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Results for “Model explainability”

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PubMed2004

Modeling the interactions between osteoblast and osteoclast activities in bone remodeling.

We propose a mathematical model explaining the interactions between osteoblasts and osteoclasts, two cell types specialized in the maintenance of the bone integrity. Bone is a dynamic, living tissue whose structure and shape continuously evolves during life. It has the ability to change architecture by removal of old bone and replacement with newly formed bone in a localized process called remodeling. The model described here is based on the idea that the relative proportions of immature and mature osteoblasts control the degree of osteoclastic activity. In addition, osteoclasts control osteoblasts differentially depending on their stage of differentiation. Despite the tremendous complexity of the bone regulatory system and its fragmentary understanding, we obtain surprisingly good correlations between the model simulations and the experimental observations extracted from the literature. The model results corroborate all behaviors of the bone remodeling system that we have simulated, including the tight coupling between osteoblasts and osteoclasts, the catabolic effect induced by continuous administration of PTH, the catabolic action of RANKL, as well as its reversal by soluble antagonist OPG. The model is also able to simulate metabolic bone diseases such as estrogen deficiency, vitamin D deficiency, senescence and glucocorticoid excess. Conversely, possible routes for therapeutic interventions are tested and evaluated. Our model confirms that anti-resorptive therapies are unable to partially restore bone loss, whereas bone formation therapies yield better results. The model enables us to determine and evaluate potential therapies based on their efficacy. In particular, the model predicts that combinations of anti-resorptive and anabolic therapies provide significant benefits compared with monotherapy, especially for certain type of skeletal disease. Finally, the model clearly indicates that increasing the size of the pool of preosteoblasts is an essential ingredient for the therapeutic manipulation of bone formation. This model was conceived as the first step in a bone turnover modeling platform. These initial modeling results are extremely encouraging and lead us to proceed with additional explorations into bone turnover and skeletal remodeling.

Bone Diseases, Metabolic↗

PubMed2002

Evidence for "unseen" transposase--DNA contacts.

In this study, evidence of novel, important interactions between a hyperactive Tn5 transposon recognition end sequence and hyperactive Tn5 transposase (Tnp) are presented. A hyperactive Tn5 end sequence, the mosaic end (ME), was isolated previously. The ME and a wild-type end sequence, the outside end (OE), differ at only three positions, yet transposition on the ME is tenfold higher than on the OE in vivo. Also, transposition on the ME is much more efficient than transposition on the OE in vitro. Here, we show that the decreased activity observed for the OE is caused by a defect in paired ends complex (PEC) formation resulting from the orientation of the A-T base-pair at position 4 of this end. Efficient PEC formation requires an interaction between the C5-methyl group (C5-Me) on the non-transferred strand thymine base at position 4 (T4) and Tnp. PEC formation on nicked substrates is much less affected by the orientation of the A-T base-pair at position 4, indicating that the C5-Me group is important only for steps preceding nicking. A recently determined co-crystal structure of Tn5 Tnp with the ME is discussed and a model explaining possible roles for the base-pair at position 4 is explored.

Bacterial Proteins↗

PubMed2005

Mechanisms involved in A/J mouse lung tumorigenesis induced by inhalation of an environmental tobacco smoke surrogate.

Lung tumors have been reproducibly induced in A/J mice exposed to a surrogate for experimental environmental tobacco smoke (ETSS) in a 5-mo inhalation period followed by 4 mo without further exposure. In order to increase our mechanistic understanding of this model, male mice were whole-body exposed for 6 h/d, 5 d/wk to ETSS with a particulate matter concentration of 100 mg/m(3). Food restriction regimens were included to model or exceed the ETSS-related impairment of body weight development. Half of the mice were pretreated with a single ip injection of urethane to study the effect of the above treatments on lung tumor development induced by this substance. At 5 mo, the tumor response was statistically the same for all groups of non-pretreated mice; however, the expected urethane-induced lung tumorigenesis was significantly inhibited by approximately 25% by ETSS and food restriction. This inhibition was accompanied by a threefold increase in blood corticosterone as a common stress marker for both ETSS and food restriction. At 9 mo, in mice not pretreated, the lung tumor incidence and multiplicity were significantly increased by twofold in the ETSS group; in the urethane-treated groups, the same high tumor multiplicity was reached regardless of previous treatment. The predominant tumor type in all groups was bronchiolo-alveolar adenoma. There was no induction of a specific K-ras mutation pattern by ETSS exposure. These data suggest a stress-induced inhibition of lung tumorigenesis in this model, explaining the need for the posttreatment period.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2004

Correlates of serum lutein + zeaxanthin: findings from the Third National Health and Nutrition Examination Survey.

The determinants of blood levels of carotenoids were previously investigated in small or select samples. The relations of serum lutein + zeaxanthin to possible diet, lifestyle, and physiological determinants in 7059 participants of the Third National Health and Nutrition Examination Survey (1988-1994), > or = 40 y old, were examined. In a fully adjusted, multiple linear regression model, lower serum lutein + zeaxanthin was significantly associated with smoking, heavy drinking, being white, female, or not being physically active, having lower dietary lutein + zeaxanthin, higher fat-free mass, a higher percentage of fat mass, a higher waist-hip ratio, lower serum cholesterol, a higher white blood cell count, and high levels of C-reactive protein (P < 0.05). The model explained 24% of the variation present in serum lutein + zeaxanthin for the current sample. The correlation between dietary and serum lutein + zeaxanthin was 0.17 and increased to 0.18 after adjusting for the effects of given covariates. Each 10% increase in dietary lutein + zeaxanthin was associated with a 1% increase in serum conditional on other terms in the model. Many factors that influence the level of serum lutein + zeaxanthin remain unknown.

Alcohol Drinking↗

PubMed1992

Maternal depression, assessment methods, and physical symptoms affect estimates of depressive symptomatology among children with cancer.

Investigated the incidence of depressive symptoms and their covariates in a sample of 99 children undergoing treatment for cancer and their mothers. Although the prevalence of depressive symptoms falling within the clinical range was low (7 to 8%), classification of these children was highly dependent upon the informant and instrument used. Interrater reliabilities did not differ from chance levels. Separate multiple regression analyses of the mother's and nurse's ratings of the child's level of depression, the child's self-report on the Child Depression Inventory, and the mother's responses to the Child Behavior Checklist depression scales revealed different statistical models for each method of assessment. However, increased severity of the mother's self-report of depressive symptoms on the Beck Depression Inventory, which was predicted by low perceived social support and hospitalization of her child, was associated with higher levels of child depression on all child- and parent-report measures. Parental adjustment, sociodemographic, and medical factors as well as methods of assessment must be addressed by models explaining the etiology of depressive symptoms among pediatric oncology patients.

Adult↗

PubMed1998

Determinants of ambulatory physician utilization among adults with chronic diseases in Quebec.

OBJECTIVES: To test the explanatory power of a model of ambulatory service use and to determine the relative roles of the main determinants of physician utilization for two chronic medical conditions in adults in Quebec. METHODS: A behavioral model based on Andersen's model was developed and tested by linking two databases: the Quebec health survey as regards patient characteristics, and the Quebec health insurance board data on physician characteristics and service use. Path analysis was used for data analysis. RESULTS: The model explained a little less than 20% of the variation in service use. The number of hospitalizations, physician's specialty and perceived health were the most important predictors of the volume of visits. CONCLUSION: Further specification of utilization, relating it to a particular medical condition, does not necessarily lead to an increase in the explanatory power of the model. We recommend that future research should put more emphasis on provider-related determinants rather than focusing on the type and purpose of utilization.

Age Factors↗

PubMed1999

Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel.

Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is widely used to correlate biological activity with observed differences in steric and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structurally diverse 5-phenylhydantoin analogues, to delineate structural and electrostatic features important for enhanced sodium channel binding. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as log IC50) and the CoMFA descriptor column generated a final non-cross-validated model with R2 = 0.988 for the training set. The final CoMFA model explained the data better than a simpler correlation with log P (R2 = 0.801) for the same training set. The CoMFA steric and electrostatic maps described two general features that result in enhanced binding to the sodium channel. These include a preferred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. This model was then utilized to accurately predict literature sodium channel activities for hydantoins 14-20, which were not included in the training set. Finally the hydantoin CoMFA model was used to design the structurally novel alpha-hydroxy-alpha-phenylamide 21. Synthesis and subsequent sodium channel evaluation of compound 21 (predicted IC50 = 9 microM, actual IC50 = 9 microM), a good binder to the sodium channel, established that the intact hydantion ring is not necessary for efficient binding to this site. Thus alpha-hydroxy-alpha-phenylamides may represent a new class of ligands that bind with increased potency to the sodium channel.

Amides↗

PubMed2006

Model structure of the prototypical non-fimbrial adhesin YadA of Yersinia enterocolitica.

Non-fimbrial adhesins, such as Yersinia YadA, Moraxella UspA1 and A2, Haemophilus Hia and Hsf, or Bartonella BadA represent an important class of molecules by which pathogenic proteobacteria adhere to their hosts. They form trimeric surface structures with a head-stalk-anchor architecture. Whereas head and stalk domains are diverse and appear (frequently repetitively) in different combinations, the anchor domains are homologous and display the properties of autotransporters. We have built a molecular model for the prototypical non-fimbrial adhesin, YadA, by combining the crystal structure of the head (PDB:1P9H) with theoretical models for the stalk and the anchor. The head domain is a single-stranded, left-handed beta-helix, connected to the stalk by a conserved trimerization element (the neck). The stalk consists of a right-handed coiled coil, containing ten 15-residue repeats with a C-terminal stutter (insertion of four residues). The stalk continues into the conserved anchor domain, which is formed by four heptads of a left-handed coiled coil, followed by four transmembrane beta-strands. Our model of the YadA coiled coil, generated with the program BeammotifCC, combines these periodicities into a structure that starts with a pronounced right-handed supercoil and ends with a canonical, left-handed conformation. The last two heptads of the coiled coil are located within a 12-stranded beta-barrel, formed by trimerization of the four transmembrane beta-strands in each monomer. We propose that this pore assembles in the outer membrane to form the opening through which the monomer chains exit the cell. After export is completed, the fiber folds and the pore is occluded by the coiled coil. Our model explains how these proteins can act as autotransporters in the absence of any homology to classical, single-chain autotransporters.

Adhesins, Bacterial↗

PubMed2005

Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination.

Mismatch repair (MMR) proteins are important for antibody class-switch recombination (CSR), but their roles are unknown. We propose a model for the function of MMR in CSR in which MMR proteins convert single-strand nicks instigated by activation-induced cytidine deaminase (AID) into the double-strand breaks (DSBs) that are required for CSR. This model does not invoke any novel functions for MMR but simply posits that, owing to numerous single-strand nicks in the switch (S) regions of both DNA strands, when MMR proteins are recruited by U:G mismatches, they excise one strand of DNA and soon reach a nick on the opposite strand. This halts excision activity and creates a DSB. This model explains why B cells that lack either S mu and MSH2 or UNG and MSH2 cannot undergo CSR.

Animals↗

PubMed2003

New graduate perception of clinical competence: testing a causal model.

The purpose of this study was to test relationships among variables hypothesized to affect new graduate perceptions of clinical competence. The proposed model was developed based on several theories in sociology, education and nursing. Seven variables were selected for their potential contributions to graduates' perceptions of clinical competence. The sample included 468 new graduates from six baccalaureate nursing programs in Thailand. Path analysis indicated that student effort, perception of clinical learning environment (CLE) and program grade point average had direct effects on perception of clinical competence whereas hardiness had an indirect effect on the outcome variables through its impacts on student effort, perception of CLE and perception of student-faculty relationship. The model explained 8-12% of variance in the subscales of clinical competence.

Adult↗

PubMed1997

The GTP effector site of ornithine decarboxylase from Lactobacillus 30a: kinetic and structural characterization.

A nucleotide effector site of the biodegradative form of ornithine decarboxylase from Lactobacillus 30a (OrnDC L30a) has been identified. OrnDC L30a activity at pH 8.0, where the enzyme is normally inactive, is stimulated by GTP and dGTP and to a lesser extent by GDP but not by ATP, CTP, or UTP. The pH profile indicates that activation by GTP is reflected by an increase in kcat/KM,orn (above pH 6.8), while Vmax remains constant over the pH range 4.0-9. 0. Scatchard plot analysis shows that GTP binds to OrnDC L30a at both pH 5.8 (KD = 0.11 microM) and pH 8.0 (KD = 1.6 microM), but unexpectedly, half-site binding is observed at the higher pH. The OrnDC L30a dodecamer dissociates into dimers at high pH in the presence or absence of GTP. The GTP binding site was located in difference electron density maps using low-resolution X-ray data. This represents a new type of GTP binding site. A model explaining the activation of OrnDC L30a by GTP is presented.

Bacterial Proteins↗

PubMed2000

1.35 and 2.07 A resolution structures of the red abalone sperm lysin monomer and dimer reveal features involved in receptor binding.

Abalone sperm use lysin to make a hole in the egg's protective vitelline envelope (VE). When released from sperm, lysin first binds to the VE receptor for lysin (VERL) then dissolves the VE by a non-enzymatic mechanism. The structures of the monomeric and dimeric forms of Haliotis rufescens (red abalone) lysin, previously solved at 1.90 and 2.75 A, respectively, have now been refined to 1.35 and 2.07 A, respectively. The monomeric form of lysin was refined using previously obtained crystallization conditions, while the dimer was solved in a new crystal form with four molecules (two dimers) per asymmetric unit. These high-resolution structures reveal alternate residue conformations, enabling a thorough analysis of the conserved residues contributing to the amphipathic nature of lysin. The availability of five independent high-resolution copies of lysin permits comparisons leading to insights on the local flexibility of lysin and alternative conformations of the hypervariable N-terminus, thought to be involved in species-specific receptor recognition. The new analysis led to the discovery of the basic nature of a cleft formed upon dimerization and a patch of basic residues in the dimer interface. Identification of these features was not possible at lower resolution. In light of this new information, a model explaining the binding of sperm lysin to egg VERL and the subsequent dissolution of the egg VE is proposed.

Animals↗

PubMed2004

Discrete molecular dynamics simulations of peptide aggregation.

We study the aggregation of peptides using the discrete molecular dynamics simulations. Specifically, at temperatures above the alpha-helix melting temperature of a single peptide, the model peptides aggregate into a multilayer parallel beta-sheet structure. This structure has an interstrand distance of 4.8 A and an intersheet distance of 10 A, which agree with experimental observations. Our model explains these results as follows: hydrogen-bond interactions give rise to the interstrand spacing in beta sheets, while Gō interactions between side chains make beta strands parallel to each other and allow beta sheets to pack into layers. An important feature of our results is that the aggregates contain free edges, which may allow for further aggregation of model peptides to form elongated fibrils.

Amyloid beta-Peptides↗

PubMed1986

What the hen can tell about her eggs: egg development on the basis of energy budgets.

By a simple model involving the state variables size and storage, it is possible to describe a wide variety of observations on the feeding, growth, energy storage and reproduction of animals. The model is based on the assumption that reproduction, growth as well as maintenance depend on the stored energy only and not directly on feeding. If an egg is thought of as a non-feeding animal, the model predicts the respiration ontogeny and growth of the embryo inside the egg. These predictions seem to hold well for published data on the development of eggs of fish and ratite, precocial and altricial birds. The latter two are known to follow different respiration ontogenies, but both are described well, differing only in one (compound) parameter value. The model explains why the incubation times of eggs of different species tend to increase linearly with egg size to the power 1/4, and why kiwis and petrels, which lay relatively large eggs, have to brood them much longer than larger birds with eggs of the same size. Conversely, it explains why the small eggs of the (parasitic) European cuckoo, hatch earlier than the still smaller eggs of their tiny hosts. Furthermore, it has been shown how the maintenance rate constant, which frequently appears in the microbial literature, can be obtained from measurements on the respiration and weight ontogeny in embryos, so linking independent lines of research. Application of the model shows an increase of the maintenance rate constant from bacteria, crustaceans, up to fish and birds, and a decrease from bacteria to green algae, suggesting lines of evolutionary development.

Animals↗

PubMed1995

Gene regulation and the origin of cancer: a new model.

The genome is a dynamical system in which regulation is achieved by the algebraic logic of Boolean functions. A model of a webbed genetic network is presented. In this, all genes lie on interconnected loops, within which each can influence the others, forming the basis of a regulatory network. The normal proto-oncogenes and tumor suppressor genes serve as gateways or switch points in the genetic circuitry, controlling the transition between different cell states. The model explains why multiple genes must be perturbed for the formation of a cancer.

Animals↗

PubMed1986

A model describing the kinetics of mating in Drosophila.

The kinetics of mating in species of Drosophila that copulate for periods of time greater than the duration of experimental observation can be described precisely by an equation that combines second order reaction kinetics with the exponential decay of a lag factor. The two rate constants for this kinetic system were estimated from mating data using a wild-type D. simulans strain, a wild-type D. melanogaster strain, and vestigial mutant D. melanogaster males with wild-type females. The results confirm the applicability of second order kinetics, and demonstrate the usefulness of the model in comparisons of mating rates among strains of flies. In most cases, the model explains more than 95% of the variance in the data, and in addition sheds light on the mechanics of the process of mating.

Animals↗

PubMed1998

Doses and models in risk assessment analysis for bronchial hyperresponsiveness.

The aims of this study are: (1) to evaluate whether the estimates of the association of risk factors with bronchial hyperresponsiveness (BHR) depends on the accumulated dose administered in challenge tests; and (2) to verify whether a model developed for survival studies (Weibull regression) is suited to analyze methacholine dose-response curves. For these purposes, 863 challenge tests, from EC Respiratory Health Survey in Italy, up to a cumulative dose of 6 mg methacholine, were analyzed by Weibull regression and by traditional methods (logistic model and linear model), both before and after truncation of the curves at 2 mg. With all methods the main risk factors for BHR were respiratory symptoms and atopy while age and airway caliber exerted a protective action. Our results confirmed that in epidemiological surveys 2 mg methacholine is enough to fully appreciate the effect of risk factors on BHR and showed that the Weibull model explains the observed variability better than linear and logistic regressions.

Adult↗

PubMed2000

Integrating competence and psychopathology: pathways toward a comprehensive science of adaptation in development.

This paper examines the conceptual and empirical connections between competence and psychopathology, two historically rich traditions for the study of adaptation in development, and what might be gained from their integration. Historical roots of these two traditions are reviewed, then overlaps in their definition are considered, with a focus on the ways in which judgments about competence enter into the nosology of mental disorders. DSM-IV is analyzed from the perspective of competence, and the debate about "harmful dysfunction" in defining mental disorder is discussed in relation to competence. Different models explaining the empirical associations of competence and psychopathology are delineated, and illustrative empirical evidence is provided. Potential explanations include confounded concepts and methods, symptoms undermining the effectiveness of adaptation in the environment, failures in age-salient developmental tasks leading to emotional and behavioral problems, transactional influences, shared vulnerability or risk factors producing both kinds of difficulties, and more complex models. The potential benefits of integrating competence and psychopathology as two major approaches to adaptation are discussed in regard to theory, classification of mental disorder, research, and intervention.

Adaptation, Psychological↗