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At least 883 records · Page 49Linked to original sources
PubMed1995

Neuronal circuitry of the lower urinary tract; central and peripheral neuronal control of the micturition cycle.

A new presentation technique is introduce to describe the neuronal circuitry involved in the control of the uropoëtic system and its control mechanisms during the micturition cycle. This method is based on the preparation of flow charts and is applied to the discussion of four qualitative models which are derived from the literature. Opinions concerning the reflex arcs and supraspinal connections said to be involved in micturition and continence are different and sometimes contradictory. Little is known about supraspinal (inter)connections and their function in micturition control is still fragmentary. The control mechanisms which terminate voiding are not totally clear. Moreover, the role of the pelvic floor musculature in the control of the lower urinary tract is probably underestimated. The flow charts presented in this paper contribute to the future design of a single complete qualitative model representing the general central and peripheral nervous connections and control mechanisms. Such a model would provide an approach for future research in neuromodulation and neurostimulation of the uropoëtic system and a reduced version could be used for quantitative modelling, e.g. in neural network simulations.

Humans↗
PubMed1990

Neural network implementation of a three-phase model of respiratory rhythm generation.

A mathematical model of the central neural mechanisms of respiratory rhythm generation is developed. This model assumes that the respiratory cycle consists of three phases: inspiration, post-inspiration, and expiration. Five respiratory neuronal groups are included: inspiratory, late-inspiratory, post-inspiratory, expiratory, and early-inspiratory neurons. Proposed interconnections among these groups are based substantially on previous physiological findings. The model produces a stable limit cycle and generally reproduces the features of the firing patterns of the 5 neuronal groups. When simulated feedback from pulmonary stretch receptors is made to excite late-inspiratory neurons and inhibit early-inspiratory neurons, the model quantitatively reproduces previous observations of the expiratory-prolonging effects of pulses and steps of vagal afferent activity presented in expiration. In addition the model reproduces expected respiratory cycle timing and amplitude responses to change of chemical drive both in the absence and in the presence of simulated stretch receptor feedback. These results demonstrate the feasibility of generating the respiratory rhythm with a simple neural network based on observed respiratory neuronal groups. Other neuronal groups not included in the model may be more important for shaping the waveforms than for generating the basic oscillation.

Animals↗
PubMed2026

Multiscale Modeling Primer: Focus on Chromatin and Epigenetics.

A central challenge in modern biology is to understand how molecular interactions produce cellular and organismal functions across vast spatiotemporal scales. Nowhere is this challenge more apparent than in the study of chromatin, where meters of DNA compact into a micron-sized nucleus. How this polymer folds is a dynamic process, regulated by epigenetic modifications-chemical changes to DNA and histones that involve only a handful of atoms. These small changes cooperate to produce emergent, higher-order structures that define cellular identity and function. To explain this system, we must integrate static, high-resolution snapshots from techniques like cryo-EM with dynamic, lower-resolution data from microscopy and genomics. Multiscale computational models are essential tools that bridge these experimental gaps and reveal the mechanisms of emergent behavior. However, the communication divide between experimental biologists and quantitative modelers often hampers progress. This primer addresses that gap. It first introduces the fundamental biology of chromatin and epigenetics at an introductory level for non-biologists audiences. We then survey the landscape of computational approaches, from atomistic to systems-level models, and connect them to the experimental data that inform and validate them at an introductory level for non-computationalists. We argue that the next frontier will require us to build integrative models that can predict how molecular perturbations mechanistically alter cellular phenotypes, which will open a new era of chromatin-targeted therapeutics.

Chromatin Dynamics↗
PubMed2004

The influence of cell and substratum surface hydrophobicities on microbial attachment.

This study investigated the role of hydrophobic/hydrophilic interaction between bacterial and support surfaces in microbial adhesion, and a model that correlates microbial adhesion and relative cell-hydrophobicity defined as the ratio of cell-support surface hydrophobicity over cell-support hydrophilicity was derived. This model quantitatively describes how cell hydrophobic and hydrophilic interactions affect microbial adhesion, and offers deep insights into the thermodynamic mechanisms of microbial adhesion. The proposed model was verified by literature data. It appears that a high cell-hydrophobicity strongly facilitates microbial adhesion on both hydrophobic and hydrophilic support surfaces.

Bacterial Adhesion↗
PubMed1997

Development of a quantitative risk assessment model for Salmonella enteritidis in pasteurized liquid eggs.

The performance of hazard analyses and the establishment of critical limits by the food industry are both hampered by the inability to directly relate food processing operations from farm-to-table with their public health impact. Using a 'unit operations' and stochastic simulation approach, data on the frequency of pathogens in raw ingredients, predictive microbiology models for growth and inactivation (thermal and non-thermal), and dose-response models for infectivity were integrated to create a quantitative risk assessment model for a Salmonella enteritidis infection from thermally processed liquid whole eggs made into mayonnaise in the home. The risk assessment indicated pasteurization provides sufficient consumer protection from a high incidence of infected birds and from temperature abuse between the farm and the egg breakers. However scenarios showed how inadequate pasteurization temperatures and/or temperature abuse during storage leads to a hazardous product. This dynamic approach to modeling risk should aid in identification and setting critical control points and assessing the impact of altering food formulations or processes.

Eggs↗
PubMedDate not supplied

Computational analysis of vertebrate phototransduction: combined quantitative and qualitative modeling of dark- and light-adapted responses in amphibian rods.

We evaluated the generality of two models of vertebrate phototransduction. The approach was to quantitatively optimize each model to the full waveform of high-quality, dark-adapted (DA), salamander rod flash responses. With the optimal parameters, each model was then used to account for signature, qualitative features of rod responses from three experimental paradigms (stimulus/response, "S/R suite"): (1) step responses; (2) the intensity dependence of the period of photocurrent saturation (Tsat vs. ln(I)); and (3) light-adapted (LA) incremental flash sensitivity as a function of background intensity. The first model was the recent successful model of Nikonov et al. (1998). The second model replaced the instantaneous Ca2+ buffering used in the Nikonov et al. model with a dynamic buffer. The results showed that, in the absence of the dynamic Ca2+ buffer, the Nikonov et al. model does not have sufficient flexibility to provide a good fit to the flash responses, and, using the same parameters, reproduce the salient features of the S/R suite--critical features at step onset and offset are absent; the Tsat function has too shallow a slope; and the model cannot generate the empirically observed I-range of Weber-Fechner LA behavior. Some features could be recovered by changing parameters, but only at the expense of the fit to the reference (Ref) data. When the dynamic buffer is added, the model is able to achieve an acceptable fit to the Ref data while reproducing several features of the S/R suite, including an empirically observed Tsat function, and an extended range of LA flash sensitivity adhering to Weber's law. The overall improved behavior of the model with a dynamic Ca2+ buffer indicates that it is an important mechanism to include in a working model of phototransduction, and that, despite the slow kinetics of amphibian rods, Ca2+ buffering should not be simulated as an instantaneous process. However, neither model was able to capture all the features with the same parameters yielding the optimal fit to the Ref data. In addition, neither model could maintain a good fit to the Ref data when five key biochemical parameters were held at their current known values. Moreover, even after optimization, a number of important parameters remained outside their empirical estimates. We conclude that other mechanisms will need to be added, including additional Ca2+-feedback mechanisms. The present research illustrates the importance of a hybrid qualitative/quantitative approach to model development, and the limitations of modeling restricted sets of data.

Adaptation, Ocular↗
PubMed2003

Using gene expression ratios to predict outcome among patients with mesothelioma.

BACKGROUND: We have recently demonstrated that simple ratios of the expression levels of selected genes in tumor samples can be used to distinguish among types of thoracic malignancies. We examined whether this technique could predict treatment-related outcome for patients with mesothelioma. METHODS: We used gene expression profiling data previously collected from 17 mesothelioma patients with different overall survival times to define two outcome-related groups of patients and to train an expression ratio-based outcome predictor model. A Student's t test was used to identify genes among the two outcome groups that had statistically significant, inversely correlated expression levels; those genes were used to form prognostic expression ratios. We used a combination of several highly accurate expression ratios and cross-validation techniques to assess the internal consistency of this predictor model, quantitative reverse transcription-polymerase chain reaction of tumor RNA to confirm the microarray data, and Kaplan-Meier survival analysis to validate the model among an independent set of 29 mesothelioma tumors. All statistical tests were two-sided. RESULTS: We developed an expression ratio-based test capable of identifying 100% (17/17) of the samples used to train the model. This test remained highly accurate (88%, 15/17) after cross-validation. A four-gene expression ratio test statistically significantly (P =.0035) predicted treatment-related patient outcome in mesothelioma independent of the histologic subtype of the tumor. CONCLUSIONS: Gene expression ratio-based analysis accurately predicts treatment-related outcome in mesothelioma samples. This technique could impact the clinical treatment of mesothelioma by allowing the preoperative identification of patients with widely divergent prognoses.

Adult↗
PubMedDate not supplied

A model system to quantitate tumor burden in locoregional lymph nodes during cancer spread.

In order to quantitate the metastatic burden of secondary tumor deposits in locoregional lymph nodes, we produced a green fluorescent protein (GFP)-expressing murine cell line (B16F1) metastatic to lymph nodes in immunocompetent mice. When implanted into the hindleg of mice, all animals developed paraaortic lymph node metastases. Fluorescence microscopy, immunohistochemistry, and RT-PCR confirmed the presence of metastatic cells in lymph nodes. Tumoral deposits occurred preferentially in marginal sinuses and spread superficially to the subcortical area. Western blot analysis showed that the local tumor burden could be quantitated in individual lymph nodes. This model system should be useful for quantitating metastatic invasion particularly of micrometastases and aid in the development of lymphotropic drugs to detect and/or treat lymph node metastases in advanced cancers.

Animals↗
PubMed1981

Discrimination of hyperplasia and carcinoma of the endometrium by quantitative microscopy--a feasibility study.

Endometrial hyperplasias and carcinomas have been investigated by quantitative microscopical methods. The aim of this study was to develop an objective method of histopathological diagnosis because of the great subjective variability of these endometrial conditions. A total of 79 cases were studied. Only those were included, which, after re-examination of the material by different pathologists, were regarded as mild atypical hyperplasia (38 cases), marked atypical (adenomatous) hyperplasia (11 cases), well and moderately differentiated adenocarcinoma (19 and 11 cases, respectively). There are many significant differences between these four groups. Stereological features contained the most important information, whilst nuclear features were less successful discriminators. The volume percentage of the epithelium and of the glands and the inner surface density of the glands showed the most significant differences between adenomatous hyperplasia and well differentiated carcinoma. On the basis of these findings, a quantitative model is suggested which might give more insight into the development of these abnormalities, assuming a gradual transition from one to another. The great advantage of the quantitative analysis of data over subjective impressions, it that is is objective, and provides consistently reproducible results. The present results may be especially useful when histopathological diagnosis is in doubt. It is concluded that application of quantitative microscopy in the discrimination of endometrial hyperplasia and carcinoma in histopathology is feasible.

Adenocarcinoma↗
PubMedDate not supplied

A comparison of three models of the inositol trisphosphate receptor.

The inositol (1,4,5)-trisphosphate receptor (IPR) plays a crucial role in calcium dynamics in a wide range of cell types, and is often a central feature in quantitative models of calcium oscillations and waves. We compare three mathematical models of the IPR, fitting each of them to the same data set to determine ranges for the parameter values. Each of the fits indicates that fast activation of the receptor, followed by slow inactivation, is an important feature of the model, and also that the speed of inositol trisphosphate IP3 binding cannot necessarily be assumed to be faster than Ca2+ activation. In addition, the model which assumed saturating binding rates of Ca2+ to the IPR demonstrated the best fit. However, lack of convergence in the fitting procedure indicates that responses to step increases of Ca2+ and IP3 provide insufficient data to determine the parameters unambiguously in any of the models.

Animals↗
PubMed2004

Models of the inositol trisphosphate receptor.

The inositol (1,4,5)-trisphosphate receptor (IPR) plays a crucial role in calcium dynamics in a wide range of cell types, and is often a central feature in quantitative models of calcium oscillations and waves. We review deterministic and stochastic mathematical models of the IPR, from the earliest ones of the 1970s and 1980s, to the most recent. The effects of IPR stochasticity on Ca2+ dynamics are briefly discussed.

Allosteric Site↗
PubMed1999

Water diffusion in rat brain in vivo as detected at very large b values is multicompartmental.

The diffusion-weighted signal attenuation of water in rat brain was measured with pulsed-field gradient nuclear magnetic resonance methods in a single voxel under in vivo and global ischemic conditions. The diffusion-attenuated water signal was observed in vivo at b values of 300 ms/microm2 (strength of diffusion weighting) and diffusion times up to 400 ms. A series of constant diffusion time (CT) experiments with varied gradient directions and diffusion times revealed a multiexponential decay with apparent diffusion coefficients (ADC) covering two orders of magnitude from 1 to 0.01 microm2/ms. In a four-exponential fit, the observed changes during global ischemia could be fully explained by changes in the relative volume fractions only with unchanged ADCs. An anisotropy of the ADC, detected at small b values, was not observed for the ADC at large b values, but for the concomitant volume fractions. An inverse Laplace Transform of the CT curves, performed with CONTIN, resulted in continuously distributed diffusion coefficients, for which the term 'diffusogram' is proposed. This approach was more appropriate than a discrete exponential model with four to six components, being related to the morphology of brain tissue and its cell size distribution. On the basis of an analytical, quantitative model, it is suggested that the measured ADC at small b values reflects mainly properties of the restricting boundaries, i.e. the relative volume fractions and the extracellular tortuosity, while the intrinsic intracellular diffusion constant and the exchange time are predicted to have minor influence.

Animals↗
PubMed1994

Differences in calcium homeostasis between retinal rod and cone photoreceptors revealed by the effects of voltage on the cGMP-gated conductance in intact cells.

We measured currents under voltage clamp in intact retinal rod photoreceptors with tight seal electrodes in the perforated patch mode. In the dark, membrane depolarization to voltages > or = +20 mV activates a time- and voltage-dependent outward current in the outer segment. This dark voltage-activated current (DVAC) increases in amplitude with a sigmoidal time course that is voltage dependent. DVAC reaches its maximum enhancement of approximately 30% in 4-6 s at +60 mV. DVAC is entirely suppressed by light and its current-voltage curve and reversal potential are the same as those of the photocurrent. Therefore, DVAC arises from the opening in darkness of the cGMP-gated channels of the outer segment. DVAC is blocked by BAPTA loaded into the cell's cytoplasm and is enhanced by lowering extracellular Ca2+ concentration. Because the cGMP-gated channels are not directly gated by voltage and because BAPTA blocks DVAC, we suggest this signal arises from a voltage-dependent decrease in cytoplasmic Ca2+ concentration that, in turn, activates guanylyl cyclase and causes cGMP synthesis. In rods loaded with high cytoplasmic Na+, membrane depolarization in darkness to voltages > or = +20 mV inactivates the outward current in the outer segment with an exponential time course. We call this DVIC (dark, voltage-inactivated current). DVIC reflects voltage-dependent closing of the cGMP-gated channel in the dark. DVIC, too, is blocked by cytoplasmic BAPTA, and it arises from a voltage-dependent rise in cytoplasmic Ca2+ in darkness, which occurs only if cytoplasmic Na is high. We develop a quantitative model to calculate the rate and extent of the voltage-dependent change in cytoplasmic Ca2+ concentration in a normal rod. We assume that this concentration is controlled by the balance between Ca2+ influx through the cGMP-gated channels and its efflux through a Na+/Ca2+, K+ exchanger. Lowered cytoplasmic Ca2+ is linked to guanylyl cyclase activation with characteristics determined from biochemical studies. The model considers the cytoplasmic buffering of both Ca2+ and cGMP. Simulated data generated by the model fit well DVAC measured in rods and also DVAC previously measured in cones. DVAC in cones is larger in magnitude and faster in time course than that in rods. The successful fit of DVAC by the model leads us to suggest that the activity and Ca2+ dependence of the enzymes of transduction are not different in rods and cones, but the quantitative features of Ca2+ homeostasis in the outer segment of the two receptor types differ profoundly.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambystoma↗
PubMed1975

Studies of energy transport in heart cells. Mitochondrial isoenzyme of creatine phosphokinase: kinetic properties and regulatory action of Mg2+ ions.

1. The kinetic properties of mitochondrial creatine phosphokinase (Km for all substrates and maximal rates of the forward and reverse reaction) have been studied. Since (a) Km value for MgADP- (0.05 mM) and creatine phosphate (0.5 mM) are significantly lower than Km for MgATP2- (0.7 mM) and creatine (5.0 mM) and (b) maximal rate of the reverse reaction (creatine phosphate + ADP leads to ATP + creatine) equal to 3.5 mumol times min-1 times mg-1 is essentially higher than maximal rate of the forward reaction (0.8 mumol times min-1 times mg-1), ATP synthesis from ADP and creatine phosphate is kinetically preferable over the forward reaction. 2. A possible regulatory role of Mg2+ ions in the creatine phosphokinase reaction has been tested. It has been shown that in the presence of all substrates and products of the reaction the ratio of the rates of forward and reverse reactions can be effectively regulated by the concentration of Mg2+ ions. At limited Mg2+ concentrations creatine phosphate is preferably synthesized while at high Mg2+ concentrations (more ATP in the reaction medium) ATP synthesis takes place. 3. The kinetic (mathematical) model of the mitochondrial creatine phosphokinase reaction has been developed. This model accounts for the existence of a variety of molecular forms of adenine nucleotides in solution and the formation of their complexes with magnesium. It is based on the assumption that the mitochondrial creatine phosphokinase reactions mechanism is analogous to that for soluble isoenzymes. 4. The dependence of the overall rate of the creatine phosphokinase reaction on the concentration of total Mg2+ ions calculated from the kinetic model quantitatively correlates with the experimentally determined dependence through a wide range of substrates (ATP, ADP, creatine and creatine phosphate) concentration. The analysis of the kinetic model demonstrates that the observed regulatory effect of Mg2+ on the overall reaction rate can be expained by (a) the sigmoidal variation in the concentration of the MgADP- complex resulting from the competition between ATP AND ADP for Mg2+ and (b) the high affinity of the enzyme to MgADP-. 5. The results predicted by the model for the behavior of mitochondrial creatine phosphokinase under conditions of oxidative phosphorylation point to an intimate functional interaction of mitochondrial creatine phosphokinase and ATP-ADP translocase.

Adenosine Diphosphate↗
PubMed1980

Parameter and structural identifiability concepts and ambiguities: a critical review and analysis.

The notion of identifiability addresses the question of whether it is at all possible to obtain unique solutions for unknown parameters of interest in a mathematical model, from data collected in well-defined stimulus-response experiments performed on a dynamic system represented by the model. This critical aspect of the modeling and data reduction problem is reviewed, analyzed, and unified, with emphasis on applications in biology. Several physiological system models are examined in detail. They illustrate the importance of identifiability analysis prior to performing a parameter estimation experiment, the algebraic difficulties, possible pitfalls, and not-so-apparent ambiguities that may be encountered--even for simple models--and the utility of the concept in experiment design. Methods for testing for identifiability also are reviewed and compared, with emphasis on applicability and limitations. The usefulness of a given model for predicting the time course of system variables (not parameters) of interest normally inaccessible to direct measurement (e.g., tissue concentrations), a common use for quantitative models, is shown to depend intimately on the identifiability properties of the model, in a manner not easy but essential to assess: state variable predictions made in this manner can be inherently ambiguous.

Kinetics↗
PubMed2002

Statistical modeling of tooth mobility after treating adult periodontitis.

The healing process following periodontal surgery for advanced adult periodontitis is described. Of the various indicators, tooth mobility (TM) is considered, and its relation to surgical treatment and the time lapse from the flap surgery is quantitatively modeled by non-parametric regression. Mobility is measured by an electronic apparatus, which also automatically performs the modeling. A new statistical method for TM prediction is demonstrated, and its quality is estimated. We show that the quality at the first step of prediction is approximately 0.7. This indicates that the prediction method is able to model the effect of surgery on the healing process, although the random scattering of TM data recorded in the examined group is relatively large. The influence of periodontal surgery on TM, alone and in combination with systemic metronidazole, is quantitatively characterized in two groups of 12 patients each. In the test group, which received metronidazole, TM decreased significantly 1 week postoperatively, compared to the control group without the antibiotic. The gingival fluid flow rate (GFFR) and the percentage of spirochete morphotypes detected by darkfield microscopy exhibited a similar dependence. Significant differences in TM, GFFR and the percentage of spirochetes between the two groups were observed over a period of several weeks. Probing depths (PD) in both groups at 2 and 12 months after surgery did not reveal any category with pockets deeper than 4 mm. A gain of clinical attachment level of more than 2 mm (CAL) was observed at measurements of 16.7% and 10.6% on the test and control groups, respectively, 1 year after surgery.

Adult↗
PubMed2004

Perturbations of malate accumulation and the endogenous rhythms of gas exchange in the Crassulacean acid metabolism plant Kalanchoë daigremontiana: testing the tonoplast-as-oscillator model.

In continuous light, leaves of the Crassulacean acid metabolism (CAM) plant Kalanchoë daigremontiana Hamet et Perrier exhibit a circadian rhythm of CO2 uptake, stomatal conductance and leaf-internal CO2 pressure. According to a current quantitative model of CAM, the pacemaking mechanism involves periodic turgor-related tension and relaxation of the tonoplast, which determines the direction of the net flux of malate between the vacuole and the cytoplasm. Cytoplasmic malate, in turn, through its inhibitory effect on phospho enolpyruvate carboxylase, controls the rate of CO2 uptake. According to this mechanism, when the accumulation of malate is disrupted by removing CO2 from the ambient air, the induction of a phase delay with respect to an unperturbed control plant is expected. First, using the mathematical model, such phase delays were observed in numerical simulations of three scenarios of CO2 removal: (i) starting at a trough of CO2 uptake, lasting for about half a cycle (ca. 12 h in vivo); (ii) with the identical starting phase, but lasting for 1.5 cycles (ca. 36 h); and (iii) starting while CO2 increases, lasting for half a cycle again. Applying the same protocols to leaves of K. daigremontiana in vivo did not induce the predicted phase shifts, i.e. after the end of the CO2 removal the perturbed rhythm adopted nearly the same phase as that of the control plant. Second, when leaves were exposed to a nitrogen atmosphere for three nights prior to onset of continuous light to prevent malate accumulation, a small, 4-h phase advance was observed instead of a delay, again contrary to the model-based expectations. Hence, vacuolar malic acid accumulation is ruled out as the central pacemaking process. This observation is in line with our earlier suggestion [T.P. Wyka, U. Lüttge (2003) J Exp Bot 54:1471-1479] that in extended continuous light, CO2 uptake switches gradually from a CAM-like to a C3-like mechanism, with oscillations of the two CO2 uptake systems being tightly coordinated. It appears that the circadian rhythm of gas exchange in this CAM plant emerges from one or several devices that are capable of generating temporal information in a robust manner, i.e. they are protected from even severe metabolic perturbations.

Carbon Dioxide↗
PubMed1994

Removing the assumption of conditional independence from Bayesian decision models by using artificial neural networks: some practical techniques and a case study.

The article describes how artificial neural networks with special designs can be applied to approximate a subjective Bayesian decision model without the assumption of conditional independence. New techniques are proposed to resolve some of the practical difficulties during the processes of problem structuring, knowledge elicitation, quantitative modeling, and model interpretation. A Bayesian model considering the conditional dependencies to predict a teenager's marijuana use was constructed by experts using these techniques, and compared to another conventional Bayesian model which assumed conditional independence. The new approach without the assumption of conditional independence had predictive power (r = 0.7) in the test of linearity compared to the conventional approach (r = 0.58) on a data set (n = 129). Its receiver operating characteristic curve dominated the alternative approach within the range (true positive fraction > 0.7) that we were interested in. The interpretations of the possible conditional dependencies provided by the artificial neural network after the training process were consistent with the expert's descriptions.

Adolescent↗