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PubMedDate not supplied

[Role of water in the thermal instability of DNA].

We studied structural changes of DNA heated for long times at temperatures between 20 to 100 degrees C at different relative humidities (range 0--100%). DNA structure was analyzed by the following criteria: solubility changes, optical melting, ultraviolet spectroscopy, potentiometry and equilibrium dialysis. It has been found that irreversible changes in DNA secondary structure take place at around 37 degrees C, temperature optimal for the function in many living systems. These irreversible changes may be interpreted as a consequence of formation of interchain contacts (non-covalent "cross-links"). We demonstrate that the whole range of relative humidities may be divided onto three regions. For each of these regions DNA has somewhat different molecular structure and peculiarities are observed in the stabilizing and destabilizing action of water on DNA three-dimensional structure. Irreversible changes of DNA secondary structure as a function of bound water are represented by a bell-shaped curve. Similarity between this curve and a curve for the survival microorganisms is discussed.

DNA↗
PubMed1998

Solution structure of a non-palindromic 16 base-pair DNA related to the HIV-1 kappa B site: evidence for BI-BII equilibrium inducing a global dynamic curvature of the duplex.

1H and 31P NMR spectroscopy have been used together with molecular modelling to determine the fine structure of a non-palindromic 16 bp DNA containing the NF-kappa B binding site. Much emphasis has been placed upon NMR optimization of both two-dimensional 31P NMR techniques to extract structural information defining the phosphodiester backbone conformation and selective homonuclear 2D COSY experiments to determine sugar conformations. NMR data show evidence for a dynamic behaviour of steps flanking the ten base-pairs of the NF-kappa B binding site. A BI-BII equilibrium at these steps is demonstrated and two models for each extreme conformation are proposed in agreement with NMR data. In the refined BII structures, the NF-kappa B binding site exhibits an intrinsic curvature towards the major groove that is magnified by the four flanking steps in the BII conformation. Furthermore, the base-pairs are translated into the major groove. Thus, we present a novel mode of dynamic intrinsic curvature compatible with the DNA curvature observed in the X-ray structure of the p50-DNA complex.

DNA, Viral↗
PubMed1995

Pharmacokinetic optimization of the treatment of oral candidiasis with fluconazole: studies with a suspension.

An open crossover study was performed in 12 healthy subjects to investigate the pharmacokinetics in saliva and plasma of a 100 mg oral dose of fluconazole, administered as either a capsule or as a suspension, the latter being used to rinse the mouth and retained for 2 min before being swallowed. In terms of fluconazole plasma concentrations the capsule and the suspension were essentially bioequivalent. While the saliva concentrations of fluconazole after capsule administration reached their peak at 3.0 +/- 0.8 micrograms/ml 4 h after dosage, administration of the suspension resulted in a mean peak concentration of 551.1 +/- 425.6 micrograms/ml 5 min after ingestion. The saliva concentrations decreased gradually after ingestion of the suspension, but were higher for 4 h than the corresponding levels from the capsule. The area under the curve (AUC) from 0 to 96 h of fluconazole in saliva was 227.7 +/- 73.8 h micrograms/ml after the suspension, compared to 123.5 +/- 25.5 h micrograms/ml after the capsule, indicating that the total drug exposure to the oral mucosa by the salivary route was enhanced more than 80% with use of the suspension. Four h after administration of the suspension, saliva and plasma concentrations of fluconazole were in equilibrium, at a saliva: plasma ratio of around 1.2. Taken together, the present results suggest that the treatment of oral candidiasis with fluconazole may be optimized by use of an oral suspension, as this delivers pharmacologically active levels of the drug to the site of infection by both topical and systemic routes.

Adult↗
PubMed2001

Metal-metal bond length variability in Co(3)(dipyridylamide)(4)Cl(2): bond-stretch isomerism, crystal field effects, or spin transition process? A DFT study.

The unprecedented structural behavior of Co(3)(dipyridylamide)(4)Cl(2), characterized in two crystalline forms in which the tricobalt framework is either symmetric or highly nonsymmetric at room temperature is investigated by means of gradient-corrected DFT calculations. The isolated molecule is assigned a single energy minimum associated with a low-spin (doublet) electronic configuration. The optimal geometry closely reproduces the X-ray structure observed for the isomer displaying equivalent metal-metal distances. However, the ground-state potential energy surface is extremely shallow with respect to a distortion of the Co(3) framework. A "weak" distortion, similar to that observed for the unsymmetrical complex at low temperature (Deltad(Co-Co) = 0.08 A at 110 K) induces a destabilization of 1.1 kcal.mol(-1) only. The distortion observed at room temperature (Deltad(Co-Co) = 0.17 A) destabilizes the isolated complex by 4.2 kcal.mol(-1). These results are rationalized in terms of the "three-electron three-center" concept applied to the sigma-bonding electrons of the cobalt framework. A phenomenological model based upon the Heisenberg Hamiltonian successfully reproduces the calculated potential energy curve and assigns the relative stability of the symmetric structure to local forces (Pauli repulsion, ligand bite, etc.) distinct from delocalized sigma bonding. In view of these results, the two structures characterized from X-rays cannot be termed "bond-stretch isomers" according to the strict definition given by Parkin. To investigate the origin of the distorted form, an electric field was applied to the isolated molecule, but it did not shift the equilibrium position toward asymmetry, despite a strong polarization of the electron density. Finally, the quartet state of lowest energy ((4)A state) has an optimal structure that is distorted and that reproduces most of the distinctive features observed in the nonsymmetric structure. Despite the high relative energy calculated for this quartet state, we assign the occurrence of the nonsymmetric form and its extreme variability with temperature to a progressive population of this excited state as temperature increases.

Journal Article↗
PubMed1996

Control analysis of unbranched enzymatic chains in states of maximal activity.

It is shown that optimized states of metabolic systems are characterized by special distributions of control coefficients. Maximization of the steady-state flux through unbranched chains leads, under the constraint of fixed total amount of enzymes within the pathway, to a proportionality between control coefficients and enzyme concentrations. A detailed analysis is presented for two types of systems involving (a) reactions with linear kinetics and (b) reactions with Michaelis kinetics, respectively. In the first case one obtains for reactions with equilibrium constants larger than unity a monotonic decrease of enzyme concentrations and of control coefficients from the upper end to the lower end of the chain. In the second case optimization is performed by optimizing the intrinsic parameters (elementary rate constants) as well as the amounts of the enzymes. In contrast to systems with linear kinetics the results for reactions with Michaelis-Menten kinetics are dependent on the concentrations of the external reactants.

Animals↗
PubMed2004

Enhanced apoptotic activity of a structurally optimized form of galectin-1.

Galectin-1 is a homodimeric protein with potent anti-inflammatory properties due to its ability to induce apoptosis in thymocytes and T cells. The galectin-1 subunits are not covalently linked but the monomers are in a dynamic equilibrium with the dimeric form. Since the affinity of the monomers for each other is rather low (in the range of 10(-5)M), the in vivo efficacy of galectin-1 is limited because the equilibrium is shifted towards the inactive monomeric form at lower concentrations. In order to overcome this problem, we designed a covalently linked form of the dimer based on the galectin-1 crystal structure. Here we show that this irreversibly dimeric form of galectin-1 is a potent inducer of apoptosis in murine thymocytes as well as murine mature T cells at concentrations 10-fold lower than wild-type galectin-1. This structurally optimized form of galectin-1 may therefore be a potentially powerful tool to treat chronic inflammatory diseases.

Amino Acid Sequence↗
PubMed2002

Arsenic adsorption onto pillared clays and iron oxides.

Arsenic adsorption was carried out on simple materials such as goethite and amorphous iron hydroxide, and more complex matrices such as clay pillared with titanium(IV), iron(III), and aluminum(III). These matrices were synthesized from a bentonite whose montmorillonitic fraction was pillared according to optimized parameters. These sorbents were characterized by various methods: XRD, FTIR, BET, DTA/TGA, surface acidity, and zetametry. Elimination of arsenite and arsenate as a function of pH was studied. Arsenate elimination was favored at acidic pH, whereas optimal arsenite elimination was obtained at 4<pH<9. For pH values above 10, the pillared clays were damaged and elimination decreased. Equilibrium time and adsorption isotherms were also determined for arsenite and arsenate at each matrix auto-equilibrium pH. Amorphous iron hydroxide had the highest adsorption capacities both towards arsenate and arsenite. Adsorption capacities of goethite and iron- and titanium-pillared clays toward arsenate were similar, but those toward arsenite were different. Desorption experiments from the various matrices were carried out. Iron- and titanium-pillared clays showed a desorption capacity above 95% and around 40% respectively, but no desorption rate could be obtained for iron (hydr)oxides as they were damaged during the process.

Adsorption↗
PubMed1997

Fourfold Clusters of Rovibrational Energies in H2Po Studied with an ab Initio Potential Energy Function

We report here an ab initio investigation of the cluster effect (i.e., the formation of four-member groups of nearly degenerate rotation-vibration energy levels at higher J and Ka values) in the H2Po molecule. The potential energy function has been calculated ab initio for a total of 143 molecular geometries by means of the CCSD(T) method, using an averaged relativistic effective potential for Po in conjunction with a newly optimized basis set. The values of the potential energy function obtained cover the region up to around 5000 cm-1 above the equilibrium energy. On the basis of the ab initio potential, the rotation-vibration energies of H2209Po have been calculated with the MORBID (Morse oscillator rigid bender internal dynamics) Hamiltonian and computer program. In particular, we have calculated the rotational energy manifolds for J </= 40 in the vibrational ground state. We find that the formation of fourfold clusters in H2Po is very similar to that in H2Te. Copyright 1997 Academic Press. Copyright 1997Academic Press

Journal Article↗
PubMed2005

Activated leukocyte cell adhesion molecule (ALCAM/CD166): signaling at the divide of melanoma cell clustering and cell migration?

Orchestrated modulation of cell adhesion is essential for development and homeostasis in multicellular organisms. It optimizes embedding of the cell in its dynamic environment and facilitates appropriate cell responses and intercellular communication. Chronic disturbance of this delicate equilibrium causes defects in tissue architecture and sometimes cancer. In tumor cell biology, dynamic control of adhesion molecules is important to proceed through the metastatic cascade and to allow cell release from the primary tumor, invasion of the surrounding matrix, intravasation and adhesion to vascular endothelial cells to facilitate extravasation. Intertwined and multiple adhesive interactions rather than individual interactions presumably play critical roles in neoplastic development. Yet, knowledge of the contribution of each individual adhesion molecule is essential to unravel this network of interactions. This review will focus on activated leukocyte cell adhesion molecule (ALCAM/CD166) and its role in human melanoma progression. It is hypothesized that ALCAM may function as a cell surface sensor to register local growth saturation and to regulate cellular signaling and dynamic responses.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1988

A game-theoretic approach to donor kidney sharing.

Graft survival in renal transplantation is a function, amongst other things, of the degree of histocompatibility lymphocyte-A (HLA) tissue matching achieved between donor and recipient. Yet a donor procured at centre A might match a transplant candidate at centre B and vice versa. This raises the question of whether, and under what circumstances, surgeons will offer and exchange donor kidneys and gain from such trade in terms of graft survival. We analyse the problem in a game-theoretic framework where the choice of strategy 'to offer or not?' is evaluated in the context of the uncertainty of reciprocation by the other player(s) in the game. The equilibrium solution to a number of variations of the game is predicted to be non-cooperation resulting in collectively sub-optimal graft survival rates. Some policy options for improving cooperation are considered including exchange incentives and coercive measures.

Cooperative Behavior↗
PubMed1997

A rationale for the absolute conservation of Asn70 and Pro71 in mitochondrial cytochromes c suggested by protein engineering.

The absolutely conserved residues Asn70 and Pro71 of mitochondrial cytochrome c have been targeted for protein engineering by semisynthesis. Neither residue has even been implicated in mechanistic schemes, and we reasoned that the conservation of this dipeptide was to fulfill a crucial structural role. Semisynthesis was through condensation by autocatalytic fragment religation of natural fragment 1-65 (H) of the horse protein and synthetic 39-residue peptides containing noncoded amino acids prepared by solid-phase methods. High yields of the purified analogs, homoserine70 and norvaline71 cytochromes c, were obtained. Functional tests revealed minor destabilization of the Hse70-containing structure, with little adverse effect in in vitro assays, but [Nva71] cytochrome c was essentially devoid of activity in these systems. This appeared to be a consequence of a shift, more pronounced than any yet reported, in the conformational equilibrium between the active state III conformer and the inactive, 'alkaline' state IV. The results support our view that this dipeptide is optimal for, and rigidifies, the right-angle bend between two alpha-helices, thus determining the conformation of the 70s loop that terminates in the sixth ligand Met80, and 'forcing' the coordination of iron by thioether sulfur in the presence of the adjacent more avid amine ligands of state IV. Not only is [Nva71] cytochrome c inactive at pH 7, but it also proves to be an extremely potent inhibitor of electron transfer by native state III, thus providing the rationale for the evolutionary conservation of a high pK for the ligand exchange reaction.

Amino Acid Sequence↗
PubMed1999

A new concept of bioartificial liver based on a fluidized bed bioreactor.

Many bioartificial livers have been developed, but most of them suffer from difficulty when being scaled up and from poor efficiency of mass transfer between the plasma and the immobilized hepatocytes. We present a new concept of bioartificial liver based on the fluidized bed motion of hepatocytes entrapped in alginate beads. The bioreactor is designed to offer stable behavior. The maximum fluid perfusion velocity is determined to avoid any bead release from the bioreactor. The fluidized bed height depends on the amount of beads and the velocity employed. Under the optimized operating conditions, the mass transfer between perfusion fluid and beads is very efficient; only 10 min are necessary to reach concentration equilibrium. Hence, this fluidized bed bioartificial liver appears to be a promising tool for a liver support system in the treatment of acute liver failure.

Bioreactors↗
PubMed2004

Elastic coupling of integral membrane protein stability to lipid bilayer forces.

It has been traditionally difficult to measure the thermodynamic stability of membrane proteins because fully reversible protocols for complete folding these proteins were not available. Knowledge of the thermodynamic stability of membrane proteins is desirable not only from a fundamental theoretical standpoint, but is also of enormous practical interest for the rational design of membrane proteins and for optimizing conditions for their structure determination by crystallography or NMR. Here, we describe the design of a fully reversible system to study equilibrium folding of the outer membrane protein A from Escherichia coli in lipid bilayers. Folding is shown to be two-state under appropriate conditions permitting data analysis with a classical folding model developed for soluble proteins. The resulting free energy and m value, i.e., a measure of cooperativity, of unfolding are DeltaG(u,H2O)(o)=3.4 kcal/mol and m = 1.1 kcal/mol M(-1), respectively, in a reference bilayer composed of palmitoyl-oleoyl-phosphatidylcholine (C(16:0)C(18:1)PC) and palmitoyloleoyl-phosphatidylglycerol (C(16:0)C(18:1)PG). These values are strong functions of the lipid bilayer environment. By systematic variation of lipid headgroup and chain composition, we show that elastic bilayer forces such as curvature stress and hydrophobic mismatch modulate the free energy and cooperativity of folding of this and perhaps many other membrane proteins.

Bacterial Outer Membrane Proteins↗
PubMed2003

A model of physical factors in the structural adaptation of microvascular networks in normotension and hypertension.

Adequate function of the microcirculation is vital to any tissue. To maintain an optimal function, microvascular networks must be able to adapt structurally to changes in the physical environment. Here we present a mathematical network model based on vessel wall mechanics. We assume based on experimental observations that longstanding change in transmural pressure elicits a change in the vascular wall-to-lumen ratio for maintaining circumferential wall stress at a certain level. In addition, experimental observations show that chronic change in fluid shear stress at the vascular wall elicits a persistent change in luminal diameter. On this basis we hypothesize that wall influencing substances released from the endothelium in response to shear stress have a certain optimal level in the vascular wall. Deviation from this level will cause vascular remodeling, i.e. a structural change in luminal diameter, until equilibrium is restored. The model explains several of the key features observed experimentally in the microcirculation in normotension and hypertension. Most importantly, it suggests a scenario where overall network structure and network hemodynamics depend on adaptation to local hemodynamic stimuli in the individual vessel. Simulated results show emanating microvascular networks with properties similar to those observed in vivo. The model points to an altered endothelial function as a key factor in the development of vascular changes characteristic of hypertension.

Adaptation, Physiological↗
PubMed1987

The salivary peroxidase system: thermodynamic, kinetic and antibacterial properties.

Enzymes are specific catalysts which optimize the rates of reactions vital to living organisms. If the oxidation of thiocyanate (which occurs, in vivo, in human saliva and salivary glands) is a vital reaction for the maintenance of oral health, then the enzyme (salivary peroxidase), which catalyzes this reaction, should function optimally under in vivo conditions. Studies have shown that salivary peroxidase maintains the SCN- oxidation reaction in an apparent state of dynamic equilibrium, that the kinetic properties of the enzyme provide optimum rates of reaction under in vivo conditions, and that the antibacterial properties of the products of the reaction are optimum under those conditions where unlimited bacterial metabolism provides the greatest threat to host tissues. The evidence indicates that the salivary peroxidase enzyme has evolved in such a way as to maximize its protective value in the oral cavity.

Bacteria↗
PubMed1999

On the design of BSB neural associative memories using semidefinite programming.

This article is concerned with the reliable search for optimally performing BSB (brain state in a box) neural associative memories given a set of prototype patterns to be stored as stable equilibrium points. By converting and/or modifying the nonlinear constraints of a known formulation for the synthesis of BSB-based associative memories into linear matrix inequalities, we recast the synthesis into semidefinite programming problems and solve them by recently developed interior point methods. The validity of this approach is illustrated by a design example.

Association↗