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PubMedDate not supplied

Hormesis: interpreting the beta-curve using control theory.

Data from experiments exposing colonial hydroids to toxic growth inhibitors have provided evidence of growth control mechanisms that respond adaptively to counter toxic inhibition. Analysis of growth data and the development of simulation models provide an interpretation of both alpha- and beta-curves. The hypothesis also suggests that hormesis is related to adaptation by growth control mechanisms that confer tolerance to subsequent exposure.

Adaptation, Physiological↗

PubMed2026

AI-enabled viral genomics: from virus discovery to host prediction and emerging variant forecasting.

The rapid expansion of metagenomic sequencing has generated vast repositories of viral sequence data that far outpace our capacity to interpret them using conventional approaches. Highly divergent sequences, sparse functional annotation, and taxonomically uneven sampling present fundamental challenges for reference-dependent methods, which lose sensitivity precisely for novel and understudied viruses with high public health relevance. Artificial intelligence (AI) provides a new avenue to address these challenges by enabling predictive inference from viral genomes and proteins while reducing dependence on sequence similarity. In this Review, we discuss representative advances in AI for virus discovery, taxonomic classification and functional annotation, prediction of host range and zoonotic potential, and efforts toward forecasting emerging variants. These advances are transforming viral genomics from a largely descriptive discipline into one with increasing predictive capability. We also critically assess the major challenges that constrain current approaches, including the availability of high-quality and representative datasets, rigorous model evaluation, biological interpretability and responsible governance for increasingly capable AI models.

Artificial Intelligence↗

PubMed2002

Validity and reliability of diastolic pulse contour analysis (windkessel model) in humans.

The present study assessed (1) the impact of the measurement site (lower versus upper extremity) on the corresponding compliance variables and (2) the overall reliability of diastolic pulse contour (Windkessel-derived) analysis in normal and hypertensive subjects. Arterial tonograms were recorded in the supine position from the radial and posterior tibial arteries in 20 normotensive (116+/-12/68+/-8 mm Hg) and 27 essential hypertensive subjects (160+/-16/94+/-14 mm Hg). Ensemble-averaged data for each subject were fitted to a first-order lumped-parameter model (basic Windkessel) to compute whole-body arterial compliance (C(A)) and to a third-order lumped-parameter model (modified Windkessel) to compute proximal compliance (C(1)) and distal compliance (C(2)). Despite high-fidelity waveforms in each subject, the first-order Windkessel model did not yield interpretable (positive) values for C(A) in 50% of normotensives and 41% of hypertensives, whereas the third-order model failed to yield interpretable C(1) or C(2) results in 15% of normotensives and 41% of hypertensives. No between-site correlations were found for the first-order time constant, 2 of the 3 third-order model curve-fitting constants, or C(A), C(1), or C(2) (P>0.50). Mean values for all 3 compliance variables were higher for the leg than the arm (P<0.05 each). We conclude that differences in Windkessel-derived compliance values in the arm and leg invalidate whole-body model assumptions and suggest a strong influence of regional circulatory properties. The validity and utility of Windkessel-derived variables is further diminished by the absence of between-site correlations and the common occurrence of uninterpretable values in hypertensive subjects.

Adult↗

PubMed1999

Mechanisms of Surface Precipitation and Dissolution of Barite: A Morphology Approach.

Barite (BaSO4) was synthesized at normal pressure and room temperature by mixing sodium sulfate and barium chloride solutions by gentle flow (0.5 ml/min.). The well-formed rectangular and rhombohedral crystals with smooth faces formed from solutions with low degrees of supersaturation. Most precipitates became single crystals. We employed the scanning electron microscope (SEM) to observe barite dissolution by chemical agent diethylenetrinitrilopentaacetic acid. Molecular modeling was used to assist the interpretation of the surface reaction. A kinetic model for the pit growth (initial dissolution) on the surface was evaluated. With SEM microanalysis of barite and kinetic model of pit growth, important surface phenomena and mechanisms of dissolution can be hypothesized. Surface phenomena and composition are very important in barite dissolution. Experimental results suggest that the initial dissolution starts on the two lowest energy surfaces: (001) and (210), and that the etch pits are elongated in one direction on the (210) surface and formed cavities on the (001) surface. The simulated surface structures by molecular modeling can aid the interpretation the pit formation on those selected surfaces. Copyright 1999 Academic Press.

Journal Article↗

PubMed2004

Evolutionary fuzzy modeling human diagnostic decisions.

Fuzzy CoCo is a methodology, combining fuzzy logic and evolutionary computation, for constructing systems able to accurately predict the outcome of a human decision-making process, while providing an understandable explanation of the underlying reasoning. Fuzzy logic provides a formal framework for constructing systems exhibiting both good numeric performance (accuracy) and linguistic representation (interpretability). However, fuzzy modeling--meaning the construction of fuzzy systems--is an arduous task, demanding the identification of many parameters. To solve it, we use evolutionary computation techniques (specifically cooperative coevolution), which are widely used to search for adequate solutions in complex spaces. We have successfully applied the algorithm to model the decision processes involved in two breast cancer diagnostic problems, the WBCD problem and the Catalonia mammography interpretation problem, obtaining systems both of high performance and high interpretability. For the Catalonia problem, an evolved system was embedded within a Web-based tool-called COBRA-for aiding radiologists in mammography interpretation.

Breast Neoplasms↗

PubMed2006

Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis.

To gain insight into the structural determinants for the matrix metalloproteinase (MMP) family, we characterized the binding sites of 56 MMP structures and one TACE (tumor necrosis factor alpha converting enzyme) structure using molecular interaction fields (MIFs). These MIFs were produced by two approaches: the GRID force field and the knowledge-based potential DrugScore. The subsequent statistical analysis using consensus principal component analysis (CPCA) for the entire binding site and each subpockets revealed both approaches to encode similar information about discriminating regions. However, the relative importance of the probes varied between both approaches. The CPCA models provided the following ranking of the six subpockets based on the opportunity for selective interactions with different MMPs: S1' > S2, S3, S3' > S1, S2'. The interpretation of these models agreed with experimental binding modes inferred from crystal structures or docking.

ADAM Proteins↗

PubMed1963

RELATION OF PROTEIN SYNTHESIS TO THE DIVISION CYCLE IN MAMMALIAN CELL CULTURES.

Protein synthesis in suspension cultures of human cells in logarithmic growth was inhibited with puromycin or chloramphenicol, and the growth rate and mitotic index were measured as a function of time. The mitotic index remained constant for about 1 hour after addition of inhibitor; this indicates that any protein synthesis necessary for mitosis is completed before the beginning of prophase. For rates of protein synthesis equal to or greater than 0.3 that of untreated cells, the index decreased over a 5- to-7-hour period and then remained constant. The final value of the index relative to that of the uninhibited control was approximately equal to the relative rate of protein synthesis. The period from the end of DNA synthesis to mitosis (G(2)) was increased by partial inhibition of protein synthesis. A mathematical model of the inhibition process has been formulated which predicts the shape of the mitotic index curves and the increase in the G(2) period. An interpretation of the model is that the rate-limiting step is the synthesis of an enzyme which catalyzes the formation of a compound necessary to initiate mitosis.

Anti-Bacterial Agents↗

PubMed2006

A model for improving student confidence and experience in diagnostic sample collection and interpretation.

Confidence and proficiency in diagnosing and treating a variety of diseases is of obvious importance to veterinary students. Traditional teaching methods relying on live-animal laboratories or teaching-hospital cases may not provide the breadth and depth of experience necessary to promote optimal development of confidence and skills. These settings also raise concerns about expense, about animal welfare when animals are used in teaching laboratories, and about the stress and potential risks associated with client-owned pets in the teaching hospital. A one-week course implemented in our veterinary curriculum provides the opportunity for students to develop self-assurance and experience in sample collection and interpretation skills in a realistic, clinical-model setting. This course provides students with significantly improved levels of confidence when performing procedures and interpreting results from a variety of procedures and helps prepare them to become clinicians entering the practice of veterinary medicine.

Case-Control Studies↗

PubMedDate not supplied

Modeling unconscious gender bias in fame judgments: finding the proper branch of the correct (multinomial) tree.

In the preceding article, Buchner and Wippich used a guessing-corrected, multinomial process-dissociation analysis to test whether a gender bias in fame judgements reported by Banaji and Greenwald (Journal of Personality and Social Psychology, 1995, 68, 181-198) was unconscious. In their two experiments, Buchner and Wippich found no evidence for unconscious mediation of this gender bias. Their conclusion can be questioned by noting that (a) the gender difference in familiarity of previously seen names that Buchner and Wippich modeled was different from the gender difference in criterion for fame judgements reported by Banaji and Greenwald, (b) the assumptions of Buchner and Wippich's multinomial model excluded processes that are plausibly involved in the fame judgement task, and (c) the constructs of Buchner and Wippich's model that corresponded most closely to Banaji and Greenwald's gender-bias interpretation were formulated so as to preclude the possibility of modeling that interpretation. Perhaps a more complex multinomial model can model the Banaji and Greenwald interpretation.

Female↗

PubMed1997

Effect of measurement error on energy-adjustment models in nutritional epidemiology.

The use and interpretation of energy-adjustment regression models in nutritional epidemiology has been vigorously debated recently. There has been little discussion, however, regarding the effect of dietary measurement error on the performance of such models. Contrary to conventional assumptions invoked in the standard treatment of the effect of measurement error in regression analysis, reporting errors in dietary studies are usually biased, correlated with true nutrient intakes and with each other, heteroscedastic, and nonnormally distributed. Methods developed in this paper allow for this more complex error structure and are therefore more appropriate for dietary data. For practical illustration, these methods are applied to data from the Women's Health Trial Vanguard Study. The results demonstrate considerable shrinkage in the magnitude of the estimated main exposure effect in energy-adjustment models due to attenuation of the true effect and contamination from the effect of an adjusting covariate. In most cases, this shrinkage causes a sharply reduced statistical power of the corresponding significance test in comparison with measurement without error. These results emphasize the need to understand the measurement error properties of dietary instruments through validation/calibration studies and, where possible, to correct for the impact of measurement error when applying energy-adjustment models.

Aged↗

PubMed2005

A conformational dynamics study of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution by NMR experiments and molecular simulations.

The conformational preference of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution has been studied by NMR spectroscopy using one-dimensional (1)H,(1)H T-ROESY experiments and measurement of trans-glycosidic (3)J(C,H) coupling constants. Molecular dynamics (MD) simulations with a CHARMM22 type of force field modified for carbohydrates were performed with water as the explicit solvent. The homonuclear cross-relaxation rates, interpreted as effective proton-proton distances, were compared to those obtained from simulation. Via a Karplus torsional relationship, (3)J(C,H) values were calculated from simulation and compared to experimental data. Good agreement was observed between experimental data and the MD simulation, except for one inter-residue T-ROE between protons in the terminal sugar residues. The results show that the trisaccharide exhibits substantial conformational flexibility, in particular along the psi glycosidic torsion angles. Notably, for these torsions, a high degree of correlation (77%) was observed in the MD simulation revealing either psi(2)(+) psi(3)(+) or psi(2)(-)psi(3)(-) states. The simulations also showed that non-exoanomeric conformations were present at the phi torsion angles, but to a limited extent, with the phi(3) state populated to a larger extent than the phi(2) state. Further NMR analysis of the trisaccharide by translational diffusion measurements and (13)C T(1) relaxation experiments quantified global reorientation using an anisotropic model together with interpretation of the internal dynamics via the "model-free" approach. Fitting of the dynamically averaged states to experimental data showed that the psi(2)(+)psi(3)(+) state is present to approximately 49%, psi(2)(-) psi(3)(-) to approximately 39%, and phi(3) (non-exo) to approximately 12%. Finally, using a dynamic and population-averaged model, (1)H,(1)H T-ROE buildup curves were calculated using a full relaxation matrix approach and were found to be in excellent agreement with experimental data, in particular for the above inter-residue proton-proton interaction between the terminal residues.

Carbohydrate Conformation↗

PubMed2000

Properties of an electron-density map derived from a limited number of experimentally determined triplet phases.

In a previous communication [Weckert et al. (1999). Acta Cryst. D55, 1320-1328], the feasibility of the measurement of a large set of triplet phases by three-beam interference was demonstrated. This paper reports the methodology for the calculation of an electron-density map from this limited amount of experimental phase information and the map's properties with respect to model building and refinement. The tetragonal form of hen egg-white lysozyme (HEWL) was chosen as a test structure for the development of this method. The quality of the electron-density map obtained from all measured triplet phases allows a straightforward and nearly complete interpretation. The starting model was refined to a final R value of 17.4%. In a second step, the minimum number of phased reflections needed for the interpretation of an electron-density map was investigated, applying criteria based on |F| and resolution.

Algorithms↗

PubMed1985

One- and two-receptor models of opioid drug action.

The history of models for opioid drug receptors is traced and two currently proposed models are compared, the first envisaging two rigid receptors, one for agonists and one for antagonists, while the second model postulates one single flexible receptor which in its native conformation fits opioid antagonists but is distorted when it binds to agonists. Important recent experiments are satisfactorily interpreted by both models but the flexible one-receptor model requires fewer assumptions and explains more facts.

Animals↗

PubMed2002

Fifty years of solvent denaturation.

The author has worked in the area of solvent denaturation and stabilization, off and on, for approximately 50 years. This paper is a personal view of the progress which has been made since 1950. The topic is limited to the development of thermodynamic molecular models for the interpretation of the unfolding and stabilization of protein structures. The story starts with the work in Kauzmann's laboratory shortly after World War II and proceeds through models for multisite binding, the linear denaturation curve, the special considerations required for understanding weak solvent exchange and a new model for the balance of solvent contact interactions and excluded volume.

Animals↗

PubMed1999

Automated protein model building combined with iterative structure refinement.

In protein crystallography, much time and effort are often required to trace an initial model from an interpretable electron density map and to refine it until it best agrees with the crystallographic data. Here, we present a method to build and refine a protein model automatically and without user intervention, starting from diffraction data extending to resolution higher than 2.3 A and reasonable estimates of crystallographic phases. The method is based on an iterative procedure that describes the electron density map as a set of unconnected atoms and then searches for protein-like patterns. Automatic pattern recognition (model building) combined with refinement, allows a structural model to be obtained reliably within a few CPU hours. We demonstrate the power of the method with examples of a few recently solved structures.

Adaptor Protein Complex alpha Subunits↗

PubMed1982

The effects of priming on picture recognition.

In two experiments we show that the prior presentation of a picture serves to facilitate the recognition of that picture in a tachistoscope up to 45 minutes later. Facilitation of recognition also occurred with prior presentation of a different picture with the same name. This cannot be explained items of a response bias, since the presentation of a word, which the subject read aloud, had no effect whatsoever upon the subsequent recognition of the picture. The data are interpreted in terms of a categorization stage for pictures which is completely independent of the verbal system. Data from other experimental paradigms are also examined. Our categorization model enables consistent interpretation of these data, which otherwise appear contradictory.

Discrimination Learning↗

PubMed2004

Homotypic signalling regulates Gata1 activity in the erythroblastic island.

Gata1 is a transcription factor essential for erythropoiesis. Erythroid cells lacking Gata1 undergo apoptosis, while overexpression of Gata1 results in a block in erythroid differentiation. However, erythroid cells overexpressing Gata1 differentiate normally in vivo when in the presence of wild-type cells. We have proposed a model, whereby a signal generated by wild-type cells (red cell differentiation signal; REDS) overcomes the intrinsic defect in Gata1-overexpressing erythroid cells. The simplest interpretation of this model is that wild-type erythroid cells generate REDS. To substantiate this notion, we have exploited a tissue specific Cre/loxP system and the process of X-inactivation to generate mice that overexpress Gata1 in half the erythroid cells and are Gata1 null in the other half. The results show that the cells supplying REDS are erythroid cells. This study demonstrates the importance of intercellular signalling in regulating Gata1 activity and that this homotypic signalling between erythroid cells is crucial to normal differentiation.

Animals↗

PubMed1993

The effects of neurotransmitters on the integrative properties of spinal neurons in the lamprey.

1. The integrative behavior of lamprey central neurons was analyzed by white noise frequency domain methods and simulated with a minimal, non-linear neuronal model consisting of two voltage-dependent processes: (i) a depolarizing inwardly directed conductance carrying calcium and monovalent ions and (ii) a repolarizing outwardly directly conductance representing a generalized potassium conductance. In addition to normal properties, the effects of neurotransmitters were interpreted with the model. Specifically, N-methyl-D-aspartate (NMDA)-induced properties were simulated under conditions where the intrinsic voltage dependence of the potassium channels was constrained by properties of lamprey neurons. However, the NMDA channel kinetics were fixed by the single-channel properties of other neurons. The effects of focally applied neurotransmitters on the membrane properties of intact spinal cord neurons were quantitatively described with a reduced neuronal model that was also used to simulate transmitter-induced responses. In addition, transmitters were also released synaptically by KCl depolarization of projecting neurons. 2. Both synaptically released transmitters and focally applied putative excitatory or inhibitory transmitters directly applied to the spinal cord generally resulted in a decrease in the magnitude of the impedance function that was modeled by a decrease in membrane resistance (shunting effect). 3. Local application of the inhibitory neurotransmitters glycine or gamma-aminobutyric acid (GABA) led to small voltage responses when recorded near the resting potential. However, large decreases in the magnitude of the impedance function were observed in both current-clamp or voltage-clamp recording modes. 4. The excitatory amino acids quisqualate, kainate and glutamate evoked depolarizations in current clamp that activated intrinsic voltage-dependent conductances and obscured the direct effects of the transmitters. Under voltage-clamp conditions these transmitters caused a small decrease in the impedance magnitude that could be modeled by a shunt. 5. In contrast to the other excitatory amino acids, NMDA elicited large increases, rather than decreases, in both the magnitude and the phase lag of the impedance function. These changes were modeled by a negative conductance (a voltage-dependent conductance that produces an inward current). 6. The reduced neuron model provides an experimentally based description of the highly oscillatory and non-linear responses observed during NMDA activation of the spinal neurons involved in the pattern generation of locomotion. Simulations of sustained oscillatory behaviors consistent with experimental observations were carried out to illustrate the NMDA-induced integrative properties of central neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗