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PubMed2000

Statistical aspects of evaluating treatment and prognostic factors for clinically localized prostate cancer.

This article reviews the fundamental assumptions for survival analysis and discusses some of the difficulties specific to the treatment evaluation and the analysis of prognostic factors in clinically localized prostate cancer. What makes clinically localized prostate cancer different from other forms of cancer is the chronic nature of the disease and the introduction of prostate-specific antigen (PSA) evaluation following a primary treatment. It is known that a study evaluating survival benefit for localized prostate cancer requires a long-term follow-up. This brings up issues of time varying treatment effect and the necessary use of cause-specific survival. In addition, biochemical failure following radiation therapy based on ASTRO consensus definition is another major topic. We question the appropriateness of the last observation approach that censors patients at their last observation and uses the Kaplan-Meier method. We show that the last observation approach can underestimate the biochemical failure rate for a treatment, especially when follow-up is short. The estimate of lower and upper bounds for biochemical failure is recommended. Examples based on Radiation Therapy Oncology Group prostate cancer trials are provided. This article concludes with a discussion of some novel statistical approaches to the design of prostate cancer studies and the analysis of trajectories of PSA values.

Cause of Death↗
PubMed1994

A connected-cluster of hydration around myoglobin: correlation between molecular dynamics simulations and experiment.

An analysis of a molecular dynamics simulation of metmyoglobin in an explicit solvent environment of 3,128 water molecules has been performed. Both statics and dynamics of the protein-solvent interface are addressed in a comparison with experiment. Three-dimensional density distributions, temperature factors, and occupancy weights are computed for the solvent by using the trajectory coordinates. Analysis of the hydration leads to the localization of more than 500 hydration sites distributed into multiple layers of solvation located between 2.6 and 6.8 A from the atomic protein surface. After locating the local solvent density maxima or hydration sites we conclude that water molecules of hydration positions and hydration sites are distinct concepts. Both global and detailed properties of the hydration cluster around myoglobin are compared with recent neutron and X-ray data on myoglobin. Questions arising from differences between X-ray and neutron data concerning the locations of the protein-bound water are investigated. Analysis of water site differences found from X-ray and neutron experiments compared with our simulation shows that the simulation gives a way to unify the hydration picture given by the two experiments.

Amino Acid Sequence↗
PubMed1999

Influence of internal dynamics on accuracy of protein NMR structures: derivation of realistic model distance data from a long molecular dynamics trajectory.

In order to study the effect of internal dynamics on the accuracy of NMR structures in detail, we generated NOE distance data from a long molecular dynamics trajectory of BPTI. Cross-relaxation rates were calculated from the trajectory by analysis of the appropriate proton-proton vector autocorrelation functions. A criterion for the convergence of correlation functions was developed, and the analysis was restricted to those correlation functions that had converged within the simulation time. Effective distances were determined from the calculated cross-relaxation rates. Internal dynamics affected the derived distances in a realistic way, since they were subject both to radial averaging (which increases the cross-relaxation rate) and angular averaging (which decreases the cross-relaxation rate). The comparison of the effective distances with average distance between the protons during the trajectory showed that for most the effects of angular and distance averaging essentially cancel out. For these distances, the effective distance derived from an NOE is therefore a very good estimate of the average distance, or the distance in the average structure. However, for about 10% of the distances, the effective distance was more than 10% larger than the average distance, while for about 5%, it was more than 10% smaller, in some cases by more than 2 A. Little correlation is observed between the effects on cross-relaxation rates to different protons of the same residue. The results of this analysis have implications for the way structures are calculated from NOE distance data. For many distances, the assumption of a rigid structure is valid, and large error bounds would result in the loss of too much information content. On the other hand, the error bounds very often employed are not wide enough for some of the effects seen in our study.

Animals↗
PubMed1997

Development of cardiovascular risk factors from ages 8 to 18 in Project HeartBeat! Study design and patterns of change in plasma total cholesterol concentration.

BACKGROUND: Project HeartBeat! is a longitudinal study of the development of cardiovascular risk factors as growth processes. Patterns of serial change, or trajectories, from ages 8 to 18 years for plasma total cholesterol concentration (TC) and percent body fat illustrate the design and synthetic cohort approach of the study. METHODS AND RESULTS: Six hundred seventy-eight children (49.1% female, 20.1% black) entered the study at ages 8, 11, and 14 years and were followed up with examinations every 4 months for < or = 4 years. Multilevel analysis demonstrated trajectories for population mean values of TC and percent body fat in sex-specific synthetic cohorts from ages 8 to 18 years. Polyphasic patterns of change in TC were confirmed, with notable sex differences in age patterns and with minimum mean values of TC of 3.85 mmol/L for females and 3.59 for males. As illustrated by data for males, the approximate 75th percentile values of mean TC ranged from 4.78 mmol/L at its early peak to 4.06 at its late-teen nadir. Percent body fat exhibited a trajectory closely parallel with that for TC only for males and appeared to be unrelated for females. CONCLUSIONS: The polyphasic trajectory for TC from ages 8 to 18 years differs between females and males, indicates marked age variation in 75th percentile values and, in males only, closely parallels the trajectory for percent body fat. These and other results indicate the value of both follow-up every 4 months across age intervals to detect rapid risk factor change and the synthetic cohort approach for gaining new insights into the dynamics and possible determinants of this change from ages 8 to 18 years.

Adipose Tissue↗
PubMed2005

Visual guidance of the human foot during a step.

When the intended foot placement changes during a step, either due to an obstacle appearing in our path or the sudden shift of a target, visual input can rapidly alter foot trajectory. However, previous studies suggest that when intended foot placement does not change, the path of the foot is fixed after it leaves the floor and vision has no further influence. Here we ask whether visual feedback can be used to improve the accuracy of foot placement during a normal, unperturbed step. To investigate this we measured foot trajectory when subjects made accurate steps, at fast and slow speeds, to stationary floor-mounted targets. Vision was randomly occluded in 50% of trials at the point of foot-off. This caused an increase in foot placement error, reflecting lower accuracy and higher variability. This effect was greatest for slow steps. Trajectory heading analysis revealed that visually guided corrections occurred as the foot neared the target (on average 64 mm away). They occurred closer to the target for the faster movements thus allowing less time and space to execute corrections. However, allowing for a fixed reaction time of 120 ms, movement errors were detected when the foot was approximately halfway to the target. These results suggest that visual information can be used to adjust foot trajectory during the swing phase of a step when stepping onto a stationary target, even for fast movements. Such fine control would be advantageous when environmental constraints place limitations on foot placement, for example when hiking over rough terrain.

Adult↗
PubMed2002

Use of sensitivity analysis to assess reliability of metabolic and physiological models.

Because ethical considerations often preclude directly determining the human health effects of treatments or interventions by experimentation, such effects are estimated by extrapolating reactions predicted from animal experiments. Under such conditions, it must be demonstrated that the reliability of the extrapolated predictions is not excessively affected by inherent data limitations and other components of model specification. This is especially true of high-level models composed of ad hoc algebraic equations whose parameters do not correspond to specific physical properties or processes. Models based on independent experimental data restricting the numerical space of parameters that do represent actual physical properties can be represented at a more detailed level. Sensitivities of the computed trajectories to parameter variations permit more detailed attribution of uncertainties in the predictions to these low-level properties. S-systems, in which parameters are estimated empirically, and physiological models, whose parameters can be estimated accurately from independent data, are used to illustrate the applicability of trajectory sensitivity analysis to lower-level models.

Animals↗
PubMed2026

Deep learning-assisted, pathogenesis-informed lung histopathology scoring in preclinical mouse models of SARS-CoV-2 and influenza A infection.

INTRODUCTION: SARS-CoV-2 and influenza A virus (IAV) cause viral pneumonia, yet their lung lesions evolve with distinct spatial organization and resolution-phase architecture. In preclinical murine studies, H&E histopathology is a primary endpoint, but burden-focused semiquantitative scoring can miss pathogen- and phase-specific differences in lesion topology, compartmental involvement, inflammatory organization, and repair. We aimed to define virus- and phase-specific morphologic signatures and translate them into a practical, pathogenesis-informed scoring guide, supported by whole-slide convolutional neural network (CNN) analysis with class activation mapping (CAM). METHODS: Mice were infected under standardized conditions and evaluated during the early, peak-injury, and late phases of infection, corresponding to 2~3, 5~8, and 14 days post-infection (dpi), respectively. Lungs were assessed by H&E with semiquantitative scoring and by immunostaining to map viral antigen distribution and epithelial tropism. Whole-slide CNN models were trained for virus- and phase-specific classification, and CAM localized discriminative regions. RESULTS: Dose titration established reproducible lethal and sublethal infection conditions for both viruses. Viral antigen kinetics diverged, with SARS-CoV-2 peaking early and declining toward clearance by the resolution phase, whereas IAV peaked later and declined by the resolution phase, paralleling distinct injury-repair trajectories. CNN/CAM analysis distinguished virus- and phase-specific histologic patterns across the early, peak-injury, and resolution phases of infection and highlighted spatial signatures consistent with expert review. At the peak-injury phase, SARS-CoV-2 lungs showed broad alveolar/interstitial involvement, whereas IAV exhibited bronchocentric inflammatory organization. During the resolution phase, IAV showed prominent epithelial regeneration with remodeling-forward architecture, while SARS-CoV-2 more often retained localized residual inflammatory foci. Across both infections, tissue inflammatory composition shifted over time, with higher neutrophil representation during the peak-injury phase and a relative increase in lymphocytic representation during the resolution phase. Integrating lesion topology/distribution, edema, epithelial injury-regeneration, remodeling features, and lymphocyte predominance, we proposed a pathogen-resolved, phase-informed histopathology scoring guide with recommended evaluation windows for each model. CONCLUSION: Together, these findings define virus- and phase-specific morphologic programs that inform respiratory virus pathogenesis in mice and can be translated into practical scoring criteria for preclinical respiratory virus studies.

Animals↗
PubMed2002

Accuracy analysis of a respirometer for activated sludge dynamic modelling.

The aim of the paper is to assess the experimental errors arising from the operation of a closed respirometer using autotrophic biomass. A closed, intermittent-flow device has been set-up for the measurement of oxygen uptake rate (OUR) and parameter calibration. After describing the device structure and operation, the factors affecting accuracy have been assessed. Inaccuracies may be caused by two groups of parameters: design parameters, including flow rate, volume, sampling time, numerical algorithm, sample injection and environmental parameters, concerning the physicochemical conditions of the experiment, such as unwanted oxygen transfer, pH, and the influence of sludge condition on "start-up" behaviour. It is shown to what extent each of them affects the final accuracy of the OUR measurement. In the second part of the paper, the respirometric data are used to calibrate a two-step nitrification model and their impact on the accuracy of the estimation of model parameters is assessed. Confidence limits are derived for the identifiable parameter combinations and the practical identifiability assessed with the aid of trajectory sensitivity analysis.

Biodegradation, Environmental↗
PubMed2000

Comparison of two-dimensional and three-dimensional techniques for determination of facial motion--absolute movement in a local face frame.

BACKGROUND AND PURPOSE: Few studies have used motion analysis in the study of facial animation. A facial animation model using an expert vision motion analysis system was developed in this study to quantitatively evaluate absolute movement during five facial animations. METHODS: Skin markers were adhered to the face of each subject at 16 anatomic landmarks selected to represent the functional movement of the facial muscles. Three of the 16 skin markers were used to establish a local face frame with the origin in the mid-point of the face. All of the coordinates measured in the laboratory frame were rotated and translated to the local face frame for analysis. The trajectory of the facial markers was evaluated from the local face frame when comparing two-dimensional (2-D) displacement of skin markers (frontal plane) with three-dimensional (3-D) values by paired Student's t-test. RESULTS: Although the correlation of 2-D and 3-D displacements of skin markers was high (r > 0.69), the differences between 2-D and 3-D motion were significant (p < 0.001). The 2-D displacement of skin markers underestimated the 3-D facial animation in each marker and animation. There were no significant differences in the movement of both mouth angles or of the eyes. Thirty repeated measurements of a subject revealed good concentration in 3-D displacement, velocity, and angle of movement in smiling. The measurement error was less than 0.06 mm. The normative displacement of individual anatomic landmarks was evaluated to avoid size differences of individual faces. CONCLUSIONS: We suggest that the expert vision motion analysis technique is feasible for quantitative evaluation of absolute facial movement and would be useful for further clinical evaluation of patients with facial palsy.

Adult↗
PubMed2000

Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II. substrate-enzyme interactions and dynamics.

Molecular dynamics simulations of protein tyrosine phosphatase 1B (PTP1B) complexed with the phosphorylated peptide substrate DADEpYL and the free substrate have been conducted to investigate 1) the physical forces involved in substrate-protein interactions, 2) the importance of enzyme and substrate flexibility for binding, 3) the electrostatic properties of the enzyme, and 4) the contribution from solvation. The simulations were performed for 1 ns, using explicit water molecules. The last 700 ps of the trajectories was used for analysis determining enthalpic and entropic contributions to substrate binding. Based on essential dynamics analysis of the PTP1B/DADEpYL trajectory, it is shown that internal motions in the binding pocket occur in a subspace of only a few degrees of freedom. In particular, relatively large flexibilities are observed along several eigenvectors in the segments: Arg(24)-Ser(28), Pro(38)-Arg(47), and Glu(115)-Gly(117). These motions are correlated to the C- and N-terminal motions of the substrate. Relatively small fluctuations are observed in the region of the consensus active site motif (H/V)CX(5)R(S/T) and in the region of the WPD loop, which contains the general acid for catalysis. Analysis of the individual enzyme-substrate interaction energies revealed that mainly electrostatic forces contribute to binding. Indeed, calculation of the electrostatic field of the enzyme reveals that only the field surrounding the binding pocket is positive, while the remaining protein surface is characterized by a predominantly negative electrostatic field. This positive electrostatic field attracts negatively charged substrates and could explain the experimentally observed preference of PTP1B for negatively charged substrates like the DADEpYL peptide.

Amino Acid Sequence↗
PubMedDate not supplied

Effect of continuation treatment on residual symptoms in late-life depression: how well is "well"?

UNLABELLED: The objectives of this report were (1) to describe residual depressive symptoms in elderly patients during continuation therapy with combined nortriptyline and interpersonal psychotherapy; (2) to determine which symptoms were persistent; (3) to determine the clinical correlates of residual depressive symptoms; and (4) to document distinct response pattern clusters during combined continuation therapy. METHOD: Box plot analyses of Hamilton depression scores and Global Assessment Scale scores, repeated twice monthly over 4 months, were conducted using data from 105 elderly depressives. Temporal trends in the data were examined via random regression analysis. Individual trajectories for each of the 105 patients were examined for patterns of response during continuation therapy. RESULTS: We observed a low mean Hamilton rating of 7 (SD = 2.3) at the start of continuation therapy and 5 (SD = 3.0) at the end. Both Hamilton and GAS scores showed modest but significant improvement over time. Hamilton variability was most apparent in symptoms of mood lowering, apathy, anxiety (psychological and somatic), feelings of guilt, anergia, insomnia, and loss of libido; other symptoms (retardation, agitation, hypochondriasis, loss of appetite, loss of weight, suicidal ideation, and loss of insight) showed clear resolution. A diagnosis of RDC situational depression was associated with higher levels of residual symptoms, while level of chronic medical burden, personality dysfunction, and social support were not. Examination of response patterns showed that a quarter of patients experienced one or more brief symptomatic exacerbations. CONCLUSION: On average, an excellent level of symptom resolution was achieved for most patients with Hamilton scores comparable to those seen in healthy elderly controls. These data support a position of therapeutic optimism in late-life depression and underscore full remission as an achievable therapeutic goal.

Aged↗
PubMed2005

An integrated approach to the characterization of cell movement.

BACKGROUND: Most phenomena in developmental biology involve or depend upon cell migration. This article describes a comprehensive framework for the characterization and analysis of trajectories defined by cell movement. The following two perspectives are considered: (a) the behavior of each individual cell and (b) interactions between neighboring pairs of cells. METHODS: The measurements considered for individual trajectories include the velocity magnitude and orientation, maximum spatial dispersion, displacement effectiveness, and displacement entropies. Interactions between two trajectories are characterized by comparing the respective velocities. RESULTS: The potential of the overall framework is illustrated using data of moving cells in different biological environments. The work shows that it is possible to use the new algorithm presented here to characterize cell motility. CONCLUSIONS: The features of the algorithm were successful in determining the motility changes under different experimental conditions.

Algorithms↗
PubMed2004

Immunoglobulin kappa light chain and its amyloidogenic mutants: a molecular dynamics study.

AL amyloidosis and LCDD are pathological conditions caused by extracellural deposition of monoclonal Ig light chain variable domains. In the former case, deposits have a form of amyloid fibrils, in the latter, amorphous aggregates. 1REI kappa light chain variable domain and its two point mutants, R61N and D82I, were chosen for the analysis in this work. Wild 1REI does not create deposits in vitro, while R61N aggregates as amyloid fibrils and D82I creates amorphous aggregates. Both mutated residues create a conserved salt bridge; thus, substitution of any of them should decrease V(L) domain stability. For these three proteins, 5 ns MD simulations were conducted in temperatures of 300 K and 400 K, with protonated and unprotonated acidic residues, mimicking acidic and neutral experimental pH conditions (3 sets: N300, N400, and A400). The analysis of trajectories focused on characterization of changes in conformational behavior and stability of Ig kappa light chain variable domain caused by single aminoacid substitutions that were experimentally proved to enhance aggregation propensity, both in the form of amyloid and amorphous aggregates. Residue D82 turns out to be involved not only in R61-D82 but also in K45-D82 interaction, which was not observed in the X-ray structure, but frequently populated simulations of 1REI. The substitution D82I excludes both interactions, resulting in substantial destabilization (i.e., easier aggregation). Examination of behavior of edge regions of V(L) beta-sandwich reveals significant alterations in D82I mutant compared to wild 1REI, while relatively small changes occur in R61N. This suggests that mild and slow destabilization is the reason of the conversion of V(L) to partially folded amyloidogenic intermediate structure.

Amino Acids, Acidic↗
PubMed2006

Molecular dynamics study of conformational changes in human serum albumin by binding of fatty acids.

Human serum albumin (HSA) binds with fatty acids under normal physiologic conditions. To date, there is little published information on the tertiary structure of HSA-fatty acid complex in aqueous solution. In the present study, we used molecular dynamics (MD) simulations to elucidate possible structural changes of HSA brought about by the binding of fatty acids. Both unliganded HSA and HSA-fatty acid complex models for MD calculations were constructed based on the X-ray crystal structures. Five myristates (MYRs) were bound in the HSA-fatty acid complex model. In the present MD study, the motion of domains I and III caused by the binding of MYR molecules increased the radius of gyration of HSA. Root-mean-square fluctuations from the MD simulations revealed that the atomic fluctuations of the specific amino acids at drug-binding site I that can regulate the drug-binding affinity were increased by the binding of MYR molecules. Primary internal motions, characterized by the first three principal components, were observed mainly at domains I and III in the principal component analysis for trajectory data. The directional motion projected on the first principal component of unliganded HSA was conserved in HSA-MYR complex as the third principal directional motion with higher frequency. However, the third principal directional motion in unliganded HSA turned into the first principal directional motion with lower frequency in the HSA-MYR complex. Thus, the present MD study provides insights into the possible conformational changes of HSA caused by the binding of fatty acids.

Binding Sites↗
PubMed1996

Cellular interactions that guide sensory and motor neurites identified in an embryo slice preparation.

We used cultured cross sections ("slices") of avian embryos to identify interactions that guide neurites during their encounters with seven tissues that impose a stereotyped gross anatomical nerve pattern. We show that cultured slices retain tissue morphology, molecular distribution patterns, and guidance cues. They also allow us to directly visualize responses of labeled sensory and motor neurons deposited on the slice's surface. This assay has high predictive power. Contact-mediated avoidance or stimulation and long-range attraction or repulsion are each distinguishable because each predicts different neurite lengths and trajectories. The analysis shows that all but one of these mechanisms contributes to guidance. Three tissues similarly stimulated neurite elongation, suggesting common responses to a contact-mediated stimulation. Four tissues similarly elicited avoidance on contact, suggesting a common contact-mediated inhibition. Neurite orientations implicate a previously unsuspected long-distance attraction to one tissue, dorsal anterior sclerotome. Long-range repulsion plays no detectable role. Each tissue elicits the same response in two different neural populations, sensory and motor neurons. These results suggest that a small set of repeated mechanisms mediates responses to tissues that axons contact serially during pathfinding.

Animals↗
PubMed2006

Approximation for limit cycles and their isochrons.

Local analysis of trajectories of dynamical systems near an attractive periodic orbit displays the notion of asymptotic phase and isochrons. These notions are quite useful in applications to biosciences. In this note, we give an expression for the first approximation of equations of isochrons in the setting of perturbations of polynomial Hamiltonian systems. This method can be generalized to perturbations of systems that have a polynomial integral factor (like the Lotka-Volterra equation).

Homeostasis↗
PubMed2005

A role for the C. elegans L1CAM homologue lad-1/sax-7 in maintaining tissue attachment.

The L1 family of cell adhesion molecules (L1CAMs) is important for neural development. Mutations in one of the human L1CAM genes, L1, can result in several neurological syndromes, the symptoms of which are variably penetrant. The physiological cause of these symptoms, collectively termed CRASH, is not clear. Caenorhabditis elegans animals genetically null for the L1CAM homologue LAD-1, exhibit variably penetrant pleiotropic phenotypes that are similar to the CRASH symptoms; thus the C. elegans lad-1 mutant provides an excellent model system to study how disruption of L1 leads to these abnormalities. These phenotypes include uncoordinated movements, variable embryonic lethality, and abnormal neuronal distribution and axon trajectories. Our analysis revealed that many of these phenotypes are likely a result of tissue detachment.

Animals↗