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PubMed2026

Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.

PURPOSE: Unravelling causal links between unique structural/copy-number variants (SV/CNV) and associated phenotypes is essential for correct genetic counselling. We investigated two families in which patients with craniosynostosis had SV/CNV potentially dysregulating a fibroblast growth factor (FGF)-encoding gene; a 730 kb dup(4)(q21.21) including FGF5; and a complex 568 kb interspersed 13q12.11 duplication, located 841 kb from FGF9. METHODS: We combined bioinformatic predictions of altered topologically-associating domain (TAD) structure, with experimental analysis (RNA- and ATAC- [assay for transposase-accessible chromatin] sequencing) of patient induced pluripotent stem cell lines (iPSCs) differentiated to neural crest (NCC) and osteoprogenitor (OPC) identities. For the dup(4)(q21.21) we generated a mouse bearing an equivalent rearrangement using CRISPR-Cas9 targeting. RESULTS: TAD analysis suggested potential dysregulation of the FGF5/FGF9 gene by bringing it into a novel genomic milieu. The RNA- and ATAC-seq assays demonstrated FGF5/FGF9 upregulation (2.7-18x) and local opening of chromatin, in 3/4 cell lines. For the dup(4)(q21.21), a causal role was supported by the mouse model, whereas interpretation of the 13q12.11 SV is confounded by a co-existing FOXP2 pathogenic variant. CONCLUSION: Patient iPSC-differentiated NCC and OPC lines, combined with TAD-based modelling to generate testable functional hypotheses, provide valuable functional evidence when evaluating causation of unique SV/CNV in craniosynostosis.

copy-number variant↗

PubMed2026

Causal circuit tracing reveals distinct computational architectures in single-cell foundation models: inhibitory dominance, biological coherence, and cross-model convergence.

MOTIVATION: Sparse autoencoders (SAEs) decompose foundation-model activations into interpretable features, but the model-internal causal interactions between those features (i.e. what ablating one feature does to the others, as distinct from the biological causal structure of the underlying cells)-and how those model-internal relationships relate to biological structure-are uncharacterized in single-cell foundation models. RESULTS: We introduce model-internal causal circuit tracing-zeroing one SAE feature at a source layer and measuring the resulting change in all downstream SAE features, for each of 120 source features-and apply it to Geneformer V2-316M and scGPT whole-human across four conditions (96 892 ablation-derived edges, 80 191 forward passes). On annotation-selected source features, edges share GO/KEGG/Reactome/STRING/TRRUST ontology terms at 50.9%-68.5%, a 2.9-6.2× enrichment over a configuration-preserving permutation null (P<.002); on 20 randomly sampled source features this attenuates to 21.5%-26.3%-still 2.5-3.1× above null-quantifying the annotation-selection contribution. Inhibitory dominance (fraction of ablation edges with d<0, i.e. source activation supports downstream target) is 65.5%-89.4%. scGPT produces larger raw per-edge effects (mean |d|=1.40 versus 1.05); after feature-share normalization, Geneformer is stronger (paired gene-pair ratio 0.64 on 33 301 shared pairs). Cross-model consensus yields 1142 architecture-invariant domain pairs (ordered pairs of GO biological-process categories "A→B" each connected by at least one ablation edge in both models; 10.6× enrichment over permutation null; P<.001). Circuit edge magnitude explains <1% of the variance in marginal driver-gene coexpression on the same cells (R2=0.010, n=31 176): the graph encodes structure beyond bivariate correlation. Against a matched-cell-type ENCODE ChIP-seq prior, circuit-predicted transcription factor (TF)→target pairs are enriched 2.06× (Fisher OR 5.84), markedly higher than 1.12× against TRRUST; direct ChIP-seq-supported target pairs show 10-30× larger CRISPRi sign-bias-corrected excess than indirect pairs. Gene-level CRISPRi validation on Replogle K562 and the noncancer RPE1 arm (and a true primary-T-cell control from Shifrut E, Carnevale J, Tobin V et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 2018; 175: 1958-71.e15) after sign-bias correction shows excess over baseline of +0.03 and +0.35 percentage points on K562 and RPE1, respectively (baseline already 52%-56% from sign marginals); effect-magnitude Spearman correlations ρ≈0. Bootstrap and per-cell-type stability (N∈{50,100,200}; B cell, CD4 + T, macrophage) give Pearson r≥0.97 on shared edges with 100% sign agreement; edge Jaccard grows monotonically with sample size. The circuit graph is therefore highly reproducible as an effect-size map, cell type specific in edge identity, consistent with coexpression encoding, and weakly but detectably enriched for ChIP-seq-supported direct regulatory edges. AVAILABILITY AND IMPLEMENTATION: https://github.com/Biodyn-AI/bio-sae-circuits (Python). Archival DOI: 10.5281/zenodo.19,633,166 (Zenodo).

Humans↗

PubMed1994

Optimizing performance through process improvement.

Health care professionals have found traditional problem solving and traditional management have not succeeded in "assuring quality." Organizations are changing the way they do business and are utilizing process improvement methodology to improve performance. Based on important functions, select dimensions of performance for processes are measured, evaluated, redesigned, and improved. Once priorities for improvement activities are determined, improvement projects can be implemented utilizing various process improvement models. The PRIDE (process, relevant, interpret, design, execute) model, designed by the authors, is one approach that can be applied in any setting.

Efficiency, Organizational↗

PubMed1988

Porcine and human insulin absorption from subcutaneous tissues in normal and insulin-dependent diabetic subjects: a deconvolution-based approach.

The mechanisms of sc insulin absorption are not understood, and models for interpreting in vivo data cannot be developed without gross simplification. To overcome this difficulty we developed a new approach which makes use of deconvolution analysis and does not require any model of the sc tissue. In five normal subjects and seven insulin-dependent diabetic (IDDM) patients endogenous insulin secretion was suppressed by means of a hypoglycemic glucose clamp procedure (approximately 2.8 mmol/L) sustained by a continuous insulin infusion (approximately 4 pmol/min.kg). A bolus injection of insulin (5.4 nmol) was administered iv, and plasma insulin concentrations were measured frequently for 2 h to assess iv insulin kinetics. Insulin then was injected sc in the abdominal region, and plasma insulin concentrations were measured for 8 h. Each subject was studied twice, with porcine and semisynthetic human insulin (Actrapid, Novo). The rate of insulin absorption was reconstructed by deconvolution from the plasma concentrations and iv insulin kinetic data. Linearity of the iv insulin kinetics, essential for deconvolution analysis, was confirmed by a dose-response study in the range of the measured concentrations (150-1800 pmol/L). In most instances, a two-compartment model was adequate to describe the iv response. The mean plasma insulin clearance rates were 15.5 +/- 1.9 (+/- SD) mL/min.kg (porcine) and 17.2 +/- 6.0 (human) in normal subjects and 20.7 +/- 8.8 (porcine) and 20.9 +/- 9.1 (human) in the IDDM patients. The rate of appearance of human insulin from sc tissue was faster than that of porcine insulin in both normal and IDDM subjects, but no significant differences were found in bioavailability, which was 55 +/- 12% (+/- SD; porcine) and 61 +/- 34% (human) in the normal subjects, and 84 +/- 28% (porcine) and 86 +/- 23% (human) in the IDDM patients. The rate of absorption and bioavailability were higher in the IDDM patients than in the normal subjects, a difference possibly related to increased sc blood flow in the IDDM patients. No differences were found with regard to glucose requirement values, normalized to plasma insulin concentrations, in agreement with the finding that the bioavailability of the two insulin species was similar.

Adolescent↗

PubMed1991

Localization of the sites of pulmonary vasomotion by use of arterial and venous occlusion.

In this study, we present a new approach for using the pressure vs. time data obtained after various vascular occlusion maneuvers in pump-perfused lungs to gain insight into the longitudinal distribution of vascular resistance with respect to vascular compliance. Occlusion data were obtained from isolated dog lung lobes under normal control conditions, during hypoxia, and during histamine or serotonin infusion. The data used in the analysis include the slope of the arterial pressure curve and the zero time intercept of the extrapolated venous pressure curve after venous occlusion, the equilibrium pressure after simultaneous occlusion of both the arterial inflow and venous outflow, and the area bounded by equilibrium pressure and the arterial pressure curve after arterial occlusion. We analyzed these data by use of a compartmental model in which the vascular bed is represented by three parallel compliances separated by two series resistances, and each of the three compliances and the two resistances can be identified. To interpret the model parameters, we view the large arteries and veins as mainly compliance vessels and the small arteries and veins as mainly resistance vessels. The capillary bed is viewed as having a high compliance, and any capillary resistance is included in the two series resistances. With this view in mind, the results are consistent with the major response to serotonin infusion being constriction of large and small arteries (a decrease in arterial compliance and an increase in arterial resistance), the major response to histamine infusion being constriction of small and large veins (an increase in venous resistance and a decrease in venous compliance), and the major response to hypoxia being constriction of the small arteries (an increase in arterial resistance). The results suggest that this approach may have utility for evaluation of the sites of action of pulmonary vasomotor stimuli.

Animals↗

PubMed1995

A spectral network model of pitch perception.

A model of pitch perception, called the spatial pitch network or SPINET model, is developed and analyzed. The model neurally instantiates ideas from the spectral pitch modeling literature and joins them to basic neural network signal processing designs to stimulate a broader range of perceptual pitch data than previous spectral models. The components of the model are interpreted as peripheral mechanical and neural processing stages, which are capable of being incorporated into a larger network architecture for separating multiple sound sources in the environment. The core of the new model transforms a spectral representation of an acoustic source into a spatial distribution of pitch strengths. The SPINET model uses a weighted "harmonic sieve" whereby the strength of activation of a given pitch depends upon a weighted sum of narrow regions around the harmonics of the nominal pitch value, and higher harmonics contribute less to a pitch than lower ones. Suitably chosen harmonic weighting functions enable computer simulations of pitch perception data involving mistuned components, shifted harmonics, and various types of continuous spectra including rippled noise. It is shown how the weighting functions produce the dominance region, how they lead to octave shifts of pitch in response to ambiguous stimuli, and how they lead to a pitch region in response to the octave-spaced Shepard tone complexes and Deutsch tritones without the use of attentional mechanisms to limit pitch choices. An on-center off-surround network in the model helps to produce noise suppression, partial masking, and edge pitch. Finally, it is shown how peripheral filtering and short-term energy measurements produce a model pitch estimate that is sensitive to certain component phase relationships.

Cochlea↗

PubMed1982

Computer simulation of metabolism of glucose-perfused rat heart in a work-jump.

A computer model of glycolysis, the tricarboxylic acid cycle, and related amino acid metabolism, is described for a glucose-perfused experimental rat heart preparation suddenly switched from low work load (Langendorff perfusion) to high work load (left atrial perfusion). Glycolytic intermediate measurements suggest activation of phosphofructokinase within a few seconds. This activation, and also that of other glycolytic enzymes, is calculated as due to a sharp increase in cytoplasmic Mg2+ level, which overcomes the inhibitory effects of a rapid fall in cytoplasmic pH to 6.77 (calculated from a rapid fall in creatine phosphate). Increased glycolytic substrate is initially supplied by glycogenolysis mediated by phosphorylase b (activated by an early rise in cytoplasmic AMP), followed by increased glucose uptake from the perfusate. Testable predictions are made by the model, especially that lactate production rate should peak early. Additional experiments are described that verify these predictions and fill gaps in the original measurements. The role of modeling in interpreting such experiments is discussed.

Amino Acids↗

PubMed1975

Mathematical modelling of cell cycle and chronobiology: preliminary results.

A mathematical model taking into account the observed diurnal variations in cell kinetics is presented. The principle of the method is to divide each phase of the cell cycle in a definite number of compartments and to assume that the fluxes into and out of the compartments corresponding to the G1 phase are the only varying parameters through the day. Theoretical evolutions of percentages of cells in M and S phase, theoretical curves for percentage labelled mitosis experiment are derived. Preliminary results of the applications of the model to interpretation of published experimental data obtained in hamster cheek pouch epithelium are shown.

Cell Division↗

PubMedDate not supplied

Removable partial denture design: a photoelastic study.

Quantifiable frozen-stress photoelastic techniques were used to analyze stresses induced in mandibular models by a conventional free-end saddle removable partial denture. Four quasi-anatomical mandibular models were constructed for processing, together with their respective calibration specimens, through identical time/temperature stress-freezing cycles. After processing and slicing, an unloaded control model demonstrated some low-order fringes adjacent to the coronal third of the abutment tooth roots, but was otherwise stress free. A lower bilateral free-end saddle partial denture was constructed and fitted in turn to each of the remaining three models. Each denture/model combination was then loaded and processed through a stress-freezing cycle. After processing, 6-mm slices were cut from selected regions for analysis for the presence of stresses. Using a polariscope with circular polarized, monochromatic light, values for maximum shear stress were calculated at selected points in the slices taken from the three loaded models. Variations up to 28% of the mean were obtained for the three experimental models as compared with the consistent results for the material fringe values obtained from the calibration specimens. The study pointed out the problems involved in using photoelastic stress analysis on complicated anatomical models. The interpretation of the results from such studies should be approached with caution.

Denture, Partial↗

PubMed1975

[Psychoanalytic interpretation of sleep-disturbances. Model of a structural-theoretical classification (author's transl)].

In psychoanalytic literature anxiety, guilt-feelings and unconscious hostility are assumed to be the most common causes of spleeplessness. The author attempts to ascribe these emotions to conflicts between the instances of the psychoanalytic personality model as a structure-theoretical classification of sleep-disturbances. Three large groups emerge: Neurotic disturbances of sleep with internalized conflicts (these correspond essentially to what are generally understood to be neurotic sleep-disturbances), neurotic disturbances of sleep with externalized conflicts (these are more common in childhood) and non-neurotic sleep disturbances. Within these groups the relative parts of effectiveness of the instances of the psychoanalytic personality-model - ego, super-ego, id and reality - are discussed.

Aggression↗

PubMedDate not supplied

Lesion spectra: radiation signatures and biological gateways.

We describe an integrative approach to the modeling of biophysical radiation effects. The model takes aim at practical applications of the knowledge provided by molecular studies of radiation-matter interactions in DNA. The central proposition is the idea that the distribution of molecular lesions (i.e., a molecular lesion spectrum, MLS) generated in DNA by exposure to a particular radiation is a characteristic of that causal radiation (i.e., is a radiation signature, RS). We have found that adaptive neural networks (ANN's) provide an efficient way to validate that proposition and that ANN's are also likely to be invaluable in any attempt to correlate cancers with radiation types (i.e., with RS's), to use RS's for evaluating individual carcinogenic susceptibilities, and to develop a low-dose personalized monitoring capability. Although efforts to identify products of radiation that are specific to radiation type and to link those with biological responses are almost a century old, the RS concept has provided the first quantitative confirmation of such causal relations. That is, RS's and radiation markers have been identified for various types of radiation, electromagnetic (EM) and particulate, and these signatures and markers may constitute a new way for fast radiation exposure estimates, risk assessment, and cumulative low-dose evaluation. In this work, while we will present a short review of the concepts and methods related to both RS's and markers, almost the entire effort will relate to the modeling and interpretation of RS's using ANN processing.

Biomarkers↗

PubMed1994

Complex dynamic order in ventricular fibrillation.

Self-sustained circus movement of excitation has long been discussed as the underlying mechanism of ventricular fibrillation. This concept now appears to have found general acceptance. Mapping studies are very expensive and do not permit observations to be isolated from varying external influences. The authors have therefore used a simple cellular automation for studying the basic principles of excitation spreading during ventricular fibrillation under various conditions. Highly ordered spiral waves, described in other computer models, previously interpreted as fibrillation were encountered. Comparisons of pseudo-electrocardiograms created by the cellular automaton with original electrocardiographic recordings showed similarity in the time series and in fast Fouriér transformation. Modulation of refractory times often led to the termination of model fibrillation. Clinical evidence suggests that maintenance of the 1/f (RR-variability) variations produced by the autonomic nervous system exerts a protective effect on the evolution of ventricular fibrillation.

Computer Simulation↗

PubMed1988

The electrical potential produced by a strand of cardiac muscle: a bidomain analysis.

Analytic expressions are derived relating the transmembrane potential to the intracellular, interstitial and external potentials in a cylindrical strand of cardiac muscle lying in a saline bath. The bidomain model is used to account for the anisotropy and interstitial space in the tissue. The implications of this model for interpreting potential data from strands of cardiac muscle are discussed.

Action Potentials↗

PubMedDate not supplied

Human sexuality in biological perspective: theoretical and methodological considerations.

An increasing number of observers are claiming that a biological model is more appropriate to an understanding of human sexuality than the conventional social-learning one. Such claims have prompted a perusal of the biological literature to ascertain whether the relevant evidence is convincing. The results of this review suggest that claims for the biological model are questionable since the evidence for that model either derives from animal studies (and is thus not generally applicable to human behavior) or is inconclusive, contradictory, or methodologically deficient. It is concluded, therefore, that behavioral scientists are at present on firm ground in using a social-learning, in preference to a biological, model to interpret most aspects of human sexual behavior.

Adolescent↗

PubMed1982

Epidemiological models of poliomyelitis and measles and their application in the planning of immunization programmes.

This report describes the construction and application of epidemiological models of measles and poliomyelitis. In these models, epidemiological classes and their age structure have been based on the natural history of these diseases in the population aged 0 - 19 years. The flow of the population through the classes has been expressed as an equation system suitable for computer interpretation. The models have been used to simulate both the natural course of the diseases and the effect of various immunization schemes. The models were also used to explore prospects for control and eradication of these diseases with specific immunization programmes, and their relative effectiveness and cost-effectiveness are discussed.

Adolescent↗

PubMed1975

Reaction mechanism and structure of the active site of proline racemase.

Proline racemase catalyzes the interconversion of D- and L-proline. Previous studies in this laboratory have established that the reaction proceeds by means of a two-base mechanism in which one base on the enzyme removes the substrate alpha-hydrogen as a proton and the conjugate acid of another base donates a proton to the opposite side of the alpha-carbon (Cardinale, G.J., and Abeles, R.H., (1968), Biochemistry 7, 3970. An assumption of the proposed mechanism was that no proton exchange occurs from the enzyme-substrate complex. In the present study, we have shown that the rate of 3H release from DL-[alpha-3H]proline, in the presence of proline racemase, decreases with increasing proline concentrations. These results establish that release of the substrate derived proton from the enzyme occurs largely, possibly exclusively, after release of the product. Under initial velocity conditions, the rate of 3H release from L-[alpha-3H]proline is not reduced with increasing L-proline concentrations. Thus, the enzyme-bound proton derived from one isomer can only be "captured" by the other isomer. We conclude that there are two forms of the enzyme; one binds L-proline and the other D-proline. Release of the substrate derived proton from enzyme is more rapid than the interconversion of these two forms. These results are consistent with the previously proposed mechanism. Proline racemase is composed of similar subunits of mol wt 38,000 as determined by gel electrophoresis in the presence of sodium dodecyl sulfate. Equilibrium dialysis experiments detect only one substrate binding site for every two subunits. When the oxidized form of the enzyme, which is inactive and cannot bind substrate, is reduced by thiol to yield active enzyme, two cysteine sulfhydryl groups per dimer become available to react with iodoacetate. Inactivation of the enzyme occurs upon modification of one of these cysteines. All iodoacetate incorporation occurs at the same point in the primary sequence of the enzyme, and can be prevented by the presence of proline or pyrrole-2-carboxylate, a substrate analog. A model is proposed in which a single active site is formed by elements of two identical subunits. Although the data are consistent with this model, another interpretation, in which half of the subunits are nonfunctional, cannot be ruled out.

Amino Acid Isomerases↗

PubMed1982

[Feasibility of the in vitro evaluation of bioavailability. 3: Method of operation of a newly-developed absorption model and results obtained with it].

In connection with the function of a newly constructed absorption model the problem of interpretation of values obtained by models in regard of bioavailability is discussed. Wrong interpretations can be obtained if nonanalogous values are compared. An interpretation is proposed to calculate a value which is analogous to the relative bioavailability (calculated bioavailability). The efficiency of the absorption model and of the interpretation method is demonstrated by three examples of preparations of phenytoin, digoxin and chloramphenicol. We compared these results with the bioavailability of these preparations and we found a good correspondence.

Absorption↗

PubMed1988

Physicochemical aspects of percutaneous penetration and its enhancement.

The classic diffusion model-based interpretation of percutaneous absorption is compared to a simple kinetic analysis. The physicochemical significance and the major deductions of the two approaches are shown to be in general agreement. In particular, the effect of penetrant oil/water partition coefficient on transdermal flux is consistently predicted by the two models. Diffusional and kinetic assessments of skin penetration enhancement are then shown to reveal similar dependencies upon penetrant physical chemistry. It is demonstrated that the requirements for successful promotion of a lipophilic drug's transdermal flux are quite different from those necessary for a hydrophilic penetrant. Finally, in light of published transport data and our increased comprehension of the stratum corneum barrier function, the evidence for (and significance of) different absorption paths across the stratum corneum is considered. In addition, the impact of penetrant "size" on transport is addressed. It is argued that currently held beliefs concerning (i) a putative "polar" route through the stratum corneum and (ii) the dependence of flux on molecular weight warrant considerable further attention before their unequivocal acceptance is appropriate.

Diffusion↗