From Blood Oxygenation Level Dependent (BOLD) Signals to Brain Temperature Maps

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to brain temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO ₂) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model, we obtain a transcendental equation relating CBF and CMRO ₂ changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bioheat equation describing the rate of temperature changes in the brain, we obtain a nonautonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. Temperature maps obtained from a real BOLD dataset registered in an attention to visual motion experiment were calculated, obtaining temperature variations in the range: (−0.15, 0.1) which is consistent with experimental results. The statistical analysis revealed that significant temperature activations have a similar distribution pattern than BOLD activations. An interesting difference was the activation of the precuneus in temperature maps, a region involved in visuospatial processing, an effect that was not observed on BOLD maps. Furthermore, temperature maps were more localized to gray matter regions than the original BOLD maps, showing less activated voxels in white matter and cerebrospinal fluid.     

A computer-based model for the regulation of mitogen activated protein kinase (MAPK) activation

Computer simulations and mathematical modeling of biological processes are becoming increasingly popular, and yet the complexity of the biochemical systems or the differences between experimental setups make it very difficult to establish a standard formula for these modeling projects. Before we can start using computer-based models for predictions or targeted experiment designs, it is very important to establish a reliable model on which those predictions can be based and experimentally tested. Here we attempt to present a computer model for the mitogen-activated protein kinase (MAPK) signaling cascade which is consistent with previously published experimental results. In this study we have focused our attention to a generic MAPK ERK (extracellular signal-regulated kinase) pathway activated by epidermal growth factor (EGF) in an attempt to understand how receptors may achieve different activation kinetics of the MAPK signaling. We successfully show that the level of receptor expression is one key determinant in this regulation, and that the binding affinity of the active receptor to adaptor proteins can have a small but albeit direct effect on the downstream activation.     

Proposed structural models of the prothrombinase (FXa-FVa) complex

Activated coagulation factor V (FVa) functions as a cofactor to factor Xa (FXa) in the conversion of prothrombin (PT) to thrombin. This essential procoagulant reaction, despite being the subject of extensive investigation, is not fully understood structurally and functionally. To elucidate the structure of the FXa-FVa complex, we have performed protein:protein (Pr:Pr) docking simulation with the pseudo-Brownian Pr:Pr docking ICM package and with the shape-complementarity Pr:Pr docking program PPD. The docking runs were carried out using a new model of full-length human FVa and the X-ray structure of human FXa. Five representative models of the FXa-FVa complex were in overall agreement with some of the available experimental data, but only one model was found to be consistent with almost all of the reported experimental results. The use of hybrid docking approach (theoretical plus experimental) is definitively important to study such large macromolecular complexes. The FXa-FVa model we have created will be instrumental for further investigation of this macromolecular system and will guide future site directed mutagenesis experiments.     

Ecological opportunity and ecomorphological convergence in Australasian robins (Petroicidae)

Ecological theories of adaptive radiation predict that ecological opportunity (EO) stimulates cladogenesis through entry into a novel environment and/or release of competition pressures. Due to its dynamic paleoclimatic and geological history, the Australo‐Papuan region constitutes an opportune scenario to study patterns of diversification in relation to the colonization of new ecological niches. Here, we employ a comparative framework using the Australasian robins (Petroicidae) as a model system to test whether the diversification of this bird family fulfils a niche‐filling process as predicted by the EO model, and to test whether the observed morphological similarity is described by a pattern of phylogenetic niche conservatism (PNC) or convergence. Although we detected an early‐burst, we did not find a slowdown in speciation or morphological evolution as expected in a niche‐filling scenario. Divergence in tarsus length and tail length (PC1) was consistent with a multi‐peak model, in which PC1 represents a convergent trait among distantly related clades sharing the same foraging strategy. Our study thus shows that convergence rather than PNC seems to explain the existence of morphological similarity across independent lineages in the Petroicidae. We also found a low level of PNC regarding annual variations in temperature and precipitation, which is in agreement with the hypothesis that diversification within the Petroicidae involved repeated radiations. We suggest two non‐mutually exclusive hypotheses to explain the overall lack of density‐dependent cladogenesis. First, the extreme spatial and temporal heterogeneity of this region may have generated a pattern of repeated ecological opportunity over time and, second, this family may not yet have reached equilibrium diversity.     

A frequency distribution for the number of hematogenous organ metastases

The number of metastases associated with a primary tumor can be a major determinant for the chance of cure. A model is proposed here where the frequency distribution of the number of experimental organ metastases is affected by Poisson statistics, and by stochastic variations in regional blood flow. The model predicts that the mean E (X) and variance var (X) of the number of metastases per organ should relate according to a power function,var (X)= E (X)(p)+E (X), where and p are the constants, and that the actual distribution has a Poisson-negative binomial form. This model was found consistent with the data derived from a meta-analysis of over 47 000 murine experimental metastases. This frequency distribution (together with knowledge of the size distribution for metastases and the fraction of clonogenic cells) could permit more accurate assessments for tumor control probabilities with adjuvant therapies.     

Estimation of neurophysiological parameters from the waking EEG using a biophysical model of brain dynamics

This paper presents the results from using electroencephalographic (EEG) data to estimate the values of key neurophysiological parameters using a detailed biophysical model of brain activity. The model incorporates spatial and temporal aspects of cortical function including axonal transmission delays, synapto-dendritic rates, range-dependent connectivities, excitatory and inhibitory neural populations, and intrathalamic, intracortical, corticocortical and corticothalamic pathways. Parameter estimates were obtained by fitting the model's theoretical spectrum to EEG spectra from each of 100 healthy human subjects. Statistical analysis was used to infer significant parameter variations occurring between eyes-closed and eyes-open states, and a correlation matrix was used to investigate links between the parameter variations and traditional measures of quantitative EEG (qEEG). Accurate fits to all experimental spectra were observed, and both inter-subject and between-state variability were accounted for by the variance in the fitted biophysical parameters, which were in turn consistent with known independent experimental and theoretical estimates. These values thus provide physiological information regarding the state. transitions (eyes-closed vs. eyes-open) and phenomena including cortical idling and alpha desynchronization. The parameters are also consistent with traditional qEEG, but are more informative, since they provide links to underlying physiological processes. To our knowledge, this is the first study where a detailed biophysical model of the brain is used to estimate neurophysiological parameters underlying the transitions in a broad range (0.25-50 Hz) of EEG spectra obtained from a large set of human data.     

A Computer‐Based Model for the Regulation of Mitogen Activated Protein Kinase (MAPK) Activation

Abstract

Computer simulations and mathematical modeling of biological processes are becoming increasingly popular, and yet the complexity of the biochemical systems or the differences between experimental setups make it very difficult to establish a standard formula for these modeling projects. Before we can start using computer‐based models for predictions or targeted experiment designs, it is very important to establish a reliable model on which those predictions can be based and experimentally tested. Here we attempt to present a computer model for the mitogen‐activated protein kinase (MAPK) signaling cascade which is consistent with previously published experimental results. In this study we have focused our attention to a generic MAPK ERK (extracellular signal‐regulated kinase) pathway activated by epidermal growth factor (EGF) in an attempt to understand how receptors may achieve different activation kinetics of the MAPK signaling. We successfully show that the level of receptor expression is one key determinant in this regulation, and that the binding affinity of the active receptor to adaptor proteins can have a small but albeit direct effect on the downstream activation.     

Cooperative binding of 2,2′‐bipyridine into polynucleotide poly(A)–poly(U‐) in an alkaline aqueous solution

UV absorption data analysis has been used to evaluate equilibrium constants of the pH‐induced interaction of 2,2′‐Bipy with polyadenylnic‐polyuridylic acid in aqueous solution. The conditional probabilities hard model has been adopted in treatment of concentration diagrams calculated by the soft modelling‐based Multivariate Curve Resolution‐Alternating Least Squares approach. Intrinsic binding constant (lgK_g = 1.93), and the cooperativity parameter (ω = 340), were calculated as the best fit. The plot of the experimental binding constant versus 2,2′‐Bipy equilibrium concentration shows two modes of ligand with polymer interactions. The equilibrium hard model correctly reproduced the binding constant variations observed in the experiment. The results indicated that ligand binding in two steps is governed by a cooperative process, that is, the enhancement of deprotonated structure stability. It would appear that proposed calculation approach can be used in future combined hard modelling theoretical and soft modelling experimental works. © 2013 Wiley Periodicals, Inc. Biopolymers 99:621–627, 2013.     

Survey of conformational role of ester bonds in a cyclic depsipeptide. Study on cyclo(-L-Ala-L-Hmb-)2 by energy calculation and NMR spectroscopy.

The effect of ester bond on the conformation of peptide molecule was studied by designing and synthesizing a model tetradepsipeptide cyclo(-L-Ala-L-Hmb-)2 and by analyzing the conformation both theoretically and experimentally. Theoretical analysis showed that both ester and peptide bonds in the calculated low-energy conformations within 3 kcal/mol of the global minimum take a trans but distorted configuration. The distortion is larger in ester bonds than in peptide bonds. Further, the four carbonyls project from one side of the plane of the cyclic backbone, whereas the side chains project from the other side. These results are consistent with the experimental results obtained by NMR measurement; first, the coupling constant deduced from 1H-NMR species in DMSO-d6 is consistent with the dihedral angles of the calculated low-energy conformations; second, results of NOE measurement can reproduce the calculated configuration of the carbonyls and side chains. From the consistency between theoretical and experimental results, it is concluded that this model tetradepsipeptide takes an all-trans backbone conformation in solution and this backbone conformation is stabilized by large distortion in the ester bond, which compensates the strain resulted from the 12-membered cyclic backbone structure consisting only of L-residues.     

A dye-binding induced conformational transition of poly-(methacrylic acid) by Auramine O in aqueous solutions. II. Theoretical interpretation and discussion of the experimental results

The binding of Auramine O to poly-(methacrylic acid) (PMA) is explained using a two-state model for the polyelectrolyte and preferential binding of the dye to the hypercoiled conformational state of PMA predominantly present for the dye-free polyelectrolyte at low degrees of neutralization. Bound-dye interactions were neglected leading to a binding isotherm as given by Monod et al. to which the experimental dialysis results could be fitted. It is shown that this model predicts a conformational transition from the more extended conformational state of PMA to the hyper-coiled one upon progressive binding of the dye. The experimental results obtained by potentiometric and viscosimetric titrations as well as the fluorcsence intensity measurements of the AuO—PMA system arc consistent with the conclusions based on this model.     

INDIVIDUAL FLOWERING TIME IN A GOLDENROD (SOLIDAGO CANADENSIS): FIELD EXPERIMENT SHOWS GENOTYPE MORE IMPORTANT THAN ENVIRONMENT

Individual plants of an old field population of the clonal perennial goldenrod, Solidago canadensis L. are consistent in rank order of flowering time over years. In order to analyze whether this consistency is due more to environmental variations among microsites of individual clones or due to genetic variation among clones, similar-sized sections of rhizomes were transplanted to an experimental garden in a randomized block design with five replicates per clone. Three years later we examined the transplants and the original plants for their flowering phenology. In the experimental garden there was an unexpected soil moisture gradient across blocks, with associated gradients in height of goldenrods and height of surrounding vegetation. No gradient was significantly correlated with the flowering time of the transplants. That is, the time of flowering of transplants was consistent among replicates of individual clones across the soil moisture gradient and regardless of the size of the transplants themselves, or the height of surrounding vegetation. Further, the flowering times of the transplants were significantly positively correlated with the flowering times of the original plants in the same year. We conclude that the differences in flowering time among clones within a goldenrod population is largely determined by genetic variation, rather than by environmental factors.     

Simulating the approximate irregular field dose distribution in radiotherapy using an ultrasound tracking technique

PurposeThis study used an ultrasound image tracking algorithm (UITA) in combination with a proposed simulation program for the approximate irregular field dose distribution (SPAD) to assess the feasibility of performing dose distribution simulations for two-dimensional radiotherapy.MethodsThis study created five different types of multileaf collimator openings, and applied a SPAD to analyze the matrix position parameters for each regular field to generate a static program-simulation dose distribution map (PDDM), whose similarity was then compared with a static radiochromic film experimental-measurement dose distribution map (EDDM). A two-dimensional respiration motion simulation system (RMSS) was used to reproduce the respiration motion, and the UITA was used to capture the respiration signals. Respiration signals were input to the SPAD to generate two dynamic PDDMs, which were compared for similarity with the dynamic EDDM.ResultsIn order to verify the dose distribution between different dose measurement techniques, the gamma passing rate with 2%/2 mm criterion was used for the EDDM and PDDM, the passing rates were between 94.31% and 99.71% in the static field analyses, and between 84.45% and 96.09% for simulations with the UITA signal input and between 89.35% and 97.78% for simulations with the original signal input in the dynamic field analyses.ConclusionsStatic and dynamic dose distribution maps can be simulated based on the proposed matrix position parameters of various fields and by using the UITA to track respiration signals during radiation therapy. The present findings indicate that it is possible to develop a reusable and time-saving dose distribution measurement tool.     

Representation of Faces in Longtailed Macaques (Macaca fascicularis)

The experiments described in this study were intended to increase our knowledge about social cognition in primates. Longtailed macaques (Macaca fascicularis) had to discriminate facial drawings of different emotional expressions. A new experimental approach was used. During the experimental sessions social interactions within the group were permitted, but the learning behaviour of individual monkeys was analysed. The procedure consisted of a simultaneous discrimination between four visual patterns under continuous reinforcement. It has implications not only for simple tasks of stimulus discrimination but also for complex problems of internal representations and visual communication. The monkeys learned quickly to discriminate faces of different emotional expressions. This discrimination ability was completely invariant with variations of colour, brightness, size, and rotation. Rotated and inverted faces were recognized perfectly. A preference test for particular features resulted in a graded estimation of particular facial components. Most important for face recognition was the outline, followed by the eye region and the mouth. An asymmetry in recognition of the left and right halves of the face was found. Further tests involving jumbled faces indicated that not only the presence of distinct facial cues but the specific relation of facial features is essential in recognizing faces. The experiment generally confirms that causal mechanisms of social cognition in non-human primates can be studied experimentally. The behavioural results are highly consistent with findings from neurophysiology and research with human subjects.     

Thermal denaturation of DNA for immunochemical staining of incorporated bromodeoxyuridine (BrdUrd): critical factors that affect the amount of fluorescence and the shape of BrdUrd/DNA histogram

Significant inter- and intraexperimental variations of the relative antibromodeoxyuridine fluorescence were found during measurement of DNA synthesis rates using flow cytometric analysis of 5-bromodeoxyuridine (BrdUrd)-labeled cells with an anti-BrdUrd antibody. Fluctuations in other endpoints associated with levels of denaturation (integrity of DNA and cell size) were also observed to vary widely among samples that were otherwise thought to have been treated identically. Therefore, the denaturation step has been carefully re-examined, and several critical factors were identified that influence the denaturation and subsequent binding of the anti-BrdUrd to the labeled DNA. These factors include cell density, volume of water, and pH of the sample during heating. Appropriate adjustments are now included in the protocol, resulting in more consistent anti-Brd-Urd measurements in the face of routine (and sometimes necessary) experimental variations.     

A three-dimensional statistical reconstruction model of grapevine (Vitis vinifera) simulating canopy structure variability within and between cultivar/training system pairs

Background and Aims

In grapevine, canopy-structure-related variations in light interception and distribution affect productivity, yield and the quality of the harvested product. A simple statistical model for reconstructing three-dimensional (3D) canopy structures for various cultivar–training system (C × T) pairs has been implemented with special attention paid to balance the time required for model parameterization and accuracy of the representations from organ to stand scales. Such an approach particularly aims at overcoming the weak integration of interplant variability using the usual direct 3D measurement methods.

Model

This model is original in combining a turbid-medium-like envelope enclosing the volume occupied by vine shoots with the use of discrete geometric polygons representing leaves randomly located within this volume to represent plant structure. Reconstruction rules were adapted to capture the main determinants of grapevine shoot architecture and their variability. Using a simplified set of parameters, it was possible to describe (1) the 3D path of the main shoot, (2) the volume occupied by the foliage around this path and (3) the orientation of individual leaf surfaces. Model parameterization (estimation of the probability distribution for each parameter) was carried out for eight contrasting C × T pairs.

Key Results and Conclusions

The parameter values obtained in each situation were consistent with our knowledge of grapevine architecture. Quantitative assessments for the generated virtual scenes were carried out at the canopy and plant scales. Light interception efficiency and local variations of light transmittance within and between experimental plots were correctly simulated for all canopies studied. The approach predicted these key ecophysiological variables significantly more accurately than the classical complete digitization method with a limited number of plants. In addition, this model accurately reproduced the characteristics of a wide range of individual digitized plants. Simulated leaf area density and the distribution of light interception among leaves were consistent with measurements. However, at the level of individual organs, the model tended to underestimate light interception.Key words: Canopy, architecture, hemispherical, picture, light interception, radiative, balance, stochastic, modelling, virtual, plants     

A multiscale computational model of YAP signaling in epithelial fingering behavior

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ordinary differential equation (ODE) model for intracellular YAP/Rac1/E-cadherin interactions. The ODE model dynamics are bistable, accounting for both motile loose cells and adherent slower cells. We incorporate this model into a cellular Potts model simulation of two-dimensional wound healing using the open-source platform Morpheus. We show that, under suitable stimuli representing topographic cues, the sheet exhibits finger-like projections and EMT. Morphological differences and quantitative differences in YAP levels as well as variations in cell speed across the sheet are consistent with previous experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knock down or overexpress YAP, inhibit Rac1, or block E-cadherin.     

Leukotriene C(4) biosynthesis in isolated August rat peritoneal leukocytes

The mixed leukocyte population obtained from the peritoneum of the August rat is a potentially important experimental model of inherent eosinophilia that has not been well characterized. In the present study, isolated cell preparations generated a concentration-dependent release of leukotriene (LT) C(4) when exposed to the Ca(2+) ionophore A23187, reaching maximal stimulation at 5.0 muM. This response was inhibited by the 5-lipoxygenase activating protein antagonist MK-886 (0.1 muM), nominally Ca(2+) and Mg(2+)-free incubation media and by activation of protein kinase C via phorbol 12-myristate 13-acetate (50 nM). These findings establish a model system for investigating LTC(4) profiles contingent with innate peritoneal eosinophilia and are consistent with the hypothesis that cellular LTC(4) biosynthesis is phosphoregulated.     

Demography of plains zebras (Equus quagga) under heavy predation

In natural ecosystems, ungulate densities show strong temporal variations. The ecological processes driving these fluctuations are complex: food limitation and predation are both important and can interact. Survival rates are central to this debate, but data are sparse for tropical ecosystems. Here, we estimate age- and sex-specific survival rates for plains zebra in Hwange National Park, a nutrient-poor savanna with a high predator–prey ratio. We estimated survival from a detailed Capture-Mark-Recapture (CMR) monitoring based on 248 individual life histories, for the first time in an African grazer. We controlled for variations in detection probabilities among adult females, which resulted from their social structure. As expected, annual survival was low during the first year (0.441); increased in yearlings (0.560) and peaked at 0.795 and 0.847 in adult males and females respectively. The survival of adult females was lower during the dry season, which probably resulted from higher predation due to predictable movements of zebras to waterholes. Survival at all ages was low compared to ungulates without predators. The demographic model we constructed showed a declining trend (λ = 0.94), which was consistent with the data from road counts ( = 0.92). Life Table Response Experiment (LTRE) analyses using the Serengeti and Kruger populations as references showed that the main cause of this declining trend in the Hwange population was low survival in yearling and adult females; low foal survival also contributed. In this ecosystem, predation is likely to be the main ecological process causing low survival, and therefore a decline in the zebra population.