Effect of Non-normality on Response to Selection in small Populations

The expressions for the r-th largest standardised deviate have been derived for beta, gamma, exponential and log-normal distributions. Using these expressions the intensities of selection have been computed for different parametric values of the distributions and of p, the proportion saved for samples of size upto 10 and compared with the corresponding values for normal distribution. The normal approximation to beta and gamma distributions is seen to be quite robust in predicting response to selection under moderately heavy and low cullings.     

On the Principle of Substance Stability and Thermodynamic Feedback in Hierarchic Systems of Bioworld

The creation of structural hierarchies in open natural biosystems within the framework of quasi-closed systems is investigated by the methods of hierarchic thermodynamics (thermostatics). During the evolution of natural open systems, every higher hierarchic level j appears as a consequence of thermodynamic self-organization (self-assembly) of the structures of the lower (j– 1)-th level. Such a self-assembly proceeds as a result of stabilization of the j-th level. This is related to the Gibbs' (Helmholtz') specific function of formation of the structure of the j-th level tending to a minimum. As a result of action of the principle of substance (matter) stability, the structures of the j-th level are enriched with less stable structures of the (j– 1)-th level in the course of evolution. This provides a thermodynamic feedback between the structures of the higher j-th level and lower (j– 1)-th level, thus preventing full structural stabilization of the j-th level and causing thermodynamic rejuvenation of biosystems. The latter enhances thermodynamic deceleration of evolution and practically unlimited maintenance of life. Examples of quantitative correlations are provided that call for further application of the substance stability principle to living and nonliving hierarchic structures.     

To what extent is a constant volume design worse than a minimum volume design for a series of CSTR's?

The balance equations for substrate in a cascade of CSTR's undergoing an enzyme-catalyzed reaction following Michaelis-Menten kinetics are developed in dimensionless form. Analytical expressions relating the intermediate concentrations are independently obtained for the cases of minimum overall volume and constant volume. The fractional deviations between the overall volumes following these two design criteria are calculated and presented for several values of the relevant parameters. For situations of practical interest, the fractional deviation is below 10%. Increasing values of the Michaelis-Menten parameter, K _m(or decreasing values of the number of reactors in the cascade, N) lead to lower values of the maximum deviation; this maximum deviation is attained at lower conversions of substrate when K _mis increased or N decreased.List of Symbols C _{S, i}mol.m^–3 concentration of substrate at the outlet of the i-th reactor - C _* ^{S, i} normalized concentration of substrate at the outlet of the i-th reactor - C _* ^{S, i, eq} normalized concentration of substrate at the outlet of the i-th reactor using the design criterion of constant volume - C _* ^{S, i, opt} normalized concentration of substrate at the outlet of the i-th reactor using the design criterion of minimum overall volume - C _{S, 0} mol.m^–3 concentration of substrate at the inlet to the first reactor - Da _i Damköhler number for the i-th reactor - Da _eq constant Damköhler number for each reactor of the cascade - Da _{tot, eq} overall Damköhler number for the cascade assuming equal-sized reactors - Da _{tot, min} minimum overall Damköhler number for the cascade - Er fractional deviation between the overall volumes using the two different design criteria - K _mmol. m^–3 Michaelis-Menten constant - K _* ^M dimensionless Michaelis-Menten constant - N number of reactors of the cascade - Q m³. s^–1 volumetric flow rate - V _im³ volume of the i-th reactor - v _max mol. m^–3. s^–1 reaction rate under saturation conditions of the enzyme with substrate - V _{tot, opt} m³ minimum overall volume of the cascade - V _{tot, eq} m³ overall volume of the cascade assuming equal-sized reactors     

Note on Rashevsky's equation for cellular growth

The equation for growth by intussusception involves the product of the internal concentrations ofn metabolites. This products is shown, in general, to satisfy a certain algebraic equation of then-th degree. Approximate solutions are exhibited for a somewhat wider class of cases than are considered by Rashevsky.     

Hybrid MC/QC simulations of water-assisted proton transfer in nucleosides. Guanosine and its analog acyclovir

To provide an in-depth insight into the molecular basis of spontaneous tautomerism in DNA and RNA base pairs, a hybrid Monte Carlo (MC)–quantum chemical (QC) methodology is implemented to map two-dimensional potential energy surfaces along the reaction coordinates of solvent-assisted proton transfer processes in guanosine and its analog acyclovir in aqueous solution. The solvent effects were simulated by explicit inclusion of water molecules that model the relevant part of the first hydration shell around the solute. The position of these water molecules was estimated by carrying out a classical Metropolis Monte Carlo simulation of dilute water solutions of the guanosine (Gs) and acyclovir (ACV) and subsequently analyzing solute–solvent intermolecular interactions in the statistically-independent MC-generated configurations. The solvent-assisted proton transfer processes were further investigated using two different ab initio MP2 quantum chemical approaches. In the first one, potential energy surfaces of the ‘bare’ finite solute–solvent clusters containing Gs/ACV and four water molecules (MP2/6-31+G(d,p) level) were explored, while within the second approach, these clusters were embedded in ‘bulk’ solvent treated as polarizable continuum (C-PCM/MP2/6-31+G(d,p) level of theory). It was found that in the gas phase and in water solution, the most stable tautomer for guanosine and acyclovir is the 1H-2-amino-6-oxo form followed by the 2-amino-6-(sZ)-hydroxy form. The energy barriers of the water-assisted proton transfer reaction in guanosine and in acyclovir are found to be very similar – 11.74 kcal mol^?1 for guanosine and 11.16 kcal mol^?1 for acyclovir, and the respective rate constants (k = 1.5?×?10¹ s^?1, guanosine and k = 4.09?×?10¹ s^?1, acyclovir), are sufficiently large to generate the 2-amino-6-(sZ)-hydroxy tautomer. The analysis of the reaction profiles in both compounds shows that the proton transfer processes occur through the asynchronous concerted mechanism.     

Almost-one Parameter Hypothesis of Individuality in Height Growth

Thus far an individual height growth curve h_ij(t) of the i-th person in the j-th period, t being his (or her) age, has been studied as a function of t associated with its velocity curve. In this note we introduce a natural scale X(t) in place of t, which linearizes this personal curve and facilitates its analysis, in the sense that this equation of growth contains apparently two personal parameters for one period but one of them plays an essential role. The effectiveness of this approach will be seen in four figures.     

Contributions of water transfer energy to protein‐ligand association and dissociation barriers: Watermap analysis of a series of p38α MAP kinase inhibitors

In our previous work, we proposed that desolvation and resolvation of the binding sites of proteins can serve as the slowest steps during ligand association and dissociation, respectively, and tested this hypothesis on two protein‐ligand systems with known binding kinetics behavior. In the present work, we test this hypothesis on another kinetically‐determined protein‐ligand system—that of p38α and eight Type II BIRB 796 inhibitor analogs. The k_on values among the inhibitor analogs are narrowly distributed (10⁴ ≤ k_on ≤ 10⁵ M^?1 s^?1), suggesting a common rate‐determining step, whereas the k_off values are widely distributed (10^?1 ≤ k_off ≤ 10^?6 s^?1), suggesting a spectrum of rate‐determining steps. We calculated the solvation properties of the DFG‐out protein conformation using an explicit solvent molecular dynamics simulation and thermodynamic analysis method implemented in WaterMap to predict the enthalpic and entropic costs of water transfer to and from bulk solvent incurred upon association and dissociation of each inhibitor. The results suggest that the rate‐determining step for association consists of the transfer of a common set of enthalpically favorable solvating water molecules from the binding site to bulk solvent. The rate‐determining step for inhibitor dissociation consists of the transfer of water from bulk solvent to specific binding site positions that are unfavorably solvated in the apo protein, and evacuated during ligand association. Different sets of unfavorable solvation are evacuated by each ligand, and the observed dissociation barriers are qualitatively consistent with the calculated solvation free energies of those sets.     

Coordinates transformation and learning control for visually-guided voluntary movement with iteration: A Newton-like method in a function space

In order to control visually-guided voluntary movements, the central nervous system (CNS) must solve the following three computational problems at different levels: (1) determination of a desired trajectory in the visual coordinates, (2) transformation of the coordinates of the desired trajectory to the body coordinates and (3) generation of motor command. In this paper, the second and the third problems are treated at computational, representational and hardware levels of Marr. We first study the problems at the computational level, and then propose an iterative learning scheme as a possible algorithm. This is a trial and error type learning such as repetitive training of golf swing. The amount of motor command needed to coordinate activities of many muscles is not determined at once, but in a step-wise, trial and error fashion in the course of a set of repetitions. Actually, the motor command in the (n+1)-th iteration is a sum of the motor command in then-th iteration plus two modification terms which are, respectively, proportional to acceleration and speed errors between the desired trajectory and the realized trajectory in then-th iteration. We mathematically formulate this iterative learning control as a Newton-like method in functional spaces and prove its convergence under appropriate mathematical conditions with use of dynamical system theory and functional analysis. Computer simulations of this iterative learning control of a robotic manipulator in the body or visual coordinates are shown. Finally, we propose that areas 2, 5, and 7 of the sensory association cortex are possible sites of this learning control. Further we propose neural network model which acquires transformation matrices from acceleration or velocity to motor command, which are used in these schemes.     

On some representations of Boolean functions. Application to the theory of switching elements nets

We consider three representations of a Boolean function, two of them in the real field and one in a Galois field modulo-2. By using these representations, an arbitrary Boolean function of n variables can always be expanded as a power series on the Boolean variables cut off to the n-th degree (n-form). Such representations are particularly useful for a unified treatment of the dynamics of a net of switching elements.     

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1‐phenyl‐1‐propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two‐phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)‐Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo‐like kinase 1 inhibitor are discussed. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.     

Cost-Efficient Density Estimation Based on Nearest Individual Distances in a Natural Forest

One useful method of estimating tree density is based on point to individual distances. Estimators are available for data on i-th nearest individual distances, i = 1, 2, 3,…, etc. This paper provides a method of deciding the optimal value of i in the sense of providing the maximum likelihood estimator of density with minimum mean square error subject to given outlay. The result derived for a Poisson forest is extended to an aggregated forest.     

Modelling of enzyme hydrolysis of maltose in a single pellet of immobilized biocatalyst

The reversible hydrolysis of maltose to glucose by immobilized glucoamylase entrapped in spherical solid particles is studied theoretically. For this purpose a known kinetic model taking into account these reversible reactions and the competitive synthesis of iso-maltose was adopted. The mass transfer limitations in the bulk liquid and in the pores of the particles containing the enzyme are considered, using Fick's law. On the basis of mathematical modelling the optimum conditions for biocatalyst performance are established. An appropriate combination of particle size and initial substrate concentration may lead to reduction of undesirable mass transfer resistance and therefore product inhibition and to an improved selectivity of the biocatalyst with respect of glucose formation.List of Symbols C _i kmoles/m³ current concentration ofi-th component along the radius - C _oi kmoles/m³ bulk concentration ofi-th component - C _i ^* kmoles/m³ concentrations ofi-th component on the pellet surface - D _si ,D _i m²/s internal and molecular diffusion coefficient ofi-th component - W _M kmoles/m³·s reaction rate of maltose hydrolysis - W _IM kmoles/m³·s reaction rate of iso-maltose formation - W _G kmoles/m³·s reaction rate of glucose production - R ₀ m pellet radius - r m current radius of the pellet - t s time coordinate - r ₀ ratio of the time step to the square of the radial coordinate - Re Reynolds number =w·R/v - Sc Schmidt number =v/D - Bi Biot number = R/D - A _j ,B, C _j coefficients in the system of linear equations, Eq. (8) - X _i dimensionless degree of transformation - NR number of independent reactions - N number of division sections of the pellet radius - G kmoles/m³ concentration of glucose - M kmoles/m³ concentration of maltose - IM kmoles/m³ concentration of isomaltose - K _m kmoles/m³ Michaelis constant - V _max kmoles/m³·s maximum reaction rate in Eq. (6) - K _i kmoles/m³ inhibition constant - K _1eq ,K _2eq equilibrium constants in Eq. (6) - , h steps along the time and radial coordinate in the pellet - m/s mass transfer coefficient - dimensionless radius of the pellet - computation accuracy Indices i number of reaction component - j index along the radius of the pellet - k index along the time coordinate This work was accomplished with thanks to the financial support of the Bulgarian National Fund for Scientific Investigations —Grant No. MU-1-BE/93.     

The effects of solvent viscosity on the kinetic parameters of myosin and heavy meromyosin ATPase

The effects of different solvent viscosities on the kinetic parameters of ATP hydrolysis by myosin and heavy meromyosin (HMM) were investigated at high and low ionic strength (i.e., 0.53 and 0.08 M KCl where myosin is polymerized into thick filament). The solvent viscosity was adjusted by the addition of appropriate amounts of sucrose. The maximum rate constants (V _m ) for both myosin and HMM decreased monotonically with increasing solvent viscosity at either ionic strength. The Michaelis constants (K _m ) for soluble myosin and HMM became minima at a viscosity nearly twice that of the solvent without sucrose, then increased abruptly with increasing solvent viscosity. On the other hand,K _m of polymerized myosin at the low ionic strength decreased monotonically with increasing solvent viscosity. These experimental results are discussed with special reference to Kramers' kinetic theory of a chemically reacting system in viscous media.     

Implication for DNA methylation involved in the host transfer of diamondback moth,Plutella xylostella (L.)

DNA methylation exerts extensive impacts on gene expression of various living organisms exposed to environmental variation. However, little is known whether DNA methylation is involved in the host transfer of diamondback moth, Plutella xylostella (L.), a worldwide destructive pest of crucifers. In this study, we found that P. xylostella genome exhibited a relatively low level of DNA methylation on the basis of the CpG O/E prediction and experimental validation. A significant positive linear correlation was observed between the stage‐specific expressions of PxDNMT1 and DNA methylation levels (5mC content). Particularly, high levels of DNA methylation and gene expression of PxDNMT1 were observed in eggs and mature females of P. xylostella. After host transfer of P. xylostella from Raphanus sativus to Arabidopsis thaliana, we identified some potential genomic loci that might have changed methylation levels. Using the method of fluorescence‐labeled methylation‐sensitive amplified polymorphism (F‐MSAP), we also found the corresponding genes primarily involved in neural system and signaling. The expressions of six candidate genes were verified by qRT‐PCR. One of the genes, Px009600, might be regulated by a DNA methylation‐mediated mechanism in response to host transfer. Our study provides evidence for a functional system of DNA methylation in P. xylostella and its possible role in adaptation during host transfer. Further studies should examine methylation as responsive factors to different host plants and environmental cues in insect pests.     

DNA, rRNA and RNA partition isotherms rapidly labeled in a saline solvent system

Partition isotherms of DNA, rRNA, and rapidly labeled RNA in a salt solvent system are determined. In the salt solvent system PMB (potassium phosphate buffer 1.50 M pH 7.0:2-methoxyethanol:2-butoxyethanol; 3:1:variable volume), equilibrated at the temperature T, the partition isotherms of animal ribosomal RNA and DNA form a series of straight lines according to the basic relation log k = B ? A_T(BuO), where k is the partition coefficient, B and A_T are parameters depending upon the base composition, the molecular weight, the helix content, and conformation of nucleic acids, and (BuO) refers to the 2-butoxyethanol amount in volume percent. This relation is also valid for other nucleic acid compounds (bases, nucleosides, nucleotides, oligoribonucleotides, and transfer RNA). For RNA fractions distributed in different Kirby salt solvent systems, log k is proportional to the relative levels of adenine and guanine expressed as the A/(A+G) ratio. Partition isotherms of high molecular weight RNA from mouse plasmocytoma, labeled during a few hours, are not straight lines. This behavior indicates a heterogeneous RNA population. By plotting the specific activity of this mixture (rRNA and rapidly labeled RNA) determined in the top phase of our salt solvent system as a function of the 2-but-oxyethanol content, we obtained a sigmoidal curve, which characterizes the nature of the RNA population investigated. Formulas are given for the calculation of the specific activities of rRNA and rapidly labeled RNA and for the calculation of their relative ratio.     

Thermodynamics of solvation for methylproline peptides

We have determined thermodynamic parameters for transfer of N-acetyl,N′-methylamide derivatives of proline and methylprolines from carbon tetrachloride and from chloroform to water. The hydrophilic nature of the diamide model peptides is demonstrated by the negative free energies and enthalpies for transfer. Chloroform solvates the peptides considerably better than carbon tetrachloride. Heats of dilution in carbon tetrachloride arise from disruption of intermolecular peptide–peptide hydrogen bonds. After extrapolation to dilute solution, differences in thermodynamic parameters among the isomeric mono-methylproline peptides are correlated with the population of the intramolecularly hydrogen-bonded C₇ conformer in the nonpolar solvent. However, the thermodynamic parameters aslo reflect differences in solvation due to the proximity of the two peptide groups and the side chain.     

Dependence ofγ-irradiated Y-peak and melting of DNA on concentration and ionic environment

Summary Y-peak is found to be a function of ionic strength and concentrations of DNA. The Y-peak reveals close dynamic interaction between DNA and solvent system. Electronic transitions responsible for Y-peak are not the same transitions that are responsible for X-peak. Y-peak's electronic transitions are indicative of charge transfer complex formation between DNA and solvent system.-irradiation induces hyperchromicity due to strand separation at lower doses. A-T base pairs are first to undergo coiled state as shown byTm spread. Strand chopping and saturation of double bonds of the exposed bases by free radicals (H° and OH°) give rise to hypochromic regions at X-peak. Rise in ionic strength and the concentration of DNA has protective effect against-damage. Y-peak is found to be a function of solvent, whereas, X-peak is independent of solvent nature.     

Theoretical investigation of the effect of sugar substitution on the antioxidant properties of flavonoids

Natural flavonoids are secondary phenolic plant metabolites known for their bioactivity as antioxidants. The evaluation of this property is generally done by the estimation of their direct free radical-scavenging activity as hydrogen or electron donating compounds. This paper reviews experimental results available in the literature for a selection of flavonoids and compares them with calculated quantities characteristic of the hydrogen or electron donation. For that purpose, bond dissociation energies, ionization potentials and electron transfer enthalpies are computed by using DFT methods and the ONIOM procedure implemented in the ab initio program Gaussian. This process has been chosen because it can be extended to the study of large molecules. When acid dissociation and interaction with the solvent are taken into account, the results present very good concordance with experimental results, enlightening the complexity of the processes involved in the classical assays which measure the ability of compounds to scavenge the (2,2′-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) radical cation (ABTS ⁺) or the 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH^·). This study demonstrates the good accuracy of theoretical calculations in obtaining the relative energies involved in free radical scavenging abilities and its capacity for predictive behaviour. It also highlights the necessity to take into account the pK_a of the compounds and the solvent interaction. The ability of the method to calculate the antioxidant properties of larger molecules are tested on glycosylated flavonoids and the effects of sugar substitution on the antioxidant properties of flavonoids are investigated, pointing out the importance of the charges on the oxygen atoms.     

Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism

pH is a ubiquitous regulator of biological activity, including protein‐folding, protein‐protein interactions, and enzymatic activity. Existing constant pH molecular dynamics (CPHMD) models that were developed to address questions related to the pH‐dependent properties of proteins are largely based on implicit solvent models. However, implicit solvent models are known to underestimate the desolvation energy of buried charged residues, increasing the error associated with predictions that involve internal ionizable residue that are important in processes like hydrogen transport and electron transfer. Furthermore, discrete water and ions cannot be modeled in implicit solvent, which are important in systems like membrane proteins and ion channels. We report on an explicit solvent constant pH molecular dynamics framework based on multi‐site λ‐dynamics (CPHMD^MSλD). In the CPHMD^MSλD framework, we performed seamless alchemical transitions between protonation and tautomeric states using multi‐site λ‐dynamics, and designed novel biasing potentials to ensure that the physical end‐states are predominantly sampled. We show that explicit solvent CPHMD^MSλD simulations model realistic pH‐dependent properties of proteins such as the Hen‐Egg White Lysozyme (HEWL), binding domain of 2‐oxoglutarate dehydrogenase (BBL) and N‐terminal domain of ribosomal protein L9 (NTL9), and the pK_a predictions are in excellent agreement with experimental values, with a RMSE ranging from 0.72 to 0.84 pK_a units. With the recent development of the explicit solvent CPHMD^MSλD framework for nucleic acids, accurate modeling of pH‐dependent properties of both major class of biomolecules—proteins and nucleic acids is now possible. Proteins 2014; 82:1319–1331. © 2013 Wiley Periodicals, Inc.     

Replacement of immobilised cell bioreactors by smaller immobilised enzyme bioreactors: unique-outcome predictability for cytochromes P450 isoforms?

Both immobilized enzymes (IME) and immobilized cells (IMC) are acceptable as the biocatalysts essential for the attainment of rapid rates of bioconversion in bioreactors. IMC can display higher than expected cellular permeability whilst IME can exhibit high catalytic constant (k_cat/K_m) despite limitations on substrate utilisation due to an unstired diffusion layer of solvent. Scale-down switching from IMC to IME involves the replacement of high-volume biotechnology by low-volume biotechnology, sometimes using IME mimics in partially non-aqueous solvent systems. Highly purified IME systems covalently immobilised to particles of, for instance, microcrystalline cellulose or porous glass, can retain both the hydrophilic and hydrophobic intermediate products in situ of the chosen sequence of enzyme reactions. These bioconversions, therefore, are as efficient as those with IMC where enzymes are often particle- or membrane-bound so that even hydrophilic intermediates are not released rapidly into solution. This mimicry of in vivo biosynthetic pathways that are compartmentalised in vivo (e.g. of lysosomes, mitochondria and endoplasmic reticulum) can replace larger IMC by IME especially in application of up to 2700 cytochromes P450 isoforms in bioprocessing. In silico investigation of appropriate model IME systems, in comparison with IMC systems, will be needed to define the optimal bioreactor configuration and parameters of operation, such as pH, T and oxygen mass transfer rate (OTR). The application solely of hazop (applied hazard and operability concepts) may, nevertheless, not be recommended to replace fully the in silico and real-lab pilot-scale and scale studies. Here, food-safe bioprocessing has to be achieved without incorporation of recognised biohazards; especially in the form of unacceptable levels of toxic metals that promote a risk-analysis uncertainty.