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Results for “Model interpretability”

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At least 199 records · Page 11Linked to original sources

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↗

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↗

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↗

PubMed1992

A coupled-oscillator model of ovarian-cycle synchrony among female rats.

The ovarian cycles of female rats become synchronized when they live together, as do the cycles of many other mammals. Ovarian cycles also become synchronized when rats live apart if they share a common air supply, indicating that ovarian-cycle synchrony is mediated by pheromones. We developed a coupled-oscillator model of ovarian-cycle synchrony to test several hypotheses about its pheromonal and neuroendocrine mechanisms and to guide our experimental research. The model spans three levels of organization: the group, the rat, and the neuroendocrine components of the ovarian system. The ovarian system (not the ovaries themselves) are modeled as an oscillating system. Coupling among ovarian systems is mediated by the exchange of two pheromones, one that delays the phase of the ovarian system and one that advances it. Computer simulation experiments showed that this coupled-oscillator model can explain the levels of ovarian-cycle synchrony observed in groups of female rats while, at the same time, matching an empirical distribution of ovarian-cycle lengths. By successfully matching computer simulation data with empirical data, we were able to infer theoretical predictions in a number of areas: (1) effect of initial conditions on the probability that a group will change to different synchrony level and phase relationships, i.e. the transition probability between all synchrony levels and phase relationships; (2) effects of individual differences in pheromone sensitivity on ovarian-cycle synchrony; (3) the timing of pheromone sensitivity during the ovarian cycle; and (4) the existence of partial luteinizing hormone surges, which may cause the "spontaneous" prolonged ovarian cycles associated with ovarian-cycle synchrony. The paper concludes by discussing the integrative role of this model for experimental research. In particular, we focus on the role of this model in interpreting theoretical aspects of ovarian-cycle synchrony as well as for guiding future experimental research into its mechanisms and functions.

Animals↗

PubMed2026

An encyclopedia of human enhancer-gene regulatory interactions.

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Humans↗

PubMedDate not supplied

[A molecular version of a probability model of radiation injury of cells].

A molecular version of cell inactivation probability model has been proposed. Formal parameters of the model are interpreted. It has been shown that yeast cell inactivation regularities can be explained by DNA double-strand breaks processing during the postirradiation cell division.

Cell Death↗

PubMed2026

Genomic signatures associated with epidemiologically defined high-risk pathogenic Escherichia coli isolates identified by interpretable machine learning.

Pathogenic Escherichia coli is a major cause of foodborne illness worldwide and includes strains capable of causing severe disease. To establish a genome-informed framework for foodborne outbreak surveillance, we analyzed 1,029 E. coli isolates from clinical, food, livestock, and environmental sources using whole-genome sequencing. Pathogenic isolates obtained from human clinical cases or linked to documented outbreaks were classified as epidemiologically defined high-risk (EpiHR), whereas the remaining pathogenic isolates were classified as non-EpiHR. Virulence-associated genomic features were extracted using a bioinformatics pipeline, and four machine learning (ML) algorithms, including gradient boosting machine, random forest (RF), and support vector machines with linear and radial basis function kernels, were evaluated. Among them, the RF model showed the best performance, achieving an area under the curve (AUC) of 0.98 and accuracy of 0.93 in 10-fold cross-validation. Additional leave-one-group-out validation showed retained discrimination across held-out sequence types and serotypes, although performance was reduced when isolates were grouped by isolation source. Evaluation using an independent test dataset of 1,908 publicly available pathogenic E. coli genomes showed an AUC of 0.97 and a sensitivity of 0.98. Feature importance analysis using Shapley additive explanations identified influential predictive features, including traT, etpB, and enterotoxin-associated genes. A reduced 10-feature model achieved an AUC of 0.79 in the independent test dataset, supporting its exploratory use for future simplified screening approaches. These results indicate that genome-based ML provides a sensitive framework for surveillance-oriented prioritization of EpiHR pathogenic E. coli isolates, with model predictions interpreted together with epidemiological information.

Escherichia coli↗

PubMed1986

Determinants of perceived mental health status and help-seeking behavior: preliminary testing of a conceptual model.

This paper presents a preliminary test of the conceptual model of cognitive determinants of the perception of mental health status. Path analysis was used to examine the causal relationships between education, awareness of higher level needs, one's definition of mental health, and self-rating of mental health status. Discriminant analyses was used to evaluate these variables and others as predictors of help-seeking behavior. Results indicate the importance of cognitive factors in the perception of mental health status and support a direct causal interpretation of model variables. Symptom checklist scores and path variables were found to be the best predictors of help-seeking behavior.

Adult↗

PubMedDate not supplied

Toward theory-based diagnostic categories.

As a social institution, nursing has a responsibility to society for the development of knowledge in the areas described by nursing diagnoses. This article focuses on the need for developing the theoretical basis of each diagnostic category. Diagnoses are viewed as summarizations of underlying conceptual models for interpreting observations, and as such, they provide a perspective for understanding and thinking about a set of clinical observations. At present many diagnostic concepts do not meet this standard and suggest primitive, pretheoretical ideas with a minimal knowledge base. The importance of having valid and reliable diagnostic categories for use in making clinical judgements and as a focus for care planning is discussed. A cycle of development is outlined in three phases: diagnostic concept identification, concept analysis-model development, and construction/reconstruction of diagnostic categories. It is suggested that a useful category captures the conceptual understanding and state of knowledge development about a phenomena in its (a) name, (b) definition, and (c) cluster of defining characteristics.

Concept Formation↗

PubMed1992

Interpretation of the X-ray scattering profiles of chromatin at various NaCl concentrations by a simple chain model.

In order to interpret the change in the X-ray scattering profiles from rat thymus chromatin, extensive model calculation was carried out. Chromatin is modelled as a string of subunits (nucleosomes) in which disorder is introduced into the positions of adjacent subunits. Disposition parameters characterizing the arrangement of subunits were estimated for various states of chromatin, so that the main feature of the scattering profiles is described. The result indicated that the structure of chromatin changes, as the NaCl concentration increases, from the extended "beads-on-a string" structure to the condensed helical structure. The latter has an outer diameter of about 26 nm with 3-4 nucleosomes per turn. In the intermediate state, it has a loose helical structure. The estimation of disorder suggested that the arrangement of subunits is appreciably disordered even in the condensed helical filament at 50 mM NaCl. Our model for chromatin condensation seems to support models of the "crossed linker" type.

Animals↗

PubMed1987

Staff resistance to interpretive psychotherapy in the in-patient community meeting.

The authors propose using the in-patient psychiatry unit community meeting for large-group interpretive psychotherapy, employing the model of Winer & Lewis (1984). This model rests heavily on interpretation of group transferences in the here and now. The staff has the task of discovering patients' veiled references to them and interpreting the patients' resistance to direct expression of their experience of the staff. The authors discuss the impact of introducing the technique upon staff members. Staff members resist this new model in order to defend against self-esteem injury, loss and regression, staff-staff conflict, and the recognition of their own disavowed internal motives. Staff self-esteem can be endangered by any programme change, by the loss of accustomed roles, by the patients' hostility and direct criticism, and by the staff's own sense of failure to realize therapeutic ambitions. Some of the resistance specific to interpretive group psychotherapy arises from the threat of group silence or alienation. The group leader, in addition, faces the difficult task of understanding the dynamics of a large group with only minimal support.

Humans↗

PubMed1992

Evaluation strategies for some nonstandard conditionals during adolescence.

380 adolescents and young adults between the ages of 11 and 29 years participated in three experiments in which they were asked to evaluate both universally quantified nonstandard and standard conditionals using items of information bearing upon them. Subjects found it much easier to avoid a biconditional interpretation with the nonstandard than with the standard conditionals, which throws doubt on the explanation of desire for symmetry of biconditional conversion. It was argued, from data of other studies, that a modified version of the Piagetian view that biconditional conversion occurs as a result of a desire to avoid the complications of dealing with three factors explains most cases of such conversion in adolescence. Results also confirmed that it is more profitable to analyse performance on tasks of this kind using a two-stage model of interpretation and information use previously developed to explain performance with standard universally quantified conditionals than to view such tasks as providing truth-table values. Such an analysis was extended to the nonstandard conditionals studied in the present paper. The origins of the dramatic differences in information-use strategies adopted by adolescents for standard and nonstandard conditionals remain unclear.

Adolescent↗

PubMed2026

Decoding TnsC Filament Assembly in CRISPR-Associated Transposons Using Interpretable Deep Learning and Molecular Simulations.

CRISPR-associated transposons (CASTs) enable programmable DNA integration, yet how the TnsC regulator forms processive filaments on DNA to coordinate RNA-guided transposition in type V-K CAST systems remains unknown. Here, we integrate large-scale molecular simulations, interpretable deep learning using graph attention networks (GATs), and causal inference analyses to define the molecular determinants of TnsC filament nucleation and elongation. We show that TnsC nucleates by inducing localized DNA deformation that propagates along extended filaments, with Granger causality revealing that TnsC motions precede and predict DNA deformation. Interpretable GAT models demonstrate that elongation is determined during early recognition between incoming and DNA-bound subunits, followed by structural reorganization that regenerates the recruitment interface and enables processive assembly. These results elucidate the molecular mechanism of processive TnsC filament assembly and explain why isolated TnsC filaments preferentially elongate in the 5' → 3' direction, while accessory transposition factors can reshape the interaction landscape and alter filament growth polarity. Together, these findings advance our understanding of CAST function and inform the engineering of programmable DNA integration platforms. Beyond CAST systems, this work introduces an interpretable GAT approach as a general and transferable deep learning strategy for uncovering molecular mechanisms in biological systems, while demonstrating the power of causal inference for dissecting directional relationships in molecular dynamics.

Deep Learning↗

PubMed1976

Interpretation of osmotic pressure in solutions of one and two nondiffusible components.

Osmotic pressure data from aqueous solutions of nondiffusible serum albumin (BSA), chondroitin sulfate (CHS), and dextran T110 (D110), taken singly and in binary combinations, were interpreted in terms of excluded volume. The principal solvent was phosphate-buffered saline, pH 7.2, at 23 degrees C. Osmotic pressures were measured with a membrane osmometer fitted with Amicon PM-10 membranes. Data from each solution were fit by stepwise regression with a three- or four-term polynomial in integral powers of total nondiffusible solute concentration in accordance with the general solution theory of McMillan and Mayer (1945, J. Chem. Phys. 13:276) as extended by Yamakawa (1971, Modern Theory of Polymer Solutions, Harper & Row, New York). The date display a high internal consistency, and the results correlate well with published molecular weights and exclusion data where available. Number average molecular weights calculated from the "first virial coefficients" are: BSA, 67,000 +/- 11%; D110, 76,000 +/- 11%, CHS, 39,000 +/- 6%. Excluded volumes (in cubic centimeters per molecule) calculated from the "second virial coefficients" are: BSA, 0.97 X 10(-18); D110, 3.04 X 10(-18); CHS, 14.3 X 10(-18); BSA-D110, 6.8 X 10(-18); BSA-CHS, 7.8 X 10(-18). Uncertainty is about 30%. An empirical model for interpretation of calculated excluded volumes is proposed. It appears that CHS has the "largest" exclusion effect of the three molecules.

Animals↗

PubMed1991

Effect of aniosmotic media on the volume of the T-lymphocyte nucleus.

Time-resolved measurements of the nuclear volume response of human peripheral T-lymphocytes, under aniosmotic conditions, are presented. In the experiments slit scanning FlowCytometry methods were used. We propose an extension to the standard solid viscoelastic model to interpret the observed dynamical behavior of the nucleus. It is shown that experimental and theoretical evidence indicates a passive nuclear response merely induced by a mechanical link (i.e., the cytoskeleton) between the cell membrane and the nuclear envelope. Implications of this work to the field of cellular mechanics and cytoskeletal rheology are surveyed.

Cell Nucleus↗

PubMed1990

Replacement of the Escherichia coli trp operon attenuation control codons alters operon expression.

To test features of the current model of transcription attenuation in amino acid biosynthetic operons, alterations were introduced into the trp operon leader region and expression of the mutated operons was examined in miaA and miaA+ Escherichia coli strains that lacked the trp repressor. The miaA mutation prevents modification of the adenosine residue immediately 3' of the anticodon of tRNAs that interact with codons beginning with uridine. The undermodified tRNA(Trp) in miaA strains is thought to increase readthrough at the trp attenuator by slowing ribosome movement over two tandem Trp codons in the 14-codon leader peptide coding region. The rate of translation of these two "control codons" is thought to be the key step in determining the extent of transcription attenuation in the trp leader region. Sequential deletion of trpL DNA specifying the leader peptide initiation region, RNA segment 1, RNA segment 2 and RNA segment 3 alternately decreased and increased trp operon expression, a result consistent with previous findings in another bacterium and the generally accepted model for transcription attenuation. Replacement of the tandem Trp control codons by AGG-UGC (Arg-Cys) codons eliminated the miaA-dependent increase in transcription readthrough. Replacement of the Trp control codons by AGG-UGA (Arg-stop) codons caused complete readthrough at the trp attenuator as well as abolishing the miaA effect. Presumably, the ribosome terminating translation at the new UGA codon mimics the effect of a stalled ribosome at the Trp control codons. This finding suggests that ribosome dissociation at some stop codons is slow relative to the time required for transcription of the trp leader region. Thus, most ribosomes translating the trp leader peptide coding region may remain attached to the natural UGA stop codon until after the attenuation decision is made. The interpretation supports models for trp operon attenuation in which the elevated basal level readthrough is determined by occasional ribosome release prior to synthesis of the 3:4 terminator hairpin.

Amino Acid Sequence↗

PubMed1992

Symmetry conditions for binding processes.

Symmetry conditions are derived for global and local binding processes in biological macromolecules. It is shown that the conditions applying in the case of the macromolecule as a whole are decoupled from those referring to individual sites. In the case of two sites, the global binding curve is always symmetric, and the individual-site binding curves are always asymmetric, unless the two sites are identical or independent. In the case of three sites or more, individual-site binding curves can show symmetric or asymmetric behavior. The conditions derived for symmetry in the local description of binding processes also apply to the case of linkage among different ligands and to steady-state kinetics. Application to the analysis of oxygen binding to human hemoglobin under physiological conditions provides a model-independent interpretation of the asymmetric nature of the binding curve. Asymmetry of the global binding curve can coexist with symmetric or asymmetric binding to the individual alpha and beta chains. If the binding curves of the two chains are symmetric, then subunit heterogeneity and asymmetric interactions must exist in the hemoglobin tetramer. On the other hand, if the binding curves of the two chains are asymmetric, then subunit heterogeneity and asymmetric interactions are not necessary for global asymmetric binding.

Allosteric Regulation↗

PubMed1992

Personality and psychopathology: an application of the five-factor model.

Our review is concerned with the relationship of the five-factor model of personality to psychopathology, focusing in particular on Axis II personality disorders and depression. The five factors provide a particularly compelling model for interpreting the Axis II personality disorders as maladaptive variants of normal personality traits. However, we also discuss methodological and conceptual limitations of this application. There has been little research on the relationship of Openness, Agreeableness, and Conscientiousness to Axis I mental disorders, but considerable attention has been given to Neuroticism and Extraversion. We focus in particular on the difficulty in distinguishing between the various ways in which personality can relate to depression, either as a predisposition to, a complication of, a pathoplastic effect upon, or a spectrum variant of the mental disorder. We conclude with recommendations for future research.

Diagnosis, Differential↗