Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Generative models”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70Linked to original sources
PubMed1993

Chromatin changes in cell transformation: progressive unfolding of the higher-order structure during the evolution of rat hepatocyte nodules. A differential scanning calorimetry study.

Using differential scanning calorimetry and complementary ultrastructural observations, we have characterized the status of chromatin during the transformation of rat hepatocytes in the resistant hepatocyte model of Solt and Farber (1976. Nature (Lond.). 263:701-703). Differential scanning calorimetry affords a measure of the degree of condensation of chromatin in situ and has therefore been used in this work for the purpose of establishing the nature of the structural changes associated with the emergence of successive cellular populations. Since the resistant hepatocyte model generates a series of synchronous phenotypic changes, it was possible to determine unambiguously the content of heterochromatin at each step of the process. The higher-order structure undergoes a partial relaxation in early developing nodules, isolated 16 weeks after initiation; the thermal transition at 90 degrees C, which is characteristic of noninteracting core particles, increases with respect to control hepatocytes. Dramatic changes occur in persistent (46-week) nodules. The 90 degrees C endotherm dominates the thermogram, while the transition at 107 degrees C, corresponding to the denaturation of the core particle packaged within the heterochromatic domains, disappears. The complete loss of the higher-order structure at this stage of transformation has been further verified by ultrastructural observations on thin nuclear sections. Ten-nm filaments, having a beaded appearance, are scattered throughout the nucleoplasm and clearly result from the decondensation of 30-nm-thick fibers. This catastrophic relaxation process cannot be related to an effective increase in gene activity. Rather, our observations suggest that during transformation chromatin is in a state of high transcriptional competence associated with the alert of general cellular programs. This view is consistent with the finding that in persistent nodules the DNA is extensively hypomethylated with respect to normal liver.

Animals↗
PubMed1995

Random walk calculations for bacterial migration in porous media.

Bacterial migration is important in understanding many practical problems ranging from disease pathogenesis to the bioremediation of hazardous waste in the environment. Our laboratory has been successful in quantifying bacterial migration in fluid media through experiment and the use of population balance equations and cellular level simulations that incorporate parameters based on a fundamental description of the microscopic motion of bacteria. The present work is part of an effort to extend these results to bacterial migration in porous media. Random walk algorithms have been used successfully to date in nonbiological contexts to obtain the diffusion coefficient for disordered continuum problems. This approach has been used here to describe bacterial motility. We have generated model porous media using molecular dynamics simulations applied to a fluid with equal sized spheres. The porosity is varied by allowing different degrees of sphere overlap. A random walk algorithm is applied to simulate bacterial migration, and the Einstein relation is used to calculate the effective bacterial diffusion coefficient. The tortuosity as a function of particle size is calculated and compared with available experimental results of migration of Pseudomonas putida in sand columns. Tortuosity increases with decreasing obstacle diameter, which is in agreement with the experimental results.

Algorithms↗
PubMed2002

Regulation of the frontocortical sodium pump by Na+ in Alzheimer's disease: difference from the age-matched control but similarity to the rat model.

The Na+ and K+ dependence of the frontocortical Na,K-ATPase in Alzheimer's disease (AD) was compared with that in human control (Co) and rat AD model. In AD, the relationship between the Na/K ratio and the Na,K-ATPase activity showed noticeable left-shift with three-fold increase in the enzyme affinity for Na+ (K(0.5)=10 and 30 mM in AD and Co, respectively). The Na+ dependence of the enzyme in AD showed two different Hill coefficients (n(H)), 1.1 and 0.3, whereas the Co value of n(H) was higher (1.4). The rat AD model generated by ibotenic acid revealed a Na+ dependence similar to AD. The K+ dependence of the Na,K-ATPase showed no significant difference in AD and Co. Compared with Co, AD produced a shift in the break of the Na,K-ATPase Arrhenius plot, suggesting remarkable alterations in the enzyme lipid environment. Our findings support the hypothesis that dysfunction of the Na,K-ATPase in AD is provoked by altered Na+ dependence of the enzyme. An impairment of the pump functionality might serve as an early mechanism of AD that should be interrupted by selective pharmacological agents.

Age Factors↗
PubMed2003

Effect of gravitational sedimentation on simulated aerosol dispersion in the human acinus.

We studied the effect of gravitational sedimentation on the dispersion of 0.5 and 1 micrometer-diameter particle boluses within a two-dimensional symmetric six-generation model of the human acinus. Boluses were introduced at the beginning of a 2-s inspiration immediately followed by a 4-s expiration, in normal gravity (1 G) and in the absence of gravity (0 G). The flow corresponded to a flow rate at the mouth of 500 ml/s. In 0 G, simulated dispersion (Hsim) was 16 ml for both particle sizes. In 1 G, Hsim was 71 and 242 ml for 0.5 and 1 micrometer-diameter particles, respectively, showing the effect of gravitational sedimentation. The difference between experimental data (J. Appl. Physiol. 86 (1999) 1402) and simulations was independent of particle size. This suggests that the residual dispersion was independent of the intrinsic properties of the particles and was more likely due to other mechanisms such as ventilation inhomogeneities, cardiogenic oscillations and alveolar wall motion.

Aerosols↗
PubMed1997

A computer model with surface friction for the prediction of total knee kinematics.

A computer model was generated which modelled the bearing surfaces of total knees, and predicted the kinematics for a set of input forces and moments. The model included friction at the bearing surfaces and soft tissue restraint forces, including the effect of cruciate resection. Predictions from the model were compared with data from a Knee Simulating Machine. There was close agreement in the shapes of the curves and in the magnitudes of the displacements and rotations under most conditions. The model predicted major differences in kinematics when friction between metal and polyethylene was included, the differences being even greater at the friction levels associated with small embedded acrylic particles. Soft tissue restraint was shown to reduce the displacements and rotations for tibial surfaces of low constraint but for moderate to high constraint, the soft tissues affected the kinematics only slightly. When the model was used to predict the motions for different condylar geometries, widely different contact paths on the tibial surface were determined. This suggested that condylar geometries which appeared to be generally similar, could have important differences in kinematics, function and wear.

Acrylic Resins↗
PubMed1981

Isoarea distributions during ectopic stimulation of isolated rabbit hearts.

These studies were designed to explore the effects of ectopic left ventricular stimulation on the area distributions recorded during the QRS, ST-T and QRST intervals. Twenty rabbit hearts were suspended in a spherical volume conductor, perfused with an electrolyte solution and stimulated from an anterior and/or a posterior subepicardial left ventricular site. ECG signals were sensed from 32 surface electrodes and were processed to compute areas under the three intervals, to construct area maps and to fit the computed areas to a single moving dipole equivalent cardiac generator model. Results demonstrated that control distributions were overtly nondipolar in 62.5% of cases. Second, ectopic pacing increased the dipolarity of the QRS and ST-T intervals significantly by both dipole ranging and isoarea methods. All area distributions became dipolar. Last, the QRST distribution response to ectopic stimulation varied widely, with major as well as minor changes in patterns occurring with alteration in excitation sequence. Thus, (1) ectopic stimulation changed electrical field properties of mean cardiac forces, and (2) QRST area distributions were dependent upon activation sequence. Each of these observations has direct bearing upon the ventricular gradient concept.

Animals↗
PubMed1990

High-dose, short-duration ribavirin aerosol therapy in children with suspected respiratory syncytial virus infection.

Nine children (aged 6 weeks to 7 years) with suspected respiratory syncytial virus infection received aerosal treatment with ribavirin, 60 mg/ml for 2-hour periods three times daily for up to 5 days. Five children received treatment via an endotracheal tube and four via an oxygen hood. Blood samples (3 to 17 per patient) and respiratory secretions (4 to 23 per patient) were assayed for ribavirin with reverse-phase high-performance liquid chromatography. Ribavirin triphosphate in erythrocytes was determined by ion-exchange high-performance liquid chromatography. The mean (+/- SD) peak ribavirin level after the first dose was 1725 +/- 2179 mumol/L in secretions and 3.8 +/- 2.6 mumol/L in plasma. Ribavirin in the secretions was rapidly cleared, with a mean (+/- SD), half-life of 1.9 +/- 0.8 hours. Plasma ribavirin increased with treatments to reach a steady state of 5 to 10 mumol/L. Mean peak ribavirin triphosphate levels were 15- to 300-fold higher than plasma ribavirin levels by the end of therapy. More than 98% reduction of viral load without the emergence of resistant virus was noted on day 3 of therapy. High-dose treatment was compatible with the aerosol equipment routinely used (small-particle aerosol generator, model 2-6000) for ribavirin administration and with ventilators. High-dose, short-duration ribavirin therapy was well tolerated by all patients, permitted easier accessibility for patient care, and may result in less environmental exposure of health care workers.

Administration, Inhalation↗
PubMed1985

Genetics of Darwinian fitness. II. Pleiotropic selection on fertility and survival.

A non-overlapping generation model is proposed which links Wright's adaptive topography concept to the rather inexact notion of Darwinian fitness as survival and reproduction. In general, evolution is seen to weight proportionate increases in survival twice as greatly as proportionate increases in fertility. Certain special cases are also delineated in which measurements of survival and fertility receive equal weight in the fitness equations. In addition, some implications of the present study for Wright's shifting balance theory and models based on Fisher's reproductive value are discussed.

Alleles↗
PubMed1998

Practical evaluation of comparative modelling and threading methods.

Six protein pairs, all with known 3D-structures, were used to evaluate different protein structure prediction tools. Firstly, alignments between a target sequence and a template sequence or structure were obtained by sequence alignment with QUANTA or by threading with THREADER, 123D and PHD Topits. Secondly, protein structure models were generated using MODELLER. The two protein structure assessment tools used were the root mean square deviation (RMSD) compared with the experimental target structure and the total 3D profile score. Also the accuracy of the active sites of models built in the absence and presence of ligands was investigated. Our study confirms that threading methods are able to yield more accurate models than comparative modelling in cases of low sequence identity (< 30%). However, a gap of 2 A (RMSD) exists between the theoretically best model and the models obtained by threading methods. For high sequence identities (> 30%) comparative modelling using MODELLER resulted in accurate models. Furthermore, the total 3D profile score was not always able to distinguish correct from incorrect folds when different alignment methods were used. Finally, we found it to be important to include possible ligands in the model-building process in order to prevent unrealistic filling of active site areas.

Algorithms↗
PubMed2003

Anti-cardiolipin/beta-2 glycoprotein activities co-exist on human anti-DNA antibody light chains.

We have recently shown that the human anti-DNA antibodies B3 and 33H11 also bind cardiolipin and that the anti-autoantigen activity resides predominantly on their lambda light chains. We now show that the two auto-antibodies possess strong reactivity to the plasma-protein 2-Glycoprotein I (beta2-GPI) also. Utilizing chain shuffling experiments involving an unrelated anti-p185 antibody 4D5 with insignificant reactivity to cardiolipin or to beta2-GPI, we now demonstrate that hybrid Fabs with constituent light chain, but not the heavy chain, of B3 or 33H11, exhibit anti-cardiolipin activity. Furthermore, the constructs possessing the auto-antibody-derived light chain also exhibited significant reactivity to beta2-GPI. The results suggest that anti-DNA, anti-cardiolipin and anti-beta2-GPI activities co-exist on the light chains of the antibodies studied and, importantly, these activities could be transferred to antibody constructs by their light chains alone. Computer-generated models of the three-dimensional structures of the auto-antibodies and their hybrids, suggest predominant interaction of their light chains with domain IV of beta2-GPI.

Amino Acid Sequence↗
PubMed2000

Understanding the heterogeneity of depression through the triad of symptoms, course and risk factors: a longitudinal, population-based study.

BACKGROUND: There is an ongoing research effort to test if depression is a homogeneous clinical syndrome and to identify valid and useful subtypes based on the number and nature of depressive symptoms. This study summarizes the patterns of depressive symptoms evident in a prospective study of the general population and examines the validity of potential subtypes by studying their course and etiologic heterogeneity. METHODS: A general population sample of 1920 adults (aged 18-96) from the Baltimore Epidemiologic Catchment Area (ECA) follow-up study (1981 to 1993/6) were examined. Data on diagnoses, symptoms, course and risk factors were collected using the Diagnostic Interview Schedule (DIS). Latent class analysis was applied to summarize symptom patterns. Course characteristics and risk factor profiles were compared among potential subtypes based on the number of symptom groups or symptom patterns. Logistic regression models were used to examine the etiologic heterogeneity among potential subtypes based on symptoms. RESULTS: The number of symptom groups gave the most efficient insight into differential etiologic processes. Severe depression (7-9 symptom groups) was associated with female gender, family history of depression but not with stressful life events before the onset of the first episode. Moderate (5-6 symptom groups) and mild depression (3-4 symptom groups) were associated with family history of depression, stressful life events before the onset, but not with female gender. The latent class model generated patterns of depressive psychopathology as follows: anhedonia, suicidal, psychomotor, and severely depressed subtypes. The Anhedonia subtype showed a course and risk factor profile distinct from the others. LIMITATIONS: The measurement of psychopathology was based on self-reported DIS interviews instead of psychiatric assessments. Recall or report bias cannot be excluded in the ascertainment of family history and stressful life events. CONCLUSIONS: Depression is heterogeneous, even below the threshold of syndromal diagnosis. The severity of an episode appears to be more informative than the pattern of symptoms, with the possible exception of a putative anhedonic subtype.

Adult↗
PubMedDate not supplied

Echocardiographic studies on elderly patients with white coat hypertension to evaluate cardiac organ damages.

This case-control study was aimed at evaluating the distribution of some echocardiographic signs of cardiac organ damages in elderly patients with white coat hypertension (WCH), as compared with a normotensive group of elderly. Correlations between the signs of cardiac organ damages and the clinical and ambulatory blood pressure parameters (obtained by means of a 24-h monitoring) have also been evaluated. The first screening covered 258 elderly subjects of both sexes, aged from 65 to 82 years, with clinical diagnosis of hypertension (systolic and diastolic blood pressures being higher than 160 and 95 mmHg, respectively). Of this group, 116 subjects remained in the final pool, and their echocardiographic parameters were compared with 33 normotensive (N) subjects. Out of the 116 clinically hypertensive patients, 29 (25%) displayed WCH, according to the established criteria. Variance analyses on the ranks followed by Dunn's test revealed no statistically significant differences between the N and WCH groups, while the hypertensive group (H) proved to be significantly different from both the N and the WCH groups. In addition to the descriptive statistics, an analysis of correlations between the pressure variables and the echocardiographic parameters has also been performed by means of a forward-stepwise multiple linear regression method. The models generated by this regression analysis covered only the ambulatory diurnal systolic pressure, and the clinical diastolic pressure in most of the cases of the echocardiographic parameters, taken as independent variables. In all these cases, the standardizecl correlation coefficient of the diurnal systolic pressure was always higher than that of the clinical diastolic pressure, indicating that the echocardiographic parameters depend more strongly on the first than on the second pressure value.

Journal Article↗
PubMed2000

Supported membranes on soft polymer cushions: fabrication, characterization and applications.

Soft biofunctional and biocompatible interfaces on solids designed by the deposition of ultrathin soft polymer films or supported membranes have numerous scientific and practical applications. These include the immobilization of glycolipids, membrane receptors and proteins to generate models of cell and tissue surfaces. Powerful surface-sensitive techniques can be applied to study protein-protein recognition processes at membranes and the control of cell adhesion by the interplay of specific 'lock-and-key' forces and universal interfacial forces. Potential practical applications include the design of smart biosensors based on electro-optical devices and the fabrication of biofunctional surfaces for the stimulation of cell proliferation and tissue growth, or for the suppression of apoptosis.

Biosensing Techniques↗
PubMed2001

Nonmanipulative determination of plant community dynamics.

Knowledge of the strengths of interactions between species in plant communities is of fundamental importance to our understanding of how communities are structured, although they are notoriously difficult to quantify. Techniques have recently been developed that allow the detailed enumeration of the strength of interactions between plant species within unmanipulated multispecies communities. Nonlinear regression analysis is used to fit competition models to long-term census data using natural variations in plant densities in lieu of manipulation. The models generated have been used to infer the intensity and importance of interactions as well as to analyse the effects of spatial and temporal variability. Theoretical work has begun to look at how different techniques for measuring competition perform in a range of systems, highlighting the importance of spatial scale. The lessons learned from applying these methods will enable improved estimation of the strength of competition in natural communities.

Journal Article↗
PubMed1997

Finite element analysis of human knee joint in varus-valgus.

OBJECTIVE: The overall response, load transmission, role of ligaments, and state of stress in various components under varus-valgus moments in the intact and collateral-deficient tibiofemoral joint are investigated. DESIGN: A non-linear finite element model consisting of bony structures (tibia and femur), their articular cartilage layers, medial and lateral menisci and four primary ligaments (cruciates and collaterals) is utilized. BACKGROUND: Valgus and varus stresses are among the primary mechanisms of injury to knee ligaments. Several in vitro studies have investigated the role of ligaments in resisting such loads and on the way deficiency in either collateral may affect the response. METHODS: Cartilage layers are isotropic while menisci are non-homogeneous composite. The articulation of cartilage layers with each other and with the intervening menisci and the wrapping of the medial collateral ligament around the tibial edge are treated as large displacement frictionless contact problems. The non-linear elastostatic response of the joint at full extension is computed under varus-valgus moments applied to the femur with the tibia fixed. Cases simulating deficiency in collaterals and constraint on femoral axial rotation are also studied. RESULTS: The response is non-linear with large coupled axial rotations, internal in varus and external in valgus. In intact and collateral-deficient states, the joint shows varus or valgus openings so that the articulation occurs at one plateau only, medial in varus and lateral in valgus. Large tensile forces in cruciates in collateral-cut models generate higher compression penalty on the loaded plateau. CONCLUSIONS: Collaterals are the primary load-bearing structures; their absence would substantially increase primary laxities, coupled axial rotations, forces in cruciates, and articular contact forces. Good agreement with measurements is found. RELEVANCE: Detailed knowledge of joint biomechanics is essential in the diagnosis, prevention and treatment of observed disorders. Absence of collateral ligaments increases the loads in cruciates and contact stresses transmitted through cartilage layers and menisci, and thus places the affected components at more risk, especially when varus-valgus is accompanied by other modes of loading as well.

Journal Article↗
PubMed2002

Latent learning, shortcuts and detours: a computational model.

Voicu and Schmajuk (Rob. Auto. Syst. 35 (2001a) 23) described a model of spatial navigation and exploration that includes an action system capable of guiding, with the help of a cognitive system, the search for specific goals as determined by a motivation system. Whereas in the original model the cognitive map stores information about the connectivity between places in the environment, in the present version the cognitive map also stores information about the paths traversed by the agent. Computer simulations show that the network correctly describes experimental results including latent learning in a maze, detours in a maze, and shortcuts in an open field. In addition, the model generates novel predictions about detours and shortcuts in an open field.

Journal Article↗
PubMed2002

Quantitative analysis of polymorphic mixtures of ranitidine hydrochloride by Raman spectroscopy and principal components analysis.

Ranitidine hydrochloride exists as two polymorphs, forms I and II, both of which are used to manufacture commercial tablets. Raman spectroscopy can be used to differentiate the two forms but univariate methods of quantitative analysis of one polymorph as an impurity in the other lack sensitivity. We have applied principal components analysis (PCA) of Raman spectra to binary mixtures of the two polymorphs and to binary mixtures prepared by adding one polymorph to powdered tablets of the other. Based on absorption measurements of seven spectral regions, it was found that >97% of the spectral variation was accounted for by three principal components. Quantitative calibration models generated by multiple linear regression predicted a detection limit and quantitation limit for either forms I or II in mixtures of the two of 0.6 and 1.8%, respectively. This study demonstrates that PCA of Raman spectroscopic data provides a sensitive method for the quantitative analysis of polymorphic impurities of drugs in commercial tablets with a quantitation limit of less than 2%.

Drug Evaluation, Preclinical↗
PubMed2001

A comparative approach to structure-function studies of mammalian aromatases.

To date, structure--function studies of aromatase cytochrome P450 (P450arom) have been advanced by point mutation analyses utilizing almost exclusively the human enzyme, in conjunction with computer-generated models of the three-dimensional form of the enzyme based on prokaryotic cytochromes P450. Recent studies have identified duplicated isozymes of porcine P450arom, the gonadal and placental forms of which appear to differ substantially in substrate utilization and inhibitor sensitivity. We present a comparative approach to define regions of P450arom responsible for specific functional characteristics using complimentary DNAs encoding the porcine isozymes. Constructs encoding the native and chimeric porcine and human P450arom enzymes were transiently expressed and activity was assessed using the tritiated water assay. Sensitivity to inhibition by the imidazole etomidate was investigated, and P450arom expression was assessed by immunoblot analysis. All constructs yielded active P450arom, suggesting that exchanging entire structural elements does not preclude catalytic function. The activity of the gonadal isozyme was shown to be inhibited by etomidate at concentrations 185 and 300-fold lower than those required to induce a similar inhibition of the placental and human enzymes, respectively. In contrast, there was only a two-fold difference in the sensitivity of the gonadal and placental isozymes to inhibition by CGS16949A. Analysis of chimeric constructs indicated that the sensitivity to etomidate was associated with residues in the B, B' and C helices of the gonadal P450arom encompassing only one of six putative substrate recognition sites. Additionally, sensitivity to etomidate was not correlated with enzyme activity among the chimeric enzymes. Therefore, it appears that residues of the porcine gonadal P450arom that are responsible for etomidate binding may be distinct from those involved in substrate recognition and metabolism. These data support the notion that a comparative approach employing the use of chimeric enzymes provides a useful tool in directing point mutational analysis to determine residues important in inhibitor and perhaps substrate recognition of P450 enzymes such as P450arom. These studies are currently in progress.

Animals↗