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PubMed1991

Implementing Boissonnat's method for generating surface models of craniofacial cartilages.

Surface modeling of embryonic craniofacial morphology typically is accomplished using data derived from planar contours. Methods currently available for reconstructing embryonic craniofacial anatomy from contour data rely on shortest-path algorithms in order to interpolate surfaces. However, these techniques either fail or require a considerable amount of user interaction when complex surfaces are modeled since foramina and structural divisions cannot be interpolated properly. Recently, a new approach has been described by Boissonnat that constructs a polyhedral volume between sets of planar contours. Surfaces are interpolated by identifying the planes formed when the contours intersect the polyhedron. The purpose of this study is to determine whether craniofacial cartilages from embryonic mice can be reconstructed in an accurate and reliable fashion using this method. Embryonic mice were collected and processed for routine histological sectioning. Serial sections of the anterior cranial base and nasal capsule were obtained, subjected to videomicroscopy, and modeled. Reconstructions of the anterior cranial base and nasal capsule from embryonic mice were compared to the same structures in age-matched specimens that were processed with whole-mount staining procedures. The models compared well with the whole-mount preparations. In addition, the reconstruction technique accurately rendered complex surface features of the embryonic anterior cranial base and nasal capsule including foramina and structural branches.

Algorithms↗
PubMed1985

Smoking behavior, cessation techniques, and the health decision model.

The magnitude of the problem of smoking challenges health providers to persuade patients of the importance of trying to quit. Smoking behavior and cessation techniques are discussed in terms of the health decision model, a third-generation model combining health beliefs, decision analysis, and behavioral decision theory. This review suggests the need for physicians to emphasize factors such as health beliefs, self-efficacy, social support, and reduction of stress in smoking cessation efforts. Patients experiencing symptoms, particularly relating to the lungs or heart, may have stronger health beliefs and are clearly more likely to quit smoking. In the absence of a clear-cut advantage for any particular smoking cessation technique, physicians should provide advice about smoking as a regular part of every patient visit.

Adult↗
PubMed1978

Computer-generated graphic models of the N2-substituted deoxyguanosine adducts of 2-acetylaminofluorene and benzo[a]pyrene and the O6-substituted deoxyguanosine adduct of 1-naphthylamine in the DNA double helix.

Computer models of three deoxyguanosine-carcinogen adducts in double-helical DNA are presented. The carcinogen moiety is rotated and the best fit within the double helix is evaluated. The 2-acetylaminofluorene (AAF) derivative, 3-(deoxyguanosin-N2-yl)-AAF, is found to be situated within the minor groove, has very little freedom of rotation and causes little helical distortion. The (+)-anti-benzo[a]-pyrene (BP)-diol epoxide-N2 adduct, 10beta-(deoxyguanosin-N2-yl)-7beta, 8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydro-BP, has a similar fit with a greater degree of steric interaction, suggesting that this adduct could cause some local destabilization. The 1-naphthylamine (NA) derivative, N1-(deoxyguanosine-O6-yl)-1-NA, resides within the major groove, does not perturb the helix and has considerable freedom of movement.

1-Naphthylamine↗
PubMed1992

Computer-generated bone models in the planning of osteotomy of multidirectional distal radius malunions.

Computer-assisted design and manufacturing technology has been used to create solid models of five unusually complex, multidirectional malunions of distal radius fractures. Preoperative planning was dramatically enhanced by the ability to perform the surgical procedure on these models, with a model of the uninjured limb used for comparison. All five patients had significant malunions, with malrotation in the horizontal plane in five and an impacted articular fragment in two. A satisfactory outcome was achieved in each case.

Adult↗
PubMed2026

CRISPR/Cpf1-mediated knockout of FLG in human induced pluripotent stem cells generates a model for studying epidermal barrier dysfunction.

Loss of filaggrin (FLG) function impairs skin barrier formation and contributes to common inflammatory skin diseases. In this study, we established a FLG knockout human induced pluripotent stem cell (iPSC) line based on KOLF2.1 J using CRISPR/Cas12a (Cpf1)-mediated genome editing. A guide RNA targeting exon 2 introduced a homozygous mutation, which was confirmed by sequencing. The edited cells maintained typical pluripotent stem cell morphology, expressed key undifferentiated markers, and retained the ability to differentiate into all three germ layers. Karyotype and copy number variation (CNV) analyses confirmed genomic stability and parental origin; the cells were free of mycoplasma. This cell line enables studies of FLG-associated skin biology and pathology.

Humans↗
PubMed2024

Model-directed generation of artificial CRISPR-Cas13a guide RNA sequences improves nucleic acid detection.

CRISPR guide RNA sequences deriving exactly from natural sequences may not perform optimally in every application. Here we implement and evaluate algorithms for designing maximally fit, artificial CRISPR-Cas13a guides with multiple mismatches to natural sequences that are tailored for diagnostic applications. These guides offer more sensitive detection of diverse pathogens and discrimination of pathogen variants compared with guides derived directly from natural sequences and illuminate design principles that broaden Cas13a targeting.

CRISPR-Cas Systems↗
PubMed1990

Neural network implementation of a three-phase model of respiratory rhythm generation.

A mathematical model of the central neural mechanisms of respiratory rhythm generation is developed. This model assumes that the respiratory cycle consists of three phases: inspiration, post-inspiration, and expiration. Five respiratory neuronal groups are included: inspiratory, late-inspiratory, post-inspiratory, expiratory, and early-inspiratory neurons. Proposed interconnections among these groups are based substantially on previous physiological findings. The model produces a stable limit cycle and generally reproduces the features of the firing patterns of the 5 neuronal groups. When simulated feedback from pulmonary stretch receptors is made to excite late-inspiratory neurons and inhibit early-inspiratory neurons, the model quantitatively reproduces previous observations of the expiratory-prolonging effects of pulses and steps of vagal afferent activity presented in expiration. In addition the model reproduces expected respiratory cycle timing and amplitude responses to change of chemical drive both in the absence and in the presence of simulated stretch receptor feedback. These results demonstrate the feasibility of generating the respiratory rhythm with a simple neural network based on observed respiratory neuronal groups. Other neuronal groups not included in the model may be more important for shaping the waveforms than for generating the basic oscillation.

Animals↗
PubMed1994

Power of segregation analysis for detection of major gene effects on quantitative traits.

The power to detect major gene effects by rejection of the "no major gene" null hypothesis against a mixed model alternative was determined in random samples of nuclear families over a variety of conditions. Benchmarks have been developed using a varying number of families whose structure includes both parents and three children. Phenotypes were simulated assuming a Mendelian major gene under either recessive or dominant inheritance, with 0-30% residual polygenic heritability. Three trait prevalences--5, 10, and 20%--were considered in combination with increasing displacement between homozygous means, spanning a range of 14 to 36% of the phenotypic variance attributable to the major gene effect. All other assumptions of the traditional mixed model were adopted in the generating models. Segregation analysis was carried out on the simulated data sets and the proportion of samples out of 200 replications in which the null hypothesis q = 0 was rejected is reported as the power. Thus, failure to detect a major gene effect in this context is solely due to sampling variation, since no other perturbations were introduced. In general, there appears to be greater power to detect dominant major gene effects as opposed to recessive ones using otherwise comparable parameter values, and the effect of varying sibship size under dominant models appears to be greater as well. The use of joint vs. conditional likelihood calculations also was evaluated: substantial drops in power were observed when using conditional likelihoods under recessive inheritance, while the differences in power appeared to be nominal under dominant inheritance. The results of this investigation are offered as a guide to assist in the design of family studies whose aim is to detect major gene effects.

Bias↗
PubMed1995

The five generations of American medical revolutions.

Current medical authors frequently use the term "revolution," yet American medicine is resisting change rather than embracing it. The last completed American medical revolutionary movement was the specialist-technologist movement of the late 19th and early 20th centuries. This paper describes a five-generational model of revolution. First-generation persons foment revolution; second-generation persons shape it into workable form and precipitate conflict; third-generation persons join the fight only when it appears to be all but won; fourth-generation persons enjoy the fruits of revolution; and fifth-generation persons, having risen to domination in the mature system, resist all attempts at reform by the next round of revolutionaries. In political revolutions, severe reactionary activity by the ruling party is often an indicator of an imminent overthrow by revolution. In scientific revolutions, the opposition of an established (specialist-technologist) paradigm to an emerging alternative (generalist) paradigm increases in intensity as the old order declines in strength; the opposition becomes most fierce just before the collapse of the old order. American specialist-technologist medicine, declining into its senescent fifth generation, will resist all but incremental change whenever possible, and accept major change only by force.

Family Practice↗
PubMed1991

Ultrastructure of chromatin. II. Three-dimensional reconstruction of isolated fibers.

Electron-microscope tomography has been used to reconstruct isolated, negatively stained chromatin fibers from Necturus maculosus erythrocytes. Tilt series micrographs from +70 degrees to -70 degrees at 5 degrees intervals were obtained, allowing a reconstruction resolution of 3.3 nm for fibers lying parallel to the tilt axis. The fibers were found to be flattened in the plane of the carbon support, and also stained differentially according to the distance from the carbon. A number of methods of presenting the three-dimensional information were explored. Especially useful was an automatic peak search method for locating putative nucleosome positions coupled with the production of a computer-generated model. Other valuable techniques included the generation of projection stereograms and construction of solid models. A peripheral location of nucleosomes in the chromatin fiber was indicated, and helical arrangements of nucleosomes were observed over short regions. However, no long-range ordering of nucleosomes was apparent. The extent to which this lack of order may be the result of events occurring during the preparation of chromatin for electron microscopy is discussed.

Animals↗
PubMed1986

Topological structure of rat mesenteric microvessel networks.

Microvascular lengths, diameters, and flow directions were determined in all vessel segments (n = 1303) between bifurcations in three complete rat mesenteric microvessel networks (25 mm2 each) using intravital video- and photomicroscopy. The classification of vessel segments as arteriolar, venular, or av-segments (all segments connecting the arteriolar to the venular tree) was based on purely topological criteria. The topological structure of the networks was analyzed using the Horton-Strahler technique and a new generation scheme. Generation numbers were assigned to the vessel segments on the basis of the number of upstream (in the arteriolar tree) and downstream (in the venular tree) bifurcations. The mean generation number of the av-segments, a characteristic parameter of the generation scheme, reflects the topological structure of the network more accurately than Horton's branching ratio Rb. Both the arteriolar and venular tree of the mesenteric networks were found to be dichotomous branching structures which were neither strictly symmetric nor strictly asymmetric. The topological information obtained was compared to network models generated by different random branching algorithms. The result of this comparison suggests that the network structure changes at a certain generation level. Distal to this generation level, the mesenteric networks resemble a model network generated by random branching at any segment, while the proximal portion is similar to a model allowing random branching at terminal segments only.

Animals↗
PubMed1992

Identification models of the nervous system.

It has been widely observed that when artificial neural networks are trained by supervised learning to do computations that also occur in the nervous system, the behavior of the model neurons often closely resembles that of the real neurons involved in the task. It is not immediately clear why this should be the case or what use can be made of models generated by supervised learning. Here, recent developments are reviewed and analysed in an attempt to clarify these issues. This analysis is facilitated by treating supervised learning models of the brain as a special case of system identification, a general and well-studied modeling paradigm. The neural systems identification paradigm provides a systematic way to generate realistic models starting with a high-level description of a hypothesized computation and some architectural and physiological constraints about the area being modeled. There is no inherent limitation to the realism that can be incorporated into identification models. This approach eliminates the need to find neural implementation algorithms by ad hoc means and provides neuroscientists with a convenient way to build models that account for observed data.

Algorithms↗