Artificial neural network based soft estimator for estimation of transducer static nonlinearity

In this work, the development of an Artificial Neural Network (ANN) based soft estimator is reported for the estimation of static-nonlinearity associated with the transducers. Under the realm of ANN based transducer modeling, only two neural models have been suggested to estimate the static-nonlinearity associated with the transducers with quite successful results. The first existing model is based on the concept of a functional link artificial neural network (FLANN) trained with mu-LMS (Least Mean Squares) learning algorithm. The second one is based on the architecture of a single layer linear ANN trained with alpha-LMS learning algorithm. However, both these models suffer from the problem of slow convergence (learning). In order to circumvent this problem, it is proposed to synthesize the direct model of transducers using the concept of a Polynomial-ANN (polynomial artificial neural network) trained with Levenberg-Marquardt (LM) learning algorithm. The proposed Polynomial-ANN oriented transducer model is implemented based on the topology of a single-layer feed-forward back-propagation-ANN. The proposed neural modeling technique provided an extremely fast convergence speed with increased accuracy for the estimation of transducer static nonlinearity. The results of convergence are very stimulating with the LM learning algorithm.     

Free energy landscape of a biomolecule in dihedral principal component space: sampling convergence and correspondence between structures and minima

Dihedral principal component analysis (dPCA) has recently been developed and shown to display complex features of the free energy landscape of a biomolecule that may be absent in the free energy landscape plotted in principal component space due to mixing of internal and overall rotational motion that can occur in principal component analysis (PCA) [Mu et al., Proteins: Struct Funct Bioinfo 2005;58:45-52]. Another difficulty in the implementation of PCA is sampling convergence, which we address here for both dPCA and PCA using a tetrapeptide as an example. We find that for both methods the sampling convergence can be reached over a similar time. Minima in the free energy landscape in the space of the two largest dihedral principal components often correspond to unique structures, though we also find some distinct minima to correspond to the same structure.     

Active manual control of object views facilitates visual recognition

Active exploration of large-scale environments leads to better learning of spatial layout than does passive observation [1] [2] [3]. But active exploration might also help us to remember the appearance of individual objects in a scene. In fact, when we encounter new objects, we often manipulate them so that they can be seen from a variety of perspectives. We present here the first evidence that active control of the visual input in this way facilitates later recognition of objects. Observers who actively rotated novel, three-dimensional objects on a computer screen later showed more efficient visual recognition than observers who passively viewed the exact same sequence of images of these virtual objects. During active exploration, the observers focused mainly on the 'side' or 'front' views of the objects (see also [4] [5] [6]). The results demonstrate that how an object is represented for later recognition is influenced by whether or not one controls the presentation of visual input during learning.     

Kinetics and thermodynamics of isothermal seed germination.

We have been successful in building a mathematical model that fits both the germination rate and the total number of seeds that germinate as a function of time. This mathematical model is the same autocatalytic reaction model that describes biochemical reactions in which enzymes play an important role. The model gives values for the initial concentration of two enzymes. From these initial enzyme concentrations an equilibrium constant is calculated and the thermodynamic model gives the change in enthalpy, entropy, free energy and the activation energy. A plot of the natural logarithm of the equilibrium constant as a function of the reciprocal of the absolute temperature gives two straight lines. The change of enthalpy for the process below 33 °C differs considerably to the change above 33 °C. The free energy as a function of the absolute temperature gives a straight line from which the change in entropy is calculated. The activation energy is determined from the slope of the natural logarithm of the rate constant as a function of the reciprocal of the absolute temperature.     

A neuromorphic architecture for object recognition and motion anticipation using burst-STDP

In this work we investigate the possibilities offered by a minimal framework of artificial spiking neurons to be deployed in silico. Here we introduce a hierarchical network architecture of spiking neurons which learns to recognize moving objects in a visual environment and determine the correct motor output for each object. These tasks are learned through both supervised and unsupervised spike timing dependent plasticity (STDP). STDP is responsible for the strengthening (or weakening) of synapses in relation to pre- and post-synaptic spike times and has been described as a Hebbian paradigm taking place both in vitro and in vivo. We utilize a variation of STDP learning, called burst-STDP, which is based on the notion that, since spikes are expensive in terms of energy consumption, then strong bursting activity carries more information than single (sparse) spikes. Furthermore, this learning algorithm takes advantage of homeostatic renormalization, which has been hypothesized to promote memory consolidation during NREM sleep. Using this learning rule, we design a spiking neural network architecture capable of object recognition, motion detection, attention towards important objects, and motor control outputs. We demonstrate the abilities of our design in a simple environment with distractor objects, multiple objects moving concurrently, and in the presence of noise. Most importantly, we show how this neural network is capable of performing these tasks using a simple leaky-integrate-and-fire (LIF) neuron model with binary synapses, making it fully compatible with state-of-the-art digital neuromorphic hardware designs. As such, the building blocks and learning rules presented in this paper appear promising for scalable fully neuromorphic systems to be implemented in hardware chips.     

Study of thermodynamic properties of symmetric and asymmetric electrolyte systems in mixture with neutral components: Monte Carlo simulation results and integral equation predictions

Monte Carlo simulation is conducted to obtain the structure, excess internal energy and Helmholtz energy for systems containing charged and neutral hard spheres of comparable concentrations. The results are compared with the thermodynamic properties predicted by solving Ornstein–Zernike equation with hypernetted chain (HNC) and mean spherical approximation (MSA) closures. The HNC approximation is found to well represent the simulation results for both structure and excess energy, while the excess energy of MSA deviates from the simulation results in the intermediate- and high-density range. A simple modification of MSA, referred to as KMSA, is proposed to accurately predict the excess internal and Helmholtz energy in the studied density range. KMSA is proved to capture the effects of neutral component, size and charge asymmetry, system temperature and dielectric constant of the background solvent, on the excess energy of electrolyte systems.     

Computational Modelling of Protein Interactions: Energy Minimization for the Refinement and Scoring of Association Decoys

The prediction of protein–protein interactions based on independently obtained structural information for each interacting partner remains an important challenge in computational chemistry. Procedures where hypothetical interaction models (or decoys) are generated, then ranked using a biochemically relevant scoring function have been garnering interest as an avenue for addressing such challenges. The program PatchDock has been shown to produce reasonable decoys for modeling the association between pig alpha-amylase and the VH-domains of camelide antibody raised against it. We designed a biochemically relevant method by which PatchDock decoys could be ranked in order to separate near-native structures from false positives. Several thousand steps of energy minimization were used to simulate induced fit within the otherwise rigid decoys and to rank them. We applied a partial free energy function to rank each of the binding modes, improving discrimination between near-native structures and false positives. Sorting decoys according to strain energy increased the proportion of near-native decoys near the bottom of the ranked list. Additionally, we propose a novel method which utilizes regression analysis for the selection of minimization convergence criteria and provides approximation of the partial free energy function as the number of algorithmic steps approaches infinity.     

Reversible reaction of 5,5'-dithiobis(2-nitrobenzoate) with the hemoglobins of the domestic cat: acetylation of NH3+ terminal group of the beta chain transforms the complex pH dependence of the forward apparent second order rate constant to a simple form

We demonstrate kinetically that the reaction of 5,5'-dithiobis(2-nitrobenzoate) with the CysF9[93]beta sulfhydryl group of domestic cat hemoglobins is a reversible process. In the major hemoglobin, in which the NH3+ terminal group of GlyNA1[1]beta is free, kf, the apparent forward second order rate constant, has a complex pH dependence profile. In the minor hemoglobin, the NH3+ terminal group of SerNA1[1]beta is acetylated, and the pH dependence profile of kf is simple. These results support the proposal that the positively charged groups at the organic phosphate binding site are electrostatically linked to CysF9[93]beta. Quantitative analyses of the complex profiles enabled us to estimate pKas of 7.47 +/- 0.3; 6.53 +/- 0.03 and 8.49 +/- 0.3 for GlyNA1[1]beta, HisH21[143]beta and other histidines within 2 nm of the sulfhydryl, and CysF9[93]beta, respectively, of the major hemoglobin. Analyses of the simple profiles gave pKas of 6.33 +/- 0.17 and 8.54 +/- 0.5 for HisH21[143]beta and other histidines within a distance of 2 nm of the sulfhydryl, and CysF9[93]beta of the minor hemoglobin, respectively.     

Temperature Dependence of the Linkage of Quantum Yield of Photosystem II to CO2 Fixation in C4 and C3 Plants

The temperature dependence of quantum yields of electron transport from photosystem II (PSII) ([phi]II, determined from chlorophyll a fluorescence) and CO2 assimilation ([phi]CO2, apparent quantum yield for CO2 assimilation) were determined simultaneously in vivo. With C4 species representing NADP-malic enzyme, NAD-malic enzyme, and phosphoenolpyruvate carboxykinase subgroups, the ratio of [phi]II/[phi]CO2 was constant over the temperature range from 15 to 40[deg]C at high light intensity (1100 [mu]mol quanta m-2 s-1). A similar response was obtained at low light intensity (300 [mu]mol quanta m-2 s-1), except the ratio of [phi]II/[phi]CO2 increased at high temperature. When the true quantum yield for CO2 fixation ([phi]CO2*) was calculated by correcting for respiration in the light (estimated from temperature dependence of dark respiration), the ratio of [phi]II/[phi]C02* remained constant with varying temperature and under both light intensities in all C4 species examined. Because the [phi]II/[phi]CO2* ratio was the same in C4 monocots representing the three subgroups, the ratio was not affected by differences in the bio-chemical mechanism of concentrating CO2 in the bundle sheath cells. The results suggest that PSII activity is closely linked to the true rate of CO2 fixation in C4 plants. The close relationship between [phi]II and [phi]CO2* in C4 species under varying temperature and light intensity conditions is apparently due to a common low level of photorespiration and a primary requirement for reductive power in the C3 pathway. In contrast, in a C3 plant the [phi] II/[phi]CO2* ratio is higher under normal atmospheric conditions than under nonphotorespiratory conditions and it increases with rising temperature. This decrease in efficiency in utilizing energy derived from PSII for CO2 fixation is due to an increase in photorespiration. In both the C3 and C4 species, photochemistry is limited under low temperature, and thus excess energy must be dissipated by nonphotochemical means.     

The force exerted by a muscle cross-bridge depends directly on the strength of the actomyosin bond

Myosin produces force in a cyclic interaction, which involves alternate tight binding to actin and to ATP. We have investigated the energetics associated with force production by measuring the force generated by skinned muscle fibers as the strength of the actomyosin bond is changed. We varied the strength of the actomyosin bond by addition of a polymer that promotes protein-protein association or by changing temperature or ionic strength. We estimated the free energy available to generate force by measuring isometric tension, as the free energy of the states that precede the working stroke are lowered with increasing phosphate. We found that the free energy available to generate force and the force per attached cross-bridge at low [Pi] were both proportional to the free energy available from the formation of the actomyosin bond. We conclude that the formation of the actomyosin bond is involved in providing the free energy driving the production of isometric tension and mechanical work. Because the binding of myosin to actin is an endothermic, entropically driven reaction, work must be performed by a "thermal ratchet" in which a thermal fluctuation in Brownian motion is captured by formation of the actomyosin bond.     

Comparative Thermodynamics of Benzodiazepine Receptor Ligand Interactions in Rat Neuronal Membranes

The effects of temperature on the interaction of various ligands with the benzodiazepine receptor were studied in rat brain membrane preparations. The affinities of all ligands studied were reduced on raising the temperature from 4 to 37 degrees C. The variation of affinity constant with temperature deviated from the classical relationship for both the anticonvulsant ligand [3H]flunitrazepam and the proconvulsant ligand [3H]ethyl beta-carboline-3-carboxylate. This implies a variation of observed enthalpy change of binding with temperature. Possible reasons for this are discussed. Gamma-Aminobutyric acid and sodium chloride both enhance the binding of [3H]flunitrazepam--the former by an increase in the entropic component of the binding energy, and the latter by an increase in the enthalpic component. In a series of ligands of different biological activities, no simple correlation was observed between biological activity and temperature dependence of binding.     

Recent developments in methodologies for calculating the entropy and free energy of biological systems by computer simulation

The Helmholtz free energy, F, plays an important role in proteins because of their rugged potential energy surface, which is 'decorated' with a tremendous number of local wells (denoted microstates, m). F governs protein folding, whereas differences DeltaF(mn) determine the relative populations of microstates that are visited by a flexible cyclic peptide or a flexible protein segment (e.g. a surface loop). Recently developed methodologies for calculating DeltaF(mn) (and entropy differences, DeltaS(mn)) mainly use thermodynamic integration and calculation of the absolute F; interesting new approaches in these categories are the adaptive integration method and the hypothetical scanning molecular dynamics method, respectively.     

Thrips (Thysanoptera) identification using artificial neural networks

We studied the use of a supervised artificial neural network (ANN) model for semi-automated identification of 18 common European species of Thysanoptera from four genera: Aeolothrips Haliday (Aeolothripidae), Chirothrips Haliday, Dendrothrips Uzel, and Limothrips Haliday (all Thripidae). As input data, we entered 17 continuous morphometric and two qualitative two-state characters measured or determined on different parts of the thrips body (head, pronotum, forewing and ovipositor) and the sex. Our experimental data set included 498 thrips specimens. A relatively simple ANN architecture (multilayer perceptrons with a single hidden layer) enabled a 97% correct simultaneous identification of both males and females of all the 18 species in an independent test. This high reliability of classification is promising for a wider application of ANN in the practice of Thysanoptera identification.     

Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning

Thrombin is a key component for chemotherapeutic and antithrombotic therapy development. As the physiologic and pathologic roles of the light chain still remain vague, here, we continue previous efforts to understand the impacts of the disease-associated single deletion of LYS9 in the light chain. By combining supervised and unsupervised machine learning methodologies and more traditional structural analyses on data from 10 μs molecular dynamics simulations, we show that the conformational ensemble of the ΔK9 mutant is significantly perturbed. Our analyses consistently indicate that LYS9 deletion destabilizes both the catalytic cleft and regulatory functional regions and result in some conformational changes that occur in tens to hundreds of nanosecond scaled motions. We also reveal that the two forms of thrombin each prefer a distinct binding mode of a Na⁺ ion. We expand our understanding of previous experimental observations and shed light on the mechanisms of the LYS9 deletion associated bleeding disorder by providing consistent but more quantitative and detailed structural analyses than early studies in literature. With a novel application of supervised learning, i.e. the decision tree learning on the hydrogen bonding features in the wild-type and ΔK9 mutant forms of thrombin, we predict that seven pairs of critical hydrogen bonding interactions are significant for establishing distinct behaviors of wild-type thrombin and its ΔK9 mutant form. Our calculations indicate the LYS9 in the light chain has both localized and long-range allosteric effects on thrombin, supporting the opinion that light chain has an important role as an allosteric effector.     

Effect of High Temperature on Photosynthesis in Beans (I. Oxygen Evolution and Chlorophyll Fluorescence)

We studied the effect of increasing temperature on photosynthesis in two bean (Phaseolus vulgaris L.) varieties known to differ in their resistance to extreme high temperatures, Blue Lake (BL), commercially available in the United Kingdom, and Barbucho (BA), noncommercially bred in Chile. We paid particular attention to the energy-transducing mechanisms and structural responses inferred from fluorescence kinetics. The study was conducted in non-photorespiratory conditions. Increases in temperature resulted in changes in the fluorescence parameters nonphotochemical quenching (qN) and photochemical quenching (qP) in both varieties, but to a different extent. In BL and BA the increase in qP and the decrease in qN were either completed at 30[deg]C or slightly changed following increases from 30 to 35[deg]C. No indication of photoinhibition was detected at any temperature, and the ratio of the quantum efficiencies of photosystem II (PSII) and O2 evolution remained constant from 20 to 35[deg]C. Measurements of 77-K fluorescence showed an increase in the photosystem I (PSI)/PSII ratio with temperature, suggesting an increase in the state transitions. In addition, measurements of fast-induction fluorescence revealed that the proportion of PSII[beta] centers increased with increasing temperatures. The extent of both changes were maximum at 30 to 35[deg]C, coinciding with the ratio of rates at temperatures differing by 10[deg]C for oxygen evolution.     

A-DNA accommodates adducts derived from diol epoxides of polycyclic aromatic hydrocarbons bound in a "side-stacking" mode

The minor groove of undistorted A-DNA provides a good binding site for planar, hydrophobic moieties such as unmetabolized polycyclic aromatic hydrocarbons (PAHs), and the base pairs at the ends of short oligodeoxynucleotide helices. It also accommodates the chief adduct derived from the metabolically activated form of the carcinogen benzo[a]pyrene. B-DNA lacks such a site. Computerized models have been generated for the major (N2-guanine-linked) adducts formed at this site by both + and - enantiomers of anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (anti-BPDE) with poly(dG).poly(dC) in the A-DNA conformation. The BPDE adducts lie in the shallow, relatively hydrophobic minor groove of the A-DNA after empirical potential energy minimization using the program AMBER. We term this binding mode "side-stacking." The side-stacked + anti-BPDE may constitute the chief carcinogenic lesion derived from benzo[a]pyrene.     

Negative co-operativity in Escherichia coli single strand binding protein-oligonucleotide interactions. II. Salt, temperature and oligonucleotide length effects

We have examined the salt and temperature dependences of the equilibrium binding of the Escherichia coli single strand binding (SSB) tetramer to a series of oligodeoxythymidylates, dT(pT)N-1, with N = 16, 28, 35, 56 and 70. Absolute binding isotherms were obtained, based on the quenching of the intrinsic protein fluorescence upon formation of the complexes. The shorter oligonucleotides, with N = 16, 28 and 35, bind to multiple sites on the SSB tetramer and negative co-operativity is observed among these binding sites. We have quantitatively analyzed these isotherms, using a statistical thermodynamic ("square") model to obtain the intrinsic binding constant KN, and the negative co-operativity constant, sigma N. For all oligonucleotides, we find that KN decreases significantly with increasing concentration of monovalent salt, indicating a large electrostatic component to the free energy of the interaction (e.g. delta log KN/delta log [NaBr] = -2.7, -4.6 and -7.1 for N = 16, 35 and 70, respectively), with contributions from both cations and anions. For oligonucleotides that span two or more subunits, there is a significant unfavorable contribution to the binding free energy for each intersubunit crossing, with an accompanying uptake of anions. Therefore, the extent of anion uptake increases as the number of intersubunit crossings increase. There is a strong temperature dependence for the intrinsic binding of dT(pT)15, such that delta Ho = -26(+/- 3) kcal/mol dT(pT)15. Negative co-operativity exists under all solution conditions tested, i.e. sigma N less than 1, and this is independent of anion concentration and type. However, the negative co-operativity constant does decrease with decreasing concentration of cation. The dependence of sigma 16 on Na+ concentration indicates that an average of one sodium ion is taken up as a result of the negative co-operativity between two dT(pT)15 binding sites. These data and the lack of a temperature dependence for sigma 16 suggest that the molecular basis for the negative co-operativity is predominantly electrostatic and may be due to the repulsion of regions of single-stranded DNA that are required to bind in close proximity on an individual SSB tetramer.     

Mapping heat exchange in an allosteric protein

Nicotinic acetylcholine receptors (AChRs) are synaptic ion channels that spontaneously isomerize (i.e., gate) between resting and active conformations. We used single-molecule electrophysiology to measure the temperature dependencies of mouse neuromuscular AChR gating rate and equilibrium constants. From these we estimated free energy, enthalpy, and entropy changes caused by mutations of amino acids located between the transmitter binding sites and the middle of the membrane domain. The range of equilibrium enthalpy change (13.4 kcal/mol) was larger than for free energy change (5.5 kcal/mol at 25°C). For two residues, the slope of the rate-equilibrium free energy relationship (Φ) was approximately constant with temperature. Mutant cycle analysis showed that both free energies and enthalpies are additive for energetically independent mutations. We hypothesize that changes in energy associated with changes in structure mainly occur close to the site of the mutation, and, hence, that it is possible to make a residue-by-residue map of heat exchange in the AChR gating isomerization. The structural correlates of enthalpy changes are discussed for 12 different mutations in the protein.