate and one for glucose utilization rate. After integration of the functions, the model yielded a relative estimate of the quantities of insulin secreted and cleared, as well as the glucose entering and utilized during each test. Using an experimental dataset composed of ten pairs of tolerance tests, the explained variations for plasma insulin and glucose concentrations were 96.0 and 98.3 % and standard errors of estimates were 0.032 nmol/l and 0.14 mmol/l respectively. Except in the early stages after injection, residual errors were low. A Jackknife analysis showed that the estimated parameters exhibited low statistical bias. This model simplifies the interpretation of both tests through a simulation based on six common parameters. Compared to a classical analysis of tolerance tests, it may improve the analysis of modifications in the key functions regulating glucose homeostasis in ruminants.
Animals↗
Interpreting aquatic toxicity QSARs: the significance of toxicant body residues at the pharmacologic endpoint.
Aquatic QSAR investigations employ bioassay data where a biological response is associated with a toxicant concentration in the exposure water. Although convenient this ignores the fundamental principle that the response is more closely related to an amount present in the organism. This problem has been examined using acute toxicity and bioconcentration QSARs employing log Kow as the molecular descriptor. Combining these QSAR relationships enables estimates of the amount of toxicant in organisms to be made. For acute narcosis (50% mortality) the toxicant level in the hydrophobic (lipid) phase of an exposed organism is, as a first approximation, constant at approximately 50 mmol l-1 of lipid. For the acute toxicity of a variety of hydrophobic narcotic organics examined by US EPA-Duluth in tests with fathead minnows, this corresponds to a whole-body residue of about 4 mmol kg-1. Although the level in the hydrophobic phase remains constant, for hydrophilic chemicals (log Kow less than 1.5) the contribution of the hydrophilic (water) phase of the organism dominates and total body residues should be similar to the respective threshold LC50s. This has important implications in simple pharmacokinetic modelling and in interpreting residue levels in organisms collected in environmental monitoring studies.
Animals↗
The ICRP working party on bioassay interpretation.
In recent years there have been many developments in modelling the behaviour of radionuclides in the human body. The current generation of models is designed to be more 'realistic' than the previous generation of simple compartment models. The International Commission on Radiological Protection (ICRP) uses these models to produce dose coefficients and recognises that there is a need to give more guidance on how these models can be used to interpret bioassay data. A working party has been set up to address the issue. This paper describes some of the problems, some approaches to solving the problems and the progress of the ICRP working party.
Advisory Committees↗
[Universal neonatal hearing screening of infants with otoacoustic emissions].
BACKGROUND: The incidence of congenital hearing impairment is 1-2/1,000--higher than for congenital hypothyroidism and phenylketonuria combined. Universal screening of hearing impairment has been introduced in many countries with portable otoacoustic emission (OAE) and/or automated auditory brainstem response (AABR), but not in Norway. This is the first Norwegian report on universal hearing screening of newborns before hospital discharge. MATERIALS AND METHODS: All newborns in Østfold County (n = 5,712) in 2000 and 2001 were offered an OAE test on the second day in nursery by a two-step model. After two tests without OAE signals bilaterally, the infants were referred to the audiology clinic. RESULTS: 98.8% of the newborns were tested. Of these, 97.0% had a pass response after two tests. 169 (3.0%) were referred to the audiology clinic; 15 were withdrawn from follow-up examination by their parents. 23 infants had auditory brainstem response audiometry done, and sensorineural hearing impairment was found in six (1.0/1,000). Three infants (0.6/1,000) had conductive hearing impairment. INTERPRETATION: Our screening model was appropriate and cost-effective. The incidence of congenital hearing impairment was similar to that reported by others. The number of parental refusals should be reduced. This may be achieved by adding an AABR to the two OAE tests.
Audiometry↗
A theoretical model of oxygen delivery and metabolism for physiologic interpretation of quantitative cerebral blood flow and metabolic rate of oxygen.
The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed "effective oxygen diffusibility (EOD)." The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations. The simulations revealed that, to maintain CMRO2 constant, a variation in CBF and Hb required active change in EOD. In contrast, unless the EOD change took place, the brain allowed small but significant nonlinear change in CMRO2 directly dependent upon oxygen delivery. Application of the present model to quantitative neuroimaging of CBF and CMRO2 enables us to evaluate the biologic response at capillary level other than Hb- and flow-dependent properties of oxygen transport and may give us another insight regarding the physiologic control of oxygen delivery in the human brain.
Biological Transport↗
What middle ear parameters tell about impedance matching and high frequency hearing.
Acoustic energy enters the mammalian cochlea aided by an anatomical impedance matching performed by the middle ear. The purpose of this paper is to analyse the functional consequences of changes in scale of the middle ear when going from the smallest mammals to the largest. Our anatomical measurements in mammals of different sizes ranging from bats to elephants indicate that middle ear proportions are largely isometric. Thus the calculated transformer ratio is basically independent of animal size, a typical value lying between 30 and 80. Similarly, the calculated specific acoustic input impedance of the inner ear is independent of animal size, the average value being about 140 kPa s/m. We show that if the high frequency hearing limit of isometric ears is limited by ossicle inertia, it should be inversely proportional to the cubic root of the ossicular mass. This prediction is in reasonable agreement with published audiogram data. We then present a three-parameter model of the middle ear where some obvious deviations from perfect isometry are taken into account. The high frequency hearing limits of different species generally agree well with the predictions of this simple model. However, the hearing limits of small rodents clearly deviate from the model calculation. We interpret this observation as indicating that the hearing limit towards very high frequencies may be set by cochlear transduction mechanisms. Further we discuss the exceptional high frequency hearing of the cat and the amphibious hearing of seals.
Acoustic Impedance Tests↗
Retirement patterns in Hong Kong: a censored regression analysis.
"This paper provides an overview of retirement patterns in Hong Kong on the basis of limited data. A censored regression model is used to infer the retirement age from people's current retirement status and their current age. This model is equivalent to a restricted probit model, and the interpretation of parameters is straightforward. The results clearly show a negative income effect on the retirement decision. The retirement age seems to be positively related to lifetime earnings but negatively related to the rate of decline of earnings with age."
Age Factors↗
Pretranstional phenomena in phospholipid/water multilayers.
We have measured the water order in monodomain phospholipid samples using 2H nuclear magnetic resonance (NMR) and analyzed the splittings in terms of critical exponents. Our data and the model developed to interpret them in terms of fluctuations provide an explanation of the puzzling sharp reduction of water order near the chain-ordering phase transition. The temperature range of the fluctuations is approximately the same as that observed for increased 22Na+ efflux from phospholipid vesicles.
1,2-Dipalmitoylphosphatidylcholine↗