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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.
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.
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.
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.
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.
Two N,N-dimethylphentermine (N,N-dimethyl-2-amino-2-methyl-3-phenylpropane) substrates differing in deuterium substitution have been used to determine the intermolecular and intramolecular isotope effects associated with the cytochrome P-450-dependent N-demethylation of this substrate. No intermolecular isotope effect was observed in Vmax or Vmax/Km when the reaction rates for this substrate were compared to those for the substrate in which both N-methyl groups contained deuterium. In contrast, identical isotope effects of 1.6 to 2.0 were observed in both Vmax and Vmax/Km when this reaction was studied with a substrate in which only one of the two N-methyl groups was substituted with deuterium. Furthermore, both the intermolecular and intramolecular isotope effects were independent of the cytochrome P-450/NADPH-cytochrome P-450 reductase mole ratio. From these data, it is concluded that: 1) the carbon-hydrogen bond cleavage step does not contribute significantly to Vmax; 2) the contribution of the carbon-hydrogen bond cleavage step to Vmax is not detectably increased through changes in the cytochrome P-450/NADPH-cytochrome P-450 reductase mole ratio; 3) the N-methyl groups are free to exchange at the enzyme active site. The basis for these conclusions is the proposal of a new kinetic model for interpretation of intramolecular isotope effects which shows that intramolecular isotope effects are not necessarily equal to intrinsic isotope effects and, in fact, may be much smaller.
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.
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.
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.
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.
Data from routine CT scan examinations are employed to illustrate the use of the polychotomous logistic regression model as a statistical diagnostic tool. The assumptions of the model, the interpretation of its parameters, and its capabilities are described in detail. In carrying out the analysis on the CT data, a large, relatively sparse data set, many technical difficulties were encountered. Modifications to the methodology that were necessary to permit its implementation are described, and it is demonstrated that an unbiased analysis of T + 1 diagnostic categories can be implemented by separately performing T individual simple logistic analyses. The limitations of the methodology are discussed. It is hoped that this paper may serve as a basis for the practical implementation of the polychotomous logistic model in similar diagnostic settings.
This paper presents some elementary principles regarding constraints on movements, which may be useful in modeling and interpreting motor control strategies for skilled movements. Movements which are optimum with respect to various objectives, or "costs", are analyzed and compared. The specific costs considered are related to movement time, distance, peak velocity, energy, peak acceleration, and rate of change of acceleration (jerk). The velocity patterns for the various minimum cost movements are compared with each other and with some skilled movement patterns. The concept of performance trade-offs between competing objectives is used to interpret the distance-time relationships observed in skilled movements. Examples of arm movements during violin bowing and jaw movements during speech are used to show how skilled movements are influenced by considerations of physical economy, or "ease", of movement. Minimum-cost solutions for the various costs, which include the effect of frictional forces, are given in Appendices.
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.
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.
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.
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.
Results of animal experiments using sinusoidal changes in inspired halothane concentration showed that the ratio of variation in end-expired concentration to the variation in inspired concentration reached a plateau in the Bode diagram. With the help of an uptake and distribution model, the interpretation of the results showed that the level of the plateau is determined by the overall ventilation-perfusion ratio. With a good selection of input frequency, tracer agent, and known ventilation, the ventilation-perfusion ratio and the lung perfusion can be consequently obtained noninvasively. Mean ventilation-perfusion ratio was determined with 20 human voluteers. At rest a mean ratio was found of 0.87 +/- 0.28 (SD). At a work load of 90 W a mean ratio was found of 1.19 +/- 0.19 (SD). In two individuals reproducibility and influence of CO2 was studied. At rest without additional CO2 the ventilation-perfusion ratio was 0.71 +/- 0.06 (SD) obtained with a constant breathing rate of 10/min. At an end-expired CO2 level of 6% the ventilation-perfusion ratio was increased almost 2.5 times. The calculated perfusion with and without increased end-expired CO2 levels under the same work load were well reproducible.
1. The pH-dependences of the second-order rate constant (k) for the reactions of papain (EC 3.4.22.2) with 2-(acetamido)ethyl 2'-pyridyl disulphide and with ethyl 2-pyridyl disulphide and of k for the reaction of benzimidazol-2-ylmethanethiol (as a minimal model of cysteine proteinase catalytic sites) with the former disulphide were determined in aqueous buffers at 25 degrees C at I 0.1. 2. Of these three pH-k profiles only that for the reaction of papain with 2-(acetamido)ethyl 2'-pyridyl disulphide has a rate maximum at pH approx. 6; the others each have a rate minimum in this pH region and a rate maximum at pH 4, which is characteristic of reactions of papain with other 2-pyridyl disulphides that do not contain a P1-P2 amide bond in the non-pyridyl part of the molecule. 3. The marked change in the form of the pH-k profile consequent upon introduction of a P1-P2 amide bond into the probe molecule for the reaction with papain but not for that with the minimal catalytic-site model is interpreted in terms of the induction by binding of the probe in the S1-S2 intersubsite region of the enzyme of a transition-state geometry in which nucleophilic attack by the -S- component of the catalytic site is assisted by association of the imidazolium ion component with the leaving group. 4. The greater definition of the rate maximum in the pH-k profile for the reaction of papain with an analogous 2-pyridyl disulphide reactivity probe containing both a P1-P2 amide bond and a potential occupant for the S2 subsite [2-(N'-acetyl-L-phenylalanylamino)ethyl 2'-pyridyl disulphide [Brocklehurst, Kowlessur, O'Driscoll, Patel, Quenby, Salih, Templeton, Thomas & Willenbrock (1987) Biochem. J. 244, 173-181]) suggests that a P2-S2 interaction substantially increases the population of transition states for the imidazolium ion-assisted reaction. 5. The overall kinetic solvent 2H-isotope effect at pL 6.0 was determined to be: for the reaction of papain with 2,2'-dipyridyl disulphide, 0.96 (i.e. no kinetic isotope effect), for its reaction with the probe containing only the P1-P2 amide bond, 0.75, for its reaction with the probe containing both the P1-P2 amide bond and the occupant for the S2 subsite, 0.61, and for kcat./Km for its catalysis of the hydrolysis of N-methoxycarbonylglycine 4-nitrophenyl ester, 0.67.(ABSTRACT TRUNCATED AT 400 WORDS)