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PubMed2000

Uniformity, specificity and variability of corticocortical connectivity.

In many studies of the mammalian brain, subjective assessments of connectivity patterns and connection strengths have been used to subdivide the cortex into separate but linked areas and to make deductions about the flow of information through the cortical network. Here we describe the results of applying statistical analyses to quantitative corticocortical connection data, and the conclusions that can be drawn from such quantitative approaches. Injections of the tracer WGA-HRP were made into different visual areas either side of the middle suprasylvian sulcus (MSS) in 11 adult cats. Retrogradely labelled cells produced by these injections were counted in selected coronal sections taken at regularly spaced intervals (1 mm) through the entire visual cortex, and their cumulative sums and relative proportions in each of 16 recognized visual cortical areas were computed. The surface dimensions of these areas were measured in each cat, from contour lines made on enlarged drawings of the same sections. A total of 116,149 labelled neurons were assigned to all visual cortical areas in the 11 cats, with 5212 others excluded because of their uncertain location. The distribution of relative connection strengths, that is, the percentage of labelled cells per cortical area, was evaluated using non-parametric cluster analyses and Monte Carlo simulation, and relationships between connection strength and area size were examined by linear regression. The absolute size of each visual cortical area was uniform across individual cats, whereas the strengths of connections between the same area pairs were extremely variable for injections in different animals. The overall distribution of labelling strengths for corticocortical connections was continuous and monotonic, rather than inherently clustered, with the highest frequencies presented by the absent (zero density) and the very-low-density connections. These two categories could not, on analytical grounds, be separated from each other. Thus it seems that any subjective description of corticocortical connectivity strengths by ordinal classes (such as 'absent', 'weak', 'moderate' or 'strong') imposes a categorization on the data, rather than recognizes a structure inherent in the data themselves. Despite the great variability of connections, similarities in the distribution profiles for the relative strengths of labelled cells in all areas could be used to identify clusters of different injection sites in the MSS. This supported the conclusion that there are four connectionally distinct subdivisions of this cortex, corresponding to areas 21a, PMLS and AMLS (in the medial bank) and to area PLLS (in the lateral bank). Even for tracer deposits in the same cortical subdivision, however, the strength of connections projecting to the site from other cortical areas varied greatly across injection in different individual animals. We further demonstrated that, on average, the strength of connections originating from any given cortical area was positively and linearly correlated with the size of its surface dimensions. When analysed by specific injection site location, however, this relationship was shown to hold for the individual connections to the medial bank MSS areas, but not for connections leading to the lateral bank area. The data suggest that connectivity of the cat's visual cortex possesses a number of uniform global features, which are locally organized in such a way as to give each cortical area unique characteristics.

Age Factors↗
PubMed1976

Mineral and nitrogen metabolic studies on Skylab flights and comparison with effects of earth long-term recumbency.

A metabolic study of the effects of space flight on various chemical elements, particularly those with special relevance to the musculo-skeletal system, was carried out on the nine astronauts who participated in the three Skylab flights of 28, 59 and 84 days in 1973-1974. The study required of the cooperating crewmen constant dietary intake, continuous 24-hour urine collections and total fecal collections for 21-31 days before each flight, throughout each flight and for 17-18 days post-flight. Increases in urinary calcium and negative calcium balances during space flight were generally similar to those found in previous immobilization and bedrest studies. The persistence of these alterations in calcium metabolism throughout the flights suggested that calcium losses would continue in weightlessness for a very long time. Significant losses of nitrogen and phosphorus occurred, associated with observed reduction in muscle tissue. Both mineral and muscle losses occurred despite vigorous exercise regimens in flight. It was concluded that unless protective measures can be developed, capable musculo-skeletal function is likely to be impaired in space flights, ultimately to be conducted to Mars, of 11/2 to 3 years duration.

Bed Rest↗
PubMed2002

Muscle distribution of the neuromuscular blocker gallamine using microdialysis.

Measurement of drug concentrations in target tissue has the potential to provide insight into the pharmacokinetics and pharmacodynamics of a drug. In this study, the distribution of the neuromuscular blocker, gallamine, into muscle tissue was investigated in urethane-anesthetized rats after an intravenous bolus dose (6 mg/kg). Microdialysis sampling was used to continuously determine gallamine concentrations in muscle interstitial fluid (MIF). In vivo microdialysis recovery of gallamine was determined as the relative loss of gallamine from the perfusate into muscle tissue after perfusion with gallamine (2 microg/mL). Recovery was determined in each rat before the pharmacokinetic studies. Terminal muscle sampling followed by homogenization was also performed to examine gallamine distribution within muscle tissue. All samples were assayed for gallamine using a validated high-performance liquid chromatography assay. Gallamine was rapidly distributed into MIF with a MIF-plasma partition coefficient of 0.9 +/- 0.1 (n = 6). By contrast, the estimated gallamine concentration in muscle tissue homogenate was only 23 +/- 5% (n = 5) of the concentration in MIF as estimated by microdialysis sampling at the terminal sampling time. These findings suggest that gallamine is not distributed uniformly within muscle but selectively distributes into MIF. Simulations using a hybrid physiologically based pharmacokinetic model which describes uptake of drug only into the interstitial space showed good agreement between predicted and observed concentration data obtained from microdialysis sampling, supporting the findings that gallamine selectively distributes into MIF. These studies demonstrate microdialysis combined with conventional terminal tissue sampling provides valuable information on intra-tissue drug distribution.

Algorithms↗
PubMed2000

Hexagonal to square lattice conversion in bilayer systems

We report the results of extensive molecular dynamics simulations of the reconstructive hexagonal to square lattice conversion in bilayer colloid systems. Two types of interparticle potential were used to represent the colloid-colloid interactions in the suspension. One potential, due to Marcus and Rice, is designed to describe the interaction of sterically stabilized colloid particles. This potential has a term that represents the attraction between colloid particles when there is incipient overlap between the stabilizing brushes on their surfaces, a (soft repulsion) term that represents the entropy cost associated with interpenetration of the stabilizing brushes, and a term that represents core-core repulsion. The other potential we used is an almost hard core repulsion with continuous derivatives. Our results clearly show that the character of the reconstructive hexagonal to square lattice conversion in bilayer colloid systems is potential dependent. For a system with colloid-colloid interactions of the Marcus-Rice type, the packing of particles in the square array exhibits a large interlayer lattice spacing, with the particles located at the minima of the attractive well. In this case the hexagonal to square lattice transition is first order. For a system with hard core colloid-colloid interactions there are two degenerate stable intermediate phases, linear and zigzag rhombic, that are separated from the square lattice by strong first order transitions, and from the hexagonal lattice by either weak first or second order transitions.

Journal Article↗
PubMed1998

Evocation and characterization of percepts of apparent motion on the face.

The percepts evoked by sequential stimulation of sites in close spatial proximity (< or = 2.5 cm) on the face were studied. Both method-of-limits and magnitude-estimation procedures were used to identify and characterize alterations in the percepts produced by systematic changes in the temporal and spatial parameters of the sequence. Each site was stimulated by a vertically oriented row of miniature vibrating probes. Apparent motion was consistently perceived when the delay between the onsets of sequentially activated rows (interstimulus onset interval, or ISOI) fell within a relatively narrow range of values, the lower limit of which approximated 5 msec. Both the upper limit and the perceived smoothness and continuity of the motion percepts (goodness of motion) increased with the duration for which each row stimulated the skin over the range evaluated, 15-185 msec. For the successive activation of only two rows, goodness of motion was not influenced by changes in their separation from 0.4 to 2.5 cm. The ISOI values at which magnitude estimates of goodness of motion were highest increased with the duration for which each row stimulated the skin. As such, maximum goodness of motion decreased with increases in the apparent velocity of motion. When the number of sequentially activated rows was increased from two to four or more, the quality of the motion percepts improved. For the successive activation of multiple closely spaced rows, values of ISOI at which numerical estimates of goodness of motion were highest approximated integral fractions of the duration for which each row stimulated the skin. In this situation, the probes rose and fell in a regular, step-locked rhythm to simulate an edge-like or rectangular object moving across the skin. The goodness of motion so attained was relatively independent of the apparent velocity of motion.

Adult↗
PubMed2006

Reducing gradient imperfections for spiral magnetic resonance spectroscopic imaging.

Spiral k-space magnetic resonance spectroscopic imaging (MRSI) requires high performance from gradient hardware systems. During the readout phase, oscillating gradients are continuously played out, which can cause undesired effects. These effects on the quality of SI data are non-intuitive because of their time-varying nature. In this work we describe the effects of undesirable gradient performance on SI. Measurements of the true readout trajectories were performed and the results were then used in the reconstruction process. The effects of these imperfections resulted in a spatially and spectrally varying amplitude and frequency modulation. The use of the measured trajectories in the reconstruction process yielded an up to 20% increase in signal amplitude recovery.

Computer Simulation↗
PubMed2004

Overgrowth competition, fragmentation and sex-ratio dynamics: a spatially explicit, sub-individual-based model.

Sessile organisms that compete for access to resources by overgrowing each other may risk the local elimination of one sex or the other, as frequently happens within clumps of the dioecious liverwort Marchantia inflexa. A multi-stage, spatially implicit differential-equation model of M. inflexa growing in an isolated patch, analysed in a previous study, indicated that long-term coexistence of the sexes within such patches may be only temporary. Here we derive a spatially explicit, sub-individual-based model to reconsider this interpretation when much more ecological realism is taken into account, including the process of fragmentation. The model tracks temporally discrete growth increments in continuous space, representing growth architecture and the overgrowth process in significant geometric detail. Results remain generally consistent with the absence of long-term coexistence of the sexes in individual patches of Marchantia. Dynamics of sex-specific growth qualitatively resemble those generated by differential-equation models, suggesting that this much simpler framework may be adequate for multi-patch metapopulation models. Direct competition between fragmenting and non-fragmenting clones demonstrates the importance of fragmentation in overgrowth competition. The results emphasize the need for empirical work on mechanisms of overgrowth and for modeling and empirical studies of life history tradeoffs and sex-ratio dynamics in multi-patch systems.

Computer Simulation↗
PubMed1998

Comprehensive, technology-based clinical education: the "virtual practicum".

This article discusses the application of technology to promote more comprehensive clinical education in the biopsychosocial aspects of primary care. Comprehensive refers to the inclusion, in addition to scientific and technical knowledge, of knowledge that is less easily characterized, quantified, and taught: empathy, intuition, the demonstration of artistry. Clinical education will be increasingly facilitated by the proliferation of computers capable of displaying combinations of text, graphics, video, and sound; broadband networks capable of delivering these multiple media to the home or office; and new methods for using these technologies for education and training. However, current models for technology-based learning are limiting, lagging behind the rapid technological evolution driving our entry into the Information Age. Some recent educational models (Schon's reflection-in-action and reflective practicums [1], Boisot's E-space [2], Kolb's learning cycle [3]) provide for a more comprehensive and complete view of health professional education. This article describes these models in depth and proposes a new model for technology-based clinical training, the "Virtual Practicum," based on them. The Virtual Practicum is illustrated with a new interactive CD-ROM program, dealing with primary care of patients with HIV/AIDS. The concepts presented here are generally useful in thinking about clinical education, regardless of the means used.

CD-ROM↗
PubMed2005

Recent enhancements to the MARS15 code.

The MARS code is under continuous development and has recently undergone substantial improvements that further increase its reliability and predictive power in numerous shielding, accelerator, detector and space applications. The major developments and new features of the MARS15 (2004) version described in this paper concern an extended list of elementary particles and arbitrary heavy ions and their interaction cross sections, inclusive and exclusive nuclear event generators, module for modelling particle electromagnetic interactions, enhanced geometry and histogramming options, improved MAD-MARS Beam Line Builder, enhanced graphical user interface and an MPI-based parallelisation of the code.

Algorithms↗
PubMed2002

Computational design and prediction of interesting not-yet-synthesized structures of inorganic materials by using building unit concepts.

The computational design of new and interesting inorganic materials is still an ongoing challenge. The motivation of these efforts is to aid the often difficult task of crystal structure determination, to rationalize different but related structure types, or to help limit the domain of structures that are possible in a given system. Over the past decade, simulation methods have continuously evolved towards the prediction of new structures using minimal input information in terms of symmetry, cell parameters, or chemical composition. So far, this task of identifying candidate structures through an analysis of the energy landscape of chemical systems has been particularly successful for predominantly ionic systems with relatively small numbers of atoms or ions in the simulation cell. After an introductory section, the second section of this work presents the historical developments of such simulation methods in this area. The following sections of the work are dedicated to the introduction of the building unit concept in simulation methods: we present simulation approaches to structure prediction employing both primary (aggregate of atoms) and secondary (aggregate of coordination polyhedra) building units. While structure prediction with primary units is a straightforward extension of established approaches, the AASBU method (automated asssembly of secondary building units) focusses on the topology of network-based structures. This method explores the possible ways to assemble predefined inorganic building units in three-dimensional space, opening the way to the manipulation of very large building units (up to 84 atoms in this work). As illustrative examples we present the prediction of candidate structures for Li(4)CO(4), the identification of topological relationships within a family of metalphosphates, ULM-n and MIL-n, and finally the generation of new topologies by using predefined large building units such as a sodalite or a double-four-ring cage, for the prediction of new and interesting zeolite-type structures.

Journal Article↗
PubMed1996

Modeling the spontaneous reactivation of experience-specific hippocampal cell assembles during sleep.

During slow-wave sleep (SWS) following periods of spatial activity, hippocampal place cells that were temporally correlated, by virtue of the overlap of their place fields, exhibit enhanced temporal correlations, even though the animal sleeps in a different location (Wilson and McNaughton [1994] Science 267:676-679). The discharge of cells with overlapped place fields is more correlated in subsequent sleep, particularly during sharp waves, than in sleep episodes prior to the behavior, or than cell pairs with non-overlapped place fields. The reactivated correlated states appear during hippocampal sharp waves (SPWs), and are weak or absent in the inter-SPW interval. A simple conceptual hypothesis for this phenomenon is developed, based on the idea that hippocampal place fields reflect a two-dimensional distribution of continuously overlapping dynamic attractors in which each location is represented by the self-sustaining activity of a small subset of neurons with overlapping place fields. A numerical simulation of this hypothesis, based on a simplified representation of the CA8 recurrent network, accounts qualitatively for the main observations, including SPW-like dynamics. It is shown that, under conditions in which the connection patterns have been previously established, either associative or nonassociative mechanisms might underlie the reactivation of recently experienced states. These two alternatives appear, under at least some conditions (e.g., sparse coding), to be indistinguishable.

Animals↗
PubMed1995

Integrated implantable device for long-term glucose monitoring.

In this study we report the development of an integrated implantable device for glucose monitoring. The dimensions of the device (5.0 x 7.0 x 1.5 cm) allow implantation under the abdominal skin of a large animal for in vivo evaluation of sensor performance. The experimental set-up includes amperometric glucose biosensor, a miniature potentiostat, an FM signal transmitter, a power supply and an antenna and receiver linked to a computer-based data acquisition system. The device performance was evaluated in vitro using a ten-day continuous test and other long-term operation experiments. The biosensor was tested in different model solutions that simulated the physiological environment in which it will be ultimately used. A linear response to glucose concentration was obtained up to 25 mM glucose, with a sensitivity of less than 0.5 microA/mM. The ability of the biosensor to measure glucose levels in serum was also tested, and a good correlation demonstrated between glucose serum levels measured by routine technique and those measured using the biosensor (R2 = 0.993; slope = 0.996). Initial results obtained from the short-term subcutaneous implantation of the sensor demonstrate its potential for the monitoring of glucose concentration in vivo.

Animals↗
PubMed1995

The refined crystallographic structure of a DD-peptidase penicillin-target enzyme at 1.6 A resolution.

The D-alanyl-D-alanine peptidase from Streptomyces sp. R61 is a 37,500 dalton exocellular enzyme that has served as a model for membrane-bound peptidases that are involved in bacterial cell wall biosynthesis. Inhibition of these enzymes by beta-lactam antibiotics ultimately leads to bacterial cell death. The X-ray crystal structure of the R61 D-alanyl-D-alanine peptidase has been solved using multiple isomorphous replacement, simulated annealing and least squares refinement. The space group and unit cell parameters are P2(1)2(1)2(1) with a = 51.1 A, b = 67.3 A and c = 102.4 A. The structure has been refined using 2 sigma data to 1.6 A resolution with a crystallographic R-factor of 0.148. The model contains 347 residues (2938 atoms) and 254 solvent molecules. The overall temperature factor is 9.6 A2, and the estimated coordinate error is 0.14 A. The protein consists of a single polypeptide chain organized into two regions. One region contains a nine-stranded antiparallel beta-sheet with helices on both faces; this region includes both the amino and carboxyl termini. The second region is all helical. Sixty percent of the residues occur in helices or beta-sheet. The reactive Ser62 is found between the two regions of the enzyme at the amino end of the protein's longest-helix which begins with one turn of 3(10) helix and continues with four turns of alpha-helix. The active site is an elongated pocket that contains four basic and four aromatic residues. An oxyanion hole is formed by Ser62 NH and Thr301 NH. The pocket also contains the few key residues that are conserved in all penicillin-binding proteins and beta-lactamases. Two of these residues, Lys65 and Tyr159, are among the 16 side-chains that take on multiple conformations in the R61 crystal structure. Three of the 12 proline rings adopt two conformations which we believe has not been previously reported. There is no anionic acid equivalent to the catalytic Glu166 found in Class A beta-lactamases. Two ordered water molecules (O507 and O644) are found buried in the active site and hydrogen-bonded to each other (2.6 A). O507 could potentially act as the hydrolytic water molecule for deacylation.

Binding Sites↗
PubMed1998

Complete Dipolar Decoupling of 13C and Its Use in Two-Dimensional Double-Quantum Solid-State NMR for Determining Polymer Conformations

A multiple-pulse technique for complete dipolar decoupling of directly bonded 13C-labeled sites is described. It achieves significant spectral simplifications in a recently introduced two-dimensional double-quantum solid-state NMR experiment for determining torsion angles. Both homonuclear and heteronuclear dipolar couplings are removed by combining a 13C multiple-pulse sequence with continuous-wave irradiation on the protons. The 13C sequence has a fundamental 10-pulse cycle which is a significantly modified magic-sandwich-echo sequence. The crucial heteronuclear decoupling is achieved by breaking the 360 degrees "inner" pulses in the magic sandwich into 90 degrees pulses and spacing them by 1H 360 degrees pulse lengths. Spectral artifacts typical of multiple-pulse sequences are eliminated by phase shifts between cycles. In contrast to many other multiple-pulse decoupling sequences, the long window in the cycle is the dwell time and can be longer than the inverse dipolar coupling, which makes the sequence practical for direct detection even with long pulse ring-down times. A modification of the sequence to scale the chemical shift and increase the effective spectral width is also presented. The 1D and double-quantum 2D experiments are demonstrated on polyethylene with 4% 13C-13C spin pairs. The potential of this approach for distinguishing segmental conformations is illustrated by spectral simulations of the two-dimensional ridge patterns that correlate double-quantum and single-quantum chemical-shift anisotropies. Copyright 1998 Academic Press.

Journal Article↗
PubMed1994

Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins.

Two major components are required for a successful prediction of the three-dimensional structure of peptides and proteins: an efficient global optimization procedure which is capable of finding an appropriate local minimum for the strongly anisotropic function of hundreds of variables, and a set of free energy components for a protein molecule in solution which are computationally inexpensive enough to be used in the search procedure, yet sufficiently accurate to ensure the uniqueness of the native conformation. We here found an efficient way to make a random step in a Monte Carlo procedure given knowledge of the energy or statistical properties of conformational subspaces (e.g. phi-psi zones or side-chain torsion angles). This biased probability Monte Carlo (BPMC) procedure randomly selects the subspace first, then makes a step to a new random position independent of the previous position, but according to the predefined continuous probability distribution. The random step is followed by a local minimization in torsion angle space. The positions, sizes and preferences for high-probability zones on phi-psi maps and chi-angle maps were calculated for different residue types from the representative set of 191 and 161 protein 3D-structures, respectively. A fast and precise method to evaluate the electrostatic energy of a protein in solution is developed and combined with the BPMC procedure. The method is based on the modified spherical image charge approximation, efficiently projected onto a molecule of arbitrary shape. Comparison with the finite-difference solutions of the Poisson-Boltzmann equation shows high accuracy for our approach. The BPMC procedure is applied successfully to the structure prediction of 12- and 16-residue synthetic peptides and the determination of protein structure from NMR data, with the immunoglobulin binding domain of streptococcal protein G as an example. The BPMC runs display much better convergence properties than the non-biased simulations. The advantage of a true global optimization procedure for NMR structure determination is its ability to cope with local minima originating from data errors and ambiguities in NMR data.

Algorithms↗
PubMed1998

"Critical slowing down" in time-to-extinction: an example of critical phenomena in ecology.

We study a model for two competing species that explicitly accounts for effects due to discreteness, stochasticity and spatial extension of populations. The two species are equally preferred by the environment and do better when surrounded by others of the same species. We observe that the final outcome depends on the initial densities (uniformly distributed in space) of the two species. The observed phase transition is a continuous one and key macroscopic quantities like the correlation length of clusters and the time-to-extinction diverge at a critical point. Away from the critical point, the dynamics can be described by a mean-field approximation. Close to the critical point, however, there is a crossover to power-law behavior because of the gross mismatch between the largest and smallest scales in the system. We have developed a theory based on surface effects, which is in good agreement with the observed behavior. The course-grained reaction-diffusion system obtained from the mean-field dynamics agrees well with the particle system.

Animals↗
PubMed2000

Human orientation and movement control in weightless and artificial gravity environments.

Our goal is to summarize what has been learned from studies of human movement and orientation control in weightless conditions. An understanding of the physics of weightlessness is essential to appreciate the dramatic consequences of the absence of continuous contact forces on orientation and posture. Eye, head, arm, leg, and whole body movements are discussed, but only experiments whose results seem relatively incontrovertible are included. Emphasis is placed on distinguishing between virtually immediate adaptive compensations to weightlessness and those with longer time courses. The limitations and difficulties of performing experiments in weightless conditions are highlighted. We stress that when astronauts and cosmonauts return from extended space flight they do so with both physical "plant" and neural "controller" structurally and functionally altered. Recent developments in adapting humans to artificial gravity conditions are discussed as a way of maintaining sensory-motor and structural integrity in extended missions involving transitions between different force environments.

Humans↗
PubMed2004

Multichip module with planar-integrated free-space optical vector-matrix-type interconnects.

Even in the semiconductor industry, free-space optical technology is nowadays seen as a prime option for solving the continually aggravating problem with VLSI chips, namely, that the interconnect technology has failed to keep pace with the increase in communication volume. To make free-space optics compatible with established lithography-based design and fabrication techniques the concept of planar integration was proposed approximately a decade ago. Here its evolution into a photonic microsystems engineering concept is described. For demonstration, a multichip module with planar-integrated freespace optical vector-matrix-type interconnects was designed and built. It contains flip-chip-bonded vertical-cavity surface emitting laser arrays and a hybrid chip with an array of multiple-quantum-well p-i-n diodes on top of a standard complementary metal-oxide semiconductor circuit as key optoelectronic hardware components. The optical system is integrated into a handy fused-silica substrate and fabricated with surface-relief diffractive phase elements. It has been optimized for the given geometrical and technological constraints and provides a good interconnection performance, as was verified in computer simulations on the basis of ray tracing and in practical experiments.

Journal Article↗