Biodynamic modeling and simulation of multistage cell mutations

The aim of this study is to present a mathematical computer simulation model for multistage carcinogenesis. The population genetic model is developed based on the reaction diffusion, logistic behavior, and Hollings Type II interactions between normal, benign, and premalignant cells. The simple form of the Fisher-Haldane-Wright equation of the genetic model of tumor suppressor gene and oncogenes is used to describe this type of interaction. Through computer simulation, we observe the behavior, stability, and traveling wave solution of the premalignant stage mutation as well as its survival under natural selection pressure. As a simple case of this model, the interaction between normal and tumor cells with one or two stages of mutations is analyzed.     

Coordinated force production in multi-finger tasks: finger interaction and neural network modeling

During maximal voluntary contraction (MVC) with several fingers, the following three phenomena are observed: (1) the total force produced by all the involved fingers is shared among the fingers in a specific manner (sharing); (2) the force produced by a given finger in a multi-finger task is smaller than the force generated by this finger in a single-finger task (force deficit); (3) the fingers that are not required to produce any force by instruction are involuntary activated (enslaving). We studied involuntary force production by individual fingers (enslaving effects, EE) during tasks when (an)other finger(s) of the hand generated maximal voluntary pressing force in isometric conditions. The subjects (n = 10) were instructed to press as hard as possible on the force sensors with one, two, three and four fingers acting in parallel in all possible combinations. The EE were (A) large, the slave fingers always producing a force ranging from 10.9% to 54.7% of the maximal force produced by the finger in the single-finger task; (B) nearly symmetrical; (C) larger for the neighboring fingers; and (D) non-additive. In most cases, the EE from two or three fingers were smaller than the EE from at least one finger (this phenomenon was coined occlusion). The occlusion cannot be explained only by anatomical musculo-tendinous connections. Therefore, neural factors contribute substantially to the EE. A neural network model that accounts for all the three effects has been developed. The model consists of three layers: the input layer that models a central neural drive; the hidden layer modeling transformation of the central drive into an input signal to the muscles serving several fingers simultaneously (multi-digit muscles); and the output layer representing finger force output. The output of the hidden layer is set inversely proportional to the number of fingers involved. In addition, direct connections between the input and output layers represent signals to the hand muscles serving individual fingers (uni-digit muscles). The network was validated using three different training sets. Single digit muscles contributed from 25% to 50% of the total finger force. The master matrix and the enslaving matrix were computed; they characterize the ability of a given finger to enslave other fingers and its ability to be enslaved. Overall, the neural network modeling suggests that no direct correspondence exists between neural command to an individual finger and finger force. To produce a desired finger force, a command sent to an intended finger should be scaled in accordance with the commands sent to the other fingers. Received: 17 October 1997 / Accepted in revised form: 12 May 1998     

Conservation, variability and the modeling of active protein kinases

The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy.     

Computer modeling of human movements]

A dynamic model for studying man's movements is proposed. Lagrange equations of the second order are used. Differential equations of the model are presented in the matrix form, and all the coefficients involved are calculated from recurrent formulae. The dynamic model described is easily algorythmized. Differentiating operations can be thus avoided which are realized on electron computers with difficulities.     

Basic functions of variability of simple pre-planned movements

A model of a pre-planned single joint movements performed without feedback is considered. Modifications of this movement result from transformation of a trajectory pattern f(t) in space and time. The control system adjusts the movement to concrete external conditions specifying values of the transform parameters before the movement performance. The preplanned movement is considered to be simple one, if the transform can be approximated by an affine transform of the movement space and time. In this case, the trajectory of the movement is x(t) = Af(t/ + s) +p, were A and 1/ are space and time scales, s and p are translations. The variability of movements is described by time profiles of variances and covariances of the trajectory x(t), velocity v(t), and acceleration a(t). It is assumed that the variability is defined only by parameters variations. From this assumption follows the main finding of this work: the variability time profiles can be expanded on a special system of basic functions corresponding to established movement parameters. Particularly, basic functions of variance time profiles, reflecting spatial and temporal scaling, are x ²(t) and t ² v ²(t) for trajectory, v ²(t) and (v(t) + t · a(t))² for velocity, and a ²(t) and (2a(t) +t · j(t))², where j(t) = d³ x(t)/dt ³, for acceleration. The variability of a model of a reaching movement was studied analytically. The model predicts certain peculiarities of the form of time profiles (e.g., the variance time profile of velocity is bi-modal, the one of acceleration is tri-modal, etc.). Experimental measurements confirmed predictions. Their consistence allows them to be considered invariant properties of reaching movement. A conclusion can be made, that reaching movement belongs to the type of simple preplanned movements. For a more complex movement, time profiles of variability are also measured and explained by the model of movements of this type. Thus, a movement can be attributed to the type of simple pre-planned ones by testing its variability.     

Growth,Yield and Fruit Quality of Grapevines under Organic and Biodynamic Management

The main objective of this study was to determine growth, yield and fruit quality of grapevines under organic and biodynamic management in relation to integrated viticultural practices. Furthermore, the mechanisms for the observed changes in growth, yield and fruit quality were investigated by determining nutrient status, physiological performance of the plants and disease incidence on bunches in three consecutive growing seasons. A field trial (Vitis vinifera L. cv. Riesling) was set up at Hochschule Geisenheim University, Germany. The integrated treatment was managed according to the code of good practice. Organic and biodynamic plots were managed according to Regulation (EC) No 834/2007 and Regulation (EC) No 889/2008 and according to ECOVIN- and Demeter-Standards, respectively. The growth and yield of the grapevines differed strongly among the different management systems, whereas fruit quality was not affected by the management system. The organic and the biodynamic treatments showed significantly lower growth and yield in comparison to the integrated treatment. The physiological performance was significantly lower in the organic and the biodynamic systems, which may account for differences in growth and cluster weight and might therefore induce lower yields of the respective treatments. Soil management and fertilization strategy could be responsible factors for these changes. Yields of the organic and the biodynamic treatments partially decreased due to higher disease incidence of downy mildew. The organic and the biodynamic plant protection strategies that exclude the use of synthetic fungicides are likely to induce higher disease incidence and might partially account for differences in the nutrient status of vines under organic and biodynamic management. Use of the biodynamic preparations had little influence on vine growth and yield. Due to the investigation of important parameters that induce changes especially in growth and yield of grapevines under organic and biodynamic management the study can potentially provide guidance for defining more effective farming systems.     

Kinematic description of variability of fast movements: analytical and experimental approaches

Analysis of variability of fast aimed movements predicts the properties of trajectory variance. The analysis is based on a kinematic model with nonlinear changes in “internal time”. The purpose of the work was to identify different sources of variability and their influence on the trajectory variance. An analytical expression for the speed-accuracy trade-off is introduced. Experiments were performed with subjects making single-joint elbow flexion movements over different distances as fast as possible with their eyes closed to memorized targets. Standard deviation of movement trajectory increased during the first part of the movement and subsequently decreased. The variance peaked after the time of peak velocity, close to the time of peak deceleration. A dependence of the trajectory variance on movement distance (speed-accuracy trade-off) was seen during the movement (at times of peak velocity and peak deceleration) but not after the movement termination. We conclude that the previously reported drop in the variability of movement trajectory during the deceleration phase does not necessarily mean a compensation by the control system but may result from purely kinematic properties of the movement. The importance of the time of measurement for analysis of the speed-accuracy trade-offs is emphasized.     

Niche variability and its consequences for species distribution modeling

When species distribution models (SDMs) are used to predict how a species will respond to environmental change, an important assumption is that the environmental niche of the species is conserved over evolutionary time-scales. Empirical studies conducted at ecological time-scales, however, demonstrate that the niche of some species can vary in response to environmental change. We use habitat and locality data of five species of stream fishes collected across seasons to examine the effects of niche variability on the accuracy of projections from Maxent, a popular SDM. We then compare these predictions to those from an alternate method of creating SDM projections in which a transformation of the environmental data to similar scales is applied. The niche of each species varied to some degree in response to seasonal variation in environmental variables, with most species shifting habitat use in response to changes in canopy cover or flow rate. SDMs constructed from the original environmental data accurately predicted the occurrences of one species across all seasons and a subset of seasons for two other species. A similar result was found for SDMs constructed from the transformed environmental data. However, the transformed SDMs produced better models in ten of the 14 total SDMs, as judged by ratios of mean probability values at known presences to mean probability values at all other locations. Niche variability should be an important consideration when using SDMs to predict future distributions of species because of its prevalence among natural populations. The framework we present here may potentially improve these predictions by accounting for such variability.     

Design, modeling, and analysis of a feedstock logistics system

Given the location of a bio-energy plant for the conversion of biomass to bio-energy, a feedstock logistics system that relies on the use of satellite storage locations (SSLs) for temporary storage and loading of round bales is proposed. Three equipment systems are considered for handling biomass at the SSLs, and they are either placed permanently or are mobile and thereby travel from one SSL to another. A mathematical programming-based approach is utilized to determine SSLs and equipment routes in order to minimize the total cost. The use of a Side-loading Rack System results in average savings of 21.3% over a Densification System while a Rear-loading Rack System is more expensive to operate than either of the other equipment systems. The utilization of mobile equipment results in average savings of 14.8% over the equipment placed permanently. Furthermore, the Densification System is not justifiable for transportation distances less than 81 km.     

Sensitivity variations in the visual system,contrast resolution and eye movements

Attention is drawn to the fact that under normal visual conditions the sensitivity of the receptor units of the visual system are subject to spatial and temporal variations, and that consequently in performing pattern recognition the visual cortex has to discriminate between external luminance structure and internal sensitivity structure. It is suggested that eye movements are the method by which this discrimination is performed. In a simplified model analysis it is shown that eye movements are a suitable mechanism for this discrimination. Implications of this model for detection threshold and stabilized retinal images are discussed. A new interpretation of the adaptation to sine wave grids is given.     

Long-term light environment variability in Lake Biwa and Lake Kasumigaura, Japan: modeling approach

Light environment variability was investigated in the two Japanese lakes Biwa and Kasumigaura, which offer a broad range of optical conditions in the water bodies due to their diverse morphometries and limnological characteristics. To elucidate their light environments, Secchi depths (SDs) were related to long-term monitored datasets of concentrations of optically active substances (OASs) using two approaches based on statistical and mechanistic models. A good estimate for the nonphytoplanktonic suspended solids (NPSS) concentration gained using a monthly factor ?? (which represents the phytoplanktonic portion in total suspended solids) from a long-term analysis was utilized to develop robust models. Using the mechanistic model, the contribution of each OAS to the SD can be understood and investigated in more detail than possible with a statistical approach, but the statistical model yields better results in terms of SD prediction. Based on the results of an analysis of the contribution of each OAS to the SD, it was clear that NPSS was the component that exerted the most influence on the light environments in the two lakes; in this respect, this study agrees with other studies that show the importance of suspended inorganic particles as the main contributor to the SD in inland waters. Using ANOVA, we analyzed how specific inherent optical properties may have changed spatially and temporally, and the results indicated that the temporal (monthly) effect was primarily responsible for the loss of accuracy in the models. In addition, the ANOVA analysis suggested that grouping the data improved the predictive performances of the statistical models. Finally, we concluded that combining the two models yields the most reliable results in terms of SD prediction and determining the contribution of each OAS to the SD at present.     

Hypocone and metaconule: identification and variability on human molars

Hypocone and metaconule variability was studied in a large sample of upper molars belonging to several human populations. The identification of these cusps does not generally show problems. However, on second and especially on third molars, it is occasionally difficult to decide if a little cup located on the crown distal border is a hypocone or a metaconule. The identification of supernumerary cusps located between the metacone and the hypocone seldom is clarified. We suggest the utility of differentiating if such cusps proceed the hypocone or metacone division and of using metacone variability in dental anthropology studies. An objective classification of the metacone size is proposed to standardize observations. Paper presented at the 4^th congress of the European Anthropology Association (Florence, Sept. 1984).     

UCSF Chimera, MODELLER, and IMP: an integrated modeling system

Structural modeling of macromolecular complexes greatly benefits from interactive visualization capabilities. Here we present the integration of several modeling tools into UCSF Chimera. These include comparative modeling by MODELLER, simultaneous fitting of multiple components into electron microscopy density maps by IMP MultiFit, computing of small-angle X-ray scattering profiles and fitting of the corresponding experimental profile by IMP FoXS, and assessment of amino acid sidechain conformations based on rotamer probabilities and local interactions by Chimera.     

An identification technique for the spike artefact of saccadic eye movements

Many subjects have a negative spike in the beginning of a saccade in electro-oculographic signals. The amplitude of the spike depends on the location of the electrodes. The spike distorts the saccades and causes errors in the parameters. The saccade spike can assist in the identification of small saccades. A syntactic technique, based on formal languages and parsing is presented which looks for spikes from the electro-oculographic signal. For calculation of the algorithm, saccades from the photoelectric signal have been concurrently recorded and compared with the electro-oculographic signal.     

Triggering loops and enzyme function: identification of loops that trigger and modulate movements

Enzyme function often involves a conformational change. There is a general agreement that loops play a vital role in correctly positioning the catalytically important residues. Nevertheless, predicting the functional loops and most importantly their role in enzyme function remains a difficult task. A major reason for this difficulty is that loops that undergo conformational change are frequently not well conserved in their primary sequence. beta1,4-Galactosyltransferase is one such enzyme. There, the amino acid sequence of a long loop that undergoes a large conformational change upon substrate binding is not well conserved. Our molecular dynamics simulations show that the large conformational change in the long loop is brought about by a second, interacting loop. Interestingly, while the structural change of the second loop is much smaller than that of the long loop, its sequence (particularly glycine residues) is highly conserved. We further examine the generality of the proposition that there are loops that trigger movements but nevertheless show little or no structural changes in crystals. We focus on two other enzymes, enolase and lipase. We chose these enzymes, since they too undergo conformational change upon ligand binding, however, they have different folds and different functions. Through multiple sets of simulations we show that the conformational change of the functional loop(s) is brought about through communication of flexibility by triggering loops that have several glycine residues. We further propose that similar to the conservation of common favorable fold types and structural motifs, evolution has also conserved common "skillful" mechanisms. Mechanisms may be conserved across different folds, sequences and functions, with adaptation to specific enzymatic roles.     

Sympatric variability of isotopic baselines influences modeling of fish trophic patterns

Stable isotope signatures of freshwater snails and mussels have been established as a convenient baseline measurement at the primary consumer level for food-web coupling studies. We measured δ¹⁵N and δ¹³C of primary consumers, including mussels (Anodonta woodiana, Cristaria plicata, and Unio douglasiae), snails (Bellamya aeruginosa and Hippeutis sp.), and zooplankton from the same habitat within a shallow eutrophic lake. Primary consumers showed positive relationship between δ¹⁵N and δ¹³C, indicating a linkage between planktonic and benthic habitats in this system. The variation in isotope ratios was higher in short-lived primary consumers (zooplankton) compared with the long-lived primary consumers (mussels and snails), suggesting limited availability of short-lived primary consumers as isotopic baselines in aquatic food-web assessment. Significant differences in isotope ratios were also found among three species of mussels, and when using these mussels separately as pelagic baselines to calculate trophic position and contribution of planktonic and benthic sources of fishes, bias and even misestimates were observed. This finding suggests that caution is needed when multiple primary consumers coexist in the same habitat, and it is important to assess potential effects of different baselines used.     

DNA barcode sequence identification incorporating taxonomic hierarchy and within taxon variability

For DNA barcoding to succeed as a scientific endeavor an accurate and expeditious query sequence identification method is needed. Although a global multiple-sequence alignment can be generated for some barcoding markers (e.g. COI, rbcL), not all barcoding markers are as structurally conserved (e.g. matK). Thus, algorithms that depend on global multiple-sequence alignments are not universally applicable. Some sequence identification methods that use local pairwise alignments (e.g. BLAST) are unable to accurately differentiate between highly similar sequences and are not designed to cope with hierarchic phylogenetic relationships or within taxon variability. Here, I present a novel alignment-free sequence identification algorithm--BRONX--that accounts for observed within taxon variability and hierarchic relationships among taxa. BRONX identifies short variable segments and corresponding invariant flanking regions in reference sequences. These flanking regions are used to score variable regions in the query sequence without the production of a global multiple-sequence alignment. By incorporating observed within taxon variability into the scoring procedure, misidentifications arising from shared alleles/haplotypes are minimized. An explicit treatment of more inclusive terminals allows for separate identifications to be made for each taxonomic level and/or for user-defined terminals. BRONX performs better than all other methods when there is imperfect overlap between query and reference sequences (e.g. mini-barcode queries against a full-length barcode database). BRONX consistently produced better identifications at the genus-level for all query types.     

Description of Haemonchus placei (Place, 1893) (Nematoda, Trichostrongylidae, Haemonchinae), identification and intra-specific morphologic variability

Haemonchus placei in cattle has never been completely described, possibly due to great morphological similarity with small ruminants Haemonchus contortus. It is newly described on one isolate from Argentina. It has clear distinct morphological features from sheep and goats Haemonchus contortus and presents only two female morphotypes (linguiform and knobbed) instead of three recorded in H. contortus. A key is proposed to identify females. Female as well as male Haemonchus placei from New World (Argentina, Mexico, USA) are morphologically different from those of Old World (Africa: Burkina-Faso, Mauritania and Ivory Coast) or Australia, possibly due to local evolution since their introduction several centuries ago from Africa or India. We propose to differentiate three sub-species, H. placei placei in Australia, H. placei africanus in western Africa and H. placei argentinensis in the New World.