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PubMed1983

Classroom use of personal computers in medical education: a practical approach.

Classroom lectures in medical schools have traditionally employed a blackboard and slides. We have developed a compact, durable, and relatively low-priced system for computer-assisted instruction which introduces audiovisual material in a random-access manner. When this system was used in the classroom to provide flexible, clinical simulations, it promoted a high level of audience-instructor interaction and facilitated problem-based learning. The system has been used successfully in lectures in our medical school, at other medical schools, at community hospitals and at national scientific meetings.

Computer-Assisted Instruction↗

PubMed2025

Molecular dynamics simulations reveal subtle consequences of H3K9 and H3K27 tri-methylation on chromatin constituents.

Epigenetic modifications of histone tails are key mechanisms of genome regulation. In particular, tri-methylation of lysines (K) 9 and K27 of the histone H3 tail is important for genome silencing. In this work, we explore, using all-atom molecular dynamics simulations, the effect of these two epigenetic marks on the structure and interactions of the H3 tail in several contexts: isolated tails, nucleosomes, chromatosomes, and stacked nucleosomes. Overall, we find that although the isolated tails do not show significant conformational changes upon methylation, a more flexible and extended H3 tail compared to the native tail results in the nucleosome systems, with K9 methylation effects more pronounced. This change could facilitate the interaction of the tail with protein readers like heterochromatin protein 1 or Polycomb group. We also observe that both methylations increase the interactions of the H3 tail with the linker DNA in the context of the chromatosome, producing a chromatosome with tighter linker DNA, which could favor chromatin compaction. For stacked nucleosomes mimicking i±2 zigzag interactions, methylation of either K9 or K27 reduces the interactions of one of the H3 tails with its parental nucleosome and increases its interactions with the nonparental nucleosome, which could also help compact the chromatin fiber. In the three nucleosome-containing systems, we observe an asymmetry between the two tails, especially in the chromatosome, where one tail extends to interact with the linker DNA. This asymmetry modulates the effect that methylation has on each tail. Thus, overall, methylations of K9 and K27 have a subtle but notable impact on the H3 tail structure and its interactions within the chromatin fiber. These results help explain how this epigenetic modification compacts chromatin fibers and promotes longer-range interactions; these changes also guide how to approximate these effects in coarse-grained chromatin models.

Histones↗

PubMed1990

Determination of the conformation of Lewis blood group oligosaccharides by simulation of two-dimensional nuclear Overhauser data.

Through control of both the nmr probe temperature and of the solvent viscosity, phase-sensitive two-dimensional 1H nuclear Overhauser data (NOESY) at 300 and 500 MHz are obtained with excellent signal-to-noise ratios for Lewis blood group penta- and hexasaccharides isolated from human milk. Relatively long mixing times are required to produce measurable NOE intensities in these oligosaccharides, which makes a full relaxation matrix analysis necessary. By measurements of selective T1 for a few isolated 1H resonances, it was possible to generate a simulation of the complete NOESY spectrum at arbitrary mixing time for comparison with the experimental data. From an exhaustive search of the conformational space, it was found that only a small range of glycosidic dihedral angles of the nonreducing terminal Lewis blood group determinant fragments of the milk oligosaccharides LNF-2 and LND-1 produce simulated spectra agreeing within experimental error to the data. Conformational energy calculations reveal that each of these conformations is also one of minimum energy. It is concluded that the Lewis(a) and Lewis(b) oligosaccharides adopt relatively compact rigid structures in solution, as shown by the observation of cross peaks between protons in nonadjacent residues. Like the blood group A and H oligosaccharides, there exists only a small dependence of the conformation for Lewis(a) and Lewis(b) oligosaccharides on solvent. The apparent lack of dependence of conformation of these oligosaccharides on DMSO in D2O suggests that modification of solvent viscosity with mixtures of DMSO:D2O may provide a useful general strategy of NOESY studies of oligosaccharides.

Carbohydrate Conformation↗

PubMed1989

A hexagonal orthogonal-oriented pyramid as a model of image representation in visual cortex.

Retinal ganglion cells represent the visual image with a spatial code, in which each cell conveys information about a small region in the image. In contrast, cells of primary visual cortex employ a hybrid space-frequency code in which each cell conveys information about a region that is local in space, spatial frequency, and orientation. Despite the presumable importance of this transformation, we lack any comprehensive notion of how it occurs. Here we describe a mathematical model for this transformation. The hexagonal orthogonal-oriented quadrature pyramid (HOP) transform, which operates on a hexagonal input lattice, employs basis functions that are orthogonal, self-similar, and localized in space, spatial frequency, orientation, and phase. The basis functions, which are generated from seven basic types through a recursive process, form an image code of the pyramid type. The seven basis functions, six bandpass and one low-pass, occupy a point and a hexagon of six nearest neighbors on a hexagonal sample lattice. The six bandpass basis functions consist of three with even symmetry, and three with odd symmetry. The three even kernels are rotations of 0, 60, and 120 degrees of a common kernel; likewise for the three odd kernels. At the lowest level, the inputs are image samples. At each higher level, the input lattice is provided by the low-pass coefficients computed at the previous level. At each level, the output is subsampled in such a way as to yield a new hexagonal lattice with a spacing square root 7 larger than the previous level, so that the number of coefficients is reduced by a factor of seven at each level. In the biological model, the input lattice is the retinal ganglion cell array. The resulting scheme provides a compact, efficient code of the image and generates receptive fields that resemble those of the primary visual cortex.

Computer Simulation↗

PubMed1992

Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis.

Structures of insulin in different crystal forms exhibit significant local and nonlocal differences, including correlated displacement of elements of secondary structure. Here we describe the solution structure and dynamics of a monomeric insulin analogue, des-pentapeptide-(B26-B30)-insulin (DPI), as determined by two-dimensional NMR spectroscopy and distance geometry/restrained molecular dynamics (DG/RMD). Although the solution structure of DPI exhibits a general similarity to its crystal structure, individual DG/RMD structures in the NMR ensemble differ by rigid-body displacements of alpha-helices that span the range of different crystal forms. These results suggest that DPI exists as a partially folded state formed by coalescence of distinct alpha-helix-associated microdomains. The physical reality of this model is investigated by comparison of the observed two-dimensional nuclear Overhauser enhancement (NOE) spectroscopy (NOESY) spectrum with that predicted from crystal and DG/RMD structures. The observed NOESY spectrum contains fewer tertiary contacts than predicted by any single simulation, but it matches their shared features; such "ensemble correspondence" is likely to reflect the effect of protein dynamics on observed NOE intensities. We propose (i) that the folded state of DPI is analogous to that of a compact protein-folding intermediate rather than a conventional native state and (ii) that the molten state is the biologically active species. This proposal (the molten-globule hypothesis) leads to testable thermodynamic predictions and has general implications for protein design.

Calorimetry↗

PubMed1985

Systems model for pupil size effect. II. Feedback model.

The human pupillary control system has been the subject of interest to biologists and engineers as an example of a sensorimotor reflex which can be embedded in a control system paradigm. We present a nonlinear feedback model whose compact structure allows us to hypothesize possible physiological mechanisms which generate the proper behavior of the pupil system. The important pupil responses, including pupil size effect, asymmetry, and response the high-frequency stimuli, are defined. This model was simulated on a digital computer and comparisons to the paradigm experimental responses were performed, demonstrating a fit to each of the observed conditions. Improvements on previous models are discussed.

Feedback↗

PubMed1992

Molecular dynamics simulations of a monofucosylated biantennary glycan of the N-acetyllactosamine type: the human lactotransferrin glycan.

Molecular dynamics simulations were carried out to explore the conformational flexibility of the antennae of N-linked glycans. They were performed over 200 ps in vacuo on the complete disialylated monofucosylated biantennary glycan of the N-acetyllactosaminic type. Starting from a bird-conformation, the 3-D-structure evolved through 9 successive transitional states to a new, compact and energetically favorable conformation which had never been previously described. In this conformation, both antennae are organized in two coplanar loops rolled in a contrary direction and oriented perpendicularly to the plane of the di-N-acetyl chitobiose residue leading to a 'lobster conformation'. All the glycosidic linkages of the disialylated monofucosylated biantennary glycan, except the Fuc(alpha 1-6)GlcNAc(beta 1-), were modified by a phase transition. Particularly, the Man(beta 1-4) GlcNAc(beta 1-) linkage, which was previously described by NMR and X-ray diffraction as a rigid one, was involved in numerous conformational changes during 83 ps, even before the first transition phase. The freedom of mobility of the torsional angles of the Man(alpha 1-6)Man(beta 1-) linkage was limited, under these simulation conditions, to the angle psi which took three values: 30 degrees, 90 degrees and 180 degrees. Moreover, from 150 ps up to the end of the simulation, the value of the torsional angle omega of the NeuAc(alpha 2-6)Gal(beta 1-) linkage of the alpha-1,6-antenna continuously swung between 60 degrees and -60 degrees. Finally, we observed that the values of the torsional angles of the three linkages: NeuAc(alpha 2-6)Gal(beta 1-), Gal(beta 1-4)GlcNAc(beta 1-) and GlcNAc(beta 1-2)Man(beta 1-) of each of the two antennae were different, demonstrating their asymmetric conformation.

Amino Sugars↗

PubMed1992

Supercoiled DNA energetics and dynamics by computer simulation.

A new formulation is presented for investigating supercoiled DNA configurations by deterministic techniques. Thus far, the computational difficulties involved in applying deterministic methods to supercoiled DNA studies have generally limited computer simulations to stochastic approaches. While stochastic methods, such as simulated annealing and Metropolis-Monte Carlo sampling, are successful at generating a large number of configurations and estimating thermodynamic properties of topoisomer ensembles, deterministic methods offer an accurate characterization of the minima and a systematic following of their dynamics. To make this feasible, we model circular duplex DNA compactly by a B-spline ribbon-like model in terms of a small number of control vertices. We associate an elastic deformation energy composed of bending and twisting integrals and represent intrachain contact by a 6-12 Lennard Jones potential. The latter is parameterized to yield an energy minimum at the observed DNA-helix diameter inclusive of a hydration shell. A penalty term to ensure fixed contour length is also included. First and second partial derivatives of the energy function have been derived by using various mathematical simplifications. First derivatives are essential for Newton-type minimization as well as molecular dynamics, and partial second-derivative information can significantly accelerate minimization convergence through preconditioning. Here we apply a new large-scale truncated-Newton algorithm for minimization and a Langevin/implicit-Euler scheme for molecular dynamics. Our truncated-Newton method exploits the separability of potential energy functions into terms of differing complexity. It relies on a preconditioned conjugate gradient method that is efficient for large-scale problems to solve approximately for the search direction at every step. Our dynamics algorithm is numerically stable over large time steps. It also introduces a frequency-discriminating mechanism so that vibrational modes with frequencies greater than a chosen cutoff frequency are essentially frozen by the method. With these tools, we rapidly identify corresponding circular and interwound energy minima for small DNA rings for a series of imposed linking-number differences. These structures are consistent with available electron microscopy data. The energetic exchange of stability between the circle and the figure-8, in very good agreement with analytical results, is also detailed. Molecular dynamics trajectories at 100 femtosecond time steps then reveal the rapid folding of the unstable circular state into supercoiled forms. Significant bending and twisting motions of the interwound structures are also observed. Such information may be useful for understanding transition states along the folding pathway and the role of enzymes that regulate supercoiling.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗

PubMed1986

Validation of a compact system for measuring gas exchange.

Measuring gas exchange in critically ill patients can provide valuable information on their nutritional status and energy expenditure. Several semiautomated machines are available for measuring oxygen consumption (VO2) and carbon dioxide production (VCO2). This study evaluated, under controlled laboratory conditions, a Gould 9000 IV prototype designed for use with mechanically ventilated patients. Various VO2 and VCO2 values were simulated at different combinations of frequency, tidal volume, minute ventilation, and inspired oxygen fraction (FIO2). Variations in frequency, tidal volume, and minute ventilation had no significant effect on the measured VO2 and VCO2, but FIO2 had a dramatic effect on the accuracy of VO2. Errors in measured VO2 were 2.6%, 3.5%, 5.9%, and 16.9% at FIO2 values of 0.22, 0.40, 0.60, and 0.80, respectively. Addition of a dead space to the spirometer dump port (to prevent room-air contamination) corrected a larger error initially found. The accuracy of VCO2 was +/- 2.6%.

Carbon Dioxide↗

PubMed2025

Phylogenetic Methods Meet Deep Learning.

Deep learning (DL) has been widely used in various scientific fields, but its integration into phylogenetics has been slower, primarily due to the complex nature of phylogenetic data. The studies that apply DL to sequencing data often limit analyses to four-taxon trees. Many of these studies serve as "proof of principle" and perform similarly to traditional phylogeny reconstruction methods. New ways of using training data, such as encoding with compact bijective ladderized vectors or transformers, enable the handling of much larger trees and genomic data sets. This short perspective focuses on the application of DL in phylogenetics, introducing prevalent DL architectures. We highlight potential problems in the field by discussing the risks of using simulation-based training data and emphasize the importance of reproducibility and robustness in computational estimates. Finally, we explore promising research areas, including the combination of phylogenetics and population genetics in DL, the analysis of neighbor dependencies, and the potential to significantly reduce computational cost compared to traditional methods. This perspective illustrates the potential of DL in complementing traditional phylogeny reconstruction methods and aiding the advancement of phylogenetic analysis, especially in performing computationally demanding tasks such as model selection or estimating branch support values.

Humans↗

PubMed1995

First-principles calculation of the folding free energy of a three-helix bundle protein.

The folding and unfolding of a three-helix bundle protein were explored with molecular-dynamics simulations, cluster analysis, and weighted-histogram techniques. The folding-unfolding process occurs by means of a "folding funnel," in which a uniform and broad distribution of conformational states is accessible outside of the native manifold. This distribution narrows near a transition region and becomes compact within the native manifold. Key thermodynamic steps in folding include initial interactions around the amino-terminal helix-turn-helix motif, interactions between helices I and II, and, finally, the docking of helix III onto the helix I-II subdomain. A metastable minimum in the calculated free-energy surface is observed at approximately 1.5 times the native volume. Folding-unfolding thermodynamics are dominated by the opposing influences of protein-solvent energy, which favors unfolding, and the overall entropy, which favors folding by means of the hydrophobic effect.

Amino Acid Sequence↗

PubMed1989

Solution structure of recombinant hirudin and the Lys-47----Glu mutant: a nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing study.

The solution structure of recombinant wild-type hirudin and of the putative active site mutant Lys-47----Glu has been investigated by nuclear magnetic resonance (NMR) spectroscopy at 600 MHz. The 1H NMR spectra of the two hirudin variants are assigned in a sequential manner with a combination of two-dimensional NMR techniques. Some assignments made in our previous paper [Sukumaran, D. K., Clore, G. M., Preuss, A., Zarbock, J., & Gronenborn, A. M. (1987) Biochemistry 26, 333-338] were found to be incorrect and are now corrected. Analysis of the NOE data indicates that hirudin consists of an N-terminal compact domain (residues 1-49) held together by three disulfide linkages and a disordered C-terminal tail (residues 50-65) which does not fold back on the rest of the protein. This last observation corrects conclusions drawn by us previously on hirudin extracted from its natural source, the leech Hirudo medicinalis. The improved sensitivity of the 600-MHz spectrometer relative to that of our old 500-MHz spectrometer, the availability of two variants with slightly different chemical shifts, and the additional information arising from stereospecific assignments of methylene beta-protons and methyl protons of valine have permitted the determination of the solution structure of hirudin with much greater precision than before. Structure calculations on the N-terminal domain using the hybrid distance geometry-dynamical simulated annealing method were based on 685 and 661 approximate interproton distance restraints derived from nuclear Overhauser enhancement (NOE) data for the wild-type and mutant hirudin, respectively, together with 16 distance restraints for 8 backbone hydrogen bonds identified on the basis of NOE and amide NH exchange data and 26 phi backbone and 18 chi 1 side-chain torsion angle restraints derived from NOE and three-bond coupling constant data. A total of 32 structures were computed for both the wild-type and mutant hirudin. The structure of residues 2-30 and 37-48 which form the core of the N-terminal domain is well determined in both cases with an average atomic rms difference between the individual structures and the respective mean structures of approximately 0.7 A for the backbone atoms and approximately 1 A for all atoms. As found previously, the orientation of the exposed finger of antiparallel beta-sheet (residues 31-36) with respect to the core could not be determined on the basis of the present data due to the absence of any long-range NOEs between the exposed finger and the core.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

Crystal structure of recombinant human interleukin-4.

The crystal structure of recombinant human interleukin-4 (rhuIL-4) was initially determined at 3.5-A resolution by multiple isomorphous replacement techniques and subsequently refined to a resolution of 2.35 A by simulated annealing. The final crystallographic R-factor, based on all data in the range 6.0-2.35 A (7470 reflections), is 0.232. Bond lengths and bond angles in the molecule have root mean square deviations from ideal values of 0.016 A and 2.4 degrees, respectively. The overall structure is highly compact and globular with a predominantly hydrophobic core. The main structural feature of rhuIL-4 is a four alpha-helix bundle, which composes approximately 58% of the structure. The helices are arranged in a left-handed antiparallel bundle with two overhand connections. Within these connections is a two-stranded antiparallel beta-sheet. Both the tertiary and secondary structures of rhuIL-4 are similar to those of human granulocyte-macrophage colony-stimulating factor. Critical regions for receptor binding are proposed.

Amino Acid Sequence↗

PubMed1990

The finite element analysis of brain oedema associated with intracranial meningiomas.

The mathematical model of vasogenic brain oedema, which was presented at the previous meeting in 1987, was applied to the analysis of peritumoural brain oedema associated with meningiomas. Magnetic resonance images of 90 patients with intracranial meningiomas were reviewed to analyze the spatial extension of peritumoural brain oedema. It is assumed that the heterogeneous pattern of distribution of peritumoural oedema reflects the variability of the compact density of the fibers in the white matter. A two dimensional finite element model was constructed with 786 triangular elements from a horizontal section of the human brain. The development of oedema, the change of interstitial pressure, the deformation of the brain and the absorption of oedema fluid could be simulated by the finite element method. The result of computer simulation represented interactive behaviour of the brain tissue, extracellular fluid, and cerebrospinal fluid in the clinical situation. The finite element method (FEM) may provide a new experimental tool to analyze the pathophysiology of vasogenic brain oedema.

Brain↗

PubMed1983

Uniform regional heating of the lower trunk: numerical evaluation of tumor temperature distributions.

The temperature distributions in deep seated tumors resulting from uniform heating of the abdominal and pelvic regions of the trunk are predicted from a one dimensional numerical solution of the bio-heat transfer equation. The effect of tumor size and location are investigated for two tumor perfusion models: uniform perfusion and a concentric annulus perfusion model. Tumor temperature distributions are considered acceptable if the range of temperatures in the tumor lie between 42 degrees C and 60 degrees C. This range of tumor temperatures is defined as Tave +/- 2 sigma where sigma is the population standard deviation of tumor temperatures from the average computed at the nodal points in the finite difference array. To simulate practical clinical restrictions, muscle and fat temperatures are not allowed to exceed 44 degrees C, significant portions of the viscera are not allowed to exceed 42 degrees C, and the total absorbed power required to maintain steady state cannot exceed two kilowatts. Over 100 possible cases are presented in a compact form. From this study it appears that heating systems with power deposition patterns approximately uniform are promising for heating deep-seated tumors. Small, detectable tumors (approximately 2 cm in size) are adequately heated for a wider range of conditions than are larger tumors. Excessively high temperatures in deep-seated, normal tissue could be a significant limitation for this technique.

Abdominal Neoplasms↗

PubMed1988

Computer simulation of neuronal circuit models of rhythmic behavior in the electroencephalogram.

A computer program for modeling some features of the electroencephalogram (EEG) recorded by scalp electrodes in terms of the time- and space-dependent interactions of populations of neurons in different hypothetical brain configurations was developed. The input of the model consists of: (1) geometric and anatomic data characterizing the brain configuration; (2) physiologic features characterizing neurons; and (3) functions describing the time-dependent afferent impulses to the brain configuration under study. The output of the model consists of plots of selected intracellular and extracellular potentials as a function of time. In application of the model to various brain configurations, some configurations were sufficiently compact spatially that propagation times of action potentials between elements were either taken to be constant or were nearly independent of distance within the accuracy of the calculations. Other configurations represented cerebral cortex alone or a combined thalamocortical system in which many elements interacted via global interconnections. The basic requirement for rhythmic behavior is the existence of circuits containing inhibitory neurons. The characteristic frequencies of rhythmic oscillations are primarily determined by the local circuit parameters and are relatively independent of global circuit parameters.

Action Potentials↗

PubMed1983

A highly simplified horizontal electrophoretic apparatus including a handmade power supply and its application.

An extremely simplified electrophoretic apparatus and power supply have been introduced for horizontal (flat-bed) electrophoresis and isoelectrofocusing. The electrophoretic apparatus consisted of a buffer tray with a plastic food container in which a gel glass plate attached to two removable bar electrodes with rubber bands was submerged. The removable bar electrode consisted of an acrylic bar plate containing holes to which platinum wire was attached. The power supply simply contained a bridge diode, fuse, capacitor, and output terminals which were also assembled in a small plastic food container. Since the output electric potential of the power supply was constant pulse dc 90 V (in the absence of a capacitor) or 140 V (in the presence of a capacitor) at 100 V ac input, the following equation was experimentally derived to control the electrophoretic current: I (mA) = aD + b, I (mA) = kF. In these, I, a, D, k, and F were electrophoretic current, constant, distance between positive and negative electrodes, constant, and dilution factor of the electrophoretic buffer which was proportional to buffer concentration, respectively. These equations indicate that electrophoretic current can be controlled by the changes of electrode distance and buffer dilution. The latter equation was theoretically derived from the theory of electrolyte conductance and Ohm's law and was simulated with a microcomputer. With the apparatus and power supply, agarose gel electrophoresis of DNA and discontinuous polyacrylamide gel electrophoresis of protein samples were successfully carried out. The construction and assembly of the system can be easily carried out in a laboratory without any special tools and machines. The high cost performance, compactness, and simplicity were superior points of this system. The applicability of the equation I = kF to tube gel and vertical slab gel electrophoresis was tested. The rheostat usage made it easy for the power supply to change dc-output potential without spoiling its cost performance. A convenient sample slot-former and gel preparation with it are also described.

Computers↗

PubMed1986

[The level of the musical loud sound and noise induced hearing impairment].

Recently, there has been an increasing number of reports concerning hearing impairment which musical loud sound is thought to be one of the causes. We are getting more of this musical loud sound as cassette tape recorders with head phones such as Walkman and so forth get popular as well as occasions to attending rock concerts and going to discotheques increase. This hearing impairment is generally called discotheque deafness and the following three types are considered; 1) deafness which have fixed by accumulation of loud sound over a long period of time as seen in people involved in musical performance such as rock musicians and mixing engineers; 2) abrupt noise induced hearing impairment triggered by loud sound and 3) state of deafness which is a progressing stage towards recovery of noise induced temporary threshold shift (NITTS), which occurs temporarily by a loud sound stimulus, and hearing ability recovers afterward. However, it is considered that these musical loud sounds not only changes every moment according to method of performing or type of music, but the volume of the sound actually reaching the auditory sense differs largely by locations and direction of the ear and speakers. So it becomes necessary to measure the accumulation of the noise which each individual is exposed under over a long period of time and at the same time carry out the regular medical checkups including hearing test to check the initiation and advancement of the noise induced hearing impairment. Then we can examine the relationship between loudness of the environmental noise and initiation and advancement of the hearing impairment. However, there has not been a device which is compact and measures noise exposure individually over a long period of time. So we have experimentally produced ultra compact noise dosimeter which we named Noise Badge, and with it we actually measured individual noise exposure over a long time in rock music, noise in discotheque and noisy factory. Then we examined the relationship between these loud sound and noise induced temporary threshold shift (NITTS) in discotheques and noise proof room using simulation of loud sound exposure. Moreover, we measured the most comfortable loudness level of head phones in each examine and different types of music with environmental noise in consideration, thus examining the relationship between musical loud sound and the hearing impairment.

Adaptation, Physiological↗