Book reviews

Consider the perturbed harmonic oscillator Ty=-y+x²y+q(x)y in L²(), where the real potential q belongs to the Hilbert space H={q, xq L²()}. The spectrum of T is an increasing sequence of simple eigenvalues _n(q)=1+2n+_n, n 0, such that _n 0 as n. Let _n(x,q) be the corresponding eigenfunctions. Define the norming constants _n(q)=lim_xlog |_n (x,q)/_n (-x,q)|. We show that for some real Hilbert space and some subspace Furthermore, the mapping :q(q)=({_n(q)}₀, {_n(q)}₀) is a real analytic isomorphism between H and is the set of all strictly increasing sequences s={s_n}₀ such that The proof is based on nonlinear functional analysis combined with sharp asymptotics of spectral data in the high energy limit for complex potentials. We use ideas from the analysis of the inverse problem for the operator -ypy, p L²(0,1), with Dirichlet boundary conditions on the unit interval. There is no literature about the spaces We obtain their basic properties, using their representation as spaces of analytic functions in the disk.     

Analysis of the periodically fragmented environment model : I – Species persistence

This paper is concerned with the study of the stationary solutions of the equationwhere the diffusion matrix A and the reaction term f are periodic in x. We prove existence and uniqueness results for the stationary equation and we then analyze the behaviour of the solutions of the evolution equation for large times. These results are expressed by a condition on the sign of the first eigenvalue of the associated linearized problem with periodicity condition. We explain the biological motivation and we also interpret the results in terms of species persistence in periodic environment. The effects of various aspects of heterogeneities, such as environmental fragmentation are also discussed.     

A cardiovascular-respiratory control system model including state delay with application to congestive heart failure in humans

This paper considers a model of the human cardiovascular-respiratory control system with one and two transport delays in the state equations describing the respiratory system. The effectiveness of the control of the ventilation rate is influenced by such transport delays because blood gases must be transported a physical distance from the lungs to the sensory sites where these gases are measured. The short term cardiovascular control system does not involve such transport delays although delays do arise in other contexts such as the baroreflex loop (see [46]) for example. This baroreflex delay is not considered here. The interaction between heart rate, blood pressure, cardiac output, and blood vessel resistance is quite complex and given the limited knowledge available of this interaction, we will model the cardiovascular control mechanism via an optimal control derived from control theory. This control will be stabilizing and is a reasonable approach based on mathematical considerations as well as being further motivated by the observation that many physiologists cite optimization as a potential influence in the evolution of biological systems (see, e.g., Kenner [29] or Swan [62]). In this paper we adapt a model, previously considered (Timischl [63] and Timischl et al. [64]), to include the effects of one and two transport delays. We will first implement an optimal control for the combined cardiovascular-respiratory model with one state space delay. We will then consider the effects of a second delay in the state space by modeling the respiratory control via an empirical formula with delay while the the complex relationships in the cardiovascular control will still be modeled by optimal control. This second transport delay associated with the sensory system of the respiratory control plays an important role in respiratory stability. As an application of this model we will consider congestive heart failure where this transport delay is larger than normal and the transition from the quiet awake state to stage 4 (NREM) sleep. The model can be used to study the interaction between cardiovascular and respiratory function in various situations as well as to consider the influence of optimal function in physiological control system performance.Supported by FWF (Austria) under grant F310 as a subproject of the Special Research Center F003 Optimization and ControlMathematics Subject Classification (2000): 92C30, 49J15     

Quantitative structure–activity relationship study on some benzodiazepine derivatives as anti-Alzheimer agents

A QSAR study was performed in an attempt to explore the pharmacophore of some benzodiazepine derivatives as anti-Alzheimer agents for the inhibition of -secretase. The study, which used the electrotopological state atom (ETSA) index, which encodes electronic and topological information, reveals the importance of two phenyl rings—one substituted and another unsubstituted, for the inhibition of the enzyme. Fluorine substitution on the substituted phenyl ring has an important contribution to the activity. R-configurations of the aliphatic chain substituents provide the exact conformation of the molecules to enter into the binding pockets of the receptor(s).Figure General structure of benzodiazepine containing -secretase inhibitors     

Stability analysis of Turing patterns generated by the Schnakenberg model

We consider the following Schnakenberg model on the interval (-1,1): where We rigorously show that the stability of symmetric N-peaked steady-states can be reduced to computing two matrices in terms of the diffusion coefficients D₁, D₂ and the number N of peaks. These matrices and their spectra are calculated explicitly and sharp conditions for linear stability are derived. The results are verified by some numerical simulations.Mathamatics Subject Classification (2000): Primary 35B40, 35B45; Secondary 35J55, 92C15, 92C40Revised version: 10 October 2003     

Determination of fuzzy logic membership functions using genetic algorithms: application to structure–odor modeling

Fuzzy logic has been used as a tool in structure–camphoraceous odor relationships. The data base studied included 99 molecules. The rules used to discriminate between camphor and non camphor molecules lead to 77% correct discrimination. Such rules account for the shape and the size of the molecule. Their adjustment by means of genetic algorithms led to 84% correct discrimination between camphor and non-camphor molecules.Figure Membership function for the chosen variables     

Density functional and docking studies of retinoids for cancer treatment

The retinoic acid receptor (RAR) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily. The ligand-binding domain contains the ligand-dependent activation function. The isotypes RAR, and are distinct pharmacological targets for retinoids involved in the treatment of various cancers and skin diseases. There is thus considerable interest in synthetic retinoids with isotype selectivity and reduced side effects. In this work we have focused on the retinoid acid receptor and three of its panagonists. We have carried out density functional geometry optimizations at the B3LYP/6-31G* level, computed two types of atomic charges and also electrostatic potentials. A docking program was used to investigate the interactions between the receptor and the three ligands. A theoretically more potent inhibitor, which was obtained by modifying one of the retinoic acids investigated, is proposed. Figure Superposition of the crystal structure (Å) of the 1FCX ligand with the proposed new inhibitor     

Chiral recognition of aromatic compounds by β-cyclodextrin based on bimodal complexation

The chiral recognition of the selected aromatic chiral compounds by native -cyclodextrin (-CD) based on bimodal complexation was studied using a flexible docking algorithm FDOCK. A quantitative empirical free energy relationship model was employed to predict the complex stability constants and the preferred binding modes. The results showed that the calculated complex stability constants are in good agreement with the experimental data. Furthermore, the main force responsible for host-guest complexation is the van der Waals force and the chiral molecules are completely included into the -CD cavity. The chiral recognition for the selected aromatic chiral compounds is the result of the van der Waals force counterbalancing with the other effects, such as the electrostatic interaction and the hydrophobic effect.Figure The favorable structures for the inclusion complexes of (S)_phenylbutyric with -CD. View in the plane normal to the Z-axis. -CD is shown in surface and (S)_phenylbutyric in CPK representation.     

Hydrogen bonding interactions in E- or Z-2-phenyl-3-( X'-pyridyl)propenoic acid ( X=2, 3 or 4) assemblies--a molecular modeling study

The agglomeration properties of stereoisomeric 2-phenyl-3-(X-pyridyl)propenoic acids (X=2, 3 or 4) were studied by the PM3 semiempirical quantum chemical method. Calculations revealed that dimers kept together by the intermolecular hydrogen bonding interactions of the carboxylic groups could be built from both stereoisomers irrespective of the position of the nitrogen heteroatom. The dimers of the Z-isomers could also be built through (aromatic)C–H...N hydrogen bonds between the dimer units. The longest agglomerate was the pentamer of the dimers when the nitrogen was in the 2 position. Longer hydrogen-bonded agglomerates than dimers could only be constructed from the E-isomer with the nitrogen in position 4. Here, the trimer of the dimers proved to be the longest hydrogen-bonded entity and similarly to the Z-isomers, the dimer units are kept together by (aromatic)C–H...N intermolecular hydrogen bonds.Figure The helical structure of the pentamer of dimers for the Z-2-phenyl-3-(2-pyridyl)propenoic acid molecule, when in the initial geometry (aromatic)C(4)–H...N close contact was enforced.     

Relationships between aqueous acidities and computed surface-electrostatic potentials and local ionization energies of substituted phenols and benzoic acids

Electrostatic potentials and average local ionization energies on the molecular surfaces of 19 phenols, 17 benzoic acids and their respective conjugate bases were computed at the HF/STO-5G(d)//B3LYP/6-311G(d,p) level. Good correlations were found between pK_as and the V_S,max values of the neutral acids and the V_S,min and of the conjugate bases for both sets of molecules. V_S,max is the most positive value of the electrostatic potential on the molecular surface and is an indicator of the ease with which the phenols and benzoic acids lose their acidic hydrogens. V_S,min and are the minimum values of the electrostatic potential and the local ionization energy computed on the molecular surface; the V_S,min and of the conjugate bases of the phenoxides and benzoates are indicative, respectively, of the tendencies of electrophiles to approach the anions (V_S,min) and to react with the anions ( ) to reform the original acids. The correlations observed between the computed molecular surface quantities, taken as single parameters, and the experimental pK_a values ranged from R=0.938 to R=0.970 for the two classes of compounds.Figure Correlation between pK_a and the computed V_S,max of the benzoic acids listed in Table 2. The linear correlation coefficient is 0.970     

Molecular modeling of B-DNA site recognition by Ru intercalators: molecular shape selection

In this work, molecular modeling methods have been applied to the interaction characterization of polypyridyl transitional-metal complexes with the oligonucleotide (B-DNA fragment). In order to explore the factors governing the groove recognition and intercalative depth, we establish a simple and practical docking method (step-by-step docking operation) to obtain potential curves while making complexes inset into B-DNA along an assigned path. Energy values in the potential curve are obtained from energy minimization of binding geometries. Modeling results clearly show that the optimum binding conformation corresponding to the global minimum in the potential curve for each complex is found to correlate well with the experimental results. Our results also confirm that minor changes of the ligand structure can lead to profound influences on binding geometries, so the molecular shape of the complexes is a predominant factor in governing the binding mode. Moreover, we find that the vdW force and water molecular effect are strongly associated with molecular-shape selection in our model. These results complement and extend the knowledge of the nature of these complexes binding to B-DNA.Figure Schematic illustration of metal complexes bound to B-DNA. The complexes are intercalated into the A₅T₆/T₆A₅ base step via a head-on fashion     

Binding affinity of hydroxamate inhibitors of matrix metalloproteinase-2

Here we report molecular dynamics (MD) and free energy perturbation (FEP) simulations applied to hydroxamate-matrix metalloproteinase-2 (MMP-2) complex systems. We have developed some new force field parameters for the hydroxamate functional group that were not included in the AMBER94 force field but were necessary in our simulations. For the representation of the active zinc center, a bonded model was adopted in which restrained electrostatic potential fitting (RESP) charges were used as the electrostatic representation of this model. Using the resulted bonded model, FEP simulations predict the relative binding free energy in good agreement with the experimental value. By analyzing the molecular dynamics (MD) trajectories of the two complex systems, we can provide an explanation of why one of the two inhibitors is favored over the other. The results provide a chemical insight into the interactions between inhibitor and enzyme, and can indicate changes in the inhibitor that would enhance inhibitor–enzyme interactions.Figure The scheme of the binding site     

Conjugal transfer of Streptococcal antibiotic resistance plasmids intoClostridium acetobutylicum

Summary Streptococcal plasmids pAM1, pVA797, pVA797Tn917 and pAM610 were transferred or mobilized toClostridium acetobútylicum fromStreptococcus sanguis,S. faecalis andS. lactis donors.Clostridum transconjugants were able to retransfer pAM1 and pVA797 to a plasmid-freeS. lactis recipient.     

AIPAR: ab initio parametrization of intermolecular potentials for computer simulations

An unambiguous, fully ab initio and automated technique denoted AIPAR (ab initio parametrization) implemented in the SJBR program has been proposed to yield intermolecular interaction potentials between polar molecules and water. The AIPAR procedure has been applied to several organic molecules covering a wide range of structure and functional groups, namely methanol, acetone (propanone), methanethiol (methyl mercaptan), imidazole (1,3-diazole), oxazole and furan. The AIPAR-derived sets of parameters compare well with the empirical OPLS ones, mainly when the all-atoms model is employed in the OPLS procedure. Monte Carlo simulations were performed for an aqueous solution of methanol and for an equimolar binary mixture methanol–water using the AIPAR and OPLS parameters. The thermodynamic and geometric results obtained with the parameters obtained with the AIPAR procedure compare favorably with the OPLS simulations, even for the binary mixture, demonstrating the precision, robustness and transferability of the parameters obtained with the AIPAR procedure.Figure Superimposed configurations of water (without the hydrogen atoms) around the methanol molecule obtained with the AGOA procedure.     

Genetic Linkage Maps of the Guppy (Poecilia reticulata): Assignment of RAPD Markers to Multipoint Linkage Groups

Genetic linkage maps of the guppy (Poecilia reticulata) were constructed from independent crosses between the Tuxedo strain and a feral line (Wildtype). Segregation patterns of random amplified polymorphic DNA (RAPD) markers and phenotypic markers were investigated in F₂ offspring of Tuxedo × Wildtype and Wildtype × Tuxedo crosses. Among the 300 and 276 RAPD markers scored for the respective crosses, linkages were identified for 230 and 212, respectively. The Tuxedo × Wildtype and Wildtype × Tuxedo maps spanned 2100 Kosambi centiMorgans (cM_K) and 1900 cM_K, respectively, in 28 linkage groups. Average marker resolution was 10 cM_K. Genome length was estimated at 4410 cM_K and 4060 cM_K for the respective crosses, with an average physical distance of 166 kbp/cM_K. Several RAPD markers were closely linked to or mapped onto the loci for the sex-determining region (SdR), and the sex-linked black caudal-peduncle (Bcp) and red tail (Rdt) genes. These primary linkage maps are the initial step toward the construction of a composite high-density map to facilitate map-based cloning and marker-assisted selection of quantitative trait loci that are essential for the development of comprehensive breeding programs for the guppy.     

Reasoning of spike glycoproteins being more vulnerable to mutations among 158 coronavirus proteins from different species

In this study, we used the probabilistic models developed by us over the last several years to analyze 158 proteins from coronaviruses in order to determine which protein is more vulnerable to mutations. The results provide three lines of evidence suggesting that the spike glycoprotein is different from the other coronavirus proteins: (1) the spike glycoprotein is more sensitive to mutations, this is the current state of the spike glycoprotein, (2) the spike glycoprotein has undergone more mutations in the past, this is the history of spike glycoprotein, and (3) the spike glycoprotein has a bigger potential towards future mutations, this is the future of spike glycoprotein. Furthermore, this study gives a clue on the species susceptibility regarding different proteins.Figure Predictable and unpredictable portions in coronavirus proteins. The data are presented as median with interquartile range. * the predictable and unpredictable portions in spike glycoprotein group are statistically different from any other protein groups at p<0.05 level, except for hemagglutinin-esterase precursor group. # the predictable and unpredictable portions in spike glycoprotein group are statistically different from hemagglutinin-esterase precursor, membrane protein and nucleocapsid protein groups at p<0.05 level. the predictable and unpredictable portions in spike glycoprotein group are statistically different from hemagglutinin-esterase precursor, and membrane protein groups at p<0.05 level.Electronic Supplementary Material is available for this article if you access the article at .     

Quantitative cytochemical demonstration of intracellular thyroglobulin in cultured human thyrocytes. Effects of fixatives, TSH and Interleukin-1β

Summary A quantitative immunocytochemical method is described for measuring intracellular thyroglobulin in human thyrocytes grown in monolayer, based on the imidazole-enhanced 3,3-diaminobenzidine/peroxidase reaction. The influence of ten different fixatives on the content of thyroglobulin immobilized on nitrocellulose filters and in single cells and the influence of thyrotropin and interleukin-1 (IL-1) on the amount of intracellular thyroglobulin were evaluated. The most suitable fixatives for single cells were 2% carbodiimide, Lison's Gendre fluid and 2 or 4% paraformaldehyde, whereas Bouin, Carnoy A and B, formalin-calcium and Lillie's formaldehyde-acetic acid-alcohol fixative all resulted in reduction of intracellular thyroglobulin. Two per cent glutaraldehyde caused a considerable reduction (p<0.0001). Nitrocellulose filters were not suitable for evaluation of the fixatives, since the results did not correspond to those obtained with single cells. Thyrotropin (1 U/I) increased intracellular thyroglobulin, whereas addition of interleukin-1 to the culture medium for three days caused a dose-dependent reduction with a plateau level at 2×10^–6 gl^–1 (10⁴ U/I_ of interleukin-1. It is concluded that changes in intracellular thyroglobulin concentration caused by either thyrotropin or IL-1 can be quantified under experimental circumstances where samples for measurements of thyroglobulin-mRNA or extracellular thyroglobulin are difficult or impossible to obtain.     

Homology modeling and PAPS ligand (cofactor) binding study of bovine phenol sulfotransferase

In order to understand the mechanisms of ligand binding and the interaction between the ligand and the bovine phenol sulfotransferase, (bSULT1A1, EC 2.8.2.1) a three-dimensional (3D) model of the bSULT1A1 is generated based on the crystal structure of the estrogen sulfotransferase (PDB code 1AQU) by using the InsightII/Homology module. With the aid of the molecular mechanics and molecular dynamics methods, the final refined model is obtained and is further assessed by Profile-3D and ProStat, which show that the refined model is reliable. With this model, a flexible docking study is performed and the results indicate that 3-phosphoadenosine-5- phosphosulfate (PAPS) is a more preferred ligand than coenzyme A (CoA), and that His108 forms hydrogen bond with PAPS, which is in good agreement with the experimental results. From these docking studies, we also suggest that Phe255, Phe24 and Tyr169 in bSULT1A1 are three important determinant residues in binding as they have strong van-der-Waals contacts with the ligand. The hydrogen–bonding interactions also play an important role for the stability of the complex. Our results may be helpful for further experimental investigations.Figure The final 3D-structure of bSULT1A1. The structure is obtained by energy minimizing an average conformation over the last 100 ps of MD simulation. The -helix is represented in red and the -sheet in yellow.     

Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index

The eccentric connectivity index, which has recently been employed successfully for the development of numerous mathematical models for the prediction of biological activities of diverse nature, has been reformed to overcome its limitations caused by degeneracy and insensitivity towards heteroatoms. The reformed eccentric connectivity index, termed the eccentric connectivity topochemical index, overcomes the limitations of the eccentric connectivity index by exhibiting very low degeneracy and displaying sensitivity to both the presence and relative position of heteroatoms without compromizing the discriminating power of the eccentric connectivity index. The relationship of the eccentric connectivity topochemical index, eccentric connectivity index and Wieners index with regard to the anti-HIV activity of 2, 3-diaryl-1, 3-thiazolidin-4-one derivatives was subsequently investigated. The values of the eccentric connectivity topochemical index, the eccentric connectivity index and Wieners index of each of 31 analogues comprizing the data set were computed using in-house computer program. Resultant data was analyzed and suitable models developed after identification of active ranges. Subsequently, each derivative was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. The accuracy of prediction using these models was found to vary from 81 to 90%. The proposed index offers a vast potential for virtual screening of combinatorial libraries, structure property/activity studies and drug design.Figure Basic structure of 2,3-diaryl-1, 3-thiazoidin-4-ones.     

Immunolocalization of complement C1s and matrix metalloproteinase 9 (92kDa gelatinase/type IV collagenase) in the primary ossification center of the human femur

The first component of complement has been shown to degrade type I and type II collagens (Yamaguchi et al. 1990), the latter of which is a major constituent of the cartilage matrix. In order to understand the physiological roles of in cartilage resorption, the expression of C1s was examined by immunohistochemistry in the primary ossification center where the matrix is removed and replaced by bone marrow. Hypertrophic chondrocytes, endothelium and hematogenous elements in the capillary buds were intensely stained by a monoclonal antibody against C1s. Matrix metalloproteinase 9 (MMP-9, 92kDa gelatinase/type IV collagenase) was also immunolocalized in hypertrophic chondrocytes, mesenchymal cells in the primitive bone marrow and the cartilage matrix adjacent to the marrow. In addition, was found to activate the zymogen of MMP-9. These observations suggest that and MMP-9 coordinately participate in matrix degradation in cartilage.Abbreviations MMP Matrix metalloproteinase - APMA 4-aminophenylmercuric acetate - DFP diisopropyl fluorophosphate, HE hematoxylin and eosin - C1s inactive C1s - activated C1s