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At least 937 records · Page 52Linked to original sources
PubMed2006

Testing the genetics underlying the co-evolution of mate choice and ornament in the wild.

One of the most debated questions in evolutionary biology is whether female choice of males with exaggerated sexual displays can evolve as a correlated response to selection acting on genes coding for male attractiveness or high overall viability. To date, empirical studies have provided support for parts of this scenario, but evidence for all key genetic components in a natural population is lacking. Here we use animal-model quantitative genetic analysis on data from over 8,500 collared flycatchers (Ficedula albicollis) followed for 24 years to quantify all of the key genetic requirements of both fisherian and 'good-genes' models on sexual selection in the wild. We found significant additive genetic variances of all the main components: male ornament (forehead patch size), female mate choice for this ornament, male fitness and female fitness. However, when the necessary genetic correlations between these components were taken into account, the estimated strength of indirect sexual selection on female mate choice was negligible. Our results show that the combined effect of environmental influences on several components reduces the potential for indirect sexual selection in the wild. This study provides insight into the field of sexual selection by showing that genes coding for mate choice for an ornament probably evolve by their own pathways instead of 'hitchhiking' with genes coding for the ornament.

Animals↗
PubMed1991

Microtubule dynamic instability: some possible physical mechanisms and their implications.

Video microscopic observation of a population of microtubules at steady state of assembly shows individual microtubules which interconvert between phases of growing and shrinking. The average duration of either phase is strongly affected by the tubulin concentration. Close to the steady-state (or 'critical') concentration, the mean excursion lengths may be of cellular dimensions, suggesting that dynamic instability can function as a control mechanism for the spatial organization of microtubule arrays. Numerical modelling, based on a limited number of assumptions, illustrates the transition behaviour, and the polar nature of this instability. The basic concept is that tubulin-GTP adds to a terminal position of the microtubule lattice and causes hydrolysis of the tubulin-GTP at a previously terminal lattice position [1, 2]. The predictions of this model can be evaluated experimentally. Further, examination of the consequences of introducing into the lattice a molecule such as a tubulin-drug complex, with altered capacity for helical propagation, provides a quantitative model for substoichiometric inhibition of microtubule dynamics and growth. This principle could have a more general relevance to mechanisms of regulation of microtubules within the cytoskeleton.

Animals↗
PubMed1991

A model for neurologic sources of aperiodicity in vocal fold vibration.

The time course of a force twitch in the thyroarytenoid muscle is modeled, and trains of twitches are summed to simulate force tetani. By incorporating means and standard deviations of motoneuron firing rates, and by applying random phase relationships between simulated motor units, a quantitative model of the ripple of vocal fold tension is obtained. From this ripple, perturbations in fundamental frequency are calculated as a function of the number of motor units in the muscle, the mean and standard deviation of the firing rate of dominant motoneurons, and the variability in the size (twitch amplitude) of the motor units. Predicted perturbations range between 0.2% and 1.2%, depending on the choice of parameters. Perturbation decreases with the number of motor units and with increased mean firing rate, but increases with the variability in motor unit size and with variability in the firing rate. Techniques are discussed by which neurologic jitter might be isolated from other sources of irregularity in vocal fold vibration.

Action Potentials↗
PubMed2004

Intrinsic noise in cultured hippocampal neurons: experiment and modeling.

Ion channels open and close stochastically. The fluctuation of these channels represents an intrinsic source of noise that affects the input-output properties of the neuron. We combined whole-cell measurements with biophysical modeling to characterize the intrinsic stochastic and electrical properties of single neurons as observed at the soma. We measured current and voltage noise in 18 d postembryonic cultured neurons from the rat hippocampus, at various subthreshold and near-threshold holding potentials in the presence of synaptic blockers. The observed current noise increased with depolarization, as ion channels were activated, and its spectrum demonstrated generalized 1/f behavior. Exposure to TTX removed a significant contribution from Na+ channels to the noise spectrum, particularly at depolarized potentials, and the resulting spectrum was now dominated by a single Lorentzian (1/f2) component. By replacing the intracellular K+ with Cs+, we demonstrated that a major portion of the observed noise was attributable to K+ channels. We compared the measured power spectral densities to a 1-D cable model of channel fluctuations based on Markov kinetics. We found that a somatic compartment, in combination with a single equivalent cylinder, described the effective geometry from the viewpoint of the soma. Four distinct channel populations were distributed in the membrane and modeled as Lorentzian current noise sources. Using the NEURON simulation program, we summed up the contributions from the spatially distributed current noise sources and calculated the total voltage and current noise. Our quantitative model reproduces important voltage- and frequency-dependent features of the data, accounting for the 1/f behavior, as well as the effects of various blockers.

Animals↗
PubMed1999

Identification of quantitative trait loci influencing traits related to energy balance in selection and inbred lines of mice.

Energy balance is a complex trait with relevance to the study of human obesity and maintenance energy requirements of livestock. The objective of this study was to identify, using unique mouse models, quantitative trait loci (QTL) influencing traits that contribute to variation in energy balance. Two F2 resource populations were created from lines of mice differing in heat loss measured by direct calorimetry as an indicator of energy expenditure. The HB F2 resource population originated from a cross between a noninbred line selected for high heat loss and an inbred line with low heat loss. Evidence for significant QTL influencing heat loss was found on chromosomes 1, 2, 3, and 7. Significant QTL influencing body weight and percentage gonadal fat, brown fat, liver, and heart were also identified. The LH F2 resource population originated from noninbred lines of mice that had undergone divergent selection for heat loss. Chromosomes 1 and 3 were evaluated. The QTL for heat loss identified on chromosome 1 in the HB population was confirmed in the LH population, although the effect was smaller. The presence of a QTL influencing 6-wk weight was also confirmed. Suggestive evidence for additional QTL influencing heat loss, percentage subcutaneous fat, and percentage heart was found for chromosome 1.

Adipose Tissue↗
PubMedDate not supplied

A link-segment model of upright human posture for analysis of head-trunk coordination.

Sensory-motor control of upright human posture may be organized in a top-down fashion such that certain head-trunk coordination strategies are employed to optimize visual and/or vestibular sensory inputs. Previous quantitative models of the biomechanics of human posture control have examined the simple case of ankle sway strategy, in which an inverted pendulum model is used, and the somewhat more complicated case of hip sway strategy, in which multisegment, articulated models are used. While these models can be used to quantify the gross dynamics of posture control, they are not sufficiently detailed to analyze head-trunk coordination strategies that may be crucial to understanding its underlying mechanisms. In this paper, we present a biomechanical model of upright human posture that extends an existing four mass, sagittal plane, link-segment model to a five mass model including an independent head link. The new model was developed to analyze segmental body movements during dynamic posturography experiments in order to study head-trunk coordination strategies and their influence on sensory inputs to balance control. It was designed specifically to analyze data collected on the EquiTest (NeuroCom International, Clackamas, OR) computerized dynamic posturography system, where the task of maintaining postural equilibrium may be challenged under conditions in which the visual surround, support surface, or both are in motion. The performance of the model was tested by comparing its estimated ground reaction forces to those measured directly by support surface force transducers. We conclude that this model will be a valuable analytical tool in the search for mechanisms of balance control.

Biomechanical Phenomena↗
PubMed1998

Estimation of maximal affinities between T-cell receptors and MHC/peptide complexes.

Recognition of peptide/MHC complexes by T-cell receptors (TCRs) is a critical step for T-cell activation. We studied T-cell activation as a function of this interaction using a mathematical model. Unlike other models analysing TCR-MHC/peptide interactions, this study takes into account that both TCRs and MHC/peptide complexes are anchored in membranes and not in solution. The proposed model quantitatively predicts several essential features of antigen-specific T-cell activation, including the experimentally determined rate of TCR-downregulation during peptide-specific T-cell stimulation. In addition, the model offers an explanation as to why the affinity of the TCR for MHC/peptide complexes is low in general and it correctly predicts the on-rates of the TCR-MHC/peptide interaction observed in different model systems. Thus, the proposed model predicts key parameters of T-cell activation and offers an explanation for the surprisingly low affinity of the TCR for its antigen.

Animals↗
PubMed2003

Modeling of ACL impingement against the intercondylar notch.

OBJECTIVE: To develop a 3-D mathematical model that accurately evaluates anterior cruciate ligament impingement against the intercondylar notch. DESIGN: The model simulated physical interactions between the anterior cruciate ligament and the intercondylar notch in tibiofemoral movement. BACKGROUND: Anterior cruciate ligament impingement has been evaluated through planar radiographic images, which may not characterize the complex 3-D notch shape associated with impingement. METHODS: After examining potential anterior cruciate ligament impingement in five cadaver knee specimens, the model was implemented using data from an individual cadaveric knee with representative impingement. The knee was loaded passively in various patterns to induce impingement, and the impingement force and six degrees-of-freedom tibiofemoral kinematics were measured. The femur, tibia, and anterior cruciate ligament were digitized. Spatial data points representing the notch surfaces were surface-fitted using bicubic splines. The model detected for impingement during the tibiofemoral movement and used a "crawling algorithm" to determine the deformed geometry of the impinging ligament. RESULTS: The model detected the impingement accurately and the ligament strain determined by the model was highly correlated with the recorded impingement force when impingement occurred during the tibiofemoral movement. Distance between the anterior cruciate ligament and the notch wall was determined when impingement was not detected. CONCLUSION: The model quantitatively characterized impingement of the anterior cruciate ligament against the intercondylar notch in 3-D space. RELEVANCE: The approach helps us better understand anterior cruciate ligament injury mechanisms in individual knees. Clinically, the model could potentially be used to analyze subject-specific potential/actual anterior cruciate ligament impingement based on the subject's MRI scans.

Anterior Cruciate Ligament↗
PubMed2006

Psychotherapy for schizophrenia in the year 2030: prognosis and prognostication.

A number of psychotherapy techniques have been developed that, to varying degrees, have empirical support demonstrating favorable effects in the treatment of schizophrenia (or serious mental illness [SMI]). These techniques, and the research, vary with respect to theoretical origins, format, treatment targets, and expected outcome. A historical perspective informs understanding of this proliferation. One landmark in psychotherapy research was the recognition of common factors: different therapies embody common therapeutic factors not central to any one school. Importantly, insights about common factors reflected a better theoretical understanding of the psychotherapy process and led to the translation of learning and conditioning theories into the psychotherapy vocabulary. This resulted in the distinction between specific and nonspecific treatment effects, which pose present-day research questions such as how common and specific factors interact, and the differentiation of techniques for specific recipients. Because psychotherapy research progresses over the next 25 years, it will be important to develop a model that can answer such questions while incorporating the proliferation of specific modalities and the search for the "right recipe." This "search" will coincide with more attention to individual differences, it will incorporate quantitative modeling, and it will spawn an array of "tools" for treating problems associated with SMI. Because self-knowledge and personhood again become recognized dimensions of recovery, traditional psychodynamic principles and techniques will be revisited. This article explicates a 4-factor model that may be a view to the future.

Cognitive Behavioral Therapy↗
PubMed2001

Signal strength in thymic selection and lineage commitment.

During development, alphabeta T cells undergo positive or negative selection and CD4(+)/CD8(+) lineage commitment-events that have a major impact on the functionality of the T cell repertoire. The precise mechanisms of these differentiative steps remain elusive. Research this year has focused on quantitative models of signaling. For positive selection, the timing and extent of ERK activation may be important. For lineage commitment, the extent of Lck recruitment and activation may be the decisive factor. Next, the search is on for the genes that commit the cell to the fate determined by these quantitative differences in signals.

Animals↗
PubMed2002

Drug design strategies for targeting G-protein-coupled receptors.

G-protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes. Since the sequencing of the human genome has revealed several hundred new members of this receptor family, many new opportunities for developing novel therapeutics have emerged. The increasing knowledge of GPCRs (biological target space) and their ligands (chemical ligand space) enables novel drug design strategies to accelerate the finding and optimization of GPCR leads: The crystal structure of rhodopsin provides the first three-dimensional GPCR information, which now supports homology modeling studies and structure-based drug design approaches within the GPCR target family. On the other hand, the classical ligand-based design approaches (for example, virtual screening, pharmacophore modeling, quantitative structure-activity relationship (QSAR)) are still powerful methods for lead finding and optimization. In addition, the cross-target analysis of GPCR ligands has revealed more and more common structural motifs and three-dimensional pharmacophores. Such GPCR privileged structural motifs have been successfully used by many pharmaceutical companies to design and synthesize combinatorial libraries, which are subsequently tested against novel GPCR targets for lead finding. In the near future structural biology and chemogenomics might allow the mapping of the ligand binding to the receptor. The linking of chemical and biological spaces will aid in generating lead-finding libraries, which are tailor-made for their respective receptor.

Amino Acid Motifs↗
PubMed2002

Computer modelling of radiation-induced bystander effect.

Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be aprotein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles.

Bystander Effect↗
PubMed1997

A decision analysis approach to neuroleptic dosing: insights from a mathematical model.

BACKGROUND: Although several published studies suggest that little benefit accrues from raising doses of conventional antipsychotic drugs above 500-800 chlorpromazine equivalents per day (CPZeq/day), institutionalized patients with schizophrenia often receive larger doses. Decision analysis could alter this practice by helping clinicians select doses through use of quantitative models that incorporate the consequences of each dose, the likelihood of those consequences, and explicit risk/benefit weightings. METHOD: This study uses representative published data to develop equations and graphs that describe dose-associated likelihoods of treatment response, side effects, and balances between benefits and incidence of side effects. RESULTS: Response rates fit a sigmoid curve that flattens at 500 CPZeq/day; a hyperbolic curve describing side effects reaches a plateau at much higher doses. Combining these curves shows that higher drug doses yield ever diminishing returns, because as the dose increases, the number of side effects per benefited patient also increases. A table and graphs show clinicians how to use these results to critique their current practices and make explicit risk/benefit judgments about dosages. CONCLUSION: Mathematical expressions for dose-related side effect and response rates are potentially useful tools for evaluating low-, intermediate-, or high-dosage neuroleptic treatment regimens.

Antipsychotic Agents↗
PubMed1988

Mathematical model of cellular mechanisms contributing to presynaptic facilitation.

Presynaptic facilitation of transmitter release from sensory neurons is an important mechanism contributing to nonassociative and associative learning in Aplysia. In a previous modeling study (28,29), we concluded that enhancement of the postsynaptic potential (PSP) during presynaptic facilitation is mediated by at least two processes; spike broadening, which has been observed experimentally, and a process that we modeled as mobilization of transmitter. In an effort to gain insight into the relative contribution of these two mechanisms of presynaptic facilitation, we have extended our earlier model to include more detailed descriptions of: a) the kinetics of the Ca2+ channel, b) the diffusion of Ca2+ through the cytoplasm, c) the process of transmitter release, and d) the PSP. The present quantitative model provides an accurate description of the input-output relationship for synapses of sensory neurons, and predicts changes in the shape of postsynaptic potentials as a function of mobilization and spike broadening. The results confirm and extend previous experimental studies (33) and indicated that cellular analogs of sensitization (facilitation of nondecremented responses) is mediated primarily by spike broadening; whereas, analogs of dishabituation (facilitation of depressed responses) require mobilization.

Animals↗
PubMed2005

Non-stochastic and stochastic linear indices of the 'molecular pseudograph's atom adjacency matrix': application to 'in silico' studies for the rational discovery of new antimalarial compounds.

Malaria is one of the most deadly diseases, affecting million of people especially in developing countries. Because of the rapidly increasing threat worldwide of malaria epidemics multidrugs resistant to therapies, there is an urgent global need to discover new classes of antimalarial compounds. In an effort to overcome this problem, we have investigated the use of structure-based classification models for the 'rational' selection/identification or design/optimization of new lead antimalarials from virtual combinatorial data sets. In this sense, TOpological MOlecular COMputer Design strategy (TOMOCOMD approach) has been introduced in order to obtain two quantitative models for the discrimination of antimalarials. A collected data set containing 597 antimalarial compounds is presented as a helpful tool not only for theoretical chemist but for other researchers in this area. The validated models (including non-stochastic and stochastic indices) classify correctly more than 90% of compounds in both training and external prediction data sets. They showed high Matthews' correlation coefficients; 0.87 and 0.82 for training and 0.86 and 0.79 for test set. The TOMOCOMD-CARDD approach implemented in this work was successfully compared with two of the most useful models for antimalarials selection reported so far. Thus we expect that these two QSAR models can be used in the identification of previously un-known antimalarials compounds.

Antimalarials↗
PubMed2001

Synchronization of glycolytic oscillations in a yeast cell population.

The mechanism of active phase synchronization in a suspension of oscillatory yeast cells has remained a puzzle for almost half a century. The difficulty of the problem stems from the fact that the synchronization phenomenon involves the entire metabolic network of glycolysis and fermentation, and consequently it cannot be addressed at the level of a single enzyme or a single chemical species. In this paper it is shown how this system in a CSTR (continuous flow stirred tank reactor) can be modelled quantitatively as a population of Stuart-Landau oscillators interacting by exchange of metabolites through the extracellular medium, thus reducing the complexity of the problem without sacrificing the biochemical realism. The parameters of the model can be derived by a systematic expansion from any full-scale model of the yeast cell kinetics with a supercritical Hopf bifurcation. Some parameter values can also be obtained directly from analysis of perturbation experiments. In the mean-field limit, equations for the study of populations having a distribution of frequencies are used to simulate the effect of the inherent variations between cells.

Algorithms↗
PubMed2006

Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia.

Obesity, diabetes, hypertension, and heart disease are highly heritable conditions that in aggregate are the major causes of morbidity and mortality in the developed world and are growing problems in developing countries. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. Family history and genetic data were used to construct a pedigree for the island. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. A protocol using loki, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait. Robust quantitative trait loci for height were found on 10q21 and 1p31. This protocol was used to map a set of metabolic traits, including plasma leptin to chromosome region 5q35; systolic blood pressure to 20p12; total cholesterol to 19p13, 12q24, and 16qter; hip circumference to 10q25 and 4q23; body mass index to 18p11 and 20q13; apolipoprotein B to 2p24-25; weight to 18q21; and fasting blood sugar to 1q31-1q43. Several of these same chromosomal regions have been identified in previous studies validating the use of loki. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes.

Body Height↗
PubMed2006

Investigations into the analysis and modeling of the cytochrome P450 cycle.

The main focus of our research is to explore the fundamental dynamics of the mechanism of the cytochrome P450 (CYP450) cycle. For this purpose we propose a system-theoretical approach, a time-dependent metabolic control analysis (tdMCA), to the analysis and quantitative modeling of the CYP450 catalytic pathway. This provides theoretical enlightenment for us to assess the transient response of the system to perturbations. In addition, the robustness of the cycle has also been observed, where perturbations elicit very weak responses and the system quickly recovers to the steady state (in an average of 10(-5) s). The tdMCA also shows that the two electron transfers to the cycle have different impacts on the system, and the cycle is more sensitive to the first electron than to the second one. Knowing the dynamics of transient fluctuations, the robustness of the cycle, and the effects from the key interim steps, one has a deeper understanding of the catalytic mechanism of cytochrome P450.

Catalysis↗