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PubMed1996

Synthesis and structure determination by NMR of a putative vacuolar targeting peptide and model of a proteinase inhibitor from Nicotiana alata.

NA-proPI is a 40.3-kDa multidomain precursor protein found in the stigma of the ornamental tobacco Nicotiana alata. It is selectively targeted to the vacuole and, as the plant matures, is processed to produce a series of five 6-kDa proteinase inhibitors (one chymotrypsin and four trypsin reactive sites) which are thought to play a vital role in plant protection against insect pests. A putative sixth domain with a chymotrypsin reactive site is likely to be formed by three disulfide bridges linking the N- and C-terminal fragments of NA-proPI. This domain contains two distinct structural elements: a 54-residue sequence with high identity to each of the five repeated PI domains, and a nonrepeated 25-residue sequence at the C-terminus which is proposed to contain a vacuolar targeting peptide. The structure of the putative sixth domain was predicted using a combination of secondary structure prediction and homology modeling based on the known structure of one of the intact domains. A 26-residue peptide corresponding to the nonrepeated C-terminal sequence and encompassing the putative vacuolar targeting sequence was synthesized and its structure determined using 1H NMR spectroscopy and simulated annealing calculations. The peptide was found to adopt an amphipathic helical structure. The calculations based on NOE data suggested that the helix is curved, with a hydrophobic concave face and a hydrophilic convex face. This curvature is consistent with an observed periodicity in backbone NH chemical shifts. The structure of the entire sixth domain was modeled by combining the experimentally determined structure of the putative vacuolar targeting peptide with the homology model of the PI domain. In this model the alpha-helix of the putative targeting peptide protrudes from the otherwise compact PI domain. This observation is consistent with the requirement for targeting sequences to be relatively exposed for recognition by the sorting apparatus. As there is no consensus on the structure of vacuolar targeting sequences, this study provides a valuable insight into their potential mechanism of interaction with the cellular sorting apparatus.

Amino Acid Sequence↗

PubMed2005

Hydration-induced changes of structure and vibrational frequencies of methylphosphocholine studied as a model of biomembrane lipids.

The chemical characteristics of the polar parts of phospholipids as the main components of biological membranes were investigated by using infrared (IR) spectroscopy and theoretical calculations with water as a probe molecule. The logical key molecule used in this study is methylphosphocholine (MePC) as it is not only a representative model for a polar lipid headgroup but itself has biological significance. Isolated MePC forms a compact (folded) structure which is essentially stabilized by two intramolecular C-H...O type hydrogen bonds. At lower hydration, considerable wavenumber shifts were revealed by IR spectroscopy: the frequencies of the (O-P-O)- stretches were strongly redshifted, whereas methyl and methylene C-H and O-P-O stretches shifted surprisingly to blue. The origin of both red- and blueshifts was rationalized, on the basis of molecular-dynamics and quantum-chemistry calculations. In more detail, the hydration-induced blueshifts of C-H stretches could be shown to arise from several origins: disruption of the intramolecular C-H...O hydrogen bonds, formation of intermolecular C-H...O(water) H-bonds. The stepwise disruption of the intramolecular hydrogen bonds appeared to be the main feature that causes partial unfolding of the compact structure. However, the transition from a folded to extended MePC structure was completed only at high hydration. One might hypothesize that the mechanism of hydration-driven conformational changes as described here for MePC could be transferred to other zwitterions with relevant internal C-H...O hydrogen bonds.

Computer Simulation↗

PubMed2003

Development of enteric-coated pectin-based matrix tablets for colonic delivery of theophylline.

The present work was aimed at developing a new colonic drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin matrix with a pH-sensitive Eudragit S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-specific delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-specificity of simple pH-dependent systems. Due to the poor compactability properties of pectin, it was used in mixture with Emdex, a hydrophilic directly-compressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and high methoxylated, or amidated), the pectin:Emdex ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimum content of Emdex for obtaining directly compressible tablets with sufficient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order profiles were obtained whose slope (i.e. the drug release rate) depended on both the Emdex content and the pectin type. Comparison of the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for specific colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-specificity of drug release. Finally, the importance of using appropriate dissolution test conditions to adequately characterize the drug release profiles from delivery systems endowed with a microflora-activated drug release triggering mechanism has been demonstrated.

Bronchodilator Agents↗

PubMed1987

Volume estimation of biological objects by systematic sections.

The absolute volume of biological objects is often estimated stereologically from an exhaustive set of systematic sections. The usual volume estimator V is the sum of the section contents times the distance between sections. For systematic sectioning with a random start, it has been recently shown that V is unbiased when m, the ratio between projected object length and section distance, is an integer number (Cruz-Orive 1985). As this quantity is no integer in the real world, we have explored the properties of V in the general and realistic situation m epsilon R. The unbiasedness of V under appropriate sampling conditions is demonstrated for the arbitrary compact set in 3 dimensions by a rigorous proof. Exploration of further properties of V for the general triaxial ellipsoid leads to a new class of non-elementary real functions with common formal structure which we denote as np-functions. The relative mean square error (CE2) of V in ellipsoids is an oscillating differentiable np-function, which reduces to the known result CE2 = 1/(5m4) for integer m. As a biological example the absolute volumes of 10 left cardiac ventricles and their internal cavities were estimated from systematic sections. Monte Carlo simulation of replicated systematic sectioning is shown to be improved by using m epsilon R instead of m epsilon N. In agreement with the geometric model of ellipsoids with some added shape irregularities, mean empirical CE was proportional to m-1.36 and m-1.73 in the cardiac ventricle and its cavity. The considerable variance reduction by systematic sectioning is shown to be a geometric realization of the principle of antithetic variates.

Animals↗

PubMedDate not supplied

Improved intramedullary nail interlocking in osteoporotic bone.

OBJECTIVE: Intramedullary nail locking bolts often fail to gain purchase or cut out in osteoporotic bone. The biomechanical stability of a bladelike device that lowers intraosseous stress levels by distributing the load over a greater volume of bone was compared with conventional locking bolts in osteoporotic bone. METHODS: Standardized simulated comminuted supracondylar femoral fractures (segmental defect) in fresh-frozen paired osteoporotic (bone mineral density <200 milligrams per cubic centimeter) human cadaveric femurs were stabilized with a retrograde unreamed distal femoral nail and distally interlocked with conventional locking bolts or a bladelike device. The distal portions of the fixator-bone constructs were tested under axial load, and the stiffness and strength were compared (pairwise). RESULTS: Interlocking with a bladelike device was 41 percent stiffer (p = 0.01) and 20 percent stronger (p = 0.02) than that with conventional locking bolts. All posttesting radiographs showed compaction of the cancellous bone distal to the interlocking devices. Even after nail displacements of twelve millimeters, only a few locking bolts were plastically deformed and no bladelike device showed gross plastic deformation. CONCLUSION: This study showed the biomechanical benefits of increasing the bone-implant interface surface for improving the acute stiffness and strength of fracture fixation in osteoporotic cancellous bone. The fixator-bone construct withstood higher forces before failure in these fragile bones.

Aged↗

PubMed2006

Individualized and time-variant model for the functional link between thermoregulation and sleep onset.

This study makes use of control system model identification techniques to examine the relationship between thermoregulation and sleep regulation. Specifically, data-based mechanistic (DBM) modelling is used to formulate and experimentally test the hypothesis, put forth by Gilbert et al., that there exists a connection between distal heat loss and sleepiness. Six healthy sleepers each spent three nights and the following day in the sleep laboratory: an adaptation, a cognitive arousal and a neutral testing day. In the cognitive arousal condition, a visit of a television camera crew took place and subjects were asked to be interviewed. During each of the three 25-min driving simulator tasks per day, the distal-to-proximal gradient and the electroencephalogram are recorded. It is observed from these experimental data that there exists a feedback connection between thermoregulation and sleep. In addition to providing experimental evidence in support of the Gilbert et al. (2004) hypothesis, the authors propose that the nature of the feedback connection is determined by the nature of sleep/wake state (i.e. NREM sleep versus unwanted sleepiness in active subjects). Besides this, an individualized and time-variant model for the linkage between thermoregulation and sleep onset is presented. This compact model feeds on real-time data regarding distal heat loss and sleepiness and contains a physically meaningful parameter that delivers an individual- and time-depending quantification of a well known biological features in the field of thermoregulation: the thermoregulatory error signal T(hypo)(t)-T(set)(t). A validation of these physical/biological features emphasizes the reliability and power of DBM in describing individual differences related to the sleep process.

Body Temperature Regulation↗

PubMed2002

The solution structure of a cardiac troponin C-troponin I-troponin T complex shows a somewhat compact troponin C interacting with an extended troponin I-troponin T component.

We have investigated the structure of the cTnC-cTnI-cTnT(198-298) calcium-saturated, ternary cardiac troponin complex by small-angle scattering with contrast variation. Shape restoration was also applied to the scattering information resulting from the deuterated cTnC subunit, the unlabeled cTnI-cTnT(198-298) subunits, and the entire complex. The experimental results and modeling indicate that cTnC adopts a partially collapsed conformation, while the cTnI-cTnT(198-298) components have an extended, rod-like structure. Shape restoration applied to the X-ray scattering data and the entire contrast variation series suggest that cTnC and the cTnI-cTnT(198-298) component lie with their long axes roughly parallel to one another with a relatively small surface area for interaction. Our findings indicate that the nature of the interactions between TnC and the TnI-TnT component differs significantly between the cardiac and skeletal isoforms as evidenced by the different degrees of compactness between the cardiac TnC and skeletal TnC in their respective ternary complexes and the fact that the cTnC subunit is not highly intertwined with the other subunits, as observed in the binary complex of the skeletal isoforms [Olah, G. A., and Trewhella, J. (1994) Biochemistry 33, 12800-12806].

Animals↗

PubMedDate not supplied

Semantic retrieval in DNA-based memories with Gibbs energy models.

At least three types of associative memories based on DNA-affinity have been proposed. Previously, we have quantified the quality of retrieval of genomic and abiotic information in simulation by comparison to state-of-the-art symbolic methods available, such as LSA (Latent Semantic Analysis). Their performance is poor when the evaluation criterion for DNA-affinity is a simple approximation of the Gibbs energy that governs duplex formation for retrievals. Here, we use a more realistic approximation of the Gibbs energy to improve semantic retrievals in DNA memories. Their performance is much closer to that of LSA, according to human expert ratings. With more realistic approximations of DNA affinity, performance is expected to improve for other, more adaptive associative memories with compaction in silico, and even more so with actual DNA molecules in vitro.

Computers, Molecular↗

PubMed2006

A simple geometrical description of the TrueFISP ideal transient and steady-state signal.

An intuitive approach is presented for assessment of the TrueFISP signal behavior in the transient phase and the steady state, based on geometrical considerations in combination with the Bloch equations. Short formulations are derived for the zenith and phase angle determining the direction of the magnetization vector for which a smooth monoexponential decay is obtained even at considerable off-resonance frequencies, thus compactly defining the target of various preparation schemes proposed in literature. A pictorial explanation is provided to illustrate how the interplay between RF excitation and relaxation governs the TrueFISP transient phase and steady state. Closed form expressions are developed that describe the signal evolution, accounting for the influence of T(1), T(2), flip angle, and resonance frequency offset in agreement with recently published studies. These results are obtained directly from basic assumptions, without the need for abstract mathematical treatment or further approximations. The validity of the conceptual framework and the analytical description is verified by simulations based on the Bloch equations as well as with MR phantom experiments. The theory may be used for contrast calculations and has the potential to facilitate improved parameter quantification with magnetization prepared TrueFISP experiments accounting for off-resonance effects.

Image Processing, Computer-Assisted↗

PubMed2006

Laser-induced fluorescence detection system for microfluidic chips based on an orthogonal optical arrangement.

In this work, a simple LIF detection system based on an orthogonal optical arrangement for microfluidic chips was developed. Highly sensitive detection was achieved by detecting the fluorescence light emitted in the microchannel through the sidewall of the chip to reduce scattered light interference from the laser source. A special crossed-channel configuration, with a 1.5-mm distance from the separation channel to the sidewall of the glass chip, was designed in order to facilitate collection of emitted fluorescence light through the sidewall. The significant difference in intensity distribution of scattered laser light on the chip plane observed in this study was fully exploited to optimize S/N ratio of detected signals by rejection of scattered light, both through systematic measurements and employing ray-tracing simulation. A fluorescence collection angle of 45 degrees in the chip plane gave the best result, with a scattered light intensity 1/38 of that obtained at an angle of 90 degrees. Sodium fluorescein and fluorescein isothiocyanate-labeled amino acids were used as model samples to demonstrate the performance of the LIF system. A detection limit (S/N = 3) of 1.1 pM fluorescein was obtained, which is comparable to that of optimized confocal LIF systems for chip-based capillary electrophoresis. Apart from the high detection power, the system also has the advantages of simple optical structure, compactness, and ease in building.

Journal Article↗

PubMed2002

Can we separate active from inactive conformations?

Molecular modeling methodologies such as molecular docking, pharmacophore modeling, and 3D-QSAR, rely on conformational searches of small molecules as a starting point. All of these methodologies seek conformations of the small molecules as they bind to target proteins, i.e., their active conformations. Thus the question as to whether active conformations can be separated from inactive conformations is extremely relevant. In this paper, 3D-descriptors that separate random conformations from active conformations of small molecules are sought. To select appropriate descriptors, 65 protein-ligand complexes were taken from the protein data bank. For each ligand the active conformation was compared to randomly generated low energy conformations. Descriptors such as solvent accessible surface area, number of internal interactions and radius of gyration appear to be useful for separating the active conformations from the random conformations. The results with all these descriptors indicate that active conformations are less compact that random conformations, i.e., they have more solvent accessible surface area, fewer internal interactions and a larger radius of gyration than random conformations. Thus these descriptors could be useful as weights to bias conformational search procedures to conformations more likely to bind to proteins or as filters to eliminate conformations unlikely to bind to any protein.

Computer Simulation↗

PubMed2004

Spherical beam volume holograms for spectroscopic applications: modeling and implementation.

The spherical beam volume hologram, recorded by a plane wave and a spherical beam, is investigated for spectroscopic applications in detail. It is shown that both the diffracted and the transmitted beam can be used for spectroscopy when the hologram is read with a collimated beam. A new method is introduced and used for analysis of the spherical beam volume hologram that can be extended for analysis of arbitrary holograms. Experimental results are consistent with the theoretical study. It is shown that the spherical beam volume hologram can be used in a compact spectroscopic configuration when the transmitted beam is monitored. Also, on the basis of the properties of the spherical beam hologram, the response of a hologram recorded by a plane wave and an arbitrary pattern is predicted. The information can be used to optimize holographic spectrometer design.

Algorithms↗

PubMed1994

Electrostatic effects in short superhelical DNA.

We present Monte Carlo simulations of the equilibrium configurations of short closed circular DNA that obeys a combined elastic, hard-sphere, and electrostatic energy potential. We employ a B-spline representation to model chain configuration and simulate the effects of salt on chain folding by varying the Debye screening parameter. We obtain global equilibrium configurations of closed circular DNA, with several imposed linking number differences, at two salt concentrations (specifically at the extremes of no added salt and the high salt regime), and for different chain lengths. Minimization of the composite elastic/long-range potential energy under the constraints of ring closure and fixed chain length is found to produce structures that are consistent with the configurations of short supercoiled DNA observed experimentally. The structures generated under the constraints of an electrostatic potential are less compact than those subjected only to an elastic term and a hard-sphere constraint. For a fixed linking number difference greater than a critical value, the interwound structures obtained under the condition of high salt are more compact than those obtained under the condition of no added salt. In the case of no added salt, the electrostatic energy plays a dominant role over the elastic energy in dictating the shape of the closed circular DNA. The DNA supercoil opens up with increasing chain length at low salt concentration. A branched three-leaf rose structure with a fixed linking number difference is higher in energy than the interwound form at both salt concentrations employed here.

DNA, Superhelical↗

PubMed2006

Analysis of a generic model of eukaryotic cell-cycle regulation.

We propose a protein interaction network for the regulation of DNA synthesis and mitosis that emphasizes the universality of the regulatory system among eukaryotic cells. The idiosyncrasies of cell cycle regulation in particular organisms can be attributed, we claim, to specific settings of rate constants in the dynamic network of chemical reactions. The values of these rate constants are determined ultimately by the genetic makeup of an organism. To support these claims, we convert the reaction mechanism into a set of governing kinetic equations and provide parameter values (specific to budding yeast, fission yeast, frog eggs, and mammalian cells) that account for many curious features of cell cycle regulation in these organisms. Using one-parameter bifurcation diagrams, we show how overall cell growth drives progression through the cell cycle, how cell-size homeostasis can be achieved by two different strategies, and how mutations remodel bifurcation diagrams and create unusual cell-division phenotypes. The relation between gene dosage and phenotype can be summarized compactly in two-parameter bifurcation diagrams. Our approach provides a theoretical framework in which to understand both the universality and particularity of cell cycle regulation, and to construct, in modular fashion, increasingly complex models of the networks controlling cell growth and division.

Cell Cycle↗

PubMed2001

Flexibility and bioactivity of insulin: an NMR investigation of the solution structure and folding of an unusually flexible human insulin mutant with increased biological activity.

The structure and folding of a novel human insulin mutant, [Thr(B27) --> Pro, Pro(B28) --> Thr]insulin (PT insulin), in aqueous solution and in mixtures of water and 2,2,2-trifluoroethanol (TFE) have been studied by NMR spectroscopy. It was found that PT insulin has a highly flexible structure in pure water and is present in at least two different conformations, although with an overall tertiary structure similar to that of native insulin. Furthermore, the native helical structures are poorly defined. Surprisingly, the mutant has a biological activity about 50% higher than native insulin. In contrast, in TFE/water solution the mutant reveals a propensity of forming a well-defined structure at the secondary structure level, similar to monomeric native insulin. Thus, as shown by a detailed determination of the structure from 208 distance restraints and 52 torsion angle restraints by distance geometry, simulated annealing, and restrained energy minimization, the native insulin helices (A2-A7, A13-A19, and B10-B19) as well as the beta-turn (B20-B23) are formed in 35% TFE. However, the amount of tertiary structure is decreased significantly in TFE/water solution. The obtained results suggest that only an overall tertiary fold, as observed for PT insulin in pure water, is necessary for expressing the biological activity of insulin, as long as the molecule is flexible and retains the propensity to form the secondary structure required for its receptor binding. In contrast, a compact secondary structure, as found for native insulin in solution, is unnecessary for the biological activity. A model for the receptor binding of insulin is suggested that relates the increased bioactivity to the enhanced flexibility of the mutant.

Amino Acid Sequence↗

PubMed2005

Chloride transport in layered soil systems with hydraulic trap effect.

The natural and engineered hydraulic trap systems in sanitary-engineered solid waste landfills were investigated using three layer one dimensional laboratory models. The models consisted of a top reservoir containing a sodium chloride source solution, a compacted upper silt layer as a primary liner, a coarse sand layer as a secondary leachate collection system or a hydraulic control layer, a compacted lower silt layer as a secondary liner, and a bottom water reservoir as a groundwater aquifer. In the first test, the natural hydraulic trap system (upward flow through the lower silt layer) was modeled. In this case, the contaminant transport mechanisms through the upper silt layer were downward advection and diffusion, and through the lower silt layer, diffusion was downward and advection was upward. The results showed that the implementation of the natural hydraulic control system could effectively reduce chloride transport to the bottom reservoir. In the second test, the natural and engineering hydraulic trap systems were simulated (upward flow from the bottom reservoir to the upper reservoir). In the third test, the engineered hydraulic trap system (downward flow through the upper silt layer and upward flow through the lower silt layer) was modeled. The results showed that the natural and engineered hydraulic trap systems have an important effect in reducing chloride migration toward the underlying aquifer. In all experiments the chloride concentrations in the silt and coarse sand layers and top and bottom reservoirs were measured and the observed concentrations were compared with concentrations calculated by a theoretical model. A good agreement was obtained between the observed and theoretical data confirming the acceptable accuracy of the experimental methodologies, observations, and the theoretical model.

Chlorides↗

PubMed2005

Soliton compression and pulse-train generation by use of microchip Q-switched pulses in Bragg gratings.

Pulse compression and pulse-train generation are demonstrated by use of kilowatt 580 ps pulses generated by a compact (15 cm x 3 cm x 3 cm) microchip Q-switched laser followed by a fiber Bragg grating. A 12-fold pulse compression to 45 ps with five times peak power enhancement is achieved at 1.4 kW through soliton effect compression in the fiber grating. At 2.5 kW, modulational instability leads to a train of high-contrast sub-100 ps pulses. These demonstrations take advantage of the ultrastrong dispersion at frequencies close to the edge of the photonic bandgap. Experimental results are discussed in the context of the nonlinear Schrödinger equation and are compared with simulations of the nonlinear coupled-mode equations.

Journal Article↗

PubMed2002

Effects of structural rearrangements on the rheology of rennet-induced casein particle gels.

During ageing of casein or skim milk gels, structural changes take place that affect gel parameters, such as pore size and storage modulus. These changes can be explained in terms of rearrangements of the gel network at various length scales. In this paper, rheological experiments on rennet-induced casein gels and a general model on rearrangements are presented. The results of experiments (e.g. microscopy, permeametry) and computer simulations, the model, and recent literature on casein gels and other types of particle gels are compared to each other. Experiments presented include measurements of storage and loss moduli and maximum linear strain of the casein gels. Parameters varied were pH (5.3 and 6.65) and temperature (25 and 30 degrees C). In addition, the casein volume fraction (5-9 vol.%) was varied, which enables application of fractal scaling models. For rennet-induced casein gels, it is demonstrated that at the lower pH, all types of rearrangements proceed significantly faster. The rearrangements include: an increase in the size of compact building blocks; partial disappearance of fractal structure; and the formation of straightened strands, some of which eventually break. All of these rearrangements seem to be a consequence of particle fusion. There are indications of universality of the relation between particle fusion and gel syneresis for gels composed of viscoelastic particles.

Animals↗