Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “continuous space simulations”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2000

Computational flow study of the continuous flow ventricular assist device, prototype number 3 blood pump.

A computational fluid dynamics study of blood flow in the continuous flow ventricular assist device, Prototype No. 3 (CFVAD3), which consists of a 4 blade shrouded impeller fully supported in magnetic bearings, was performed. This study focused on the regions within the pump where return flow occurs to the pump inlet, and where potentially damaging shear stresses and flow stagnation might occur: the impeller blade passages and the narrow gap clearance regions between the impeller-rotor and pump housing. Two separate geometry models define the spacing between the pump housing and the impeller's hub and shroud, and a third geometry model defines the pump's impeller and curved blades. The flow fields in these regions were calculated for various operating conditions of the pump. Pump performance curves were calculated, which compare well with experimentally obtained data. For all pump operating conditions, the flow rates within the gap regions were predicted to be toward the inlet of the pump, thus recirculating a portion of the impeller flow. Two smaller gap clearance regions were numerically examined to reduce the recirculation and to improve pump efficiency. The computational and geometry models will be used in future studies of a smaller pump to determine increased pump efficiency and the risk of hemolysis due to shear stress, and to insure the washing of blood through the clearance regions to prevent thrombosis.

Computer Simulation↗
PubMed1982

Organic syntheses from CH4-N2 atmospheres: implications for Titan.

Numerous experiments have already been performed, simulating the evolution of gaseous mixtures containing CH4 when submitted to energy flux. From their results, it appears that a variety of organic compounds, including unsaturated hydrocarbons and nitriles such as HCN, can be synthesized into noticeable amounts from CH4-N2 mixtures. In particular, systematic studies of the influence of the composition of the mixture on the nature and amount of synthesized compounds show that organic volatile nitriles, and particularly cyanoacetylene and cyanogen, are formed only in media rich in nitrogen. Those nitriles have been identified very recently in the atmosphere of Titan, and thus, data from such laboratory experiments may provide important indirect information on the organic chemistry occurring at the periphery of this satellite of Saturn. However, during these experiments, there is a continuous formation and accumulation of molecular hydrogen, which does not occur in the atmosphere of Titan, because of H2 escape. In order to reassess the data already available from this type of laboratory studies, experiments on CH4-N2 atmospheres, with and without H2 escape, have been recently performed. The influence of this parameter on the chemical evolution of the atmosphere and on the nature and relative quantities of organic compounds has been studied. After reviewing these experiments, implications of the obtained results on the organic chemistry at the periphery of Titan are discussed.

Chemical Phenomena↗
PubMed2002

Computer modeling of three-dimensional structure of DNA-packaging RNA (pRNA) monomer, dimer, and hexamer of Phi29 DNA packaging motor.

A striking common feature in the maturation of all linear double-stranded DNA viruses is that their lengthy genome is translocated with remarkable velocity into the limited space within a preformed protein shell and packaged into near crystalline density. A DNA-translocating motor, powered by ATP hydrolysis, accomplishes this task, which would otherwise be energetically unfavorable. DNA-packaging RNA, pRNA, forms a hexameric complex to serve as a vital component of the DNA translocating motor of bacterial virus Phi29. The sequential action of six pRNA ensures continual function in the DNA translocation process. The Phi29 motor has been assembled with purified components synthesized by chemical or biotechnological approaches and is able to pump the viral DNA into the protein shell in vitro. pRNA dimers are the building blocks of the hexamer. The computer models of the three-dimensional structure of the motor was constructed based on experimental data derived from photoaffinity cross-linking by psoralen, phenphi (cis-Rh(1,10-phenanthroline)(9,10-phenan-threnequinone diimine)Cl(2)(+)), and azidophenacyl; chemical modification and chemical modification interference with dimethyl sulfate, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate, and kethoxal; complementary modification; and nuclease probing by single- and double-stranded specific RNases. The shapes of these computer models are very similar to the published pRNA images of cryo-atomic force microscopy. pRNA hexamer docking with the connector crystal structure reveals a very impressive match with the available biochemical, genetic, and physical data.

Bacteriophages↗
PubMed2005

Charting epilepsy by searching for intelligence in network space with the help of evolving autonomous agents.

The problem of demarcating neural network space is formidable. A simple fully connected recurrent network of five units (binary activations, synaptic weight resolution of 10) has 3.2 *10(26) possible initial states. The problem increases drastically with scaling. Here we consider three complementary approaches to help direct the exploration to distinguish epileptic from healthy networks. [1] First, we perform a gross mapping of the space of five-unit continuous recurrent networks using randomized weights and initial activations. The majority of weight patterns (>70%) were found to result in neural assemblies exhibiting periodic limit-cycle oscillatory behavior. [2] Next we examine the activation space of non-periodic networks demonstrating that the emergence of paroxysmal activity does not require changes in connectivity. [3] The next challenge is to focus the search of network space to identify networks with more complex dynamics. Here we rely on a major available indicator critical to clinical assessment but largely ignored by epilepsy modelers, namely: behavioral states. To this end, we connected the above network layout to an external robot in which interactive states were evolved. The first random generation showed a distribution in line with approach [1]. That is, the predominate phenotypes were fixed-point or oscillatory with seizure-like motor output. As evolution progressed the profile changed markedly. Within 20 generations the entire population was able to navigate a simple environment with all individuals exhibiting multiply-stable behaviors with no cases of default locked limit-cycle oscillatory motor behavior. The resultant population may thus afford us a view of the architectural principles demarcating healthy biological networks from the pathological. The approach has an advantage over other epilepsy modeling techniques in providing a way to clarify whether observed dynamics or suggested therapies are pointing to computational viability or dead space.

Action Potentials↗
PubMed2000

Continuous monitoring of change in hemodilution during water immersion in humans: effect of water temperature.

BACKGROUND: The present study was designed to examine whether water temperature during head-out immersion (HOI) modifies hemodilution dynamics. METHODS: We made continuous measurements of blood density (rho(b)) during HOI at 3 different water temperatures; the lower critical (32 degrees C), neutral (34.5 degrees C), and upper critical (36 degrees C) temperatures in 6 healthy male volunteers. Blood was withdrawn continuously from the antecubital vein for measurement of rho(b) during 60 min of water immersion with a 10-min control period before the immersion. The density was measured with the mechanical oscillator technique. Hematocrit (Hct), plasma density (rho(p)), and osmolality were measured at 5-min intervals. Erythrocyte density (rho(e)) was calculated from rho(b), rho(p) and Hct. Cardiac output and BP were measured to calculate total peripheral resistance. RESULTS: Hct, rho(b), and rho(p) decreased rapidly in the first 20-25 min of immersion and were maintained at a reduced level during immersion. Plasma volume calculated from rho(p) and Hct increased with the rho(b) reduction. These immersion-induced changes were independent of these water temperatures. Plasma osmolality and rho(e) remained constant throughout the experimental period in the three temperature conditions, indicating that the increase in plasma volume and hence hemodilution was induced by an isotonic fluid shift from extravascular space. The total peripheral resistance increased inversely in proportion to the water temperature during HOI. CONCLUSION: In the present condition, water temperature did not modify the net transcapillary fluid transfer during HOI in the presence of the temperature dependent increase in vascular tone.

Adult↗
PubMed2006

Cytoskeleton changes and impaired motility of monocytes at modelled low gravity.

Investigations performed in space have shown that gravity changes affect important cellular mechanisms like proliferation, differentiation, genetic expression, cytoskeletal architecture, and motility in lymphocytes, monocytes, and other mammalian cells. In particular, a dramatic depression of the mitogenic in vitro activation of human peripheral blood lymphocytes was observed at low gravity. The hypothesis of the present work is that a reduced interaction between T lymphocytes and monocytes, essential for the second signalling pathway, might be one of the reasons for the observed depression of the in vitro activation of human lymphocytes. Cell motility and with it a continuous rearrangement of the cytoskeletal network within the cell is essential for cell-to-cell contacts. Whereas nonactivated lymphocytes in suspension are highly motile at low gravity, no data are available so far on the motility of adherent monocytes. It thus can be argued that impaired monocyte locomotion and cytoskeletal changes could be responsible for a reduced interaction of monocytes with T lymphocytes. In this study, the locomotion ability of J-111 cells, an adherent monocyte cell line, attached to colloidal gold particles on coverslips and exposed to modelled low gravity in the random positioning machine was found to be severely reduced compared with that of controls and the structures of actin, tubulin, and vinculin were affected.

Actin Cytoskeleton↗
PubMed1999

Development of the aortic baroreflex system under conditions of microgravity.

The mechanism of autonomic regulation of the cardiovascular system develops postnatally like as various functions of the somatic system in the mammal including human. Normal development of the mechanisms is undoubtedly fundamental for maturation of individual. Therefore it is one of important problems to be urgently solved for the human life in the coming space era to understand the process of development of the regulation mechanism of the blood circulation in the growing animal in space. We have studied ontogenesis of the aortic baroreflex in the rabbit and rat to clarify the development process of the autonomic regulation of the cardiovascular system, and found the following facts. 1) Myelinated fibers of the aortic nerve which is the afferent of the reflex continue to increase in number, thickness of myelin and the diameter of axon after birth. 2) In the rabbit the increase of the number of myelinated fibers correlates lineally with the age related increase of the basal mean arterial pressure which is probably caused by in part increases of cardiac output accompanied with the growth of body. 3) Response of the integrated activity of the aortic nerve to increases in arterial pressure is smaller in the young rat and rabbit than in the mature animals. 4) Bradycardia response of the aortic baroreflex is less or slower in the young rabbit than in the mature animal. 5) The composition of the aortic nerve in both animals and bradycardia response in the rabbit become the mature type around eight weeks of age. On the basis of the background of these evidences we have investigated the effect of microgravity on the development of the aortic baroreflex system. The following is the outlines of our investigation.

Animals↗
PubMed1995

Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery.

Elevated interstitial fluid pressure (IFP) may constitute a significant physiological barrier to drug delivery in solid tumors. Strategies for overcoming this barrier have not been developed to date. To identify and characterize various mechanisms regulating IFP and to develop strategies for overcoming the IFP barrier, we modeled the tumor as a poroelastic solid. We used this model to simulate the effect of changes in microvascular pressure and tumor blood flow (TBF) on IFP. To test model predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in the center of an isolated tumor was predicted to follow variation of the arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally. Following a cessation of TBF, the time constant of the drop in IFP was predicted to be of the order of 1000 s and was found to be 1500 +/- 900 s experimentally. The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the interstitial matrix. Relying on the good agreement between theoretical predictions and experimental data, we estimated the effect of blood pressure modulation on macromolecular uptake in solid tumors. Our results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure. On the other hand, higher uptake would result from periodic modulation of blood pressure. Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.

Animals↗
PubMed1997

Estimating pesticide exposure in tidal streams of Leadenwah Creek, South Carolina.

This article estimates the potential exposure of estuarine organisms to two pesticides (azinphosmethyl and fenvalerate) in a tidal stream of Leadenwah Creek near the Edisto River, South Carolina, during four runoff episodes. Exposure is calculated from simulation runs of the one-dimensional transport equation solved by an implicit finite difference method. Calibration was done for each episode by adjusting three conditions (runoff starting time, duration, and flow) and a correction to the dispersion coefficient in order to match the continuously measured salinity transients. First-order rate constants used by the fate component were calculated from half-life values reported in the literature. Baseline scenarios for each episode and each pesticide were derived by using the same conditions obtained in the salinity runs and adjusting the pesticide loading in order to mimic the few data points of measured pesticide concentrations. In all baseline scenarios, pesticide concentration rises following the initial burst of runoff (also noticeable as an abrupt drop in salinity) and then oscillates, forced by the tidal cycle. These oscillations are dominated by transport, while fate imposes a secular decaying trend. Ten additional scenarios for each episode were obtained from the baseline scenario by randomly varying three pesticide load parameters (starting time and duration of runoff, and pesticide discharge) using a Latin hypercubes design. Two exposure metrics were calculated from the simulated and the measured pesticide concentration: maximum and time average, which was obtained by integrating the curve and dividing by the time period. The metrics calculated from the baseline runs are relatively close to the data-derived metrics, because the baseline runs attempted to mimic the data. For each one of the two metrics and all pesticide-episode combinations, several statistics of the set of 11 scenarios were also calculated: minimum and maximum, mid-range, mean, standard deviation, and median. The mean +/- standard deviation interval of the simulation-derived value consistently brackets the data-derived value for the maximum metric, but not for the time-average metric. This may indicate that even if the maximum value is correctly captured in the field sample, the time-average exposure could be in error when calculated directly from the field data due to undersampling of the pesticide time series. The methodology developed here attempts to reconstruct the possible exposure from the sparse sampling of the pesticide concentration during the runoff episodes; only when the number of field samples is high and regularly spaced is it possible to have confidence in the reconstruction of the curve. The shape of the curve cannot be inferred from the field measurements alone; as expected, tidal movement makes the pesticide concentration swing up and down. This result has important implications because the biological community would be subject to repetitive pulses of exposure to the chemicals. The baseline simulations can be used to derive a pulse-exposure metric by calculating the sum of ratios of the time average of the threshold-exceeding concentrations to the time average of the toxic threshold during intervals of above-threshold concentration. This metric is species specific and extrapolates laboratory toxicity data in order to compare pulse exposure to mortality rates measured in the field.

Azinphosmethyl↗
PubMed2003

Kinematics and the implementation of an elephant's trunk manipulator and other continuum style robots.

Traditionally, robot manipulators have been a simple arrangement of a small number of serially connected links and actuated joints. Though these manipulators prove to be very effective for many tasks, they are not without their limitations, due mainly to their lack of maneuverability or total degrees of freedom. Continuum style (i.e., continuous "back-bone") robots, on the other hand, exhibit a wide range of maneuverability, and can have a large number of degrees of freedom. The motion of continuum style robots is generated through the bending of the robot over a given section; unlike traditional robots where the motion occurs in discrete locations, i.e., joints. The motion of continuum manipulators is often compared to that of biological manipulators such as trunks and tentacles. These continuum style robots can achieve motions that could only be obtainable by a conventionally designed robot with many more degrees of freedom. In this paper we present a detailed formulation and explanation of a novel kinematic model for continuum style robots. The design, construction, and implementation of our continuum style robot called the elephant trunk manipulator is presented. Experimental results are then provided to verify the legitimacy of our model when applied to our physical manipulator. We also provide a set of obstacle avoidance experiments that help to exhibit the practical implementation of both our manipulator and our kinematic model.

Animals↗
PubMed1988

Comparative morphometry of fibers and capillaries in soleus following weightlessness (SL-3) and suspension.

This work is a continuation of efforts to assess responses of rat skeletal muscle to weightlessness and earthside laboratory experiments with unloading of hind limbs. The soleus is a slow twitch, load bearing (antigravity) muscle. Both exposure to weightlessness (W) and to the hypokinesia/hypodynamia of whole body suspension (WBS) results in soleus atrophy. Cross sectional areas of both slow and fast twitch fibers decrease during 7 days of W, and 7 or 14 days of WBS. Density and area changes tended to reverse to control levels during 7 days of recovery (R) following WBS. Capillary density was increased with 7 days of W, and 7 or 14 days of WBS. During 7 days of R the capillary density returned toward control levels. In summary, the reduction in fiber cross sectional areas and increase in fiber and capillary densities support the hypothesis that in both forms of disuse, i.e., W and WBS, there is a loss in soleus muscle cell mass and not in fiber numbers.

Animals↗
PubMed2003

Use of cardiac electric near-field measurements to determine activation times.

In a recent paper, we described the behavior of the cardiac electric near-field, E, parallel to the tissue surface during continuous conduction. We found that T(E), the time at which the peak near-field, E, occurs, is an accurate marker of local activation time. Examination of experimentally recorded E vector loops revealed a large variety of morphologies. We postulated that propagation around an obstacle could lead to the observed deviations in loop morphology. The purpose of this study was to determine if this was plausible, and if so, whether T(E) remains an accurate time marker of local activation under these conditions. We used a monodomain computer model of a sheet of cardiac tissue with a central conduction obstacle immersed in an unbounded volume conductor. Activation times T(Im), T(phi), and T(E) were derived from the transmembrane current I(m), the extracellular potential phi(e), and E, respectively. The obstacle led to deformations of the vector loops, morphologically similar to those observed experimentally, particularly during the initial and terminal phases, and to a lesser degree near the time of E. Despite these loop deformations, T(E) was an accurate time marker of local activation. We found that T(E) was significantly closer to T(Im) than T(phi). We concluded that isochrone maps computed from T(E) better reflect intracellular activation patterns than those computed from T(phi). For a given electrode spacing of 60 microm, the sensitivity to noise of E was significantly less than that of phi(e). Hence, T(E) was less affected by noise than T(phi).

Animals↗
PubMedDate not supplied

A continuous attractor network model without recurrent excitation: maintenance and integration in the head direction cell system.

Motivated by experimental observations of the head direction system, we study a three population network model that operates as a continuous attractor network. This network is able to store in a short-term memory an angular variable (the head direction) as a spatial profile of activity across neurons in the absence of selective external inputs, and to accurately update this variable on the basis of angular velocity inputs. The network is composed of one excitatory population and two inhibitory populations, with inter-connections between populations but no connections within the neurons of a same population. In particular, there are no excitatory-to-excitatory connections. Angular velocity signals are represented as inputs in one inhibitory population (clockwise turns) or the other (counterclockwise turns). The system is studied using a combination of analytical and numerical methods. Analysis of a simplified model composed of threshold-linear neurons gives the conditions on the connectivity for (i) the emergence of the spatially selective profile, (ii) reliable integration of angular velocity inputs, and (iii) the range of angular velocities that can be accurately integrated by the model. Numerical simulations allow us to study the proposed scenario in a large network of spiking neurons and compare their dynamics with that of head direction cells recorded in the rat limbic system. In particular, we show that the directional representation encoded by the attractor network can be rapidly updated by external cues, consistent with the very short update latencies observed experimentally by Zugaro et al. (2003) in thalamic head direction cells.

Action Potentials↗
PubMed2003

Top-level modeling of an ALS system utilizing object-oriented techniques.

The possible configuration of an Advanced Life Support (ALS) System capable of supporting human life for long-term space missions continues to evolve as researchers investigate potential technologies and configurations. To facilitate the decision process the development of acceptable, flexible, and dynamic mathematical computer modeling tools capable of system level analysis is desirable. Object-oriented techniques have been adopted to develop a dynamic top-level model of an ALS system. This approach has several advantages; among these, object-oriented abstractions of systems are inherently modular in architecture. Thus, models can initially be somewhat simplistic, while allowing for adjustments and improvements. In addition, by coding the model in Java, the model can be implemented via the World Wide Web, greatly encouraging the utilization of the model. Systems analysis is further enabled with the utilization of a readily available backend database containing information supporting the model. The subsystem models of the ALS system model include Crew, Biomass Production, Waste Processing and Resource Recovery, Food Processing and Nutrition, and the Interconnecting Space. Each subsystem model and an overall model have been developed. Presented here is the procedure utilized to develop the modeling tool, the vision of the modeling tool, and the current focus for each of the subsystem models.

Astronauts↗
PubMedDate not supplied

Real-time continuous measurement of right ventricular volume using a conductance catheter.

The authors propose using a multi-electrode conductance catheter to measure continuous right ventricular volume. True ventricular volume measurements are affected by four main sources of error. 1) field non-uniformity, 2) catheter curvature, 3) blood conductivity changes, and 4) leakage of current through surrounding tissues. Three-dimensional finite-element models were developed to investigate the effects of these sources of error and to devise schemes for correcting them. The models include an axisymmetric cylindrical model, a rectangular block model, and a heart model with left and right ventricular chambers. The heart model is built from conical primitives, with major dimensions derived from the literature. Finite-element simulations showed that volume measurements were underestimated due to field nonuniformity to as much as 1/25th actual volume in segments near the exciting electrodes. The extent of underestimation in a segment decreased with increasing distance of the segment from the exciting electrodes and increased for larger segmental volumes. Catheter curvature overestimated measured volume by as much as 4.5 times when the curvature was increased from 0.0 to 1.25 (from a straight catheter to a very curved one). The leakage of current through surrounding tissues overestimated volume by nearly 30%. The sensitivity of volume measurement to blood resistivity changes was found to be very high, at 70%. Correction factors established with the computer models compensate for field nonuniformity. Mathematical mapping of the curved catheter onto a fictitious straight catheter corrects for the catheter curvature error. Correction for both nonuniform field and catheter curvature allowed measurement of total ventricular volume with an error of 7%. Leakage current is determined by using different frequencies to build the catheter electric field and to separate tissue and blood resistance paths. Using this scheme, the percentage overestimation in volume measurement due to leakage could be determined with an accuracy of 85%. The proposed correction scheme for blood conductivity changes involves the in-vivo measurement of blood conductivity with the catheter itself. It was found that blood conductivity could be determined with insignificant error (< 0.5%) so long as the blood volume around the exciting electrodes had a radius of more than the electrode spacing.

Animals↗
PubMed2004

Modeling neuromuscular modulation in Aplysia. III. Interaction of central motor commands and peripheral modulatory state for optimal behavior.

Recent work in computational neuroethology has emphasized that "the brain has a body": successful adaptive behavior is not simply commanded by the nervous system, but emerges from interactions of nervous system, body, and environment. Here we continue our study of these issues in the accessory radula closer (ARC) neuromuscular system of Aplysia. The ARC muscle participates in the animal's feeding behaviors, a set of cyclical, rhythmic behaviors driven by a central pattern generator (CPG). Patterned firing of the ARC muscle's two motor neurons, B15 and B16, releases not only ACh to elicit the muscle's contractions but also peptide neuromodulators that then shape the contractions through a complex network of actions on the muscle. These actions are dynamically complex: some are fast, but some are slow, so that they are temporally uncoupled from the motor neuron firing pattern in the current cycle. Under these circumstances, how can the nervous system, through just the narrow channel of the firing patterns of the motor neurons, control the contractions, movements, and behavior in the periphery? In two earlier papers, we developed a realistic mathematical model of the B15/B16-ARC neuromuscular system and its modulation. Here we use this model to study the functional performance of the system in a realistic behavioral task. We run the model with two kinds of inputs: a simple set of regular motor neuron firing patterns that allows us to examine the entire space of patterns, and the real firing patterns of B15 and B16 previously recorded in a 2 1/2-h-long meal of 749 cycles in an intact feeding animal. These real patterns are extremely irregular. Our main conclusions are the following. 1) The modulation in the periphery is necessary for superior functional performance. 2) The components of the modulatory network interact in nonlinear, context- and task-dependent combinations for best performance overall, although not necessarily in any particular cycle. 3) Both the fast and the slow dynamics of the modulatory state make important contributions. 4) The nervous system controls different components of the periphery to different degrees. To some extent the periphery operates semiautonomously. However, the structure of the peripheral modulatory network ensures robust performance under all circumstances, even with the irregular motor neuron firing patterns and even when the parameters of the functional task are randomly varied from cycle to cycle to simulate a variable feeding environment. In the variable environment, regular firing patterns, which are fine-tuned to one particular task, fail to provide robust performance. We propose that the CPG generates the irregular firing patterns, which nevertheless are guaranteed to give robust performance overall through the actions of the peripheral modulatory network, as part of a trial-and-error feeding strategy in a variable, uncertain environment.

Action Potentials↗
PubMedDate not supplied

Effect of slow-release sodium fluoride on cancellous bone histology and connectivity in osteoporosis.

We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 +/- 0.176 g/cm2 SD to 0.872 +/- 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 +/- 0.4 microns/d to 1.1 +/- 0.7, p = 0.0078) and adjusted apposition rate (0.4 +/- 0.3 microns/d to 0.6 +/- 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 +/- 878 microns to 1052 +/- 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm2 of cancellous tissue area (0.22 +/- 0.12 vs. 0.39 +/- 0.27, p = 0.0077), the mean node to free-end ratio (0.23 +/- 0.21 vs. 0.41 +/- 0.46, p < 0.05), and in the mean node to node strut length per mm2 of cancellous area (0.098 +/- 0.101 vs. 0.212 +/- 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1991

The molecular structure of wild-type and a mutant Fis protein: relationship between mutational changes and recombinational enhancer function or DNA binding.

The 98-amino acid Fis protein from Escherichia coli functions in a variety of reactions, including promotion of Hin-mediated site-specific DNA inversion when bound to an enhancer sequence. It is unique among site-specific DNA-binding proteins in that it binds to a large number of different DNA sequences, for which a consensus sequence is difficult to establish. X-ray crystal structure analyses have been carried out at 2.3 A resolution for wild-type Fis and for an Arg-89----Cys mutant that does not stimulate DNA inversion. Each monomer of the Fis dimer has four alpha-helices, A-D; the first 19 residues are disordered in the crystal. The end of each C helix is hydrogen bonded to the beginning of helix B' from the opposite subunit in what effectively is one long continuous, although bent, helix. The four helices, C, B', C', and B, together define a platform through the center of the Fis molecule: helices A and A' are believed to be involved with Hin recombinase on one side, and helices D and D' interact with DNA lying on the other side of the platform. Helices C and D of each subunit comprise a helix-turn-helix (HTH) DNA-binding element. The spacing of these two HTH elements in the dimer, 25 A, is too short to allow insertion into adjacent major grooves of a straight B-DNA helix. However, bending the DNA at discrete points, to an overall radius of curvature of 62 A, allows efficient docking of a B-DNA helix with the Fis molecule. The proposed complex explains the experimentally observed patterns of methylation protection and DNase I cleavage hypersensitivity. The x-ray structure accounts for the effects of mutations in the Fis sequence. Those that affect DNA inversion but not DNA binding are located within the N-terminal disordered region and helix A. This inversion activation domain is physically separated in the Fis molecule from the HTH elements and may specify a region of contact with the Hin recombinase. In contrast, mutations that affect HTH helices C and D, or interactions of these with helix B, have the additional effect of decreasing or eliminating binding to DNA.

Amino Acid Sequence↗