Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy,Resulting in Myocardial Inflammation and Heart Failure

We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure.     

Two cases of interspecific hybridization among captive Australian boid snakes

A comparative study of external morphology and electrophoresis of blood proteins showed that two broods of Australian boid snakes, conceived and born in captivity, were the progeny of interspecific and intergeneric matings. Unequivocal identification of parents of the Python spilotes × P amethistinus cross was possible; evidence suggested that a P amethistinus female found coiled about the clutch of eggs was not the snake that laid them. The cross between P spilotes × Liasis mackloti was consistent with other evidence suggesting a close relationship between species of Python and Liasis in the Australian-Papuan region.     

Intérêt de la scintigraphie pulmonaire de perfusion dans les dilatations des bronches de l’enfant

IntroductionBronchiectasis is a chronic disease of the lungs by repeated respiratory infection. An early and adequate diagnosis and management reduce the morbidity and mortality of this disease. The aim of this study is to emphasize the importance of the combination of Computer Tomography (CT) and lung perfusion scan (SPP) in the diagnosis and therapeutic approach.Materials and methodsForty-three children were referred in the nuclear medicine department with a clinical diagnosis of bronchiectasis; they underwent a CT and a SPP.Results and conclusionBy analyzing the results of the SPP and CT separately, we conclude that there is no significant difference between the two investigations. The combination of the two explorations provides a gain in most surgical therapeutic orientation.     

Examination “Selection Pressures” in Biology

Class Work with Fungi. H. A. DADE and JEAN GUNNELL. Pp. 64. London: Commonwealth Mycological Institute, Kew. 1969. 10s. Review by B. M. Jones

The Insects: Structure and Function. R. F. CHAPMAN. Pp. xiii + 819 + 509 figs. London: The English Universities Press Ltd., 1969. £4.25. Review by T. G. Onions

An Introduction to the Principles of Plant Physiology. WALTER STILES and E. C. COCKING. Pp. 633. London: Methuen &; Co., Ltd. Third edition, 1969. 168s. Review by B. M. Jones

Background Notes to the Study of Human Biology for Nurses. T. ROBERTS. Pp. 80. London: Edward Arnold. Semistiff Back, 10s. (50p.). Review by J. H. Elliott     

Effect of implementing magnetic resonance imaging for patient-specific OpenSim models on lower-body kinematics and knee ligament lengths

BackgroundOpenSim models are typically based on cadaver findings that are generalized to represent a wide range of populations, which curbs their validity. Patient-specific modelling through incorporating magnetic resonance imaging (MRI) improves the model’s biofidelity with respect to joint alignment and articulations, muscle wrapping, and ligament insertions. The purpose of this study was to determine if the inclusion of an MRI-based knee model would elicit differences in lower limb kinematics and resulting knee ligament lengths during a side cut task.MethodsEleven participants were analyzed with the popular Rajagopal OpenSim model, two variations of the same model to include three and six degrees of freedom knee (DOF), and a fourth version featuring a four DOF MRI-based knee model. These four models were used in an inverse kinematics analysis of a side cut task and the resulting lower limb kinematics and knee ligament lengths were analyzed.ResultsThe MRI-based model was more responsive to the movement task than the original Rajagopal model while less susceptible to soft tissue artifact than the unconstrained six DOF model. Ligament isometry was greatest in the original Rajagopal model and smallest in the six DOF model.ConclusionsWhen using musculoskeletal modelling software, one must acutely consider the model choice as the resulting kinematics and ligament lengths are dependent on this decision. The MRI-based knee model is responsive to the kinematics and ligament lengths of highly dynamic tasks and may prove to be the most valid option for continuing with late-stage modelling operations such as static optimization.     

An interfacial equilibria model for the electrokinetic properties of a fat emulsion. Part III: A predictive computer model

Abstract

The semi-empirical thermodynamic model for the binding of metal ions to an emulsion (intralipid 20%) reported previously (Hall et al., 1991 ; Gaskin et al., 1993) is incorporated into a thermodynamic computer model. This permits the zeta potential and emulsion stability together with precipitate formation to be estimated for any intravenous nutrition regimen. A regimen frequently used in the intravenous nutrition of patients is considered in this modeling study. The effect of solution pH and calcium on the zeta potential of the emulsion is predicted. Calcium and magnesium are the only metal cations which are predicted to be of importance when considering stability of this emulsion.     

Multi-state survival models with treatment effects and biomarkers: Simulations for study design assessment

BackgroundComparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment.MethodsOverall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns.ResultsEvent-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting.ConclusionQuantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.     

A Molecular Dynamics Computer Simulation Performance Comparison of Java Versus C

Abstract

The relative performance of molecular dynamics (MD) computer simulations of fluids written in ANSI C is compared to that achieved by a comparable program written in Java. The performance of the Java program is shown to be dependent upon its runtime environment. The Java Runtime Environment (JRE) from the Java Development Kit (JDK) 1.2 provides a Just-In-Time (JIT) compiler option on Solaris and Windows 95 platforms which decreases the execution time by approximately 4–10× compared to the standard Java interpreter. The compiled Java implementation of the MD computer simulation runs between 30–100% slower. depending on the platform, compared to the equivalent C implementation. The stability of the two simulations, as measured by conservation of energy is shown to be identical to within ～ 1% over 10⁵ time steps.     

Thermoregulation in premature infants: A mathematical model

PurposeIn 2010, approximately 14.9 million babies (11.1%) were born preterm. Because preterm infants suffer from an immature thermoregulatory system they have difficulty maintaining their core body temperature at a constant level. Therefore, it is essential to maintain their temperature at, ideally, around 37 °C. For this, mathematical models can provide detailed insight into heat transfer processes and body-environment interactions for clinical applications.MethodsA new multi-node mathematical model of the thermoregulatory system of newborn infants is presented. It comprises seven compartments, one spherical and six cylindrical, which represent the head, thorax, abdomen, arms and legs, respectively. The model is customizable, i.e. it meets individual characteristics of the neonate (e.g. gestational age, postnatal age, weight and length) which play an important role in heat transfer mechanisms. The model was validated during thermal neutrality and in a transient thermal environment.ResultsDuring thermal neutrality the model accurately predicted skin and core temperatures. The difference in mean core temperature between measurements and simulations averaged 0.25±0.21 °C and that of skin temperature averaged 0.36±0.36 °C. During transient thermal conditions, our approach simulated the thermoregulatory dynamics/responses. Here, for all infants, the mean absolute error between core temperatures averaged 0.12±0.11 °C and that of skin temperatures hovered around 0.30 °C.ConclusionsThe mathematical model appears able to predict core and skin temperatures during thermal neutrality and in case of a transient thermal conditions.     

Simulated four-dimensional CT for markerless tumor tracking using a deep learning network with multi-task learning

IntroductionOur markerless tumor tracking algorithm requires 4DCT data to train models. 4DCT cannot be used for markerless tracking for respiratory-gated treatment due to inaccuracies and a high radiation dose. We developed a deep neural network (DNN) to generate 4DCT from 3DCT data.MethodsWe used 2420 thoracic 4DCT datasets from 436 patients to train a DNN, designed to export 9 deformation vector fields (each field representing one-ninth of the respiratory cycle) from each CT dataset based on a 3D convolutional autoencoder with shortcut connections using deformable image registration. Then 3DCT data at exhale were transformed using the predicted deformation vector fields to obtain simulated 4DCT data. We compared markerless tracking accuracy between original and simulated 4DCT datasets for 20 patients. Our tracking algorithm used a machine learning approach with patient-specific model parameters. For the training stage, a pair of digitally reconstructed radiography images was generated using 4DCT for each patient. For the prediction stage, the tracking algorithm calculated tumor position using incoming fluoroscopic image data.ResultsDiaphragmatic displacement averaged over 40 cases for the original 4DCT were slightly higher (<1.3 mm) than those for the simulated 4DCT. Tracking positional errors (95th percentile of the absolute value of displacement, “simulated 4DCT” minus “original 4DCT”) averaged over the 20 cases were 0.56 mm, 0.65 mm, and 0.96 mm in the X, Y and Z directions, respectively.ConclusionsWe developed a DNN to generate simulated 4DCT data that are useful for markerless tumor tracking when original 4DCT is not available. Using this DNN would accelerate markerless tumor tracking and increase treatment accuracy in thoracoabdominal treatment.     

Computer Dependence of An Improvement of The Cell Neighbour-Table Method For Short-Range Potentials

Abstract

A comparative test is presented for molecular dynamics, MD, computer simulation between the original Cell Neighbour-Table method, CNT, and a later development, the Link-Cell Neighbour-Table, LCNT. The test was simultaneously carried out on a vector Convex 210 computer and on a scalar Pentium 120. The comparison of the two methods for very large systems (up to 100000 particles) and for two short-range pair potentials (Weeks-Chandler-Andersen, WCA, and Lennard-Jones, LJ) showed that on the Convex, in vectorial mode, the LCNT method is about 25% more efficient in time than the CNT method for the shorter-range WCA potential, the difference being unnoticeable (less than 5%) for the LJ potential. However, when the scalar mode is on in the Convex, the difference disappears. In the Pentium, which was found to be systematically faster than the Convex even in vectorial mode, no significant difference of any kind between the both methods was found, with the either of the two potentials.     

Computer Simulation of Liquid Crystal Films

Abstract

We present the results of extensive Monte Carlo simulations of liquid crystal films of various thicknesses. A simple nearest-neighbour lattice model, the Lebwohl-Lasher model, is employed, with periodic boundaries in two directions and free, planar, surfaces in the third. Particular attention is devoted to locating the temperature of the order-disorder (nematic-isotropic) phase transition. Weak first-order behaviour apparently persists in systems as thin as 8 layers across, but below this the transition cannot be detected. The shift of the transition temperature from its bulk value approaches the expected asymptotic linear dependence on inverse thickness, but significant deviations from this are seen for films of 10 layers thickness and less. These results enable an accurate estimate to be made of the bulk phase transition temperature in the thermodynamic limit, and the result is consistent with that extrapolated from systems with full periodic boundaries.     

Online Classification of Multiple Motor Imagery Tasks Using Filter Bank Based Maximum-a-Posteriori Common Spatial Pattern Filters

ObjectiveThe main objective of this paper is to propose a novel technique, called filter bank maximum a-posteriori common spatial pattern (FB-MAP-CSP) algorithm, for online classification of multiple motor imagery activities using electroencephalography (EEG) signals. The proposed technique addresses the overfitting issue of CSP in addition to utilizing the spectral information of EEG signals inside the framework of filter banks while extending it to more than two conditions.Materials and methodsThe classification of motor imagery signals is based upon the detection of event-related de-synchronization (ERD) phenomena in the μ and β rhythms of EEG signals. Accordingly, two modifications in the existing MAP-CSP technique are presented: (i) The (pre-processed) EEG signals are spectrally filtered by a bank of filters lying in the μ and β brainwave frequency range, (ii) the framework of MAP-CSP is extended to deal with multiple (more than two) motor imagery tasks classification and the spatial filters thus obtained are calculated for each sub-band, separately. Subsequently, the most imperative features over all sub-bands are selected and un-regularized linear discriminant analysis is employed for classification of multiple motor imagery tasks.ResultsPublicly available dataset (BCI Competition IV Dataset I) is used to validate the proposed method i.e. FB-MAP-CSP. The results show that the proposed method yields superior classification results, in addition to be computationally more efficient in the case of online implementation, as compared to the conventional CSP based techniques and its variants for multiclass motor imagery classification.ConclusionThe proposed FB-MAP-CSP algorithm is found to be a potential / superior method for classifying multi-condition motor imagery EEG signals in comparison to FBCSP based techniques.     

Thermal Sensitivity as a Specialization for Prey Capture and Feeding in Snakes

Behavior can be regarded as a result of various processes ofdecision based on the information provided by the sensory organs.In this review the role of the so-called additional heat sense,next to vision, smell and mechanoreception is discussed withrespect to the feeding behavior of snakes. The hierarchy ofthe sensory information in various phases of the feeding behaviordiffers between snakes possessing heat receptors (e.g., speciesof the Crotalinae and Pythoninae) and those without (e.g., speciesof the Viperinae and Colubrinae). Probably depending on theinfluence of ecological demands, visual or chemical cues arethe main information in the behavioral phases before the strikeHowever, in situations with little visual input, e.g., in darkness,rodents' burrows, etc., hunting behavior is guided in the firstplace by radiation of warm objects in Crotalus, Python and Trimeresurusflavoviridis, and by substrate vibrations in Vipera aspis, Pituophismelanoleucus and Boa constrictor. I suggest that in the sensoryhierarchy, heat information functionally replaces the mechanicalinformation which is utilized by snakes without pit organs.Poststrike behavior on the other hand is mainly guided by chemicalcues in all snakes.     

A Model of Human Muscle Energy Expenditure

A model of muscle energy expenditure was developed for predicting thermal, as well as mechanical energy liberation during simulated muscle contractions. The model was designed to yield energy (heat and work) rate predictions appropriate for human skeletal muscle contracting at normal body temperature. The basic form of the present model is similar to many previous models of muscle energy expenditure, but parameter values were based almost entirely on mammalian muscle data, with preference given to human data where possible. Nonlinear phenomena associated with submaximal activation were also incorporated. The muscle energy model was evaluated at varying levels of complexity, ranging from simulated contractions of isolated muscle, to simulations of whole body locomotion. In all cases, acceptable agreement was found between simulated and experimental energy liberation. The present model should be useful in future studies of the energetics of human movement using forward dynamic computer simulation.     

Computer Determination of Contact Stress Distribution and Size of Weight Bearing Area in the Human Hip Joint

The mathematical models and the corresponding computer program for determination of the hip joint contact force, the contact stress distribution, and the size of the weight bearing area from a standard anteroposterior radiograph are described. The described method can be applied in clinical practice to predict an optimal stress distribution after different operative interventions in the hip joint and to analyze the short and long term outcome of the treatment of various pathological conditions in the hip. A group of dysplastic hips and a group of normal hips were examined, with respect to the peak contact stress normalized by the body weight, and with respect to the functional angle of the weight bearing area. It is shown that both these parameters can be used in the assessment of hip dysplasia.     

Simulating the free energy of passive membrane permeation for small molecules

Abstract

Computer simulations of passive membrane permeation provide important microscopic insights into the molecular mechanism of this important biological process that are complementary to experimental data. Our review focuses on the main approaches for calculating the free energy, or potential of mean force, for permeation of small molecules through lipid bilayers. The theoretical background for most currently used methods for potential of mean force calculation is described, including particle insertion, thermodynamic integration, umbrella sampling, metadynamics, adaptive biasing force and milestoning. A brief comparison of strengths and weaknesses of the competing approaches is presented. This is followed by a survey of results obtained by the different methods, with special attention to describing the mechanistic insights generated by modelling and illustrating capabilities of the different techniques. We conclude with a discussion of recent advances and future directions in modelling membrane permeation, including latest methodological enhancements, consideration of multiple slow variables and memory effects.     

Backbone Structure Confirmation and Side Chain Conformation Refinement of a Bradykinin Mimic BKM-824 by Comparing Calculated 1H, 13C and 19F Chemical Shifts with Experiment

Abstract

Calculated and experimental ¹H, ¹³C and ¹⁹F chemical shifts were compared in BKM-824, a cyclic bradykinin antagonist mimic, c[Ava¹-Igl²-Ser³-DF5F⁴-Oic⁵-Arg⁶] (Ava=5-amino- valeric acid, Igl=α-(2-indanyl)glycine, DF5F=pentafluorophenylalanine, Oic=(2S,3aS,7aS)- octahydroindole-2-carboxylic acid). The conformation of BKM-824 has been studied earlier by NMR spectroscopy (M. Miskolzie et al., J. Biomolec. Struct. Dyn. 17, 947–955 (2000)). All NMR structures have qualitatively the same backbone structure but there is considerable variation in the side chain conformations. We have carried out quantum mechanical optimization for three representative NMR structures at the B3LYP/6–31G* level, constraining the backbone dihedral angles at their NMR structure values, followed by NMR chemical shift calculations at the optimized structures with the 6–311G** basis set. There is an intramolecular hydrogen bond at Ser³ in the optimized structures.

The experimental ¹³C chemical shifts at five C^α positions as well as at the C^β, C^γ and Cδ position of Ava¹, which forms part of the backbone, are well reproduced by the calculations, confirming the NMR backbone structure. A comparison between the calculated and experimental H^β chemical shifts in Igl² shows that the dominant conformation at this residue is gauche. Changes of proton chemical shifts with the scan of the χ1 angle in DF5F⁴ suggest that χ1 ≈180°. The calculated ¹H and ¹³C chemical shifts are in good agreement with experiment at the rigid residue Oic⁵. None of the models gives accurate results for Arg⁶, presumably because of its positive charge. Our study indicates that calculated NMR shifts can be used as additional constraints in conjunction with NMR data to determine protein conformations. However, to be computationally effective, a database of chemical shifts in small peptide fragments should be precalculated.     

A Computer-simulation Model Relating Bone-cell Metabolism to Mechanical Adaptation of Trabecular Architecture

The architecture of trabecular bone is thought to be an optimal mechanical structure in terms of maximal strength and stiffness, and minimal weight. The structural optimality seems to be maintained during growth and adulthood by adaptation of mass and structure through a relationship with actual mechanical usage. The formation and maintenance of the architecture is realized by bone-resorbing osteoclasts and bone-forming osteoblasts, the effector cells of bone metabolism. Hence, a feedback regulatory mechanism between external load and metabolism must exist. We have developed an FEA-based computer-simulation model to study explanations for the workings of such regulatory schemes (1: Huiskes et al. (2000), Nature, 404, 704-706). The model is based on a mechanosensory function of osteocytes, which are thought to react to the local strain-energy-density rate in the mineralized tissue, produced by dynamic external loading on the bone. As an effect of this signal, osteocytes are assumed to transfer an osteoblast recruitment stimulus to the surface, enhancing bone formation. Osteoclasts are assumed to resorb bone that is disused or damaged, in a spatially random manner. This model provides an explanation for the maintenance and adaptation of trabecular bone architecture as an optimal structure. In this article, the mathematical background of the model is specified.     

A Computer Model for Reshaping of Cells in Epithelia Due to In-plane Deformation and Annealing

Although cell reshaping is fundamental to the mechanics of epithelia, technical barriers have prevented the methods of mechanics from being used to investigate it. These barriers have recently been overcome by the cell-based finite element formulation of Chen and Brodland. Here, parameters to describe the fabric of an epithelium in terms of cell shape and orientation and cell edge density are defined. Then, rectangular "patches" of model epithelia having various initial fabric parameters are generated and are either allowed to anneal or are subjected to one of several patterns of in-plane deformation. The simulations show that cell reshaping lags the deformation history, that it is allayed by cell rearrangement and that it causes the epithelium as a whole to exhibit viscoelastic mechanical properties. Equations to describe changes in cell shape due to annealing and in-plane deformation are presented.