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PubMed1984

[Statistical weights of conformers of thyroliberin molecule and the averaging of its calculated structural characteristics].

A statistical ensemble of thyroliberin conformations has been generated using Monte-Carlo techniques. The averaged vicinal coupling constants for the peptide backbone and His side chain, percentage of prolyl cis-isomers and characteristics of possible intramolecular hydrogen bonds have been calculated. The obtained mean values are in good agreement with the experimental results. This fact indicates that the generated statistical ensemble is similar to the true one and evidences against the existence in solution of a single unique structure of thyroliberin.

Monte Carlo Method↗
PubMedDate not supplied

Condition monitoring of rotary blood pumps.

Long-term, trouble-free operation of ventricular assist devices (VADs) is critical to the patient. A catastrophic failure of the VAD could cost the patient's life, thus defeating the purpose of the device. The targeted 90% 5 year reliability also implies that the average device life would exceed the 5 year limit. Time based explantation of the device after the fifth year will replace many devices with significant additional life, subject the patient to unnecessary surgical risk, and increase costs. To preclude the need for time based replacements and prevent catastrophic failures, a condition monitor is proposed in this article for early detection of faults in VADs. To develop this monitor, the effectiveness of various sensing and monitoring methods for determining the VAD condition is investigated. A Hemadyne pump was instrumented with a set of eight sensors, and a series of experiments were performed to record and analyze signals from the normal and abnormal pumps with five different faults. Statistical, spectral, envelope, and ensemble averaging analyses were performed to characterize changes in sensor signals due to faults. Experimental results indicate that statistical and frequency information from the acceleration and dynamic pressure signals can clearly detect and identify various VAD faults.

Biomedical Engineering↗
PubMed1991

A new method for building protein conformations from sequence alignments with homologues of known structure.

We describe a largely automatic procedure for building protein structures from sequence alignments with homologues of known structure. This procedure uses simple rules by which multiple sequence alignments can be translated into distance and chirality constraints, which are then used as input for distance geometry calculations. By this means one obtains an ensemble of conformations for the unknown structure that are compatible with the rules employed, and the differences among these conformations provide an indication of the reliability of the structure prediction. The overall approach is demonstrated here by applying it to several Kazal-type trypsin inhibitors, for which experimentally determined structures are available. On the basis of our experience with these test problems, we have further predicted the conformation of the human pancreatic secretory trypsin inhibitor, for which no experimentally determined structure is presently available.

Algorithms↗
PubMed2006

Toward a rational design of beta-peptide structures.

Intrinsic conformational characteristics of beta-peptides built up from simple achiral and chiral beta-amino acid residues (i.e., HCO-beta-Ala-NH2, HCO-beta-Abu-NH2) were studied using quantum chemical calculations and 1H-NMR spectroscopy. A conformer-based systematic and uniform nomenclature was introduced to differentiate conformers. Geometry optimizations were performed on all homoconformers of both HCO-(beta-Ala)(k)-NH2 and HCO-(beta-Abu)(k)-NH2 (1 < or = k < or = 6) model systems at the RHF/3-21G and RHF/6-311++G(d, p) levels of theory. To test for accuracy and precision, additional computations were carried out at several levels of theory [e.g., RHF/6-31G(d), and B3LYP/6-311++G(d, p)]. To display the folding preference, the relative stability of selected conformers as function of the length of the polypeptide chain was determined. Ab initio population distribution of hexapeptides and the conformational ensemble of synthetic models composed of beta-Ala and beta-Abu studied using 1H-NMR in different solvents were compared at a range of temperatures. Helical preference induced by various steric effects of nonpolar side chains was tested using higher level ab initio methods for well-known model systems such as: HCO-(beta-HVal-beta-HAla-beta-HLeu)2-NH2, HCO-(ACHC)6-NH2, HCO-(trans-ACPC)6-NH2, and HCO-(cis-ACPC)6-NH2. The relative stabilities determined by theoretical methods agreed well with most experimental data, supporting the theory that the local conformational preference influenced by steric effects is a key determining factor of the global fold both in solution and in the gas phase.

Magnetic Resonance Spectroscopy↗
PubMed2004

Thermal conductivity of molten alkali halides from equilibrium molecular dynamics simulations.

The thermal conductivity of molten sodium chloride and potassium chloride has been computed through equilibrium molecular dynamics Green-Kubo simulations in the microcanonical ensemble (N,V,E). In order to access the temperature dependence of the thermal conductivity coefficient of these materials, the simulations were performed at five different state points. The form of the microscopic energy flux for ionic systems whose Coulombic interactions are calculated through the Ewald method is discussed in detail and an efficient formula is used by analogy with the methods used to evaluate the stress tensor in Coulombic systems. The results show that the Born-Mayer-Huggins-Tosi-Fumi potential predicts a weak negative temperature dependence for the thermal conductivity of NaCl and KCl. The simulation results are in agreement with part of the experimental data available in the literature with simulation values generally overpredicting the thermal conductivity by 10%-20%.

Journal Article↗
PubMed2004

Single-molecule and transient kinetics investigation of the interaction of dihydrofolate reductase with NADPH and dihydrofolate.

The interaction of dihydrofolate (H(2)F) and NADPH with a fluorescent derivative of H(2)F reductase (DHFR) was studied by using transient and single-molecule techniques. The fluorescent moiety Alexa 488 was attached to the structural loop that closes over the substrates after they are bound. Fluorescence quenching was found to accompany the binding of both substrates and the hydride transfer reaction. For the binding of H(2)F to DHFR, the simplest mechanism consistent with the data postulates that the enzyme exists as slowly interconverting conformers, with the substrate binding preferentially to one of the conformers. At pH 7.0, the binding reaction has a bimolecular rate constant of 1.8 x 10(7) M(-1).s(-1), and the formation of the initial complex is followed by a conformational change. The binding of NADPH to DHFR is more complex and suggests multiple conformers of the enzyme exist. NADPH binds to a different conformer than H(2)F with a bimolecular rate constant of 2.6-5.7 x 10(6) M(-1).s(-1), with the former value obtained from single-molecule kinetics and the latter from stopped-flow kinetics. Single-molecule studies of DHFR in equilibrium with substrates and products revealed a reaction with ensemble average rate constants of 170 and 470 s(-1) at pH 8.5. The former rate constant has an isotope effect of >2 when NADPD is substituted for NADPH and probably is associated with hydride transfer. The results from stopped-flow and single-molecule methods are complementary and demonstrate that multiple conformations of both the enzyme and enzyme-substrate complexes exist.

Escherichia coli↗
PubMed1984

Patch and whole cell calcium currents recorded simultaneously in snail neurons.

The flow of Ca ions through single Ca channels has been examined. The gigaseal method was used on identifiable snail neurons that were voltage clamped using a two-microelectrode voltage clamp method. Average Ca patch currents and whole cell currents have similar time courses. They are affected similarly by changes in temperature. The differences in amplitude and inactivation between Ba and Ca whole cell currents were present in the patch records. The stationary noise spectra recorded from ensembles of multichannel patches have two components with fast and slow time constants equivalent to two components in the whole cell tail current relaxations. Elementary current amplitudes measured from the variance-mean relationship and from noise spectra gave values comparable to measurements from single channels. The single channel I-V relationship was curvilinear and the maximum slope conductance in 40 mM Cao was 7 pS. The amplitude of unitary currents was unchanged at long times when inactivation had occurred; hence depletion is not involved in this process. Channel density was approximately 3 microns-2 and was the same for Ba and Ca currents. The whole cell asymmetry currents gave very large values for the gating charge per channel. Changes in temperature from 29 to 9 degrees C had only a slight effect on the two Ca tail current tau's at potentials where turn-on of patch and whole cell currents was markedly slowed and the peak amplitudes were reduced by one-third. Single channel recordings were obtained at these two temperatures, and the mean open time and the fast component of the closed times were scarcely affected. Unit amplitudes were reduced by 30% and the slow closed time component was doubled. Therefore, peak currents and the slow closed time component was doubled. Therefore, peak currents were reduced partly as a result of the reduction in unit amplitude, but mainly as a result of a reduction in opening probability, the latter arising from an increase of the long closed times. It is concluded that the behavior of single Ca channels in membrane patches is the same as it is in whole cells. Cooling from 29 to 9 degrees C acts primarily on transitions among closed states and has little effect on the open to closed transition.

Animals↗
PubMed2006

Theoretical study of penalized-likelihood image reconstruction for region of interest quantification.

Region of interest (ROI) quantification is an important task in emission tomography (e.g., positron emission tomography and single photon emission computed tomography). It is essential for exploring clinical factors such as tumor activity, growth rate, and the efficacy of therapeutic interventions. Statistical image reconstruction methods based on the penalized maximum-likelihood (PML) or maximum a posteriori principle have been developed for emission tomography to deal with the low signal-to-noise ratio of the emission data. Similar to the filter cut-off frequency in the filtered backprojection method, the regularization parameter in PML reconstruction controls the resolution and noise tradeoff and, hence, affects ROI quantification. In this paper, we theoretically analyze the performance of ROI quantification in PML reconstructions. Building on previous work, we derive simplified theoretical expressions for the bias, variance, and ensemble mean-squared-error (EMSE) of the estimated total activity in an ROI that is surrounded by a uniform background. When the mean and covariance matrix of the activity inside the ROI are known, the theoretical expressions are readily computable and allow for fast evaluation of image quality for ROI quantification with different regularization parameters. The optimum regularization parameter can then be selected to minimize the EMSE. Computer simulations are conducted for small ROIs with variable uniform uptake. The results show that the theoretical predictions match the Monte Carlo results reasonably well.

Algorithms↗
PubMed1993

A model of auditory pattern analysis based on component-relative-entropy.

Recently results from detection and information theory have been used to predict performance of human observers in experiments involving the discriminability of changes in individual components of unfamiliar or uncertain tone patterns [R. A. Lutfi, J. Acoust. Soc. Am. 91, 3391-3401 (1992)]. In this paper, the theoretical analysis is expanded to yield a general rule of pattern analysis that accounts for nearly all of the major results of such experiments conducted over the last 18 years. The rule can be stated as follows: Component discriminability in an unfamiliar tone pattern (profile or sequence) is a linearly increasing function of the component's relative entropy (CoRE) in the pattern. Ancillary: The threshold for detection of a change decreases by one order of magnitude (factor of 10) for each one bit increase in CoRE. This precise relation of threshold to CoRE is demonstrated repeatedly in a review of past studies, and is shown to account for the relative effects of a variety of important variables and their interactions. Such variables include the total duration of the pattern; the number of tones in the pattern; the number of tones subject to change; the relative level and duration of individual tones in the pattern; the relative variability and the physical dimension of the tones' parameters that are subject to change; the number and position of targets in the pattern; the psychophysical procedure used (method of adjustment versus same-different), the type of discrimination task (frequency versus intensity discrimination), and the manner of presentation of the tones (simultaneous or sequential). The CoRE rule seems to reflect a general property of auditory analysis wherein the perception of patterns in an ensemble is dominated by those features that dominate the variance of the ensemble.

Auditory Perception↗
PubMed2004

Noise assessment of a Fourier transform infrared spectroradiometer subject to the stability of a conventional laboratory blackbody source.

A method is described for the measurement of the noise-equivalent spectral radiance (NESR) of Fourier transform infrared (FTIR) spectroradiometers at all wave numbers of a selected range. The method requires minimal detailed knowledge of the sensor and no support equipment beyond a blackbody source. The NESRs of the FTIR spectroradiometer are determined at every wave-number increment in the 700-1300 cm(-1) range, for six resolutions, with a conventional blackbody source and ensembles of differential spectra. The NESRs are well behaved and consistent with the expected dependence on resolution; however, they depend on source temperature at the highest (1 cm(-1)) and lowest (32 cm(-1)) resolutions, with little or no statistical dependence at intermediate resolutions. Residual source drift is shown to be the likely cause of the dependence at 1 cm(-1); the dependence on the source at 32 cm(-1) resolution is shown to be most probably due to photon noise. At intermediate resolutions the sensor noise is dominant.

Journal Article↗
PubMed2006

Optimization of a stochastically simulated gene network model via simulated annealing.

By rearranging naturally occurring genetic components, gene networks can be created that display novel functions. When designing these networks, the kinetic parameters describing DNA/protein binding are of great importance, as these parameters strongly influence the behavior of the resulting gene network. This article presents an optimization method based on simulated annealing to locate combinations of kinetic parameters that produce a desired behavior in a genetic network. Since gene expression is an inherently stochastic process, the simulation component of simulated annealing optimization is conducted using an accurate multiscale simulation algorithm to calculate an ensemble of network trajectories at each iteration of the simulated annealing algorithm. Using the three-gene repressilator of Elowitz and Leibler as an example, we show that gene network optimizations can be conducted using a mechanistically realistic model integrated stochastically. The repressilator is optimized to give oscillations of an arbitrary specified period. These optimized designs may then provide a starting-point for the selection of genetic components needed to realize an in vivo system.

Algorithms↗
PubMed2000

The paradigms of causality and treatment for autoimmune disease.

A key concept in medicine is that rational therapy rests on accurate diagnosis; quite simply, therapy that is not tuned to the cause of the disease will not cure the patient. This does not mean that effective treatments cannot emerge from faulty diagnoses. In truth, much of our therapeutic ensemble is composed of drugs developed as a result of chance observation, random screening, intuition or prescientific tradition. Nevertheless, the way to effective therapy is best paved by understanding. Effects are inherent in their causes, so if we want to cure autoimmune diseases using the scientific method, we are obliged to inquire into their causes. By reducing the discordant complexity of the disease to the single cause that underlies it, we can hope to learn the most efficient way to manipulate the disease process. How do we identify a cause when we see one? Quite simply, a single cause is that which is both necessary and sufficient to produce the effect. Here, I explore the general paradigm of autoimmune causality, using multiple sclerosis as a specific example.

Autoimmune Diseases↗
PubMed1994

Synchrony detection in neural assemblies.

The identification of synchronously active neural assemblies in simultaneous recordings of neuron activities is an important research issue and a difficult algorithmic problem. A gravitational analysis method has been developed to detect and identify groups of neurons that tend to generate action potentials in near-synchrony from among a larger population of simultaneously recorded units. In this paper, an improved algorithm is used for the gravitational clustering method and its performance is characterized. Whereas the original algorithm ran in n3 time (n = the number of neurons), the new algorithm runs in n2 time. Neurons are represented as particles in n-space that 'gravitate' towards one another whenever near-synchronous electrical activity occurs. Ensembles of neurons that tend to fire together then become clustered together. The gravitational technique not only identifies the synchronous groups present but also shows graphically the changing activity patterns and changing synchronies.

Action Potentials↗
PubMed2006

Activated hopping and dynamical fluctuation effects in hard sphere suspensions and fluids.

Single particle Brownian dynamics simulation methods are employed to establish the full trajectory level predictions of our nonlinear stochastic Langevin equation theory of activated hopping dynamics in glassy hard sphere suspensions and fluids. The consequences of thermal noise driven mobility fluctuations associated with the barrier hopping process are determined for various ensemble-averaged properties and their distributions. The predicted mean square displacements show classic signatures of transient trapping and anomalous diffusion on intermediate time and length scales. A crossover to a stronger volume fraction dependence of the apparent nondiffusive exponent occurs when the entropic barrier is of order the thermal energy. The volume fraction dependences of various mean relaxation times and rates can be fitted by empirical critical power laws with parameters consistent with ideal mode-coupling theory. However, the results of our divergence-free theory are largely a consequence of activated dynamics. The experimentally measurable alpha relaxation time is found to be very similar to the theoretically defined mean reaction time for escape from the barrier-dominated regime. Various measures of decoupling have been studied. For fluid states with small or nonexistent barriers, relaxation times obey a simple log-normal distribution, while for high volume fractions the relaxation time distributions become Poissonian. The product of the self-diffusion constant and mean alpha relaxation time increases roughly as a logarithmic function of the alpha relaxation time. The cage scale incoherent dynamic structure factor exhibits nonexponential decay with a modest degree of stretching. A nearly universal collapse of the different volume fraction results occurs if time is scaled by the mean alpha relaxation time. Hence, time-volume fraction superposition holds quite well, despite the presence of stretching and volume fraction dependent decoupling associated with the stochastic barrier hopping process. The relevance of other origins of dynamic heterogeneity (e.g., mesoscopic domains), and comparison of our results with experiments, simulations, and alternative theories, is discussed.

Journal Article↗
PubMed2000

A thermodynamic coupling mechanism for the disaggregation of a model peptide substrate by chaperone secB.

Molecular chaperones prevent protein aggregation in vivo and in vitro. In a few cases, multichaperone systems are capable of dissociating aggregated state(s) of substrate proteins, although little is known of the mechanism of the process. SecB is a cytosolic chaperone, which forms part of the precursor protein translocation machinery in Escherichia coli. We have investigated the interaction of the B-chain of insulin with chaperone SecB by light scattering, pyrene excimer fluorescence, and electron spin resonance spectroscopy. We show that SecB prevents aggregation of the B-chain of insulin. We show that SecB is capable of dissociating soluble B-chain aggregates as monitored by pyrene fluorescence spectroscopy. The kinetics of dissociation of the B-chain aggregate by SecB has been investigated to understand the mechanism of dissociation. The data suggests that SecB does not act as a catalyst in dissociation of the aggregate to individual B-chains, rather it binds the small population of free B-chains with high affinity, thereby shifting the equilibrium from the ensemble of the aggregate toward the individual B-chains. Thus SecB can rescue aggregated, partially folded/misfolded states of target proteins by a thermodynamic coupling mechanism when the free energy of binding to SecB is greater than the stability of the aggregate. Pyrene excimer fluorescence and ESR methods have been used to gain insights on the bound state conformation of the B-chain to chaperone SecB. The data suggests that the B-chain is bound to SecB in a flexible extended state in a hydrophobic cleft on SecB and that the binding site accommodates approximately 10 residues of substrate.

Bacterial Proteins↗
PubMed2006

Isoprenaline enhances local Ca2+ release in cardiac myocytes.

AIM: Contraction of cardiac myocytes is controlled by the generation and amplification of intracellular Ca2+ signals. The key step of this process is the coupling between sarcolemma L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). Beta-adrenergic stimulation is an important regulatory mechanism for this coupling process. But the details underlied the global level, which require local Ca2+ release study are still unclear. The present study is to explore the effects of beta-adrenergic stimulation on local Ca2+ release. METHODS: Using confocal microscopy combined with loose-seal patch-clamp approaches, effects of isoprenaline (1 micromol/L), a beta-adrenergic agonist, on local SR Ca2+ release triggered by Ca2+ influx through LCCs in intact rat cardiac myocytes were investigated. RESULTS: Isoprenaline increased the intensity of ensemble averaged local Ca2+ transients, the peak of which displayed a typical bell-shaped voltage-dependence over the membrane voltages ranging from approximately -40 mV to approximately +35 mV. Further analysis showed that this enhancement could be explained by the increased coupling fidelity (which refers the increased probability of RyRs activation upon depolarization), and the increased amplitude of evoked Ca2+ sparks [due to more Ca2+ releases through local RyRs]. In addition, isoprenaline decreased the first latency, which displayed a typical 'U ' shaped voltage-dependence, showing the available acceleration and synchronization of beta-adrenergic stimulation on intracellular calcium release. CONCLUSIONS: Isoprenaline enhances local Ca2+ release in cardiac myocytes. These results underscore the importance of regulation of beta-adrenergic stimulation on local intermolecular signals between LCCs and RyRs in heart cells.

Adrenergic beta-Agonists↗
PubMed2005

Finite volume analysis of temperature effects induced by active MRI implants with cylindrical symmetry: 1. Properly working devices.

BACKGROUND: Active Magnetic Resonance Imaging implants are constructed as resonators tuned to the Larmor frequency of a magnetic resonance system with a specific field strength. The resonating circuit may be embedded into or added to the normal metallic implant structure. The resonators build inductively coupled wireless transmit and receive coils and can amplify the signal, normally decreased by eddy currents, inside metallic structures without affecting the rest of the spin ensemble. During magnetic resonance imaging the resonators generate heat, which is additional to the usual one described by the specific absorption rate. This induces temperature increases of the tissue around the circuit paths and inside the lumen of an active implant and may negatively influence patient safety. METHODS: This investigation provides an overview of the supplementary power absorbed by active implants with a cylindrical geometry, corresponding to vessel implants such as stents, stent grafts or vena cava filters. The knowledge of the overall absorbed power is used in a finite volume analysis to estimate temperature maps around different implant structures inside homogeneous tissue under worst-case assumptions. The "worst-case scenario" assumes thermal heat conduction without blood perfusion inside the tissue around the implant and mostly without any cooling due to blood flow inside vessels. RESULTS: The additional power loss of a resonator is proportional to the volume and the quality factor, as well as the field strength of the MRI system and the specific absorption rate of the applied sequence. For properly working devices the finite volume analysis showed only tolerable heating during MRI investigations in most cases. Only resonators transforming a few hundred mW into heat may reach temperature increases over 5 K. This requires resonators with volumes of several ten cubic centimeters, short inductor circuit paths with only a few 10 cm and a quality factor above ten. Using MR sequences, for which the MRI system manufacturer declares the highest specific absorption rate of 4 W/kg, vascular implants with a realistic construction, size and quality factor do not show temperature increases over a critical value of 5 K. CONCLUSION: The results show dangerous heating for the assumed "worst-case scenario" only for constructions not acceptable for vascular implants. Realistic devices are safe with respect to temperature increases. However, this investigation discusses only properly working devices. Ruptures or partial ruptures of the wires carrying the electric current of the resonance circuits or other defects can set up a power source inside an extremely small volume. The temperature maps around such possible "hot spots" should be analyzed in an additional investigation.

Body Temperature↗
PubMed2005

Spectral phase based medical image processing.

RATIONALE AND OBJECTIVES: To exploit the spectral phase characteristics of digital or digitized mammograms for early detection of microcalcifications, shape, and sizes of suspected lesions and to demonstrate its use for training radiologists to discriminate signal features in different spatially varying backgrounds. MATERIALS AND METHODS: We propose two algorithms: in the phase-only image (POI) reconstruction algorithm the spectral phase of the digital mammogram is extracted from its Fourier spectrum. This is coupled with unit magnitude and inverse Fourier transformed to reconstruct the POI thus enhancing the features of interest such as microcalcifications, shape, and sizes of suspected lesions. In the algorithm for image reconstruction from a priori phase-only information, spectral phase is used to extract signal features of the digital mammogram and then this is combined with spectral magnitude that is extracted and averaged over an ensemble of unrelated digital mammograms. RESULTS: The results for several digital phantoms and mammograms show that POI reconstructs only high spatial frequencies related to the features such as microcalcifications, shape, and size of masses like cysts and tumors. The results on image reconstruction from a priori phase-only information demonstrate the changes in the visibility of signal features when buried in a wide variety of real world mammogram backgrounds with different densities. CONCLUSION: The POI can aid radiologists in early detection of microcalcifications, lesions, and other masses of interest in digital mammograms. This reconstruction method is self-adaptive to changes in the background. The image reconstruction from a priori phase-only information can help the radiologist as a training tool in his decision-making process. Preliminary experiments indicate the potential of the techniques for early diagnosis of breast cancer. Clinical studies on these algorithm procedures are in progress for application as a diagnostic CAD tool in digital mammography. These methods can in general be applied to other medical images such as CT and MRI images.

Algorithms↗