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PubMed2006

[Impact of sodium chloride concentration on pH-metricdetermination of the rate of erythrocytic hemolysis on heating].

The impact of the concentration of a base electrolyte (0.57; 0.85, 2.28% NaCl) on the pH-metric study of ionic equilibrium was studied in theerythrocytic suspensions obtained from the peripheral blood of healthy individuals, patients with various diseases and in the latter after their treatment. The use of the isotonic concentration of the base electrolyte at an ionic force of micro = 0.15 (0.85% NaCl) is optimal in terms of the accuracy of establishment of the most important parameters of denaturation erythrograms at an elevated temperature (58 degrees C), by continuously recording the pH value of a native red blood cell suspension.

Arthritis, Rheumatoid↗
PubMed1989

Purification of the yeast centromere binding protein CP1 and a mutational analysis of its binding site.

CP1 is a yeast protein which binds to the highly conserved DNA element I (CDEI) of yeast centromeres. We have purified CP1 to near homogeneity; it is comprised of a single polypeptide of molecular weight 58,400. When bound to yeast CEN3 DNA, CP1 protects a 12-15-base pair region centered over CDEI. Methylation interference experiments show that methylations of residues located outside of the 8-base pair CDEI sequence have no detectable effect on CP1 binding, suggesting that the DNA sequences important for CP1 recognition are confined to the CDEI octanucleotide. The equilibrium constant for CP1 binding to CEN3 DNA is relatively low, 3 x 10(8) M-1. Using a novel method to determine relative DNA binding constants, we analyzed the effect of CDEI mutations on CP1 binding. A C to T point mutation at position 5 (CO1) reduces the equilibrium constant about 35-fold, while the insertion of an additional T at this position (CAT) reduces the equilibrium constant 1,400-fold. The effect of these mutations on mitotic centromere function in vivo was assessed using a plasmid stability assay. While the CO1 mutation had a slight effect, the CAT mutation significantly impaired function, implying that CP1 binding is required for the optimal mitotic function of yeast centromeres.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

High mass clearance of autoantibodies from a murine model of lupus nephritis by immunoadsorption using star-configured polyethylene glycols.

The extracorporeal immunoadsorption of antibodies as part of the therapy for human autoimmune diseases has been limited by technology with inadequate and nonselective mass clearance or problems with bioincompatibility. To overcome these shortcomings, we designed a method utilizing star-configured polyethylene glycols (star-PEGs) having up to 63 free arms with immunoreactive (tresylate ester) end-groups for each arm immobilized to a polymer support substrate. The flexibility and length of the arms are thought to allow optimization of epitope presentation and to permit interaction with immunoligands on adjacent arms. To demonstrate efficacy we used an in vitro murine antibody model of human lupus nephritis, wherein we could study the kinetics and mass clearance of hybridoma derived antihistone antibodies from human plasma. Histones were covalently bound to the star-PEG end-groups and the kinetics of antibody adsorption were assessed using a surface plasmon resonance technique. The equilibrium constants of antihistone antibody binding to histone-star-PEGs that were linked to a support grid demonstrated high affinity with a KA of 3.56E + 07 and a KD of 2.81E - 08. The optimum reaction conditions were determined to accomplish the hydrophilization of polysulfone (PS; by an aqueous nitration method) and polymethylmethacrylate substrates (PMMA; by hydrazine), using sheet casts of both polymer substances. Hollow fiber devices of these polymers (commercial hemodialyzers) were modified so that histone-bound star-PEGs were linked to their intracapillary luminal surfaces, using a process which we have shown retains their immunoadsorption properties for antihistone antibodies. A closed loop recirculating model was constructed to measure mass clearance of antibodies from a reservoir. After optimizing conditions using extraction from saline solutions, the removal of antibody from human plasma by control and surface-modified devices was assessed over 4 h. There was no measurable antibody clearance by the control fibers over this time interval. The 2.1 m2 luminal surface area PMMA devices removed 5.0 +/- 1.1 mg, with a maximum of 7.0 mg. The 1.8 m2 PS device cleared 11.3 +/- 6.2 mg with a maximum of 17.5 mg. In summary, star-PEG immunoadsorption is a promising technique for the treatment of human autoimmune disease because it can achieve very high-mass clearance of autoantibodies using modified biocompatible hollow-fiber polymer devices.

Animals↗
PubMed2005

The removal of uranium(VI) from aqueous solutions onto activated carbon: kinetic and thermodynamic investigations.

The adsorption of uranium(VI) from aqueous solutions onto activated carbon has been studied using a batch adsorber. The parameters that affect the uranium(VI) adsorption, such as contact time, solution pH, initial uranium(VI) concentration, and temperature, have been investigated and optimized conditions determined (contact time 240 min; pH 3.0+/-0.1; initial uranium concentration 100 mg/L; temperature 293.15 K). The experimental data were analyzed using sorption kinetic models (pseudo-first- and pseudo-second-order equations) to determine the equation that fits best our experimental results. Equilibrium isotherm studies were used to evaluate the maximum sorption capacity of activated carbon and experimental results showed this to be 28.30 mg/g. The Freundlich, Langmuir, and Dubinin-Radushkevich (D-R) models have been applied and the data correlate well with Freundlich model and that the sorption is physical in nature (the activation energy Ea=7.91 kJ/mol). Thermodynamic parameters (DeltaHads0=-50.53 kJ/mol, DeltaSads0=-98.76 J/mol K, DeltaGads(293.15 K)0=-21.61 kJ/mol) showed the exothermic heat of adsorption and the feasibility of the process.

Journal Article↗
PubMed2005

Vibrational spectroscopic studies, conformations and ab initio calculations of 3,3,3-trifluoropropyltrichlorosilane.

Infrared spectra of 3,3,3-trifluoropropyltrichlorosilane (CF3CH2CH2SiCl3) were obtained in the vapour, amorphous and crystalline solid phases in the range 4000-50 cm-1. Additional spectra in argon matrices at 5.0 K were recorded before and after annealing to 20-36 K. Raman spectra of the compound as a liquid were recorded at various temperatures between 298 and 210 K and spectra of the amorphous and crystalline solids were obtained. The spectra suggested the existence of two conformers (anti and gauche) in the fluid phases and in the matrix. When the vapour was shock-frozen on a cold finger at 80 K and subsequently annealed to 120-150 K, six weak or very weak Raman bands vanished in the crystal. Similar variations were observed in the corresponding infrared spectra after annealing and four very weak IR bands disappeared after crystallization. From intensity variations between 298 and 210 K of three Raman band pairs an average value Delta(conf)H degrees (gauche-anti)=6.1+/-0.5 kJmol-1 was obtained in the liquid. Annealing experiments indicate that the anti conformer also has a lower energy in the argon matrices. The conformational equilibrium is highly shifted towards anti in the liquid, and the low energy conformer also forms the crystal. The spectra of the abundant anti conformer and the few bands ascribed to the gauche conformer have been interpreted. Ab initio calculations at the HF/6-311G(**) and B3LYP/6-311G(**) gave optimized geometries, infrared and Raman intensities and vibrational frequencies for the anti and gauche conformers. The conformational energy differences derived were 11.8 and 9.2 kJmol-1 from the HF and the B3LYP calculations, respectively.

Cold Temperature↗
PubMed2002

Relative damping improves linear mass-spring models of goal-directed movements.

A limitation of a simple linear mass-spring model in describing goal directed movements is that it generates rather slow movements when the parameters are kept within a realistic range. Does this imply that the control of fast movements cannot be approximated by a linear system? In servo-control theory, it has been proposed that an optimal controller should control movement velocity in addition to position. Instead of explicitly controlling the velocity, we propose to modify a simple linear mass-spring model. We replaced the damping relative to the environment (absolute damping) with damping with respect to the velocity of the equilibrium point (relative damping). This gives the limb a tendency to move as fast as the equilibrium point. We show that such extremely simple models can generate rapid single-joint movements. The resulting maximal movement velocities were almost equal to those of the equilibrium point, which provides a simple mechanism for the control of movement speed. We further show that peculiar experimental results, such as an 'N-shaped' equilibrium trajectory and the difficulties to measure damping in dynamic conditions, may result from fitting a model with absolute damping where one with relative damping would be more appropriate. Finally, we show that the model with relative damping can be used to model subtle differences between multi-joint interceptions. The model with relative damping fits the data much better than a version of the model with absolute damping.

Attention↗
PubMed2005

Modular approach toward supramolecular functional assemblies: characterization of Donor-spacer-acceptor ternary complexes.

It is shown that the noncovalent donor-spacer-acceptor (DSA) motif is useful in constructing an electron-transfer assembly. As a representative example, the equilibrium and structure of one of the DSA assemblies, consisting of Zn-tetraphenylporphyrin, a spacer unit bearing pyridine and amidinium moieties, and 3,4-dinitrobenzoic acid, were studied in detail by the extensive use of UV-vis titration, fluorescence spectroscopy, and 1H NMR, with the help of a three-component equilibrium model. Complex formation and fluorescence quenching in 20 different DSA complexes constructed from a library of five donors, two spacers, and two acceptors were investigated. It has been experimentally shown that supramolecular modular approach is useful for a systematic and quick search for a functionally optimized assembly.

Journal Article↗
PubMed2000

Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity.

Single-chain antibody mutants have been evolved in vitro with antigen-binding equilibrium dissociation constant K(d) = 48 fM and slower dissociation kinetics (half-time > 5 days) than those for the streptavidin-biotin complex. These mutants possess the highest monovalent ligand-binding affinity yet reported for an engineered protein by over two orders of magnitude. Optimal kinetic screening of randomly mutagenized libraries of 10(5)-10(7) yeast surface-displayed antibodies enabled a >1,000-fold decrease in the rate of dissociation after four cycles of affinity mutagenesis and screening. The consensus mutations are generally nonconservative by comparison with naturally occurring mouse Fv sequences and with residues that do not contact the fluorescein antigen in the wild-type complex. The existence of these mutants demonstrates that the antibody Fv architecture is not intrinsically responsible for an antigen-binding affinity ceiling during in vivo affinity maturation.

Animals↗
PubMed2006

Equilibration of adenylates in the mitochondrial intermembrane space maintains respiration and regulates cytosolic metabolism.

Adenylate kinase (AK) uses one each of Mg-complexed and free adenylates as substrates in both directions of its reaction. It is very active in the mitochondrial intermembrane space (IMS), but is absent from the mitochondrial matrix where low [ADP] upon intensive respiration limits the respiratory rate. AK activity in the IMS is linked to ATP/ADP exchange across the inner mitochondrial membrane by using ATP (imported from the matrix) and AMP as substrates, the latter provided by apyrase and other AMP-generating reactions. The ADP formed by AK is exported to the matrix (in exchange for ATP), providing a mechanism for regeneration of ADP during respiration. From the AK equilibrium, and taking pH values characteristic of subcellular compartments, [Mg2+] in the IMS is calculated as 0.4-0.5 mM and in the cytosol as 0.2-0.3 mM, whereas the MgATP:MgADP ratio in the IMS and cytosol is 6-9 and 10-15, respectively. These represent optimal conditions for transport of adenylates (via the maintenance of an ATPfree:ADPfree ratio close to 1) and mitochondrial respiratory rates (via the maintenance of submillimolar [ADPfree] in the IMS). This, in turn, has important consequences for mitochondrial and cytosolic metabolism, including regulation of the protein phosphorylation rate (via changes in the MgATP:AMPfree ratio) and allosteric regulation of mitochondrial and cytosolic enzymes. Metabolomic consequences are discussed in connection with the calculation of metabolic fluxes from subcompartmental distributions of total adenylates and Mg2+.

Adenine Nucleotides↗
PubMed1988

Selective loss of binding sites for the iodinated alpha-neurotoxin I from Naja mossambica mossambica venom upon enzymatic deglycosylation of Torpedo electric organ membranes.

Removal of asparagine-linked carbohydrate chains from Torpedo marmorata electric organ membranes was found to inhibit the binding of the iodinated alpha-neurotoxin I from Naja mossambica mossambica snake venom to its receptor. Optimal deglycosylation of membranes by endoglycosidase F resulted in a 55% inhibition of alpha-neurotoxin-I-saturable binding. Under these conditions, up to 70% of concanavalin A binding was also lost, indicating an efficient removal of mannose-rich carbohydrate chains. Saturation binding experiments at equilibrium on membranes incubated in the absence of endoglycosidase F indicated, when analyzed by Scatchard plots, the presence of two classes of high-affinity binding sites for alpha-neurotoxin I (kd = 9 pM and 68 pM respectively) with capacities of 24 and 14 pmol/mg membrane proteins, respectively. After endoglycosidase F treatment, only the former class of binding sites (Kd = 11 pM) was recovered together with a 45% reduction in the number of total binding sites. Dissociation experiments further confirmed the presence of two types of toxin-receptor complexes in control membranes and the selective loss of the rapidly dissociating component upon deglycosylation. The binding of alpha-neurotoxin I to its receptor, deglycosylated or not, was totally inhibited by carbamoylcholine, d-tubocurarine or alpha-bungarotoxin. These findings show that the neurotoxin binding sites present on the acetylcholine receptor can be discriminated on the basis of their differential susceptibility to the removal of asparagine-linked carbohydrate chains.

Animals↗
PubMed1984

Pulmonary transit time and diffusing capacity in mammals.

Allometry is used as a tool to explain the apparent mismatch of oxygen consumption and diffusing capacity in the mammalian lung. By combining equations for pulmonary capillary volume and cardiac output, it is apparent that erythrocyte transit time through the lung must scale disproportionately to body mass. This inequality is a consequence of physical and mechanical properties setting optimal cardiac and respiratory frequencies. Because of much shorter transit times, the mean alveolar-capillary oxygen pressure difference increases as body size decreases. The time course of oxygen binding to hemoglobin may limit maximum oxygen consumption in the smallest mammals. To assure carbon dioxide diffusion equilibrium, levels of carbonic anhydrase are much higher in small than in large mammals. Because of the differences in transit time, the pulmonary diffusing capacity must scale linearly to body mass to assure adequate oxygen delivery in all mammals.

Animals↗
PubMed2002

Glucose binding to molecularly imprinted polymers.

The main goal of this study was to prepare molecularly imprinted polymers (MIPs) with glucose recognition sites and to evaluate their glucose-binding properties for potential applications in glucose sensing and self-regulating insulin delivery devices. To mimic glucose-binding sites of natural proteins, monomers possessing functional groups similar to amino acids were used. Vinyl acetic acid (VAA), acrylamide (AAm), 4-pentenoic acid (PA), and allyl benzene (AB) were copolymerized with a cross-linking agent (N,N'-methylenebisacrylamide, BIS) in the presence of glucose as a template. The binding affinity of glucose to MIPs was examined by using an equilibrium dialysis technique. The dissociation constants of the MIPs were determined by Scatchard analysis. MIPs showed glucose-binding affinity, while polymers synthesized in the absence of glucose template did not show a glucose-binding property. MIPs composed of VAA, AAm, PA, and AB at optimized mole ratios of monomers and cross-linker showed the highest glucose-binding affinity, KD = 1.66 mM, which is comparable to that of a well-known glucose binding protein, concanavalin A (KD = 1.84 mM). The affinity between monomer and glucose was in the order VAA > AAm > AB > PA.

Binding Sites↗
PubMed2004

A revised view of the dynamics, physiology, and treatment of occlusion: a new paradigm.

A new perspective is proposed regarding the functional dynamics of occlusion, the masticatory muscles, and mandibular placement. Each is analyzed on the basis of a new criterion: force. Stomatognathic function is represented as an ongoing equilibrium maintained between the three-dimensional set of individual occlusal forces and the three-dimensional set of bilateral muscle forces. Mandibular placement is of prime importance, mediating as it does between the two. The conclusion is drawn that occlusion and the muscles can correlate optimally with each other only when the mandible occupies its neuromuscular position (NMP), herein defined as that placement where muscle accommodation is at its absolute minimum. The conclusion is that only the muscles themselves are capable of establishing the NMP and that customary conventional technology is inadequate. A new technology, hydrostatics, is needed to create the special (not existing naturally) occlusal conditions essential to optimally integrating occlusion, mandibular placement, and muscles. Preliminary EMG data is offered in support of this conclusion.

Bite Force↗
PubMed1992

Influence of suckling on tubulin-dependent GTPase activity in the anterior pituitary lobe of the lactating rat.

A GTPase assay was employed to determine the relative proportions of the enzymatic activity in soluble and polymerized tubulin pools in the anterior pituitary lobe of the lactating rat. The GTPase activity in the tubulin fractions was estimated in 25-50 micrograms protein using [gamma-32P]GTP. The liberation of inorganic phosphate (Pi) was proportional to the protein concentration with either of the tubulin fractions. The enzymatic activity appeared to reach equilibrium by 1 min. Antitubulin antibodies inhibited the enzymatic activity in a concentration-dependent manner in both the tubulin fractions; at a final dilution of 1:2000 the antibody maximally inhibited the enzyme activity in both the tubulin fractions by 39-44%. After establishing the optimal conditions for the GTPase assay, the effect of suckling on pituitary GTPase activity was studied. Soluble and polymerized tubulin fractions were prepared from anterior pituitaries obtained from lactating rats killed after suckling for 30, 60, and 90 min; GTPase activity was assayed in both the tubulin fractions in the absence of antitubulin antibody. Compared to the nonsuckled control, suckling for 60 and 90 min stimulated the enzymatic activity in the soluble tubulin fraction by 80% and 44%, respectively (P less than 0.05). The enzymatic activity in the polymerized tubulin fraction increased by 30% at 60 min and decreased by about 20% at 90 min (P less than 0.05). The suckling-stimulated GTPase activity in the two pituitary fractions cannot be attributed to tubulin alone since there are other proteins also capable of hydrolyzing GTP. Therefore, GTPase activity was assayed in the pituitary tubulin fractions in the presence of antitubulin antibody (1:2000 dilution); tubulin-GTPase activity is the difference between the activity assayed in the absence of the antibody and that which was determined in the presence of the antibody. In the soluble tubulin fraction, tubulin-GTPase activity increased by 166% at 30 min suckling (P less than 0.05), decreased by 40% at 60 min (P less than 0.05), and again increased by 148% at 90 min (P less than 0.05). In the polymerized tubulin fraction, the enzyme activity decreased by 82% at 30 min (P less than 0.05), increased by 742% at 60 min (P less than 0.05), and again decreased by 95% at 90 min (P less than 0.05). Thus, an inverse relationship between tubulin-GTPase activities in the two pituitary fractions was observed and provides further evidence in support of our hypothesis that microtubules are recruited to transport PRL granules from the Golgi apparatus to the plasma membrane.

Animals↗
PubMedDate not supplied

[Rate limitations in the elongation working cycle and the action mechanisms of GTP-complexed elongation protein factors].

Kinetic aspects of the peptide chain elongation process, proper role and the working mechanisms of the GTP-complexed protein elongation factors are discussed. High rates of the codon-dependent binding of aminoacyl-tRNA and translocation are shown to need the mutually exclusive properties of the ribosomal A centre which in the absence of some additional events seems to be unable to possess simultaneously these properties. A centre of translating ribosome is postulated to have a character of dynamic structure providing unsimultaneous consecutive optimization of the aminoacyl-tRNA binding and translocation conditions in accordance with the principle "either binding or translocation". According to this suggestion the rate of elongation is limited by the rate of reversible changes of the A centre structure fitting into the scheme A in equilibrium with B. Each step of this scheme is specifically promoted by corresponding GTP-complexed protein factor. Thus, elongation factors are suggested to be specific modulators of the A centre affinity for the codon-appropriate tRNA and to play a role of complex ligands carrying out an allosteric regulation of the ribosomal functional activity.

Codon↗
PubMed2003

Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats.

The aim of this work was to prepare and characterize inhalation dry powders of human parathyroid hormone (PTH), as well as to assess their efficacy for systemic delivery of the peptide and safety in rats. The powders were prepared by spray-drying using PTH, sugars, dipalmitoylphosphatidylcholine, and/or albumin. They presented an average primary particle diameter of 4.5 microm and tap density of 0.06 g/cm(3), a mass median aerodynamic diameter between 3.9 and 5.9 microm, and reached up to 98% emitted dose and up to 61% fine particle fraction in the multi-stage liquid impinger using a Spinhaler inhaler device. Varying the airflow rate from 30 to 100 L/min had limited influence on the aerodynamic behavior of the aerosols. The absolute PTH bioavailability was 21% after intratracheal administration of the powder formed of PTH/albumin/lactose/dipalmitoylphosphatidylcholine and 18% after subcutaneous injection in rats. Equilibrium dialysis revealed a 78% binding of PTH to albumin and the withdrawal of albumin from the powder increased absolute bioavailability after inhalation from 21 to 34%. No acute inflammation appeared in the lung up to 48 h after a single inhalation. The increased bioavailability of the optimized powder aerosol of PTH makes it a promising alternative to subcutaneous injection.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1986

Studies on calcium binding to brush-border membranes from rabbit small intestine.

A study was made of the uptake of Ca2+ by brush-border membrane vesicles prepared from rabbit small intestine. The process was found to be time, temperature and substrate concentration dependent, displayed saturability, did not depend on added energy sources and occurred optimally in a pH range of 7.5-8.0. Although the transport of D-glucose by these membrane vesicles responded to changes in osmotic pressure as modified by adding cellobiose to the medium, the uptake of Ca2+ was found not to be osmotically-sensitive. Moreover, the equilibrium uptake value obtained when vesicles were exposed to 0.36 mM Ca2+ was some 60-fold higher than the amount that could have been accommodated by the intravesicular space, calculated from the equilibrium uptake of D-glucose. It was concluded from these results that the uptake involved complete binding of the Ca2+ to the membrane. The ionophore A23187 enhanced the rates of uptake and efflux of Ca2+ without affecting equilibrium values, which suggests that the binding of Ca2+ measured under our conditions was to interior sites of the membrane. The binding capacity was decreased in the presence of 10 mM lidocaine as indicated by a diminution of the equilibrium binding values. Generating an electrochemical potential (negative inside) by addition of valinomycin to vesicles pre-equilibrated with K2SO4, enhanced the rate of uptake of Ca2+. Addition of metal ions, on the other hand, inhibited the uptake, La3+ and Tb3+ being most effective followed by Mn2+, Ba2+ and Mg2+. Na+ and K+ were the least inhibitory. The properties of the Ca2+ uptake process found in rabbit brush-border membranes were compared to those of similar processes occurring in other species.

Adenosine Triphosphate↗
PubMed2001

A simple model for gene targeting.

Sequence-specific binding to genomic-size DNA sequences by artificial agents is of major interest for the development of gene-targeting strategies, gene-diagnostic applications, and biotechnical tools. The binding of one such agent, peptide nucleic acid (PNA), to a randomized human genome has been modeled with statistical mass action calculations. With the length of the PNA probe, the average per-base binding constant k(0), and the binding affinity loss of a mismatched base pair as main parameters, the specificity was gauged as a "therapeutic ratio" G = maximum safe [PNA](tot)/minimal efficient [PNA](tot). This general, though simple, model suggests that, above a certain threshold length of the PNA, the microscopic binding constant k(0) is the primary determinant for optimal discrimination, and that only a narrow range of rather low k(0) values gives a high therapeutic ratio G. For diagnostic purposes, the value of k(0) could readily be modulated by changing the temperature, due to the substantial Delta H degrees associated with the binding equilibrium. Applied to gene therapy, our results stress the need for appropriate control of the binding constant and added amount of the gene-targeting agent, to meet the varying conditions (ionic strength, presence of competing DNA-binding molecules) found in the cell.

Base Pair Mismatch↗