WorldWideScience

Sample records for models bearing mutations

  1. New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease

    Science.gov (United States)

    Gómez-Grau, Marta; Albaigès, Júlia; Casas, Josefina; Auladell, Carme; Dierssen, Mara; Vilageliu, Lluïsa; Grinberg, Daniel

    2017-01-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009 G > A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554-1009 G > A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7–8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC. PMID:28167839

  2. Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation

    Directory of Open Access Journals (Sweden)

    Laura A. Martin

    2014-08-01

    Full Text Available Pathogenic de novo mutations increase with fathers’ age and could be amplified through competition between genetically distinct subpopulations of spermatogonial stem cells (SSCs. Here, we tested the fitness of SSCs bearing wild-type human FGFR2 or an Apert syndrome mutant, FGFR2 (S252W, to provide experimental evidence for SSC competition. The S252W allele conferred enhanced FGFR2-mediated signaling, particularly at very low concentrations of ligand, and also subtle changes in gene expression. Mutant SSCs exhibited improved competitiveness in vitro and increased stem cell activity in vivo upon transplantation. The fitness advantage in vitro only occurred in low concentrations of fibroblast growth factor (FGF, was independent of FGF-driven proliferation, and was accompanied by increased response to glial cell line-derived neurotrophic factor (GDNF. Our studies provide experimental evidence of enhanced stem cell fitness in SSCs bearing a paternal age-associated mutation. Our model will be useful for interrogating other candidate mutations in the future to reveal mechanisms of disease risk.

  3. Markov models for accumulating mutations

    CERN Document Server

    Beerenwinkel, Niko

    2007-01-01

    We introduce and analyze a waiting time model for the accumulation of genetic changes. The continuous time conjunctive Bayesian network is defined by a partially ordered set of mutations and by the rate of fixation of each mutation. The partial order encodes constraints on the order in which mutations can fixate in the population, shedding light on the mutational pathways underlying the evolutionary process. We study a censored version of the model and derive equations for an EM algorithm to perform maximum likelihood estimation of the model parameters. We also show how to select the maximum likelihood poset. The model is applied to genetic data from different cancers and from drug resistant HIV samples, indicating implications for diagnosis and treatment.

  4. Bear

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The famous physicist made for his scholars this riddle. A fellow encountered a bear in a wasteland. There was nobody else there. Both were frightened and ran away. Fellow to the north, bear to the west. Suddenly the fellow stopped, aimed his gun to the south and shot the bear. What colour was the bear?

  5. Direct Model Reference Adaptive Control for a Magnetic Bearing

    Energy Technology Data Exchange (ETDEWEB)

    Durling, Mike [Rensselaer Polytechnic Inst., Troy, NY (United States)

    1999-11-01

    A Direct Model Reference Adaptive Controller (DMRAC) is applied to a magnetic bearing test stand. The bearing of interest is the MBC 500 Magnetic Bearing System manufactured by Magnetic Moments, LLC. The bearing model is presented in state space form and the system transfer function is measured directly using a closed-loop swept sine technique. Next, the bearing models are used to design a phase-lead controller, notch filter and then a DMRAC. The controllers are tuned in simulations and finally are implemented using a combination of MATLAB, SIMULINK and dSPACE. The results show a successful implementation of a DMRAC on the magnetic bearing hardware.

  6. A Wide Bandwidth Model for the Electrical Impedance of Magnetic BearingS

    Science.gov (United States)

    Meeker, David C.; Maslen, Eric H.; Noh, Myounggyu D.

    1996-01-01

    Magnetic bearings are often designed using magnetic circuit theory. When these bearings are built, however, effects not included in the usual circuit theory formulation have a significant influence on bearing performance. Two significant sources of error in the circuit theory approach are the neglect of leakage and fringing effects and the neglect of eddy current effects. This work formulates an augmented circuit model in which eddy current and flux leakage and fringing effects are included. Through the use of this model, eddy current power losses and actuator bandwidth can be derived. Electrical impedance predictions from the model are found to be in good agreement with experimental data from a typical magnetic bearing.

  7. Bearing tester data compilation, analysis and reporting and bearing math modeling, volume 1

    Science.gov (United States)

    Marshall, D. D.; Montgomery, E. E.; New, L. S.; Stone, M. A.; Tiller, B. K.

    1984-01-01

    Thermal and mechanical models of high speed angular contact ball bearings operating in LOX and LN2 were developed and verified with limited test data in an effort to further understand the parameters that determine or effect the SSME turbopump bearing operational characteristics and service life. The SHABERTH bearing analysis program which was adapted to evaluate shaft bearing systems in cryogenics is not capable of accommodating varying thermal properties and two phase flow. A bearing model with this capability was developed using the SINDA thermal analyzer. Iteration between the SHABERTH and the SINDA models enable the establishment of preliminary bounds for stable operation in LN2. These limits were established in terms of fluid flow, fluid inlet temperature, and axial load for a shaft speed of 30,000 RPM.

  8. Biological evolution model with conditional mutation rates

    Science.gov (United States)

    Saakian, David B.; Ghazaryan, Makar; Bratus, Alexander; Hu, Chin-Kun

    2017-05-01

    We consider an evolution model, in which the mutation rates depend on the structure of population: the mutation rates from lower populated sequences to higher populated sequences are reduced. We have applied the Hamilton-Jacobi equation method to solve the model and calculate the mean fitness. We have found that the modulated mutation rates, directed to increase the mean fitness.

  9. Experimental Grey Box Model Identification of an Active Gas Bearing

    DEFF Research Database (Denmark)

    Theisen, Lukas Roy Svane; Pierart Vásquez, Fabián Gonzalo; Niemann, Hans Henrik;

    2014-01-01

    in a dynamic model of an active gas bearing and subsequent control loop design. A grey box model is determined based on experiments where piezo actuated valves are used to perturb the journal and hence excite the rotor-bearing system. Such modelling from actuator to output is shown to effciently support...

  10. Modeling of Tilting-Pad Journal Bearings with Transfer Functions

    Directory of Open Access Journals (Sweden)

    J. A. Vázquez

    2001-01-01

    Full Text Available Tilting-pad journal bearings are widely used to promote stability in modern rotating machinery. However, the dynamics associated with pad motion alters this stabilizing capacity depending on the operating speed of the machine and the bearing geometric parameters, particularly the bearing preload. In modeling the dynamics of the entire rotor-bearing system, the rotor is augmented with a model of the bearings. This model may explicitly include the pad degrees of freedom or may implicitly include them by using dynamic matrix reduction methods. The dynamic reduction models may be represented as a set of polynomials in the eigenvalues of the system used to determine stability. All tilting-pad bearings can then be represented by a fixed size matrix with polynomial elements interacting with the rotor. This paper presents a procedure to calculate the coefficients of polynomials for implicit bearing models. The order of the polynomials changes to reflect the number of pads in the bearings. This results in a very compact and computationally efficient method for fully including the dynamics of tilting-pad bearings or other multiple degrees of freedom components that interact with rotors. The fixed size of the dynamic reduction matrices permits the method to be easily incorporated into rotor dynamic stability codes. A recursive algorithm is developed and presented for calculating the coefficients of the polynomials. The method is applied to stability calculations for a model of a typical industrial compressor.

  11. Fatigue Life Analysis of Rolling Bearings Based on Quasistatic Modeling

    Directory of Open Access Journals (Sweden)

    Wei Guo

    2015-01-01

    Full Text Available Rolling bearings are widely used in aeroengine, machine tool spindles, locomotive wheelset, and so forth. Rolling bearings are usually the weakest components that influence the remaining life of the whole machine. In this paper, a fatigue life prediction method is proposed based on quasistatic modeling of rolling bearings. With consideration of radial centrifugal expansion and thermal deformations on the geometric displacement in the bearings, the Jones’ bearing model is updated, which can predict the contact angle, deformation, and load between rolling elements and bearing raceways more accurately. Based on Hertz contact theory and contact mechanics, the contact stress field between rolling elements and raceways is calculated. A coupling model of fatigue life and damage for rolling bearings is given and verified through accelerated life test. Afterwards, the variation of bearing life is investigated under different working conditions, that is, axial load, radial load, and rotational speed. The results suggested that the working condition had a great influence on fatigue life of bearing parts and the order in which the damage appears on bearing parts.

  12. Foothills model forest grizzly bear study : project update

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2002-01-01

    This report updates a five year study launched in 1999 to ensure the continued healthy existence of grizzly bears in west-central Alberta by integrating their needs into land management decisions. The objective was to gather better information and to develop computer-based maps and models regarding grizzly bear migration, habitat use and response to human activities. The study area covers 9,700 square km in west-central Alberta where 66 to 147 grizzly bears exist. During the first 3 field seasons, researchers captured and radio collared 60 bears. Researchers at the University of Calgary used remote sensing tools and satellite images to develop grizzly bear habitat maps. Collaborators at the University of Washington used trained dogs to find bear scat which was analyzed for DNA, stress levels and reproductive hormones. Resource Selection Function models are being developed by researchers at the University of Alberta to identify bear locations and to see how habitat is influenced by vegetation cover and oil, gas, forestry and mining activities. The health of the bears is being studied by researchers at the University of Saskatchewan and the Canadian Cooperative Wildlife Health Centre. The study has already advanced the scientific knowledge of grizzly bear behaviour. Preliminary results indicate that grizzlies continue to find mates, reproduce and gain weight and establish dens. These are all good indicators of a healthy population. Most bear deaths have been related to poaching. The study will continue for another two years. 1 fig.

  13. On The Modelling Of Hybrid Aerostatic - Gas Journal Bearings

    DEFF Research Database (Denmark)

    Morosi, Stefano; Santos, Ilmar

    2011-01-01

    Gas journal bearing have been increasingly adopted in modern turbo-machinery applications, as they meet the demands of operation at higher rotational speeds, in clean environment and great efficiency. Due to the fact that gaseous lubricants, typically air, have much lower viscosity than more...... modeling for hybrid lubrication of a compressible fluid film journal bearing. Additional forces are generated by injecting pressurized air into the bearing gap through orifices located on the bearing walls. A modified form of the compressible Reynolds equation for active lubrication is derived. By solving...

  14. Habitat suitability index model for black bear (Ursus americanus)

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This descriptive model applies only to black bear in the coastal forests and adjacent vegetative communities, which extend from Afognak Island and the shores of...

  15. Mini hemoreliable axial flow LVAD with magnetic bearings: part 3: modeling of demo-magnetic bearing and verification.

    Science.gov (United States)

    Goldowsky, Michael

    2002-01-01

    This paper discusses my previous work on aerospace magnetic bearings during the 1970s and 1980s. Modeling of the magnetic field in the bearing is discussed and stiffness test data are provided, which verifies the model. An LVAD this small was made possible by the use of axial field fringing ring magnetic bearings that are much stronger than the radial field bearings currently used in turbo pumps. The analytical design of a first prototype bearing is discussed in detail that is mainly of interest to bearing designers. Modeling was accurately done without finite element analysis (FEA), which readily provided design insights not easily obtained through FEA. This bearing was not meant to satisfy all specifications of a blood pump. The next prototype, to be reported at the 2001 ASAIO conference, will meet these specifications.

  16. Hibernating bears as a model for preventing disuse osteoporosis

    Science.gov (United States)

    Donahue, S.W.; McGee, M.E.; Harvey, K.B.; Vaughan, M.R.; Robbins, C.T.

    2006-01-01

    The hibernating bear is an excellent model for disuse osteoporosis in humans because it is a naturally occurring large animal model. Furthermore, bears and humans have similar lower limb skeletal morphology, and bears walk plantigrade like humans. Black bears (Ursus americanus) may not develop disuse osteoporosis during long periods of disuse (i.e. hibernation) because they maintain osteoblastic bone formation during hibernation. As a consequence, bone volume, mineral content, porosity, and strength are not adversely affected by annual periods of disuse. In fact, cortical bone bending strength has been shown to increase with age in hibernating black bears without a significant change in porosity. Other animals require remobilization periods 2-3 times longer than the immobilization period to recover the bone lost during disuse. Our findings support the hypothesis that black bears, which hibernate for as long as 5-7 months annually, have evolved biological mechanisms to mitigate the adverse effects of disuse on bone porosity and strength. ?? 2005 Elsevier Ltd. All rights reserved.

  17. Autoregressive modelling for rolling element bearing fault diagnosis

    Science.gov (United States)

    Al-Bugharbee, H.; Trendafilova, I.

    2015-07-01

    In this study, time series analysis and pattern recognition analysis are used effectively for the purposes of rolling bearing fault diagnosis. The main part of the suggested methodology is the autoregressive (AR) modelling of the measured vibration signals. This study suggests the use of a linear AR model applied to the signals after they are stationarized. The obtained coefficients of the AR model are further used to form pattern vectors which are in turn subjected to pattern recognition for differentiating among different faults and different fault sizes. This study explores the behavior of the AR coefficients and their changes with the introduction and the growth of different faults. The idea is to gain more understanding about the process of AR modelling for roller element bearing signatures and the relation of the coefficients to the vibratory behavior of the bearings and their condition.

  18. Stationary solutions for metapopulation Moran models with mutation and selection

    Science.gov (United States)

    Constable, George W. A.; McKane, Alan J.

    2015-03-01

    We construct an individual-based metapopulation model of population genetics featuring migration, mutation, selection, and genetic drift. In the case of a single "island," the model reduces to the Moran model. Using the diffusion approximation and time-scale separation arguments, an effective one-variable description of the model is developed. The effective description bears similarities to the well-mixed Moran model with effective parameters that depend on the network structure and island sizes, and it is amenable to analysis. Predictions from the reduced theory match the results from stochastic simulations across a range of parameters. The nature of the fast-variable elimination technique we adopt is further studied by applying it to a linear system, where it provides a precise description of the slow dynamics in the limit of large time-scale separation.

  19. Seismic base isolation: Elastomer characterization, bearing modeling and system response

    Energy Technology Data Exchange (ETDEWEB)

    Kulak, R.F.; Wang, C.Y.; Hughes, T.H.

    1991-01-01

    This paper discusses several major aspects of seismic base isolation systems that employ laminated elastomer bearings. Elastomer constitutive models currently being used to represent the nonlinear elastic and hysteretic behavior are discussed. Some aspects of mechanical characterization testing of elastomers is presented along with representative tests results. The development of a finite element based mesh generator for laminated elastomer bearings is presented. Recent advances in the simulation of base isolated structures to earthquake motions are presented along with a sample problem. 13 refs., 19 figs., 1 tab.

  20. Advanced Control of Active Bearings - Modelling, Design and Experiments

    DEFF Research Database (Denmark)

    Theisen, Lukas Roy Svane

    In all rotating machines relative movements between the stationary parts and the rotating parts imply energy loss and, in many critical cases, vibration problems. This energy loss leads to higher overall energy consumption of the system. Research activities towards the reduction of friction......, the enhancement of damping, the extension of operating range and the minimisation of critical vibrations in machine elements are of fundamental importance. The main component to tackle the energy-loss-related problems is the bearing. The area of design of active bearings, while very promising, is still in its...... the critical speeds. The feedback control law is preferably designed from a simple model, which captures the dominant dynamics of the machine in the frequency range of interest. This thesis offers two main original contributions in the field of active bearings. First, an experimental technique is proposed...

  1. Modeling and Development of RMD Configuration Magnetic Bearing

    Directory of Open Access Journals (Sweden)

    K.P. Lijesh

    2015-06-01

    Full Text Available The low load carrying capacity of Passive Magnetic Bearings (PMBs has restricted their use in many industrial applications. The Rotation Magnetized Direction (RMD configuration has emerged as a strong and viable method that is able to substantially enhance the load carrying capacity of passive magnetic bearings. It consists of both radially and axially polarized passive magnets. But the physical realization of a radially polarized magnet is difficult to achieve. In the present work, a RMD structure consisting of aluminum ring and cubical shaped magnets is proposed by developing the radially polarized magnets required for RMD structure. A theoretical model is derived by simulating the cuboid magnets in form of sector magnets by developing equivalent surface area. An experimental setup was designed and developed to conduct experimental verification. The theoretical model is validated by conducting experiments on RMD configuration magnetic bearing and axially magnetized full ring bearing. The comparison of the load carrying capacity by different configuration is performed and results are presented.

  2. SSME Bearing and Seal Tester Data Compilation, Analysis, and Reporting; and Refinement of the Cryogenic Bearing Analysis Mathematical Model

    Science.gov (United States)

    Moore, James; Marty, Dave; Cody, Joe

    2000-01-01

    SRS and NASA/MSFC have developed software with unique capabilities to couple bearing kinematic modeling with high fidelity thermal modeling. The core thermomechanical modeling software was developed by SRS and others in the late 1980's and early 1990's under various different contractual efforts. SRS originally developed software that enabled SHABERTH (Shaft Bearing Thermal Model) and SINDA (Systems Improved Numerical Differencing Analyzer) to exchange data and autonomously allowing bearing component temperature effects to propagate into the steady state bearing mechanical model. A separate contract was issued in 1990 to create a personal computer version of the software. At that time SRS performed major improvements to the code. Both SHABERTH and SINDA were independently ported to the PC and compiled. SRS them integrated the two programs into a single program that was named SINSHA. This was a major code improvement.

  3. Planetary Suit Hip Bearing Model for Predicting Design vs. Performance

    Science.gov (United States)

    Cowley, Matthew S.; Margerum, Sarah; Harvil, Lauren; Rajulu, Sudhakar

    2011-01-01

    Designing a planetary suit is very complex and often requires difficult trade-offs between performance, cost, mass, and system complexity. In order to verifying that new suit designs meet requirements, full prototypes must eventually be built and tested with human subjects. Using computer models early in the design phase of new hardware development can be advantageous, allowing virtual prototyping to take place. Having easily modifiable models of the suit hard sections may reduce the time it takes to make changes to the hardware designs and then to understand their impact on suit and human performance. A virtual design environment gives designers the ability to think outside the box and exhaust design possibilities before building and testing physical prototypes with human subjects. Reductions in prototyping and testing may eventually reduce development costs. This study is an attempt to develop computer models of the hard components of the suit with known physical characteristics, supplemented with human subject performance data. Objectives: The primary objective was to develop an articulating solid model of the Mark III hip bearings to be used for evaluating suit design performance of the hip joint. Methods: Solid models of a planetary prototype (Mark III) suit s hip bearings and brief section were reverse-engineered from the prototype. The performance of the models was then compared by evaluating the mobility performance differences between the nominal hardware configuration and hardware modifications. This was accomplished by gathering data from specific suited tasks. Subjects performed maximum flexion and abduction tasks while in a nominal suit bearing configuration and in three off-nominal configurations. Performance data for the hip were recorded using state-of-the-art motion capture technology. Results: The results demonstrate that solid models of planetary suit hard segments for use as a performance design tool is feasible. From a general trend perspective

  4. Experimental Investigation of Friction Effect on Liner Model Rolling Bearings for Large Diameter Thrust Bearing Design

    Directory of Open Access Journals (Sweden)

    S. Babu

    2012-12-01

    Full Text Available Studying friction coefficient has significant importance, especially when dealing with high load and temperature applications that have frequent starting and stopping points. Towards that, two sets of angular contact Linear Model Mockup Bearings (LMMB were designed and fabricated. This linear model assembly was made up of high precision, grounded raceways (AISI 4140 and commercially purchased balls (AISI 52100. The experimental studies were carried out by placing different number of balls between the raceways under different loads at dry lubricating condition. The static friction coefficients were measured using two different experiments: viz gravitation-based experiment and direct linear force measurement experiment. And Digital Image Correlation (DIC technique was used to find the stiffness of LMMB set.

  5. An Integrated Magnetic Circuit Model and Finite Element Model Approach to Magnetic Bearing Design

    Science.gov (United States)

    Provenza, Andrew J.; Kenny, Andrew; Palazzolo, Alan B.

    2003-01-01

    A code for designing magnetic bearings is described. The code generates curves from magnetic circuit equations relating important bearing performance parameters. Bearing parameters selected from the curves by a designer to meet the requirements of a particular application are input directly by the code into a three-dimensional finite element analysis preprocessor. This means that a three-dimensional computer model of the bearing being developed is immediately available for viewing. The finite element model solution can be used to show areas of magnetic saturation and make more accurate predictions of the bearing load capacity, current stiffness, position stiffness, and inductance than the magnetic circuit equations did at the start of the design process. In summary, the code combines one-dimensional and three-dimensional modeling methods for designing magnetic bearings.

  6. A new nonlinear dynamic model of the rotor-bearing system considering preload and varying contact angle of the bearing

    Science.gov (United States)

    Zhang, Xuening; Han, Qinkai; Peng, Zhike; Chu, Fulei

    2015-05-01

    A great deal of research work has been done on the dynamic behaviors of the rotor-bearing system. However, the important effects of load and variation of contact angle on the bearing performance have not been focused on sufficiently. In this paper, a five-degree-of-freedom load distribution model is set up considering the bearing preload and the loads due to the rotor imbalance. Utilizing this model, the variation of the bearing contact angle is investigated thoroughly. The comparisons of the obtained contact angle against the results from literature validate that the proposed load distribution model is effective. With this model, the static ball deformations are obtained considering variation of the contact angle. Through resolving the dynamic displacements of the rotor, the dynamic ball deformations could also be obtained. Then the total restoring forces and moments of the bearings could be formulated. By introducing these nonlinear forces and moments into the rotating system, a new dynamic model considering the preload and the variation of contact angle is set up. The present analyses indicate that the bearing contact angle will be changed remarkably with the effect of bearing load. The deflection vibration of the rotor-bearing system will be underestimated without considering the varying contact angle. With the effect of varying contact angle, the ball passage frequency and its combinations with the shaft rotating frequency become more noticeable. The main resonance regions for the rotor-bearing system shift to the lower speed ranges when the variation of contact angle is taken into account.

  7. Vertical bearing capacity of pile based on load transfer model

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ming-hua; YANG Ming-hui; ZOU Xin-jun

    2005-01-01

    The load transfer analytical method is applied to study the bearing mechanism of piles with vertical load in this paper. According to the different hardening rules of soil or rock around the pile shaft, such as work-softening, ideal elasto-plastic and work-hardening, a universal tri-linear load transfer model is suggested for the development of side and tip resistance by various types of soil (rock) with the consideration of sediment at the bottom of the pile. Based on the model, a formula is derived for the relationship between the settlement and load on the pile top to determine the vertical bearing capacity, taking into account such factors as the characteristics of the stratum, the side resistance along the shaft, and tip resistance under the pile tip. A close agreement of the calculated results with the measured data from a field test pile lends confidence to the future application of the present approach in engineering practice.

  8. Parton Branching in Color Mutation Model

    CERN Document Server

    Hwa, R C

    1999-01-01

    The soft production problem in hadronic collisions as described in the eikonal color mutation branching model is improved in the way that the initial parton distribution is treated. Furry branching of the partons is considered as a means of describing the nonperturbative process of parton reproduction in soft interaction. The values of all the moments, and $C_q$, for q=2,...,5, as well as their energy dependences can be correctly determined by the use of only two parameters.

  9. A Cumulative Damage Reliability Model on the Basis of Contact Fatigue of the Rolling Bearing

    Institute of Scientific and Technical Information of China (English)

    HUANG Li

    2006-01-01

    A cumulative damage reliability model of contact fatigue of the rolling bearing is more identical with the actual conditions. It is put forward on the basis of contact fatigue life probability distribution of the rolling bearing that obey Weibull distribution and rest on the Miner cumulative damage theory. Finally a case is given to predict the reliability of bearing roller by using these models.

  10. KINEMATICS AND DYNAMICS MODELS OF CYLINDRICAL ROLLER BEARING OF RAILWAY TRANSPORT

    Directory of Open Access Journals (Sweden)

    A. V. Gaydamaka

    2014-05-01

    Full Text Available Purpose. Lack of kinematics models and imperfection of the known dynamics models of the roller bearings of railway rolling stock axle-boxes do not allow designing the optimal structure of bearing cages, providing the required service life and reliability of bearing units of wheel sets for cars and locomotives. The studies of kinematics and dynamics of roller bearings of axle boxes for cars and locomotives and modeling of their parts interaction to create the analytical method of bearing cages calculation are necessary. Methodology. This purpose has been achieved due to the modeling of kinematics of the ideal (without gaps and real (taking account the gaps, manufacturing and installation errors bearings, substantiation of the transfer mechanism of motion from the rollers to bearing cage, modeling the dynamics of rolling, research of interaction forces of the rollers with bearing cage. Findings. It is established that the kinematics of ideal bearing is determined by the contact deformations of the rollers and rings, when the kinematics of real bearing depends mainly on the side gaps in the windows of the bearing cage. On the basis of studies of the real bearing kinematics the dynamics models of the rollers and bearing cage interaction were constructed. The conducted studies of kinematics and dynamics of rolling bearings have changed our view of them as of the planetary mechanism, explained the reason of bearing cage loading, and confirmed the possibility of destruction during operation. Originality. It was first proposed a mechanism for motion transfer from the rollers to the bearing cage of roller bearings, consisting in that the side gap in the bearing cage window is reduced gradually multiple of the number of rollers of radial loading area according to the bearing cage motion. The models of roller bearing dynamics, which allow calculating the interaction forces of parts for all modes of operation, were improved. Practical value. Use of the

  11. Rotordynamic Modelling and Response Characteristics of an Active Magnetic Bearing Rotor System

    Science.gov (United States)

    Free, April M.; Flowers, George T.; Trent, Victor S.

    1996-01-01

    Auxiliary bearings are a critical feature of any magnetic bearing system. They protect the soft iron core of the magnetic bearing during an overload or failure. An auxiliary bearing typically consists of a rolling element bearing or bushing with a clearance gap between the rotor and the inner race of the support. The dynamics of such systems can be quite complex. It is desired to develop a rotordynamic model which describes the dynamic behavior of a flexible rotor system with magnetic bearings including auxiliary bearings. The model is based upon an experimental test facility. Some simulation studies are presented to illustrate the behavior of the model. In particular, the effects of introducing sideloading from the magnetic bearing when one coil fails is studied. These results are presented and discussed.

  12. Constitutive Models for Debris-bearing Ice Layers

    Science.gov (United States)

    Moore, P. L.

    2013-12-01

    Rock debris is incorporated within many glaciers and ice sheets, particularly in basal ice layers and englacial debris bands. Field observations and laboratory experiments have shown that debris inclusions can both strengthen and weaken ice by as much as two orders of magnitude compared to debris-free ice under the same conditions. Nevertheless, models of glacier flow usually neglect any effect of debris-bearing layers. Where debris-bearing ice is present, proper treatment of its deformation could profoundly impact model results. A three-phase mechanical model is presented that reproduces many of the key observations of debris-bearing ice rheology. First order variables in the model are limited to debris concentration, particle size, solute concentration and temperature. At low debris concentrations (less than about 40% by volume), the mixture is treated under the framework of a dispersion-strengthened metal alloy but with a fluidity that is enhanced by premelted water at ice-debris interfaces. While debris strengthens the ice by interfering with the motion of dislocations, thermally-activated detachment can reduce the effect at temperatures close to melting. At these warm temperatures, recovery aided by unfrozen interfacial water acts to weaken the mixture, an effect that is further ehnanced by the presence of solutes at particle surfaces. Whether the debris-bearing ice is stronger or weaker than debris-free ice in the model depends strongly on the specific surface area of the debris and on a parameter that describes the thermal detachment of dislocations. As debris concentrations exceed about 40%, dispersion-strengthened ice flow still governs bulk deformation but the effective viscosity is further increased by enhanced strain rates in the ice "matrix" as the average inter-particle distance declines. At still higher concentrations (greater than about 52% by volume for sand), deformation is primarily frictional. The mixture is thus treated as a dilatant Coulomb

  13. Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin.

    Science.gov (United States)

    Quentmeier, H; Martelli, M P; Dirks, W G; Bolli, N; Liso, A; Macleod, R A F; Nicoletti, I; Mannucci, R; Pucciarini, A; Bigerna, B; Martelli, M F; Mecucci, C; Drexler, H G; Falini, B

    2005-10-01

    We recently identified a new acute myeloid leukemia (AML) subtype characterized by mutations at exon-12 of the nucleophosmin (NPM) gene and aberrant cytoplasmic expression of NPM protein (NPMc+). NPMc+ AML accounts for about 35% of adult AML and it is associated with normal karyotype, wide morphological spectrum, CD34-negativity, high frequency of FLT3-ITD mutations and good response to induction therapy. In an attempt to identify a human cell line to serve as a model for the in vitro study of NPMc+ AML, we screened 79 myeloid cell lines for mutations at exon-12 of NPM. One of these cell lines, OCI/AML3, showed a TCTG duplication at exon-12 of NPM. This mutation corresponds to the type A, the NPM mutation most frequently observed in primary NPMc+ AML. OCI/AML3 cells also displayed typical phenotypic features of NPMc+ AML, that is, expression of macrophage markers and lack of CD34, and the immunocytochemical hallmark of this leukemia subtype, that is, the aberrant cytoplasmic expression of NPM. The OCI/AML3 cell line easily engrafts in NOD/SCID mice and maintains in the animals the typical features of NPMc+ AML, such as the NPM cytoplasmic expression. For all these reasons, the OCI/AML3 cell line represents a remarkable tool for biomolecular studies of NPMc+ AML.

  14. Modelling mutational landscapes of human cancers in vitro

    Science.gov (United States)

    Olivier, Magali; Weninger, Annette; Ardin, Maude; Huskova, Hana; Castells, Xavier; Vallée, Maxime P.; McKay, James; Nedelko, Tatiana; Muehlbauer, Karl-Rudolf; Marusawa, Hiroyuki; Alexander, John; Hazelwood, Lee; Byrnes, Graham; Hollstein, Monica; Zavadil, Jiri

    2014-03-01

    Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data.

  15. Modeling of Hybrid Permanent Magnetic-Gas Bearings

    DEFF Research Database (Denmark)

    Morosi, Stefano; Santos, Ilmar

    2009-01-01

    Modern turbomachinery applications require nowadays ever-growing rotational speeds and high degree of reliability. It then becomes natural to focus the attention of the research to contact-free bearings elements. The present alternatives focus on gas lubricated journal bearings or magnetic bearings....... In the present paper both the technologies are combined with the aim of developing a new kind of hybrid permanent magnetic - gas bearing. This new kind of machine is intended to exploit the benefits of the two technologies while minimizing their drawbacks. The poor start-up and low speed operation performance...... of the gas bearing is balanced by the properties of the passive magnetic one. At high speeds the dynamic characteristics of the gas bearing are improved by offsetting the stator ring of the permanent magnetic bearing. Furthermore this design shows a kind of redundancy, which offers soft failure properties...

  16. On The Modeling Of Hybrid Aerostatic - Gas Journal Bearings

    DEFF Research Database (Denmark)

    Morosi, Stefano; Santos, Ilmar

    2010-01-01

    Gas journal bearing have been increasingly adopted in modern turbo-machinery applications, as they meet the demands of operation at higher rotational speeds, in clean environment and great efficiency. Due to the fact that gaseous lubricants, typically air, have much lower viscosity than more...... of a compressible fluid film journal bearing. Control forces are generated by injecting pressurized air into the bearing gap through orifices located on the bearing walls. A modified form of the compressible Reynolds equation for active lubrication is derived. By solving this equation, stiffness and damping...

  17. MATHEMATICAL MODELLING OF QUAZISTEADY MODE OF BEARING AIR BUFFER FILLING

    Directory of Open Access Journals (Sweden)

    E. D. Chertov

    2014-01-01

    Full Text Available Summary. Today the only way to eliminate contact with the product during the manufacturing process is to provide a support surface under its support surface air buffer layer formed due to the expiration of the working environment through holes perforated gas distribution grids forms. There proposed the method of contactless formation of products consisting of composite materials by the means of air buffer in the article. The results of theoretical and experimental investigations of hydro-gas-dynamic processes occurring when casting of organic- mineral composite material onto the bearing air buffer expressed in the form of mathematical description realizing original hypotheses reflected in the choice of transformation algorithm and limiting conditions are presented. On the base of obtained mathematical model the algorithm of calculation of optimum parameters of transporting systems with discretely powered gas buffer is developed. The method of deduction of a semi-finished product on the gas buffer, which allows to level the pressure field under the bearing surface of the deduction object due to the usage of devices of pseudo fluidized granular material in pneumatic chambers is offered. The application of this method allows to eliminate the possibility of contact between the composite material and the working surface of the equipment and also to reduce the cost of production of pneumatic devices, to improve operational characteristics of this equipment. Submitted depending allowed to develop the methodology and implementation of engineering calculation device for non-contact casting composite materials on air buffer, semi-industrial and industrial variants were created and put into production.

  18. Positive mutations and mutation-dependent Verhulst factor in Penna ageing model

    Science.gov (United States)

    Moss de Oliveira, S.; Stauffer, D.; de Oliveira, P. M. C.; Sá Martins, J. S.

    2004-02-01

    We modify twice the Penna model for biological ageing. First, we introduce back (good) mutations and a memory for them into the model. It allows us to observe an improvement of the species fitness over long-time scales as well as punctuated equilibrium. Second, we adopt a food/space competition factor that depends on the number of accumulated mutations in the individuals genomes, and get rid of the fixed limiting number of allowed mutations. Besides reproducing the main results of the standard model, we also observe a mortality maximum for the oldest old.

  19. Modeling of dynamically loaded hydrodynamic bearings at low Sommerfeld numbers

    DEFF Research Database (Denmark)

    Thomsen, Kim

    . The challenging main bearing operation conditions in a wind turbine pose a demanding development task for the design of a hydrodynamic bearing. In general these conditions include operation at low Reynolds numbers with frequent start and stop at high loads as well as difficult operating conditions dictated...

  20. Variable viscosity condition in the modeling of a slider bearing

    CERN Document Server

    Uprety, Kedar Nath

    2014-01-01

    To reduce tear and wear of machinery lubrication is essential. Lubricants form a layer between two surfaces preventing direct contact and reduce friction between moving parts and hence reduce wear. In this short letter the lubrication of two slider bearings with parallel and nonparallel is studied. First, we show that bearings with parallel plates cannot support any load. For bearings with nonparallel plates we are interested on how constant and temperature dependent viscosity affects the properties of the bearings. Also, a critical temperature for which the bearings would fail due to excess in temperature is found for both latter cases. If the viscosity is constant, the critical temperature is given by an explicit formula, while for the non-constant viscosity the critical temperature can be always found from a closed form formula involving Weber functions

  1. Modeling of Hybrid Permanent Magnetic-Gas Bearings

    DEFF Research Database (Denmark)

    Morosi, Stefano; Santos, Ilmar

    2009-01-01

    Modern turbomachinery applications require nowadays ever-growing rotational speeds and high degree of reliability. It then becomes natural to focus the attention of the research to contact-free bearings elements. The present alternatives focus on gas lubricated journal bearings or magnetic bearings...... concentric rings with radial magnetic orientation - analytical expressions for the calculation of the magnetic flux density and forces are employed, opposed to the main literature trend where finite element software is utilized at least for the calculation of the B-field. Numerical analysis shows how...... the rotor equilibrium position can be made independent on the rotational speed and applied load; it becomes function of the passive magnetic bearing offset. By adjusting the offset it is possible to significantly influence the dynamic coefficients of the hybrid bearing....

  2. Optimal mutation rates in dynamic environments: The eigen model

    Science.gov (United States)

    Ancliff, Mark; Park, Jeong-Man

    2011-03-01

    We consider the Eigen quasispecies model with a dynamic environment. For an environment with sharp-peak fitness in which the most-fit sequence moves by k spin-flips each period T we find an asymptotic stationary state in which the quasispecies population changes regularly according to the regular environmental change. From this stationary state we estimate the maximum and the minimum mutation rates for a quasispecies to survive under the changing environment and calculate the optimum mutation rate that maximizes the population growth. Interestingly we find that the optimum mutation rate in the Eigen model is lower than that in the Crow-Kimura model, and at their optimum mutation rates the corresponding mean fitness in the Eigen model is lower than that in the Crow-Kimura model, suggesting that the mutation process which occurs in parallel to the replication process as in the Crow-Kimura model gives an adaptive advantage under changing environment.

  3. Modeling survival: application of the Andersen-Gill model to Yellowstone grizzly bears

    Science.gov (United States)

    Johnson, Christopher J.; Boyce, Mark S.; Schwartz, Charles C.; Haroldson, Mark A.

    2004-01-01

     Wildlife ecologists often use the Kaplan-Meier procedure or Cox proportional hazards model to estimate survival rates, distributions, and magnitude of risk factors. The Andersen-Gill formulation (A-G) of the Cox proportional hazards model has seen limited application to mark-resight data but has a number of advantages, including the ability to accommodate left-censored data, time-varying covariates, multiple events, and discontinuous intervals of risks. We introduce the A-G model including structure of data, interpretation of results, and assessment of assumptions. We then apply the model to 22 years of radiotelemetry data for grizzly bears (Ursus arctos) of the Greater Yellowstone Grizzly Bear Recovery Zone in Montana, Idaho, and Wyoming, USA. We used Akaike's Information Criterion (AICc) and multi-model inference to assess a number of potentially useful predictive models relative to explanatory covariates for demography, human disturbance, and habitat. Using the most parsimonious models, we generated risk ratios, hypothetical survival curves, and a map of the spatial distribution of high-risk areas across the recovery zone. Our results were in agreement with past studies of mortality factors for Yellowstone grizzly bears. Holding other covariates constant, mortality was highest for bears that were subjected to repeated management actions and inhabited areas with high road densities outside Yellowstone National Park. Hazard models developed with covariates descriptive of foraging habitats were not the most parsimonious, but they suggested that high-elevation areas offered lower risks of mortality when compared to agricultural areas.

  4. Modelling and Identification for Control of Gas Bearings

    DEFF Research Database (Denmark)

    Theisen, Lukas Roy Svane; Niemann, Hans Henrik; Santos, Ilmar

    2015-01-01

    Gas bearings are popular for their high speed capabilities, low friction and clean operation, but suffer from poor damping, which poses challenges for safe operation in presence of disturbances. Enhanced damping can be achieved through active lubrication techniques using feedback control laws...... to industrial rotating machinery with gas bearings and to allow for subsequent control design. The paper shows how piezoelectric actuators in a gas bearing are efficiently used to perturb the gas film for identification over relevant ranges of rotational speed and gas injection pressure. Parameter...

  5. On the simplifications for the thermal modeling of tilting-pad journal bearings under thermoelastohydrodynamic regime

    DEFF Research Database (Denmark)

    Cerda Varela, Alejandro Javier; Fillon, Michel; Santos, Ilmar

    2012-01-01

    The relevance of calculating accurately the oil film temperature build up when modeling tilting-pad journal bearings is well established within the literature on the subject. This work studies the feasibility of using a thermal model for the tilting-pad journal bearing which includes a simplified...

  6. Dissecting genetic and environmental mutation signatures with model organisms.

    Science.gov (United States)

    Segovia, Romulo; Tam, Annie S; Stirling, Peter C

    2015-08-01

    Deep sequencing has impacted on cancer research by enabling routine sequencing of genomes and exomes to identify genetic changes associated with carcinogenesis. Researchers can now use the frequency, type, and context of all mutations in tumor genomes to extract mutation signatures that reflect the driving mutational processes. Identifying mutation signatures, however, may not immediately suggest a mechanism. Consequently, several recent studies have employed deep sequencing of model organisms exposed to discrete genetic or environmental perturbations. These studies exploit the simpler genomes and availability of powerful genetic tools in model organisms to analyze mutation signatures under controlled conditions, forging mechanistic links between mutational processes and signatures. We discuss the power of this approach and suggest that many such studies may be on the horizon.

  7. The rich phase structure of a mutator model

    Science.gov (United States)

    Saakian, David B.; Yakushkina, Tatiana; Hu, Chin-Kun

    2016-10-01

    We propose a modification of the Crow-Kimura and Eigen models of biological molecular evolution to include a mutator gene that causes both an increase in the mutation rate and a change in the fitness landscape. This mutator effect relates to a wide range of biomedical problems. There are three possible phases: mutator phase, mixed phase and non-selective phase. We calculate the phase structure, the mean fitness and the fraction of the mutator allele in the population, which can be applied to describe cancer development and RNA viruses. We find that depending on the genome length, either the normal or the mutator allele dominates in the mixed phase. We analytically solve the model for a general fitness function. We conclude that the random fitness landscape is an appropriate choice for describing the observed mutator phenomenon in the case of a small fraction of mutators. It is shown that the increase in the mutation rates in the regular and the mutator parts of the genome should be set independently; only some combinations of these increases can push the complex biomedical system to the non-selective phase, potentially related to the eradication of tumors.

  8. The bear in Eurasian plant names: motivations and models.

    Science.gov (United States)

    Kolosova, Valeria; Svanberg, Ingvar; Kalle, Raivo; Strecker, Lisa; Özkan, Ayşe Mine Gençler; Pieroni, Andrea; Cianfaglione, Kevin; Molnár, Zsolt; Papp, Nora; Łuczaj, Łukasz; Dimitrova, Dessislava; Šeškauskaitė, Daiva; Roper, Jonathan; Hajdari, Avni; Sõukand, Renata

    2017-02-21

    Ethnolinguistic studies are important for understanding an ethnic group's ideas on the world, expressed in its language. Comparing corresponding aspects of such knowledge might help clarify problems of origin for certain concepts and words, e.g. whether they form common heritage, have an independent origin, are borrowings, or calques. The current study was conducted on the material in Slavonic, Baltic, Germanic, Romance, Finno-Ugrian, Turkic and Albanian languages. The bear was chosen as being a large, dangerous animal, important in traditional culture, whose name is widely reflected in folk plant names. The phytonyms for comparison were mostly obtained from dictionaries and other publications, and supplemented with data from databases, the co-authors' field data, and archival sources (dialect and folklore materials). More than 1200 phytonym use records (combinations of a local name and a meaning) for 364 plant and fungal taxa were recorded to help find out the reasoning behind bear-nomination in various languages, as well as differences and similarities between the patterns among them. Among the most common taxa with bear-related phytonyms were Arctostaphylos uva-ursi (L.) Spreng., Heracleum sphondylium L., Acanthus mollis L., and Allium ursinum L., with Latin loan translation contributing a high proportion of the phytonyms. Some plants have many and various bear-related phytonyms, while others have only one or two bear names. Features like form and/or surface generated the richest pool of names, while such features as colour seemed to provoke rather few associations with bears. The unevenness of bear phytonyms in the chosen languages was not related to the size of the language nor the present occurence of the Brown Bear in the region. However, this may, at least to certain extent, be related to the amount of the historical ethnolinguistic research done on the selected languages.

  9. Analytical Model for the End-Bearing Capacity of Tapered Piles Using Cavity Expansion Theory

    Directory of Open Access Journals (Sweden)

    Suman Manandhar

    2012-01-01

    Full Text Available On the basis of evidence from model tests on increasing the end-bearing behavior of tapered piles at the load-settlement curve, this paper proposes an analytical spherical cavity expansion theory to evaluate the end-bearing capacity. The angle of tapering is inserted in the proposed model to evaluate the end-bearing capacity. The test results of the proposed model in different types of sands and different relative densities show good effects compared to conventional straight piles. The end-bearing capacity increases with increases in the tapering angle. The paper then propounds a model for prototypes and real-type pile tests which predicts and validates to evaluate the end-bearing capacity.

  10. Model Specification for Rework of Aircraft Engine, Power Transmission, and Accessory/Auxiliary Ball and Roller Bearings

    Science.gov (United States)

    Zaretsky, Erwin V.; Branzai, Emanuel V.

    2007-01-01

    This document provides a model specification for the rework and/or repair of bearings used in aircraft engines, helicopter main power train transmissions, and auxiliary bearings determined to be critical by virtue of performance, function, or availability. The rolling-element bearings to be processed under the provisions of this model specification may be used bearings removed after service, unused bearings returned from the field, or certain rejected bearings returned for reinspection and salvage. In commercial and military aircraft application, it has been a practice that rolling-element bearings removed at maintenance or overhaul be reworked and returned to service. Depending on the extent of rework and based upon theoretical analysis, representative life factors (LF) for bearings subject to rework ranged from 0.87 to 0.99 the lives of new bearings. Based on bearing endurance data, 92 percent of the bearing sets that would be subject to rework would result in L(sub 10) lives equaling and/or exceeding that predicted for new bearings. The remaining 8 percent of the bearings have the potential to achieve the analytically predicted life of new bearings when one of the rings is replaced at rework. The potential savings from bearing rework varies from 53 to 82 percent of that of new bearings depending on the cost, size, and complexity of the bearing

  11. A single predator multiple prey model with prey mutation

    Science.gov (United States)

    Mullan, Rory; Abernethy, Gavin M.; Glass, David H.; McCartney, Mark

    2016-11-01

    A multiple species predator-prey model is expanded with the introduction of a coupled map lattice for the prey, allowing the prey to mutate discretely into other prey species. The model is examined in its single predator, multiple mutating prey form. Two unimodal maps are used for the underlying dynamics of the prey species, with different predation strategies being used. Conclusions are drawn on how varying the control parameters of the model governs the overall behaviour and survival of the species. It is observed that in such a complex system, with multiple mutating prey, a large range of non-linear dynamics is possible.

  12. Toward a 3D dynamic model of a faulty duplex ball bearing

    Science.gov (United States)

    Kogan, Gideon; Klein, Renata; Kushnirsky, Alex; Bortman, Jacob

    2015-03-01

    Bearings are vital components for safe and proper operation of machinery. Increasing efficiency of bearing diagnostics usually requires training of health and usage monitoring systems via expensive and time-consuming ground calibration tests. The main goal of this research, therefore, is to improve bearing dynamics modeling tools in order to reduce the time and budget needed to implement the health and usage monitoring approach. The proposed three-dimensional ball bearing dynamic model is based on the classic dynamic and kinematic equations. Interactions between the bodies are simulated using non-linear springs combined with dampers described by Hertz-type contact relation. The force friction is simulated using the hyperbolic-tangent function. The model allows simulation of a wide range of mechanical faults. It is validated by comparison to known bearing behavior and to experimental results. The model results are verified by demonstrating numerical convergence. The model results for the two cases of single and duplex angular ball bearings with axial deformation in the outer ring are presented. The qualitative investigation provides insight into bearing dynamics, the sensitivity study generalizes the qualitative findings for similar cases, and the comparison to the test results validates model reliability. The article demonstrates the variety of the cases that the 3D bearing model can simulate and the findings to which it may lead. The research allowed the identification of new patterns generated by single and duplex bearings with axially deformed outer race. It also enlightened the difference between single and duplex bearing manifestation. In the current research the dynamic model enabled better understanding of the physical behavior of the faulted bearings. Therefore, it is expected that the modeling approach has the potential to simplify and improve the development process of diagnostic algorithms. • A deformed outer race of a single axially loaded bearing is

  13. Modelling of LEG tilting pad journal bearings with active lubrication

    DEFF Research Database (Denmark)

    Cerda Varela, Alejandro Javier; García, Asier Bengoechea; Santos, Ilmar

    2017-01-01

    This work constitutes the first step in a research effort aimed at studying the feasibility of introducing an active lubrication concept in tilting pad journal bearings (TPJBs) that feature the leading edge groove (LEG) lubrication system. The modification of the oil flow into each pad supply gro...

  14. A comparative bear model for immobility-induced osteopenia

    Science.gov (United States)

    Milbury, P. E.; Vaughan, M. R.; Farley, S.; Matula, G. J. Jr; Convertino, V. A.; Matson, W. R.

    1998-01-01

    The National Institutes of Health (NIH) and the National Aeronautics and Space Administration (NASA) are seeking solutions to the human problem of osteopenia, or immobility-induced bone loss. Bears, during winter dormancy, appear uniquely exempted from the debilitating effects of immobility osteopenia. NIH and ESA, Inc. are creating a large database of metabolic information on human ambulatory and bedrest plasma samples for comparison with metabolic data obtained from bear plasma samples collected in different seasons. The database generated from NASA's HR113 human bedrest study showed a clear difference between plasma samples of ambulatory and immobile subjects through cluster analysis using compounds determined by high performance liquid chromatography with coulometric electrochemical array detection (HPLC-EC). We collected plasma samples from black bears (Ursus americanus) across 4 seasons and from 3 areas and subjected them to similar analysis, with particular attention to compounds that changed significantly in the NASA human study. We found seasonal differences in 28 known compounds and 33 unknown compounds. A final database contained 40 known and 120 unknown peaks that were reliably assayed in all bear and human samples; these were the primary data set for interspecies comparison. Six unidentified compounds changed significantly but differentially in wintering bears and immobile humans. The data are discussed in light of current theories regarding dormancy, starvation, and anabolic metabolism. Work is in progress by ESA Laboratories on a larger database to confirm these findings prior to a chemical isolation and identification effort. This research could lead to new pharmaceuticals or dietary interventions for the treatment of immobility osteopenia.

  15. Bearing Degradation Process Prediction Based on the Support Vector Machine and Markov Model

    Directory of Open Access Journals (Sweden)

    Shaojiang Dong

    2014-01-01

    Full Text Available Predicting the degradation process of bearings before they reach the failure threshold is extremely important in industry. This paper proposed a novel method based on the support vector machine (SVM and the Markov model to achieve this goal. Firstly, the features are extracted by time and time-frequency domain methods. However, the extracted original features are still with high dimensional and include superfluous information, and the nonlinear multifeatures fusion technique LTSA is used to merge the features and reduces the dimension. Then, based on the extracted features, the SVM model is used to predict the bearings degradation process, and the CAO method is used to determine the embedding dimension of the SVM model. After the bearing degradation process is predicted by SVM model, the Markov model is used to improve the prediction accuracy. The proposed method was validated by two bearing run-to-failure experiments, and the results proved the effectiveness of the methodology.

  16. Fractional model for heat conduction in polar bear hairs

    Directory of Open Access Journals (Sweden)

    Wang Qing-Li

    2012-01-01

    Full Text Available Time-fractional differential equations can accurately describe heat conduction in fractal media, such as wool fibers, goose down and polar bear hair. The fractional complex transform is used to convert time-fractional heat conduction equations with the modified Riemann-Liouville derivative into ordinary differential equations, and exact solutions can be easily obtained. The solution process is straightforward and concise.

  17. Analysis of a Rough Elliptic Bore Journal Bearing using Expectancy Model of Roughness Characterization

    Directory of Open Access Journals (Sweden)

    P.C. Mishra

    2014-06-01

    Full Text Available Performance characteristics of a rough elliptic bore journal bearing are studied. The bearing bore of isotropic roughness orientation is characterized by stochastic function and the film geometry is quantified to elliptic shape. There after the Reynolds equation and energy equation are descretized for pressure and temperature respectively. A finite difference model is developed to evaluate hydrodynamic pressure and oil temperature. Solution to this model is done using effective influence Newton-Raphson method. Performance parameters such as load bearing ability, friction, flow-in and side leakages are computed and discussed.

  18. Measurement of Pressure Fluctuations inside a Model Thrust Bearing Using PVDF Sensors.

    Science.gov (United States)

    Youssef, Andrew; Matthews, David; Guzzomi, Andrew; Pan, Jie

    2017-04-16

    Thrust bearings play a vital role in propulsion systems. They rely on a thin layer of oil being trapped between rotating surfaces to produce a low friction interface. The "quality" of this bearing affects many things from noise transmission to the ultimate catastrophic failure of the bearing itself. As a result, the direct measure of the forces and vibrations within the oil filled interface would be very desirable and would give an indication of the condition of the bearing in situ. The thickness of the oil film is, however, very small and conventional vibration sensors are too cumbersome to use in this confined space. This paper solves this problem by using a piezoelectric polymer film made from Polyvinylidine Fluoride (PVDF). These films are very thin (50 m) and flexible and easy to install in awkward spaces such as the inside of a thrust bearing. A model thrust bearing was constructed using a 3D printer and PVDF films inserted into the base of the bearing. In doing so, it was possible to directly measure the force fluctuations due to the rotating pads and investigate various properties of the thrust bearing itself.

  19. Fitness effects of beneficial mutations: the mutational landscape model in experimental evolution

    DEFF Research Database (Denmark)

    Betancourt, Andrea J.; Bollback, Jonathan Paul

    2006-01-01

    of beneficial mutations should be roughly exponentially distributed. The prediction appears to be borne out by most of these studies, at least qualitatively. Another study showed that a modified version of the model was able to predict, with reasonable accuracy, which of a ranked set of beneficial alleles...

  20. Model-Based Control Design for Flexible Rotors Supported by Active Gas Bearings - Theory & Experiment

    DEFF Research Database (Denmark)

    Pierart Vásquez, Fabián Gonzalo

    Gas journal bearings have been increasingly adopted in modern turbo-machinery due to their numerous indisputable advantages. They can operate at higher speed than most bearing designs, almost without noise or heat generation and in most cases, as in this work, the gas used is air which is cheap...... work, the control signal design is based on a theoretical model. This approach enables easy modifications of any of the numerous physical parameters in the system if needed. The theoretical model used is based on a modifed version of Reynolds equation where an extra term is added in order to include...... frequencies and damping ratios of the rotor-bearing system) is performed and finally to design controllers that allows improvement of the dynamic properties of the rotor-active gas bearings system and lets the systemto safely cross the critical speeds, using the theoretical model as a design tool. The results...

  1. Mathematical Modeling of the Induced Mutation Process in Bacterial Cells

    Science.gov (United States)

    Belov, Oleg V.; Krasavin, Evgeny A.; Parkhomenko, Alexander Yu.

    2010-01-01

    A mathematical model of the ultraviolet (UV) irradiation-induced mutation process in bacterial cells Escherichia coli is developed. Using mathematical approaches, the whole chain of events is tracked from a cell exposure to the damaging factor to mutation formation in the DNA chain. An account of the key special features of the regulation of this genetic network allows predicting the effects induced by the cell exposure to certain UV energy fluence.

  2. Ball bearing defect models: A study of simulated and experimental fault signatures

    Science.gov (United States)

    Mishra, C.; Samantaray, A. K.; Chakraborty, G.

    2017-07-01

    Numerical model based virtual prototype of a system can serve as a tool to generate huge amount of data which replace the dependence on expensive and often difficult to conduct experiments. However, the model must be accurate enough to substitute the experiments. The abstraction level and details considered during model development depend on the purpose for which simulated data should be generated. This article concerns development of simulation models for deep groove ball bearings which are used in a variety of rotating machinery. The purpose of the model is to generate vibration signatures which usually contain features of bearing defects. Three different models with increasing level-of-complexity are considered: a bearing kinematics based planar motion block diagram model developed in MATLAB Simulink which does not explicitly consider cage and traction dynamics, a planar motion model with cage, traction and contact dynamics developed using multi-energy domain bond graph formalism in SYMBOLS software, and a detailed spatial multi-body dynamics model with complex contact and traction mechanics developed using ADAMS software. Experiments are conducted using Spectra Quest machine fault simulator with different prefabricated faulted bearings. The frequency domain characteristics of simulated and experimental vibration signals for different bearing faults are compared and conclusions are drawn regarding usefulness of the developed models.

  3. Model Driven Mutation Applied to Adaptative Systems Testing

    CERN Document Server

    Bartel, Alexandre; Munoz, Freddy; Klein, Jacques; Mouelhi, Tejeddine; Traon, Yves Le

    2012-01-01

    Dynamically Adaptive Systems modify their behav- ior and structure in response to changes in their surrounding environment and according to an adaptation logic. Critical sys- tems increasingly incorporate dynamic adaptation capabilities; examples include disaster relief and space exploration systems. In this paper, we focus on mutation testing of the adaptation logic. We propose a fault model for adaptation logics that classifies faults into environmental completeness and adaptation correct- ness. Since there are several adaptation logic languages relying on the same underlying concepts, the fault model is expressed independently from specific adaptation languages. Taking benefit from model-driven engineering technology, we express these common concepts in a metamodel and define the operational semantics of mutation operators at this level. Mutation is applied on model elements and model transformations are used to propagate these changes to a given adaptation policy in the chosen formalism. Preliminary resul...

  4. Late-Quaternary biogeographic scenarios for the brown bear ( Ursus arctos), a wild mammal model species

    Science.gov (United States)

    Davison, John; Ho, Simon Y. W.; Bray, Sarah C.; Korsten, Marju; Tammeleht, Egle; Hindrikson, Maris; Østbye, Kjartan; Østbye, Eivind; Lauritzen, Stein-Erik; Austin, Jeremy; Cooper, Alan; Saarma, Urmas

    2011-02-01

    This review provides an up-to-date synthesis of the matrilineal phylogeography of a uniquely well-studied Holarctic mammal, the brown bear. We extend current knowledge by presenting a DNA sequence derived from one of the earliest known fossils of a polar bear (dated to 115 000 years before present), a species that shares a paraphyletic mitochondrial association with brown bears. A molecular clock analysis of 140 mitochondrial DNA sequences, including our new polar bear sequence, provides novel insights into the times of origin for different brown bear clades. We propose a number of regional biogeographic scenarios based on genetic data, divergence time estimates and paleontological records. The case of the brown bear provides an example for researchers working with less well-studied taxa: it shows clearly that phylogeographic models based on patterns of modern genetic variation alone can be substantially improved by including data on historical patterns of genetic diversity in the form of ancient DNA sequences derived from accurately dated samples and by using an approach to divergence-time estimation that suits the data under analysis. Using such approaches it has been possible to (i) establish that the processes shaping modern genetic diversity in brown bears acted recently, within the last three glacial cycles; (ii) distinguish among hypotheses concerning species' responses to climatic oscillations in accordance with the lack of phylogeographic structure that existed in brown bears prior to the last glacial maximum (LGM); (iii) reassess theories linking monophyletic brown bear populations to particular LGM refuge areas; and (iv) identify vicariance events and track analogous patterns of migration by brown bears out of Eurasia to North America and Japan.

  5. Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif.

    Science.gov (United States)

    Wiedenfeld, E A; Fernandez-Viña, M; Berzofsky, J A; Carbone, D P

    1994-03-01

    Short peptide fragments of intracellular proteins that fit a defined sequence motif bind to the most common human major histocompatibility complex class I molecule, HLA A*0201, and mediate killing by cytotoxic T-cells [D.F. Hunt et al., Science (Washington DC), 255: 1261-1263, 1992; K. Falk et al., Nature (Lond.), 351: 290-296, 1991]. The existence of such a motif allows prediction of whether novel peptides derived from mutant oncoporteins might be presented on the surface of cancer cells bearing that HLA allele. Clinical cancer might develop only when these mutations occur outside a major histocompatibility complex binding motif or in those cells that acquire defects in antigen presentation. Here, we find that missense mutations of p53 from a variety of tumors fall within the HLA A*0201 motif less often than would be expected if the location of mutations and motifs were independent. When we analyzed the HLA subtype of lung cancer cell lines with known p53 missense mutations, we found that all of the mutant oncopeptides predicted to be presentable by HLA A*0201 came from tumors that either did not carry the A*0201 allele or had lost that allele in the process of tumorigenesis. Presentation of mutant oncogene peptides on class I major histocompatibility complex might thus represent a physiologically significant selection pressure in the development of human cancer.

  6. Hydrodynamic and hydrostatic modelling of hydraulic journal bearings considering small displacement condition

    Science.gov (United States)

    Chen, Chi-Yin; Chuang, Jen-Chen; Tu, Jia-Ying

    2016-09-01

    This paper proposes modified coefficients for the dynamic model of hydraulic journal bearing system that integrates the hydrodynamic and hydrostatic properties. In recent years, design of hydraulic bearing for machine tool attracts worldwide attention, because hydraulic bearings are able to provide higher capacity and accuracy with lower friction, compared to conventional bearing systems. In order to achieve active control of the flow pressure and enhance the operation accuracy, the dynamic model of hydraulic bearings need to be developed. Modified coefficients of hydrostatic stiffness, hydrodynamic stiffness, and squeeze damping of the dynamic model are presented in this work, which are derived referring to small displacement analysis from literature. The proposed modified coefficients and model, which consider the pressure variations, relevant geometry size, and fluid properties of the journal bearings, are able to characterise the hydrodynamic and hydrostatic properties with better precision, thus offering the following pragmatic contribution: (1) on-line prediction of the eccentricity and the position of the shaft in the face of external force that results in vibration; (2) development of active control system to regulate the supply flow pressure and to minimize the eccentricity of the shaft. Theoretical derivation and simulation results with different vibration cases are discussed to verify the proposed techniques.

  7. A Mutation Model from First Principles of the Genetic Code.

    Science.gov (United States)

    Thorvaldsen, Steinar

    2016-01-01

    The paper presents a neutral Codons Probability Mutations (CPM) model of molecular evolution and genetic decay of an organism. The CPM model uses a Markov process with a 20-dimensional state space of probability distributions over amino acids. The transition matrix of the Markov process includes the mutation rate and those single point mutations compatible with the genetic code. This is an alternative to the standard Point Accepted Mutation (PAM) and BLOcks of amino acid SUbstitution Matrix (BLOSUM). Genetic decay is quantified as a similarity between the amino acid distribution of proteins from a (group of) species on one hand, and the equilibrium distribution of the Markov chain on the other. Amino acid data for the eukaryote, bacterium, and archaea families are used to illustrate how both the CPM and PAM models predict their genetic decay towards the equilibrium value of 1. A family of bacteria is studied in more detail. It is found that warm environment organisms on average have a higher degree of genetic decay compared to those species that live in cold environments. The paper addresses a new codon-based approach to quantify genetic decay due to single point mutations compatible with the genetic code. The present work may be seen as a first approach to use codon-based Markov models to study how genetic entropy increases with time in an effectively neutral biological regime. Various extensions of the model are also discussed.

  8. Spatial Fleming-Viot models with selection and mutation

    CERN Document Server

    Dawson, Donald A

    2014-01-01

    This book constructs a rigorous framework for analysing selected phenomena in evolutionary theory of populations arising due to the combined effects of migration, selection and mutation in a spatial stochastic population model, namely the evolution towards fitter and fitter types through punctuated equilibria. The discussion is based on a number of new methods, in particular multiple scale analysis, nonlinear Markov processes and their entrance laws, atomic measure-valued evolutions and new forms of duality (for state-dependent mutation and multitype selection) which are used to prove ergodic theorems in this context and are applicable for many other questions and renormalization analysis for a variety of phenomena (stasis, punctuated equilibrium, failure of naive branching approximations, biodiversity) which occur due to the combination of rare mutation, mutation, resampling, migration and selection and make it necessary to mathematically bridge the gap (in the limit) between time and space scales.

  9. Dynamic Model and Fault Feature Research of Dual-Rotor System with Bearing Pedestal Looseness

    Directory of Open Access Journals (Sweden)

    Nanfei Wang

    2016-01-01

    Full Text Available The paper presents a finite element model of dual-rotor system with pedestal looseness stemming from loosened bolts. Dynamic model including bearing pedestal looseness is established based on the dual-rotor test rig. Three-degree-of-freedom (DOF planar rigid motion of loose bearing pedestal is fully considered and collision recovery coefficient is also introduced in the model. Based on the Timoshenko beam elements, using the finite element method, rigid body kinematics, and the Newmark-β algorithm for numerical simulation, dynamic characteristics of the inner and outer rotors and the bearing pedestal plane rigid body motion under bearing pedestal looseness condition are studied. Meanwhile, the looseness experiments under two different speed combinations are carried out, and the experimental results are basically the same. The simulation results are compared with the experimental results, indicating that vibration displacement waveforms of loosened rotor have “clipping” phenomenon. When the bearing pedestal looseness fault occurs, the inner and outer rotors vibration spectrum not only contains the difference and sum frequency of the two rotors’ fundamental frequency but also contains 2X and 3X component of rotor with loosened support, and so forth; low frequency spectrum is more, containing dividing component, and so forth; the rotor displacement spectrums also contain fewer combination frequency components, and so forth; when one side of the inner rotor bearing pedestal is loosened, the inner rotor axis trajectory is drawn into similar-ellipse shape.

  10. Prognosticating fault development rate in wind turbine generator bearings using local trend models

    DEFF Research Database (Denmark)

    Skrimpas, Georgios Alexandros; Palou, Jonel; Sweeney, Christian Walsted;

    2016-01-01

    Generator bearing defects, e.g. ball, inner and outer race defects, are ranked among the most frequent mechanical failures encountered in wind turbines. Diagnosis and prognosis of bearing faults can be successfully implemented using vibration based condition monitoring systems, where tracking...... the signal energy between 10Hz to 1000Hz is utilized as feature to characterize the severity of developing bearing faults. Furthermore, local trend models are employed to predict the progression of bearing defects from a vibration standpoint in accordance with the limits suggested in ISO 10816. Predictions...... of vibration trends from multi-megawatt wind turbine generators are presented, showing the effectiveness of the suggested approach on the calculation of the RUL and fault progression rate....

  11. Reliability estimation and remaining useful lifetime prediction for bearing based on proportional hazard model

    Institute of Scientific and Technical Information of China (English)

    王鹭; 张利; 王学芝

    2015-01-01

    As the central component of rotating machine, the performance reliability assessment and remaining useful lifetime prediction of bearing are of crucial importance in condition-based maintenance to reduce the maintenance cost and improve the reliability. A prognostic algorithm to assess the reliability and forecast the remaining useful lifetime (RUL) of bearings was proposed, consisting of three phases. Online vibration and temperature signals of bearings in normal state were measured during the manufacturing process and the most useful time-dependent features of vibration signals were extracted based on correlation analysis (feature selection step). Time series analysis based on neural network, as an identification model, was used to predict the features of bearing vibration signals at any horizons (feature prediction step). Furthermore, according to the features, degradation factor was defined. The proportional hazard model was generated to estimate the survival function and forecast the RUL of the bearing (RUL prediction step). The positive results show that the plausibility and effectiveness of the proposed approach can facilitate bearing reliability estimation and RUL prediction.

  12. Design, Modeling and Control of Magnetic Bearings for a Ring-Type Flywheel Energy Storage System

    Directory of Open Access Journals (Sweden)

    Chow-Shing Toh

    2016-12-01

    Full Text Available This study is concerned with the magnetic force models of magnetic bearing in a flywheel energy storage system (FESS. The magnetic bearing is of hybrid type, with axial passive magnetic bearing (PMB and radial hybrid magnetic bearing (HMB. For the PMB, a pair of ring-type Halbach arrays of permanent magnets are arranged vertically to support the rotor weight. For the HMB, a set of ring-type Halbach array is placed on the rotor side, which corresponds to coil sets on the stator side. The HMB can produce both attraction and repulsion forces on the radial direction, depending on the direction of the coil currents. It is found that the ring-type configuration and the differential winding scheme for coil sets can yield linear magnetic force models for both PMB and HMB. Based on the obtained magnetic force model, an integral sliding mode controller is designed for the stable rotor levitation in the radial direction. The experimental results show that the rotor can be stabilized to the bearing center, verifying the accuracy of the magnetic force models and effectiveness of the levitation controller.

  13. Experimental investigation of the flow in a simplified model of water lubricated axial thrust bearing

    Science.gov (United States)

    Kirschner, O.; Ruprecht, A.; Riedelbauch, S.

    2014-03-01

    In hydropower plants the axial thrust bearing takes up the hydraulic axial thrust of the runner and, in case of vertical shafts, the entire weight of all rotating masses. The use of water lubricated bearings can eliminate the oil leakage risk possibly contaminating the environment. A complex flow is generated by the smaller film thickness due to the lower viscosity of water compared with oil. Measurements on a simplified hydrostatic axial trust bearing model were accomplished for validating CFD analysis of water lubricated bearings. In this simplified model, fixed pads are implemented and the width of the gap was enlarged to create a higher resolution in space for the measurements. Most parts of the model were manufactured from acrylic glass to get optical access for measurement with PIV. The focus of these measurements is on the flow within the space between two pads. Additional to the PIV- measurement, the pressure on the wall of the rotating disk is captured by pressure transducers. The model bearing measurement results are presented for varied operating conditions.

  14. Degradation Assessment and Fault Diagnosis for Roller Bearing Based on AR Model and Fuzzy Cluster Analysis

    Directory of Open Access Journals (Sweden)

    Lingli Jiang

    2011-01-01

    Full Text Available This paper proposes a new approach combining autoregressive (AR model and fuzzy cluster analysis for bearing fault diagnosis and degradation assessment. AR model is an effective approach to extract the fault feature, and is generally applied to stationary signals. However, the fault vibration signals of a roller bearing are non-stationary and non-Gaussian. Aiming at this problem, the set of parameters of the AR model is estimated based on higher-order cumulants. Consequently, the AR parameters are taken as the feature vectors, and fuzzy cluster analysis is applied to perform classification and pattern recognition. Experiments analysis results show that the proposed method can be used to identify various types and severities of fault bearings. This study is significant for non-stationary and non-Gaussian signal analysis, fault diagnosis and degradation assessment.

  15. Predicting 21st-century polar bear habitat distribution from global climate models

    Science.gov (United States)

    Durner, G.M.; Douglas, D.C.; Nielson, R.M.; Amstrup, Steven C.; McDonald, T.L.; Stirling, I.; Mauritzen, Mette; Born, E.W.; Wiig, O.; Deweaver, E.; Serreze, M.C.; Belikov, Stanislav; Holland, M.M.; Maslanik, J.; Aars, J.; Bailey, D.A.; Derocher, A.E.

    2009-01-01

    Projections of polar bear (Ursus maritimus) sea ice habitat distribution in the polar basin during the 21st century were developed to understand the consequences of anticipated sea ice reductions on polar bear populations. We used location data from satellitecollared polar bears and environmental data (e.g., bathymetry, distance to coastlines, and sea ice) collected from 1985 to 1995 to build resource selection functions (RSFs). RSFs described habitats that polar bears preferred in summer, autumn, winter, and spring. When applied to independent data from 1996 to 2006, the RSFs consistently identified habitats most frequently used by polar bears. We applied the RSFs to monthly maps of 21st-century sea ice concentration projected by 10 general circulation models (GCMs) used in the Intergovernmental Panel of Climate Change Fourth Assessment Report, under the A1B greenhouse gas forcing scenario. Despite variation in their projections, all GCMs indicated habitat losses in the polar basin during the 21st century. Losses in the highest-valued RSF habitat (optimal habitat) were greatest in the southern seas of the polar basin, especially the Chukchi and Barents seas, and least along the Arctic Ocean shores of Banks Island to northern Greenland. Mean loss of optimal polar bear habitat was greatest during summer; from an observed 1.0 million km2 in 1985-1995 (baseline) to a projected multi-model mean of 0.32 million km2 in 2090-2099 (-68% change). Projected winter losses of polar bear habitat were less: from 1.7 million km2 in 1985-1995 to 1.4 million km2 in 2090-2099 (-17% change). Habitat losses based on GCM multi-model means may be conservative; simulated rates of habitat loss during 1985-2006 from many GCMs were less than the actual observed rates of loss. Although a reduction in the total amount of optimal habitat will likely reduce polar bear populations, exact relationships between habitat losses and population demographics remain unknown. Density and energetic

  16. Optimal design of laminated-MRE bearings with multi-scale model

    Science.gov (United States)

    Chen, Shiwei; Wang, Xiaojie; Zhang, Ze; Mu, Wenjun; Li, Rui

    2016-10-01

    In the design of a laminated magneto-rheological elastomeric bearing (MREB), the passive rubbers are replaced with composite layers of rubber and MREs. The applied magnetic field, produced by the built-in electromagnet through the input current, changes the stiffness and damping of MREs, and thus that of the device. Typically, a good MREB should possess higher adjustable properties with less activating power in avoiding overheating problem. Thus an optimized design of MREB should integrate the MRE material design into mechanical and electromagnetic components to achieve a trade-off between power consumption and adjustability of stiffness. In this study, we propose a method to analyze and design a laminated MRE bearing, in which the optimal parameters of materials and mechanical structure of the MRE bearing are determined. Based on the multi-scale and magneto-mechanical coupling theories, we establish a multi-scale model for the MRE bearing considering the influence of particle volume fraction, particle distribution, and thickness of MRE laminated layers on its mechanical performance. Within the micro-scale analysis, the representative volume unit is used to address the effect of particle volume fraction and distribution on mechanical and magnetic properties of MRE itself. Within the macro-scale analysis, we build both mechanical and magnetic models for the laminated MRE bearing. Based on the theoretical analysis, a laminated MRE bearing with four-layer MRE is designed and fabricated. The performance of the MRE bearing has been tested by using MTS test bench. The results are compared with that of model analysis. Both experimental and theoretical results indicate that optimal design of MREB depends on the MRE’s particle volume fraction which is related with MREB’s input power limitation.

  17. Spatial patterns of breeding success of grizzly bears derived from hierarchical multistate models.

    Science.gov (United States)

    Fisher, Jason T; Wheatley, Matthew; Mackenzie, Darryl

    2014-10-01

    Conservation programs often manage populations indirectly through the landscapes in which they live. Empirically, linking reproductive success with landscape structure and anthropogenic change is a first step in understanding and managing the spatial mechanisms that affect reproduction, but this link is not sufficiently informed by data. Hierarchical multistate occupancy models can forge these links by estimating spatial patterns of reproductive success across landscapes. To illustrate, we surveyed the occurrence of grizzly bears (Ursus arctos) in the Canadian Rocky Mountains Alberta, Canada. We deployed camera traps for 6 weeks at 54 surveys sites in different types of land cover. We used hierarchical multistate occupancy models to estimate probability of detection, grizzly bear occupancy, and probability of reproductive success at each site. Grizzly bear occupancy varied among cover types and was greater in herbaceous alpine ecotones than in low-elevation wetlands or mid-elevation conifer forests. The conditional probability of reproductive success given grizzly bear occupancy was 30% (SE = 0.14). Grizzly bears with cubs had a higher probability of detection than grizzly bears without cubs, but sites were correctly classified as being occupied by breeding females 49% of the time based on raw data and thus would have been underestimated by half. Repeated surveys and multistate modeling reduced the probability of misclassifying sites occupied by breeders as unoccupied to grizzly bear occupancy varied across the landscape. Those patches with highest probabilities of breeding occupancy-herbaceous alpine ecotones-were small and highly dispersed and are projected to shrink as treelines advance due to climate warming. Understanding spatial correlates in breeding distribution is a key requirement for species conservation in the face of climate change and can help identify priorities for landscape management and protection.

  18. A fully coupled air foil bearing model considering friction – Theory & experiment

    DEFF Research Database (Denmark)

    von Osmanski, Alexander Sebastian; Larsen, Jon Steffen; Santos, Ilmar

    2017-01-01

    The dynamics of air foil bearings (AFBs) are not yet fully captured by any model. The recent years have, however, seen promising results from nonlinear time domain models, and simultaneously coupled formulations are now available, avoiding the previous requirements for undesirably small time step...

  19. Linking landscape characteristics to local grizzly bear abundance using multiple detection methods in a hierarchical model

    Science.gov (United States)

    Graves, T.A.; Kendall, K.C.; Royle, J. Andrew; Stetz, J.B.; Macleod, A.C.

    2011-01-01

    Few studies link habitat to grizzly bear Ursus arctos abundance and these have not accounted for the variation in detection or spatial autocorrelation. We collected and genotyped bear hair in and around Glacier National Park in northwestern Montana during the summer of 2000. We developed a hierarchical Markov chain Monte Carlo model that extends the existing occupancy and count models by accounting for (1) spatially explicit variables that we hypothesized might influence abundance; (2) separate sub-models of detection probability for two distinct sampling methods (hair traps and rub trees) targeting different segments of the population; (3) covariates to explain variation in each sub-model of detection; (4) a conditional autoregressive term to account for spatial autocorrelation; (5) weights to identify most important variables. Road density and per cent mesic habitat best explained variation in female grizzly bear abundance; spatial autocorrelation was not supported. More female bears were predicted in places with lower road density and with more mesic habitat. Detection rates of females increased with rub tree sampling effort. Road density best explained variation in male grizzly bear abundance and spatial autocorrelation was supported. More male bears were predicted in areas of low road density. Detection rates of males increased with rub tree and hair trap sampling effort and decreased over the sampling period. We provide a new method to (1) incorporate multiple detection methods into hierarchical models of abundance; (2) determine whether spatial autocorrelation should be included in final models. Our results suggest that the influence of landscape variables is consistent between habitat selection and abundance in this system. ?? 2011 The Authors. Animal Conservation ?? 2011 The Zoological Society of London.

  20. Predictive modeling and mapping of Malayan Sun Bear (Helarctos malayanus) distribution using maximum entropy.

    Science.gov (United States)

    Nazeri, Mona; Jusoff, Kamaruzaman; Madani, Nima; Mahmud, Ahmad Rodzi; Bahman, Abdul Rani; Kumar, Lalit

    2012-01-01

    One of the available tools for mapping the geographical distribution and potential suitable habitats is species distribution models. These techniques are very helpful for finding poorly known distributions of species in poorly sampled areas, such as the tropics. Maximum Entropy (MaxEnt) is a recently developed modeling method that can be successfully calibrated using a relatively small number of records. In this research, the MaxEnt model was applied to describe the distribution and identify the key factors shaping the potential distribution of the vulnerable Malayan Sun Bear (Helarctos malayanus) in one of the main remaining habitats in Peninsular Malaysia. MaxEnt results showed that even though Malaysian sun bear habitat is tied with tropical evergreen forests, it lives in a marginal threshold of bio-climatic variables. On the other hand, current protected area networks within Peninsular Malaysia do not cover most of the sun bears potential suitable habitats. Assuming that the predicted suitability map covers sun bears actual distribution, future climate change, forest degradation and illegal hunting could potentially severely affect the sun bear's population.

  1. Predictive modeling and mapping of Malayan Sun Bear (Helarctos malayanus distribution using maximum entropy.

    Directory of Open Access Journals (Sweden)

    Mona Nazeri

    Full Text Available One of the available tools for mapping the geographical distribution and potential suitable habitats is species distribution models. These techniques are very helpful for finding poorly known distributions of species in poorly sampled areas, such as the tropics. Maximum Entropy (MaxEnt is a recently developed modeling method that can be successfully calibrated using a relatively small number of records. In this research, the MaxEnt model was applied to describe the distribution and identify the key factors shaping the potential distribution of the vulnerable Malayan Sun Bear (Helarctos malayanus in one of the main remaining habitats in Peninsular Malaysia. MaxEnt results showed that even though Malaysian sun bear habitat is tied with tropical evergreen forests, it lives in a marginal threshold of bio-climatic variables. On the other hand, current protected area networks within Peninsular Malaysia do not cover most of the sun bears potential suitable habitats. Assuming that the predicted suitability map covers sun bears actual distribution, future climate change, forest degradation and illegal hunting could potentially severely affect the sun bear's population.

  2. Active lubrication applied to radial gas journal bearings. Part 2: Modelling improvement and experimental validation

    DEFF Research Database (Denmark)

    Pierart, Fabián G.; Santos, Ilmar F.

    2016-01-01

    Actively-controlled lubrication techniques are applied to radial gas bearings aiming at enhancing one of their most critical drawbacks, their lack of damping. A model-based control design approach is presented using simple feedback control laws, i.e. proportional controllers. The design approach...... by finite element method and the global model is used as control design tool. Active lubrication allows for significant increase in damping factor of the rotor-bearing system. Very good agreement between theory and experiment is obtained, supporting the multi-physic design tool developed....

  3. Finding all BRCA pathogenic mutation carriers: best practice models.

    Science.gov (United States)

    Hoogerbrugge, Nicoline; Jongmans, Marjolijn Cj

    2016-09-01

    Identifying germline BRCA pathogenic mutations in patients with ovarian or breast cancer is a crucial component in the medical management of affected patients. Furthermore, the relatives of affected patients can be offered genetic testing. Relatives who test positive for a germline BRCA pathogenic mutation can take appropriate action to prevent cancer or have cancer diagnosed as early as possible for better treatment options. The recent discovery that BRCA pathogenic mutation status can inform treatment decisions in patients with ovarian cancer has led to an increased demand for BRCA testing, with testing taking place earlier in the patient care pathway. New approaches to genetic counselling may be required to meet this greater demand for BRCA testing. This review discusses the need for best practices for genetic counselling and BRCA testing; it examines the challenges facing current practice and looks at adapted models of genetic counselling.

  4. Dasatinib inhibits proliferation and induces apoptosis in the KASUMI-1 cell line bearing the t(8;21)(q22;q22) and the N822K c-kit mutation.

    Science.gov (United States)

    Mpakou, Vassiliki E; Kontsioti, Frieda; Papageorgiou, Sotiris; Spathis, Aris; Kottaridi, Christine; Girkas, Kostas; Karakitsos, Petros; Dimitriadis, George; Dervenoulas, Ioannis; Pappa, Vasiliki

    2013-02-01

    Activating mutations of the c-kit gene are frequently found in CBF (core binding factor) leukemias. We evaluated the effect of tyrosine kinase inhibitor dasatinib in leukemic cell lines bearing or not c-kit mutations. Our data demonstrate that in the AML Kasumi-1 cell line, bearing the N822K c-kit mutation, dasatinib is a potent suppressor of c-kit and Src kinase activity and inhibits the phosphorylation of their downstream target AKT, possibly through the Src-mediated VEGF/VEGFR receptor type 2 pathway. Dasatinib also effectively blocks proliferation and induces apoptosis through caspase-3 activation in Kasumi-1 cells. These data further encourage the integration of dasatinib in the treatment of CBF AML with c-kit mutations in the context of clinical trials, which are eagerly anticipated. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. An exactly solvable, spatial model of mutation accumulation in cancer

    Science.gov (United States)

    Paterson, Chay; Nowak, Martin A.; Waclaw, Bartlomiej

    2016-12-01

    One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours, even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model.

  6. Nonlinear dynamic modeling of rotor system supported by angular contact ball bearings

    Science.gov (United States)

    Wang, Hong; Han, Qinkai; Zhou, Daning

    2017-02-01

    In current bearing dynamic models, the displacement coordinate relations are usually utilized to approximately obtain the contact deformations between the rolling element and raceways, and then the nonlinear restoring forces of the rolling bearing could be calculated accordingly. Although the calculation efficiency is relatively higher, the accuracy is lower as the contact deformations should be solved through iterative analysis. Thus, an improved nonlinear dynamic model is presented in this paper. Considering the preload condition, surface waviness, Hertz contact and elastohydrodynamic lubrication, load distribution analysis is solved iteratively to more accurately obtain the contact deformations and angles between the rolling balls and raceways. The bearing restoring forces are then obtained through iteratively solving the load distribution equations at every time step. Dynamic tests upon a typical rotor system supported by two angular contact ball bearings are conducted to verify the model. Through comparisons, the differences between the nonlinear dynamic model and current models are also pointed out. The effects of axial preload, rotor eccentricity and inner/outer waviness amplitudes on the dynamic response are discussed in detail.

  7. Metformin treatment of diabetes mellitus increases the risk for pancreatitis in patients bearing the CFTR-mutation S573C.

    Science.gov (United States)

    Kongsuphol, Patthara; Cassidy, Diane; Romeiras, Francisco; Schreiber, Rainer; Mehta, Anil; Kunzelmann, Karl

    2010-01-01

    Metformin use in diabetes can cause acidosis and might be linked to pancreatitis. Here, we mechanistically focus on this relationship via a point mutation in the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7). CFTR is an ATP-hydrolyzing, cAMP/PKA-activated anion channel regulating pancreatic bicarbonate/chloride secretion across duct-facing apical membranes in epithelia. CFTR has two nucleotide binding domains (NBD1/2) which clamp two ATP molecules across their opposed, inverted interfacial surfaces which generates anion-conductance after ATP hydrolysis. Notably, CFTR mutations not causal for classical cystic fibrosis segregate with unexplained pancreatitis and one of these lies in NBD1 near its ATP-clamp (S573C; close to the Walker B aspartate D572). We recently showed that after raising [cAMP], wt-CFTR chloride-conductance, when expressed in Xenopus oocytes, remains elevated despite the presence of metformin. Yet here, we find that S573C-CFTR manifests a metformin-inhibitable whole cell chloride-conductance after cAMP elevation. In the absence of metformin, cAMP-activated S573C-CFTR also displays a reduced anion-conductance relative to wt-CFTR. Furthermore, intra-oocyte acidification inhibited wt-CFTR and abolished S573C-CFTR conductance. We conclude that defective S573C-CFTR remains both poorly conducting and inhibited by metformin and intracellular acidosis. This might explain the propensity to pancreatitis with this rare CF mutation.

  8. Fatigue behaviour FEM modeling of deep groove ball bearing mounted in automotive alternator submitted to variable loading

    Directory of Open Access Journals (Sweden)

    Azianou Ayao. E.

    2014-06-01

    Full Text Available Ball bearings subsurface materials are subjected to rolling contact fatigue with multiaxial stress state during loading cycle. The complex operating conditions of automotive bearings are different from classic operating conditions their fatigue crack initiation predicted by standards can be seen underestimated. This work presents a numerical approach of ball bearings to evaluate its fatigue behaviour in order to predict the life. A preliminary study has been done to evaluate the load distribution in the bearings. The results are integrated in a numerical dynamic model to study the bearing material rolling fatigue behaviour in constant and variable loading cases. By using fatigue criteria and damage laws, the analysis of stress state in bearing material leads to life prediction or the number of cycles before crack initiations. These results are compared to current standard methods used for ball bearing life prediction.

  9. Thin layer flow and film decay modeling for grease lubricated rolling bearings

    NARCIS (Netherlands)

    Venner, Cornelis H.; van Zoelen, M.T.; Lugt, Pieter Martin

    2012-01-01

    A model is presented to predict lubricant supply layer changes on tracks in rolling bearings due to centrifugal forces and elastohydrodynamic contact pressure. Experimental validation is shown for centrifugal force driven free surface flow, and layer thickness (film thickness) decay in single elasto

  10. Model-based temperature measurement system development for marine methane hydrate-bearing sediments

    Energy Technology Data Exchange (ETDEWEB)

    Fukuhara, Masafumi; Sugiyama, Hitoshi; Igarashi, Juei; Fujii, Kasumi; Shun' etsu, Onodera; Tertychnyi, Vladimir; Shandrygin, Alexander; Pimenov, Viacheslav; Shako, Valery; Matsubayashi, Osamu; Ochiai, Koji

    2005-07-01

    This paper describes the effect of the sensor installation on the temperature of the hydrate-bearing sediments through modeling, how the system was deployed in Nankai Trough area in Japan, and the features of the marine methane hydrate temperature measurement system. (Author)

  11. Analytic Modeling of the Hydrodynamic, Thermal, and Structural Behavior of Foil Thrust Bearings

    Science.gov (United States)

    Bruckner, Robert J.; DellaCorte, Christopher; Prahl, Joseph M.

    2005-01-01

    A simulation and modeling effort is conducted on gas foil thrust bearings. A foil bearing is a self acting hydrodynamic device capable of separating stationary and rotating components of rotating machinery by a film of air or other gaseous lubricant. Although simple in appearance these bearings have proven to be complicated devices in analysis. They are sensitive to fluid structure interaction, use a compressible gas as a lubricant, may not be in the fully continuum range of fluid mechanics, and operate in the range where viscous heat generation is significant. These factors provide a challenge to the simulation and modeling task. The Reynolds equation with the addition of Knudsen number effects due to thin film thicknesses is used to simulate the hydrodynamics. The energy equation is manipulated to simulate the temperature field of the lubricant film and combined with the ideal gas relationship, provides density field input to the Reynolds equation. Heat transfer between the lubricant and the surroundings is also modeled. The structural deformations of the bearing are modeled with a single partial differential equation. The equation models the top foil as a thin, bending dominated membrane whose deflections are governed by the biharmonic equation. A linear superposition of hydrodynamic load and compliant foundation reaction is included. The stiffness of the compliant foundation is modeled as a distributed stiffness that supports the top foil. The system of governing equations is solved numerically by a computer program written in the Mathematica computing environment. Representative calculations and comparisons with experimental results are included for a generation I gas foil thrust bearing.

  12. NASTRAN structural model for the large ground antenna pedestal with applications to hydrostatic bearing of film

    Science.gov (United States)

    Chian, C. T.

    1986-01-01

    Investigations were conducted on the 64-meter antenna hydrostatic bearing oil film thickness under a variety of loads and elastic moduli. These parametric studies used a NASTRAN pedestal structural model to determine the deflections under the hydrostatic bearing pad. The deflections formed the input for a computer program to determine the hydrostratic bearing oil film thickness. For the future 64-meter to 70-meter antenna extension and for the 2.2-meter (86-in.) haunch concrete replacement cases, the program predicted safe oil film thickness (greater than 0.13 mm (0.005 in.) at the corners of the pad). The effects of varying moduli of elasticity for different sections of the pedestal and the film height under stressed runner conditions were also studied.

  13. Mathematical model of determination of die bearing length in design of aluminum profile extrusion die

    Institute of Scientific and Technical Information of China (English)

    闫洪; 王高潮; 夏巨谌; 李志刚

    2004-01-01

    Based on the finite element simulation of profile extrusion process, the effect of local extrusion ratio, die bearing area and the distance between extrusion cylindrical center and local die orfice center on mental flow velocity was investigated. The laws of deformed metalflow on profile extrusion process were obtained. The smaller the local extrusion ratio, the faster the metal flow velocity; the smaller the area of die bearing, the faster the metal flow velocity; the smaller the distance of position of local die orifice(the closer the distance of position of local die orifice from extrusion cylindrical axis), the faster the metal flow velocity. The effect of main parameters of die structure on metal flow velocity was integrated and the mathematical model of determination of die bearing length in design of aluminum profile extrusion die was proposed. The calculated results with proposed model were well compared with the experimental results. The proposed model can be applied to determine die bearing length in design of aluminum profile extrusion die.

  14. Clustering diagnosis of rolling element bearing fault based on integrated Autoregressive/Autoregressive Conditional Heteroscedasticity model

    Science.gov (United States)

    Wang, Guofeng; Liu, Chang; Cui, Yinhu

    2012-09-01

    Feature extraction plays an important role in the clustering analysis. In this paper an integrated Autoregressive (AR)/Autoregressive Conditional Heteroscedasticity (ARCH) model is proposed to characterize the vibration signal and the model coefficients are adopted as feature vectors to realize clustering diagnosis of rolling element bearings. The main characteristic is that the AR item and ARCH item are interrelated with each other so that it can depict the excess kurtosis and volatility clustering information in the vibration signal more accurately in comparison with two-stage AR/ARCH model. To testify the correctness, four kinds of bearing signals are adopted for parametric modeling by using the integrated and two-stage AR/ARCH model. The variance analysis of the model coefficients shows that the integrated AR/ARCH model can get more concentrated distribution. Taking these coefficients as feature vectors, K means based clustering is utilized to realize the automatic classification of bearing fault status. The results show that the proposed method can get more accurate results in comparison with two-stage model and discrete wavelet decomposition.

  15. Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): studies of cybrid cells bearing 11,778 mutation.

    Science.gov (United States)

    Haroon, Mohammad Fahad; Fatima, Ambrin; Schöler, Susanne; Gieseler, Anne; Horn, Thomas F W; Kirches, Elmar; Wolf, Gerald; Kreutzmann, Peter

    2007-12-01

    Leber's hereditary optic neuropathy (LHON) is a retinal neurodegenerative disorder caused by mitochondrial DNA point mutations. Complex I of the respiratory chain affected by the mutation results in a decrease in ATP and an increase of reactive oxygen species production. Evaluating the efficacy of minocycline in LHON, the drug increased the survival of cybrid cells in contrast to the parental cells after thapsigargin-induced calcium overload. Similar protection was observed by treatment with cyclosporine A, a blocker of the mitochondrial permeability transition pore (mPTP). Ratiometric Ca(2+) imaging reveals that acetylcholine/thapsigargin triggered elevation of the cytosolic calcium concentration is alleviated by minocycline and cyclosporine A. The mitochondrial membrane potential of LHON cybrids was significantly conserved and the active-caspase-3/procaspase-3 ratio was decreased in both treatments. Our observations show that minocycline inhibits permeability transition induced by thapsigargin in addition to its antioxidant effects. In relation with its high safety profile, these results would suggest minocycline as a promising neuroprotective agent in LHON.

  16. Comparison of Models for the Steady-State Analysis of Tilting-Pad Thrust Bearings

    DEFF Research Database (Denmark)

    Heinrichson, Niels; Santos, Ilmar

    2005-01-01

    model requires different levels of detail. The two dimensional Reynolds equation for pressure in the oil film can be solved isothermally or considering viscosity variations in two or three dimensions, requiring solution of the equations for thermal equilibrium in oil and pad. Knowing the temperature......-state operation of a 228 mm outer diameter bearing. It is found that for the given bearing a two dimensional model is sufficient to estimate the minimum oil film thickness and the maximum temperature on the pad surface. Three dimensional modelling does not improve the quality of the results....... distribution the deflection of the pad due to pressure and thermal bending can be calculated using a flat plate approximation. At the five free sides of the pad heat transfer can be modelled. The temperature distribution at the inlet to the pad can be calculated through equilibrium of thermal energy...

  17. GNAR-GARCH model and its application in feature extraction for rolling bearing fault diagnosis

    Science.gov (United States)

    Ma, Jiaxin; Xu, Feiyun; Huang, Kai; Huang, Ren

    2017-09-01

    Given its simplicity of modeling and sensitivity to condition variations, time series model is widely used in feature extraction to realize fault classification and diagnosis. However, nonlinear and nonstationary characteristics common in fault signals of rolling bearing bring challenges to the diagnosis. In this paper, a hybrid model, the combination of a general expression for linear and nonlinear autoregressive (GNAR) model and a generalized autoregressive conditional heteroscedasticity (GARCH) model, (i.e., GNAR-GARCH), is proposed and applied to rolling bearing fault diagnosis. An exact expression of GNAR-GARCH model is given. Maximum likelihood method is used for parameter estimation and modified Akaike Information Criterion is adopted for structure identification of GNAR-GARCH model. The main advantage of this novel model over other models is that the combination makes the model suitable for nonlinear and nonstationary signals. It is verified with statistical tests that contain comparisons among the different time series models. Finally, GNAR-GARCH model is applied to fault diagnosis by modeling mechanical vibration signals including simulation and real data. With the parameters estimated and taken as feature vectors, k-nearest neighbor algorithm is utilized to realize the classification of fault status. The results show that GNAR-GARCH model exhibits higher accuracy and better performance than do other models.

  18. MEASURING AND MODELING OF THE MECHANICAL PROPERTIES OF COMPOSITE BEARING PAD MADE OF PLASTIC MATRIX AND FINE BRONZE ELASTIC SPRINGS

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The viscoelastic properties of the normal PTFE plastic and strengthened PTFE plastic for bearing pad are measured. The mechanical properties of the composite material for bearing pad, which is made of the aforementioned plastics as matrix reinforced by fine bronze elastic springs, are modeled and relaxation modulus of the material are presented. The difference between these two kinds of PTFE is studied. The results show that the complex modulus of PTFE plastics for bearing pad is higher than that of normal PTFE plastics.

  19. Exact Solution of Mutator Model with Linear Fitness and Finite Genome Length

    Science.gov (United States)

    Saakian, David B.

    2017-08-01

    We considered the infinite population version of the mutator phenomenon in evolutionary dynamics, looking at the uni-directional mutations in the mutator-specific genes and linear selection. We solved exactly the model for the finite genome length case, looking at the quasispecies version of the phenomenon. We calculated the mutator probability both in the statics and dynamics. The exact solution is important for us because the mutator probability depends on the genome length in a highly non-trivial way.

  20. Assessment of Brown Bear\\'s (Ursus arctos syriacus Winter Habitat Using Geographically Weighted Regression and Generalized Linear Model in South of Iran

    Directory of Open Access Journals (Sweden)

    A. A. Zarei

    2016-03-01

    Full Text Available Winter dens are one of the important components of brown bear's (Ursus arctos syriacus habitat, affecting their reproduction and survival. Therefore identification of factors affecting the habitat selection and suitable denning areas in the conservation of our largest carnivore is necessary. We used Geographically Weighted Logistic Regression (GWLR and Generalized Linear Model (GLM for modeling suitability of denning habitat in Kouhkhom region in Fars province. In the present research, 20 dens (presence locations and 20 caves where signs of bear were not found (absence locations were used as dependent variables and six environmental factors were used for each location as independent variables. The results of GLM showed that variables of distance to settlements, altitude, and distance to water were the most important parameters affecting suitability of the brown bear's denning habitat. The results of GWLR showed the significant local variations in the relationship between occurrence of brown bear dens and the variable of distance to settlements. Based on the results of both models, suitable habitats for denning of the species are impassable areas in the mountains and inaccessible for humans.

  1. Characteristics analysis and dynamic responses of micro-gas-lubricated journal bearings with a new slip model

    Science.gov (United States)

    Zhang, Wen-Ming; Meng, Guang; Huang, Hai; Zhou, Jian-Bin; Chen, Jie-Yu; Chen, Di

    2008-08-01

    In this paper, a new slip model based on kinetic theory of gases for gas-lubricated journal bearings in micro-electro-mechanical systems (MEMS) is applied using a physical approach. The corresponding modified governing equation and mathematic model are presented and the flow rate is plotted versus the inverse Knudsen number. Pressure distributions along the gas bearing at various Knudsen numbers and bearing numbers are plotted and the load carrying capacities are also obtained. A numerical analysis of a rigid rotor supported by gas-lubricated journal bearings is presented for dynamic behaviour. The slip flow effect on the properties, including pressure distribution, load carrying capacity and dynamic coefficients, of the micro-gas-lubricated journal bearings and dynamic responses of the micro rotor-bearing system are estimated and analysed in detail. It is shown that the dynamic coefficients increase with increasing bearing number except for two damping coefficients and the rotor-bearing system runs at a much higher rotating speed to keep stable when slip flow occurs. Moreover, the oscillation period of the rotor operating with the slip model is longer than that with the continuum flow. In addition, the whirl frequency is reduced from 0.422 to 0.079 under the slip effect. Therefore, the results of this study contribute to a further understanding of the characteristics and nonlinear dynamics of gas-film rotor-bearing systems in MEMS.

  2. Robustness and epistasis in mutation-selection models

    Science.gov (United States)

    Wolff, Andrea; Krug, Joachim

    2009-09-01

    We investigate the fitness advantage associated with the robustness of a phenotype against deleterious mutations using deterministic mutation-selection models of a quasispecies type equipped with a mesa-shaped fitness landscape. We obtain analytic results for the robustness effect which become exact in the limit of infinite sequence length. Thereby, we are able to clarify a seeming contradiction between recent rigorous work and an earlier heuristic treatment based on mapping to a Schrödinger equation. We exploit the quantum mechanical analogy to calculate a correction term for finite sequence lengths and verify our analytic results by numerical studies. In addition, we investigate the occurrence of an error threshold for a general class of epistatic landscapes and show that diminishing epistasis is a necessary but not sufficient condition for error threshold behaviour.

  3. Hydrodynamic bearings

    CERN Document Server

    Bonneau, Dominique; Souchet, Dominique

    2014-01-01

    This Series provides the necessary elements to the development and validation of numerical prediction models for hydrodynamic bearings. This book describes the rheological models and the equations of lubrication. It also presents the numerical approaches used to solve the above equations by finite differences, finite volumes and finite elements methods.

  4. Small populations corrections for selection-mutation models

    CERN Document Server

    Jabin, Pierre-Emmanuel

    2012-01-01

    We consider integro-differential models describing the evolution of a population structured by a quantitative trait. Individuals interact competitively, creating a strong selection pressure on the population. On the other hand, mutations are assumed to be small. Following the formalism of Diekmann, Jabin, Mischler, and Perthame, this creates concentration phenomena, typically consisting in a sum of Dirac masses slowly evolving in time. We propose a modification to those classical models that takes the effect of small populations into accounts and corrects some abnormal behaviours.

  5. Simulating polar bear energetics during a seasonal fast using a mechanistic model.

    Directory of Open Access Journals (Sweden)

    Paul D Mathewson

    Full Text Available In this study we tested the ability of a mechanistic model (Niche Mapper™ to accurately model adult, non-denning polar bear (Ursus maritimus energetics while fasting during the ice-free season in the western Hudson Bay. The model uses a steady state heat balance approach, which calculates the metabolic rate that will allow an animal to maintain its core temperature in its particular microclimate conditions. Predicted weight loss for a 120 day fast typical of the 1990s was comparable to empirical studies of the population, and the model was able to reach a heat balance at the target metabolic rate for the entire fast, supporting use of the model to explore the impacts of climate change on polar bears. Niche Mapper predicted that all but the poorest condition bears would survive a 120 day fast under current climate conditions. When the fast extended to 180 days, Niche Mapper predicted mortality of up to 18% for males. Our results illustrate how environmental conditions, variation in animal properties, and thermoregulation processes may impact survival during extended fasts because polar bears were predicted to require additional energetic expenditure for thermoregulation during a 180 day fast. A uniform 3°C temperature increase reduced male mortality during a 180 day fast from 18% to 15%. Niche Mapper explicitly links an animal's energetics to environmental conditions and thus can be a valuable tool to help inform predictions of climate-related population changes. Since Niche Mapper is a generic model, it can make energetic predictions for other species threatened by climate change.

  6. Vibration Propagation of Gear Dynamics in a Gear-Bearing-Housing System Using Mathematical Modeling and Finite Element Analysis

    Science.gov (United States)

    Parker, Robert G.; Guo, Yi; Eritenel, Tugan; Ericson, Tristan M.

    2012-01-01

    Vibration and noise caused by gear dynamics at the meshing teeth propagate through power transmission components to the surrounding environment. This study is devoted to developing computational tools to investigate the vibro-acoustic propagation of gear dynamics through a gearbox using different bearings. Detailed finite element/contact mechanics and boundary element models of the gear/bearing/housing system are established to compute the system vibration and noise propagation. Both vibration and acoustic models are validated by experiments including the vibration modal testing and sound field measurements. The effectiveness of each bearing type to disrupt vibration propagation is speed-dependent. Housing plays an important role in noise radiation .It, however, has limited effects on gear dynamics. Bearings are critical components in drivetrains. Accurate modeling of rolling element bearings is essential to assess vibration and noise of drivetrain systems. This study also seeks to fully describe the vibro-acoustic propagation of gear dynamics through a power-transmission system using rolling element and fluid film wave bearings. Fluid film wave bearings, which have higher damping than rolling element bearings, could offer an energy dissipation mechanism that reduces the gearbox noise. The effectiveness of each bearing type to disrupt vibration propagation in explored using multi-body computational models. These models include gears, shafts, rolling element and fluid film wave bearings, and the housing. Radiated noise is mapped from the gearbox surface to surrounding environment. The effectiveness of rolling element and fluid film wave bearings in breaking the vibro-acoustic propagation path from the gear to the housing is investigated.

  7. A double-superconducting axial bearing system for an energy storage flywheel model

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Z; Lin, Q; Ma, G; Zheng, J; Zhang, Y; Wang, S; Wang, J [Applied Superconductivity Laboratory, Mail Stop 152, Southwest Jiaotong University, Chengdu, 610031 (China)], E-mail: jsywang@home.swjtu.edu.cn

    2008-02-15

    The bulk high temperature superconductors (HTSCs) with unique flux-pinning property have been applied to fabricate two superconducting axial bearings for an energy storage flywheel model. The two superconducting axial bearings are respectively fixed at two ends of the vertical rotational shaft, whose stator is composed of seven melt-textured YBa{sub 2}Cu{sub 3}O{sub 7-x} (YBCO) bulks with diameter of 30 mm, height of 18 mm and rotor is made of three cylindrical axial-magnetized NdFeB permanent magnets (PM) by superposition with diameter of 63 mm, height of 27 mm. The experimental results show the total levitation and lateral force produced by the two superconducting bearings are enough to levitate and stabilize the 2.4 kg rotational shaft. When the two YBCO stators were both field cooled to the liquid nitrogen temperature at respective axial distances above or below the PM rotor, the shaft could be automatically levitated between the two stators without any contact. In the case of a driving motor, it can be stably rotated along the central axis besides the resonance frequency. This double-superconducting axial bearing system can be used to demonstrate the flux-pinning property of bulk HTSC for stable levitation and suspension and the principle of superconducting flywheel energy storage system to visitors.

  8. The influence of selecting the correlation model on soil parameters and bearing capacity

    Science.gov (United States)

    Pieczynska-Kozlowska, Joanna M.

    2016-04-01

    Consideration of soil spatial variability in the geotechnical design is still marginalized. The design process is based on taking the average parameters, which often results the oversize of geotechnical constructions. This procedure works until there are no geotechnical design problems. In most cases, geotechnical constructions represent a small percentage of the total investment so effects lacking developed of optimization procedures. If the optimization is needed requires the most accurate mapping of the soil. The basic background for statistical interpretation of soil spatially variables are Cone Penetration Tests, which represents variable nature of the soil with depth. Assuming the soil structure as a spatially random variable can be applied by description based on random fields. Field parameters are the probability distribution and correlation model dependent of a scale of fluctuation estimated from CPT. The main goal of this study is to contribute to the understanding on how the choice of correlation model affects random soil properties and for example shallow foundation bearing capacity. The study is particularly focused on scale of fluctuation as related to the reduction of bearing capacity. Scale of fluctuation were estimated using two effective methods: Vanmarcke and Rice. Soil properties were analyzed from 12 Cone Penetration Tests distributed throughout the regions of Świebodzice (Lower Silesia, Poland). While the project was developed in hilly terrain the macrolevelling were taken involving the displacement of native soil mass to form a working platform for shallow foundation. The construction of embankment has been tested by cone resistance tests to determine the parameters for the design. The procedure adopted to this study include the modeling soil variability from the CPT results and calculate the bearing capacity of shallow foundation using random finite element method and different correlation models. The aim of study was to answer questions

  9. Model of converter dusts and iron-bearing slurries management in briquetting

    Directory of Open Access Journals (Sweden)

    P. Gara

    2016-07-01

    Full Text Available An important problem in metallurgy of iron and steel is management of hydrated, fine-grained, iron-bearing waste which can be formed as a result of gas scrubbing. The article presents a model of application of converter slurry in a closed-circuit flow system. The correct preparation of slag, namely briquetting with defined additives, allows for application of such slag in the steel-making process as the substitute for scrap metal.

  10. Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway.

    Science.gov (United States)

    Kan, Rui; Sun, Xianfei; Kolas, Nadine K; Avdievich, Elena; Kneitz, Burkhard; Edelmann, Winfried; Cohen, Paula E

    2008-03-01

    The DNA mismatch repair (MMR) family functions in a variety of contexts to preserve genome integrity in most eukaryotes. In particular, members of the MMR family are involved in the process of meiotic recombination in germ cells. MMR gene mutations in mice result in meiotic disruption during prophase I, but the extent of this disruption often differs between male and female meiocytes. To address the role of MMR proteins specifically in female meiosis, we explored the progression of oocytes through prophase I and the meiotic divisions in mice harboring deletions in members of the MMR pathway (Mlh1, Mlh3, Exo1, and an ATPase-deficient variant of Mlh1, Mlh1(G67R)). The colocalization of MLH1 and MLH3, key proteins involved in stabilization of nascent crossovers, was dependent on intact heterodimer formation and was highly correlated with the ability of oocytes to progress through to metaphase II. The exception was Exo1(-/-) oocytes, in which normal MLH1/MLH3 localization was observed followed by failure to proceed to metaphase II. All mutant oocytes were able to resume meiosis after dictyate arrest, but they showed a dramatic decline in chiasmata (to less than 25% of normal), accompanied by varied progression through metaphase I. Taken together, these results demonstrate that MMR function is required for the formation and stabilization of crossovers in mammalian oocytes and that, in the absence of a functional MMR system, the failure to maintain chiasmata results in a reduced ability to proceed normally through the first and second meiotic divisions, despite near-normal levels of meiotic resumption after dictyate arrest.

  11. Active Magnetic Bearing Rotor Model Updating Using Resonance and MAC Error

    Directory of Open Access Journals (Sweden)

    Yuanping Xu

    2015-01-01

    Full Text Available Modern control techniques can improve the performance and robustness of a rotor active magnetic bearing (AMB system. Since those control methods usually rely on system models, it is important to obtain a precise rotor AMB analytical model. However, the interference fits and shrink effects of rotor AMB cause inaccuracy to the final system model. In this paper, an experiment based model updating method is proposed to improve the accuracy of the finite element (FE model used in a rotor AMB system. Modelling error is minimized by applying a numerical optimization Nelder-Mead simplex algorithm to properly adjust FE model parameters. Both the error resonance frequencies and modal assurance criterion (MAC values are minimized simultaneously to account for the rotor natural frequencies as well as for the mode shapes. Verification of the updated rotor model is performed by comparing the experimental and analytical frequency response. The close agreements demonstrate the effectiveness of the proposed model updating methodology.

  12. Dynamic Model for Hydro-Turbine Generator Units Based on a Database Method for Guide Bearings

    Directory of Open Access Journals (Sweden)

    Yong Xu

    2013-01-01

    Full Text Available A suitable dynamic model of rotor system is of great significance not only for supplying knowledge of the fault mechanism, but also for assisting in machine health monitoring research. Many techniques have been developed for properly modeling the radial vibration of large hydro-turbine generator units. However, an applicable dynamic model has not yet been reported in literature due to the complexity of the boundary conditions and exciting forces. In this paper, a finite element (FE rotor dynamic model of radial vibration taking account of operating conditions is proposed. A brief and practical database method is employed to model the guide bearing. Taking advantage of the method, rotating speed and bearing clearance can be considered in the model. A novel algorithm, which can take account of both transient and steady-state analysis, is proposed to solve the model. Dynamic response for rotor model of 125 MW hydro-turbine generator units in Gezhouba Power Station is simulated. Field data from Optimal Maintenance Information System for Hydro power plants (HOMIS are analyzed compared with the simulation. Results illustrate the application value of the model in providing knowledge of the fault mechanism and in failure diagnosis.

  13. MODELING INFLUENCE OF ROLLING BEARING BUSH AND VIBRATION DAMPING IN CATCHING OF TOOTHED WHEELS

    Directory of Open Access Journals (Sweden)

    P. V. Diachenko

    2010-11-01

    Full Text Available On the base of dynamic scheme of toothing, a mathematical model for study of the influence of constructive parameters of radial bearings such as a factor of friction, reduced masses and stiffnesses on damping the vibrations in gearing is developed. The solution for the model is obtained using a simulation modeling in the Simulink environment with checking the validity of results in the system MathCad. The oscillograms of the vibrations under investigation and the conclusions on the base of their analysis are presented.

  14. A new model of water-lubricated rubber bearings for vibration analysis of flexible multistage rotor systems

    Science.gov (United States)

    Liu, Shibing; Yang, Bingen

    2015-08-01

    Flexible multistage rotating systems that are supported or guided by long water-lubricated rubber bearings (WLRBs) have a variety of engineering applications. Vibration analysis of this type of machinery for performance and duality requires accurate modeling of WLRBs and related rotor-bearing assemblies. This work presents a new model of WLRBs, with attention given to the determination of bearing dynamic coefficients. Due to its large length-to-diameter ratio, a WLRB cannot be described by conventional pointwise bearing models with good fidelity. The bearing model proposed in this paper considers spatially distributed bearing forces. For the first time in the literature, the current study addresses the issue of mixed lubrication in the operation of WLRBs, which involves interactions of shaft vibration, elastic deformation of rubber material and fluid film pressure, and validates the WLRB model in experiments. Additionally, with the new bearing model, vibration analysis of WLRB-supported flexible multistage rotating systems is performed through use of a distributed transfer function method, which delivers accurate and closed-form analytical solutions of steady-state responses without discretization.

  15. Analysis of HD Journal Bearings Considering Elastic Deformation and Non-Newtonian Rabinowitsch Fluid Model

    Directory of Open Access Journals (Sweden)

    J. Javorova

    2016-06-01

    Full Text Available The purpose of this paper is to study the performance of a finite length journal bearing, taking into account effects of non-Newtonian Rabinowitsch flow rheology and elastic deformations of the bearing liner. According to the Rabinowitsch fluid model, the cubic-stress constitutive equation is used to account for the non-Newtonian effects of pseudoplastic and dilatant lubricants. Integrating the continuity equation across the film, the nonlinear non-Newtonian Reynolds-type equation is derived. The elasticity part of the problem is solved on the base of Vlassov model of an elastic foundation. The numerical solution of the modified Reynolds equation is carried out by using FDM with over-relaxation technique. The results for steady state bearing performance characteristics have been calculated for various values of nonlinear factor and elasticity parameters. It was concluded that in comparison with the Newtonian lubricants, higher values of film pressure and load carrying capacity have been obtained for dilatant lubricants, while the case was reversed for pseudoplastic lubricants.

  16. Feature Extraction Method of Rolling Bearing Fault Signal Based on EEMD and Cloud Model Characteristic Entropy

    Directory of Open Access Journals (Sweden)

    Long Han

    2015-09-01

    Full Text Available The randomness and fuzziness that exist in rolling bearings when faults occur result in uncertainty in acquisition signals and reduce the accuracy of signal feature extraction. To solve this problem, this study proposes a new method in which cloud model characteristic entropy (CMCE is set as the signal characteristic eigenvalue. This approach can overcome the disadvantages of traditional entropy complexity in parameter selection when solving uncertainty problems. First, the acoustic emission signals under normal and damage rolling bearing states collected from the experiments are decomposed via ensemble empirical mode decomposition. The mutual information method is then used to select the sensitive intrinsic mode functions that can reflect signal characteristics to reconstruct the signal and eliminate noise interference. Subsequently, CMCE is set as the eigenvalue of the reconstructed signal. Finally, through the comparison of experiments between sample entropy, root mean square and CMCE, the results show that CMCE can better represent the characteristic information of the fault signal.

  17. A constitutive mechanical model for gas hydrate bearing sediments incorporating inelastic mechanisms

    KAUST Repository

    Sánchez, Marcelo

    2016-11-30

    Gas hydrate bearing sediments (HBS) are natural soils formed in permafrost and sub-marine settings where the temperature and pressure conditions are such that gas hydrates are stable. If these conditions shift from the hydrate stability zone, hydrates dissociate and move from the solid to the gas phase. Hydrate dissociation is accompanied by significant changes in sediment structure and strongly affects its mechanical behavior (e.g., sediment stiffenss, strength and dilatancy). The mechanical behavior of HBS is very complex and its modeling poses great challenges. This paper presents a new geomechanical model for hydrate bearing sediments. The model incorporates the concept of partition stress, plus a number of inelastic mechanisms proposed to capture the complex behavior of this type of soil. This constitutive model is especially well suited to simulate the behavior of HBS upon dissociation. The model was applied and validated against experimental data from triaxial and oedometric tests conducted on manufactured and natural specimens involving different hydrate saturation, hydrate morphology, and confinement conditions. Particular attention was paid to model the HBS behavior during hydrate dissociation under loading. The model performance was highly satisfactory in all the cases studied. It managed to properly capture the main features of HBS mechanical behavior and it also assisted to interpret the behavior of this type of sediment under different loading and hydrate conditions.

  18. Textile solar light collectors based on models for polar bear hair

    Energy Technology Data Exchange (ETDEWEB)

    Bahners, Thomas; Schlosser, Uwe; Schollmeyer, Eckhard [Deutsches Textilforschungszentrum Nord-West e.V., Adlerstr. 1, D-47798 Krefeld (Germany); Gutmann, Rainer [Institut fuer Textilchemie und Chemiefasern, Koerschtalstr. 26, D-73770 Denkendorf (Germany)

    2008-12-15

    Concepts of technical fibers following models for the polar bear hair to be used for textile solar collectors are discussed. The approach to coat fibers with a thin layer into which fluorescent dyestuff was dispersed was studied experimentally. Modified fibers made of different polymers were characterized with respect to optical properties relevant for the bionic model. In the case of poly(methylmethacrylate) fibers, the envisaged effect could be achieved to high efficiency. The optical performance could be enhanced by ultrasonic dispersion of the dyestuff in the coating matrix. The effect is less significant in semi-crystalline fibers such as poly(ethylene terephthalate), which is attributed to diffuse scattering. (author)

  19. Modeling and Analysis of Coupling Performance of Dynamic Stiffness Models for a Novel Combined Radial-Axial Hybrid Magnetic Bearing

    Directory of Open Access Journals (Sweden)

    Bangcheng Han

    2014-01-01

    Full Text Available The combined radial-axial magnetic bearing (CRAMB with permanent magnet creating bias flux can reduce the size, cost, and mass and save energy of the magnetic bearing. The CRAMB have three-degree-of-freedom control ability, so its structure and magnetic circuits are more complicated compared to those of the axial magnetic bearing (AMB or radial magnetic bearing (RMB. And the eddy currents have a fundamental impact on the dynamic performance of the CRAMB. The dynamic stiffness model and its cross coupling problems between different degrees of freedom affected for the CRAMB are proposed in this paper. The dynamic current stiffness and the dynamic displacement stiffness models of the CRAMB are deduced by using the method of equivalent magnetic circuit including eddy current effect, but the dynamic current stiffness of the RMB unit is approximately equal to its static current stiffness. The analytical results of an example show that the bandwidth of the dynamic current stiffness of the AMB unit and the dynamic displacement stiffness of the CRAMB is affected by the time-varying control currents or air gap, respectively. And the dynamic current stiffness and the dynamic displacement stiffness between the AMB unit and the RMB unit are decoupled due to few coupling coefficients.

  20. Nonlocal sparse model with adaptive structural clustering for feature extraction of aero-engine bearings

    Science.gov (United States)

    Zhang, Han; Chen, Xuefeng; Du, Zhaohui; Li, Xiang; Yan, Ruqiang

    2016-04-01

    Fault information of aero-engine bearings presents two particular phenomena, i.e., waveform distortion and impulsive feature frequency band dispersion, which leads to a challenging problem for current techniques of bearing fault diagnosis. Moreover, although many progresses of sparse representation theory have been made in feature extraction of fault information, the theory also confronts inevitable performance degradation due to the fact that relatively weak fault information has not sufficiently prominent and sparse representations. Therefore, a novel nonlocal sparse model (coined NLSM) and its algorithm framework has been proposed in this paper, which goes beyond simple sparsity by introducing more intrinsic structures of feature information. This work adequately exploits the underlying prior information that feature information exhibits nonlocal self-similarity through clustering similar signal fragments and stacking them together into groups. Within this framework, the prior information is transformed into a regularization term and a sparse optimization problem, which could be solved through block coordinate descent method (BCD), is formulated. Additionally, the adaptive structural clustering sparse dictionary learning technique, which utilizes k-Nearest-Neighbor (kNN) clustering and principal component analysis (PCA) learning, is adopted to further enable sufficient sparsity of feature information. Moreover, the selection rule of regularization parameter and computational complexity are described in detail. The performance of the proposed framework is evaluated through numerical experiment and its superiority with respect to the state-of-the-art method in the field is demonstrated through the vibration signals of experimental rig of aircraft engine bearings.

  1. Detection and diagnosis of bearing faults using shift-invariant dictionary learning and hidden Markov model

    Science.gov (United States)

    Zhou, Haitao; Chen, Jin; Dong, Guangming; Wang, Ran

    2016-05-01

    Many existing signal processing methods usually select a predefined basis function in advance. This basis functions selection relies on a priori knowledge about the target signal, which is always infeasible in engineering applications. Dictionary learning method provides an ambitious direction to learn basis atoms from data itself with the objective of finding the underlying structure embedded in signal. As a special case of dictionary learning methods, shift-invariant dictionary learning (SIDL) reconstructs an input signal using basis atoms in all possible time shifts. The property of shift-invariance is very suitable to extract periodic impulses, which are typical symptom of mechanical fault signal. After learning basis atoms, a signal can be decomposed into a collection of latent components, each is reconstructed by one basis atom and its corresponding time-shifts. In this paper, SIDL method is introduced as an adaptive feature extraction technique. Then an effective approach based on SIDL and hidden Markov model (HMM) is addressed for machinery fault diagnosis. The SIDL-based feature extraction is applied to analyze both simulated and experiment signal with specific notch size. This experiment shows that SIDL can successfully extract double impulses in bearing signal. The second experiment presents an artificial fault experiment with different bearing fault type. Feature extraction based on SIDL method is performed on each signal, and then HMM is used to identify its fault type. This experiment results show that the proposed SIDL-HMM has a good performance in bearing fault diagnosis.

  2. Radial Domany-Kinzel models with mutation and selection

    Science.gov (United States)

    Lavrentovich, Maxim O.; Korolev, Kirill S.; Nelson, David R.

    2013-01-01

    We study the effect of spatial structure, genetic drift, mutation, and selective pressure on the evolutionary dynamics in a simplified model of asexual organisms colonizing a new territory. Under an appropriate coarse-graining, the evolutionary dynamics is related to the directed percolation processes that arise in voter models, the Domany-Kinzel (DK) model, contact process, and so on. We explore the differences between linear (flat front) expansions and the much less familiar radial (curved front) range expansions. For the radial expansion, we develop a generalized, off-lattice DK model that minimizes otherwise persistent lattice artifacts. With both simulations and analytical techniques, we study the survival probability of advantageous mutants, the spatial correlations between domains of neutral strains, and the dynamics of populations with deleterious mutations. “Inflation” at the frontier leads to striking differences between radial and linear expansions. For a colony with initial radius R0 expanding at velocity v, significant genetic demixing, caused by local genetic drift, occurs only up to a finite time t*=R0/v, after which portions of the colony become causally disconnected due to the inflating perimeter of the expanding front. As a result, the effect of a selective advantage is amplified relative to genetic drift, increasing the survival probability of advantageous mutants. Inflation also modifies the underlying directed percolation transition, introducing novel scaling functions and modifications similar to a finite-size effect. Finally, we consider radial range expansions with deflating perimeters, as might arise from colonization initiated along the shores of an island.

  3. Numerical modelling of the flow in the annular multi-recess hydrostatic thrust bearing using CFD methods

    Directory of Open Access Journals (Sweden)

    Drbáková S.

    2013-04-01

    Full Text Available The current research of hydrostatic bearings and hydrostatic slide-ways is far from being over. The topic is constantly evolving, creating new geometries of the sliding bearings, developing new types of friction materials and lubricants. The control elements of hydraulic mechanisms that serve to regulation of the hydrostatic bearings tipping are still in progress. Almost every application has different requirements for the bearings, whether in terms of loading capacity, speed rotation, and also the price. All these aspects should be included in the design of hydrostatic thrust bearings. Thanks to great advances in the development of computer technology and software for numerical modelling, we can simulate real movement of viscous fluids. To create a numerical model of hydrostatic thrust bearing, Ansys Fluent 14.0 software package has been applied. The article describes the basic methods of numerical modelling of the given problem and evaluates the pressure field and the loading capacity of annular multi-recess hydrostatic thrust bearing and its dependence on the change in static pressure.

  4. Witches' brooms in Siberian stone pine as somatic mutations and initial genetic material for breeding of nut-bearing and ornamental cultivars

    Directory of Open Access Journals (Sweden)

    M. S. Yamburov

    2013-12-01

    Full Text Available For the raising of the Siberian stone pine (Pinus sibirica Du Tour nut-bearing and ornamental cultivars, the most important traits are adense crown, slow growth and precocity. Generative mutations of this kind are eliminated by natural selection, therefore, somatic mutationrsearch is important. Among somatic mutations, the most promising one is the so-called 'witches' brooms' (WB where crown fragments demonstrate slowed growth and intensive branching. WB occasionally occurs in native populations. According to phytopathology textbooks, WB are caused by various pathogen species (viruses, mycoplasmas, fungi. The WB of this kind are characterized by a sickly look, full suppression of reproductive functions, a short life and a nidus patternof distribution. There are also WB of different types: with a high vitality and fertility, a long life and sporadic distribution. They occur very rarely(about 1 per 10 000 trees across the species' range. We investigated 18 trees with WB of this type. The size of WB ranged from 0.3 to 30 m, age varied from 30 to 300 years. Male cones were absent inall WB. Female cone initiation was normal if the WB was located in the top part of a crown. Scions from WB and a normal crown (NC of the same tree were grafted on identical rootstocks. On average,the height of 7-year-old WB grafts (WBG was 2 times lower, and the stem diameter was 2 times higher than in the NC grafts (NCG. It wasachieved due to the fundamental differences in the shoot system morphogenesis. Here are three principal differences in decreasing order of importance: (i WBGs were characterized by the absence or near absence of apical dominance. The NCG had no more than 3 orders of branching, and the length of the 1st order axis was on average 5times larger than the axis of the 3rd order. The WBG had 6-7 orders of branching, and the length of shoots of 5-6th orders averaged 80-90% of the length of the first orders. (ii At an

  5. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

    Science.gov (United States)

    Gulsuner, Suleyman; Stapleton, Gail A.; Walsh, Tom; Lee, Ming K.; Mandell, Jessica B.; Morales, Augusto; Klevit, Rachel E.; King, Mary-Claire; Rogers, R. Curtis

    2016-01-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  6. Evolutionary Stability of Minimal Mutation Rates in an Evo-epidemiological Model.

    Science.gov (United States)

    Birch, Michael; Bolker, Benjamin M

    2015-11-01

    We consider the evolution of mutation rate in a seasonally forced, deterministic, compartmental epidemiological model with a transmission-virulence trade-off. We model virulence as a quantitative genetic trait in a haploid population and mutation as continuous diffusion in the trait space. There is a mutation rate threshold above which the pathogen cannot invade a wholly susceptible population. The evolutionarily stable (ESS) mutation rate is the one which drives the lowest average density, over the course of one forcing period, of susceptible individuals at steady state. In contrast with earlier eco-evolutionary models in which higher mutation rates allow for better evolutionary tracking of a dynamic environment, numerical calculations suggest that in our model the minimum average susceptible population, and hence the ESS, is achieved by a pathogen strain with zero mutation. We discuss how this result arises within our model and how the model might be modified to obtain a nonzero optimum.

  7. Depression of p53-independent Akt survival signals in human oral cancer cells bearing mutated p53 gene after exposure to high-LET radiation

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, Yosuke [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Takahashi, Akihisa [Advanced Scientific Research Leader Development Unit, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511 (Japan); Kajihara, Atsuhisa; Yamakawa, Nobuhiro; Imai, Yuichiro [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ota, Ichiro; Okamoto, Noritomo [Department of Otorhinolaryngology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Mori, Eiichiro [Department of Radiation Oncology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Noda, Taichi [Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Furusawa, Yoshiya [Heavy-ion Radiobiology Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Kirita, Tadaaki [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ohnishi, Takeo, E-mail: tohnishi@naramed-u.ac.jp [Department of Radiation Oncology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer High-LET radiation induces efficiently apoptosis regardless of p53 gene status. Black-Right-Pointing-Pointer We examined whether high-LET radiation depresses the Akt-survival signals. Black-Right-Pointing-Pointer High-LET radiation depresses of survival signals even in the mp53 cancer cells. Black-Right-Pointing-Pointer High-LET radiation activates Caspase-9 through depression of survival signals. Black-Right-Pointing-Pointer High-LET radiation suppresses cell growth through depression of survival signals. -- Abstract: Although mutations and deletions in the p53 tumor suppressor gene lead to resistance to low linear energy transfer (LET) radiation, high-LET radiation efficiently induces cell lethality and apoptosis regardless of the p53 gene status in cancer cells. Recently, it has been suggested that the induction of p53-independent apoptosis takes place through the activation of Caspase-9 which results in the cleavage of Caspase-3 and poly (ADP-ribose) polymerase (PARP). This study was designed to examine if high-LET radiation depresses serine/threonine protein kinase B (PKB, also known as Akt) and Akt-related proteins. Human gingival cancer cells (Ca9-22 cells) harboring a mutated p53 (mp53) gene were irradiated with 2 Gy of X-rays or Fe-ion beams. The cellular contents of Akt-related proteins participating in cell survival signaling were analyzed with Western Blotting 1, 2, 3 and 6 h after irradiation. Cell cycle distributions after irradiation were assayed with flow cytometric analysis. Akt-related protein levels decreased when cells were irradiated with high-LET radiation. High-LET radiation increased G{sub 2}/M phase arrests and suppressed the progression of the cell cycle much more efficiently when compared to low-LET radiation. These results suggest that high-LET radiation enhances apoptosis through the activation of Caspase-3 and Caspase-9, and suppresses cell growth by suppressing Akt-related signaling, even in mp

  8. Weighted low-rank sparse model via nuclear norm minimization for bearing fault detection

    Science.gov (United States)

    Du, Zhaohui; Chen, Xuefeng; Zhang, Han; Yang, Boyuan; Zhai, Zhi; Yan, Ruqiang

    2017-07-01

    It is a fundamental task in the machine fault diagnosis community to detect impulsive signatures generated by the localized faults of bearings. The main goal of this paper is to exploit the low-rank physical structure of periodic impulsive features and further establish a weighted low-rank sparse model for bearing fault detection. The proposed model mainly consists of three basic components: an adaptive partition window, a nuclear norm regularization and a weighted sequence. Firstly, due to the periodic repetition mechanism of impulsive feature, an adaptive partition window could be designed to transform the impulsive feature into a data matrix. The highlight of partition window is to accumulate all local feature information and align them. Then, all columns of the data matrix share similar waveforms and a core physical phenomenon arises, i.e., these singular values of the data matrix demonstrates a sparse distribution pattern. Therefore, a nuclear norm regularization is enforced to capture that sparse prior. However, the nuclear norm regularization treats all singular values equally and thus ignores one basic fact that larger singular values have more information volume of impulsive features and should be preserved as much as possible. Therefore, a weighted sequence with adaptively tuning weights inversely proportional to singular amplitude is adopted to guarantee the distribution consistence of large singular values. On the other hand, the proposed model is difficult to solve due to its non-convexity and thus a new algorithm is developed to search one satisfying stationary solution through alternatively implementing one proximal operator operation and least-square fitting. Moreover, the sensitivity analysis and selection principles of algorithmic parameters are comprehensively investigated through a set of numerical experiments, which shows that the proposed method is robust and only has a few adjustable parameters. Lastly, the proposed model is applied to the

  9. A Canine Non-Weight-Bearing Model with Radial Neurectomy for Rotator Cuff Repair.

    Directory of Open Access Journals (Sweden)

    Xiaoxi Ji

    Full Text Available The major concern of using a large animal model to study rotator cuff repair is the high rate of repair retears. The purpose of this study was to test a non-weight-bearing (NWB canine model for rotator cuff repair research.First, in the in vitro study, 18 shoulders were randomized to 3 groups. 1 Full-width transections repaired with modified Mason-Allen sutures using 3-0 polyglactin suture, 2 Group 1 repaired using number 2 (#2 polyester braid and long-chain polyethylene suture, and 3 Partial-width transections leaving the superior 2 mm infraspinatus tendon intact without repair. In the in vivo study of 6 dogs, the infraspinatus tendon was partially transected as the same as the in vitro group 3. A radial neurectomy was performed to prevent weight bearing. The operated limb was slung in a custom-made jacket for 6 weeks.In the in vitro study, mean ultimate tensile load and stiffness in Group 2 were significantly higher than Group 1 and 3 (p<0.05. In the in vivo study, gross inspection and histology showed that the preserved superior 2-mm portion of the infraspinatus tendon remained intact with normal structure.Based on the biomechanical and histological findings, this canine NWB model may be an appropriate and useful model for studies of rotator cuff repair.

  10. Model evaporation of FeO-bearing liquids: Application to chondrules

    Science.gov (United States)

    Ebel, Denton S.

    2005-06-01

    Models for thermodynamic behavior of FeO-bearing liquids are required for understanding the separate roles of evaporation, condensation and crystallization in the formation of free-floating silicate liquid droplets in the early solar nebula. These droplets, frozen as chondrules, are common in chondritic meteorites. Evaporation coefficients for Fe and FeO of ˜0.2 are calculated here from existing data using silicate liquid activity models. These models, used to describe gas-liquid-solid equilibria and to constrain kinetic processes, are compared and found similar, and the effects of liquid non-ideality are assessed. A general approach is presented for predicting the evaporation behavior of FeO-bearing Al 2O 3-CaO-SiO 2-MgO liquids in H 2-rich gas above 1400 K at low total pressure. Results are vapor pressure curves for Fe, FeO and other gas species above typical chondrule liquids, suitable for predicting compositional trajectories of residual liquids evaporating in a hydrogen-dominated vapor. These predictions are consistent with chondrule formation in the protoplanetary disk in heating events of short duration, such as those expected from shock wave or current sheet models.

  11. A Canine Non-Weight-Bearing Model with Radial Neurectomy for Rotator Cuff Repair

    Science.gov (United States)

    Ji, Xiaoxi; Bao, Nirong; An, Kai-Nan; Amadio, Peter C.; Steinmann, Scott P.; Zhao, Chunfeng

    2015-01-01

    Background The major concern of using a large animal model to study rotator cuff repair is the high rate of repair retears. The purpose of this study was to test a non-weight-bearing (NWB) canine model for rotator cuff repair research. Methods First, in the in vitro study, 18 shoulders were randomized to 3 groups. 1) Full-width transections repaired with modified Mason-Allen sutures using 3-0 polyglactin suture, 2) Group 1 repaired using number 2 (#2) polyester braid and long-chain polyethylene suture, and 3) Partial-width transections leaving the superior 2 mm infraspinatus tendon intact without repair. In the in vivo study of 6 dogs, the infraspinatus tendon was partially transected as the same as the in vitro group 3. A radial neurectomy was performed to prevent weight bearing. The operated limb was slung in a custom-made jacket for 6 weeks. Results In the in vitro study, mean ultimate tensile load and stiffness in Group 2 were significantly higher than Group 1 and 3 (pinfraspinatus tendon remained intact with normal structure. Conclusions Based on the biomechanical and histological findings, this canine NWB model may be an appropriate and useful model for studies of rotator cuff repair. PMID:26107616

  12. A Canine Non-Weight-Bearing Model with Radial Neurectomy for Rotator Cuff Repair.

    Science.gov (United States)

    Ji, Xiaoxi; Bao, Nirong; An, Kai-Nan; Amadio, Peter C; Steinmann, Scott P; Zhao, Chunfeng

    2015-01-01

    The major concern of using a large animal model to study rotator cuff repair is the high rate of repair retears. The purpose of this study was to test a non-weight-bearing (NWB) canine model for rotator cuff repair research. First, in the in vitro study, 18 shoulders were randomized to 3 groups. 1) Full-width transections repaired with modified Mason-Allen sutures using 3-0 polyglactin suture, 2) Group 1 repaired using number 2 (#2) polyester braid and long-chain polyethylene suture, and 3) Partial-width transections leaving the superior 2 mm infraspinatus tendon intact without repair. In the in vivo study of 6 dogs, the infraspinatus tendon was partially transected as the same as the in vitro group 3. A radial neurectomy was performed to prevent weight bearing. The operated limb was slung in a custom-made jacket for 6 weeks. In the in vitro study, mean ultimate tensile load and stiffness in Group 2 were significantly higher than Group 1 and 3 (pinfraspinatus tendon remained intact with normal structure. Based on the biomechanical and histological findings, this canine NWB model may be an appropriate and useful model for studies of rotator cuff repair.

  13. Models for Gas Hydrate-Bearing Sediments Inferred from Hydraulic Permeability and Elastic Velocities

    Science.gov (United States)

    Lee, Myung W.

    2008-01-01

    Elastic velocities and hydraulic permeability of gas hydrate-bearing sediments strongly depend on how gas hydrate accumulates in pore spaces and various gas hydrate accumulation models are proposed to predict physical property changes due to gas hydrate concentrations. Elastic velocities and permeability predicted from a cementation model differ noticeably from those from a pore-filling model. A nuclear magnetic resonance (NMR) log provides in-situ water-filled porosity and hydraulic permeability of gas hydrate-bearing sediments. To test the two competing models, the NMR log along with conventional logs such as velocity and resistivity logs acquired at the Mallik 5L-38 well, Mackenzie Delta, Canada, were analyzed. When the clay content is less than about 12 percent, the NMR porosity is 'accurate' and the gas hydrate concentrations from the NMR log are comparable to those estimated from an electrical resistivity log. The variation of elastic velocities and relative permeability with respect to the gas hydrate concentration indicates that the dominant effect of gas hydrate in the pore space is the pore-filling characteristic.

  14. Haplotypes in tribal Indians bearing the sickle gene: evidence for the unicentric origin of the beta S mutation and the unicentric origin of the tribal populations of India.

    Science.gov (United States)

    Labie, D; Srinivas, R; Dunda, O; Dode, C; Lapoumeroulie, C; Devi, V; Devi, S; Ramasami, K; Elion, J; Ducrocq, R

    1989-08-01

    To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the beta gene cluster in beta S-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the beta S gene are linked in 91% of the cases to the "Asian" (Arab-Indian) haplotype (although 25% of the haplotypes had the epsilon polymorphic site negative, making the 5' portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high G gamma expression (67.2 +/- 5.9%) and a high percentage of Hb F (15.5 +/- 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to beta S in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the beta S gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (-alpha) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The beta S gene linkage to a high Hb F-expressing haplotype and the high incidence of alpha-thalassemia predict a mild phenotypical expression of sickle cell anemia in India.

  15. Dynamic behavior of dissymmetric rotor bearings modelled with a periodic coefficient large system

    Science.gov (United States)

    Guilhen, P. M.; Berthier, P.; Ferraris, G.; Lalanne, M.

    1987-01-01

    The instability and unbalance response of dissymmetric rotor-bearing systems containing periodic coefficients when modeling produces matrices with a large number of degrees of freedom are discussed. It is important to solve the equations and then predict the dynamic behavior of the system. This can be done knowing the instability areas and the unbalance response in the stable areas. One deals here with a large number of equations and a reduction of the number of degrees of freedom of the system is achieved through a pseudo modal method. This method is shown to give satisfactory results.

  16. Kurtosis based weighted sparse model with convex optimization technique for bearing fault diagnosis

    Science.gov (United States)

    Zhang, Han; Chen, Xuefeng; Du, Zhaohui; Yan, Ruqiang

    2016-12-01

    The bearing failure, generating harmful vibrations, is one of the most frequent reasons for machine breakdowns. Thus, performing bearing fault diagnosis is an essential procedure to improve the reliability of the mechanical system and reduce its operating expenses. Most of the previous studies focused on rolling bearing fault diagnosis could be categorized into two main families, kurtosis-based filter method and wavelet-based shrinkage method. Although tremendous progresses have been made, their effectiveness suffers from three potential drawbacks: firstly, fault information is often decomposed into proximal frequency bands and results in impulsive feature frequency band splitting (IFFBS) phenomenon, which significantly degrades the performance of capturing the optimal information band; secondly, noise energy spreads throughout all frequency bins and contaminates fault information in the information band, especially under the heavy noisy circumstance; thirdly, wavelet coefficients are shrunk equally to satisfy the sparsity constraints and most of the feature information energy are thus eliminated unreasonably. Therefore, exploiting two pieces of prior information (i.e., one is that the coefficient sequences of fault information in the wavelet basis is sparse, and the other is that the kurtosis of the envelope spectrum could evaluate accurately the information capacity of rolling bearing faults), a novel weighted sparse model and its corresponding framework for bearing fault diagnosis is proposed in this paper, coined KurWSD. KurWSD formulates the prior information into weighted sparse regularization terms and then obtains a nonsmooth convex optimization problem. The alternating direction method of multipliers (ADMM) is sequentially employed to solve this problem and the fault information is extracted through the estimated wavelet coefficients. Compared with state-of-the-art methods, KurWSD overcomes the three drawbacks and utilizes the advantages of both family

  17. Active magnetic bearing control loop modeling for a finite element rotordynamics code

    Science.gov (United States)

    Genta, Giancarlo; Delprete, Cristiana; Carabelli, Stefano

    1994-05-01

    A mathematical model of an active electromagnetic bearing which includes the actuator, the sensor and the control system is developed and implemented in a specialized finite element code for rotordynamic analysis. The element formulation and its incorporation in the model of the machine are described in detail. A solution procedure, based on a modal approach in which the number of retained modes is controlled by the user, is then shown together with other procedures for computing the steady-state response to both static and unbalance forces. An example of application shows the numerical results obtained on a model of an electric motor suspended on a five active-axis magnetic suspension. The comparison of some of these results with the experimental characteristics of the actual system shows the ability of the present model to predict its performance.

  18. Modeling of Self-Vibratory Drilling Head-Spindle System for Predictions of Bearings Lifespan

    Directory of Open Access Journals (Sweden)

    F. Forestier

    2011-01-01

    Full Text Available The machining of deep holes is limited due to inadequate chip evacuation, which induces tool breakage. To limit this drawback, retreat cycles and lubrication are used. An alternative response to the evacuation problem is based on high-speed vibratory drilling. A specific tool holder induces axial self-maintained vibration of the drill, which enables the chips to be split. The chips are thus of a small size and can be evacuated. To anticipate the potential risk of decreased spindle lifespan associated with these vibrations, a model of the behavior of the system (spindle—self-vibrating drilling head—tool is elaborated. In order to assess the dynamic behavior of the system, this study develops a rotor-based finite element model, integrated with the modelling of component interfaces. The current results indicate that the simulations are consistent with the experimental measurements. The influence of spindle speed and feed rate on bearing lifespan is highlighted.

  19. Microwave emissivity of freshwater ice, Part II: Modelling the Great Bear and Great Slave Lakes

    CERN Document Server

    Mills, Peter

    2012-01-01

    Lake ice within three Advanced Microwave Scanning Radiometer on EOS (AMSR-E) pixels over the Great Bear and Great Slave Lakes have been simulated with the Canadian Lake Ice Model (CLIMo). The resulting thicknesses and temperatures were fed to a radiative transfer-based ice emissivity model and compared to the satellite measurements at three frequencies---6.925 GHz, 10.65 GHz and 18.7 GHz. Excluding the melt season, the model was found to have strong predictive power, returning a correlation of 0.926 and a residual of 0.78 Kelvin at 18 GHz, vertical polarization. Discrepencies at melt season are thought to be caused by the presence of dirt in the snow cover which makes the microwave signature more like soil rather than ice. Except at 18 GHz, all results showed significant bias compared to measured values. Further work needs to be done to determine the source of this bias.

  20. Modeling of NOx Destruction Options for INEEL Sodium-Bearing Waste Vitrification

    Energy Technology Data Exchange (ETDEWEB)

    Wood, Richard Arthur

    2001-09-01

    Off-gas NOx concentrations in the range of 1-5 mol% are expected as a result of the proposed vitrification of sodium-bearing waste at the Idaho National Engineering and Environmental Laboratory. An existing kinetic model for staged combustion (originally developed for NOx abatement from the calcination process) was updated for application to vitrification offgas. In addition, two new kinetic models were developed to assess the feasibility of using selective non-catalytic reduction (SNCR) or high-temperature alone for NOx abatement. Each of the models was developed using the Chemkin code. Results indicate that SNCR is a viable option, reducing NOx levels to below 1000 ppmv. In addition, SNCR may be capable of simultaneously reducing CO emissions to below 100 ppmv. Results for using high-temperature alone were not as promising, indicating that a minimum NOx concentration of 3950 ppmv is achievable at 3344°F.

  1. Wright-Fisher model with negative mutation rates

    CERN Document Server

    Pal, Soumik

    2010-01-01

    We study a family of multidimensional diffusions taking values in the unit simplex of vectors with non-negative coordinates that add up to one. The family of processes satisfy stochastic differential equations which are similar to the ones for the classical Wright-Fisher model, except that the "mutation rates" are now nonpositive. This model, suggested by Aldous, appears in the study of a conjectured diffusion limit for a Markov chain on Cladograms. The striking feature of these models is that the boundary is not reflecting, and we kill the process once it hits the boundary. We derive the explicit exit distribution from the simplex, and probabilistic bounds on the exit time. We also prove that these processes can be viewed as a "stochastic time-reversal" of a Wright-Fisher process of increasing dimensions and conditioned at a random time. A key idea in our proofs is a skew-product construction using certain one-dimensional diffusions called Bessel-square processes of negative dimensions which have been recent...

  2. Systemic and local injections of lupeol inhibit tumor growth in a melanoma-bearing mouse model.

    Science.gov (United States)

    Nitta, Makiko; Azuma, Kazuo; Hata, Keishi; Takahashi, Saori; Ogiwara, Kikumi; Tsuka, Takeshi; Imagawa, Tomohiro; Yokoe, Inoru; Osaki, Tomohiro; Minami, Saburo; Okamoto, Yoshiharu

    2013-07-01

    Melanoma is the most aggressive type of skin cancer and it is procured from activated or genetically altered epidermal melanocytes. In the present study, the tumor-suppressive effects of systemic and local injections of lupeol, a triterpene extracted from Indian lettuce (Lactuca indica), in a melanoma-bearing mouse model were evaluated. Mice were injected once with lupeol or olive oil (solvent control) subcutaneously into the skin of the back or into the tumor tissue. Seven days after the injection, the tumor growth rates were calculated and the tumor tissues were collected. Immunohistochemical staining for Ki-67 and proliferating cell nuclear antigen (PCNA) were performed. The tumor growth rates in the lupeol-injected group were significantly decreased compared to those observed in the non-treated (NT) and solvent control groups. Lupeol also significantly decreased the areas positively stained for Ki-67 and PCNA in the tumor tissues compared to those in the NT and solvent control groups. The results of the present study demonstrated that systemic and local injections of lupeol suppress tumor growth and induce cell cycle arrest in a melanoma-bearing mouse model. These data suggest that lupeol may be effective as a novel therapeutic option for melanoma patients.

  3. Composite model to reproduce the mechanical behaviour of methane hydrate bearing soils

    Science.gov (United States)

    De la Fuente, Maria

    2016-04-01

    Methane hydrate bearing sediments (MHBS) are naturally-occurring materials containing different components in the pores that may suffer phase changes under relative small temperature and pressure variations for conditions typically prevailing a few hundreds of meters below sea level. Their modelling needs to account for heat and mass balance equations of the different components, and several strategies already exist to combine them (e.g., Rutqvist & Moridis, 2009; Sánchez et al. 2014). These equations have to be completed by restrictions and constitutive laws reproducing the phenomenology of heat and fluid flows, phase change conditions and mechanical response. While the formulation of the non-mechanical laws generally includes explicitly the mass fraction of methane in each phase, which allows for a natural update of parameters during phase changes, mechanical laws are, in most cases, stated for the whole solid skeleton (Uchida et al., 2012; Soga et al. 2006). In this paper, a mechanical model is proposed to cope with the response of MHBS. It is based on a composite approach that allows defining the thermo-hydro-mechanical response of mineral skeleton and solid hydrates independently. The global stress-strain-temperature response of the solid phase (grains + hydrate) is then obtained by combining both responses according to energy principle following the work by Pinyol et al. (2007). In this way, dissociation of MH can be assessed on the basis of the stress state and temperature prevailing locally within the hydrate component. Besides, its structuring effect is naturally accounted for by the model according to patterns of MH inclusions within soil pores. This paper describes the fundamental hypothesis behind the model and its formulation. Its performance is assessed by comparison with laboratory data presented in the literature. An analysis of MHBS response to several stress-temperature paths representing potential field cases is finally presented. References

  4. MATHEMATICAL MODEL OF OSCILLATIONS OF BEARING BODY FRAME OF EMERGENCY AND REPAIR RAILCARS

    Directory of Open Access Journals (Sweden)

    Galina KHROMOVA

    2017-04-01

    Full Text Available Nowadays, the importance of maintenance and effective use of available railcars in the railway transport is growing, and researchers and technical experts are working to address this issue with the use of various techniques. The authors address the use of analytical technique, which includes mathematical solutions for flexural and longitudinal fluctuations of the bearing framework of a railcar body frame. The calculation is performed in connection with the modernization of the body frame of emergency and repair rail service car, taking into account the variability in section, mass, longitudinal stiffness, and bending stiffness. It allows for extension of the useful life of their operation, with special focus on vehicles owned by Joint-Stock Company "Uzbekistan Railways". The simulation of equivalent bearing body frame of emergency and repair rail service car was carried out using an elastic rod with variable parameters including stiffness and mass. The difference between the proposed model and the existing ones is due to the variability in cross section, mass, and the longitudinal and bending stiffness along the length of equivalent beam, which corresponds to the actual conditions of operation and data of the experimental studies conducted by the authors on the bearing frames of electric locomotives’ variable sections. The frequency analysis that was carried out with the use of the Mathcad 14 programming showed that the frequencies of natural oscillations change on n harmonicas = 1, 2, 3 … 5. As regards longitudinal oscillations of system, in case of introduction of the damping subfloor, the frequency of natural oscillations of the upgraded rail car frame λ1mn increases on comparing with standard λ1n (for example, in case of n = 5 the frequency is 0.587 and 0.602 Hz/m, respectively.

  5. Modeling evolutionary dynamics of epigenetic mutations in hierarchically organized tumors.

    Directory of Open Access Journals (Sweden)

    Andrea Sottoriva

    2011-05-01

    Full Text Available The cancer stem cell (CSC concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model.

  6. A simple model of asymmetric quasi-species: network sustained by emergent high mutation rates

    Science.gov (United States)

    Iwasaki, Yuishi; Yonezawa, Fumiko

    1999-02-01

    A simple model of adaptive mutation rates is studied to understand asymmetric adaptive systems. In the model, two sources of asymmetries are introduced. One is a spin-glass-type energy function and gives an asymmetry of the fitness landscape. The other is the variable mutation rate associated with each gene and gives an asymmetry of the transition probabilities. A control parameter is a selection pressure rather than a mutation rate. We find that the model shows three results: (i) High mutation rates emerge in the iterative Darwinian selection process. (ii) Detailed balance is satisfied in the diverse system sustained by the emergent high mutation rates. (iii) A transition from the positive Darwinian selection (ordered state) to the nearly neutral selection (disordered state) takes place as the selection pressure decreases. Based on these results, we study the asymmetric network sustained by emergent high mutation rates.

  7. Submicro-battery effect and selective bio-oxidation model of gold-bearing arsenopyrite by Thiobacillus ferrooxidans

    Institute of Scientific and Technical Information of China (English)

    杨洪英; 杨立; 赵玉山; 陈刚; 吕久吉; 范有静

    2002-01-01

    Through the study by electronic probe it was found that many new cracks and holes appear on the surface of gold-bearing arsenopyrite crystal oxidized by Thiobacillus ferrooxidans, which are along with some directions. Then the selective bio-oxidation model of gold-bearing arsenopyrite was set up. The selective bio-oxidation resulting from the submicro-battery effect of gold/ arsenopyrite mineral pairs naturally forms in the gold-bearing arsenopyrite crystal. Thiobacillus ferrooxidans has priority to oxidize the place of gold-rich and oxidizes selectedly along with the crystal border, crystal face and crack. The bacteria oxidation process of gold-bearing arsenopyrite is divided into three stages: the first stage is the surface oxidation, the second stage is restraining oxidation and the third stage is the filament oxidation, bacteria oxidize along with cracks of arsenopyrite.

  8. Process Options Description for Vitrification Flowsheet Model of INEEL Sodium Bearing Waste

    Energy Technology Data Exchange (ETDEWEB)

    Nichols, Todd Travis; Taylor, Dean Dalton; Lauerhass, Lance; Barnes, Charles Marshall

    2001-02-01

    The purpose of this document is to provide the technical information to Savannah River Site (SRS) personnel that is required for the development of a basic steady-state process simulation of the vitrification treatment train of sodium bearing waste (SBW) at Idaho National Engineering and nvironmental Laboratory (INEEL). INEEL considers simulation to have an important role in the integration/optimization of treatment process trains for the High Level Waste (HLW) Program. This project involves a joint Technical Task Plan (TTP ID77WT31, Subtask C) between SRS and INEEL. The work scope of simulation is different at the two sites. This document addresses only the treatment of SBW at INEEL. The simulation model(s) is to be built by SRS for INEEL in FY-2001.

  9. Hot deformation behaviors and flow stress model of GCr15 bearing steel

    Institute of Scientific and Technical Information of China (English)

    LIAO Shu-lun; ZHANG Li-wen; YUE Chong-xiang; PEI Ji-bin; GAO Hui-ju

    2008-01-01

    The hot deformation behaviors of GCr15 bearing steel were investigated by isothermal compression tests, performed on a Gleeble-3800 thermal-mechanical simulator at temperatures between 950℃ and 1 150 ℃ and strain rates between 0.1 and 10s-1.The peak stress and peak strain as functions of processing parameters were obtained. The dependence of peak stress on strain rate and temperature obeys a hyperbolic sine equation with a Zener-Hollomon parameter. By regression analysis, in the temperature range of 950-1150℃ and strain rate range of 0.1-10 s-1, the mean activation energy and the stress exponent were determined to be 351kJ/mol and 4.728, respectively. Meanwhile, models of flow stress and dynamic recrystallization (DRX) grain size were also established. The model predictions show good agreement with experimental results.

  10. Regression Models for the Bearing Capacity of Crude Oil Contaminated Soils in Ekakpamre and Kwale, Niger Delta, Nigeria.

    Directory of Open Access Journals (Sweden)

    2016-11-01

    Full Text Available The Niger Delta Region of Nigeria has suffered severe environmental pollution due to ever increasing oil exploration and exploitation activities in the region making the communities highly vulnerable to the effects of oil spill and other associated environmental degradation. Using eight soil samples collected from two oil-rich communities in two Local Government Areas of Delta State, the effects of oil spill on the load bearing properties of the soils were examined and used to develop regression models for the bearing capacity (for strip foundation footing of oil contaminated soils. The triaxial test showed the mean values of the bearing capacity of the uncontaminated soil samples (which served as control as 170.718 KN/m2 and 601.49KN/m2 . The samples were then thoroughly mixed with crude oil(to simulate the site conditions at 5%, 10%, 15%, and 20%. The result of the triaxial test showed that oil reduces the bearing capacity of the soil and as the percentage increased to 20% oil, the bearing capacity dropped to 56.60KN/m2 and 61.50 KN/m2 respectively for the two study locations. Regression models were then developed to estimate the bearing capacity of the oil contaminated soils at any level of contamination in the study locations.

  11. Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.

    Directory of Open Access Journals (Sweden)

    Alexander G Bassuk

    Full Text Available CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

  12. Modeling multi-scale resource selection for bear rub trees in northwestern Montana

    Science.gov (United States)

    Morgan Henderson, Matthew J.; Hebblewhite, Mark; Mitchell, Michael S.; Stetz, Jeffrey B.; Kendall, Katherine C.; Carlson, Ross T.

    2015-01-01

    Both black (Ursus americanus) and grizzly bears (U. arctos) are known to rub on trees and other objects, producing a network of repeatedly used and identifiable rub sites. In 2012, we used a resource selection function to evaluate hypothesized relationships between locations of 887 bear rubs in northwestern Montana, USA, and elevation, slope angle, density of open roads and distance from areas of heightened plant-productivity likely containing forage for bears. Slope and density of open roads were negatively correlated with rub presence. No other covariates were supported as explanatory variables. We also hypothesized that bear rubs would be more strongly associated with closed roads and developed trails than with game trails. The frequencies of bear rubs on 30 paired segments of developed tracks and game trails were not different. Our results suggest bear rubs may be associated with bear travel routes, and support their use as “random” sampling devices for non-invasive spatial capture–recapture population monitoring.

  13. Development of a multichemical food web model: application to PBDEs in Lake Ellasjoen, Bear Island, Norway.

    Science.gov (United States)

    Gandhi, Nilima; Bhavsar, Satyendra P; Gewurtz, Sarah B; Diamond, Miriam L; Evenset, Anita; Christensen, Guttorm N; Gregor, Dennis

    2006-08-01

    A multichemical food web model has been developed to estimate the biomagnification of interconverting chemicals in aquatic food webs. We extended a fugacity-based food web model for single chemicals to account for reversible and irreversible biotransformation among a parent chemical and transformation products, by simultaneously solving mass balance equations of the chemicals using a matrix solution. The model can be applied to any number of chemicals and organisms or taxonomic groups in a food web. The model was illustratively applied to four PBDE congeners, BDE-47, -99, -100, and -153, in the food web of Lake Ellasjøen, Bear Island, Norway. In Ellasjøen arctic char (Salvelinus alpinus), the multichemical model estimated PBDE biotransformation from higher to lower brominated congeners and improved the correspondence between estimated and measured concentrations in comparison to estimates from the single-chemical food web model. The underestimation of BDE-47, even after considering bioformation due to biotransformation of the otherthree congeners, suggests its formation from additional biotransformation pathways not considered in this application. The model estimates approximate values for congener-specific biotransformation half-lives of 5.7,0.8,1.14, and 0.45 years for BDE-47, -99, -100, and -153, respectively, in large arctic char (S. alpinus) of Lake Ellasjøen.

  14. Precambrian uranium-bearing quartz-pebble conglomerates: exploration model and United States resource potential

    Energy Technology Data Exchange (ETDEWEB)

    Houston, R.S.; Karlstrom, K.E.

    1979-11-01

    Uranium has been discovered in fluvial quartz-pebble conglomerates in most of the Precambrian shield areas of the world, including the Canadian, African, South American, Indian, Baltic, and Australian shields. Occurrences in these and other areas are shown. Two of these occurrences, the Huronian supergroup of Canada and the Witwatersrand deposit of South Africa contain 20 to 30 percent of the planet's known uranium reserves. Thus it is critical that we understand the origin of these deposits and develop exploration models that can aid in finding new deposits. Inasmuch as these uranium-bearing conglomerates are confined almost entirely to rocks of Precambrian age, Part I of this review begins with a discussion of Precambrian geology as it applies to the conglomerates. This is followed by a discussion of genetic concepts, a discussion of unresolved problems, and finally a suggested exploration model. Part II summarizes known and potential occurrences of Precambrian fossil placers in the world and evaluates them in terms of the suggested exploration model. Part III discusses the potential for important Precambrian fossil-placer uranium deposits in the United States and includes suggestions that may be helpful in establishing an exploration program in this country. Part III also brings together new (1975-1978) data on uranium occurrences in the Precambrian of the Wyoming Province. Part IV is a complete bibliography of Precambrian fossil placers, divided according to geographical areas. In total, this paper is designed to be a comprehensive review of Precambrian uranium-bearing fossil placers which will be of use to uranium explorationists and to students of Precambrian geology.

  15. A fault diagnosis methodology for rolling element bearings based on advanced signal pretreatment and autoregressive modelling

    Science.gov (United States)

    Al-Bugharbee, Hussein; Trendafilova, Irina

    2016-05-01

    This study proposes a methodology for rolling element bearings fault diagnosis which gives a complete and highly accurate identification of the faults present. It has two main stages: signals pretreatment, which is based on several signal analysis procedures, and diagnosis, which uses a pattern-recognition process. The first stage is principally based on linear time invariant autoregressive modelling. One of the main contributions of this investigation is the development of a pretreatment signal analysis procedure which subjects the signal to noise cleaning by singular spectrum analysis and then stationarisation by differencing. So the signal is transformed to bring it close to a stationary one, rather than complicating the model to bring it closer to the signal. This type of pretreatment allows the use of a linear time invariant autoregressive model and improves its performance when the original signals are non-stationary. This contribution is at the heart of the proposed method, and the high accuracy of the diagnosis is a result of this procedure. The methodology emphasises the importance of preliminary noise cleaning and stationarisation. And it demonstrates that the information needed for fault identification is contained in the stationary part of the measured signal. The methodology is further validated using three different experimental setups, demonstrating very high accuracy for all of the applications. It is able to correctly classify nearly 100 percent of the faults with regard to their type and size. This high accuracy is the other important contribution of this methodology. Thus, this research suggests a highly accurate methodology for rolling element bearing fault diagnosis which is based on relatively simple procedures. This is also an advantage, as the simplicity of the individual processes ensures easy application and the possibility for automation of the entire process.

  16. TOPICAL REVIEW: Superconducting bearings

    Science.gov (United States)

    Hull, John R.

    2000-02-01

    The physics and technology of superconducting bearings is reviewed. Particular attention is given to the use of high-temperature superconductors (HTSs) in rotating bearings. The basic phenomenology of levitational forces is presented, followed by a brief discussion of the theoretical models that can be used for conceptual understanding and calculations. The merits of various HTS bearing designs are presented, and the behaviour of HTS bearings in typical situations is discussed. The article concludes with a brief survey of various proposed applications for HTS bearings.

  17. Wayside Bearing Fault Diagnosis Based on a Data-Driven Doppler Effect Eliminator and Transient Model Analysis

    Directory of Open Access Journals (Sweden)

    Fang Liu

    2014-05-01

    Full Text Available A fault diagnosis strategy based on the wayside acoustic monitoring technique is investigated for locomotive bearing fault diagnosis. Inspired by the transient modeling analysis method based on correlation filtering analysis, a so-called Parametric-Mother-Doppler-Wavelet (PMDW is constructed with six parameters, including a center characteristic frequency and five kinematic model parameters. A Doppler effect eliminator containing a PMDW generator, a correlation filtering analysis module, and a signal resampler is invented to eliminate the Doppler effect embedded in the acoustic signal of the recorded bearing. Through the Doppler effect eliminator, the five kinematic model parameters can be identified based on the signal itself. Then, the signal resampler is applied to eliminate the Doppler effect using the identified parameters. With the ability to detect early bearing faults, the transient model analysis method is employed to detect localized bearing faults after the embedded Doppler effect is eliminated. The effectiveness of the proposed fault diagnosis strategy is verified via simulation studies and applications to diagnose locomotive roller bearing defects.

  18. Wayside bearing fault diagnosis based on a data-driven Doppler effect eliminator and transient model analysis.

    Science.gov (United States)

    Liu, Fang; Shen, Changqing; He, Qingbo; Zhang, Ao; Liu, Yongbin; Kong, Fanrang

    2014-05-05

    A fault diagnosis strategy based on the wayside acoustic monitoring technique is investigated for locomotive bearing fault diagnosis. Inspired by the transient modeling analysis method based on correlation filtering analysis, a so-called Parametric-Mother-Doppler-Wavelet (PMDW) is constructed with six parameters, including a center characteristic frequency and five kinematic model parameters. A Doppler effect eliminator containing a PMDW generator, a correlation filtering analysis module, and a signal resampler is invented to eliminate the Doppler effect embedded in the acoustic signal of the recorded bearing. Through the Doppler effect eliminator, the five kinematic model parameters can be identified based on the signal itself. Then, the signal resampler is applied to eliminate the Doppler effect using the identified parameters. With the ability to detect early bearing faults, the transient model analysis method is employed to detect localized bearing faults after the embedded Doppler effect is eliminated. The effectiveness of the proposed fault diagnosis strategy is verified via simulation studies and applications to diagnose locomotive roller bearing defects.

  19. Joint inference of microsatellite mutation models, population history and genealogies using transdimensional Markov Chain Monte Carlo.

    Science.gov (United States)

    Wu, Chieh-Hsi; Drummond, Alexei J

    2011-05-01

    We provide a framework for Bayesian coalescent inference from microsatellite data that enables inference of population history parameters averaged over microsatellite mutation models. To achieve this we first implemented a rich family of microsatellite mutation models and related components in the software package BEAST. BEAST is a powerful tool that performs Bayesian MCMC analysis on molecular data to make coalescent and evolutionary inferences. Our implementation permits the application of existing nonparametric methods to microsatellite data. The implemented microsatellite models are based on the replication slippage mechanism and focus on three properties of microsatellite mutation: length dependency of mutation rate, mutational bias toward expansion or contraction, and number of repeat units changed in a single mutation event. We develop a new model that facilitates microsatellite model averaging and Bayesian model selection by transdimensional MCMC. With Bayesian model averaging, the posterior distributions of population history parameters are integrated across a set of microsatellite models and thus account for model uncertainty. Simulated data are used to evaluate our method in terms of accuracy and precision of estimation and also identification of the true mutation model. Finally we apply our method to a red colobus monkey data set as an example.

  20. Identification of High-Impact cis-Regulatory Mutations Using Transcription Factor Specific Random Forest Models.

    Directory of Open Access Journals (Sweden)

    Dmitry Svetlichnyy

    2015-11-01

    Full Text Available Cancer genomes contain vast amounts of somatic mutations, many of which are passenger mutations not involved in oncogenesis. Whereas driver mutations in protein-coding genes can be distinguished from passenger mutations based on their recurrence, non-coding mutations are usually not recurrent at the same position. Therefore, it is still unclear how to identify cis-regulatory driver mutations, particularly when chromatin data from the same patient is not available, thus relying only on sequence and expression information. Here we use machine-learning methods to predict functional regulatory regions using sequence information alone, and compare the predicted activity of the mutated region with the reference sequence. This way we define the Predicted Regulatory Impact of a Mutation in an Enhancer (PRIME. We find that the recently identified driver mutation in the TAL1 enhancer has a high PRIME score, representing a "gain-of-target" for MYB, whereas the highly recurrent TERT promoter mutation has a surprisingly low PRIME score. We trained Random Forest models for 45 cancer-related transcription factors, and used these to score variations in the HeLa genome and somatic mutations across more than five hundred cancer genomes. Each model predicts only a small fraction of non-coding mutations with a potential impact on the function of the encompassing regulatory region. Nevertheless, as these few candidate driver mutations are often linked to gains in chromatin activity and gene expression, they may contribute to the oncogenic program by altering the expression levels of specific oncogenes and tumor suppressor genes.

  1. Model and test in a fungus of the probability that beneficial mutations survive drift

    NARCIS (Netherlands)

    Gifford, D.R.; Visser, de J.A.G.M.; Wahl, L.M.

    2013-01-01

    Determining the probability of fixation of beneficial mutations is critically important for building predictive models of adaptive evolution. Despite considerable theoretical work, models of fixation probability have stood untested for nearly a century. However, recent advances in experimental and t

  2. Model and test in a fungus of the probability that beneficial mutations survive drift

    NARCIS (Netherlands)

    Gifford, D.R.; Visser, de J.A.G.M.; Wahl, L.M.

    2013-01-01

    Determining the probability of fixation of beneficial mutations is critically important for building predictive models of adaptive evolution. Despite considerable theoretical work, models of fixation probability have stood untested for nearly a century. However, recent advances in experimental and

  3. Modeling the Etiology of p53-mutated Cancer Cells.

    Science.gov (United States)

    Perez, Ricardo E; Shen, Hong; Duan, Lei; Kim, Reuben H; Kim, Terresa; Park, No-Hee; Maki, Carl G

    2016-05-06

    p53 gene mutations are among the most common alterations in cancer. In most cases, missense mutations in one TP53 allele are followed by loss-of-heterozygosity (LOH), so tumors express only mutant p53. TP53 mutations and LOH have been linked, in many cases, with poor therapy response and worse outcome. Despite this, remarkably little is known about how TP53 point mutations are acquired, how LOH occurs, or the cells involved. Nutlin-3a occupies the p53-binding site in MDM2 and blocks p53-MDM2 interaction, resulting in the stabilization and activation of p53 and subsequent growth arrest or apoptosis. We leveraged the powerful growth inhibitory activity of Nutlin-3a to select p53-mutated cells and examined how TP53 mutations arise and how the remaining wild-type allele is lost or inactivated. Mismatch repair (MMR)-deficient colorectal cancer cells formed heterozygote (p53 wild-type/mutant) colonies when cultured in low doses of Nutlin-3a, whereas MMR-corrected counterparts did not. Placing these heterozygotes in higher Nutlin-3a doses selected clones in which the remaining wild-type TP53 was silenced. Our data suggest silencing occurred through a novel mechanism that does not involve DNA methylation, histone methylation, or histone deacetylation. These data indicate MMR deficiency in colorectal cancer can give rise to initiating TP53 mutations and that TP53 silencing occurs via a copy-neutral mechanism. Moreover, the data highlight the use of MDM2 antagonists as tools to study mechanisms of TP53 mutation acquisition and wild-type allele loss or silencing in cells with defined genetic backgrounds.

  4. A Doppler Transient Model Based on the Laplace Wavelet and Spectrum Correlation Assessment for Locomotive Bearing Fault Diagnosis

    Directory of Open Access Journals (Sweden)

    Changqing Shen

    2013-11-01

    Full Text Available The condition of locomotive bearings, which are essential components in trains, is crucial to train safety. The Doppler effect significantly distorts acoustic signals during high movement speeds, substantially increasing the difficulty of monitoring locomotive bearings online. In this study, a new Doppler transient model based on the acoustic theory and the Laplace wavelet is presented for the identification of fault-related impact intervals embedded in acoustic signals. An envelope spectrum correlation assessment is conducted between the transient model and the real fault signal in the frequency domain to optimize the model parameters. The proposed method can identify the parameters used for simulated transients (periods in simulated transients from acoustic signals. Thus, localized bearing faults can be detected successfully based on identified parameters, particularly period intervals. The performance of the proposed method is tested on a simulated signal suffering from the Doppler effect. Besides, the proposed method is used to analyze real acoustic signals of locomotive bearings with inner race and outer race faults, respectively. The results confirm that the periods between the transients, which represent locomotive bearing fault characteristics, can be detected successfully.

  5. An analysis of heat conduction in polar bear hairs using one-dimensional fractional model

    Directory of Open Access Journals (Sweden)

    Zhu Wei-Hong

    2016-01-01

    Full Text Available Hairs of a polar bear are of superior properties such as the excellent thermal protection. The polar bears can perennially live in an extremely cold environment and can maintain body temperature at around 37 °C. Why do polar bears can resist such cold environment? Its membrane-pore structure plays an important role. In the previous work, we established a 1-D fractional heat conduction equation to reveal the hidden mechanism for the hairs. In this paper, we further discuss solutions and parameters of the equation established and analyze heat conduction in polar bear hairs.

  6. Modeling and Development of a Magnetic Bearing Controller for a High Speed Flywheel System

    Science.gov (United States)

    Dever, Timothy P.; Brown, Gerald V.; Duffy, Kirsten P.; Jansen, Ralph H.

    2005-01-01

    This paper describes a modeling effort used to develop an improved type of magnetic bearing controller, called a modal controller, for use on high speed flywheel systems. The controller design is based on models of the flywheel system, is designed to directly control the natural dynamics of the spinning rotor, and is generic enough to be readily adapted to future flywheel systems. Modeling and development are described for two key controller subsystems: the modal controller subsystem, which allows direct control over the rotor rigid body modes, and the bending mode compensation subsystem, which tracks, and prevents interference from, the rotor bending modes during flywheel operation. Integration of modeling results into the final controller is described and data taken on the NASA Glenn D1 flywheel module during high speed operation are presented and discussed. The improved modal controller described in this paper has been successfully developed and implemented and has been used for regular hands-free operation of the D1 flywheel module up to its maximum operating speed of 60,000 RPM.

  7. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.

    Science.gov (United States)

    Sportoletti, P; Varasano, E; Rossi, R; Mupo, A; Tiacci, E; Vassiliou, G; Martelli, M P; Falini, B

    2015-02-01

    Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct biological and clinical features that led to its inclusion as a provisional disease entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. Studies of the molecular mechanisms underlying the pathogenesis of NPM1-mutated AML have benefited greatly from several mouse models of this leukemia developed over the past few years. Immunocompromised mice xenografted with NPM1-mutated AML served as the first valuable tool for defining the biology of the disease in vivo. Subsequently, genetically engineered mouse models of the NPM1 mutation, including transgenic and knock-in alleles, allowed the generation of mice with a constant genotype and a reproducible phenotype. These models have been critical for investigating the nature of the molecular effects of these mutations, defining the function of leukemic stem cells in NPM1-mutated AML, identifying chemoresistant preleukemic hemopoietic stem cells and unraveling the key molecular events that cooperate with NPM1 mutations to induce AML in vivo. Moreover, they can serve as a platform for the discovery and validation of new antileukemic drugs in vivo. Advances derived from the analysis of these mouse models promise to greatly accelerate the development of new molecularly targeted therapies for patients with NPM1-mutated AML.

  8. Empirical evaluation reveals best fit of a logistic mutation model for human Y-chromosomal microsatellites.

    Science.gov (United States)

    Jochens, Arne; Caliebe, Amke; Rösler, Uwe; Krawczak, Michael

    2011-12-01

    The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.

  9. Enhanced model of gear transmission dynamics for condition monitoring applications: Effects of torque, friction and bearing clearance

    Science.gov (United States)

    Fernandez-del-Rincon, A.; Garcia, P.; Diez-Ibarbia, A.; de-Juan, A.; Iglesias, M.; Viadero, F.

    2017-02-01

    Gear transmissions remain as one of the most complex mechanical systems from the point of view of noise and vibration behavior. Research on gear modeling leading to the obtaining of models capable of accurately reproduce the dynamic behavior of real gear transmissions has spread out the last decades. Most of these models, although useful for design stages, often include simplifications that impede their application for condition monitoring purposes. Trying to filling this gap, the model presented in this paper allows us to simulate gear transmission dynamics including most of these features usually neglected by the state of the art models. This work presents a model capable of considering simultaneously the internal excitations due to the variable meshing stiffness (including the coupling among successive tooth pairs in contact, the non-linearity linked with the contacts between surfaces and the dissipative effects), and those excitations consequence of the bearing variable compliance (including clearances or pre-loads). The model can also simulate gear dynamics in a realistic torque dependent scenario. The proposed model combines a hybrid formulation for calculation of meshing forces with a non-linear variable compliance approach for bearings. Meshing forces are obtained by means of a double approach which combines numerical and analytical aspects. The methodology used provides a detailed description of the meshing forces, allowing their calculation even when gear center distance is modified due to shaft and bearing flexibilities, which are unavoidable in real transmissions. On the other hand, forces at bearing level were obtained considering a variable number of supporting rolling elements, depending on the applied load and clearances. Both formulations have been developed and applied to the simulation of the vibration of a sample transmission, focusing the attention on the transmitted load, friction meshing forces and bearing preloads.

  10. Active lubrication applied to radial gas journal bearings. Part 1: Modeling

    DEFF Research Database (Denmark)

    Morosi, Stefano; Santos, Ilmar

    2011-01-01

    by regulating radial injection of lubricant through the means of piezoelectric actuators mounted on the back of the bearing sleeves. A feedback law is used to couple the dynamic of a simplified rotor-bearing system with the pneumatic and dynamic characteristics of a piezoelectric actuated valve system. Selected...

  11. Comparison of Models for the Steady-State Analysis of Tilting-Pad Thrust Bearings

    DEFF Research Database (Denmark)

    Heinrichson, Niels; Santos, Ilmar

    2005-01-01

    Prediction of the minimum oil film thickness and the maximum temperature on the surface of the bearing pad is crucial in the design and dimensioning of bearings. Friction loss, oil bath temperature and pad deflection are other parameters of interest. Depending on the desired information a numeric...

  12. Multivariate model of female black bear habitat use for a Geographic Information System

    Science.gov (United States)

    Clark, Joseph D.; Dunn, James E.; Smith, Kimberly G.

    1993-01-01

    Simple univariate statistical techniques may not adequately assess the multidimensional nature of habitats used by wildlife. Thus, we developed a multivariate method to model habitat-use potential using a set of female black bear (Ursus americanus) radio locations and habitat data consisting of forest cover type, elevation, slope, aspect, distance to roads, distance to streams, and forest cover type diversity score in the Ozark Mountains of Arkansas. The model is based on the Mahalanobis distance statistic coupled with Geographic Information System (GIS) technology. That statistic is a measure of dissimilarity and represents a standardized squared distance between a set of sample variates and an ideal based on the mean of variates associated with animal observations. Calculations were made with the GIS to produce a map containing Mahalanobis distance values within each cell on a 60- × 60-m grid. The model identified areas of high habitat use potential that could not otherwise be identified by independent perusal of any single map layer. This technique avoids many pitfalls that commonly affect typical multivariate analyses of habitat use and is a useful tool for habitat manipulation or mitigation to favor terrestrial vertebrates that use habitats on a landscape scale.

  13. Modeling on the gas-generating amount of sediments hydrate-bearing

    Energy Technology Data Exchange (ETDEWEB)

    Gong, J.M.; Cao, Z.M. [Ocean Univ. of China, Qingdao (China); Jian-Ming, G.; Chen, J.W. [Qingdao Inst. of Marine Geology, Qingdao (China); Zhang, M.; Yang, G.F. [Yangtze Univ., Jingzhou (China); Li, J. [PetroChina, HeBei (China). Langfang Branch, Research Inst. of Petroleum Exploration and Development

    2008-07-01

    Gas hydrate is a form of clean fossil energy. It has the characteristics of extensive distribution, large reserve, high-energy capacity and less pollution after combustion. It also has a great energy value, generating interest from governments and scientists in different countries. This paper discussed a study in which methane generating hydrate-bearing sediments were investigated. A total of 58 sediment samples from 4 sites of ODP Leg 204 were modeled by 5 temperature points. ODP Leg 204 lies offshore western United States, in the Hydrate Ridge region (Oregon) of the Pacific. It is one of the most studied areas and clearest about hydrate distribution in the world. The paper described the study area and sample preparation. It also discussed the modeling and geochemical characteristics of the gas-generating samples. A model section revealed bacteria species, substrate deployment, selection of culture flask, and sample culture. The geochemical characteristics of the gas-generating samples were also described. It was concluded that the sediments within 1,200 meters below the seafloor were the main gas source of the biogenic gas hydrate. The organic matter abundance of the sediments at this depth and the migration passage of the fluids in the strata were important for the formation and preservation of the gas hydrate deposits. 21 refs., 1 tab., 6 figs.

  14. Laser-optical and numerical Research of the flow inside the lubricating gap of a journal bearing model

    Science.gov (United States)

    Nobis, M.; Stücke, P.; Schmidt, M.; Riedel, M.

    2013-04-01

    The laser-optical research of the flow inside the lubricating gap of a journal bearing model is one important task in a larger overall project. The long-term objective is the development of an easy-to-work calculation tool which delivers information about the causes and consequences of cavitation processes in hydrodynamically lubricated journal bearings. Hence, it will be possible to find statements for advantageous and disadvantageous geometrical shapes of the bushings. In conclusion such a calculation tool can provide important insights for the construction and design of future journal bearings. Current design programs are based on a two-dimensional approach for the lubricating gap. The first dimension is the breath of the bearing and the second dimension is the circumferential direction of the bearing. The third dimension, the expansion of the gap in radial direction, will be neglected. Instead of an exact resolution of the flow pattern inside the gap, turbulence models are in use. Past studies on numerical and experimental field have shown that inside the lubricating gap clearly organized and predominantly laminar flow structures can be found. Thus, for a detailed analysis of the reasons and effects of cavitation bubbles, a three-dimensional resolution of the lubricating gap is inevitable. In addition to the qualitative evaluation of the flow with visualization experiments it is possible to perform angle-based velocity measurements inside the gap with the help of a triggered Laser-Doppler- Velocimeter (LDV). The results of these measurements are used to validate three-dimensional CFD flow simulations, and to optimize the numerical mesh structure and the boundary conditions. This paper will present the experimental setup of the bearing model, some exemplary results of the visualization experiments and LDV measurements as well as a comparison between experimental and numerical results.

  15. Pathways to Tumorigenesis—Modeling Mutation Acquisition in Stem Cells and Their Progeny1

    Science.gov (United States)

    Ashkenazi, Rina; Gentry, Sara N; Jackson, Trachette L

    2008-01-01

    Most adult tissues consist of stem cells, progenitors, and mature cells, and this hierarchical architecture may play an important role in the multistep process of carcinogenesis. Here, we develop and discuss the important predictions of a simple mathematical model of cancer initiation and early progression within a hierarchically structured tissue. This work presents a model that incorporates both the sequential acquisition of phenotype altering mutations and tissue hierarchy. The model simulates the progressive effect of accumulating mutations that lead to an increase in fitness or the induction of genetic instability. A novel aspect of the model is that symmetric self-renewal, asymmetric division, and differentiation are all incorporated, and this enables the quantitative study of the effect of mutations that deregulate the normal, homeostatic stem cell division pattern. The model is also capable of predicting changes in both tissue composition and in the progression of cells along their lineage at any given time and for various sequences of mutations. Simulations predict that the specific order in which mutations are acquired is crucial for determining the pace of cancer development. Interestingly, we find that the importance of genetic stability differs significantly depending on the physiological expression of mutations related to symmetric self-renewal and differentiation of stem and progenitor cells. In particular, mutations that lead to the alteration of the stem cell division pattern or the acquisition of some degree of immortality in committed progenitors lead to an early onset of cancer and diminish the impact of genetic instability. PMID:18953426

  16. Pathways to Tumorigenesis—Modeling Mutation Acquisition in Stem Cells and Their Progeny

    Directory of Open Access Journals (Sweden)

    Rina Ashkenazi

    2008-11-01

    Full Text Available Most adult tissues consist of stem cells, progenitors, and mature cells, and this hierarchical architecture may play an important role in the multistep process of carcinogenesis. Here, we develop and discuss the important predictions of a simple mathematical model of cancer initiation and early progression within a hierarchically structured tissue. This work presents a model that incorporates both the sequential acquisition of phenotype altering mutations and tissue hierarchy. The model simulates the progressive effect of accumulating mutations that lead to an increase in fitness or the induction of genetic instability. A novel aspect of the model is that symmetric self-renewal, asymmetric division, and differentiation are all incorporated, and this enables the quantitative study of the effect of mutations that deregulate the normal, homeostatic stem cell division pattern. The model is also capable of predicting changes in both tissue composition and in the progression of cells along their lineage at any given time and for various sequences of mutations. Simulations predict that the specific order in which mutations are acquired is crucial for determining the pace of cancer development. Interestingly, we find that the importance of genetic stability differs significantly depending on the physiological expression of mutations related to symmetric self-renewal and differentiation of stem and progenitor cells. In particular, mutations that lead to the alteration of the stem cell division pattern or the acquisition of some degree of immortality in committed progenitors lead to an early onset of cancer and diminish the impact of genetic instability.

  17. A non-linear mathematical model for dynamic analysis of spur gears including shaft and bearing dynamics

    Science.gov (United States)

    Ozguven, H. Nevzat

    1991-01-01

    A six-degree-of-freedom nonlinear semi-definite model with time varying mesh stiffness has been developed for the dynamic analysis of spur gears. The model includes a spur gear pair, two shafts, two inertias representing load and prime mover, and bearings. As the shaft and bearing dynamics have also been considered in the model, the effect of lateral-torsional vibration coupling on the dynamics of gears can be studied. In the nonlinear model developed several factors such as time varying mesh stiffness and damping, separation of teeth, backlash, single- and double-sided impacts, various gear errors and profile modifications have been considered. The dynamic response to internal excitation has been calculated by using the 'static transmission error method' developed. The software prepared (DYTEM) employs the digital simulation technique for the solution, and is capable of calculating dynamic tooth and mesh forces, dynamic factors for pinion and gear, dynamic transmission error, dynamic bearing forces and torsions of shafts. Numerical examples are given in order to demonstrate the effect of shaft and bearing dynamics on gear dynamics.

  18. A non-linear mathematical model for dynamic analysis of spur gears including shaft and bearing dynamics

    Science.gov (United States)

    Özgüven, H. N.

    1991-03-01

    A six-degree-of-freedom non-linear semi-definite model with time varying mesh stiffness has been developed for the dynamic analysis of spur gears. The model includes a spur gear pair, two shafts, two inertias representing load and prime mover, and bearings. As the shaft and bearing dynamics have also been considered in the model, the effect of lateral-torsional vibration coupling on the dynamics of gears can be studied. In the non-linear model developed several factors such as time varying mesh stiffness and damping, separation of teeth, backlash, single- and double-sided impacts, various gear errors and profile modifications have been considered. The dynamic response to internal excitation has been calculated by using the "static transmission error method" developed. The software prepared (DYTEM) employs the digital simulation technique for the solution, and is capable of calculating dynamic tooth and mesh forces, dynamic factors for pinion and gear, dynamic transmission error, dynamic bearing forces and torsions of shafts. Numerical examples are given in order to demonstrate the effect of shaft and bearing dynamics on gear dynamics.

  19. NASTRAN Structural Model for the Large 64-meter Antenna Pedestal. Part 3: Applications to Hydrostatic Bearing Oil Film

    Science.gov (United States)

    Chian, C. T.; Schonfeld, D.

    1984-01-01

    Investigations are conducted on the 64-meter antenna hydrostatic bearing oil film thickness under a variety of loads and elastic moduli. These parametric studies use a NASTRAN pedestal structural model to determine the deflections under the hydrostatic bearing pad. The deflections form the input for a computer program to determine the hydrostatic bearing oil film thickness. For the future 64-meter to 70-meter antenna extension and for the 2.2-meter (86-in.) haunch concrete replacement cases, safe oil film thickness (greater than 0.13 mm (0.005 in.) at the corners of the pad) are predicted. The effects of varying moduli of elasticity for different sections of the pedestal and the film height under distressed runner conditions are also studied.

  20. Finding all BRCA pathogenic mutation carriers : best practice models

    NARCIS (Netherlands)

    Hoogerbrugge, Nicoline; Jongmans, Marjolijn CJ

    2016-01-01

    Identifying germline BRCA pathogenic mutations in patients with ovarian or breast cancer is a crucial component in the medical management of affected patients. Furthermore, the relatives of affected patients can be offered genetic testing. Relatives who test positive for a germline BRCA pathogenic m

  1. Snow and ice on Bear Lake (Alaska – sensitivity experiments with two lake ice models

    Directory of Open Access Journals (Sweden)

    Tido Semmler

    2012-03-01

    Full Text Available Snow and ice thermodynamics of Bear Lake (Alaska are investigated with a simple freshwater lake model (FLake and a more complex snow and ice thermodynamic model (HIGHTSI. A number of sensitivity experiments have been carried out to investigate the influence of snow and ice parameters and of different complexity on the results. Simulation results are compared with observations from the Alaska Lake Ice and Snow Observatory Network. Adaptations of snow thermal and optical properties in FLake can largely improve accuracy of the results. Snow-to-ice transformation is important for HIGHTSI to calculate the total ice mass balance. The seasonal maximum ice depth is simulated in FLake with a bias of −0.04 m and in HIGHTSI with no bias. Correlation coefficients between ice depth measurements and simulations are high (0.74 for FLake and 0.9 for HIGHTSI. The snow depth simulation can be improved by taking into account a variable snow density. Correlation coefficients for surface temperature are 0.72 for FLake and 0.81 for HIGHTSI. Overall, HIGHTSI gives slightly more accurate surface temperature than FLake probably due to the consideration of multiple snow and ice layers and the expensive iteration calculation procedure.

  2. Process Options Description for Vitrification Flowsheet Model of INEEL Sodium Bearing Waste

    Energy Technology Data Exchange (ETDEWEB)

    Nichols, T.T.; Taylor, D.D.; Lauerhass, L.; Barnes, C.M.

    2002-02-21

    The technical information required for the development of a basic steady-state process simulation of the vitrification treatment train of sodium bearing waste (SBW) at Idaho National Engineering and Environmental Laboratory (INEEL) is presented. The objective of the modeling effort is to provide the predictive capability required to optimize an entire treatment train and assess system-wide impacts of local changes at individual unit operations, with the aim of reducing the schedule and cost of future process/facility design efforts. All the information required a priori for engineers to construct and link unit operation modules in a commercial software simulator to represent the alternative treatment trains is presented. The information is of a mid- to high-level nature and consists of the following: (1) a description of twenty-four specific unit operations--their operating conditions and constraints, primary species and key outputs, and the initial modeling approaches that will be used in the first year of the simulation's development; (2) three potential configurations of the unit operations (trains) and their interdependencies via stream connections; and (3) representative stream compositional makeups.

  3. A numerical test method of California bearing ratio on graded crushed rocks using particle flow modeling

    Directory of Open Access Journals (Sweden)

    Yingjun Jiang

    2015-04-01

    Full Text Available In order to better understand the mechanical properties of graded crushed rocks (GCRs and to optimize the relevant design, a numerical test method based on the particle flow modeling technique PFC2D is developed for the California bearing ratio (CBR test on GCRs. The effects of different testing conditions and micro-mechanical parameters used in the model on the CBR numerical results have been systematically studied. The reliability of the numerical technique is verified. The numerical results suggest that the influences of the loading rate and Poisson's ratio on the CBR numerical test results are not significant. As such, a loading rate of 1.0–3.0 mm/min, a piston diameter of 5 cm, a specimen height of 15 cm and a specimen diameter of 15 cm are adopted for the CBR numerical test. The numerical results reveal that the CBR values increase with the friction coefficient at the contact and shear modulus of the rocks, while the influence of Poisson's ratio on the CBR values is insignificant. The close agreement between the CBR numerical results and experimental results suggests that the numerical simulation of the CBR values is promising to help assess the mechanical properties of GCRs and to optimize the grading design. Besides, the numerical study can provide useful insights on the mesoscopic mechanism.

  4. Cyanopolyynes and sulphur bearing species in hot cores: Chemical and line excitation models

    CERN Document Server

    Chapman, J F; Millar, T J; Burton, M G; Walsh, A J

    2008-01-01

    We present results from a time dependent gas phase chemical model of a hot core based on the physical conditions of G305.2+0.2. While the cyanopolyyne HC_3N has been observed in hot cores, the longer chained species, HC_5N, HC_7N, and HC_9N have not been considered typical hot core species. We present results which show that these species can be formed under hot core conditions. We discuss the important chemical reactions in this process and, in particular, show that their abundances are linked to the parent species acetylene which is evaporated from icy grain mantles. The cyanopolyynes show promise as `chemical clocks' which may aid future observations in determining the age of hot core sources. The abundance of the larger cyanopolyynes increase and decrease over relatively short time scales, ~10^2.5 years. We also discuss several sulphur bearing species. We present results from a non-LTE statistical equilibrium excitation model as a series of density, temperature and column density dependent contour plots w...

  5. Process Options Description for Vitrification Flowsheet Model of INEEL Sodium Bearing Waste

    Energy Technology Data Exchange (ETDEWEB)

    Nichols, T.T.; Taylor, D.D.; Lauerhass, L.; Barnes, C.M.

    2002-02-21

    The technical information required for the development of a basic steady-state process simulation of the vitrification treatment train of sodium bearing waste (SBW) at Idaho National Engineering and Environmental Laboratory (INEEL) is presented. The objective of the modeling effort is to provide the predictive capability required to optimize an entire treatment train and assess system-wide impacts of local changes at individual unit operations, with the aim of reducing the schedule and cost of future process/facility design efforts. All the information required a priori for engineers to construct and link unit operation modules in a commercial software simulator to represent the alternative treatment trains is presented. The information is of a mid- to high-level nature and consists of the following: (1) a description of twenty-four specific unit operations--their operating conditions and constraints, primary species and key outputs, and the initial modeling approaches that will be used in the first year of the simulation's development; (2) three potential configurations of the unit operations (trains) and their interdependencies via stream connections; and (3) representative stream compositional makeups.

  6. Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling

    Directory of Open Access Journals (Sweden)

    Lorenzo Rakesh Sewanan

    2016-10-01

    Full Text Available Point mutations to the human gene TPM1 have been implicated in the development of both hypertrophic and dilated cardiomyopathies. Such observations have led to studies investigating the link between single residue changes and the biophysical behavior of the tropomyosin molecule. However, the degree to which these molecular perturbations explain the performance of intact sarcomeres containing mutant tropomyosin remains uncertain. Here, we present a modeling approach that integrates various aspects of tropomyosin’s molecular properties into a cohesive paradigm representing their impact on muscle function. In particular, we considered the effects of tropomyosin mutations on (1 persistence length, (2 equilibrium between thin filament blocked and closed regulatory states, and (3 the crossbridge duty cycle. After demonstrating the ability of the new model to capture Ca-dependent myofilament responses during both dynamic and steady-state activation, we used it to capture the effects of hypertrophic cardiomyopathy (HCM related E180G and D175N mutations on skinned myofiber mechanics. Our analysis indicates that the fiber-level effects of the two mutations can be accurately described by a combination of changes to the three tropomyosin properties represented in the model. Subsequently, we used the model to predict mutation effects on muscle twitch. Both mutations led to increased twitch contractility as a consequence of diminished cooperative inhibition between thin filament regulatory units. Overall, simulations suggest that a common twitch phenotype for HCM-linked tropomyosin mutations includes both increased contractility and elevated diastolic tension.

  7. Reduced-order modeling for rotating rotor-bearing systems with cracked impellers using three-dimensional finite element models

    Science.gov (United States)

    Wang, Shuai; Wang, Yu; Zi, Yanyang; Li, Bing; He, Zhengjia

    2015-10-01

    A novel reduced-order modeling method is presented in this paper for dynamics analysis of rotating impeller-shaft-bearing assembly with cracked impellers. Based on three-dimensional finite element model, the complex component mode synthesis (CMS) method is employed to generate an efficient reduced-order model (ROM) for studying the effects of crack on the global vibration of the rotating assembly. First, a modeling framework for impeller-shaft-bearing systems in rotating frame is presented. Rotational effects, including Coriolis matrix and centrifugal softening, have been taken into account. Then, the governing equation of motion of the damped gyroscopic system is reduced by the complex CMS method. Finally, the obtained ROM is employed to study the effects of crack on assembly's vibration. During the steady-state response analysis, external excitations on the impeller due to rotor-stator interactions have been taken into account, which was however neglected in previous investigations on rotordynamics. Numerical results show that the lower-order eigenvalues and the unbalance response of the assembly are not sensitive to the local crack on impeller. Nevertheless, the flexible coupling between impeller and shaft becomes more complex when the air flow-induced excitations are considered. Under EO1 traveling wave excitations, a crack leads to slight changes in the assembly's response. In contrast, the effect of crack becomes significant when the assembly is excited by EO2 and higher EO excitations. Moreover, the nonlinear crack breathing effects affect the assembly's response obviously. Finally, a potential technique for detecting the crack on impeller during operation is discussed.

  8. Journal bearing

    Science.gov (United States)

    Menke, John R.; Boeker, Gilbert F.

    1976-05-11

    1. An improved journal bearing comprising in combination a non-rotatable cylindrical bearing member having a first bearing surface, a rotatable cylindrical bearing member having a confronting second bearing surface having a plurality of bearing elements, a source of lubricant adjacent said bearing elements for supplying lubricant thereto, each bearing element consisting of a pair of elongated relatively shallowly depressed surfaces lying in a cylindrical surface co-axial with the non-depressed surface and diverging from one another in the direction of rotation and obliquely arranged with respect to the axis of rotation of said rotatable member to cause a flow of lubricant longitudinally along said depressed surfaces from their distal ends toward their proximal ends as said bearing members are rotated relative to one another, each depressed surface subtending a radial angle of less than 360.degree., and means for rotating said rotatable bearing member to cause the lubricant to flow across and along said depressed surfaces, the flow of lubricant being impeded by the non-depressed portions of said second bearing surface to cause an increase in the lubricant pressure.

  9. Fluid-solid coupling model for studying wellbore instability in drilling of gas hydrate bearing sediments

    Institute of Scientific and Technical Information of China (English)

    程远方; 李令东; 崔青

    2013-01-01

    As the oil or gas exploration and development activities in deep and ultra-deep waters become more and more, encountering gas hydrate bearing sediments (HBS) is almost inevitable. The variation in temperature and pressure can destabilize gas hydrate in nearby formation around the borehole, which may reduce the strength of the formation and result in wellbore instability. A non-isothermal, transient, two-phase, and fluid-solid coupling mathematical model is proposed to simulate the complex stability performance of a wellbore drilled in HBS. In the model, the phase transition of hydrate dissociation, the heat exchange between drilling fluid and formation, the change of mechanical and petrophysical properties, the gas-water two-phase seepage, and its interaction with rock deformation are considered. A finite element simulator is developed, and the impact of drilling mud on wellbore instability in HBS is simulated. Results indicate that the re-duction in pressure and the increase in temperature of the drilling fluid can accelerate hydrate decomposition and lead to mechanical properties getting worse tremendously. The cohesion decreases by 25% when the hydrate totally dissociates in HBS. This easily causes the wellbore instability accordingly. In the first two hours after the formation is drilled, the regions of hydrate dissociation and wellbore instability extend quickly. Then, with the soaking time of drilling fluid increasing, the regions enlarge little. Choosing the low temperature drilling fluid and increasing the drilling mud pressure appropriately can benefit the wellbore stability of HBS. The established model turns out to be an efficient tool in numerical studies of the hydrate dissociation behavior and wellbore stability of HBS.

  10. Thirty-eight-year follow-up of two sibling Lipoid Congenital Adrenal Hyperplasia patients due to homozygous Steroidogenic Acute Regulatory (STARD1 protein Mutation. Molecular structure and modeling of the STARD1 L275P mutation.

    Directory of Open Access Journals (Sweden)

    Jean-Guy Lehoux

    2016-11-01

    Full Text Available Objective: Review the impact of StAR (STARD1 mutations on steroidogenesis and fertility in LCAH patients. Examine the endocrine mechanisms underlying the pathology of the disorder and the appropriate therapy for promoting fertility and pregnancies.Design: Published data in the literature and a detailed 38-year follow-up of two sibling LCAH patients. Molecular structure and modeling of the STARD1 L275P mutation.Setting : University hospital.Patients: Patient A (46,XY female phenotype and patient B (46,XX female with LCAH bearing the L275P mutation in STARD1.Interventions : Since early-age diagnosis, both patients underwent corticoid replacement therapy. Patient A received estrogen therapy at pubertal age. Clomiphene therapy was given to Patient B to induce ovulation. Pregnancies were protected with progesterone administration.Main Outcome Measures : Clinical and molecular assessment of adrenal and gonadal functions.Results: Both patients have classic manifestations of corticosteroid deficiency observed in LCAH. Time of onset and severity were different. Patient A developed into a female phenotype due to early and severe damage of Leydig cells. Patient B started a progressive pubertal development, menarche and regular non-ovulatory cycle. She was able to have successful pregnancies.Conclusions: Understanding the molecular structure and function of STARD1 in all steroidogenic tissues is the key for comprehending the heterogeneous clinical manifestations of LCAH, and the development of an appropriate strategy for the induction of ovulation and protecting pregnancies in this disease.

  11. Low resistivity oil(gas)-bearing reservoir conductive model --Dual water clay matrix conductive model in the north area of Tarim Basin, Xinjiang, China

    Institute of Scientific and Technical Information of China (English)

    潘和平; 王家映; 樊政军; 马勇; 柳建华; 李明强

    2001-01-01

    Shaly sands reservoir is one of the most distributive types of the oil(gas)-bearing reservoirs discovered in China, and low resistivity oil(gas)-bearing reservoirs are mostly shaly sands reservoirs. Therefore, shaly sands reservoir conductive model is the key to evaluate low resistivity oil(gas)-bearing reservoirs using logging information. Some defects were found when we studied the clay distribution type conductive model, dual-water conductive model, conductive rock matrix model, etc. Some models could not distinguish the conductive path and nature of microporosity water and clay water and some models did not consider the clay distribution type and the mount of clay volume. So, we utilize the merits,overcome the defects of the above models, and put forward a new shaly sands conductive model-dual water clay matrix conductive model (DWCMCM) in which dual water is the free water and the microporosity water in shaly sands and the clay matrix(wet clay) is the clay grain containing water. DWCMCM is presented here, the advantages of which can tell the nature and conductive path from different water (microporosity water and freewater), in consid-eration of the clay distribution type and the mount of clay volume in shaly sands. So, the results of logging interpretation in the oil(gas)-bearing reservoirs in the north of Tarim Basin area, China with DWCMCM are better than those interpreted by the above models.

  12. Model and test in a fungus of the probability that beneficial mutations survive drift.

    Science.gov (United States)

    Gifford, Danna R; de Visser, J Arjan G M; Wahl, Lindi M

    2013-02-23

    Determining the probability of fixation of beneficial mutations is critically important for building predictive models of adaptive evolution. Despite considerable theoretical work, models of fixation probability have stood untested for nearly a century. However, recent advances in experimental and theoretical techniques permit the development of models with testable predictions. We developed a new model for the probability of surviving genetic drift, a major component of fixation probability, for novel beneficial mutations in the fungus Aspergillus nidulans, based on the life-history characteristics of its colony growth on a solid surface. We tested the model by measuring the probability of surviving drift in 11 adapted strains introduced into wild-type populations of different densities. We found that the probability of surviving drift increased with mutant invasion fitness, and decreased with wild-type density, as expected. The model accurately predicted the survival probability for the majority of mutants, yielding one of the first direct tests of the extinction probability of beneficial mutations.

  13. Approximate sampling formulas for general finite-alleles models of mutation

    CERN Document Server

    Bhaskar, Anand; Song, Yun S

    2011-01-01

    Many applications in genetic analyses utilize sampling distributions, which describe the probability of observing a sample of DNA sequences randomly drawn from a population. In the one-locus case with special models of mutation such as the infinite-alleles model or the finite-alleles parent-independent mutation model, closed-form sampling distributions under the coalescent have been known for many decades. However, no exact formula is currently known for more general models of mutation that are of biological interest. Models with finitely-many alleles are considered in this paper, and approximate closed-form sampling formulas are derived for an arbitrary recurrent mutation model or for a reversible recurrent mutation model, depending on whether the number of distinct observed allele types is at most three or four, respectively. Two different approaches---one based on perturbation expansion and the other on an urn construction related to the coalescent---are developed here. Computation in the former approach i...

  14. Mathematical Model and Analysis of the Water-Lubricated Hydrostatic Journal Bearings considering the Translational and Tilting Motions

    Directory of Open Access Journals (Sweden)

    Hui-Hui Feng

    2014-01-01

    Full Text Available The water-lubricated bearings have been paid attention for their advantages to reduce the power loss and temperature rise and increase load capacity at high speed. To fully study the complete dynamic coefficients of two water-lubricated, hydrostatic journal bearings used to support a rigid rotor, a four-degree-of-freedom model considering the translational and tilting motion is presented. The effects of tilting ratio, rotary speed, and eccentricity ratio on the static and dynamic performances of the bearings are investigated. The bulk turbulent Reynolds equation is adopted. The finite difference method and a linear perturbation method are used to calculate the zeroth- and first-order pressure fields to obtain the static and dynamic coefficients. The results suggest that when the tilting ratio is smaller than 0.4 or the eccentricity ratio is smaller than 0.1, the static and dynamic characteristics are relatively insensitive to the tilting and eccentricity ratios; however, for larger tilting or eccentricity ratios, the tilting and eccentric effects should be fully considered. Meanwhile, the rotary speed significantly affects the performance of the hydrostatic, water-lubricated bearings.

  15. A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures.

    Science.gov (United States)

    Shiraishi, Yuichi; Tremmel, Georg; Miyano, Satoru; Stephens, Matthew

    2015-12-01

    Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https

  16. Grizzly bear

    Science.gov (United States)

    Schwartz, C.C.; Miller, S.D.; Haroldson, M.A.; Feldhamer, G.; Thompson, B.; Chapman, J.

    2003-01-01

    The grizzly bear inspires fear, awe, and respect in humans to a degree unmatched by any other North American wild mammal. Like other bear species, it can inflict serious injury and death on humans and sometimes does. Unlike the polar bear (Ursus maritimus) of the sparsely inhabited northern arctic, however, grizzly bears still live in areas visited by crowds of people, where presence of the grizzly remains physically real and emotionally dominant. A hike in the wilderness that includes grizzly bears is different from a stroll in a forest from which grizzly bears have been purged; nighttime conversations around the campfire and dreams in the tent reflect the presence of the great bear. Contributing to the aura of the grizzly bear is the mixture of myth and reality about its ferocity. unpredictable disposition, large size, strength, huge canines, long claws, keen senses, swiftness, and playfulness. They share characteristics with humans such as generalist life history strategies. extended periods of maternal care, and omnivorous diets. These factors capture the human imagination in ways distinct from other North American mammals. Precontact Native American legends reflected the same fascination with the grizzly bear as modern stories and legends (Rockwell 1991).

  17. Active tilting-pad journal bearings supporting flexible rotors: Part II–The model-based feedback-controlled lubrication

    DEFF Research Database (Denmark)

    Salazar, Jorge Andrés González; Santos, Ilmar

    2017-01-01

    This is part II of a twofold paper series dealing with the design and implementation of model-based controllers meant for assisting the hybrid and developing the feedback-controlled lubrication regimes in active tilting pad journal bearings (active TPJBs). In both papers theoretical and experimen......This is part II of a twofold paper series dealing with the design and implementation of model-based controllers meant for assisting the hybrid and developing the feedback-controlled lubrication regimes in active tilting pad journal bearings (active TPJBs). In both papers theoretical...... and experimental analyses are presented with focus on the reduction of rotor lateral vibration. This part is devoted to synthesising model-based LQG optimal controllers (LQR regulator + Kalman Filter) for the feedback-controlled lubrication and is based upon the mathematical model of the rotor-bearing system...... derived in part I. Results show further suppression of resonant vibrations when using the feedback-controlled or active lubrication, overweighting the reduction already achieved with hybrid lubrication, thus improving the whole machine dynamic performance....

  18. Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data

    Science.gov (United States)

    Sachithanandham, Jaiprasath; Konda Reddy, Karnati; Solomon, King; David, Shoba; Kumar Singh, Sanjeev; Vadhini Ramalingam, Veena; Alexander Pulimood, Susanne; Cherian Abraham, Ooriyapadickal; Rupali, Pricilla; Sridharan, Gopalan; Kannangai, Rajesh

    2016-01-01

    The degree of sequence variation in HIV-1 integrase genes among infected patients and their impact on clinical response to Anti retroviral therapy (ART) is of interest. Therefore, we collected plasma samples from 161 HIV-1 infected individuals for subsequent integrase gene amplification (1087 bp). Thus, 102 complete integrase gene sequences identified as HIV-1 subtype-C was assembled. This sequence data was further used for sequence analysis and multiple sequence alignment (MSA) to assess position specific frequency of mutations within pol gene among infected individuals. We also used biophysical geometric optimization technique based molecular modeling and docking (Schrodinger suite) methods to infer differential function caused by position specific sequence mutations towards improved inhibitor selection. We thus identified accessory mutations (usually reduce susceptibility) leading to the resistance of some known integrase inhibitors in 14% of sequences in this data set. The Stanford HIV-1 drug resistance database provided complementary information on integrase resistance mutations to deduce molecular basis for such observation. Modeling and docking analysis show reduced binding by mutants for known compounds. The predicted binding values further reduced for models with combination of mutations among subtype C clinical strains. Thus, the molecular basis implied for the consequence of mutations in different variants of integrase genes of HIV-1 subtype C clinical strains from South India is reported. This data finds utility in the design, modification and development of a representative yet an improved inhibitor for HIV-1 integrase.

  19. CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa.

    Science.gov (United States)

    Wu, Wen-Hsuan; Tsai, Yi-Ting; Justus, Sally; Lee, Ting-Ting; Zhang, Lijuan; Lin, Chyuan-Sheng; Bassuk, Alexander G; Mahajan, Vinit B; Tsang, Stephen H

    2016-08-01

    Massive parallel sequencing enables identification of numerous genetic variants in mutant organisms, but determining pathogenicity of any one mutation can be daunting. The most commonly studied preclinical model of retinitis pigmentosa called the "rodless" (rd1) mouse is homozygous for two mutations: a nonsense point mutation (Y347X) and an intronic insertion of a leukemia virus (Xmv-28). Distinguishing which mutation causes retinal degeneration is still under debate nearly a century after the discovery of this model organism. Here, we performed gene editing using the CRISPR/Cas9 system and demonstrated that the Y347X mutation is the causative variant of disease. Genome editing in the first generation produced animals that were mosaic for the corrected allele but still showed neurofunction preservation despite low repair frequencies. Furthermore, second-generation CRISPR-repaired mice showed an even more robust rescue and amelioration of the disease. This predicts excellent outcomes for gene editing in diseased human tissue, as Pde6b, the mutated gene in rd1 mice, has an orthologous intron-exon relationship comparable with the human PDE6B gene. Not only do these findings resolve the debate surrounding the source of neurodegeneration in the rd1 model, but they also provide the first example of homology-directed recombination-mediated gene correction in the visual system.

  20. Structure Based Thermostability Prediction Models for Protein Single Point Mutations with Machine Learning Tools.

    Science.gov (United States)

    Jia, Lei; Yarlagadda, Ramya; Reed, Charles C

    2015-01-01

    Thermostability issue of protein point mutations is a common occurrence in protein engineering. An application which predicts the thermostability of mutants can be helpful for guiding decision making process in protein design via mutagenesis. An in silico point mutation scanning method is frequently used to find "hot spots" in proteins for focused mutagenesis. ProTherm (http://gibk26.bio.kyutech.ac.jp/jouhou/Protherm/protherm.html) is a public database that consists of thousands of protein mutants' experimentally measured thermostability. Two data sets based on two differently measured thermostability properties of protein single point mutations, namely the unfolding free energy change (ddG) and melting temperature change (dTm) were obtained from this database. Folding free energy change calculation from Rosetta, structural information of the point mutations as well as amino acid physical properties were obtained for building thermostability prediction models with informatics modeling tools. Five supervised machine learning methods (support vector machine, random forests, artificial neural network, naïve Bayes classifier, K nearest neighbor) and partial least squares regression are used for building the prediction models. Binary and ternary classifications as well as regression models were built and evaluated. Data set redundancy and balancing, the reverse mutations technique, feature selection, and comparison to other published methods were discussed. Rosetta calculated folding free energy change ranked as the most influential features in all prediction models. Other descriptors also made significant contributions to increasing the accuracy of the prediction models.

  1. Which melanoma patient carries a BRAF-mutation? A comparison of predictive models

    Science.gov (United States)

    Eigentler, Thomas; Assi, Zeinab; Hassel, Jessica C.; Heinzerling, Lucie; Starz, Hans; Berneburg, Mark; Bauer, Jürgen; Garbe, Claus

    2016-01-01

    Background In patients with advanced melanoma the detection of BRAF mutations is considered mandatory before the initiation of an expensive treatment with BRAF/MEK inhibitors. Sometimes it is difficult to perform such an analysis if archival tumor tissue is not available and fresh tissue has to be collected. Results 514 of 1170 patients (44%) carried a BRAF mutation. All models revealed age and histological subtype of melanoma as the two major predictive variables. Accuracy ranged from 0.65–0.71, being best in the random forest model. Sensitivity ranged 0.76–0.84, again best in the random forest model. Specificity was low in all models ranging 0.51–0.55. Methods We collected the clinical data and mutational status of 1170 patients with advanced melanoma and established three different predictive models (binary logistic regression, classification and regression trees, and random forest) to forecast the BRAF status. Conclusions Up to date statistical models are not able to predict BRAF mutations in an acceptable accuracy. The analysis of the mutational status by sequencing or immunohistochemistry must still be considered as standard of care. PMID:27150060

  2. Structure Based Thermostability Prediction Models for Protein Single Point Mutations with Machine Learning Tools.

    Directory of Open Access Journals (Sweden)

    Lei Jia

    Full Text Available Thermostability issue of protein point mutations is a common occurrence in protein engineering. An application which predicts the thermostability of mutants can be helpful for guiding decision making process in protein design via mutagenesis. An in silico point mutation scanning method is frequently used to find "hot spots" in proteins for focused mutagenesis. ProTherm (http://gibk26.bio.kyutech.ac.jp/jouhou/Protherm/protherm.html is a public database that consists of thousands of protein mutants' experimentally measured thermostability. Two data sets based on two differently measured thermostability properties of protein single point mutations, namely the unfolding free energy change (ddG and melting temperature change (dTm were obtained from this database. Folding free energy change calculation from Rosetta, structural information of the point mutations as well as amino acid physical properties were obtained for building thermostability prediction models with informatics modeling tools. Five supervised machine learning methods (support vector machine, random forests, artificial neural network, naïve Bayes classifier, K nearest neighbor and partial least squares regression are used for building the prediction models. Binary and ternary classifications as well as regression models were built and evaluated. Data set redundancy and balancing, the reverse mutations technique, feature selection, and comparison to other published methods were discussed. Rosetta calculated folding free energy change ranked as the most influential features in all prediction models. Other descriptors also made significant contributions to increasing the accuracy of the prediction models.

  3. Resilience and risk: a demographic model to inform conservation planning for polar bears

    Science.gov (United States)

    Regehr, Eric V.; Wilson, Ryan R.; Rode, Karyn D.; Runge, Michael C.

    2015-01-01

    Climate change is having widespread ecological effects, including loss of Arctic sea ice. This has led to listing of the polar bear (Ursus maritimus) and other ice-dependent marine mammals under the U.S. Endangered Species Act (ESA). Methods are needed to evaluate the effects of climate change on population persistence to inform recovery planning for listed species. For polar bears, this includes understanding interactions between climate and secondary factors, such as subsistence harvest, which provide economic, nutritional, or cultural value to humans.

  4. SVM classification model in depression recognition based on mutation PSO parameter optimization

    Directory of Open Access Journals (Sweden)

    Zhang Ming

    2017-01-01

    Full Text Available At present, the clinical diagnosis of depression is mainly through structured interviews by psychiatrists, which is lack of objective diagnostic methods, so it causes the higher rate of misdiagnosis. In this paper, a method of depression recognition based on SVM and particle swarm optimization algorithm mutation is proposed. To address on the problem that particle swarm optimization (PSO algorithm easily trap in local optima, we propose a feedback mutation PSO algorithm (FBPSO to balance the local search and global exploration ability, so that the parameters of the classification model is optimal. We compared different PSO mutation algorithms about classification accuracy for depression, and found the classification accuracy of support vector machine (SVM classifier based on feedback mutation PSO algorithm is the highest. Our study promotes important reference value for establishing auxiliary diagnostic used in depression recognition of clinical diagnosis.

  5. A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model.

    Science.gov (United States)

    Min, Wonki; Angileri, Francesca; Luo, Haibin; Lauria, Antonino; Shanmugasundaram, Maruda; Almerico, Anna Maria; Cappello, Francesco; de Macario, Everly Conway; Lednev, Igor K; Macario, Alberto J L; Robb, Frank T

    2014-10-27

    Chaperonins mediate protein folding in a cavity formed by multisubunit rings. The human CCT has eight non-identical subunits and the His147Arg mutation in one subunit, CCT5, causes neuropathy. Knowledge is scarce on the impact of this and other mutations upon the chaperone's structure and functions. To make progress, experimental models must be developed. We used an archaeal mutant homolog and demonstrated that the His147Arg mutant has impaired oligomeric assembly, ATPase activity, and defective protein homeostasis functions. These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog. The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective. Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.

  6. Mutational effects and population dynamics during viral adaptation challenge current models.

    Science.gov (United States)

    Miller, Craig R; Joyce, Paul; Wichman, Holly A

    2011-01-01

    Adaptation in haploid organisms has been extensively modeled but little tested. Using a microvirid bacteriophage (ID11), we conducted serial passage adaptations at two bottleneck sizes (10(4) and 10(6)), followed by fitness assays and whole-genome sequencing of 631 individual isolates. Extensive genetic variation was observed including 22 beneficial, several nearly neutral, and several deleterious mutations. In the three large bottleneck lines, up to eight different haplotypes were observed in samples of 23 genomes from the final time point. The small bottleneck lines were less diverse. The small bottleneck lines appeared to operate near the transition between isolated selective sweeps and conditions of complex dynamics (e.g., clonal interference). The large bottleneck lines exhibited extensive interference and less stochasticity, with multiple beneficial mutations establishing on a variety of backgrounds. Several leapfrog events occurred. The distribution of first-step adaptive mutations differed significantly from the distribution of second-steps, and a surprisingly large number of second-step beneficial mutations were observed on a highly fit first-step background. Furthermore, few first-step mutations appeared as second-steps and second-steps had substantially smaller selection coefficients. Collectively, the results indicate that the fitness landscape falls between the extremes of smooth and fully uncorrelated, violating the assumptions of many current mutational landscape models.

  7. Properties and modeling of GWAS when complex disease risk is due to non-complementing, deleterious mutations in genes of large effect.

    Directory of Open Access Journals (Sweden)

    Kevin R Thornton

    Full Text Available Current genome-wide association studies (GWAS have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE. This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders, and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated.

  8. MATHEMATICAL AND COMPUTER MODELING OF AUTOMATIC CONTROL SYSTEM FOR HYDROSTATIC BEARING

    Directory of Open Access Journals (Sweden)

    N. A. Pelevin

    2016-09-01

    Full Text Available The paper presents simulation results of hydrostatic bearing dynamics in spindle assembly of standard flexible production module with throttled circuit. The necessity of dynamic quality increase for automatic control system of the hydrostatic bearing with the use of correcting means in the form of RC-chains is shown. The features of correction parameters choice coming from the existence of the crossing connections in automatic control system structure are noted. We propose the block diagram of automatic control system of the hydrostatic bearing in Simulink working field and cyclic algorithm for determination program of RC-chain parameters implemented in MATLAB taking into account typical thermal processes for the finishing treatment. Graphic-analytical method for the correction parameters choice is presented based on the stability stock phase gradient for dynamic quality determination of automatic control system. Researches of the method estimability in case of using the standard metal bellow valve as the hydrocapacity for RC-chain are also carried out. Recommendations for the bellow valve choice are formulated. The check of dynamic quality indicators concerning transition processes calculated by means of the appropriate programs developed for MATLAB is performed. Examples are given for phase stability factor gradient schedules with partition of various areas of hydrostatic bearing dynamic quality for different frequencies of spindle rotation and procedure description of data cursor function application on MATLAB toolbar. Improvement of hydrostatic bearing dynamics under typical low loadings for finishing treatment is noted. Also, decrease of dynamic indicators for high loadings treatment in case of roughing treatment is marked.

  9. A Comparison of Grizzly Bear Demographic Parameters Estimated from Non-Spatial and Spatial Open Population Capture-Recapture Models.

    Directory of Open Access Journals (Sweden)

    Jesse Whittington

    Full Text Available Capture-recapture studies are frequently used to monitor the status and trends of wildlife populations. Detection histories from individual animals are used to estimate probability of detection and abundance or density. The accuracy of abundance and density estimates depends on the ability to model factors affecting detection probability. Non-spatial capture-recapture models have recently evolved into spatial capture-recapture models that directly include the effect of distances between an animal's home range centre and trap locations on detection probability. Most studies comparing non-spatial and spatial capture-recapture biases focussed on single year models and no studies have compared the accuracy of demographic parameter estimates from open population models. We applied open population non-spatial and spatial capture-recapture models to three years of grizzly bear DNA-based data from Banff National Park and simulated data sets. The two models produced similar estimates of grizzly bear apparent survival, per capita recruitment, and population growth rates but the spatial capture-recapture models had better fit. Simulations showed that spatial capture-recapture models produced more accurate parameter estimates with better credible interval coverage than non-spatial capture-recapture models. Non-spatial capture-recapture models produced negatively biased estimates of apparent survival and positively biased estimates of per capita recruitment. The spatial capture-recapture grizzly bear population growth rates and 95% highest posterior density averaged across the three years were 0.925 (0.786-1.071 for females, 0.844 (0.703-0.975 for males, and 0.882 (0.779-0.981 for females and males combined. The non-spatial capture-recapture population growth rates were 0.894 (0.758-1.024 for females, 0.825 (0.700-0.948 for males, and 0.863 (0.771-0.957 for both sexes. The combination of low densities, low reproductive rates, and predominantly negative

  10. A Comparison of Grizzly Bear Demographic Parameters Estimated from Non-Spatial and Spatial Open Population Capture-Recapture Models.

    Science.gov (United States)

    Whittington, Jesse; Sawaya, Michael A

    2015-01-01

    Capture-recapture studies are frequently used to monitor the status and trends of wildlife populations. Detection histories from individual animals are used to estimate probability of detection and abundance or density. The accuracy of abundance and density estimates depends on the ability to model factors affecting detection probability. Non-spatial capture-recapture models have recently evolved into spatial capture-recapture models that directly include the effect of distances between an animal's home range centre and trap locations on detection probability. Most studies comparing non-spatial and spatial capture-recapture biases focussed on single year models and no studies have compared the accuracy of demographic parameter estimates from open population models. We applied open population non-spatial and spatial capture-recapture models to three years of grizzly bear DNA-based data from Banff National Park and simulated data sets. The two models produced similar estimates of grizzly bear apparent survival, per capita recruitment, and population growth rates but the spatial capture-recapture models had better fit. Simulations showed that spatial capture-recapture models produced more accurate parameter estimates with better credible interval coverage than non-spatial capture-recapture models. Non-spatial capture-recapture models produced negatively biased estimates of apparent survival and positively biased estimates of per capita recruitment. The spatial capture-recapture grizzly bear population growth rates and 95% highest posterior density averaged across the three years were 0.925 (0.786-1.071) for females, 0.844 (0.703-0.975) for males, and 0.882 (0.779-0.981) for females and males combined. The non-spatial capture-recapture population growth rates were 0.894 (0.758-1.024) for females, 0.825 (0.700-0.948) for males, and 0.863 (0.771-0.957) for both sexes. The combination of low densities, low reproductive rates, and predominantly negative population growth

  11. LDA-SVM-based EGFR mutation model for NSCLC brain metastases: an observational study.

    Science.gov (United States)

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-02-01

    Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non-small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of

  12. LDA-SVM-Based EGFR Mutation Model for NSCLC Brain Metastases

    Science.gov (United States)

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-01-01

    Abstract Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non–small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this

  13. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    Science.gov (United States)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  14. Damper bearing rotordynamics

    Science.gov (United States)

    Elrod, David A.

    1990-01-01

    High side loads reduce the life of the Space Shuttle Main Engine (SSME) High Pressure Oxygen Turbopump (HPOTP) bearings. High stiffness damper seals were recommended to reduce the loads on the pump and turbine end bearings in the HPOTP. The seals designed for use on the pump end are expected to adequately reduce the bearing loads; the predicted performance of the planned turbine end seal is marginal. An alternative to the suggested turbine end seal design is a damper bearing with radial holes from the pressurized center of the turbopump rotor, feeding a smooth land region between two rough-stator/smooth-rotor annular seals. An analysis was prepared to predict the leakage and rotor dynamic coefficients (stiffness, damping, and added mass) of the damper bearing. Governing equations of the seal analysis modified to model the damper bearing; differences between the upstream conditions of the damper bearing and a typical annular seal; prediction of the damper bearing analysis; and assumptions of the analysis which require further investigation are described.

  15. Testing a coupled hydro-thermo-chemo-geomechanical model for gas hydrate bearing sediments using triaxial compression lab experiments

    CERN Document Server

    Gupta, Shubhangi; Haeckel, Matthias; Helmig, Rainer; Wohlmuth, Barbara

    2015-01-01

    The presence of gas hydrates influences the stress-strain behavior and increases the load-bearing capacity of sub-marine sediments. This stability is reduced or completely lost when gas hydrates become unstable. Since natural gas hydrate reservoirs are considered as potential resources for gas production on industrial scales, there is a strong need for numerical production simulators with geomechanical capabilities. To reliably predict the mechanical behavior of gas hydrate-bearing sediments during gas production, numerical tools must be sufficiently calibrated against data from controlled experiments or field tests, and the models must consider thermo-hydro-chemo-mechanical process coupling in a suitable manner. In this study, we perform a controlled triaxial volumetric strain test on a sediment sample in which methane hydrate is first formed under controlled isotropic effective stress and then dissociated via depressurization under controlled total stress. Sample deformations were kept small, and under thes...

  16. 3D modeling of gas/water distribution in water-bearing carbonate gas reservoirs: the Longwangmiao gas field, China

    Science.gov (United States)

    Ou, Chenghua; Li, ChaoChun; Ma, Zhonggao

    2016-10-01

    A water-bearing carbonate gas reservoir is an important natural gas resource being developed worldwide. Due to the long-term water/rock/gas interaction during geological evolution, complex gas/water distribution has formed under the superposed effect of sedimentary facies, reservoir space facies and gravity difference of fluid facies. In view of these challenges, on the basis of the conventional three-stage modeling method, this paper presents a modelling method controlled by four-stage facies to develop 3D model of a water-bearing carbonate gas reservoir. Key to this method is the reservoir property modelling controlled by two-stage facies, and the fluid property modelling controlled by another two-stage facies. The prerequisite of this method is a reliable database obtained from solid geological investigation. On the basis of illustrating the principles of the modelling method controlled by four-stage facies, this paper further implements systematically modeling of the heterogeneous gas/water distribution of the Longwangmiao carbonate formation in the Moxi-Gaoshiti area, Sichuan basin, China.

  17. THCM Coupled Model for Hydrate-Bearing Sediments: Data Analysis and Design of New Field Experiments (Marine and Permafrost Settings)

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez, Marcelo J. [Texas A & M Univ., College Station, TX (United States); Santamarina, J. Carlos [King Abdullah Univ. of Science and Technology (Saudi Arabia)

    2017-02-14

    Gas hydrates are solid compounds made of water molecules clustered around low molecular weight gas molecules such as methane, hydrogen, and carbon dioxide. Methane hydrates form under pressure (P) and temperature (T) conditions that are common in sub-permafrost layers and in deep marine sediments. Stability conditions constrain the occurrence of gas hydrates to submarine sediments and permafrost regions. The amount of technically recoverable methane trapped in gas hydrate may exceed 104tcf. Gas hydrates are a potential energy resource, can contribute to climate change, and can cause large-scale seafloor instabilities. In addition, hydrate formation can be used for CO2 sequestration (also through CO2-CH4 replacement), and efficient geological storage seals. The experimental study of hydrate bearing sediments has been hindered by the very low solubility of methane in water (lab testing), and inherent sampling difficulties associated with depressurization and thermal changes during core extraction. This situation has prompted more decisive developments in numerical modeling in order to advance the current understanding of hydrate bearing sediments, and to investigate/optimize production strategies and implications. The goals of this research has been to addresses the complex thermo-hydro-chemo-mechanical THCM coupled phenomena in hydrate-bearing sediments, using a truly coupled numerical model that incorporates sound and proven constitutive relations, satisfies fundamental conservation principles. Analytical solutions aimed at verifying the proposed code have been proposed as well. These tools will allow to better analyze available data and to further enhance the current understanding of hydrate bearing sediments in view of future field experiments and the development of production technology.

  18. Genetic characterization of Kenai brown bears (Ursus arctos): Microsatellite and mitochondrial DNA control region variation in brown bears of the Kenai Peninsula, south central Alaska

    Science.gov (United States)

    Jackson, J.V.; Talbot, S.L.; Farley, S.

    2008-01-01

    We collected data from 20 biparentally inherited microsatellite loci, and nucleotide sequence from the maternally inherited mitochondrial DNA (mtDNA) control region, to determine levels of genetic variation of the brown bears (Ursus arctos L., 1758) of the Kenai Peninsula, south central Alaska. Nuclear genetic variation was similar to that observed in other Alaskan peninsular populations. We detected no significant inbreeding and found no evidence of population substructuring on the Kenai Peninsula. We observed a genetic signature of a bottleneck under the infinite alleles model (IAM), but not under the stepwise mutation model (SMM) or the two-phase model (TPM) of microsatellite mutation. Kenai brown bears have lower levels of mtDNA haplotypic diversity relative to most other brown bear populations in Alaska. ?? 2008 NRC.

  19. Performance of a Ferrofluid Based Rough Parallel Plate Slider Bearing: A Comparison of Three Magnetic Fluid Flow Models

    Directory of Open Access Journals (Sweden)

    Jimit R. Patel

    2016-01-01

    Full Text Available Efforts have been made to present a comparison of all the three magnetic fluid flow models (Neuringer-Rosensweig model, Shliomis model, and Jenkins model so far as the performance of a magnetic fluid based parallel plate rough slider bearing is concerned. The stochastic model of Christensen and Tonder is adopted for the evaluation of effect of transverse surface roughness. The stochastically averaged Reynolds-type equation is solved with suitable boundary conditions to obtain the pressure distribution resulting in the calculation of load carrying capacity. The graphical results establish that for a bearing’s long life period the Shliomis model may be employed for higher loads. However, for lower to moderate loads, the Neuringer-Rosensweig model may be deployed.

  20. Inferring Sequential Order of Somatic Mutations during Tumorgenesis based on Markov Chain Model.

    Science.gov (United States)

    Kang, Hao; Cho, Kwang-Hyun; Zhang, Xiaohua Douglas; Zeng, Tao; Chen, Luonan

    2015-01-01

    Tumors are developed and worsen with the accumulated mutations on DNA sequences during tumorigenesis. Identifying the temporal order of gene mutations in cancer initiation and development is a challenging topic. It not only provides a new insight into the study of tumorigenesis at the level of genome sequences but also is an effective tool for early diagnosis of tumors and preventive medicine. In this paper, we develop a novel method to accurately estimate the sequential order of gene mutations during tumorigenesis from genome sequencing data based on Markov chain model as TOMC (Temporal Order based on Markov Chain), and also provide a new criterion to further infer the order of samples or patients, which can characterize the severity or stage of the disease. We applied our method to the analysis of tumors based on several high-throughput datasets. Specifically, first, we revealed that tumor suppressor genes (TSG) tend to be mutated ahead of oncogenes, which are considered as important events for key functional loss and gain during tumorigenesis. Second, the comparisons of various methods demonstrated that our approach has clear advantages over the existing methods due to the consideration on the effect of mutation dependence among genes, such as co-mutation. Third and most important, our method is able to deduce the ordinal sequence of patients or samples to quantitatively characterize their severity of tumors. Therefore, our work provides a new way to quantitatively understand the development and progression of tumorigenesis based on high throughput sequencing data.

  1. Disheveled hair and ear (Dhe, a spontaneous mouse Lmna mutation modeling human laminopathies.

    Directory of Open Access Journals (Sweden)

    Paul R Odgren

    Full Text Available BACKGROUND: Investigations of naturally-occurring mutations in animal models provide important insights and valuable disease models. Lamins A and C, along with lamin B, are type V intermediate filament proteins which constitute the proteinaceous boundary of the nucleus. LMNA mutations in humans cause a wide range of phenotypes, collectively termed laminopathies. To identify the mutation and investigate the phenotype of a spontaneous, semi-dominant mutation that we have named Disheveled hair and ear (Dhe, which causes a sparse coat and small external ears in heterozygotes and lethality in homozygotes by postnatal day 10. FINDINGS: Genetic mapping identified a point mutation in the Lmna gene, causing a single amino acid change, L52R, in the coiled coil rod domain of lamin A and C proteins. Cranial sutures in Dhe/+ mice failed to close. Gene expression for collagen types I and III in sutures was deficient. Skulls were small and disproportionate. Skeletons of Dhe/+ mice were hypomineralized and total body fat was deficient in males. In homozygotes, skin and oral mucosae were dysplastic and ulcerated. Nuclear morphometry of cultured cells revealed gene dose-dependent blebbing and wrinkling. CONCLUSION: Dhe mice should provide a useful new model for investigations of the pathogenesis of laminopathies.

  2. Numerical solution of the Penna model of biological aging with age-modified mutation rate

    Science.gov (United States)

    Magdoń-Maksymowicz, M. S.; Maksymowicz, A. Z.

    2009-06-01

    In this paper we present results of numerical calculation of the Penna bit-string model of biological aging, modified for the case of a -dependent mutation rate m(a) , where a is the parent’s age. The mutation rate m(a) is the probability per bit of an extra bad mutation introduced in offspring inherited genome. We assume that m(a) increases with age a . As compared with the reference case of the standard Penna model based on a constant mutation rate m , the dynamics of the population growth shows distinct changes in age distribution of the population. Here we concentrate on mortality q(a) , a fraction of items eliminated from the population when we go from age (a) to (a+1) in simulated transition from time (t) to next time (t+1) . The experimentally observed q(a) dependence essentially follows the Gompertz exponential law for a above the minimum reproduction age. Deviation from the Gompertz law is however observed for the very old items, close to the maximal age. This effect may also result from an increase in mutation rate m with age a discussed in this paper. The numerical calculations are based on analytical solution of the Penna model, presented in a series of papers by Coe [J. B. Coe, Y. Mao, and M. E. Cates, Phys. Rev. Lett. 89, 288103 (2002)]. Results of the numerical calculations are supported by the data obtained from computer simulation based on the solution by Coe

  3. Magnetic Bearing

    Science.gov (United States)

    1996-01-01

    AVCON, Inc. produces advanced magnetic bearing systems for industrial use, offering a unique technological approach based on contract work done at Marshall Space Flight Center and Lewis Research Center. Designed for the turbopump of the Space Shuttle main engine, they are now used in applications such as electric power generation, petroleum refining, machine tool operation and natural gas pipelines. Magnetic bearings support moving machinery without physical contact; AVCON's homopolar approach is a hybrid of permanent and electromagnets which are one-third the weight, smaller and more power- efficient than previous magnetic bearings.

  4. Exact and Direct Modeling Technique for Rotor-Bearing Systems with Arbitrary Selected Degrees-of-Freedom

    Directory of Open Access Journals (Sweden)

    Shilin Chen

    1994-01-01

    Full Text Available An exact and direct modeling technique is proposed for modeling of rotor-bearing systems with arbitrary selected degrees-of-freedom. This technique is based on the combination of the transfer and dynamic stiffness matrices. The technique differs from the usual combination methods in that the global dynamic stiffness matrix for the system or the subsystem is obtained directly by rearranging the corresponding global transfer matrix. Therefore, the dimension of the global dynamic stiffness matrix is independent of the number of the elements or the substructures. In order to show the simplicity and efficiency of the method, two numerical examples are given.

  5. Prognostic model for brain metastases from lung adenocarcinoma identified with epidermal growth factor receptor mutation status.

    Science.gov (United States)

    Li, Hongwei; Wang, Weili; Jia, Haixia; Lian, Jianhong; Cao, Jianzhong; Zhang, Xiaqin; Song, Xing; Jia, Sufang; Li, Zhengran; Cao, Xing; Zhou, Wei; Han, Songye; Yang, Weihua; Xi, Yanfen; Lian, Shenming

    2017-09-01

    Several indices have been developed to predict survival of brain metastases (BM) based on prognostic factors. However, such models were designed for general brain metastases from different kinds of cancers, and prognostic factors vary between cancers and histological subtypes. Recently, studies have indicated that epidermal growth factor receptor (EGFR) mutation status may be a potential prognostic biological factor in BM from lung adenocarcinoma. Thus, we sought to define the role of EGFR mutation in prognoses and introduce a prognostic model specific for BM from lung adenocarcinoma. Data of 256 patients with BM from lung adenocarcinoma identified with EGFR mutations were collected. Independent prognostic factors were confirmed using a Cox regression model. The new prognostic model was developed based on the results of multivariable analyses. The score of each factor was calculated by six-month survival. Prognostic groups were divided into low, medium, and high risk based on the total scores. The prediction ability of the new model was compared to the three existing models. EGFR mutation and Karnofsky performance status were independent prognostic factors and were thus integrated into the new prognostic model. The new model was superior to the three other scoring systems regarding the prediction of three, six, and 12-month survival by pairwise comparison of the area under the curve. Our proposed prognostic model specific for BM from lung adenocarcinoma incorporating EGFR mutation status was valid in predicting patient survival. Further verification is warranted, with prospective testing using large sample sizes. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  6. Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype

    Science.gov (United States)

    Pierson, Christopher R.; Dulin-Smith, Ashley N.; Durban, Ashley N.; Marshall, Morgan L.; Marshall, Jordan T.; Snyder, Andrew D.; Naiyer, Nada; Gladman, Jordan T.; Chandler, Dawn S.; Lawlor, Michael W.; Buj-Bello, Anna; Dowling, James J.; Beggs, Alan H.

    2012-01-01

    X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype–phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies. PMID:22068590

  7. Foil bearings

    Science.gov (United States)

    Elrod, David A.

    1993-01-01

    The rolling element bearings (REB's) which support many turbomachinery rotors offer high load capacity, low power requirements, and durability. Two disadvantages of REB's are: (1) rolling or sliding contact within the bearing has life-limiting consequences; and (2) REB's provide essentially no damping. The REB's in the Space Shuttle Main Engine (SSME) turbopumps must sustain high static and dynamic loads, at high speeds, with a cryogenic fluid as lubricant and coolant. The pump end ball bearings limit the life of the SSME high pressure oxygen turbopump (HPOTP). Compliant foil bearing (CFB) manufacturers have proposed replacing turbopump REB's with CFB's CFB's work well in aircraft air cycle machines, auxiliary power units, and refrigeration compressors. In a CFB, the rotor only contracts the foil support structure during start up and shut down. CFB damping is higher than REB damping. However, the load capacity of the CFB is low, compared to a REB. Furthermore, little stiffness and damping data exists for the CFB. A rotordynamic analysis for turbomachinery critical speeds and stability requires the input of bearing stiffness and damping coefficients. The two basic types of CFB are the tension-dominated bearing and the bending-dominated bearing. Many investigators have analyzed and measured characteristics of tension-dominated foil bearings, which are applied principally in magnetic tape recording. The bending-dominated CFB is used more in rotating machinery. This report describes the first phase of a structural analysis of a bending-dominated, multileaf CFB. A brief discussion of CFB literature is followed by a description and results of the present analysis.

  8. Foil bearings

    Science.gov (United States)

    Elrod, David A.

    1993-11-01

    The rolling element bearings (REB's) which support many turbomachinery rotors offer high load capacity, low power requirements, and durability. Two disadvantages of REB's are: (1) rolling or sliding contact within the bearing has life-limiting consequences; and (2) REB's provide essentially no damping. The REB's in the Space Shuttle Main Engine (SSME) turbopumps must sustain high static and dynamic loads, at high speeds, with a cryogenic fluid as lubricant and coolant. The pump end ball bearings limit the life of the SSME high pressure oxygen turbopump (HPOTP). Compliant foil bearing (CFB) manufacturers have proposed replacing turbopump REB's with CFB's CFB's work well in aircraft air cycle machines, auxiliary power units, and refrigeration compressors. In a CFB, the rotor only contracts the foil support structure during start up and shut down. CFB damping is higher than REB damping. However, the load capacity of the CFB is low, compared to a REB. Furthermore, little stiffness and damping data exists for the CFB. A rotordynamic analysis for turbomachinery critical speeds and stability requires the input of bearing stiffness and damping coefficients. The two basic types of CFB are the tension-dominated bearing and the bending-dominated bearing. Many investigators have analyzed and measured characteristics of tension-dominated foil bearings, which are applied principally in magnetic tape recording. The bending-dominated CFB is used more in rotating machinery. This report describes the first phase of a structural analysis of a bending-dominated, multileaf CFB. A brief discussion of CFB literature is followed by a description and results of the present analysis.

  9. A quantitative quasispecies theory-based model of virus escape mutation under immune selection.

    Science.gov (United States)

    Woo, Hyung-June; Reifman, Jaques

    2012-08-07

    Viral infections involve a complex interplay of the immune response and escape mutation of the virus quasispecies inside a single host. Although fundamental aspects of such a balance of mutation and selection pressure have been established by the quasispecies theory decades ago, its implications have largely remained qualitative. Here, we present a quantitative approach to model the virus evolution under cytotoxic T-lymphocyte immune response. The virus quasispecies dynamics are explicitly represented by mutations in the combined sequence space of a set of epitopes within the viral genome. We stochastically simulated the growth of a viral population originating from a single wild-type founder virus and its recognition and clearance by the immune response, as well as the expansion of its genetic diversity. Applied to the immune escape of a simian immunodeficiency virus epitope, model predictions were quantitatively comparable to the experimental data. Within the model parameter space, we found two qualitatively different regimes of infectious disease pathogenesis, each representing alternative fates of the immune response: It can clear the infection in finite time or eventually be overwhelmed by viral growth and escape mutation. The latter regime exhibits the characteristic disease progression pattern of human immunodeficiency virus, while the former is bounded by maximum mutation rates that can be suppressed by the immune response. Our results demonstrate that, by explicitly representing epitope mutations and thus providing a genotype-phenotype map, the quasispecies theory can form the basis of a detailed sequence-specific model of real-world viral pathogens evolving under immune selection.

  10. Fisher's model and the genomics of adaptation: restricted pleiotropy, heterogenous mutation, and parallel evolution.

    Science.gov (United States)

    Chevin, Luis-Miguel; Martin, Guillaume; Lenormand, Thomas

    2010-11-01

    Genetic theories of adaptation generally overlook the genes in which beneficial substitutions occur, and the likely variation in their mutational effects. We investigate the consequences of heterogeneous mutational effects among loci on the genetics of adaptation. We use a generalization of Fisher's geometrical model, which assumes multivariate Gaussian stabilizing selection on multiple characters. In our model, mutation has a distinct variance-covariance matrix of phenotypic effects for each locus. Consequently, the distribution of selection coefficients s varies across loci. We assume each locus can only affect a limited number of independent linear combinations of phenotypic traits (restricted pleiotropy), which differ among loci, an effect we term "orientation heterogeneity." Restricted pleiotropy can sharply reduce the overall proportion of beneficial mutations. Orientation heterogeneity has little impact on the shape of the genomic distribution, but can substantially increase the probability of parallel evolution (the repeated fixation of beneficial mutations at the same gene in independent populations), which is highest with low pleiotropy. We also consider variation in the degree of pleiotropy and in the mean s across loci. The latter impacts the genomic distribution of s, but has a much milder effect on parallel evolution. We discuss these results in the light of evolution experiments. © 2010 The Author(s). Evolution© 2010 The Society for the Study of Evolution.

  11. Selection and mutation in X-linked recessive diseases epidemiological model.

    Science.gov (United States)

    Verrilli, Francesca; Kebriaei, Hamed; Glielmo, Luigi; Corless, Martin; Del Vecchio, Carmen

    2015-01-01

    To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive.

  12. Mathematical modeling on bacterial resistance to multiple antibiotics caused by spontaneous mutations.

    Science.gov (United States)

    Ibargüen-Mondragón, Eduardo; Mosquera, Saulo; Cerón, Miller; Burbano-Rosero, Edith Mariela; Hidalgo-Bonilla, Sandra P; Esteva, Lourdes; Romero-Leitón, Jhoana P

    2014-03-01

    We formulate a mathematical model that describes the population dynamics of bacteria exposed to multiple antibiotics simultaneously, assuming that acquisition of resistance is through mutations due to antibiotic exposure. Qualitative analysis reveals the existence of a free-bacteria equilibrium, resistant-bacteria equilibrium and an endemic equilibrium where both bacteria coexist.

  13. Neb: a zebrafish model of nemaline myopathy due to nebulin mutation.

    Science.gov (United States)

    Telfer, William R; Nelson, Darcee D; Waugh, Trent; Brooks, Susan V; Dowling, James J

    2012-05-01

    Nemaline myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with nemaline myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of nemaline myopathy. This model, termed neb, harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human nemaline myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of nemaline myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder.

  14. neb: a zebrafish model of nemaline myopathy due to nebulin mutation

    Directory of Open Access Journals (Sweden)

    William R. Telfer

    2012-05-01

    Nemaline myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with nemaline myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of nemaline myopathy. This model, termed neb, harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human nemaline myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of nemaline myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder.

  15. Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins.

    Science.gov (United States)

    Bang, Marie-Louise

    2017-01-01

    The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Alphavirus mutator variants present host-specific defects and attenuation in mammalian and insect models.

    Science.gov (United States)

    Rozen-Gagnon, Kathryn; Stapleford, Kenneth A; Mongelli, Vanesa; Blanc, Hervé; Failloux, Anna-Bella; Saleh, Maria-Carla; Vignuzzi, Marco

    2014-01-01

    Arboviruses cycle through both vertebrates and invertebrates, which requires them to adapt to disparate hosts while maintaining genetic integrity during genome replication. To study the genetic mechanisms and determinants of these processes, we use chikungunya virus (CHIKV), a re-emerging human pathogen transmitted by the Aedes mosquito. We previously isolated a high fidelity (or antimutator) polymerase variant, C483Y, which had decreased fitness in both mammalian and mosquito hosts, suggesting this residue may be a key molecular determinant. To further investigate effects of position 483 on RNA-dependent RNA-polymerase (RdRp) fidelity, we substituted every amino acid at this position. We isolated novel mutators with decreased replication fidelity and higher mutation frequencies, allowing us to examine the fitness of error-prone arbovirus variants. Although CHIKV mutators displayed no major replication defects in mammalian cell culture, they had reduced specific infectivity and were attenuated in vivo. Unexpectedly, mutator phenotypes were suppressed in mosquito cells and the variants exhibited significant defects in RNA synthesis. Consequently, these replication defects resulted in strong selection for reversion during infection of mosquitoes. Since residue 483 is conserved among alphaviruses, we examined the analogous mutations in Sindbis virus (SINV), which also reduced polymerase fidelity and generated replication defects in mosquito cells. However, replication defects were mosquito cell-specific and were not observed in Drosophila S2 cells, allowing us to evaluate the potential attenuation of mutators in insect models where pressure for reversion was absent. Indeed, the SINV mutator variant was attenuated in fruit flies. These findings confirm that residue 483 is a determinant regulating alphavirus polymerase fidelity and demonstrate proof of principle that arboviruses can be attenuated in mammalian and insect hosts by reducing fidelity.

  17. Alphavirus mutator variants present host-specific defects and attenuation in mammalian and insect models.

    Directory of Open Access Journals (Sweden)

    Kathryn Rozen-Gagnon

    2014-01-01

    Full Text Available Arboviruses cycle through both vertebrates and invertebrates, which requires them to adapt to disparate hosts while maintaining genetic integrity during genome replication. To study the genetic mechanisms and determinants of these processes, we use chikungunya virus (CHIKV, a re-emerging human pathogen transmitted by the Aedes mosquito. We previously isolated a high fidelity (or antimutator polymerase variant, C483Y, which had decreased fitness in both mammalian and mosquito hosts, suggesting this residue may be a key molecular determinant. To further investigate effects of position 483 on RNA-dependent RNA-polymerase (RdRp fidelity, we substituted every amino acid at this position. We isolated novel mutators with decreased replication fidelity and higher mutation frequencies, allowing us to examine the fitness of error-prone arbovirus variants. Although CHIKV mutators displayed no major replication defects in mammalian cell culture, they had reduced specific infectivity and were attenuated in vivo. Unexpectedly, mutator phenotypes were suppressed in mosquito cells and the variants exhibited significant defects in RNA synthesis. Consequently, these replication defects resulted in strong selection for reversion during infection of mosquitoes. Since residue 483 is conserved among alphaviruses, we examined the analogous mutations in Sindbis virus (SINV, which also reduced polymerase fidelity and generated replication defects in mosquito cells. However, replication defects were mosquito cell-specific and were not observed in Drosophila S2 cells, allowing us to evaluate the potential attenuation of mutators in insect models where pressure for reversion was absent. Indeed, the SINV mutator variant was attenuated in fruit flies. These findings confirm that residue 483 is a determinant regulating alphavirus polymerase fidelity and demonstrate proof of principle that arboviruses can be attenuated in mammalian and insect hosts by reducing fidelity.

  18. Towards Symbolic Model-Based Mutation Testing: Combining Reachability and Refinement Checking

    CERN Document Server

    Aichernig, Bernhard K; 10.4204/EPTCS.80.7

    2012-01-01

    Model-based mutation testing uses altered test models to derive test cases that are able to reveal whether a modelled fault has been implemented. This requires conformance checking between the original and the mutated model. This paper presents an approach for symbolic conformance checking of action systems, which are well-suited to specify reactive systems. We also consider nondeterminism in our models. Hence, we do not check for equivalence, but for refinement. We encode the transition relation as well as the conformance relation as a constraint satisfaction problem and use a constraint solver in our reachability and refinement checking algorithms. Explicit conformance checking techniques often face state space explosion. First experimental evaluations show that our approach has potential to outperform explicit conformance checkers.

  19. Modeling Impact of BRCA1 and BRCA2 Mutations in Mammary Epithelial Cells

    Science.gov (United States)

    2012-09-01

    personalize” the management and treatment of BRCA1 and BRCA2 mutations, to enhance the quality of life of women who harbor deleterious mutations. Supported by DAMD W81XWH-10-1-0720 to MEK. ...lines, called MCK cells, from women opting for prophylactic mastectomy . These lines have been isolated from pre-neoplastic breast tissue that is not...breast cancer have been identified. We proposed to create a model system of BRCA1 and BRCA2 heterozygous cell lines from women opting for prophylactic

  20. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  1. Nonlethal Fraction of Virus Population in Evolution Models with Lethal Mutations

    Science.gov (United States)

    Yakushkina, Tatiana; Saakian, David B.

    2017-03-01

    Lethal mutations are very common in asexual evolution, both in RNA viruses and in the clonal evolution of cancer cells. In a special case of lethal mutations (truncated selection), after a critical total number of mutations the replicator (the virus or the cell) has no offspring. We consider the Eigen and Crow-Kimura models with truncated fitness landscapes, and calculate the fraction of viable replicators (that do have offspring) in the population. We derive a formula for the fraction of the population with nonlethal replicators for the case of a uniform distribution of lethal sequences in the sequence space. We assume that our results can be applied to the origin of life and cancer biology.

  2. Mutations in MAPT give rise to aneuploidy in animal models of tauopathy.

    Science.gov (United States)

    Rossi, Giacomina; Conconi, Donatella; Panzeri, Elena; Paoletta, Laura; Piccoli, Elena; Ferretti, Maria Giulia; Mangieri, Michela; Ruggerone, Margherita; Dalprà, Leda; Tagliavini, Fabrizio

    2014-03-01

    Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration.

  3. Effects of new mutations on fitness: insights from models and data.

    Science.gov (United States)

    Bataillon, Thomas; Bailey, Susan F

    2014-07-01

    The rates and properties of new mutations affecting fitness have implications for a number of outstanding questions in evolutionary biology. Obtaining estimates of mutation rates and effects has historically been challenging, and little theory has been available for predicting the distribution of fitness effects (DFE); however, there have been recent advances on both fronts. Extreme-value theory predicts the DFE of beneficial mutations in well-adapted populations, while phenotypic fitness landscape models make predictions for the DFE of all mutations as a function of the initial level of adaptation and the strength of stabilizing selection on traits underlying fitness. Direct experimental evidence confirms predictions on the DFE of beneficial mutations and favors distributions that are roughly exponential but bounded on the right. A growing number of studies infer the DFE using genomic patterns of polymorphism and divergence, recovering a wide range of DFE. Future work should be aimed at identifying factors driving the observed variation in the DFE. We emphasize the need for further theory explicitly incorporating the effects of partial pleiotropy and heterogeneity in the environment on the expected DFE.

  4. Hydrodynamic Effects on Modeling and Control of a High Temperature Active Magnetic Bearing Pump with a Canned Rotor

    Energy Technology Data Exchange (ETDEWEB)

    Melin, Alexander M [ORNL; Kisner, Roger A [ORNL; Fugate, David L [ORNL; Holcomb, David Eugene [ORNL

    2015-01-01

    Embedding instrumentation and control Embedding instrumentation and control (I\\&C) at the component level in nuclear power plants can improve component performance, lifetime, and resilience by optimizing operation, reducing the constraints on physical design, and providing on-board prognostics and diagnostics. However, the extreme environments that many nuclear power plant components operate in makes embedding instrumentation and control at the component level difficult. Successfully utilizing embedded I\\&C requires developing a deep understanding of the system's dynamics and using that knowledge to overcome material and physical limitations imposed by the environment. In this paper, we will develop a coupled dynamic model of a high temperature (700 $^\\circ$C) canned rotor pump that incorporates rotordynamics, hydrodynamics, and active magnetic bearing dynamics. Then we will compare two control design methods, one that uses a simplified decoupled model of the system and another that utilizes the full coupled system model. It will be seen that utilizing all the available knowledge of the system dynamics in the controller design yield an order of magnitude improvement in the magnitude of the magnetic bearing response to disturbances at the same level of control effort, a large reduction in the settling time of the system, and a smoother control action.

  5. Dsp rul: a spontaneous mouse mutation in desmoplakin as a model of Carvajal-Huerta syndrome.

    Science.gov (United States)

    Herbert Pratt, C; Potter, Christopher S; Fairfield, Heather; Reinholdt, Laura G; Bergstrom, David E; Harris, Belinda S; Greenstein, Ian; Dadras, Soheil S; Liang, Bruce T; Schofield, Paul N; Sundberg, John P

    2015-04-01

    Studies of spontaneous mutations in mice have provided valuable disease models and important insights into the mechanisms of human disease. Ruffled (rul) is a new autosomal recessive mutation causing abnormal hair coat in mice. The rul allele arose spontaneously in the RB156Bnr/EiJ inbred mouse strain. In addition to an abnormal coat texture, we found diffuse epidermal blistering, abnormal electrocardiograms (ECGs), and ventricular fibrosis in mutant animals. Using high-throughput sequencing (HTS) we found a frameshift mutation at 38,288,978bp of chromosome 13 in the desmoplakin gene (Dsp). The predicted mutant protein is truncated at the c-terminus and missing the majority of the plakin repeat domain. The phenotypes found in Dsp(rul) mice closely model a rare human disorder, Carvajal-Huerta syndrome. Carvajal-Huerta syndrome (CHS) is a rare cardiocutaneous disorder that presents in humans with wooly hair, palmoplantar keratoderma and ventricular cardiomyopathy. CHS results from an autosomal recessive mutation on the 3' end of desmoplakin (DSP) truncating the full length protein. The Dsp(rul) mouse provides a new model to investigate the pathogenesis of CHS, as well as the underlying basic biology of the adhesion molecules coded by the desmosomal genes.

  6. Calculation of water-bearing primary basalt and estimation of source mantle conditions beneath arcs: PRIMACALC2 model for WINDOWS

    Science.gov (United States)

    Kimura, Jun-Ichi; Ariskin, Alexey A.

    2014-04-01

    present a new method for estimating the composition of water-bearing primary arc basalt and its source mantle conditions. The PRIMACALC2 model uses a thermodynamic fractional crystallization model COMAGMAT3.72 and runs with an Excel macro to examine the mantle equilibrium and trace element calculations of a primary basalt. COMAGMAT3.72 calculates magma fractionation in 0-10 kb at various compositions, pressure, oxygen fugacity, and water content, but is only applicable for forward calculations. PRIMACALC2 first calculates the provisional composition of a primary basalt from an observed magma. The basalt composition is then calculated by COMAGMAT3.72 for crystallization. Differences in elemental concentrations between observed and the closest-match calculated magmas are then adjusted in the primary basalt. Further iteration continues until the calculated magma composition converges with the observed magma, resulting in the primary basalt composition. Once the fitting is satisfied, back calculations of trace elements are made using stepwise addition of fractionated minerals. Mantle equilibrium of the primary basalt is tested using the Fo-NiO relationship of olivine in equilibrium with the primary basalt, and thus with the source mantle. Source mantle pressure, temperature, and degree of melting are estimated using petrogenetic grids based on experimental data obtained in anhydrous systems. Mantle melting temperature in a hydrous system is computed by adjusting T with a parameterization for a water-bearing system. PRIMACALC2 can be used either in dry or water-bearing arc magmas and is also applicable to mid-ocean ridge basalts and nonalkalic ocean island basalts.

  7. An experimental test of the accumulated copying error model of cultural mutation for Acheulean handaxe size.

    Science.gov (United States)

    Kempe, Marius; Lycett, Stephen; Mesoudi, Alex

    2012-01-01

    Archaeologists interested in explaining changes in artifact morphology over long time periods have found it useful to create models in which the only source of change is random and unintentional copying error, or 'cultural mutation'. These models can be used as null hypotheses against which to detect non-random processes such as cultural selection or biased transmission. One proposed cultural mutation model is the accumulated copying error model, where individuals attempt to copy the size of another individual's artifact exactly but make small random errors due to physiological limits on the accuracy of their perception. Here, we first derive the model within an explicit mathematical framework, generating the predictions that multiple independently-evolving artifact chains should diverge over time such that their between-chain variance increases while the mean artifact size remains constant. We then present the first experimental test of this model in which 200 participants, split into 20 transmission chains, were asked to faithfully copy the size of the previous participant's handaxe image on an iPad. The experimental findings supported the model's prediction that between-chain variance should increase over time and did so in a manner quantitatively in line with the model. However, when the initial size of the image that the participants resized was larger than the size of the image they were copying, subjects tended to increase the size of the image, resulting in the mean size increasing rather than staying constant. This suggests that items of material culture formed by reductive vs. additive processes may mutate differently when individuals attempt to replicate faithfully the size of previously-produced artifacts. Finally, we show that a dataset of 2601 Acheulean handaxes shows less variation than predicted given our empirically measured copying error variance, suggesting that other processes counteracted the variation in handaxe size generated by perceptual

  8. The water retention curve and relative permeability for gas production from hydrate-bearing sediments: pore-network model simulation

    Science.gov (United States)

    Mahabadi, Nariman; Dai, Sheng; Seol, Yongkoo; Sup Yun, Tae; Jang, Jaewon

    2016-08-01

    The water retention curve and relative permeability are critical to predict gas and water production from hydrate-bearing sediments. However, values for key parameters that characterize gas and water flows during hydrate dissociation have not been identified due to experimental challenges. This study utilizes the combined techniques of micro-focus X-ray computed tomography (CT) and pore-network model simulation to identify proper values for those key parameters, such as gas entry pressure, residual water saturation, and curve fitting values. Hydrates with various saturation and morphology are realized in the pore-network that was extracted from micron-resolution CT images of sediments recovered from the hydrate deposit at the Mallik site, and then the processes of gas invasion, hydrate dissociation, gas expansion, and gas and water permeability are simulated. Results show that greater hydrate saturation in sediments lead to higher gas entry pressure, higher residual water saturation, and steeper water retention curve. An increase in hydrate saturation decreases gas permeability but has marginal effects on water permeability in sediments with uniformly distributed hydrate. Hydrate morphology has more significant impacts than hydrate saturation on relative permeability. Sediments with heterogeneously distributed hydrate tend to result in lower residual water saturation and higher gas and water permeability. In this sense, the Brooks-Corey model that uses two fitting parameters individually for gas and water permeability properly capture the effect of hydrate saturation and morphology on gas and water flows in hydrate-bearing sediments.

  9. Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Umayal Sivagnanalingam

    Full Text Available Cytogenetically normal acute myeloid leukemia (CN-AML patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH. Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.

  10. Complementing mutations in core binding factor leukemias: from mouse models to clinical applications.

    Science.gov (United States)

    Müller, A M S; Duque, J; Shizuru, J A; Lübbert, M

    2008-10-02

    A great proportion of acute myeloid leukemias (AMLs) display cytogenetic abnormalities including chromosomal aberrations and/or submicroscopic mutations. These abnormalities significantly influence the prognosis of the disease. Hence, a thorough genetic work-up is an essential constituent of standard diagnostic procedures. Core binding factor (CBF) leukemias denote AMLs with chromosomal aberrations disrupting one of the CBF transcription factor genes; the most common examples are translocation t(8;21) and inversion inv(16), which result in the generation of the AML1-ETO and CBFbeta-MYH11 fusion proteins, respectively. However, in murine models, these alterations alone do not suffice to generate full-blown leukemia, but rather, complementary events are required. In fact, a substantial proportion of primary CBF leukemias display additional activating mutations, mostly of the receptor tyrosine kinase (RTK) c-KIT. The awareness of the impact and prognostic relevance of these 'second hits' is increasing with a wider range of mutations tested in clinical trials. Furthermore, novel agents targeting RTKs are emanating rapidly and entering therapeutic regimens. Here, we present a concise review on complementing mutations in CBF leukemias including pathophysiology, mouse models, and clinical implications.

  11. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor.

    Science.gov (United States)

    Tan, Karen; Pogozheva, Irina D; Yeo, Giles S H; Hadaschik, Dirk; Keogh, Julia M; Haskell-Leuvano, Carrie; O'Rahilly, Stephen; Mosberg, Henry I; Farooqi, I Sadaf

    2009-01-01

    Mutations in the melanocortin 4 receptor (MC4R) gene are the most common known cause of monogenic human obesity. The MC4R gene was sequenced in 2000 subjects with severe early-onset obesity. We detected seven different nonsense and 19 nonsynonymous mutations in a total of 94 probands, some of which have been reported previously by others. We functionally characterized the 11 novel obesity associated missense mutations. Seven of these mutants (L54P, E61K, I69T, S136P, M161T, T162I, and I269N) showed impaired cell surface trafficking, reduced level of maximal binding of the radioligand [125I]NDP-MSH, and reduced ability to generate cAMP in response to ligand. Four mutant MC4Rs (G55V, G55D, S136F, and A303T) displayed cell surface expression and agonist binding similar to the wild-type receptor but showed impaired cAMP production, suggesting that these residues are likely to be critical for conformational rearrangement essential for receptor activation. Homology modeling of these mutants using a model of MC4R based on the crystal structure of the beta2-adrenoreceptor was used to provide insights into the possible structural basis for receptor dysfunction. Transmembrane (TM) domains 1, 3, 6, 7, and peripheral helix 8 appear to participate in the agonist-induced conformational rearrangement necessary for coupling of ligand binding to signaling. We conclude that G55V, G55D, S136F, and A303T mutations are likely to strengthen helix-helix interactions between TM1 and TM2, TM3 and TM6, and TM7 and helix 8, respectively, preventing relative movement of these helices during receptor activation. The combination of functional studies and structural modeling of naturally occurring pathogenic mutations in MC4R can provide valuable information regarding the molecular mechanism of MC4R activation and its dysfunction in human disease.

  12. Modeling the effects of human activity on Katmai brown bears (Ursus arctos) through the use of survival analysis

    Science.gov (United States)

    Smith, T.S.; Johnson, B.A.

    2004-01-01

    Brown bear-human interactions were observed in 1993, 1995, and 1997 at Kulik River in Katmai National Park and Preserve, Alaska. We analyzed these interactions using survival analysis, creating survival curves for the time that bears remained on the river in the presence, and absence, of human activity. Bear-only survival curves did not vary significantly between years (p = 0.067). Ninety-seven percent of bears left the river within 70 minutes of arrival in all years. Temporal patterns of bear activity were unaffected by the presence of humans as long as the bears did not share river zones with humans (p = 0.062 to p = 0.360). When people and bears did not share river zones, 38.6% (1993), 36.0% (1995), and 37.0% (1997) of bears remained on the river for at least 10 minutes after arrival. In contrast, when people and bears shared river zones, fewer bears remained on the river after the first 10 minutes, with 28.6% (1993), 25.0% (1995), and 32.6% (1997) observed in each year. We conclude that human activity displaced 26.0% (1993), 30.5% (1995), and 12.0% (1997) of the bears using the river, which otherwise would likely have remained longer. Over the three years of study, habituation to human activity may account for observed changes in bears' use of the river.

  13. Estimation of Mutation Frequencies of Mice Caused by Radiation -- Application of LDM Model I

    CERN Document Server

    Manabe, Yuichiro

    2012-01-01

    In a separate paper [Y. Manabe et al: arxiv:1204.2324], we propose a mathematical model to estimate biological damage caused by radiation, which we call LDM (Low Dose Meeting) Model, hereafter. By using LDM model, we calculate the mutation frequency of mice and compare our results with the existing data, the frequency of transmitted specific-locus mutations induced in mouse spermatogonia stem-cells, which was reported by Russell and Kelly [W. L. Russell. et al: Proc. Natl. Acad. Sci. USA 79 (1982), 542-544]. By fixing the two parameters of LDM model, c and {\\mu}, we can reproduce the observed data almost well. They are determined by experimental value of mutation frequency together with the corresponding total dose and dose rate. For a moment, we had to adopt simple assumption due to the lack of detailed information. If we have information of the exposure process exactly, it is easy to estimate the dose-rate effectiveness factor (DDREF) almost exactly. Thus LDM model may be applied to total dose and dose rate...

  14. Incorporating experimental design and error into coalescent/mutation models of population history.

    Science.gov (United States)

    Knudsen, Bjarne; Miyamoto, Michael M

    2007-08-01

    Coalescent theory provides a powerful framework for estimating the evolutionary, demographic, and genetic parameters of a population from a small sample of individuals. Current coalescent models have largely focused on population genetic factors (e.g., mutation, population growth, and migration) rather than on the effects of experimental design and error. This study develops a new coalescent/mutation model that accounts for unobserved polymorphisms due to missing data, sequence errors, and multiple reads for diploid individuals. The importance of accommodating these effects of experimental design and error is illustrated with evolutionary simulations and a real data set from a population of the California sea hare. In particular, a failure to account for sequence errors can lead to overestimated mutation rates, inflated coalescent times, and inappropriate conclusions about the population. This current model can now serve as a starting point for the development of newer models with additional experimental and population genetic factors. It is currently implemented as a maximum-likelihood method, but this model may also serve as the basis for the development of Bayesian approaches that incorporate experimental design and error.

  15. SLC4A11 Three-Dimensional Homology Model Rationalizes Corneal Dystrophy-Causing Mutations.

    Science.gov (United States)

    Badior, Katherine E; Alka, Kumari; Casey, Joseph R

    2017-03-01

    We studied the structural effects of point mutations of a membrane protein that cause genetic disease. SLC4A11 is a membrane transport protein (OH(-) /H(+) /NH3 /H2 O) of basolateral corneal endothelium, whose mutations cause some cases of congenital hereditary endothelial dystrophy and Fuchs endothelial corneal dystrophy. We created a three-dimensional homology model of SLC4A11 membrane domain, using Band 3 (SLC4A1) crystal structure as template. The homology model was assessed in silico and by analysis of mutants designed on the basis of the model. Catalytic pathway mutants p.Glu675Gln, p.His724Arg, and p.His724Ala impaired SLC4A11 transport. p.Ala720Leu, in a region of extended structure of the proposed translocation pore, failed to mature to the cell surface. p.Gly509Lys, located in an open region at the core domain/gate domain interface, had wild-type level of transport function. The molecular phenotype of 37 corneal dystrophy-causing point mutants was rationalized, based on their location in the homology model. Four map to the substrate translocation pathway, 25 to regions of close transmembrane helix packing, three to the dimeric interface, and five lie in extramembraneous loops. The model provides a view of the spectrum of effects of disease mutations on membrane protein structure and provides a tool to analyze pathogenicity of additional newly discovered SLC4A11 mutants. © 2016 WILEY PERIODICALS, INC.

  16. Characterization of Fault Size in Bearings

    Science.gov (United States)

    2014-12-23

    0.3 and 1.2 mm into the outer-race of the bearing, which simulates realistic faults that often can be found in damaged bearings. A 3D dynamic model ...3 4. MODEL DESCRIPTION A 3D dynamic ball bearing model was developed to study the effect of faults on the bearing dynamic behavior. The aim of the...understanding of the effects of fault size on the bearing dynamics. The research methodology combines dynamic modeling of the faulty bearing with

  17. Colored petri nets to model gene mutation and amino acids classification.

    Science.gov (United States)

    Yang, Jinliang; Gao, Rui; Meng, Max Q-H; Tarn, Tzyh-Jong

    2012-05-07

    The genetic code is the triplet code based on the three-letter codons, which determines the specific amino acid sequences in proteins synthesis. Choosing an appropriate model for processing these codons is a useful method to study genetic processes in Molecular Biology. As an effective modeling tool of discrete event dynamic systems (DEDS), colored petri net (CPN) has been used for modeling several biological systems, such as metabolic pathways and genetic regulatory networks. According to the genetic code table, CPN is employed to model the process of genetic information transmission. In this paper, we propose a CPN model of amino acids classification, and further present the improved CPN model. Based on the model mentioned above, we give another CPN model to classify the type of gene mutations via contrasting the bases of DNA strands and the codons of amino acids along the polypeptide chain. This model is helpful in determining whether a certain gene mutation will cause the changes of the structures and functions of protein molecules. The effectiveness and accuracy of the presented model are illustrated by the examples in this paper.

  18. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation.

    Directory of Open Access Journals (Sweden)

    Sian E Piret

    Full Text Available Chronic kidney disease (CKD is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2 expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the

  19. Modeling seismic wave propagation in a coal-bearing porous medium by a staggered-grid finite difference method

    Institute of Scientific and Technical Information of China (English)

    Zou Guangui; Peng Suping; Yin Caiyun; Deng Xiaojuan; Chen Fengying; Xu Yanyong

    2011-01-01

    A staggered-grid finite difference method is used to model seismic wave records in a coal bearing,porous medium.The variables analyzed include the order of the difference calculations,the use of a perfect match layer to provide absorbing boundary conditions,the source location,the stability conditions,and dispersion in the medium.The results show that the location of the first derivative of the dynamic variable with respect to space is coincident with the location of the first derivative of the kinematic variable with respect to time.Outgoing waves are effectively absorbed and reflection at the boundary is very weak when more than 20 perfect match layer cells are used.Biot theory considers the liquid phase to be homogeneous so the ratio of liquid to solid exposure of the seismic source depends upon the medium porosity.Numerical dispersion and generation of false frequencies is reduced by increasing the accuracy of the difference calculations and by reducing the grid size and time step.Temporal second order accuracy,a tenth order spatial accuracy,and a wavelength over more than ten grid points gave acceptable numerical results.Larger grid step sizes in the lateral direction and smaller grid sizes in the vertical direction allow control of dispersion when the medium is a low speed body.This provides a useful way to simulate seismic waves in a porous coal bearing medium.

  20. Src mutation induces acquired lapatinib resistance in ERBB2-amplified human gastroesophageal adenocarcinoma models.

    Directory of Open Access Journals (Sweden)

    Yong Sang Hong

    Full Text Available ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired SrcE527K mutation in a subset of LR OE19 subclones. Cells with this mutant allele harbour increased Src phosphorylation. Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib. Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells. Ectopic expression of SrcE527K mutation also was sufficient to induce lapatinib resistance in drug-naïve cells. These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB2 inhibition in ERBB2-amplified gastroesophageal cancer. Although Src mutation has not been described in primary tumor samples, we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB2 inhibition in esophageal and gastric adenocarcinoma.

  1. Genetic Algorithm Based on New Evaluation Function and Mutation Model for Training of BPNN

    Institute of Scientific and Technical Information of China (English)

    周祥; 何小荣; 陈丙珍

    2002-01-01

    A local minimum is frequently encountered in the training of back propagation neural networks (BPNN), which sharply slows the training process. In this paper, an analysis of the formation of local minima is presented, and an improved genetic algorithm (GA) is introduced to overcome local minima. The Sigmoid function is generally used as the activation function of BPNN nodes. It is the flat characteristic of the Sigmoid function that results in the formation of local minima. In the improved GA, pertinent modifications are made to the evaluation function and the mutation model. The evaluation of the solution is associated with both the training error and gradient. The sensitivity of the error function to network parameters is used to form a self-adapting mutation model. An example of industrial application shows the advantage of the improved GA to overcome local minima.

  2. Multi-mutational model for cancer based on age-time patterns of radiation effects: 2. Biological aspects

    Energy Technology Data Exchange (ETDEWEB)

    Mendelsohn, M.L.; Pierce, P.A.

    1997-09-04

    Biological properties of relevance when modeling cancers induced in the atom bomb survivors include the wide distribution of the induced cancers across all organs, their biological indistinguishability from background cancers, their rates being proportional to background cancer rates, their rates steadily increasing over at least 50 years as the survivors age, and their radiation dose response being linear. We have successfully described this array of properties with a modified Armitage-Doll model using 5 to 6 somatic mutations, no intermediate growth, and the dose-related replacement of any one of these time-driven mutations by a radiation-induced mutation. Such a model is contrasted to prevailing models that use fewer mutations combined with intervening growth. While the rationale and effectiveness of our model is compelling for carcinogenesis in the atom bomb survivors, the lack of a promotional component may limit the generality of the model for other types of human carcinogenesis.

  3. Cavitation Estimates by Orbit Prediction of a Journal Bearing - Finite Element Modelling and Experimental Studies Cavitation Estimates by Orbit Prediction of a Journal Bearing - Finite Element Modelling and Experimental Studies

    DEFF Research Database (Denmark)

    Christiansen, Christian Kim; Klit, Peder; Walther, Jens Honore;

    2015-01-01

    The paper presents a two-sided approach to establish understanding of the cavitation phenomenon in dynamically loaded journal bearings, more specifically the engine bearings of large two-stroke marine diesel engines. One disadvantage of the journal bearing is the converging-diverging geometry...... making it prone to cavitation which again affects the load carrying capacity of the bearing. In combustion engines the journal bearing plays a vital role especiallyas main and crosshead bearings transmitting the combustion forces. Those forces vary highly during one combustion cycle which is further....... Validation of the results is done against the Ruston and Hornsby 6VEB-X Mk III engine. Besides the numerical investigations a cavitation test rig has been developed. With this rig it is possible to generate cavitation under controlled conditions in terms ofload/eccentricity and rotational speed...

  4. Markov Chain-Like Quantum Biological Modeling of Mutations, Aging, and Evolution

    Directory of Open Access Journals (Sweden)

    Ivan B. Djordjevic

    2015-08-01

    Full Text Available Recent evidence suggests that quantum mechanics is relevant in photosynthesis, magnetoreception, enzymatic catalytic reactions, olfactory reception, photoreception, genetics, electron-transfer in proteins, and evolution; to mention few. In our recent paper published in Life, we have derived the operator-sum representation of a biological channel based on codon basekets, and determined the quantum channel model suitable for study of the quantum biological channel capacity. However, this model is essentially memoryless and it is not able to properly model the propagation of mutation errors in time, the process of aging, and evolution of genetic information through generations. To solve for these problems, we propose novel quantum mechanical models to accurately describe the process of creation spontaneous, induced, and adaptive mutations and their propagation in time. Different biological channel models with memory, proposed in this paper, include: (i Markovian classical model, (ii Markovian-like quantum model, and (iii hybrid quantum-classical model. We then apply these models in a study of aging and evolution of quantum biological channel capacity through generations. We also discuss key differences of these models with respect to a multilevel symmetric channel-based Markovian model and a Kimura model-based Markovian process. These models are quite general and applicable to many open problems in biology, not only biological channel capacity, which is the main focus of the paper. We will show that the famous quantum Master equation approach, commonly used to describe different biological processes, is just the first-order approximation of the proposed quantum Markov chain-like model, when the observation interval tends to zero. One of the important implications of this model is that the aging phenotype becomes determined by different underlying transition probabilities in both programmed and random (damage Markov chain-like models of aging, which

  5. Markov Chain-Like Quantum Biological Modeling of Mutations, Aging, and Evolution.

    Science.gov (United States)

    Djordjevic, Ivan B

    2015-08-24

    Recent evidence suggests that quantum mechanics is relevant in photosynthesis, magnetoreception, enzymatic catalytic reactions, olfactory reception, photoreception, genetics, electron-transfer in proteins, and evolution; to mention few. In our recent paper published in Life, we have derived the operator-sum representation of a biological channel based on codon basekets, and determined the quantum channel model suitable for study of the quantum biological channel capacity. However, this model is essentially memoryless and it is not able to properly model the propagation of mutation errors in time, the process of aging, and evolution of genetic information through generations. To solve for these problems, we propose novel quantum mechanical models to accurately describe the process of creation spontaneous, induced, and adaptive mutations and their propagation in time. Different biological channel models with memory, proposed in this paper, include: (i) Markovian classical model, (ii) Markovian-like quantum model, and (iii) hybrid quantum-classical model. We then apply these models in a study of aging and evolution of quantum biological channel capacity through generations. We also discuss key differences of these models with respect to a multilevel symmetric channel-based Markovian model and a Kimura model-based Markovian process. These models are quite general and applicable to many open problems in biology, not only biological channel capacity, which is the main focus of the paper. We will show that the famous quantum Master equation approach, commonly used to describe different biological processes, is just the first-order approximation of the proposed quantum Markov chain-like model, when the observation interval tends to zero. One of the important implications of this model is that the aging phenotype becomes determined by different underlying transition probabilities in both programmed and random (damage) Markov chain-like models of aging, which are mutually

  6. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

    NARCIS (Netherlands)

    A. Liso (Arcangelo); F. Castiglione (Filippo); A. Cappuccio (Antonio); F. Stracci (Fabrizio); R.F. Schlenk (Richard); S. Amadori (Sergio); C. Thiede (Christian); S. Schnittger (Susanne); P.J.M. Valk (Peter); K. Döhner (Konstanze); M.F. Martelli (Massimo F.); M. Schaich (Markus); J. Krauter; A. Ganser (Arnold); N. Bolli (Niccolò); B. Löwenberg (Bob); T. Haferlach (Torsten); G. Ehninger (Gerhard); F. Mandelli (Franco); F. Michor (Franziska); B. Falini

    2008-01-01

    textabstractAcute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc+acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, an

  7. Grease lubrication in rolling bearings

    CERN Document Server

    Lugt, Piet M

    2012-01-01

    The definitive book on the science of grease lubrication for roller and needle bearings in industrial and vehicle engineering. Grease Lubrication in Rolling Bearings provides an overview of the existing knowledge on the various aspects of grease lubrication (including lubrication systems) and the state of the art models that exist today. The book reviews the physical and chemical aspects of grease lubrication, primarily directed towards lubrication of rolling bearings. The first part of the book covers grease composition, properties and rheology, including thermal

  8. 3D mechanical analysis of aeronautical plain bearings: Validation of a finite element model from measurement of displacement fields by digital volume correlation and optical scanning tomography

    Science.gov (United States)

    Germaneau, A.; Peyruseigt, F.; Mistou, S.; Doumalin, P.; Dupré, J.-C.

    2010-06-01

    On Airbus aircraft, spherical plain bearings are used on many components; in particular to link engine to pylon or pylon to wing. Design of bearings is based on contact pressure distribution on spherical surfaces. To determine this distribution, a 3D analysis of the mechanical behaviour of aeronautical plain bearing is presented in this paper. A numerical model has been built and validated from a comparison with 3D experimental measurements of kinematic components. For that, digital volume correlation (DVC) coupled with optical scanning tomography (OST) is employed to study the mechanical response of a plain bearing model made in epoxy resin. Experimental results have been compared with the ones obtained from the simulated model. This comparison enables us to study the influence of various boundary conditions to build the FE model. Some factors have been highlighted like the fitting behaviour which can radically change contact pressure distribution. This work shows the contribution of a representative mechanical environment to study precisely mechanical response of aeronautical plain bearings.

  9. Dynamic modeling for rigid rotor bearing systems with a localized defect considering additional deformations at the sharp edges

    Science.gov (United States)

    Liu, Jing; Shao, Yimin

    2017-06-01

    Rotor bearing systems (RBSs) play a very valuable role for wind turbine gearboxes, aero-engines, high speed spindles, and other rotational machinery. An in-depth understanding of vibrations of the RBSs is very useful for condition monitoring and diagnosis applications of these machines. A new twelve-degree-of-freedom dynamic model for rigid RBSs with a localized defect (LOD) is proposed. This model can formulate the housing support stiffness, interfacial frictional moments including load dependent and load independent components, time-varying displacement excitation caused by a LOD, additional deformations at the sharp edges of the LOD, and lubricating oil film. The time-varying displacement model is determined by a half-sine function. A new method for calculating the additional deformations at the sharp edges of the LOD is analytical derived based on an elastic quarter-space method presented in the literature. The proposed dynamic model is utilized to analyze the influences of the housing support stiffness and LOD sizes on the vibration characteristics of the rigid RBS, which cannot be predicted by the previous dynamic models in the literature. The results show that the presented method can give a new dynamic modeling method for vibration formulation for a rigid RBS with and without the LOD on the races.

  10. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Garza, Rene [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Hudson, Robert A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); McMahan, C. Alex [Department of Pathology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Walter, Christi A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); South Texas Veterans Healthcare System, San Antonio, TX 78229 (United States); Vogel, Kristine S. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States)]. E-mail: vogelk@uthscsa.edu

    2007-02-03

    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  11. Modeling the Relationship between Vibration Features and Condition Parameters Using Relevance Vector Machines for Health Monitoring of Rolling Element Bearings under Varying Operation Conditions

    Directory of Open Access Journals (Sweden)

    Lei Hu

    2015-01-01

    Full Text Available Rotational speed and load usually change when rotating machinery works. Both this kind of changing operational conditions and machine fault could make the mechanical vibration characteristics change. Therefore, effective health monitoring method for rotating machinery must be able to adjust during the change of operational conditions. This paper presents an adaptive threshold model for the health monitoring of bearings under changing operational conditions. Relevance vector machines (RVMs are used for regression of the relationships between the adaptive parameters of the threshold model and the statistical characteristics of vibration features. The adaptive threshold model is constructed based on these relationships. The health status of bearings can be indicated via detecting whether vibration features exceed the adaptive threshold. This method is validated on bearings running at changing speeds. The monitoring results show that this method is effective as long as the rotational speed is higher than a relative small value.

  12. A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

    Directory of Open Access Journals (Sweden)

    Greger Abrahamsen

    2013-03-01

    Hereditary spastic paraplegia (HSP leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

  13. Completing the Remedial Sequence and College-Level Credit-Bearing Math: Comparing Binary, Cumulative, and Continuation Ratio Logistic Regression Models

    Science.gov (United States)

    Davidson, J. Cody

    2016-01-01

    Mathematics is the most common subject area of remedial need and the majority of remedial math students never pass a college-level credit-bearing math class. The majorities of studies that investigate this phenomenon are conducted at community colleges and use some type of regression model; however, none have used a continuation ratio model. The…

  14. Completing the Remedial Sequence and College-Level Credit-Bearing Math: Comparing Binary, Cumulative, and Continuation Ratio Logistic Regression Models

    Science.gov (United States)

    Davidson, J. Cody

    2016-01-01

    Mathematics is the most common subject area of remedial need and the majority of remedial math students never pass a college-level credit-bearing math class. The majorities of studies that investigate this phenomenon are conducted at community colleges and use some type of regression model; however, none have used a continuation ratio model. The…

  15. Mutation-selection models of codon substitution and their use to estimate selective strengths on codon usage

    DEFF Research Database (Denmark)

    Yang, Ziheng; Nielsen, Rasmus

    2008-01-01

    Current models of codon substitution are formulated at the levels of nucleotide substitution and do not explicitly consider the separate effects of mutation and selection. They are thus incapable of inferring whether mutation or selection is responsible for evolution at silent sites. Here we...... to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection. Application of the test to the mammalian data led to rejection of the null hypothesis in most genes, suggesting that natural selection may be a driving force in the evolution of synonymous...... codon usage in mammals. Estimates of selection coefficients nevertheless suggest that selection on codon usage is weak and most mutations are nearly neutral. The sensitivity of the analysis on the assumed mutation model is discussed....

  16. Non-coding cancer driver candidates identified with a sample- and position-specific model of the somatic mutation rate

    Science.gov (United States)

    Juul, Malene; Bertl, Johanna; Guo, Qianyun; Nielsen, Morten Muhlig; Świtnicki, Michał; Hornshøj, Henrik; Madsen, Tobias; Hobolth, Asger; Pedersen, Jakob Skou

    2017-01-01

    Non-coding mutations may drive cancer development. Statistical detection of non-coding driver regions is challenged by a varying mutation rate and uncertainty of functional impact. Here, we develop a statistically founded non-coding driver-detection method, ncdDetect, which includes sample-specific mutational signatures, long-range mutation rate variation, and position-specific impact measures. Using ncdDetect, we screened non-coding regulatory regions of protein-coding genes across a pan-cancer set of whole-genomes (n = 505), which top-ranked known drivers and identified new candidates. For individual candidates, presence of non-coding mutations associates with altered expression or decreased patient survival across an independent pan-cancer sample set (n = 5454). This includes an antigen-presenting gene (CD1A), where 5’UTR mutations correlate significantly with decreased survival in melanoma. Additionally, mutations in a base-excision-repair gene (SMUG1) correlate with a C-to-T mutational-signature. Overall, we find that a rich model of mutational heterogeneity facilitates non-coding driver identification and integrative analysis points to candidates of potential clinical relevance. DOI: http://dx.doi.org/10.7554/eLife.21778.001 PMID:28362259

  17. P-V-T Equation of State of (Al,Fe)-bearing Mantle Perovskite and its Implications for Mantle Models

    Science.gov (United States)

    Fei, Y.; Ricolleau, A.; Litasov, K.; Prakapenka, V.

    2008-12-01

    We have made significant progress on accurate measurements of P-V-T equations-of-state of mantle minerals that are of fundamental importance for developing compositional and mineralogical models of the Earth's mantle. In this study, we report new compression data on (Al,Fe)-bearing mantle perovskite up to simultaneous pressure and temperature of 113 GPa and 2120 K. The mantle perovskite was synthesized in the multi-anvil apparatus at 27 GPa and 2073 K, with chemical compositions expected in a peridotitic mantle. It contains 5.86 wt% FeO and 3.84 wt% Al2O3. The pre-synthesized perovsite mixed with Au powder was compressed in neon pressure medium in a symmetric diamond anvil cell. The sample was heated with a double-sided laser-heating system at the GSECARS 13-ID-D beamline (Advanced Photon Source). We performed 8 heating cycles in the pressure range of 30-113 GPa and temperatures up to 2560 K. In-situ synchrotron X-ray diffraction data were collected within a uniformly heated area, using a MAR-CCD area detector. The diffraction pattern contains peaks of orthorhombic perovskite, internal standard Au, and pressure medium Ne. The triplet (020, 112, and 200 diffraction peaks) of the orthorhombic perovskite is well resolve. The present dataset covers the entire P-T range of the lower mantle and requires no extrapolation to compare the mantle density profile derived from seismic observations. In light of the new P-V-T data on the (Al,Fe)-bearing mantle perovskite combined with our recent density data and spin transition of ferropericlase, we finally discuss the compositional and mineralogical models of the lower mantle.

  18. Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology.

    LENUS (Irish Health Repository)

    2011-01-01

    Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.

  19. Modeling and experimental assessment of a buried Leu–Ile mutation in dengue envelope domain III

    Energy Technology Data Exchange (ETDEWEB)

    Kulkarni, Manjiri R. [Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Nakamachi, Koganei-shi, Tokyo, 184-8588 (Japan); Numoto, Nobutaka; Ito, Nobutoshi [Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima Bunkyo-ku, Tokyo, 113-8510 (Japan); Kuroda, Yutaka, E-mail: ykuroda@cc.tuat.ac.jp [Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Nakamachi, Koganei-shi, Tokyo, 184-8588 (Japan)

    2016-02-26

    Envelope protein domain III (ED3) of the dengue virus is important for both antibody binding and host cell interaction. Here, we focused on how a L387I mutation in the protein core could take place in DEN4 ED3, but cannot be accommodated in DEN3 ED3 without destabilizing its structure. To this end, we modeled a DEN4-L387I structure using the Penultimate Rotamer Library and taking the DEN4 ED3 main-chain as a fixed template. We found that three out of seven Ile{sup 387} conformers fit in DEN4 ED3 without introducing the severe atomic clashes that are observed when DEN3 serotype’s ED3 is used as a template. A more extensive search using 273 side-chain rotamers of the residues surrounding Ile{sup 387} confirmed this prediction. In order to assess the prediction, we determined the crystal structure of DEN4-L387I at 2 Å resolution. Ile{sup 387} indeed adopted one of the three predicted rotamers. Altogether, this study demonstrates that the effects of single mutations are to a large extent successfully predicted by systematically modeling the side-chain structures of the mutated as well as those of its surrounding residues using fixed main-chain structures and assessing inter-atomic steric clashes. More accurate and reliable predictions require considering sub-angstrom main-chain deformation, which remains a challenging task. - Highlights: • We mutated L387I of DEN4 ED3 and examined its effects on structure and stability. • We modeled the side-chain of Ile{sup 387} using DEN4 ED3's structure as a template. • We determined the crystal structure of DEN4-L387I and confirmed the modeling. • Side-chain repacking occurring around Ile{sup 387} involved >3 inter-connected residues. • These results explained why L387I mutation in DEN4 ED3 conserves thermostability.

  20. Modeling the induced mutation process in bacterial cells with defects in excision repair system

    Science.gov (United States)

    Bugay, A. N.; Vasilyeva, M. A.; Krasavin, E. A.; Parkhomenko, A. Yu.

    2015-12-01

    A mathematical model of the UV-induced mutation process in Escherichia coli cells with defects in the uvrA and polA genes has been developed. The model describes in detail the reaction kinetics for the excision repair system. The number of mismatches as a result of translesion synthesis is calculated for both wild-type and mutant cells. The effect of temporal modulation of the number of single-stranded DNA during postreplication repair has been predicted. A comparison of effectiveness of different repair systems has been conducted.

  1. Rolling Element Bearing Stiffness Matrix Determination (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Y.; Parker, R.

    2014-01-01

    Current theoretical bearing models differ in their stiffness estimates because of different model assumptions. In this study, a finite element/contact mechanics model is developed for rolling element bearings with the focus of obtaining accurate bearing stiffness for a wide range of bearing types and parameters. A combined surface integral and finite element method is used to solve for the contact mechanics between the rolling elements and races. This model captures the time-dependent characteristics of the bearing contact due to the orbital motion of the rolling elements. A numerical method is developed to determine the full bearing stiffness matrix corresponding to two radial, one axial, and two angular coordinates; the rotation about the shaft axis is free by design. This proposed stiffness determination method is validated against experiments in the literature and compared to existing analytical models and widely used advanced computational methods. The fully-populated stiffness matrix demonstrates the coupling between bearing radial, axial, and tilting bearing deflections.

  2. Predictive Modeling and Mapping of Malayan Sun Bear (Helarctos malayanus) Distribution Using Maximum Entropy

    OpenAIRE

    Mona Nazeri; Kamaruzaman Jusoff; Nima Madani; Ahmad Rodzi Mahmud; Abdul Rani Bahman; Lalit Kumar

    2012-01-01

    One of the available tools for mapping the geographical distribution and potential suitable habitats is species distribution models. These techniques are very helpful for finding poorly known distributions of species in poorly sampled areas, such as the tropics. Maximum Entropy (MaxEnt) is a recently developed modeling method that can be successfully calibrated using a relatively small number of records. In this research, the MaxEnt model was applied to describe the distribution and identify ...

  3. Testing landscape modeling approaches for environmental impact assessment of mining land use on grizzly bears (Ursus arctos horribilis) in the foothills region of west central Alberta

    Energy Technology Data Exchange (ETDEWEB)

    Symbaluk, M.D. [Elk Valley Coal Corp., Hinton, AB (Canada). Cardinal River Operations

    2008-07-01

    The Cheviot open pit coal mine is located on the front range of the Rocky Mountains in Alberta. The environmental impact assessment (EIA) requirements for the mining project included an assessment of the cumulative effects of past, existing, and immanent activities on a 3040 km{sup 2} study area radiating approximately 25 km around the proposed project area. The grizzly bear was identified as a flagship valued ecosystem component (VEC) for assessing the regional cumulative effects of the proposed Cheviot project. In this portion of the study, a grizzly bear habitat effectiveness model was used to monitor grizzly bear response to mining land use in the study area. An investigation of grizzly bear movement paths prior to and during mine disturbances demonstrated that mining land use does not present significant barriers to grizzly bear activities. The study demonstrated the importance of using inductive modelling tools at appropriate scales, as well as the use of site-specific empirical data. It was concluded that continued monitoring of mining sites is needed to ensure that adaptive management processes are improved. A review of the Cheviot cumulative environmental effects (CEA) process was also provided. 17 refs., 1 fig.

  4. Structural basis for drug resistance conferred by β-tubulin mutations: a molecular modeling study on native and mutated tubulin complexes with epothilone B.

    Science.gov (United States)

    Navarrete, Karen R; Alderete, Joel B; Jiménez, Verónica A

    2015-01-01

    Using molecular modeling, we have investigated the structure and dynamic properties of epothilone B-tubulin complexes with wild-type and mutated tubulin, aimed at identifying the molecular factors involved in the emergence of drug resistance induced by four protein mutations at Phe270Val, Thr274Ile, Arg282Gln, and Gln292Glu. Our results revealed that tubulin mutations render significant changes in the protein conformation in regions involved either in the binding of the ligand or in interdimer contacts that are relevant to the assembly of stable microtubules. In addition, point mutations induce drastic changes in the binding pose of the ligand and in the interaction networks responsible for the epothilone-tubulin association. Large ligand displacements inside the binding pocket and an overall decrease in the strength of drug-receptor polar contacts suggest a looser binding of the ligand in tubulin mutants. These results explain the loss of activity for epothilone B against cancer cells that contain tubulin mutants and provide valuable information to enhance the understanding of the atomic source of epothilones' activity, which can be helpful to conduct further research on the rational design of more potent therapeutic tubulin-binding agents.

  5. Development and validation of a weight-bearing finite element model for total knee replacement.

    Science.gov (United States)

    Woiczinski, M; Steinbrück, A; Weber, P; Müller, P E; Jansson, V; Schröder, Ch

    2016-01-01

    Total knee arthroplasty (TKA) is a successful procedure for osteoarthritis. However, some patients (19%) do have pain after surgery. A finite element model was developed based on boundary conditions of a knee rig. A 3D-model of an anatomical full leg was generated from magnetic resonance image data and a total knee prosthesis was implanted without patella resurfacing. In the finite element model, a restarting procedure was programmed in order to hold the ground reaction force constant with an adapted quadriceps muscle force during a squat from 20° to 105° of flexion. Knee rig experimental data were used to validate the numerical model in the patellofemoral and femorotibial joint. Furthermore, sensitivity analyses of Young's modulus of the patella cartilage, posterior cruciate ligament (PCL) stiffness, and patella tendon origin were performed. Pearson's correlations for retropatellar contact area, pressure, patella flexion, and femorotibial ap-movement were near to 1. Lowest root mean square error for retropatellar pressure, patella flexion, and femorotibial ap-movement were found for the baseline model setup with Young's modulus of 5 MPa for patella cartilage, a downscaled PCL stiffness of 25% compared to the literature given value and an anatomical origin of the patella tendon. The results of the conducted finite element model are comparable with the experimental results. Therefore, the finite element model developed in this study can be used for further clinical investigations and will help to better understand the clinical aspects after TKA with an unresurfaced patella.

  6. Mutation induction by inhaled radon progeny modeled at the tissue level.

    Science.gov (United States)

    Madas, Balázs G; Balásházy, Imre

    2011-11-01

    The observable responses of living systems to ionizing radiation depend on the level of biological organization studied. Understanding the relationships between the responses characteristic of the different levels of organization is of crucial importance. The main objective of the present study is to investigate how some cellular effects of radiation manifest at the tissue level by modeling mutation induction due to chronic exposure to inhaled radon progeny. For this purpose, a mathematical model of the bronchial epithelium was elaborated to quantify cell nucleus hits and cell doses. Mutagenesis was modeled considering endogenous as well as radiation-induced DNA damages and cell cycle shortening due to cell inactivation. The model parameters describing the cellular effects of radiation are obtained from experimental data. Cell nucleus hits, cell doses, and mutation induction were computed for the activity hot spots of the large bronchi at different exposures. Results demonstrate that the mutagenic effect of densely ionizing radiation is dominated by cell cycle shortening due to cell inactivation and not by DNA damages. This suggests that radiation burdens of non-progenitor cells play a significant role in mutagenesis in case of protracted exposures to densely ionizing radiation. Mutation rate as a function of dose rate exhibits a convex shape below a threshold. This threshold indicates the exhaustion of the tissue regeneration capacity of local progenitor cells. It is suggested that progenitor cell hyperplasia occurs beyond the threshold dose rate, giving a possible explanation of the inverse dose-rate effect observed in the epidemiology of lung cancer among uranium miners.

  7. Focused ultrasound enhanced molecular imaging and gene therapy for multifusion reporter gene in glioma-bearing rat model.

    Science.gov (United States)

    Yang, Feng-Yi; Chang, Wen-Yuan; Lin, Wei-Ting; Hwang, Jeng-Jong; Chien, Yi-Chun; Wang, Hsin-Ell; Tsai, Min-Lan

    2015-11-03

    The ability to monitor the responses of and inhibit the growth of brain tumors during gene therapy has been severely limited due to the blood-brain barrier (BBB). A previous study has demonstrated the feasibility of noninvasive in vivo imaging with 123I-2'-fluoro-2'-deoxy-5-iodo-1-β-D-arabinofuranosyluracil (123I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here, we tested the enhancement of SPECT with 123I-FIAU and ganciclovir (GCV) treatment in brain tumors after BBB disruption induced by focused ultrasound (FUS) in the presence of microbubbles. We established an orthotopic F98 glioma-bearing rat model with trifusion reporter genes. The results of this study showed that the rat model of HSV1-tk-expressing glioma cells could be successfully detected by SPECT imaging after FUS-induced BBB disruption on day 10 after implantation. Compared to the control group, animals receiving the GCV with or without sonication exhibited a significant antitumor activity (P therapy in brain diseases.

  8. Adaptive hidden Markov model-based online learning framework for bearing faulty detection and performance degradation monitoring

    Science.gov (United States)

    Yu, Jianbo

    2017-01-01

    This study proposes an adaptive-learning-based method for machine faulty detection and health degradation monitoring. The kernel of the proposed method is an "evolving" model that uses an unsupervised online learning scheme, in which an adaptive hidden Markov model (AHMM) is used for online learning the dynamic health changes of machines in their full life. A statistical index is developed for recognizing the new health states in the machines. Those new health states are then described online by adding of new hidden states in AHMM. Furthermore, the health degradations in machines are quantified online by an AHMM-based health index (HI) that measures the similarity between two density distributions that describe the historic and current health states, respectively. When necessary, the proposed method characterizes the distinct operating modes of the machine and can learn online both abrupt as well as gradual health changes. Our method overcomes some drawbacks of the HIs (e.g., relatively low comprehensibility and applicability) based on fixed monitoring models constructed in the offline phase. Results from its application in a bearing life test reveal that the proposed method is effective in online detection and adaptive assessment of machine health degradation. This study provides a useful guide for developing a condition-based maintenance (CBM) system that uses an online learning method without considerable human intervention.

  9. Elastic velocity models for gas-hydrate-bearing sediments-a comparison

    Science.gov (United States)

    Chand, Shyam; Minshull, Tim A.; Gei, Davide; Carcione, José M.

    2004-11-01

    The presence of gas hydrate in oceanic sediments is mostly identified by bottom-simulating reflectors (BSRs), reflection events with reversed polarity following the trend of the seafloor. Attempts to quantify the amount of gas hydrate present in oceanic sediments have been based mainly on the presence or absence of a BSR and its relative amplitude. Recent studies have shown that a BSR is not a necessary criterion for the presence of gas hydrates, but rather its presence depends on the type of sediments and the in situ conditions. The influence of hydrate on the physical properties of sediments overlying the BSR is determined by the elastic properties of their constituents and on sediment microstructure. In this context several approaches have been developed to predict the physical properties of sediments, and thereby quantify the amount of gas/gas hydrate present from observed deviations of these properties from those predicted for sediments without gas hydrate. We tested four models: the empirical weighted equation (WE); the three-phase effective-medium theory (TPEM); the three-phase Biot theory (TPB) and the differential effective-medium theory (DEM). We compared these models for a range of variables (porosity and clay content) using standard values for physical parameters. The comparison shows that all the models predict sediment properties comparable to field values except for the WE model at lower porosities and the TPB model at higher porosities. The models differ in the variation of velocity with porosity and clay content. The variation of velocity with hydrate saturation is also different, although the range is similar. We have used these models to predict velocities for field data sets from sediment sections with and without gas hydrates. The first is from the Mallik 2L-38 well, Mackenzie Delta, Canada, and the second is from Ocean Drilling Program (ODP) Leg 164 on Blake Ridge. Both data sets have Vp and Vs information along with the composition and

  10. Exact Phase Diagram of a Quasispecies Model with a Mutation Rate Modifier

    Science.gov (United States)

    Nagar, Apoorva; Jain, Kavita

    2009-01-01

    We consider an infinite asexual population with a mutator allele which can elevate mutation rates. With probability f, a transition from nonmutator to mutator state occurs but the reverse transition is forbidden. We find that at f=0, the population is in the state with minimum mutation rate, and at f=fc, a phase transition occurs between a mixed phase with both nonmutators and mutators and a pure mutator phase. We calculate the critical probability fc and the total mutator fraction Q in the mixed phase exactly. Our predictions for Q are in agreement with those seen in microbial populations in static environments.

  11. Cellular replication limits in the Luria-Delbrück mutation model

    Science.gov (United States)

    Rodriguez-Brenes, Ignacio A.; Wodarz, Dominik; Komarova, Natalia L.

    2016-08-01

    Originally developed to elucidate the mechanisms of natural selection in bacteria, the Luria-Delbrück model assumed that cells are intrinsically capable of dividing an unlimited number of times. This assumption however, is not true for human somatic cells which undergo replicative senescence. Replicative senescence is thought to act as a mechanism to protect against cancer and the escape from it is a rate-limiting step in cancer progression. Here we introduce a Luria-Delbrück model that explicitly takes into account cellular replication limits in the wild type cell population and models the emergence of mutants that escape replicative senescence. We present results on the mean, variance, distribution, and asymptotic behavior of the mutant population in terms of three classical formulations of the problem. More broadly the paper introduces the concept of incorporating replicative limits as part of the Luria-Delbrück mutational framework. Guidelines to extend the theory to include other types of mutations and possible applications to the modeling of telomere crisis and fluctuation analysis are also discussed.

  12. Validation of transgenic models of breast cancer: ductal carcinoma in situ (DCIS) and Brca1-mutation-related breast cancer.

    Science.gov (United States)

    Frech, M S; Jones, L P; Furth, P A

    2005-08-01

    Available mouse models of ductal carcinoma in situ (DCIS) and BRCA1-mutation-related breast cancer are reviewed. The best validated mouse models of human DCIS are the conditional estrogen receptor α in mammary tissue (CERM) model initiated by deregulated estrogen receptor α and the serial explant mouse model initiated by p53 deficiency. At present the most useful and best validated mouse model of BRCA1-mutation-related breast cancer uses the cre-lox system to make a conditional Brca1 deletion targeted to mammary epithelial cells. The major shortcoming of the non-conditional Brca1 models is the high incidence of non-mammary tumor development. The use of mammary gland transplants or explants from these mice into nude hosts is one approach that could be used to circumvent this deficiency. Development and validation of a Brca1-mutation-related mouse model of basal cell breast cancer is an important next step.

  13. Variable epitope library carrying heavily mutated survivin-derived CTL epitope variants as a new class of efficient vaccine immunogen tested in a mouse model of breast cancer.

    Science.gov (United States)

    NoeDominguez-Romero, Allan; Zamora-Alvarado, Rubén; Servín-Blanco, Rodolfo; Pérez-Hernández, Erendira G; Castrillon-Rivera, Laura E; Munguia, Maria Elena; Acero, Gonzalo; Govezensky, Tzipe; Gevorkian, Goar; Manoutcharian, Karen

    2014-01-01

    The antigenic variability of tumor cells leading to dynamic changes in cancer epitope landscape along with escape from immune surveillance by down-regulating tumor antigen expression/presentation and immune tolerance are major obstacles for the design of effective vaccines. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response as well as HIV-neutralizing antibodies. In this proof-of-concept study, we tested immunogenic properties and anti-tumor effects of the VELs bearing survivin-derived CTL epitope (GWEPDDNPI) variants in an aggressive metastatic mouse 4T1 breast tumor model. The constructed VELs had complexities of 10,500 and 8,000 individual members, generated as combinatorial M13 phage display and synthetic peptide libraries, respectively, with structural composition GWXPXDXPI, where X is any of 20 natural amino acids. Statistically significant tumor growth inhibition was observed in BALB/c mice immunized with the VELs in both prophylactic and therapeutic settings. Vaccinated mice developed epitope-specific spleen cell and CD8+ IFN-γ+ T-cell responses that recognize more than 50% of the panel of 87 mutated epitope variants, as demonstrated in T-cell proliferation assays and FACS analysis. These data indicate the feasibility of the application of this new class of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against cancer.

  14. Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations

    Directory of Open Access Journals (Sweden)

    Katarzyna eKazmierczak

    2014-09-01

    Full Text Available Cardiac hypertrophy represents one of the most important cardiovascular problems yet the mechanisms responsible for hypertrophic remodeling of the heart are poorly understood. In this report we aimed to explore the molecular pathways leading to two different phenotypes of cardiac hypertrophy in transgenic mice carrying mutations in the human ventricular myosin essential light chain (ELC. Mutation-induced alterations in the heart structure and function were studied in two transgenic (Tg mouse models carrying the A57G (alanine to glycine substitution or lacking the N-terminal 43 amino acid residues (Δ43 from the ELC sequence. The first model represents an HCM disease as the A57G mutation was shown to cause malignant HCM outcomes in humans. The second mouse model is lacking the region of the ELC that was shown to be important for a direct interaction between the ELC and actin during muscle contraction. Our earlier studies demonstrated that >7 month old Tg-Δ43 mice developed substantial cardiac hypertrophy with no signs of histopathology or fibrosis. Tg mice did not show abnormal cardiac function compared to Tg-WT expressing the full length human ventricular ELC. Previously reported pathological morphology in Tg-A57G mice included extensive disorganization of myocytes and interstitial fibrosis with no abnormal increase in heart mass observed in >6 month-old animals. In this report we show that strenuous exercise can trigger hypertrophy and pathologic cardiac remodeling in Tg-A57G mice as early as 3 months of age. In contrast, no exercise-induced changes were noted for Tg-Δ43 hearts and the mice maintained a non-pathological cardiac phenotype. Based on our results, we suggest that exercise-elicited heart remodeling in Tg-A57G mice follows the pathological pathway leading to HCM, while it induces no abnormal response in Tg-Δ43 mice.

  15. Film Thickness Model for Grease-Lubricated Bearing Seals with an Axial Contacting Lip

    NARCIS (Netherlands)

    Baart, P.; van Zoelen, M.T.; Lugt, Pieter Martin

    2013-01-01

    A theoretical model is presented to predict the oil film thickness in an axial sealing contact based on grease properties and operating conditions. It is assumed that a small amount of grease will form an oil reservoir on the rotating part and slowly supply oil to the sealing contact. The oil bleed

  16. Model Test Research on the End Bearing Behavior of the Large-Diameter Cast-in-Place Concrete Pile for Jointed Rock Mass

    Directory of Open Access Journals (Sweden)

    Jingwei Cai

    2016-01-01

    Full Text Available For large-diameter, cast-in-place concrete piles, the end bearing capacity of a single pile is affected by discontinuous surfaces that exist in natural rock masses when the bearing layer of the pile end is located in the rock layer. In order to study the influence of the jointed dip angle on the bearing characteristics of the pile end, the discrete element models are adopted to simulate the mechanical characteristics of the jointed rock masses, and the model tests of the failure mode of the jointed rock masses were also designed. The results of the numerical calculations and modeling tests show that the joints, which have a filtering effect on the internal stress of the bedrock located at the pile end, change the load transferring paths. And the failure mode of the jointed rock foundation also changes as jointed dip angle changes. The rock located at the pile end generally presents a wedge failure mode. In addition, the Q-S curves obtained by model tests show that the ultimate end bearing capacity of a single pile is influenced by the jointed dip angle. The above results provide an important theoretical basis for how to correctly calculate end resistance for a cast-in-place concrete pile.

  17. Existence and qualitative properties of travelling waves for an epidemiological model with mutations

    Science.gov (United States)

    Griette, Quentin; Raoul, Gaël

    2016-05-01

    In this article, we are interested in a non-monotonic system of logistic reaction-diffusion equations. This system of equations models an epidemic where two types of pathogens are competing, and a mutation can change one type into the other with a certain rate. We show the existence of travelling waves with minimal speed, which are usually non-monotonic. Then we provide a description of the shape of those constructed travelling waves, and relate them to some Fisher-KPP fronts with non-minimal speed.

  18. Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer.

    Science.gov (United States)

    Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J; Zhao, Mei; Pickering, Curtis R; Zhou, Ge; Sandulache, Vlad C; Wheeler, David A; Gibbs, Richard A; Caulin, Carlos; Myers, Jeffrey N

    2011-11-01

    To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings. Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared. These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations. HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. ©2011 AACR

  19. Treatment of dispersed iron-bearing raw materials and modeling of the protection systems against air-pollution

    Directory of Open Access Journals (Sweden)

    Zoran Anđić

    2016-12-01

    Full Text Available Based on the analysis of the non-standard iron-bearing raw materials treatment process and the results of real composition measurements of the flue gas, the study of hazards by identification of harmful substances that occur in the accident, as well as the modeling of the system of protection against air-pollution due to the cancellation of work the bag filter was carried out. Applying the model (Aloha software package provides an overview of possible developments of events and zones of propagation of the precipitated particulate matter through the share of cadmium (Cd in them. In the case of malfunction of filter system, emissions of particulate matter enormously exceed the permitted values. In the conditions of the simulated accident, particle velocity of flue gases was amounted E≈738mg/s or 2657g/h of dust. The propagation of the precipitated particulate matter in the lower layer of the atmosphere, downwind, given trough the share of Cd in them, is 100m from the source of pollution for the characteristic density of 5mg/m2×day and 140m for the characteristic density of 2mg/m2×day, in the stable state of the atmosphere, i.e. 870m and 1100m, respectively, in the neutral state of the atmosphere.

  20. Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice.

    Science.gov (United States)

    Rozkalne, Anete; Hyman, Bradley T; Spires-Jones, Tara L

    2011-03-01

    Synapse loss is the strongest correlate of cognitive decline in Alzheimer's disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques that dendrites surrounding plaques become dystrophic and lose postsynaptic dendritic spines. Furthermore, we found strong evidence that plaque-associated dendritic changes are mediated by calcineurin, a calcium-dependent phosphatase involved in cell signaling, using in vitro models and genetically encoded inhibitors in mouse models. In this study, we pharmacologically inhibited calcineurin with FK506 treatment to test the hypothesis that calcineurin inhibition will allow recovery of plaque-associated synapse loss. We found that in plaque bearing transgenic mice, short term (1 week) FK506 treatment results in an amelioration of dendritic spine loss. We also observe an effect on spine morphology in wild-type mice with FK506 treatment. These data show that systemic FK506 administration, and hence calcineurin inhibition, may be neuroprotective for amyloid beta induced synaptic alterations.

  1. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia

    Science.gov (United States)

    Lee, Yi-Ching; Song, I-Wen; Pai, Ya-Ju; Chen, Sheng-De; Chen, Yuan-Tsong

    2017-01-01

    Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 (FGFR3). Currently, there is no effective treatment for ACH. The development of an appropriate human-relevant model is important for testing potential therapeutic interventions before human clinical trials. Here, we have generated an ACH mouse model in which the endogenous mouse Fgfr3 gene was replaced with human FGFR3G380R (FGFR3ACH) cDNA, the most common mutation in human ACH. Heterozygous (FGFR3ACH/+) and homozygous (FGFR3ACH/ACH) mice expressing human FGFR3G380R recapitulate the phenotypes observed in ACH patients, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development. We also observed premature fusion of the cranial sutures and low bone density in newborn FGFR3G380R mice. The severity of the disease phenotypes corresponds to the copy number of activated FGFR3G380R, and the phenotypes become more pronounced during postnatal skeletal development. This mouse model offers a tool for assessing potential therapeutic approaches for skeletal dysplasias related to over-activation of human FGFR3, and for further studies of the underlying molecular mechanisms. PMID:28230213

  2. Bayesian modeling for genetic anticipation in presence of mutational heterogeneity: a case study in Lynch syndrome.

    Science.gov (United States)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G; Nilbert, Mef; Moreno, Victor; Gruber, Stephen B

    2011-12-01

    Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype. In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect inferential conclusions. We compare the fit of four-candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding effect of changes in secular trends, screening, and medical practices that may affect time to disease detection across birth cohorts. Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts. Our motivating case study comes from a Danish cancer register of 124 families with mutations in mismatch repair (MMR) genes known to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families.

  3. Improvement of journal bearing operation at heavy misalignment using bearing flexibility and compliant liners

    DEFF Research Database (Denmark)

    Thomsen, Kim; Klit, Peder

    2012-01-01

    A flexure journal bearing design is proposed that will improve operational behaviour of a journal bearing at pronounced misalignment. Using a thermoelastohydrodynamic model, it is shown that the proposed flexure journal bearing has vastly increased the hydrodynamic performance compared to the stiff...... bearing when misaligned. The hydrodynamic performance is evaluated on lubricant film thickness, pressure and temperature. Furthermore, the influence of a compliant bearing liner is investigated and it is found that it increases the hydrodynamic performance when applied to a stiff bearing, whereas...... the liner has practically no influence on the flexure journal bearing's performance....

  4. Graph-Theoretic Models of Mutations in the Nucleotide Binding Domain 1 of the Cystic Fibrosis Transmembrane Conductance Regulator

    Directory of Open Access Journals (Sweden)

    Debra J. Knisley

    2013-01-01

    Full Text Available Cystic fibrosis is one of the most common inherited diseases and is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR. This protein serves as a chloride channel and regulates the viscosity of mucus lining the ducts of a number of organs. Although much has been learned about the consequences of mutations on the energy landscape and the resulting disrupted folding pathway of CFTR, a level of understanding needed to correct the misfolding has not been achieved. The most common mutations of CFTR are located in one of two nucleotide binding domains, namely, the nucleotide binding domain 1 (NBD1. We model NBD1 using a nested graph model. The vertices in the lowest layer each represent an atom in the structure of an amino acid residue, while the vertices in the mid layer each represent the residue. The vertices in the top layer each represent a subdomain of the nucleotide binding domain. We use this model to quantify the effects of a single point mutation on the protein domain. We compare the wildtype structure with eight of the most common mutations. The graph-theoretic model provides insight into how a single point mutation can have such profound structural consequences.

  5. Stable isotopes to detect food-conditioned bears and to evaluate human-bear management

    Science.gov (United States)

    Hopkins, John B.; Koch, Paul L.; Schwartz, Charles C.; Ferguson, Jake M.; Greenleaf, Schuyler S.; Kalinowski, Steven T.

    2012-01-01

    We used genetic and stable isotope analysis of hair from free-ranging black bears (Ursus americanus) in Yosemite National Park, California, USA to: 1) identify bears that consume human food, 2) estimate the diets of these bears, and 3) evaluate the Yosemite human–bear management program. Specifically, we analyzed the isotopic composition of hair from bears known a priori to be food-conditioned or non-food-conditioned and used these data to predict whether bears with an unknown management status were food-conditioned (FC) or non-food-conditioned (NFC). We used a stable isotope mixing model to estimate the proportional contribution of natural foods (plants and animals) versus human food in the diets of FC bears. We then used results from both analyses to evaluate proactive (population-level) and reactive (individual-level) human–bear management, and discussed new metrics to evaluate the overall human–bear management program in Yosemite. Our results indicated that 19 out of 145 (13%) unknown bears sampled from 2005 to 2007 were food-conditioned. The proportion of human food in the diets of known FC bears likely declined from 2001–2003 to 2005–2007, suggesting proactive management was successful in reducing the amount of human food available to bears. In contrast, reactive management was not successful in changing the management status of known FC bears to NFC bears, or in reducing the contribution of human food to the diets of FC bears. Nine known FC bears were recaptured on 14 occasions from 2001 to 2007; all bears were classified as FC during subsequent recaptures, and human–bear management did not reduce the amount of human food in the diets of FC bears. Based on our results, we suggest Yosemite continue implementing proactive human–bear management, reevaluate reactive management, and consider removing problem bears (those involved in repeated bear incidents) from the population.

  6. Targeting Mitogen-Activated Protein Kinase Signaling in Mouse Models of Cardiomyopathy Caused by Lamin A/C Gene Mutations.

    Science.gov (United States)

    Muchir, Antoine; Worman, Howard J

    2016-01-01

    The most frequently occurring mutations in the gene encoding nuclear lamin A and nuclear lamin C cause striated muscle diseases virtually always involving the heart. In this review, we describe the approaches and methods used to discover that cardiomyopathy-causing lamin A/C gene mutations increase MAP kinase signaling in the heart and that this plays a role in disease pathogenesis. We review different mouse models of cardiomyopathy caused by lamin A/C gene mutations and how transcriptomic analysis of one model identified increased cardiac activity of the ERK1/2, JNK, and p38α MAP kinases. We describe methods used to measure the activity of these MAP kinases in mouse hearts and then discuss preclinical treatment protocols using pharmacological inhibitors to demonstrate their role in pathogenesis. Several of these kinase inhibitors are in clinical development and could potentially be used to treat human subjects with cardiomyopathy caused by lamin A/C gene mutations.

  7. Physico-Chemical Modeling of the Sulfo-Arsenide System of Gold Bearing Ore Deposits

    Directory of Open Access Journals (Sweden)

    N. V. VILOR

    2010-12-01

    Full Text Available The existence of gold-arsenic mineralization, the presence of enhanced concentrations of gold in arsenopyrite, especially in its fine grain varieties showing positive gold-arsenic ratios in gold-quartz and gold-pyritic ores indicate the important role of As in hydrothermal gold transport. The most accessible approach to the investigation of these complicated systems is provided by physico-chemical modeling. In the present work the isobaric isothermal potentials (DG°f 298 of thioarsenides, the most important group of arsenic compounds in the solution, have been determined and refined on the basis of the creation of physico-chemical models using the data on the As sulfide solubility in the As – S – O – H system. The data obtained were reconciled with the thermodynamic data available by solving the reverse thermodynamic problem. Numerical physico-chemical modeling has been carried out for a series of tests in both pure water and hydrogen sulfide solutions (0.0032 - 0.011m with the initial pH values from 1.14 to 8.4 in the 25-250°C temperature range under saturated water steam pressure. The computer-calculated constants are included in the modeling of tests on orpiment dissolution in sulfide-sodium solutions. The As2S3ryst solubility in the 25-250°C temperature range has first been obtained. A specific feature of the process is a sharp increase in dissolved arsenic total concentration as the pH value of the hydrothermal phase rises from 4 to 6-7. Concentration increases and gradient decreases with temperature rise. The predominant forms are represented by thioarsenites. Just as in acidic, so in weakly and moderately alkaline solutions the orpiment solubility is caused by the concentration combination of thioarsenous acid H3AsS3 and its oligomers H4As2S50 and H2As2S40. At a temperature of over 200-250°C these concentrations can be compared only with that of the AsOH (HS2o complex of mixed composition.

  8. A review of mouse critical size defect models in weight bearing bones.

    Science.gov (United States)

    Harris, Jonathan S; Bemenderfer, Thomas B; Wessel, Alexander R; Kacena, Melissa A

    2013-07-01

    Current and future advances in orthopedic treatment are aimed at altering biological interactions to enhance bone healing. Currently, several clinical scenarios exist for which there is no definitive treatment, specifically segmental bone loss from high-energy trauma or surgical resection - and it is here that many are aiming to find effective solutions. To test experimental interventions and better understand bone healing, researchers employ critical size defect (CSD) models in animal studies. Here, an overview of CSDs is given that includes the specifications of varying models, a discussion of current scaffold and bone graft designs, and current outcome measures used to determine the extent of bone healing. Many promising graft designs have been discovered along with promising adjunctive treatments, yet a graft that offers biomechanical support while allowing for neovascularization with eventual complete resorption and remodeling remains to be developed. An overview of this important topic is needed to highlight current advances and provide a clear understanding of the ultimate goal in CSD research--develop a graft for clinical use that effectively treats the orthopedic conundrum of segmental bone loss.

  9. Establishment of a Tumor-bearing Mouse Model Stably Expressing EGFP Labeled Human MUC1 VNTRs

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shu-zi; ZHANG Hai-hong; ZHANG Wa; SHI He-liang; YU Xiang-hui; KONG Wei; LI Wei

    2008-01-01

    Two eukaryotic vectors expressing 9 tandem repeats of human MUCI(VNTR),VRI012-VNTR,and pEGFP-VNTR,were constructed by cloning VNTR gene into VR1012 and pEGFP,respectively,VNTR stably expressing murine Lewis lung carcinoma(LLC) cell Iine(VNTR+ LLC) was established by Lipofectamine-mediated transfection of pEGFP-VNTR into LLC cells,The EGFP expression was observed under a fluorescent microscope and VNTR expression in VNTR+ LLC cells was confirmed by means of Western blotting,A syngenic graft tumor model was generated by subcutaneous injection of VNTR+ LLC cells into C57/BL6 mice and tumor size increased rapidly with time and in a cell number dependent manner,VNTR mRNA expression in the tumor formed was confirmed by RT-PCR.After the third immunization mice were challenged subcutaneously with 5x10 5 VNTR* LLC cells,a significant reduction of subcutaneous tumor growth was observed in the groups immunized with VNTR plasmid DNA compared with that in the groups immunized with the vector DNA alone,Thus,the suppression of subcutaneous tumor was antigen-specific,This model is useful for the development of tumor vaccines targeting MUCI VNTRs.

  10. Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber.

    Directory of Open Access Journals (Sweden)

    Vivek Iyer

    Full Text Available Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

  11. Experimental modeling of the chemical remanent magnetization and Thellier procedure on titanomagnetite-bearing basalts

    Science.gov (United States)

    Gribov, S. K.; Dolotov, A. V.; Shcherbakov, V. P.

    2017-03-01

    The results of the experimental studies on creating chemical and partial thermal remanent magnetizations (or their combination), which are imparted at the initial stage of the laboratory process of the oxidation of primary magmatic titanomagnetites (Tmts) contained in the rock, are presented. For creating chemical remanent magnetization, the samples of recently erupted Kamchatka basalts were subjected to 200-h annealing in air in the temperature interval from 400 to 500°C under the action of the magnetic field on the order of the Earth's magnetic field. After creation of this magnetization, the laboratory modeling of the Thellier-Coe and Wilson-Burakov paleointensity determination procedures was conducted on these samples. It is shown that when the primary magnetization is chemical, created at the initial stage of oxidation, and the paleointensity determined by these techniques is underestimated by 15-20% relative to its true values.

  12. Effects of Human Alpha-Synuclein A53T-A30P Mutations on SVZ and Local Olfactory Bulb Cell Proliferation in a Transgenic Rat Model of Parkinson Disease

    Directory of Open Access Journals (Sweden)

    Faustine Lelan

    2011-01-01

    Full Text Available A transgenic Sprague Dawley rat bearing the A30P and A53T α-synuclein (α-syn human mutations under the control of the tyrosine hydroxylase promoter was generated in order to get a better understanding of the role of the human α-syn mutations on the neuropathological events involved in the progression of the Parkinson’s disease (PD. This rat displayed olfactory deficits in the absence of motor impairments as observed in most early PD cases. In order to investigate the role of the mutated α-syn on cell proliferation, we focused on the subventricular zone (SVZ and the olfactory bulbs (OB as a change of the proliferation could affect OB function. The effect on OB dopaminergic innervation was investigated. The human α-syn co-localized in TH-positive OB neurons. No human α-syn was visualized in the SVZ. A significant increase in resident cell proliferation in the glomerular but not in the granular layers of the OB and in the SVZ was observed. TH innervation was significantly increased within the glomerular layer without an increase in the size of the glomeruli. Our rat could be a good model to investigate the role of human mutated α-syn on the development of olfactory deficits.

  13. Comparison of risk assessment models of BRCA1 and BRCA2 mutation carrier in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Rybchenko L.A.

    2013-12-01

    Full Text Available Analysis of efficiency of the algorithm BOADICEA using and Manchester scoring system to predict the carrier of BRCA1 and BRCA2 mutations in Ukranian patients with breast cancer was performed. Materials for this study were the results of clinical, imunogistological, pathogistological, genealogical, molecular genetic researches of 146 patients with breast cancer. Calculations of mutations risk were performed using BOADICEA algorithm and Manchester scoring system. In the total group of patients the area under the curve while predicting BRCA1 mutations with algorithm BOADICEA was 0.86, with Manchester scoring system - 0.84, and in calculation of the combined risk of BRCA mutations - 0.83 and 0.84, respectively. However, statistical difference between the areas of algorithms has not been established (p> 0.05, it indicates to the same discriminatory power of the test models. Better sensitivity, specificity, positive and negative predictive value of results of BOADICEA algorithm was reached in 6% of BRCA1 probability and in 8% threshold of BRCA1/2 mutations. The Manchester scoring system has showed the best operating characteristics with 6 and 13-point probability of BRCA1 and BRCA1/2 mutations respectively. Patients with probability of mutations with such thresholds may be offered molecular study of pathogenic alleles.

  14. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G;

    2011-01-01

    inferential conclusions. We compare the fit of four-candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding effect of changes in secular trends, screening, and medical practices that may affect time to disease detection across...... to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....... birth cohorts. Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts. Our motivating case study comes from a Danish cancer register of 124 families with mutations in mismatch repair (MMR) genes known...

  15. Modeling Pathogenic Mutations of Human Twinkle in Drosophila Suggests an Apoptosis Role in Response to Mitochondrial Defects

    Science.gov (United States)

    Sanchez-Martinez, Alvaro; Calleja, Manuel; Peralta, Susana; Matsushima, Yuichi; Hernandez-Sierra, Rosana; Whitworth, Alexander J.; Kaguni, Laurie S.; Garesse, Rafael

    2012-01-01

    The human gene C10orf2 encodes the mitochondrial replicative DNA helicase Twinkle, mutations of which are responsible for a significant fraction of cases of autosomal dominant progressive external ophthalmoplegia (adPEO), a human mitochondrial disease caused by defects in intergenomic communication. We report the analysis of orthologous mutations in the Drosophila melanogaster mitochondrial DNA (mtDNA) helicase gene, d-mtDNA helicase. Increased expression of wild type d-mtDNA helicase using the UAS-GAL4 system leads to an increase in mtDNA copy number throughout adult life without any noteworthy phenotype, whereas overexpression of d-mtDNA helicase containing the K388A mutation in the helicase active site results in a severe depletion of mtDNA and a lethal phenotype. Overexpression of two d-mtDNA helicase variants equivalent to two human adPEO mutations shows differential effects. The A442P mutation exhibits a dominant negative effect similar to that of the active site mutant. In contrast, overexpression of d-mtDNA helicase containing the W441C mutation results in a slight decrease in mtDNA copy number during the third instar larval stage, and a moderate decrease in life span in the adult population. Overexpression of d-mtDNA helicase containing either the K388A or A442P mutations causes a mitochondrial oxidative phosphorylation (OXPHOS) defect that significantly reduces cell proliferation. The mitochondrial impairment caused by these mutations promotes apoptosis, arguing that mitochondria regulate programmed cell death in Drosophila. Our study of d-mtDNA helicase overexpression provides a tractable Drosophila model for understanding the cellular and molecular effects of human adPEO mutations. PMID:22952820

  16. Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening

    DEFF Research Database (Denmark)

    Norn, Christoffer; Pedersen, Maria Hauge; Engelstoft, Maja S.

    2015-01-01

    multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol to det. the binding conformation of AR231453, a small-mol. agonist, in the GPR119 receptor. Resulting models converge to one conformation that explains the majority of data from mutation studies...... and is consistent with the structure-activity relationship for a large no. of AR231453 analogs. Another key property of the refined models is their success in sepg. active ligands from decoys in a large-scale virtual screening. These results demonstrate that mutation-guided receptor modeling can provide predictions...

  17. Linking changes in epithelial morphogenesis to cancer mutations using computational modeling.

    Directory of Open Access Journals (Sweden)

    Katarzyna A Rejniak

    Full Text Available Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini. In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini

  18. Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities

    Directory of Open Access Journals (Sweden)

    Kimihiko Banno

    2016-05-01

    Full Text Available Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

  19. Dependence of the crossing time on the sequence length in the continuous-time mutation-selection model

    Energy Technology Data Exchange (ETDEWEB)

    Gill, Wonpyong [Pusan National University, Busan (Korea, Republic of)

    2010-08-15

    The dependence of the crossing time on the sequence length in the coupled and the decoupled continuous-time mutation-selection models in an asymmetric sharply-peaked landscape with a positive asymmetric parameter, r, was examined for a fixed extension parameter, E, which is defined as the average Hamming distance from the optimal allele of the initial quasispecies divided by the sequence length. Two versions of the coupled mutation-selection model, the continuous-time version and discrete-time version, were found to have the same boundary between the deterministic and the stochastic regions, which is different from the boundary between the deterministic and the stochastic regions in the decoupled continuous-time mutation-selection model. The maximum sequence length for a finite population that can evolve through the fitness barrier, e.g., within 10{sup 6} generations in the decoupled continuous-time mutation-selection model, increased by approximately eight sequence elements with increasing population size by a factor of a thousand when E = 0.1 and r = 0.1. The crossing time for a finite population in the decoupled model in the stochastic region was shorter than the crossing time for a finite population in the coupled model, and the maximum evolvable sequence length for a finite population in the decoupled model was longer than the maximum evolvable sequence length for a finite population in the coupled model. This suggests that a mutation allowed at any time during the life cycle might be more effective than a mutation allowed only at reproduction events when a finite population transits to a higher fitness peak through the fitness barrier in an asymmetric sharply-peaked landscape.

  20. Acanthus ilicifolius plant extract prevents DNA alterations in a transplantable Ehrlich ascites carcinoma-bearing murine model

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the chemopreventive efficacy of the Indian medicinal plant Acanthus ilicifolius L Acanthaceae in a transplantable Ehrlich ascites carcinoma (EAC)-bearing murine model.METHODS: Male Swiss albino mice were divided into four groups: Group A was the untreated normal control; Group B was the EAC control mice group that received serial, intraperitoneal (ip) inoculations of rapidly proliferating 2 × 105 viable EAC cells in 0.2 mL of sterile phosphate buffered saline; Group C was the plant extract-treated group that received the aqueous leaf extract (ALE) of the plant at a dose of 2.5 mg/kg body weight by single ip injections, once daily for 10, 20 and 30 consecutive days following tumour inoculation (ALE control); and Group D was the EAC + ALE-treatment group. The chemopreventive potential of the ALE was evaluated in a murine model by studying various biological parameters and genotoxic markers,such as tumour cell count, mean survival of the animals,haematological indices, hepatocellular histology,immunohistochemical expression of liver metallothionein (MT) protein, sister-chromatid exchanges (SCEs), and DNA alterations.RESULTS: Treatment of the EAC-bearing mice with the ALE significantly (P < 0.001) reduced viable tumour cell count by 68.34% (228.7 × 106 ± 0.53) when compared to EAC control mice (72.4 × 106 ± 0.49), and restored body and organ weights almost to the normal values.ALE administration also increased (P < 0.001) mean survival of the hosts from 35 ± 3.46 d in EAC control mice to 83 ± 2.69 d in EAC + ALE-treated mice.Haematological indices also showed marked improvement with administration of ALE in EAC-bearing animals. There was a significant increase in RBC count (P < 0.001),hemoglobin percent (P < 0.001), and haematocrit value (P < 0.001) from 4.3 ± 0.12, 6.4 ± 0.93, and 17.63 ± 0.72 respectively in EAC control mice to 7.1 ± 0.13, 12.1 ±0.77, and 30.23 ± 0.57 respectively in EAC + ALE-treated group, along with

  1. Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families

    DEFF Research Database (Denmark)

    Gerdes, Anne-Marie; Cruger, D G; Thomassen, M;

    2006-01-01

    To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have...... undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high-risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance...

  2. A model for triplet mutation formation based on error-prone translesional DNA synthesis opposite UV photolesions.

    Science.gov (United States)

    Ikehata, Hironobu; Ono, Tetsuya; Tanaka, Kiyoji; Todo, Takeshi

    2007-05-01

    A triplet mutation is defined as multiple base substitutions or frameshifts within a three-nucleotide sequence which includes a dipyrimidine sequence. Triplet mutations have recently been identified as a new type of UV-specific mutation, although the mechanism of their formation is unknown. A total of 163 triplet mutations were identified through an extensive search of previously published data on UV-induced mutations, including mutations from skin, skin cancer, and cultured mammalian cells. Seven common patterns of sequence changes were found: Type I, NTC-->TTT; Type IIa, NCC-->PyTT or PyCT (Py, pyrimidine); Type IIb, TCC-->PuTT or PuCT (Pu, purine); Type III, NCC-->NAT or NTA; Type IV, NTT-->AAT; Type Va, NCT-->NTX; and Type Vb, PuCT-->XTT (N and X, independent anonymous bases). Furthermore, it is suggested that the type of UV lesion responsible for each of these triplet mutation classes are (a) pyrimidine(6-4)pyrimidone photoproducts for Types I, IIb, III, IV and Vb, (b) cyclobutane pyrimidine dimers for Type Va, and (c) Dewar valence isomers for Types IIa and IIb. These estimations are based primarily on results from previous studies using photolyases specific for each type of UV lesion. A model is proposed to explain the formation of each type of triplet mutation, based on error-prone translesional DNA synthesis opposite UV-specific photolesions. The model is largely consistent with the 'A-rule', and predicts error-prone insertions not only opposite photolesions but also opposite the undamaged template base one-nucleotide downstream from the lesions.

  3. Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy.

    Science.gov (United States)

    Evans, Jacquelyn M; Cox, Melissa L; Huska, Jonathan; Li, Frank; Gaitero, Luis; Guo, Ling T; Casal, Margaret L; Granzier, Henk L; Shelton, G Diane; Clark, Leigh Anne

    2016-10-01

    Nemaline myopathy (NM) is a congenital muscle disorder associated with muscle weakness, hypotonia, and rod bodies in the skeletal muscle fibers. Mutations in 10 genes have been implicated in human NM, but spontaneous cases in dogs have not been genetically characterized. We identified a novel recessive myopathy in a family of line-bred American bulldogs (ABDs); rod bodies in muscle biopsies established this as NM. Using SNP profiles from the nuclear family, we evaluated inheritance patterns at candidate loci and prioritized TNNT1 and NEB for further investigation. Whole exome sequencing of the dam, two affected littermates, and an unaffected littermate revealed a nonsense mutation in NEB (g.52734272 C>A, S8042X). Whole tissue gel electrophoresis and western blots confirmed a lack of full-length NEB in affected tissues, suggesting nonsense-mediated decay. The pathogenic variant was absent from 120 dogs of 24 other breeds and 100 unrelated ABDs, suggesting that it occurred recently and may be private to the family. This study presents the first molecularly characterized large animal model of NM, which could provide new opportunities for therapeutic approaches.

  4. Gestational mutations in radiation carcinogenesis

    Science.gov (United States)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  5. Journal and Wave Bearing Impedance Calculation Software

    Science.gov (United States)

    Hanford, Amanda; Campbell, Robert

    2012-01-01

    The wave bearing software suite is a MALTA application that computes bearing properties for user-specified wave bearing conditions, as well as plain journal bearings. Wave bearings are fluid film journal bearings with multi-lobed wave patterns around the circumference of the bearing surface. In this software suite, the dynamic coefficients are outputted in a way for easy implementation in a finite element model used in rotor dynamics analysis. The software has a graphical user interface (GUI) for inputting bearing geometry parameters, and uses MATLAB s structure interface for ease of interpreting data. This innovation was developed to provide the stiffness and damping components of wave bearing impedances. The computational method for computing bearing coefficients was originally designed for plain journal bearings and tilting pad bearings. Modifications to include a wave bearing profile consisted of changing the film thickness profile given by an equation, and writing an algorithm to locate the integration limits for each fluid region. Careful consideration was needed to implement the correct integration limits while computing the dynamic coefficients, depending on the form of the input/output variables specified in the algorithm.

  6. A Novel Fault Diagnosis Model for Bearing of Railway Vehicles Using Vibration Signals Based on Symmetric Alpha-Stable Distribution Feature Extraction

    Directory of Open Access Journals (Sweden)

    Yongjian Li

    2016-01-01

    Full Text Available Axle box bearings are the most critical mechanical components of railway vehicles. Condition monitoring is of great benefit to ensure the healthy status of bearings in the railway train. In this paper, a novel fault diagnosis model for axle box bearing based on symmetric alpha-stable distribution feature extraction and least squares support vector machines (LS-SVM using vibration signals is proposed which is conducted in three main steps. Firstly, fast nonlocal means is used for denoising and ensemble empirical mode decomposition is applied to extract fault feature information. Then a new statistical method of feature extraction, symmetric alpha-stable distribution, is employed to obtain representative features from intrinsic mode functions. Additionally, the hybrid fault feature sets are input into LS-SVM to identify the fault type. To enhance the performance of LS-SVM in the case of small-scale samples, Morlet wavelet kernel function is combined with LS-SVM for the classification of fault type and fault severity and the particle swarm optimization is used for the optimization of LS-WSVM parameters. Finally, the experimental results demonstrate that the proposed approach performs more effectively and robustly than the other methods in small-scale samples for fault detection and classification of railway vehicle bearings.

  7. Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling.

    Science.gov (United States)

    Zheng, Y Z; Sakata, T; Matsusue, T; Umeyama, H; Kato, H; Miyata, T

    1994-10-01

    The molecular basis of protein C deficiency was studied in three type I and three type II heterozygotes. Three probands showed thrombotic complications. All the exons and intron/exon junctions of the protein C gene were studied using a strategy combining by the polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, and DNA sequencing of the PCR-amplified fragments. Six missense mutations were identified, including three novel ones. One was located in exon II, in which the initiating translation codon (ATG) encoding for Met at position -42 was replaced by ACG encoding for Thr. The other five were located in exon IX, and included TAC(Tyr399)-->CAC(His), CCG(Pro327)-->CTG(Leu), GAC(Asp359)-->AAC(Asn) in two cases, and GGG(Gly350)-->AGG(Arg). Four of the six missense mutations occurred in CG dinucleotide. Sequence analysis of the other exons excluded additional mutations. By restriction enzyme analysis, co-segregation of the mutation with protein C deficiency was observed in four families. The other two mutations at amino acid positions -42 and 350 were also considered to be associated with protein C deficiency due to the absence of these mutations in 50 normal individuals. A structural model of the protease domain of mutant activated protein C was constructed by the chimeric modelling method, and the resultant model suggested conformational changes due to each missense mutation identified in protein C deficiency. The present data also provide some evidence regarding the genetic heterogeneity of protein C deficiency.

  8. State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics

    Directory of Open Access Journals (Sweden)

    Peter W. Tse

    2017-02-01

    Full Text Available Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL. Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions.

  9. Cavitation Estimates by Orbit Prediction of a Journal Bearing - Finite Element Modelling and Experimental Studies Cavitation Estimates by Orbit Prediction of a Journal Bearing - Finite Element Modelling and Experimental Studies

    DEFF Research Database (Denmark)

    Christiansen, Christian Kim; Klit, Peder; Walther, Jens Honore;

    2015-01-01

    influencing the load carrying capacity and ultimately the chances of fatal shaft-sleeve contact. By solving Reynolds equation numerically using finite elements and incorporating a cavitation algorithm, the dynamic coefficients can be used to establish the journal orbit for a given bearing and load pattern...

  10. The possibility of using the equivalent plane wave model to increase the efficiency of taking bearings of low-frequency signals in shallow water

    Science.gov (United States)

    Kuznetsov, G. N.; Lebedev, O. V.

    2012-09-01

    The possibility of approximating the sound field in the region of interference maxima using the equivalent plane wave model with the actual amplitude and the average "effective" phase velocity calculated or measured by the phase gradient at the array aperture is discussed. The method is substantiated by studying the mode, interference, and phase structures of the low-frequency sound field along with the spatial responses of an extended linear array. For bottom-moored or towed geophysical arrays whose sizes are large compared to the wavelength, both the necessity and the possibility of reducing the error in taking the bearing of a sound source in a waveguide are justified. The use of the proposed model is recommended for approximate matching of the array to the transfer function of the waveguide to reduce the bearing error.

  11. Reproductive performance in East Greenland polar bears (Ursus maritimus) may be affected by organohalogen contaminants as shown by physiologically-based pharmacokinetic (PBPK) modelling

    DEFF Research Database (Denmark)

    Sonne, Christian; Gustavson, Kim; Rigét, Frank F.

    2009-01-01

    quotient (RQ) evaluation to more quantitatively evaluate the effect risk on reproduction (embryotoxicity and teratogenicity) based on the critical body residue (CBR) concept and using a physiologically-based pharmacokinetic (PBPK) model. We applied modelling approaches to PCBs, p,p′-DDE, dieldrin......, oxychlordane, HCHs, HCB, PBDEs and PFOS in East Greenland polar bears based on known OHC pharmacokinetics and dynamics in laboratory rats (Rattus rattus). The results showed that subcutaneous adipose tissue concentrations of dieldrin (range: 79–1271 ng g−1 lw) and PCBs (range: 4128–53 923 ng g−1 lw) reported...... and for dieldrin (range: 43–640 ng g−1 lw), PCBs (range: 3491–13 243 ng g−1 lw) and PFOS (range: 1332–6160 ng g−1 ww) in the year 2006. The concentrations of oxychlordane, DDTs, HCB and HCHs in polar bears resulted in RQs

  12. Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    Science.gov (United States)

    Jiang, Pingping; Liang, Min; Zhang, Chaofan; Zhao, Xiaoxu; He, Qiufen; Cui, Limei; Liu, Xiaoling; Sun, Yan-Hong; Fu, Qun; Ji, Yanchun; Bai, Yidong; Huang, Taosheng; Guan, Min-Xin

    2016-08-15

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρ(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.

  13. FOXL2 gene mutations and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES): a novel mutation detected in a Chinese family and a statistic model for summarizing previous reported records.

    Science.gov (United States)

    Xu, Yan; Lei, Huo; Dong, Hong; Zhang, Liping; Qin, Qionglian; Gao, Jianmei; Zou, Yunlian; Yan, Xinmin

    2009-09-01

    Previous studies found that the forkhead transcription factor 2 (FOXL2) gene mutations are responsible for both types of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) but have not established any systematic statistic model for the complex and even contradictory results about genotype-phenotype correlations between them. This study is aimed to find possible mutations of FOXL2 gene in a Chinese family with type II BPES by using DNA sequencing and to further clarify genotype-phenotype correlations between FOXL2 mutations and BPES by using a systematic statistical method, namely Multifactor Dimensionality Reduction (MDR). A novel mutation (g.933_965dup) which could result in an expansion of the polyalanine (polyAla) tract was detected in all patients of this family. MDR analysis for intragenic mutations of FOXL2 gene reported in previous BPES studies indicated that the mutations which led to much stronger disturbance of amino acid sequence were responsible for more type I BPES, while other kinds of mutation were responsible for more type II BPES. In conclusion, the present study found a novel FOXL2 gene mutation in a Chinese BPES family and a new general genotype-phenotype correlation tendency between FOXL2 intragenic mutations and BPES, both of which expanded the knowledge about FOXL2 gene and BPES.

  14. Automated Assistance for Designing Active Magnetic Bearings

    Science.gov (United States)

    Imlach, Joseph

    2008-01-01

    MagBear12 is a computer code that assists in the design of radial, heteropolar active magnetic bearings (AMBs). MagBear12 was developed to help in designing the system described in "Advanced Active-Magnetic-Bearing Thrust-Measurement System". Beyond this initial application, MagBear12 is expected to be useful for designing AMBs for a variety of rotating machinery. This program incorporates design rules and governing equations that are also implemented in other, proprietary design software used by AMB manufacturers. In addition, this program incorporates an advanced unpublished fringing-magnetic-field model that increases accuracy beyond that offered by the other AMB-design software.

  15. Functional and molecular modelling studies of two hereditary fructose intolerance-causing mutations at arginine 303 in human liver aldolase.

    Science.gov (United States)

    Santamaria, R; Esposito, G; Vitagliano, L; Race, V; Paglionico, I; Zancan, L; Zagari, A; Salvatore, F

    2000-09-15

    We have identified a novel hereditary fructose intolerance mutation in the aldolase B gene (i.e. liver aldolase) that causes an arginine-to-glutamine substitution at residue 303 (Arg(303)-->Gln). We previously described another mutation (Arg(303)-->Trp) at the same residue. We have expressed the wild-type protein and the two mutated proteins and characterized their kinetic properties. The catalytic efficiency of protein Gln(303) is approx. 1/100 that of the wild-type for substrates fructose 1,6-bisphosphate and fructose 1-phosphate. The Trp(303) enzyme has a catalytic efficiency approx. 1/4800 that of the wild-type for fructose 1,6-bisphosphate; no activity was detected with fructose 1-phosphate. The mutation Arg(303)-->Trp thus substitution impairs enzyme activity more than Arg(303)-->Gln. Three-dimensional models of wild-type, Trp(303) and Gln(303) aldolase B generated by homology-modelling techniques suggest that, because of its larger size, tryptophan exerts a greater deranging effect than glutamine on the enzyme's three-dimensional structure. Our results show that the Arg(303)-->Gln substitution is a novel mutation causing hereditary fructose intolerance and provide a functional demonstration that Arg(303), a conserved residue in all vertebrate aldolases, has a dominant role in substrate binding during enzyme catalysis.

  16. Presenilin-2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Toshihiko Toda

    2011-01-01

    Full Text Available In order to clarify the pathophysiological role of presenilin-2 (PS2 carrying the Volga German Kindred mutation (N141I in a conventional mouse model of Alzheimer's disease (AD expressing amyloid precursor protein (APP with the Swedish mutation (Tg2576 line, we generated a double transgenic mouse (PS2Tg2576 by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies.

  17. Coevolutionary modeling of protein sequences: Predicting structure, function, and mutational landscapes

    Science.gov (United States)

    Weigt, Martin

    Over the last years, biological research has been revolutionized by experimental high-throughput techniques, in particular by next-generation sequencing technology. Unprecedented amounts of data are accumulating, and there is a growing request for computational methods unveiling the information hidden in raw data, thereby increasing our understanding of complex biological systems. Statistical-physics models based on the maximum-entropy principle have, in the last few years, played an important role in this context. To give a specific example, proteins and many non-coding RNA show a remarkable degree of structural and functional conservation in the course of evolution, despite a large variability in amino acid sequences. We have developed a statistical-mechanics inspired inference approach - called Direct-Coupling Analysis - to link this sequence variability (easy to observe in sequence alignments, which are available in public sequence databases) to bio-molecular structure and function. In my presentation I will show, how this methodology can be used (i) to infer contacts between residues and thus to guide tertiary and quaternary protein structure prediction and RNA structure prediction, (ii) to discriminate interacting from non-interacting protein families, and thus to infer conserved protein-protein interaction networks, and (iii) to reconstruct mutational landscapes and thus to predict the phenotypic effect of mutations. References [1] M. Figliuzzi, H. Jacquier, A. Schug, O. Tenaillon and M. Weigt ''Coevolutionary landscape inference and the context-dependence of mutations in beta-lactamase TEM-1'', Mol. Biol. Evol. (2015), doi: 10.1093/molbev/msv211 [2] E. De Leonardis, B. Lutz, S. Ratz, S. Cocco, R. Monasson, A. Schug, M. Weigt ''Direct-Coupling Analysis of nucleotide coevolution facilitates RNA secondary and tertiary structure prediction'', Nucleic Acids Research (2015), doi: 10.1093/nar/gkv932 [3] F. Morcos, A. Pagnani, B. Lunt, A. Bertolino, D. Marks, C

  18. Eastern slopes grizzly bear project

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-01-01

    The cumulative effects of human activities on the grizzly bears in the central Canadian Rockies are not well known. As a result, a project was initiated in 1994 to address the urgent requirement for accurate scientific information on the habitat and populations of grizzly bears in the area of the Banff National Park and Kananaskis Country. This area is probably the most heavily used and developed area where the grizzly still survives. The information gathered throughout the course of this study will be used to better protect and manage the bears and other sensitive carnivores in the region. Using telemetry, researchers are monitoring 25 grizzly bears which were radio-collared in a 22,000 square-kilometer area in the upper Bow Valley drainage of the eastern Alberta slopes. The researchers involved in the project are working with representatives from Husky Oil and Talisman Energy on the sound development of the Moose Mountain oil and gas field without adversely affecting the grizzly bear population. Information collected over seven years indicated that the grizzly bears have few and infrequent offspring. Using the information gathered so far, the location of the Moose Mountain to Jumping Pound pipeline was carefully selected, since the bears recover very slowly from high mortality, and also considering that the food and cover had already been compromised by the high number of roads, trails and other human activities in the area. The status of the population and habitat of the grizzly bear will be assessed upon the conclusion of the field research phase in 2001. Models will be updated using the data obtained during eight years and will assist in the understanding of complex variables that affect grizzly bears.

  19. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    Science.gov (United States)

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  20. A developmental systems perspective on epistasis: computational exploration of mutational interactions in model developmental regulatory networks.

    Directory of Open Access Journals (Sweden)

    Jayson Gutiérrez

    Full Text Available The way in which the information contained in genotypes is translated into complex phenotypic traits (i.e. embryonic expression patterns depends on its decoding by a multilayered hierarchy of biomolecular systems (regulatory networks. Each layer of this hierarchy displays its own regulatory schemes (i.e. operational rules such as +/- feedback and associated control parameters, resulting in characteristic variational constraints. This process can be conceptualized as a mapping issue, and in the context of highly-dimensional genotype-phenotype mappings (GPMs epistatic events have been shown to be ubiquitous, manifested in non-linear correspondences between changes in the genotype and their phenotypic effects. In this study I concentrate on epistatic phenomena pervading levels of biological organization above the genetic material, more specifically the realm of molecular networks. At this level, systems approaches to studying GPMs are specially suitable to shed light on the mechanistic basis of epistatic phenomena. To this aim, I constructed and analyzed ensembles of highly-modular (fully interconnected networks with distinctive topologies, each displaying dynamic behaviors that were categorized as either arbitrary or functional according to early patterning processes in the Drosophila embryo. Spatio-temporal expression trajectories in virtual syncytial embryos were simulated via reaction-diffusion models. My in silico mutational experiments show that: 1 the average fitness decay tendency to successively accumulated mutations in ensembles of functional networks indicates the prevalence of positive epistasis, whereas in ensembles of arbitrary networks negative epistasis is the dominant tendency; and 2 the evaluation of epistatic coefficients of diverse interaction orders indicates that, both positive and negative epistasis are more prevalent in functional networks than in arbitrary ones. Overall, I conclude that the phenotypic and fitness effects of

  1. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

    Science.gov (United States)

    Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-01

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

  2. A new modal-based approach for modelling the bump foil structure in the simultaneous solution of foil-air bearing rotor dynamic problems

    Science.gov (United States)

    Bin Hassan, M. F.; Bonello, P.

    2017-05-01

    Recently-proposed techniques for the simultaneous solution of foil-air bearing (FAB) rotor dynamic problems have been limited to a simple bump foil model in which the individual bumps were modelled as independent spring-damper (ISD) subsystems. The present paper addresses this limitation by introducing a modal model of the bump foil structure into the simultaneous solution scheme. The dynamics of the corrugated bump foil structure are first studied using the finite element (FE) technique. This study is experimentally validated using a purpose-made corrugated foil structure. Based on the findings of this study, it is proposed that the dynamics of the full foil structure, including bump interaction and foil inertia, can be represented by a modal model comprising a limited number of modes. This full foil structure modal model (FFSMM) is then adapted into the rotordynamic FAB problem solution scheme, instead of the ISD model. Preliminary results using the FFSMM under static and unbalance excitation conditions are proven to be reliable by comparison against the corresponding ISD foil model results and by cross-correlating different methods for computing the deflection of the full foil structure. The rotor-bearing model is also validated against experimental and theoretical results in the literature.

  3. Mutation rates among RNA viruses

    OpenAIRE

    Drake, John W.; Holland, John J.

    1999-01-01

    The rate of spontaneous mutation is a key parameter in modeling the genetic structure and evolution of populations. The impact of the accumulated load of mutations and the consequences of increasing the mutation rate are important in assessing the genetic health of populations. Mutation frequencies are among the more directly measurable population parameters, although the information needed to convert them into mutation rates is often lacking. A previous analysis of mutation rates in RNA viru...

  4. Dynamic analysis of centrifugal machines rotors supported on ball bearings by combined application of 3D and beam finite element models

    Science.gov (United States)

    Pavlenko, I. V.; Simonovskiy, V. I.; Demianenko, M. M.

    2017-08-01

    This research paper is aimed to investigating rotor dynamics of multistage centrifugal machines with ball bearings by using the computer programs “Critical frequencies of the rotor” and “Forced oscillations of the rotor,” which are implemented the mathematical model based on the use of beam finite elements. Free and forces oscillations of the rotor for the multistage centrifugal oil pump NPS 200-700 are observed by taking into account the analytical dependence of bearing stiffness on rotor speed, which is previously defined on the basis of results’ approximation for the numerical simulation in ANSYS by applying 3D finite elements. The calculations found that characteristic and constrained oscillations of rotor and corresponded to them forms of vibrations, as well as the form of constrained oscillation on the actual frequency for acceptable residual unbalance are determined.

  5. Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of 'easy to apply' probability models.

    NARCIS (Netherlands)

    Bodmer, D.; Ligtenberg, M.J.L.; Hout, A.H. van der; Gloudemans, S.; Ansink, K.; Oosterwijk-Wakka, J.C.; Hoogerbrugge-van der Linden, N.

    2006-01-01

    To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of

  6. Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ' easy to apply ' probability models

    NARCIS (Netherlands)

    Bodmer, D.; Ligtenberg, M. J. L.; van der Hout, A. H.; Gloudemans, S.; Ansink, K.; Oosterwijk, J. C.; Hoogerbrugge, N.

    2006-01-01

    To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of

  7. Transmitochondrial mice as models for primary prevention of diseases caused by mutation in the tRNA(Lys) gene.

    Science.gov (United States)

    Shimizu, Akinori; Mito, Takayuki; Hayashi, Chisato; Ogasawara, Emi; Koba, Ryusuke; Negishi, Issei; Takenaga, Keizo; Nakada, Kazuto; Hayashi, Jun-Ichi

    2014-02-25

    We generated transmitochondrial mice (mito-mice) that carry a mutation in the tRNA(Lys) gene encoded by mtDNA for use in studies of its pathogenesis and transmission profiles. Because patients with mitochondrial diseases frequently carry mutations in the mitochondrial tRNA(Lys) and tRNA(Leu(UUR)) genes, we focused our efforts on identifying somatic mutations of these genes in mouse lung carcinoma P29 cells. Of the 43 clones of PCR products including the tRNA(Lys) or tRNA(Leu(UUR)) genes in mtDNA of P29 cells, one had a potentially pathogenic mutation (G7731A) in the tRNA(Lys) gene. P29 subclones with predominant amounts of G7731A mtDNA expressed respiration defects, thus suggesting the pathogenicity of this mutation. We then transferred G7731A mtDNA into mouse ES cells and obtained F0 chimeric mice. Mating these F0 mice with C57BL/6J (B6) male mice resulted in the generation of F1 mice with G7731A mtDNA, named "mito-mice-tRNA(Lys7731)." Maternal inheritance and random segregation of G7731A mtDNA occurred in subsequent generations. Mito-mice-tRNA(Lys7731) with high proportions of G7731A mtDNA exclusively expressed respiration defects and disease-related phenotypes and therefore are potential models for mitochondrial diseases due to mutations in the mitochondrial tRNA(Lys) gene. Moreover, the proportion of mutated mtDNA varied markedly among the pups born to each dam, suggesting that selecting oocytes with high proportions of normal mtDNA from affected mothers with tRNA(Lys)-based mitochondrial diseases may be effective as a primary prevention for obtaining unaffected children.

  8. Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

    Science.gov (United States)

    Attard, M; Jean, G; Forestier, L; Cherqui, S; van't Hoff, W; Broyer, M; Antignac, C; Town, M

    1999-12-01

    Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused by a defect in the transport of cystine across the lysosomal membrane and characterized by early onset of renal proximal tubular dysfunction. Late-onset cystinosis, a rarer form of the disorder, is characterized by onset of symptoms between 12 and 15 years of age. We previously characterized the cystinosis gene, CTNS, and identified pathogenic mutations in patients with infantile nephropathic cystinosis, including a common, approximately 65 kb deletion which encompasses exons 1-10. Structure predictions suggested that the gene product, cystinosin, is a novel integral lysosomal membrane protein. We now examine the predicted effect of mutations on this model of cystinosin. In this study, we screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis and patients whose phenotype does not fit the classical definitions. We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 patients with infantile nephropathic cystinosis, 12 have two severely truncating mutations, which is consistent with a loss of functional protein, and 13 have missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations found in two late-onset patients affect functionally unimportant regions of cystinosin, which accounts for their milder phenotype. For three patients, the age of onset of cystinosis was <7 years but the course of the disease was milder than the infantile nephropathic form. This suggests that the missense mutations found in these individuals allow production of functional protein and may also indicate regions of cystinosin which are not functionally important.

  9. Modelling the effects of selection temperature and mutation on the prisoner's dilemma game on a complete oriented star.

    Science.gov (United States)

    Ren, Jianguo; Xu, Yonghong

    2014-01-01

    This paper models the prisoner's dilemma game based on pairwise comparison in finite populations on a complete oriented star (COS). First, we derive a linear system on a COS for calculating the corresponding fixation probabilities that imply dependence of the selection temperature and mutation. Then we observe and analyze the effects of two parameters on fixation probability under different population sizes. In particular, it is found through the experimental results that (1) high mutation is more sensitive to the fixation probability than the low one when population size is increasing, while the opposite is the case when the number of cooperators is increasing, and (2) selection temperature demotes the fixation probability.

  10. Biochemical investigation of a human pathogenic mutation in the nuclear ATP5E gene using yeast as a model

    Directory of Open Access Journals (Sweden)

    Elodie eSardin

    2015-04-01

    Full Text Available F1F0-ATP synthase is a key enzyme of the mitochondrial energetic metabolism responsible for the production of most cellular ATP in humans. Mayr et al. (Mayr JA, Havlickova V, Zimmermann F, Magler I, Kaplanova V, Jesina P, Pecinova A, Nuskova H, Koch J, Sperl W and Houstek J. 2010. Hum Mol Genet recently described a patient with a homozygote (Y12C mutation in the nuclear gene ATP5E encoding the ε-subunit of ATP synthase. To better define how it affects ATP synthase, we have modelled this mutation in the yeast Saccharomyces cerevisiae. A yeast equivalent of this mutation (Y11C had no significant effect on the growth of yeast on non-fermentable carbon sources (glycerol/ethanol or lactate, conditions under which the activity of the mitochondrial energy transducing system is absolutely essential. In addition, similar to what was observed in patient, this mutation in yeast has a minimal effect on the ATPase/synthase activities. On the contrary, this mutation which has been shown to have a strong impact on the assembly of the ATP synthase complex in humans, shows no significant impact on the assembly/stability of this complex in yeast, suggesting that biogenesis of this complex differs significantly.

  11. Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

    Science.gov (United States)

    Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S; Srivas, Rohith; Rivera, Janell; Stone, Nicole R; Pratt, Karishma; Mohamed, Tamer M A; Fu, Ji-Dong; Spencer, C Ian; Tippens, Nathaniel D; Li, Molong; Narasimha, Anil; Radzinsky, Ethan; Moon-Grady, Anita J; Yu, Haiyuan; Pruitt, Beth L; Snyder, Michael P; Srivastava, Deepak

    2016-12-15

    Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. A two level mutation-selection model of cultural evolution and diversity.

    Science.gov (United States)

    Salazar-Ciudad, Isaac

    2010-11-21

    Cultural evolution is a complex process that can happen at several levels. At the level of individuals in a population, each human bears a set of cultural traits that he or she can transmit to its offspring (vertical transmission) or to other members of his or her society (horizontal transmission). The relative frequency of a cultural trait in a population or society can thus increase or decrease with the relative reproductive success of its bearers (individual's level) or the relative success of transmission (called the idea's level). This article presents a mathematical model on the interplay between these two levels. The first aim of this article is to explore when cultural evolution is driven by the idea's level, when it is driven by the individual's level and when it is driven by both. These three possibilities are explored in relation to (a) the amount of interchange of cultural traits between individuals, (b) the selective pressure acting on individuals, (c) the rate of production of new cultural traits, (d) the individual's capacity to remember cultural traits and to the population size. The aim is to explore the conditions in which cultural evolution does not lead to a better adaptation of individuals to the environment. This is to contrast the spread of fitness-enhancing ideas, which make individual bearers better adapted to the environment, to the spread of "selfish" ideas, which spread well simply because they are easy to remember but do not help their individual bearers (and may even hurt them). At the same time this article explores in which conditions the adaptation of individuals is maximal. The second aim is to explore how these factors affect cultural diversity, or the amount of different cultural traits in a population. This study suggests that a larger interchange of cultural traits between populations could lead to cultural evolution not improving the adaptation of individuals to their environment and to a decrease of cultural diversity.

  13. On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population.

    Science.gov (United States)

    Traulsen, Arne; Lenaerts, Tom; Pacheco, Jorge M; Dingli, David

    2013-02-01

    The theory of the clonal origin of cancer states that a tumour arises from one cell that acquires mutation(s) leading to the malignant phenotype. It is the current belief that many of these mutations give a fitness advantage to the mutant population allowing it to expand, eventually leading to disease. However, mutations that lead to such a clonal expansion need not give a fitness advantage and may in fact be neutral--or almost neutral--with respect to fitness. Such mutant clones can be eliminated or expand stochastically, leading to a malignant phenotype (disease). Mutations in haematopoietic stem cells give rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal nocturnal haemoglobinuria (PNH). Although neutral drift often leads to clonal extinction, disease is still possible, and in this case, it has important implications both for the incidence of disease and for therapy, as it may be more difficult to eliminate neutral mutations with therapy. We illustrate the consequences of such dynamics, using CML and PNH as examples. These considerations have implications for many other tumours as well.

  14. Axial Halbach Magnetic Bearings

    Science.gov (United States)

    Eichenberg, Dennis J.; Gallo, Christopher A.; Thompson, William K.

    2008-01-01

    Axial Halbach magnetic bearings have been investigated as part of an effort to develop increasingly reliable noncontact bearings for future high-speed rotary machines that may be used in such applications as aircraft, industrial, and land-vehicle power systems and in some medical and scientific instrumentation systems. Axial Halbach magnetic bearings are passive in the sense that unlike most other magnetic bearings that have been developed in recent years, they effect stable magnetic levitation without need for complex active control.

  15. Effect of gradual weight-bearing on regenerated articular cartilage after joint distraction and motion in a rabbit model.

    Science.gov (United States)

    Nishino, Tomofumi; Ishii, Tomoo; Chang, Fei; Yanai, Takaji; Watanabe, Arata; Ogawa, Takeshi; Mishima, Hajime; Nakai, Kenjiro; Ochiai, Naoyuki

    2010-05-01

    The purpose of this study was to clarify the effect of gradual weight bearing (GWB) on regenerating cartilage. We developed a novel external fixation device (EFD) with a controllable weight-bearing system and continuous passive motion (CPM). A full-thickness defect was created by resection of the entire articular surface of the tibial plateau after the EFD was fixed in the rabbit's left knee. In the GWB group (n=6), GWB was started 6 weeks after surgery. In the CPM group (n=6), CPM with EFD was applied in the same manner without GWB. The control group (n=5) received only joint distraction. All rabbits were sacrificed 9 weeks after surgery. The central one-third of the regenerated tissue was assessed and scored blindly using a grading scale modified from the International Cartilage Repair Society visual histological assessment scale. The areas stained by Safranin-O and type II collagen antibody were measured, and the percentage of each area was calculated. There was no significant difference in the histological assessment scale among the groups. The percentage of the type II collagen-positive area was significantly larger in the GWB group than in the CPM group. The present study suggests that optimal mechanical stress, such as GWB, may affect regeneration of cartilage, in vivo.

  16. Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model.

    Science.gov (United States)

    Chang, Ken-Ming; Chen, Huang-Hui; Wang, Tai-Chi; Chen, I-Li; Chen, Yu-Tsen; Yang, Shyh-Chyun; Chen, Yeh-Long; Chang, Hsin-Huei; Huang, Chih-Hsiang; Chang, Jang-Yang; Shih, Chuan; Kuo, Ching-Chuan; Tzeng, Cherng-Chyi

    2015-12-01

    We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2-phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation.

  17. A new F131V mutation in Chlamydomonas phytoene desaturase locates a cluster of norflurazon resistance mutations near the FAD-binding site in 3D protein models.

    Directory of Open Access Journals (Sweden)

    Julio V Suarez

    Full Text Available The green alga Chlamydomonas reinhardtii provides a tractable genetic model to study herbicide mode of action using forward genetics. The herbicide norflurazon inhibits phytoene desaturase, which is required for carotenoid synthesis. Locating amino acid substitutions in mutant phytoene desaturases conferring norflurazon resistance provides a genetic approach to map the herbicide binding site. We isolated a UV-induced mutant able to grow in very high concentrations of norflurazon (150 µM. The phytoene desaturase gene in the mutant strain contained the first resistance mutation to be localised to the dinucleotide-binding Rossmann-likedomain. A highly conserved phenylalanine amino acid at position 131 of the 564 amino acid precursor protein was changed to a valine in the mutant protein. F131, and two other amino acids whose substitution confers norflurazon resistance in homologous phytoene desaturase proteins, map to distant regions in the primary sequence of the C. reinhardtii protein (V472, L505 but in tertiary models these residues cluster together to a region close to the predicted FAD binding site. The mutant gene allowed direct 5 µM norflurazon based selection of transformants, which were tolerant to other bleaching herbicides including fluridone, flurtamone, and diflufenican but were more sensitive to beflubutamid than wild type cells. Norflurazon resistance and beflubutamid sensitivity allow either positive or negative selection against transformants expressing the mutant phytoene desaturase gene.

  18. Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism

    Directory of Open Access Journals (Sweden)

    Camilla Ceccatelli Berti

    2015-04-01

    Full Text Available Mutations in nuclear genes associated with defective coenzyme A biosynthesis have been identified as responsible for some forms of neurodegeneration with brain iron accumulation (NBIA, namely PKAN and CoPAN. PKAN are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of NBIA, whereas mutations in CoA synthase COASY have been recently reported as the second inborn error of CoA synthesis leading to CoPAN. As reported previously, yeast cells expressing the pathogenic mutation exhibited a temperature-sensitive growth defect in the absence of pantothenate and a reduced CoA content. Additional characterization revealed decreased oxygen consumption, reduced activities of mitochondrial respiratory complexes, higher iron content, increased sensitivity to oxidative stress and reduced amount of lipid droplets, thus partially recapitulating the phenotypes found in patients and establishing yeast as a potential model to clarify the pathogenesis underlying PKAN and CoPAN diseases.

  19. Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities.

    Science.gov (United States)

    Banno, Kimihiko; Omori, Sayaka; Hirata, Katsuya; Nawa, Nobutoshi; Nakagawa, Natsuki; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Sakuma, Tetsushi; Yamamoto, Takashi; Toki, Tsutomu; Ito, Etsuro; Yamamoto, Toshiyuki; Kokubu, Chikara; Takeda, Junji; Taniguchi, Hidetoshi; Arahori, Hitomi; Wada, Kazuko; Kitabatake, Yasuji; Ozono, Keiichi

    2016-05-10

    Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Cryogenic Hybrid Magnetic Bearing

    Science.gov (United States)

    Meeks, Crawford R.; Dirusso, Eliseo; Brown, Gerald V.

    1994-01-01

    Cryogenic hybrid magnetic bearing is example of class of magnetic bearings in which permanent magnets and electromagnets used to suspend shafts. Electromagnets provide active control of position of shaft. Bearing operates at temperatures from -320 degrees F (-196 degrees C) to 650 degrees F (343 degrees C); designed for possible use in rocket-engine turbopumps, where effects of cryogenic environment and fluid severely limit lubrication of conventional ball bearings. This and similar bearings also suitable for terrestrial rotating machinery; for example, gas-turbine engines, high-vacuum pumps, canned pumps, precise gimbals that suspend sensors, and pumps that handle corrosive or gritty fluids.

  1. Connecting Sarcomere Protein Mutations to Pathogenesis in Cardiomyopathies: The Development of ‘Disease in a Dish’ Models

    Directory of Open Access Journals (Sweden)

    Rebecca Zaunbrecher

    2016-11-01

    Full Text Available Recent technological and protocol developments have greatly increased the ability to utilize stem cells transformed into cardiomyocytes as models to study human heart muscle development and how this is affected by disease associated mutations in a variety of sarcomere proteins. In this perspective we provide an overview of these emerging technologies and how they are being used to create better models of ‘disease in a dish’ for both research and screening assays. We also consider the value of these assays as models to explore the seminal processes in initiation of the disease development and the possibility of early interventions.

  2. Single-Nucleotide Mutation Matrix: A New Model for Predicting the NF-κB DNA Binding Sites

    OpenAIRE

    Wenxin Du; Jing Gao; Tingting Wang; Jinke Wang

    2014-01-01

    In this study, we established a single nucleotide mutation matrix (SNMM) model based on the relative binding affinities of NF-κB p50 homodimer to a wild-type binding site (GGGACTTTCC) and its all single-nucleotide mutants detected with the double-stranded DNA microarray. We evaluated this model by scoring different groups of 10-bp DNA sequences with this model and analyzing the correlations between the scores and the relative binding affinities detected with three wet experiments, including t...

  3. A Comparison of Experimental and Theoretical Results for Magnetic Bearings

    Science.gov (United States)

    Hibbs, Robert I., Jr.; Scharrer, Joseph K.; Galvin, Bonnie A.; Galvin, Mark W.

    2000-01-01

    A comprehensive program was undertaken to experimentally characterize the static and dynamic characteristics of a heteropolar magnetic bearing and to develop nonlinear theoretical models capable of accurately predicting magnetic bearing performance. This paper presents the results for the static characteristics of the magnetic bearing and a comparison with the predictions from the analytical model. The results indicate that the nonlinear theoretical model can accurately predict the static characteristics of the magnetic bearing.

  4. Teddy Bear Stories

    DEFF Research Database (Denmark)

    van Leeuwen, Theo; Caldas-Coulthardt, Carmen

    2014-01-01

    This paper presents a semiotic analysis of a key cultural artefact, the teddy bear. After introducing the iconography of the teddy bear, it analyses different kinds of stories to show how teddy bears are endowed with meaning in everyday life: stories from children's books, reminiscenses by adults...... about their childhood teddy bears, and children's accounts of what they do with teddy bears, both written for school and told 'out of school', The chapter sees teddy bears as artefacts that provide a cultural channeling for the child's need of a transitional object and argues that the meanings of teddy...... bears have traditionally centred on interpersonal relations within the nuclear family, but have recently been institutionalized and commercialized....

  5. Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

    Science.gov (United States)

    Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

    2008-12-01

    The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

  6. Bond graph modeling and experimental verification of a novel scheme for fault diagnosis of rolling element bearings in special operating conditions

    Science.gov (United States)

    Mishra, C.; Samantaray, A. K.; Chakraborty, G.

    2016-09-01

    Vibration analysis for diagnosis of faults in rolling element bearings is complicated when the rotor speed is variable or slow. In the former case, the time interval between the fault-induced impact responses in the vibration signal are non-uniform and the signal strength is variable. In the latter case, the fault-induced impact response strength is weak and generally gets buried in the noise, i.e. noise dominates the signal. This article proposes a diagnosis scheme based on a combination of a few signal processing techniques. The proposed scheme initially represents the vibration signal in terms of uniformly resampled angular position of the rotor shaft by using the interpolated instantaneous angular position measurements. Thereafter, intrinsic mode functions (IMFs) are generated through empirical mode decomposition (EMD) of resampled vibration signal which is followed by thresholding of IMFs and signal reconstruction to de-noise the signal and envelope order tracking to diagnose the faults. Data for validating the proposed diagnosis scheme are initially generated from a multi-body simulation model of rolling element bearing which is developed using bond graph approach. This bond graph model includes the ball and cage dynamics, localized fault geometry, contact mechanics, rotor unbalance, and friction and slip effects. The diagnosis scheme is finally validated with experiments performed with the help of a machine fault simulator (MFS) system. Some fault scenarios which could not be experimentally recreated are then generated through simulations and analyzed through the developed diagnosis scheme.

  7. Sedimentary facies and depositional model of shallow water delta dominated by fluvial for Chang 8 oil-bearing group of Yanchang Formation in southwestern Ordos Basin, China

    Institute of Scientific and Technical Information of China (English)

    陈林; 陆永潮; 吴吉元; 邢凤存; 刘璐; 马义权; 饶丹; 彭丽

    2015-01-01

    A systematic analysis of southwestern Ordos Basin’s sedimentary characteristics, internal architectural element association styles and depositional model was illustrated through core statistics, well logging data and outcrop observations in Chang 8 oil-bearing group. This analysis indicates that shallow water delta sediments dominated by a fluvial system is the primary sedimentary system of the Chang 8 oil-bearing group of the Yanchang Formation in southwestern Ordos Basin. Four microfacies with fine grain sizes are identified: distributary channels, sheet sandstone, mouth bar and interdistributary fines. According to the sandbody’s spatial distribution and internal architecture, two types of sandbody architectural element associations are identified: amalgamated distributary channels and thin-layer lobate sandstone. In this sedimentary system, net-like distributary channels at the delta with a narrow ribbon shape compose the skeleton of the sandbody that extends further into the delta front and shades into contiguous lobate distribution sheet sandstone in the distal delta front. The mouth bar is largely absent in this system. By analyzing the palaeogeomorphology, the palaeostructure background, sedimentary characteristics, sedimentary facies types and spatial distribution of sedimentary facies during the Chang 8 period, a distinctive depositional model of the Chang 8 shallow water fluvial-dominated delta was established, which primarily consists of straight multi-phase amalgamated distributary channels in the delta plain, net-like distributary channels frequently diverting and converging in the proximal delta front, sheet sandstones with dispersing contiguous lobate shapes in the distal delta front, and prodelta or shallow lake mudstones.

  8. MODELING AND ANALYSIS OF DYNAMICS IN BEARING SYSTEM OF DRILLING, MILLING AND BORING MACHINE WITH MONO-COLUMN

    Directory of Open Access Journals (Sweden)

    Yu. V. Vasilevich

    2015-01-01

    Full Text Available  FEM-analysis of dynamics in the bearing system of a heavy-duty machine tool has been carried out in the paper. This is a prospective variant for a large-size multi-purpose machine tool with a horizontal sliding ram. A saddle and a ram are moving vertically along a subtle mono-column. A rigid double-column is used in the existing analog machine tool. A static, modal and harmonic analysis of the bearing system with the mono-column has been made in the paper. It has been done with the help of FEM-simulation prior to fabrication of a prototype sample. Previously conducted calculations for the analog machine tool have shown good compatibility of FEM-calculation with experiments.Six common machine tool resonances have been revealed for the bearing system. Their oscillating cutting forces are actively exciting three-four resonance modes. Ranges of a flexure-torsion resonance (20–40 Hz and nose-diving resonances (70–90 Hz have been determined in the paper. The paper shows that the range of multi-wave resonances starts significantly higher from 140 Hz. These resonances are interconnected with bending oscillations of the ram and bucklings of the column walls which are matched with the oscillations. The paper demonstrates stability in resonance pattern. The torsional resonance of the column on the frequency of nearly 40 Hz is considered as the more dangerous one. Spindle rigidity goes down up to 3.8 Н/μm. It is possible to observe self-stabilization of the torsional resonance. Frequency of the torsional oscillations is practically unchangeable when there is a lifting or lowering down of the saddle and the ram. It is related to the migration of dynamical axis of torsion.Frequency-response characteristics of the bearing system have been constructed for various saddle positions on the column. Three frequency intervals that make it possible to carry out machining operation have been determined in the paper. The first interval is a static one. The

  9. Approximate analytical model of oil-film force for finite length elliptical journal bearing%有限长椭圆瓦轴承油膜力近似解析模型

    Institute of Scientific and Technical Information of China (English)

    王永亮; 刘占生; 钱大帅; 何鹏

    2012-01-01

    基于动态油膜边界条件,利用分离变量法求解Reynolds方程,获得了有限长圆瓦滑动轴承油膜压力分布表达式,推导了圆瓦轴承油膜力近似解析模型.在此基础上,根据椭圆瓦轴承油膜边界条件,建立了有限长椭圆瓦轴承油膜力近似解析模型.与有限差分法模型、长轴承模型、短轴承模型对比的结果显示,有限长椭圆瓦轴承油膜力模型能够适应任意长径比,且具有较高计算精度.基于给出的模型,利用Runge-Kutta法分析了刚性转子-椭圆瓦轴承系统的动力学特性,仿真结果表明,该模型能够较好描述椭圆瓦轴承油膜动力特性.%The Reynolds equation of plain journal bearing lubrication was solved by separation of variables method, the pressure distribution expression of oil-film in plain journal bearing was obtained based on dynamic boundary conditions, and the approximate analytical expression of plain journal bearing oil force was deduced. The boundary conditions of elliptical bearing were analyzed. The approximate analytical model of elliptical bearing oil-film was obtained by combining the oil film boundary conditions of elliptical bearing with oil film force expression of plain journal bearing. The oil film force is verified with high accuracy and suitability for any aspect ratio by comparing with the finite difference method, long bearing model, and the short bearing model. The nonlinear rotordynamic behavior of a rigid rotor on elliptical bearing was investigated by Runge-Kutta method, the results of numerical simulation show that the model can describe the dynamic characteristics of elliptical bearing oil film well.

  10. Mechanism of the Quorum-Quenching Lactonase (AiiA) from Bacillus thuringiensis. 2. Substrate Modeling and Active Site Mutations

    Energy Technology Data Exchange (ETDEWEB)

    Momb, Jessica; Wang, Canhui; Liu, Dali; Thomas, Pei W.; Petsko, Gregory A.; Guo, Hua; Ringe, Dagmar; Fast, Walter (UNM); (Brandeis); (Texas)

    2008-12-02

    The N-acyl-l-homoserine lactone hydrolases (AHL lactonases) have attracted considerable attention because of their ability to quench AHL-mediated quorum-sensing pathways in Gram-negative bacteria and because of their relation to other enzymes in the metallo-{beta}-lactamase superfamily. To elucidate the detailed catalytic mechanism of AHL lactonase, mutations are made on residues that presumably contribute to substrate binding and catalysis. Steady-state kinetic studies are carried out on both the wild-type and mutant enzymes using a spectrum of substrates. Two mutations, Y194F and D108N, present significant effects on the overall catalysis. On the basis of a high-resolution structural model of the enzyme-product complex, a hybrid quantum mechanical/molecular mechanical method is used to model the substrate binding orientation and to probe the effect of the Y194F mutation. Combining all experimental and computational results, we propose a detailed mechanism for the ring-opening hydrolysis of AHL substrates as catalyzed by the AHL lactonase from Bacillus thuringiensis. Several features of the mechanism that are also found in related enzymes are discussed and may help to define an evolutionary thread that connects the hydrolytic enzymes of this mechanistically diverse superfamily.

  11. Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center.

    Directory of Open Access Journals (Sweden)

    Isabella Giovannoni

    Full Text Available Familial intrahepatic cholestases (FICs are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC or a benign recurrent intrahepatic cholestasis (BRIC. For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5'UTR- exon 18 in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission.

  12. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenoty...

  13. Application of Two- and Four-Mutation Carcinogenesis Models to UV induced Skin Tumours in Mice

    NARCIS (Netherlands)

    Venema LB; Leenhouts HP; LSO

    1995-01-01

    Dit rapport bevat de resultaten van de analyse van de incidentie van huidtumoren bij muizen na blootstelling aan ultra-violette straling (UV). Twee soorten modellen, gebaseerd op het meerstadiumkarakter van het carcinogenese proces, werden gebruikt om de incidentie te beschrijven: een twee-mutat

  14. Correlation between oncogenic mutations and parameter sensitivity of the apoptosis pathway model.

    Directory of Open Access Journals (Sweden)

    Jia Chen

    2014-01-01

    Full Text Available One of the major breakthroughs in oncogenesis research in recent years is the discovery that, in most patients, oncogenic mutations are concentrated in a few core biological functional pathways. This discovery indicates that oncogenic mechanisms are highly related to the dynamics of biologic regulatory networks, which govern the behaviour of functional pathways. Here, we propose that oncogenic mutations found in different biological functional pathways are closely related to parameter sensitivity of the corresponding networks. To test this hypothesis, we focus on the DNA damage-induced apoptotic pathway--the most important safeguard against oncogenesis. We first built the regulatory network that governs the apoptosis pathway, and then translated the network into dynamics equations. Using sensitivity analysis of the network parameters and comparing the results with cancer gene mutation spectra, we found that parameters that significantly affect the bifurcation point correspond to high-frequency oncogenic mutations. This result shows that the position of the bifurcation point is a better measure of the functionality of a biological network than gene expression levels of certain key proteins. It further demonstrates the suitability of applying systems-level analysis to biological networks as opposed to studying genes or proteins in isolation.

  15. Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center

    Science.gov (United States)

    Giovannoni, Isabella; Callea, Francesco; Bellacchio, Emanuele; Torre, Giuliano; De Ville De Goyet, Jean; Francalanci, Paola

    2015-01-01

    Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission. PMID:26678486

  16. Modelling the effects of selection temperature and mutation on the prisoner's dilemma game on a complete oriented star.

    Directory of Open Access Journals (Sweden)

    Jianguo Ren

    Full Text Available This paper models the prisoner's dilemma game based on pairwise comparison in finite populations on a complete oriented star (COS. First, we derive a linear system on a COS for calculating the corresponding fixation probabilities that imply dependence of the selection temperature and mutation. Then we observe and analyze the effects of two parameters on fixation probability under different population sizes. In particular, it is found through the experimental results that (1 high mutation is more sensitive to the fixation probability than the low one when population size is increasing, while the opposite is the case when the number of cooperators is increasing, and (2 selection temperature demotes the fixation probability.

  17. Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model

    Directory of Open Access Journals (Sweden)

    Huang FYJ

    2015-01-01

    Full Text Available Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc showed a high relationship between cell number and its bioluminescent intensity (R2=0.99 in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05. As a result, the

  18. The Bearing Capacity of Circular Footings in Sand: Comparison between Model Tests and Numerical Simulations Based on a Nonlinear Mohr Failure Envelope

    Directory of Open Access Journals (Sweden)

    Sven Krabbenhoft

    2012-01-01

    Full Text Available This paper presents the results of a series of triaxial tests with dry sand at confining pressures varying from 1.5 kPa to 100 kPa at relative densities of 0.20, 0.59, and 0.84. The results, which are in reasonable accordance with an equation given by Bolton, show that the friction angle is strongly dependent on the stress level and on the basis of the test results, a nonlinear Mohr failure criterion has been proposed. This yield criterion has been implemented in a finite element program and an analysis of the bearing capacity of a circular shaped model foundation, diameter 100 mm, has been conducted. Comparisons have been made with results from 1g model scale tests with a foundation of similar size and a good agreement between numerical results and test results has been found.

  19. Amino- and Carboxyl-Terminal CCR5 Mutations in Brazilian HIV-1-Infected Women and Homology Model of p.L55Q CCR5 Mutant.

    Science.gov (United States)

    Costa, Giselle Calasans de Souza; Nunes, Marcio Roberto T; Jesus, Jaqueline Goes; Novaes, Thiago; Cardoso, Jedson Ferreira; Sousa Júnior, Edivaldo Costa; Santos, Edson de Souza; Galvão-Castro, Bernardo; Zanette, Dalila Luciola; Gonçalves, Marilda de Souza; Alcantara, Luiz Carlos Junior

    2015-07-01

    Genetic factors from an HIV-1 host can affect the rate of progression to AIDS and HIV infection. To investigate the frequency of mutations in the CCR5 gene, HIV-1 samples from infected women and uninfected individuals were selected for sequencing of the CCR5 gene regions encoding the N- and C-terminal protein domains. Physicochemical CCR5 modeling and potential protein domain analysis were performed in order to evaluate the impact of the mutations found in the properties and structure of CCR5. The p.L55Q mutation in the N-terminal protein domain was observed only in uninfected individuals, with an allelic frequency of 1.8%. Physicochemical analysis revealed that the p.L55Q mutation magnified the flexibility and accessibility profiles and the modeling of CCR5 structures showed resulting in a small deviation to the right, as well as a hydrophobic to hydrophilic property alteration. The p.L55Q mutation also resulted in a slight modification of the electrostatic load of this region. Additionally, three novel silent mutations were found at the C-terminal coding region among HIV-1-infected women. The results suggest that the p.L55Q mutation might alter CCR5 conformation. Further studies should be conducted to verify the role of this mutation in HIV-1 susceptibility.

  20. SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.

    Science.gov (United States)

    Praveen, Kavita; Wen, Ying; Gray, Kelsey M; Noto, John J; Patlolla, Akash R; Van Duyne, Gregory D; Matera, A Gregory

    2014-08-01

    Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  1. SMA-causing missense mutations in survival motor neuron (Smn display a wide range of phenotypes when modeled in Drosophila.

    Directory of Open Access Journals (Sweden)

    Kavita Praveen

    2014-08-01

    Full Text Available Mutations in the human survival motor neuron 1 (SMN gene are the primary cause of spinal muscular atrophy (SMA, a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs, core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  2. Influence of backup bearings and support structure dynamics on the behavior of rotors with active supports

    Science.gov (United States)

    Flowers, George T.

    1995-02-01

    This semiannual status report lists specific accomplishments made on the research of the influence of backup bearings and support structure dynamics on the behavior of rotors with active supports. Papers have been presented representing work done on the T-501 engine model; an experimental/simulation study of auxiliary bearing rotordynamics; and a description of a rotordynamical model for a magnetic bearing supported rotor system, including auxiliary bearing effects. A finite element model for a foil bearing has been developed. Additional studies of rotor/bearing/housing dynamics are currently being performed as are studies of the effects of sideloading on auxiliary bearing rotordynamics using the magnetic bearing supported rotor model.

  3. Towards Biogeochemical Modeling of Anaerobic Oxidation of Methane: Characterization of Microbial Communities in Methane-bearing North American Continental Margin Sediments

    Science.gov (United States)

    Graw, M. F.; Solomon, E. A.; Chrisler, W.; Krause, S.; Treude, T.; Ruppel, C. D.; Pohlman, J.; Colwell, F. S.

    2015-12-01

    Methane advecting through continental margin sediments may enter the water column and potentially contribute to ocean acidification and increase atmospheric methane concentrations. Anaerobic oxidation of methane (AOM), mediated by syntrophic consortia of anaerobic methanotrophic archaea and sulfate-reducing bacteria (ANME-SRB), consumes nearly all dissolved methane in methane-bearing sediments before it reaches the sediment-water interface. Despite the significant role ANME-SRB play in carbon cycling, our knowledge of these organisms and their surrounding microbial communities is limited. Our objective is to develop a metabolic model of ANME-SRB within methane-bearing sediments and to couple this to a geochemical reaction-transport model for these margins. As a first step towards this goal, we undertook fluorescent microscopic imaging, 16S rRNA gene deep-sequencing, and shotgun metagenomic sequencing of sediments from the US Pacific (Washington) and northern Atlantic margins where ANME-SRB are present. A successful Illumina MiSeq sequencing run yielded 106,257 bacterial and 857,834 archaeal 16S rRNA gene sequences from 12 communities from the Washington Margin using both universal prokaryotic and archaeal-specific primer sets. Fluorescent microscopy confirmed the presence of cells of the ANME-2c lineage in the sequenced communities. Microbial community characterization was coupled with measurements of sediment physical and geochemical properties and, for samples from the US Atlantic margin, 14C-based measurements of AOM rates and 35S-based measurements of sulfate reduction rates. These findings have the potential to increase understanding of ANME-SRB, their surrounding microbial communities, and their role in carbon cycling within continental margins. In addition, they pave the way for future efforts at developing a metabolic model of ANME-SRB and coupling it to geochemical models of the US Washington and Atlantic margins.

  4. Volume-based solvation models out-perform area-based models in combined studies of wild-type and mutated protein-protein interfaces

    Directory of Open Access Journals (Sweden)

    Warwicker Jim

    2008-10-01

    Full Text Available Abstract Background Empirical binding models have previously been investigated for the energetics of protein complexation (ΔG models and for the influence of mutations on complexation (i.e. differences between wild-type and mutant complexes, ΔΔG models. We construct binding models to directly compare these processes, which have generally been studied separately. Results Although reasonable fit models were found for both ΔG and ΔΔG cases, they differ substantially. In a dataset curated for the absence of mainchain rearrangement upon binding, non-polar area burial is a major determinant of ΔG models. However this ΔG model does not fit well to the data for binding differences upon mutation. Burial of non-polar area is weighted down in fitting of ΔΔG models. These calculations were made with no repacking of sidechains upon complexation, and only minimal packing upon mutation. We investigated the consequences of more extensive packing changes with a modified mean-field packing scheme. Rather than emphasising solvent exposure with relatively extended sidechains, rotamers are selected that exhibit maximal packing with protein. This provides solvent accessible areas for proteins that are much closer to those of experimental structures than the more extended sidechain regime. The new packing scheme increases changes in non-polar burial for mutants compared to wild-type proteins, but does not substantially improve agreement between ΔG and ΔΔG binding models. Conclusion We conclude that solvent accessible area, based on modelled mutant structures, is a poor correlate for ΔΔG upon mutation. A simple volume-based, rather than solvent accessibility-based, model is constructed for ΔG and ΔΔG systems. This shows a more consistent behaviour. We discuss the efficacy of volume, as opposed to area, approaches to describe the energetic consequences of mutations at interfaces. This knowledge can be used to develop simple computational screens for

  5. Mice overexpressing both non-mutated human SOD1 and mutated SOD1G93A genes: a competent experimental model for studying iron metabolism in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Anna eGajowiak

    2016-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive neurodegenerative disease characterized by degeneration and loss of motor neurons in the spinal cord, brainstem and motor cortex. Up to 10% of ALS cases are inherited (familial, fALS and associated with mutations, frequently in the superoxide dismutase 1 (SOD1 gene. Rodent transgenic models of ALS are often used to elucidate a complex pathogenesis of this disease. Of importance, both ALS patients and animals carrying mutated human SOD1 gene show symptoms of oxidative stress and iron metabolism misregulation. The aim of our study was to characterize changes in iron metabolism in one of the most commonly used models of ALS – transgenic mice overexpressing human mutated SOD1G93A gene. We analyzed the expression of iron-related genes in asymptomatic, 2-month old and symptomatic, 4-month old SOD1G93A mice. In parallel, respective age-matched mice overexpressing human non-mutated SOD1 transgene and control mice were analyzed. We demonstrate that the overexpression of both SOD1 and SOD1G93A genes account for a substantial increase in SOD1 protein levels and activity in selected tissues and that not all the changes in iron metabolism genes expression are specific for the overexpression of the mutated form of SOD1.

  6. Calculating the Number of People with Alzheimer's Disease in any Country Using Saturated Mutation Models of Brain Cell Loss that also Predict Widespread Natural Immunity to the Disease

    Directory of Open Access Journals (Sweden)

    Ivan Kramer

    2010-01-01

    Full Text Available The series of mutations that cause brain cells to spontaneously and randomly die leading to Alzheimer's disease (AD is modelled. The prevalence of AD as a function of age in males and females is calculated from two very different mutation models of brain cell death. Once the prevalence functions are determined, the number of people with AD in any country or city can be estimated.

  7. EcoBears

    DEFF Research Database (Denmark)

    Nielsen, Nick; Pedersen, Sandra Bleuenn; Sørensen, Jens Ager

    2015-01-01

    In this paper, we introduce the EcoBears concept that aims to augment household appliances with functional and aesthetic features to promote their "use'' and "longevity of use'' to prevent their disposal. The EcoBears also aim to support the communication of environmental issues in the home setting....... We present our initial design and implementation of the EcoBears that consist of two bear modules (a mother and her cub). We also present our preliminary concept validations and lessons learned to be considered for future directions....

  8. A predictive model for the transport of copper by HCl-bearing water vapour in ore-forming magmatic-hydrothermal systems: Implications for copper porphyry ore formation

    Science.gov (United States)

    Migdisov, Art. A.; Bychkov, A. Yu.; Williams-Jones, A. E.; van Hinsberg, V. J.

    2014-03-01

    The solubility of copper chloride and metallic copper in low-density homogenous HCl-bearing aqueous fluids was investigated experimentally at temperatures between 350 and 550 °C. Analysis of the resulting data and those on the solubility of copper chloride reported in Archibald et al. (2002) for temperatures between 280 and 320 °C suggests that at temperatures <450 °C, the solubility of copper chloride is controlled by a species having a Cu:Cl ratio of 1:1. The data also suggest that the solubility of copper chloride is controlled by the formation of hydrated copper clusters, i.e., CuCl:(H2O)n, and increases exponentially with H2O fugacity rather than linearly, as previously assumed. The hydration number (n) of the predominant cluster increases systematically with increasing pressure, and each of the gaseous solutions investigated at temperatures <450 °C contains a mixture of clusters with different hydration numbers that predominate at different pressures. A model is proposed for the quantitative evaluation of the stability of these clusters based on the observation that the Gibbs free energy of formation of the clusters determined from the experimental data shows a strong linear correlation with reciprocal temperature. This model reliably predicts the fugacity of copper in chlorine-bearing water vapour determined from solubility and liquid-vapour partitioning reported in the literature. At temperatures above 450 °C, the stoichiometry of the dominant form of the dissolved copper chloride changes from copper monochloride (Cu:Cl = 1:1) to copper dichloride (Cu:Cl = 1:2) and the hydration numbers of the corresponding clusters are constant for the range of temperatures and pressures investigated. We did not manage to determine the valence state of copper in these species, and therefore interpreted our stability data separately for two alternative sets of hydration clusters, namely; one containing monovalent copper (CuCl:HCl or CuCl2H), and the other containing

  9. Mutational meltdown in laboratory yeast populations

    NARCIS (Netherlands)

    Zeyl, C.; Mizesko, M.; Visser, de J.A.G.M.

    2001-01-01

    In small or repeatedly bottlenecked populations, mutations are expected to accumulate by genetic drift, causing fitness declines. In mutational meltdown models, such fitness declines further reduce population size, thus accelerating additional mutation accumulation and leading to extinction. Because

  10. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Shi-Yu Yang

    2017-03-01

    Full Text Available Numerically the most important risk factor for the development of Parkinson's disease (PD is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.

  11. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.

    Science.gov (United States)

    Taylor, James G; Cheuk, Adam T; Tsang, Patricia S; Chung, Joon-Yong; Song, Young K; Desai, Krupa; Yu, Yanlin; Chen, Qing-Rong; Shah, Kushal; Youngblood, Victoria; Fang, Jun; Kim, Su Young; Yeung, Choh; Helman, Lee J; Mendoza, Arnulfo; Ngo, Vu; Staudt, Louis M; Wei, Jun S; Khanna, Chand; Catchpoole, Daniel; Qualman, Stephen J; Hewitt, Stephen M; Merlino, Glenn; Chanock, Stephen J; Khan, Javed

    2009-11-01

    Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS.

  12. Insights into the mutation-induced HHH syndrome from modeling human mitochondrial ornithine transporter-1.

    Directory of Open Access Journals (Sweden)

    Jing-Fang Wang

    Full Text Available Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109-113. Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii the mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and

  13. Insights into the mutation-induced HHH syndrome from modeling human mitochondrial ornithine transporter-1.

    Science.gov (United States)

    Wang, Jing-Fang; Chou, Kuo-Chen

    2012-01-01

    Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109-113). Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i) the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii) the mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii) the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective

  14. A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations

    Directory of Open Access Journals (Sweden)

    Hong-Li Liu

    2017-08-01

    Full Text Available Hydroxyflutamide (HF, an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR. However, a drug resistance problem appears after about one year’s treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA method have been carried out to analyze the interaction mechanism between HF and wild-type (WT/mutant ARs. The obtained results indicate that AR helix 12 (H12 plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12. When H12 closes to the AR ligand-binding domain (LBD like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per-residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF.

  15. MuSE: accounting for tumor heterogeneity using a sample-specific error model improves sensitivity and specificity in mutation calling from sequencing data.

    Science.gov (United States)

    Fan, Yu; Xi, Liu; Hughes, Daniel S T; Zhang, Jianjun; Zhang, Jianhua; Futreal, P Andrew; Wheeler, David A; Wang, Wenyi

    2016-01-01

    Subclonal mutations reveal important features of the genetic architecture of tumors. However, accurate detection of mutations in genetically heterogeneous tumor cell populations using next-generation sequencing remains challenging. We develop MuSE ( http://bioinformatics.mdanderson.org/main/MuSE ), Mutation calling using a Markov Substitution model for Evolution, a novel approach for modeling the evolution of the allelic composition of the tumor and normal tissue at each reference base. MuSE adopts a sample-specific error model that reflects the underlying tumor heterogeneity to greatly improve the overall accuracy. We demonstrate the accuracy of MuSE in calling subclonal mutations in the context of large-scale tumor sequencing projects using whole exome and whole genome sequencing.

  16. Single-nucleotide mutation matrix: a new model for predicting the NF-κB DNA binding sites.

    Directory of Open Access Journals (Sweden)

    Wenxin Du

    Full Text Available In this study, we established a single nucleotide mutation matrix (SNMM model based on the relative binding affinities of NF-κB p50 homodimer to a wild-type binding site (GGGACTTTCC and its all single-nucleotide mutants detected with the double-stranded DNA microarray. We evaluated this model by scoring different groups of 10-bp DNA sequences with this model and analyzing the correlations between the scores and the relative binding affinities detected with three wet experiments, including the electrophoresis mobility shift assay (EMSA, the protein-binding microarray (PBM and the systematic evolution of ligands by exponential enrichment-sequencing (SELEX-Seq. The results revealed that the SNMM scores were strongly correlated with the detected binding affinities. We also scored the DNA sequences with other three models, including the principal coordinate (PC model, the position weight matrix scoring algorithm (PWMSA model and the Match model, and analyzed the correlations between the scores and the detected binding affinities. In comparison with these models, the SNMM model achieved reliable results. We finally determined 0.747 as the optimal threshold for predicting the NF-κB DNA-binding sites with the SNMM model. The SNMM model thus provides a new alternative model for scoring the relative binding affinities of NF-κB to the 10-bp DNA sequences and predicting the NF-κB DNA-binding sites.

  17. Single-nucleotide mutation matrix: a new model for predicting the NF-κB DNA binding sites.

    Science.gov (United States)

    Du, Wenxin; Gao, Jing; Wang, Tingting; Wang, Jinke

    2014-01-01

    In this study, we established a single nucleotide mutation matrix (SNMM) model based on the relative binding affinities of NF-κB p50 homodimer to a wild-type binding site (GGGACTTTCC) and its all single-nucleotide mutants detected with the double-stranded DNA microarray. We evaluated this model by scoring different groups of 10-bp DNA sequences with this model and analyzing the correlations between the scores and the relative binding affinities detected with three wet experiments, including the electrophoresis mobility shift assay (EMSA), the protein-binding microarray (PBM) and the systematic evolution of ligands by exponential enrichment-sequencing (SELEX-Seq). The results revealed that the SNMM scores were strongly correlated with the detected binding affinities. We also scored the DNA sequences with other three models, including the principal coordinate (PC) model, the position weight matrix scoring algorithm (PWMSA) model and the Match model, and analyzed the correlations between the scores and the detected binding affinities. In comparison with these models, the SNMM model achieved reliable results. We finally determined 0.747 as the optimal threshold for predicting the NF-κB DNA-binding sites with the SNMM model. The SNMM model thus provides a new alternative model for scoring the relative binding affinities of NF-κB to the 10-bp DNA sequences and predicting the NF-κB DNA-binding sites.

  18. A trs20 mutation that mimics an SEDT-causing mutation blocks selective and non-selective autophagy: a model for TRAPP III organization.

    Science.gov (United States)

    Brunet, Stephanie; Shahrzad, Nassim; Saint-Dic, Djenann; Dutczak, Hartley; Sacher, Michael

    2013-10-01

    TRAPP is a multisubunit complex that functions in membrane traffic. Mutations in the mammalian TRAPP protein C2 are linked to the skeletal disorder spondyloepiphyseal dysplasia tarda (SEDT) that is thought to arise from an inability to secrete procollagen from the endoplasmic reticulum. Here, we show that C2 binds to the SNARE protein Syntaxin 5 and this interaction is weakened by an SEDT-causing missense mutation (D47Y). Interestingly, the equivalent mutation (D46Y) in the yeast C2 homolog Trs20p does not block anterograde traffic but did affect endocytosis. The trs20D46Y mutation interfered with the interaction between Trs20p and Trs85p (TRAPP III-specific subunit), Trs120p and Trs130p (TRAPP II-specific subunits). Size exclusion chromatography suggested that this yeast mutation destabilized the TRAPP III complex that is involved in autophagy. We further show that this mutation blocks both the selective cytosol-to-vacuole (cvt) pathway as well as non-selective autophagy. We demonstrate that the apparent molecular size of the TRAPP III complex is dependent upon membranes, and that the presence of TRAPP III is dependent upon Atg9p. Finally, we demonstrate that lipidated Bet3p is enriched in TRAPP III and that lipidation increases the efficiency of autophagy. Our study suggests that Trs20p acts as an adaptor for Trs85p and Trs120p and reveals complexities in TRAPP III assembly and function. The implications of C2D47Y in SEDT are discussed. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Unbalanced Magnetic Pull Effect on Stiffness Models of Active Magnetic Bearing due to Rotor Eccentricity in Brushless DC Motor Using Finite Element Method

    Directory of Open Access Journals (Sweden)

    Bangcheng Han

    2013-01-01

    Full Text Available We firstly report on an investigation into the unbalanced magnetic pull (UMP effect on the static stiffness models of radial active magnetic bearing (RAMB in brushless DC motor (BDCM in no-loaded and loaded conditions using the finite element method (FEM. The influences of the UMP on the force-control current, force-position, current stiffness, and position stiffness of RAMB are clarified in BDCM with 100 kW rated power. We found the position stiffness to be more susceptible to UMP. The primary source of UMP is the permanent magnets of BDCM. In addition, the performance of RAMB is affected by the UMP ripples during motor commutation and also periodically affected by the angular position of rotor. The characteristic curves of RAMB force versus control current (or rotor position and angular position of rotor affected by the UMP are given. The method is useful in design and optimization of RAMB in magnetically suspended BDCMs.

  20. From disease modelling to personalised therapy in patients with CEP290 mutations [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Elisa Molinari

    2017-05-01

    Full Text Available Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. When transcripts containing these changes are generated, they are usually rapidly removed by the cell through the process of nonsense-mediated decay. Here we discuss observed changes in transcripts of the centrosomal protein CEP290 resulting not from degradation, but from changes in exon usage. We also comment on a landmark paper (Drivas et al. Sci Transl Med. 2015 where modelling this process of exon usage may be used to predict disease severity in CEP290 ciliopathies, and how understanding this process may potentially be used for therapeutic benefit in the future.

  1. On Controllable Elastohydrodynamic Fluid Film Bearings

    DEFF Research Database (Denmark)

    Haugaard, Martin Asger

    This thesis gives a theoretical description of the active tilting-pad journal bearing (ATPJB). It provides the qualified reader with the tools to model an ATPJB, while staying clear of pitfalls. The model is based on well known techniques and allows for local stability analyses, harmonic stationary...... are performed for a tilting-pad journal bearing (TPJB) and an ATPJB under static conditions, followed by a generalisation to dynamic conditions (transient as well as stationary harmonic). These analyses will be of interest to experimentalists, since they permit experiments performed on scaled down test rigs...... the addition of a control system may just as well harm rotor-bearing performance as improve it....

  2. Trends in Controllable Oil Film Bearings

    DEFF Research Database (Denmark)

    Santos, Ilmar

    2011-01-01

    This work gives an overview about the theoretical and experimental achievements of mechatronics applied to oil film bearings, with the aim of: controlling the lateral vibration of flexible rotating shafts; modifying bearing dynamic characteristics, as stiffness and damping properties; increasing...... the rotational speed ranges by improving damping and eliminating instability problems, for example, by compensating cross-coupling destabilizing effects; reducing startup torque and energy dissipation in bearings; compensating thermal effects. It is shown that such controllable bearings can act as "smart......" components and be applied to rotating machines with the goal of avoiding unexpected stops of plants, performing rotordynamic tests and identifying model parameters "on site". Emphasis is given to the controllable lubrication (active lubrication) applied to different types of oil film bearings, i...

  3. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case-Study in Lynch Syndrome

    Science.gov (United States)

    Boonstra, Philip S.; Mukherjee, Bhramar; Taylor, Jeremy M. G.; Nilbert, Mef; Moreno, Victor M.; Gruber, Stephen B.

    2011-01-01

    Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation sub-types known to be associated with the disease phenotype. In this paper, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect inferential conclusions. We compare the fit of four candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding effect of changes in secular trends, screening and medical practices that may affect time to disease detection across birth cohorts. Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts. Our motivating case-study comes from a Danish cancer register of 124 families with mutations in mismatch repair genes known to cause hereditary non-polyposis colorectal cancer, also called Lynch syndrome. We find evidence for a decrease in AOO between generations in this study. Our model predicts family level anticipation effects which are potentially useful in genetic counseling clinics for high risk families. PMID:21627626

  4. Temperature distribution and scuffing of tapered roller bearing

    Science.gov (United States)

    Wang, Ailin; Wang, Jiugen

    2014-11-01

    In the field of aerospace, high-speed trains and automobile, etc, analysis of temperature filed and scuffing failure of tapered roller bearings are more important than ever, and the scuffing failure of elements of such rolling bearings under heavy load and high speed still cannot be effectively predicted yet. A simplified model of tapered roller bearings consisted of one inner raceway, one outer raceway and a tapered roller was established, in which the interaction of several heat sources is ignored. The contact mechanics model, temperature model and model of scuffing failure are synthesized, and the corresponding computer programs are developed to analyze the effects of bearings parameters, different material and operational conditions on thermal performance of bearings, and temperature distribution and the possibility of surface scuffing are obtained. The results show that load, speed, thermal conductivity and tapered roller materials influence temperature rise and scuffing failure of bearings. Ceramic material of tapered roller results in the decrease of scuffing possibility of bearings to a high extent than the conventional rolling bearing steel. Compared with bulk temperature, flash temperature on the surfaces of bearing elements has a little influence on maximum temperature rise of bearing elements. For the rolling bearings operated under high speed and heavy load, this paper proposes a method which can accurately calculate the possibility of scuffing failure of rolling bearings.

  5. Temperature Distribution and Scuffing of Tapered Roller Bearing

    Institute of Scientific and Technical Information of China (English)

    WANG Ailin; WANG Jiugen

    2014-01-01

    In the field of aerospace, high-speed trains and automobile, etc, analysis of temperature filed and scuffing failure of tapered roller bearings are more important than ever, and the scuffing failure of elements of such rolling bearings under heavy load and high speed still cannot be effectively predicted yet. A simplified model of tapered roller bearings consisted of one inner raceway, one outer raceway and a tapered roller was established, in which the interaction of several heat sources is ignored. The contact mechanics model, temperature model and model of scuffing failure are synthesized, and the corresponding computer programs are developed to analyze the effects of bearings parameters, different material and operational conditions on thermal performance of bearings, and temperature distribution and the possibility of surface scuffing are obtained. The results show that load, speed, thermal conductivity and tapered roller materials influence temperature rise and scuffing failure of bearings. Ceramic material of tapered roller results in the decrease of scuffing possibility of bearings to a high extent than the conventional rolling bearing steel. Compared with bulk temperature, flash temperature on the surfaces of bearing elements has a little influence on maximum temperature rise of bearing elements. For the rolling bearings operated under high speed and heavy load, this paper proposes a method which can accurately calculate the possibility of scuffing failure of rolling bearings.

  6. The salmon bears: giants of the great bear rainforest

    National Research Council Canada - National Science Library

    McAllister, I; Read, N

    2010-01-01

    The Salmon Bears explores the delicate balance that exists between the grizzly, black and spirit bears of the Great Bear Rainforest and their natural environment on the central coast of British Columbia...

  7. Mutation Screening of 1,237 Cancer Genes across Six Model Cell Lines of Basal-Like Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Eleonor Olsson

    Full Text Available Basal-like breast cancer is an aggressive subtype generally characterized as poor prognosis and lacking the expression of the three most important clinical biomarkers, estrogen receptor, progesterone receptor, and HER2. Cell lines serve as useful model systems to study cancer biology in vitro and in vivo. We performed mutational profiling of six basal-like breast cancer cell lines (HCC38, HCC1143, HCC1187, HCC1395, HCC1954, and HCC1937 and their matched normal lymphocyte DNA using targeted capture and next-generation sequencing of 1,237 cancer-associated genes, including all exons, UTRs and upstream flanking regions. In total, 658 somatic variants were identified, of which 378 were non-silent (average 63 per cell line, range 37-146 and 315 were novel (not present in the Catalogue of Somatic Mutations in Cancer database; COSMIC. 125 novel mutations were confirmed by Sanger sequencing (59 exonic, 48 3'UTR and 10 5'UTR, 1 splicing, with a validation rate of 94% of high confidence variants. Of 36 mutations previously reported for these cell lines but not detected in our exome data, 36% could not be detected by Sanger sequencing. The base replacements C/G>A/T, C/G>G/C, C/G>T/A and A/T>G/C were significantly more frequent in the coding regions compared to the non-coding regions (OR 3.2, 95% CI 2.0-5.3, P<0.0001; OR 4.3, 95% CI 2.9-6.6, P<0.0001; OR 2.4, 95% CI 1.8-3.1, P<0.0001; OR 1.8, 95% CI 1.2-2.7, P = 0.024, respectively. The single nucleotide variants within the context of T[C]T/A[G]A and T[C]A/T[G]A were more frequent in the coding than in the non-coding regions (OR 3.7, 95% CI 2.2-6.1, P<0.0001; OR 3.8, 95% CI 2.0-7.2, P = 0.001, respectively. Copy number estimations were derived from the targeted regions and correlated well to Affymetrix SNP array copy number data (Pearson correlation 0.82 to 0.96 for all compared cell lines; P<0.0001. These mutation calls across 1,237 cancer-associated genes and identification of novel variants will aid in

  8. Regulation of Anabaena sp. strain PCC 7120 glutamine synthetase activity in a Synechocystis sp. strain PCC 6803 derivative strain bearing the Anabaena glnA gene and a mutated host glnA gene.

    Science.gov (United States)

    Mérida, A; Flores, E; Florencio, F J

    1992-01-01

    The glnA gene from Synechocystis sp. strain PCC 6803 was cloned by hybridization with the glnA gene from Anabaena sp. strain PCC 7120, and a deletion-insertion mutation of the Synechocystis gene was generated in vitro. A strain derived from Synechocystis sp. strain PCC 6803 which contained integrated into the chromosome, in addition to its own glnA gene, the Anabaena glnA gene was constructed. From that strain, a Synechocystis sp. glnA mutant could be obtained by transformation with the inactivated Synechocystis glnA gene; this mutant grew by using Anabaena glutamine synthetase and was not a glutamine auxotroph. A Synechocystis sp. glnA mutant could not be obtained, however, from the wild-type Synechocystis sp. The Anabaena glutamine synthetase enzyme was subject to ammonium-promoted inactivation when expressed in the Synechocystis strain but not in the Anabaena strain itself.

  9. Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation

    Directory of Open Access Journals (Sweden)

    Mario Rotondi

    2016-01-01

    Full Text Available CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.. Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL alone or in combination with TNF-α (10 ng/mL for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; p<0.00001 and the TNFα-stimulated (ANOVA F: 15.309; p<0.00001 CXCL8 secretions in BCPAP but not in TPC-1 cells (NS. On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP (p<0.05 and TPC-1 (p<0.05 cells. Transwell migration assay showed that (i CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii IFNγ significantly reduced the migration only of BCPAP cells; and (iii CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line.

  10. Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation

    Science.gov (United States)

    Rotondi, Mario; Coperchini, Francesca; Awwad, Oriana; Di Buduo, Christian A.; Abbonante, Vittorio; Magri, Flavia; Balduini, Alessandra

    2016-01-01

    CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.). Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL) alone or in combination with TNF-α (10 ng/mL) for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; p < 0.00001) and the TNFα-stimulated (ANOVA F: 15.309; p < 0.00001) CXCL8 secretions in BCPAP but not in TPC-1 cells (NS). On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP (p < 0.05) and TPC-1 (p < 0.05) cells. Transwell migration assay showed that (i) CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii) IFNγ significantly reduced the migration only of BCPAP cells; and (iii) CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line. PMID:27555670

  11. Mutational spectrum drives the rise of mutator bacteria.

    Directory of Open Access Journals (Sweden)

    Alejandro Couce

    Full Text Available Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  12. Insights into the latent multinomial model through mark-resight data on female grizzly bears with cubs-of-the-year

    Science.gov (United States)

    Higgs, Megan D.; Link, William; White, Gary C.; Haroldson, Mark A.; Bjornlie, Daniel D

    2013-01-01

    Mark-resight designs for estimation of population abundance are common and attractive to researchers. However, inference from such designs is very limited when faced with sparse data, either from a low number of marked animals, a low probability of detection, or both. In the Greater Yellowstone Ecosystem, yearly mark-resight data are collected for female grizzly bears with cubs-of-the-year (FCOY), and inference suffers from both limitations. To overcome difficulties due to sparseness, we assume homogeneity in sighting probabilities over 16 years of bi-annual aerial surveys. We model counts of marked and unmarked animals as multinomial random variables, using the capture frequencies of marked animals for inference about the latent multinomial frequencies for unmarked animals. We discuss undesirable behavior of the commonly used discrete uniform prior distribution on the population size parameter and provide OpenBUGS code for fitting such models. The application provides valuable insights into subtleties of implementing Bayesian inference for latent multinomial models. We tie the discussion to our application, though the insights are broadly useful for applications of the latent multinomial model.

  13. Active magnetic bearings used as exciters for rolling element bearing outer race defect diagnosis.

    Science.gov (United States)

    Xu, Yuanping; Di, Long; Zhou, Jin; Jin, Chaowu; Guo, Qintao

    2016-03-01

    The active health monitoring of rotordynamic systems in the presence of bearing outer race defect is considered in this paper. The shaft is assumed to be supported by conventional mechanical bearings and an active magnetic bearing (AMB) is used in the mid of the shaft location as an exciter to apply electromagnetic force to the system. We investigate a nonlinear bearing-pedestal system model with the outer race defect under the electromagnetic force. The nonlinear differential equations are integrated using the fourth-order Runge-Kutta algorithm. The simulation and experimental results show that the characteristic signal of outer race incipient defect is significantly amplified under the electromagnetic force through the AMBs, which is helpful to improve the diagnosis accuracy of rolling element bearing׳s incipient outer race defect. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

  14. 计及边缘效应的交流混合磁轴承建模%Modeling for AC Hybrid Magnetic Bearings Considering Edge Effect

    Institute of Scientific and Technical Information of China (English)

    朱熀秋; 丁书玲

    2016-01-01

    在混合磁轴承(hybrid magnetic bearing,HMB)建模过程中,通常忽略涡流效应、边缘效应和漏磁等因素,使得悬浮力数学模型精度降低。为了提高模型精度,提出了计及磁极端部边缘效应的混合磁轴承改进模型。该文以交流径向混合磁轴承为例分析其工作原理和磁通分布特性,采用磁场分割法分别求解不同边缘磁通区域的磁导,通过叠加原则获得单个磁极下的总磁导,根据等效磁路法建立径向悬浮力的精确数学模型。实验结果表明:改进前模型计算所得悬浮力与实验所得悬浮力误差接近10%,改进后的数学模型所得悬浮力与实验所得悬浮力误差小于5%。比较结果证明了计及边缘效应能有效提高悬浮力数学模型的精度。%In modeling proceeding of hybrid magnetic bearings (HMBs), factors such as the eddy current effect, the edge effect and the flux leakage are commonly ignored, which decreases the precision of the mathematical model of suspension forces. In order to improve the precision, an improved mathematical model of hybrid magnetic bearings considering the edge effect was established. An AC hybrid magnetic bearing was taken as an example, its working principle and features of flux distribution were analyzed. Then, the magnetic field division method was employed to calculate the permeances of different regions located around the end portion of the pole. The permeances were added by the superposition principle, and the total permeance of the single pole was obtained. The accurate model was obtained by using the equivalent magnetic circuit method. The experimental results show that the error between original model values and experimental values is about 10%, the error between improved model values and experimental values is less than 5%. The results of the comparison have verified that the consideration of the edge effect can effectively improve the precision of the mathematical model

  15. Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta.

    Science.gov (United States)

    Lindert, Uschi; Weis, Mary Ann; Rai, Jyoti; Seeliger, Frank; Hausser, Ingrid; Leeb, Tosso; Eyre, David; Rohrbach, Marianne; Giunta, Cecilia

    2015-07-17

    Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.

  16. A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.

    Science.gov (United States)

    McDonald, David A; Shenkar, Robert; Shi, Changbin; Stockton, Rebecca A; Akers, Amy L; Kucherlapati, Melanie H; Kucherlapati, Raju; Brainer, James; Ginsberg, Mark H; Awad, Issam A; Marchuk, Douglas A

    2011-01-15

    Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes into a mismatch repair-deficient Msh2(-/-) background. Ccm1(+/-)Msh2(-/-) mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the Ccm2(+/-)Msh2(-/-) mice lacked cerebrovascular lesions. The CCM1 mouse model provides an in vivo tool to investigate CCM pathogenesis and new therapies.

  17. A naturally occurring mouse model of achromatopsia: characterization of the mutation in cone transducin and subsequent retinal phenotype.

    Science.gov (United States)

    Jobling, Andrew I; Vessey, Kirstan A; Waugh, Michelle; Mills, Samuel A; Fletcher, Erica L

    2013-05-09

    This work investigates a novel, naturally occurring mouse model of achromatopsia. The specific missense mutation within the Gnat2 gene was identified and the subsequent retinal phenotype characterized. The Gnat2 sequence was amplified using PCR from BALB/c and Gnat2(c.518A>G) retinae and the product sequenced. Retinal function was assessed at 3, 6, 9, and 12 months using the electroretinogram. Transducin and opsin expression were assessed at 3 and 12 months using immunohistochemistry and quantitative PCR. Retinal remodeling and Müller cell gliosis were investigated using immunocytochemistry. An A to G missense mutation at position 518 of the Gnat2 gene was identified that resulted in an aspartic acid to glycine substitution. Gnat2(c.518A>G) animals showed no cone response, while the rod response was normal except for a decrease in the photoreceptor response at 12 months (a-wave, -14%). Gnat2(c.518A>G) retinal sections showed no transducin immunolabeling; however, protein was detected via Western blot. Gnat2 gene expression was only decreased at 12 months of age (-27%). There was reduced cone number at 12 months (-27%) and M-opsin showed evidence of mislocalization. Displaced photoreceptor terminals and altered horizontal cell, cone/rod bipolar cell morphology were evident at 3 months, becoming more extensive at 12 months with the emergence of Müller cell gliosis. The Gnat2(c.518A>G) mouse contains a missense mutation that results in no cone function due to a misfolding of transducin. Cone photoreceptors also show signs of opsin mislocalization, retinal remodeling and degeneration. This naturally occurring model shows all the hallmark signs of achromatopsia.

  18. TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Song Min

    2011-08-01

    Full Text Available Abstract Background Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD, are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs, a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aβ deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aβ deposits start. Methods Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. Results While no difference was found in cerebral Aβ load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg was less than that in a TLR4 wild-type AD model (TLR4W Tg. At 9 months, TLR4M Tg mice had increased Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes. Conclusion This is the first demonstration of TLR4

  19. Modeling of air-gas and dynamic processes in driving development workings in the gas-bearing coal seams

    Energy Technology Data Exchange (ETDEWEB)

    Presler, V.T. [Russian Academy of Science, Kemerovo (Russian Federation). Siberian Branch, Inst. of Coal & Coal Fuel Chemistry

    2002-04-01

    The models for air-gas processes of different hierarchical level are considered in designing and driving development workings in the coal seams. The procedure is proposed for model adaptation according to the on-line data, which makes it possible to estimate the state of medium and working capacity of measuring equipment.

  20. Touchdown Ball-Bearing System for Magnetic Bearings

    Science.gov (United States)

    Kingsbury, Edward P.; Price, Robert; Gelotte, Erik; Singer, Herbert B.

    2003-01-01

    The torque-limited touchdown bearing system (TLTBS) is a backup mechanical-bearing system for a high-speed rotary machine in which the rotor shaft is supported by magnetic bearings in steady-state normal operation. The TLTBS provides ball-bearing support to augment or supplant the magnetic bearings during startup, shutdown, or failure of the magnetic bearings. The TLTBS also provides support in the presence of conditions (in particular, rotational acceleration) that make it difficult or impossible to control the magnetic bearings or in which the magnetic bearings are not strong enough (e.g., when the side load against the rotor exceeds the available lateral magnetic force).

  1. Kin selection-mutation balance: a model for the origin, maintenance, and consequences of social cheating.

    Science.gov (United States)

    Van Dyken, J David; Linksvayer, Timothy A; Wade, Michael J

    2011-03-01

    Social conflict, in the form of intraspecific selfish "cheating," has been observed in a number of natural systems. However, a formal, evolutionary genetic theory of social cheating that provides an explanatory, predictive framework for these observations is lacking. Here we derive the kin selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton's rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater lineages are transient and do not invade. Instead, cheating lineages are eliminated by kin selection but are constantly reintroduced by mutation, maintaining a stable equilibrium frequency of cheaters. The presence of cheaters at equilibrium creates a "cheater load" that selects for mechanisms of cheater control, such as policing. We find that increasing relatedness reduces the cheater load more efficiently than does policing the costs and benefits of cooperation. Our results provide new insight into the effects of genetic systems, mating systems, ecology, and patterns of sex-limited expression on social evolution. We offer an explanation for the widespread cheater/altruist polymorphism found in nature and suggest that the common fear of conflict-induced social collapse is unwarranted.

  2. DNA Repair Domain Modeling Can Predict Cell Death and Mutation Frequency for Wide Range Spectrum of Radiation

    Science.gov (United States)

    Viger, Louise; Ponomarev, Artem L.; Plante, Ianik; Evain, Trevor; Penninckx, Sebastien; Blattnig, Steve R.; Costes, Sylvain V.

    2017-01-01

    Exploration missions to Mars and other destinations raise many questions about the health of astronauts. The continuous exposure of astronauts to galactic cosmic rays is one of the main concerns for long-term missions. Cosmic ionizing radiations are composed of different ions of various charges and energies notably, highly charged energy (HZE) particles. The HZE particles have been shown to be more carcinogenic than low-LET radiation, suggesting the severity of chromosomal aberrations induced by HZE particles is one possible explanation. However, most mathematical models predicting cell death and mutation frequency are based on directly fitting various HZE dose response and are in essence empirical approaches. In this work, we assume a simple biological mechanism to model DNA repair and use it to simultaneously explain the low- and high-LET response using the exact same fitting parameters. Our work shows that the geometrical position of DNA repair along tracks of heavy ions are sufficient to explain why high-LET particles can induce more death and mutations. Our model is based on assuming DNA double strand breaks (DSBs) are repaired within repair domain, and that any DSBs located within the same repair domain cluster into one repair unit, facilitating chromosomal rearrangements and increasing the probability of cell death. We introduced this model in 2014 using simplified microdosimetry profiles to predict cell death. In this work, we collaborated with NASA Johnson Space Center to generate more accurate microdosimetry profiles derived by Monte Carlo techniques, taking into account track structure of HZE particles and simulating DSBs in realistic cell geometry. We simulated 224 data points (D, A, Z, E) with the BDSTRACKS model, leading to a large coverage of LET from 10 to 2,400 keV/µm. This model was used to generate theoretical RBE for various particles and energies for both cell death and mutation frequencies. The RBE LET dependence is in agreement with

  3. Kinetic network models of tryptophan mutations in β-hairpins reveal the importance of non-native interactions.

    Science.gov (United States)

    Razavi, Asghar M; Voelz, Vincent A

    2015-06-09

    We present an analysis of the most extensive explicit-solvent simulations of β-hairpins to date (9.4 ms in aggregate), with the aim of probing the effects of tryptophan mutations on folding. From molecular simulations of GB1 hairpin, trpzip4, trpzip5, and trpzip6 performed on Folding@home, Markov State Models (MSMs) were constructed using a unified set of metastable states, enabling objective comparison of folding mechanisms. MSM models display quantitative agreement with experimental structural observables and folding kinetics, and predict multimodal kinetics due to specific non-native kinetic traps, which be identified as on- or off-pathway from the network topology. We quantify kinetic frustration by several means, including the s-ensemble method to evaluate glasslike behavior. Free-energy profiles and transition state movement clearly show stabilization of non-native states as Trp mutations are introduced. Remarkably, we find that "β-capped" sequences (trpzip4 and trpzip5) are able to overcome this frustration and remain cooperative two-state folders with a large time-scale gap. These results suggest that, while β-capping motifs are robust, fold stabilization by tryptophan generally may require overcoming significant non-native kinetic traps, perhaps explaining their under-representation in natural proteins.

  4. Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease

    Directory of Open Access Journals (Sweden)

    Timo Friedrich

    2012-03-01

    Analysis of zebrafish mutants that demonstrate abnormal locomotive behavior can elucidate the molecular requirements for neural network function and provide new models of human disease. Here, we show that zebrafish quetschkommode (que mutant larvae exhibit a progressive locomotor defect that culminates in unusual nose-to-tail compressions and an inability to swim. Correspondingly, extracellular peripheral nerve recordings show that que mutants demonstrate abnormal locomotor output to the axial muscles used for swimming. Using positional cloning and candidate gene analysis, we reveal that a point mutation disrupts the gene encoding dihydrolipoamide branched-chain transacylase E2 (Dbt, a component of a mitochondrial enzyme complex, to generate the que phenotype. In humans, mutation of the DBT gene causes maple syrup urine disease (MSUD, a disorder of branched-chain amino acid metabolism that can result in mental retardation, severe dystonia, profound neurological damage and death. que mutants harbor abnormal amino acid levels, similar to MSUD patients and consistent with an error in branched-chain amino acid metabolism. que mutants also contain markedly reduced levels of the neurotransmitter glutamate within the brain and spinal cord, which probably contributes to their abnormal spinal cord locomotor output and aberrant motility behavior, a trait that probably represents severe dystonia in larval zebrafish. Taken together, these data illustrate how defects in branched-chain amino acid metabolism can disrupt nervous system development and/or function, and establish zebrafish que mutants as a model to better understand MSUD.

  5. Ultra-precision bearings

    CERN Document Server

    Wardle, F

    2015-01-01

    Ultra-precision bearings can achieve extreme accuracy of rotation, making them ideal for use in numerous applications across a variety of fields, including hard disk drives, roundness measuring machines and optical scanners. Ultraprecision Bearings provides a detailed review of the different types of bearing and their properties, as well as an analysis of the factors that influence motion error, stiffness and damping. Following an introduction to basic principles of motion error, each chapter of the book is then devoted to the basic principles and properties of a specific type of bearin

  6. A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State.

    Science.gov (United States)

    Liu, Ying; Yen, Hai-Yun; Austria, Theresa; Pettersson, Jonas; Peti-Peterdi, Janos; Maxson, Robert; Widschwendter, Martin; Dubeau, Louis

    2015-10-01

    Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P < 0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.

  7. A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State

    Directory of Open Access Journals (Sweden)

    Ying Liu

    2015-10-01

    Full Text Available Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30% rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P < 0.0001, attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.

  8. Control of a flexible rotor active magnetic bearing test rig:a characteristic model based all-coefficient adaptive control approach

    Institute of Scientific and Technical Information of China (English)

    Long DI; Zongli LIN

    2014-01-01

    Active magnetic bearings (AMBs) have found a wide range of applications in high-speed rotating machinery industry. The instability and nonlinearity of AMBs make controller designs difficult, and when AMBs are coupled with a flexible rotor, the resulting complex dynamics make the problems of stabilization and disturbance rejection, which are critical for a stable and smooth operation of the rotor AMB system, even more difficult. Proportional-integral-derivative (PID) control dominates the current AMB applications in the field. Even though PID controllers are easy to implement, there are critical performance limitations associated with them that prevent the more advanced applications of AMBs, which usually require stronger robustness and performance offered by modern control methods such as H-infinity control andμ-synthesis. However, these advanced control designs rely heavily on the relatively accurate plant models and uncertainty characterizations, which are sometimes difficult to obtain. In this paper, we explore and report on the use of the characteristic model based all-coefficient adaptive control method to stabilize a flexible rotor AMB test rig. In spite of the simple structure of such a characteristic model based all-coefficient adaptive controller, both simulation and experimental results show its strong performance.

  9. Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of zebrafish alpha-dystroglycan and comparison with the murine model.

    Directory of Open Access Journals (Sweden)

    Davide Pirolli

    Full Text Available A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG, identified in dag1-mutated zebrafish, results in a reduced transcription and a complete absence of the protein. Lacking experimental structural data for zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D C-terminal domain of alpha-DG from zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the zebrafish protein whereas local effects have been detected in the murine protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of the alpha-DG C-terminal Ig-like domain that could possibly affect and propagate to the entire DG complex. The structural features herein identified may be of crucial help to understand the molecular basis of primary dystroglycanopathies.

  10. Research on Bored Bearing Characteristics in Xi’an

    Directory of Open Access Journals (Sweden)

    Zhang Lipeng

    2015-01-01

    Full Text Available To analyze the influence of different soil properties on pile foundation load-bearing characteristics, taking a section of railway in Xi’an and a bridge of Xi’an as test area, and by field static load test to study load transfer characteristics after the test piles under axial pressure, including the distribution of axial force, pile lateral friction, tip resistance traits, ultimate bearing capacity determine, and compare with the theory bearing capacity. Experimental results show that, adjacent soil properties change large, axial force and lateral friction mutation at the junction of corresponding soil layer. Silty clay in different parts is below ground, and its lateral friction plays much difference. Pile lateral friction plays an important role in bearing capacity, but the role of round gravel soil end bearing capacity to pile bearing capacity can’t be ignored. Tests calculate pile bearing capacity significantly larger than standardized formula calculation bearing capacity, which are respectively 55.35% and 119.1%. And give the similar project condition the suggested values of pile bearing capacity and soil friction, to provide reference for similar pile foundation design.

  11. Passive Magnetic Bearing With Ferrofluid Stabilization

    Science.gov (United States)

    Jansen, Ralph; DiRusso, Eliseo

    1996-01-01

    A new class of magnetic bearings is shown to exist analytically and is demonstrated experimentally. The class of magnetic bearings utilize a ferrofluid/solid magnet interaction to stabilize the axial degree of freedom of a permanent magnet radial bearing. Twenty six permanent magnet bearing designs and twenty two ferrofluid stabilizer designs are evaluated. Two types of radial bearing designs are tested to determine their force and stiffness utilizing two methods. The first method is based on the use of frequency measurements to determine stiffness by utilizing an analytical model. The second method consisted of loading the system and measuring displacement in order to measure stiffness. Two ferrofluid stabilizers are tested and force displacement curves are measured. Two experimental test fixtures are designed and constructed in order to conduct the stiffness testing. Polynomial models of the data are generated and used to design the bearing prototype. The prototype was constructed and tested and shown to be stable. Further testing shows the possibility of using this technology for vibration isolation. The project successfully demonstrated the viability of the passive magnetic bearing with ferrofluid stabilization both experimentally and analytically.

  12. Zebrafish dracula encodes ferrochelatase and its mutation provides a model for erythropoietic protoporphyria.

    Science.gov (United States)

    Childs, S; Weinstein, B M; Mohideen, M A; Donohue, S; Bonkovsky, H; Fishman, M C

    2000-08-24

    Exposure to light precipitates the symptoms of several genetic disorders that affect both skin and internal organs. It is presumed that damage to non-cutaneous organs is initiated indirectly by light, but this is difficult to study in mammals. Zebrafish have an essentially transparent periderm for the first days of development. In a previous large-scale genetic screen we isolated a mutation, dracula (drc), which manifested as a light-dependent lysis of red blood cells [1]. We report here that protoporphyrin IX accumulates in the mutant embryos, suggesting a deficiency in the activity of ferrochelatase, the terminal enzyme in the pathway for heme biosynthesis. We find that homozygous drc(m248) mutant embryos have a G-->T transversion at a splice donor site in the ferrochelatase gene, creating a premature stop codon. The mutant phenotype, which shows light-dependent hemolysis and liver disease, is similar to that seen in humans with erythropoietic protoporphyria, a disorder of ferrochelatase.

  13. Genomic evidence for island population conversion resolves conflicting theories of polar bear evolution.

    Science.gov (United States)

    Cahill, James A; Green, Richard E; Fulton, Tara L; Stiller, Mathias; Jay, Flora; Ovsyanikov, Nikita; Salamzade, Rauf; St John, John; Stirling, Ian; Slatkin, Montgomery; Shapiro, Beth

    2013-01-01

    Despite extensive genetic analysis, the evolutionary relationship between polar bears (Ursus maritimus) and brown bears (U. arctos) remains unclear. The two most recent comprehensive reports indicate a recent divergence with little subsequent admixture or a much more ancient divergence followed by extensive admixture. At the center of this controversy are the Alaskan ABC Islands brown bears that show evidence of shared ancestry with polar bears. We present an analysis of genome-wide sequence data for seven polar bears, one ABC Islands brown bear, one mainland Alaskan brown bear, and a black bear (U. americanus), plus recently published datasets from other bears. Surprisingly, we find clear evidence for gene flow from polar bears into ABC Islands brown bears but no evidence of gene flow from brown bears into polar bears. Importantly, while polar bears contributed <1% of the autosomal genome of the ABC Islands brown bear, they contributed 6.5% of the X chromosome. The magnitude of sex-biased polar bear ancestry and the clear direction of gene flow suggest a model wherein the enigmatic ABC Island brown bears are the descendants of a polar bear population that was gradually converted into brown bears via male-dominated brown bear admixture. We present a model that reconciles heretofore conflicting genetic observations. We posit that the enigmatic ABC Islands brown bears derive from a population of polar bears likely stranded by the receding ice at the end of the last glacial period. Since then, male brown bear migration onto the island has gradually converted these bears into an admixed population whose phenotype and genotype are principally brown bear, except at mtDNA and X-linked loci. This process of genome erosion and conversion may be a common outcome when climate change or other forces cause a population to become isolated and then overrun by species with which it can hybridize.

  14. Genomic evidence for island population conversion resolves conflicting theories of polar bear evolution.

    Directory of Open Access Journals (Sweden)

    James A Cahill

    Full Text Available Despite extensive genetic analysis, the evolutionary relationship between polar bears (Ursus maritimus and brown bears (U. arctos remains unclear. The two most recent comprehensive reports indicate a recent divergence with little subsequent admixture or a much more ancient divergence followed by extensive admixture. At the center of this controversy are the Alaskan ABC Islands brown bears that show evidence of shared ancestry with polar bears. We present an analysis of genome-wide sequence data for seven polar bears, one ABC Islands brown bear, one mainland Alaskan brown bear, and a black bear (U. americanus, plus recently published datasets from other bears. Surprisingly, we find clear evidence for gene flow from polar bears into ABC Islands brown bears but no evidence of gene flow from brown bears into polar bears. Importantly, while polar bears contributed <1% of the autosomal genome of the ABC Islands brown bear, they contributed 6.5% of the X chromosome. The magnitude of sex-biased polar bear ancestry and the clear direction of gene flow suggest a model wherein the enigmatic ABC Island brown bears are the descendants of a polar bear population that was gradually converted into brown bears via male-dominated brown bear admixture. We present a model that reconciles heretofore conflicting genetic observations. We posit that the enigmatic ABC Islands brown bears derive from a population of polar bears likely stranded by the receding ice at the end of the last glacial period. Since then, male brown bear migration onto the island has gradually converted these bears into an admixed population whose phenotype and genotype are principally brown bear, except at mtDNA and X-linked loci. This process of genome erosion and conversion may be a common outcome when climate change or other forces cause a population to become isolated and then overrun by species with which it can hybridize.

  15. Rotor Vibration Reduction via Active Hybrid Bearings

    DEFF Research Database (Denmark)

    Nicoletti, Rodrigo; Santos, Ilmar

    2002-01-01

    The use of fluid power to reduce and control rotor vibration in rotating machines is investigated. An active hybrid bearing is studied, whose main objective is to reduce wear and vibration between rotating and stationary machinery parts. By injecting pressurised oil into the oil film, through...... orifices machined in the bearing pads, one can alter the machine dynamic characteristics, thus enhancing its operational range. A mathematical model of the rotor-bearing system, as well as of the hydraulic system, is presented. Numerical results of the system frequency response show good agreement...

  16. Gear bearing drive

    Science.gov (United States)

    Weinberg, Brian (Inventor); Mavroidis, Constantinos (Inventor); Vranish, John M. (Inventor)

    2011-01-01

    A gear bearing drive provides a compact mechanism that operates as an actuator providing torque and as a joint providing support. The drive includes a gear arrangement integrating an external rotor DC motor within a sun gear. Locking surfaces maintain the components of the drive in alignment and provide support for axial loads and moments. The gear bearing drive has a variety of applications, including as a joint in robotic arms and prosthetic limbs.

  17. Rolling bearing analysis

    CERN Document Server

    Harris, Tedric A

    2001-01-01

    One of the most well-known experts in the field brings cutting-edge research to practitioners in the new edition of this important reference. Covers the improved mathematical calculations for rolling bearing endurance developed by the American Society of Mechanical Engineers and the Society of Lubrication and Tribology Engineers. Updated with new material on Condition-Based Maintenance, new testing methods, and new bearing materials.

  18. My Little Teddy Bear

    Institute of Scientific and Technical Information of China (English)

    钱佳楠

    2005-01-01

    @@ As Valentine's Day came closer,every shop was full of colourful gifts such as cookies in the shape of heart, chocolates,Teddy Bears and so on.When I step into a shop on February 14th,I felt most lonely as I was alone.With mv eves fixed on a lovely Teddy Bear, I wished that someone could send me this stuffed toy.

  19. Analysis of thermoelastohydrodynamic performance of journal misaligned engine main bearings

    Science.gov (United States)

    Bi, Fengrong; Shao, Kang; Liu, Changwen; Wang, Xia; Zhang, Jian

    2015-05-01

    To understand the engine main bearings' working condition is important in order to improve the performance of engine. However, thermal effects and thermal effect deformations of engine main bearings are rarely considered simultaneously in most studies. A typical finite element model is selected and the effect of thermoelastohydrodynamic(TEHD) reaction on engine main bearings is investigated. The calculated method of main bearing's thermal hydrodynamic reaction and journal misalignment effect is finite difference method, and its deformation reaction is calculated by using finite element method. The oil film pressure is solved numerically with Reynolds boundary conditions when various bearing characteristics are calculated. The whole model considers a temperature-pressure-viscosity relationship for the lubricant, surface roughness effect, and also an angular misalignment between the journal and the bearing. Numerical simulations of operation of a typical I6 diesel engine main bearing is conducted and importance of several contributing factors in mixed lubrication is discussed. The performance characteristics of journal misaligned main bearings under elastohydrodynamic(EHD) and TEHD loads of an I6 diesel engine are received, and then the journal center orbit movement, minimum oil film thickness and maximum oil film pressure of main bearings are estimated over a wide range of engine operation. The model is verified through the comparison with other present models. The TEHD performance of engine main bearings with various effects under the influences of journal misalignment is revealed, this is helpful to understand EHD and TEHD effect of misaligned engine main bearings.

  20. Fault Tolerant Homopolar Magnetic Bearings

    Science.gov (United States)

    Li, Ming-Hsiu; Palazzolo, Alan; Kenny, Andrew; Provenza, Andrew; Beach, Raymond; Kascak, Albert

    2003-01-01

    Magnetic suspensions (MS) satisfy the long life and low loss conditions demanded by satellite and ISS based flywheels used for Energy Storage and Attitude Control (ACESE) service. This paper summarizes the development of a novel MS that improves reliability via fault tolerant operation. Specifically, flux coupling between poles of a homopolar magnetic bearing is shown to deliver desired forces even after termination of coil currents to a subset of failed poles . Linear, coordinate decoupled force-voltage relations are also maintained before and after failure by bias linearization. Current distribution matrices (CDM) which adjust the currents and fluxes following a pole set failure are determined for many faulted pole combinations. The CDM s and the system responses are obtained utilizing 1D magnetic circuit models with fringe and leakage factors derived from detailed, 3D, finite element field models. Reliability results are presented vs. detection/correction delay time and individual power amplifier reliability for 4, 6, and 7 pole configurations. Reliability is shown for two success criteria, i.e. (a) no catcher bearing contact following pole failures and (b) re-levitation off of the catcher bearings following pole failures. An advantage of the method presented over other redundant operation approaches is a significantly reduced requirement for backup hardware such as additional actuators or power amplifiers.

  1. Active Magnetic Bearings – Magnetic Forces

    DEFF Research Database (Denmark)

    Kjølhede, Klaus

    2006-01-01

    Parameter identification procedures and model validation are major steps towards intelligent machines supported by active magnetic bearings (AMB). The ability of measuring the electromagnetic bearing forces, or deriving them from measuring the magnetic flux, strongly contributes to the model...... validation and leads to novel approaches in identifying crucial rotor parameters. This is the main focus of this paper, where an intelligent AMB is being developed with the aim of aiding the accurate identification of damping and stiffness coefficients of journal bearings and seals. The main contribution...... of the magnetic forces are led by using different experimental tests: (I) by using hall sensors mounted directly on the poles (precise measurements of the magnetic flux) and by an auxiliary system, composed of strain gages and flexible beams attached to the rotor; (II) by measuring the input current and bearing...

  2. Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors.

    Science.gov (United States)

    Burgess, Ralph; Yang, Ziheng

    2008-09-01

    Estimation of population parameters for the common ancestors of humans and the great apes is important in understanding our evolutionary history. In particular, inference of population size for the human-chimpanzee common ancestor may shed light on the process by which the 2 species separated and on whether the human population experienced a severe size reduction in its early evolutionary history. In this study, the Bayesian method of ancestral inference of Rannala and Yang (2003. Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics. 164:1645-1656) was extended to accommodate variable mutation rates among loci and random species-specific sequencing errors. The model was applied to analyze a genome-wide data set of approximately 15,000 neutral loci (7.4 Mb) aligned for human, chimpanzee, gorilla, orangutan, and macaque. We obtained robust and precise estimates for effective population sizes along the hominoid lineage extending back approximately 30 Myr to the cercopithecoid divergence. The results showed that ancestral populations were 5-10 times larger than modern humans along the entire hominoid lineage. The estimates were robust to the priors used and to model assumptions about recombination. The unusually low X chromosome divergence between human and chimpanzee could not be explained by variation in the male mutation bias or by current models of hybridization and introgression. Instead, our parameter estimates were consistent with a simple instantaneous process for human-chimpanzee speciation but showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species.

  3. Polar bears and sea ice habitat change

    Science.gov (United States)

    Durner, George M.; Atwood, Todd C.; Butterworth, Andy

    2017-01-01

    The polar bear (Ursus maritimus) is an obligate apex predator of Arctic sea ice and as such can be affected by climate warming-induced changes in the extent and composition of pack ice and its impacts on their seal prey. Sea ice declines have negatively impacted some polar bear subpopulations through reduced energy input because of loss of hunting habitats, higher energy costs due to greater ice drift, ice fracturing and open water, and ultimately greater challenges to recruit young. Projections made from the output of global climate models suggest that polar bears in peripheral Arctic and sub-Arctic seas will be reduced in numbers or become extirpated by the end of the twenty-first century if the rate of climate warming continues on its present trajectory. The same projections also suggest that polar bears may persist in the high-latitude Arctic where heavy multiyear sea ice that has been typical in that region is being replaced by thinner annual ice. Underlying physical and biological oceanography provides clues as to why polar bear in some regions are negatively impacted, while bears in other regions have shown no apparent changes. However, continued declines in sea ice will eventually challenge the survival of polar bears and efforts to conserve them in all regions of the Arctic.

  4. Establishment of a Tumor-bearing Mouse Model Stably Expressing Human Tumor Antigens Survivin and MUC1 VNTRs

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li-xing; DU Jian-shi; WANG Yu-qian; LIU Chen-lu; XIA Qiu; ZHANG Xi-zhen; CONG Xian-ling; ZHANG Hai-hong

    2012-01-01

    The eukaryotic vectors VR1012 expressing survivin or 33 tandem repeats of human mucin 1(MUC1)(VNTRs),namely,VR1012-S and VR1012-VNTR(VNTR=variable number of tandem repeat),were constructed by cloning survivin and VNTR genes into VR1012,respectively.The eukaryotic vector pEGFP expressing survivin and MUC1 VNTRs fusion gene pEGFP-MS was also constructed.Mouse melanoma cell line(B16)stably expressing survivin and MUC1 VNTRs(MS+B16)was established by Lipofectamine-mediated transfection of pEGFP-MS into B16 cells.EGFP expression in MS+B16 cells was observed using a fluorescent microscope and survivin and MUC1 VNTRs(MS)expression was confirmed by means of Western blot analysis.A syngenic graft tumor model was generated by subcutaneous injection of MS+B16 cells into C57/BL6 mice and tumor size increased rapidly with time in a cell number dependent manner.After the third immunization,mice were challenged subcutaneously with 5×105 MS+B16 cells.Compared with that of the negative control immunized with phosphate-buffered saline(PBS),a significant reduction of tumor growth was observed in groups immunized with survivin plasmid DNA and MUC1 VNTRs plasmid DNA.Thus,the suppression of subcutaneous tumor was antigen-specific.This model is useful for the development of tumor vaccines targeting survivin and MUCI VNTRs.

  5. Using the sulfide replacement petrology in lunar breccia 67915 to construct a thermodynamic model of S-bearing fluid in the lunar crust

    Science.gov (United States)

    Bell, Aaron S.; Shearer, Charles; deMoor, J. Maarten; Provencio, Paula

    2015-12-01

    In this work, we investigate the compositions and origin of metasomatic fluids responsible for the formation of sulfide replacement textures in Mg-Suite lithologies of lunar samples 67915-149 and 67915-150. We have constructed a quantitative thermodynamic model of the composition of the metasomatic fluid using fO2, fS2, and temperature constraints derived from a thermodynamic analysis of the metasomatic fluid-mineral reactions and the measured compositions of the phases in the sulfide assemblages. Results from this modeling indicate that the metasomatic fluid responsible for the formation of the sulfide replacement textures was likely dominated by a combination of H2 and CH4, with minor abundances of H2O, CO, and H2S. The modeling indicates that H2S was, by orders of magnitude, the dominant S-species present in the metasomatic fluid and S isotopes in the replacement sulfides suggest that the fluid experienced significant removal of H2S by sulfide precipitation. The calculated H2 and H2O contents of the metasomatic fluid are consistent with those that might be expected for the late stage degassing of shallowly emplaced, intrusive magma bodies. Sulfur, heat, and other volatile constituents (i.e., chalcophile metals and carbon) were sourced from the breccia-producing impactor; the volatile phase produced by the impact event subsequently metasomatized the crust (Haskin and Warren, 1991); The sulfide metasomatism occurred in an ejecta blanket, where both the heat and sulfur that were produced by the impactor re-mobilized volatiles, causing hydrothermal circulation within the crust that redistributed both sulfur and chalcophile elements to produce sulfide-silicate intergrowths (Haskin and Warren, 1991); and Sulfur, heat, and other volatile constituents, sourced from degassing intrusive magmas and sulfur-bearing fluid from the degassing magma, percolated into surrounding crust, metasomatizing the adjacent country rock (Norman et al., 1995). The development of these models

  6. Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis.

    Science.gov (United States)

    Todorov, Tihomir; Todorova, Albena; Motoescu, Cristina; Dimova, Petia; Iancu, Daniela; Craiu, Dana; Stoian, Daniela; Barbarii, Ligia; Bojinova, Veneta; Mitev, Vanyo

    2012-06-01

    Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation-mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321_322insGAAG, p.(Lys107_Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584_624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms.

  7. Targeted Mutation of Nuclear Bone Morphogenetic Protein 2 Impairs Secondary Immune Response in a Mouse Model

    Directory of Open Access Journals (Sweden)

    Daniel S. Olsen

    2015-01-01

    Full Text Available We recently identified a nuclear variant of the BMP2 growth factor, called nBMP2. In an effort to understand the function of this variant protein, we generated a mouse line in which BMP2 is expressed and functions normally, but nBMP2 is excluded from the nucleus. This novel mutation allows the study of nBMP2 without compromising BMP2 function. To determine whether nBMP2 plays a role in immune function, we performed a series of experiments in which we compared mouse survival, organ weights, immune cells numbers, and bacterial load in wild type and nBmp2NLStm mice following primary and secondary challenges with Staphylococcus aureus. Following primary challenge with S. aureus, wild type and nBmp2NLStm mice showed no differences in survival or bacterial load and generated similar numbers and types of leukocytes, although mutant spleens were smaller than wild type. Secondary bacterial challenge with S. aureus, however, produced differences in survival, with increased mortality seen in nBmp2NLStm mice. This increased mortality corresponded to higher levels of bacteremia in nBmp2NLStm mice and to a reduced enlargement of mutant spleens in response to the secondary infection. Together, these results suggest that the recently described nuclear variant of BMP2 is necessary for efficient secondary immune responses.

  8. Magnetic Bearing Consumes Low Power

    Science.gov (United States)

    Studer, P. A.

    1982-01-01

    Energy-efficient linear magnetic bearing maintains a precise small separation between its moving and stationary parts. Originally designed for cryogenic compressors on spacecraft, proposed magnetic bearing offers an alternative to roller or gas bearing in linear motion system. Linear noncontacting bearing operates in environments where lubricants cannot be used.

  9. A Two-Mutation Model of Carcinogenesis: Application to Ra-226 Induced Osteosarcoma Prevalence in Beagles

    NARCIS (Netherlands)

    Venema LB; Leenhouts HP; LSO

    1994-01-01

    Dit rapport is een aanvulling op het RIVM-rapport (nr. 749251001) van Leenhouts en Chadwick en is bedoeld als achtergrond-document voor het twee-mutatie-carcinogenese model en voor zijn implementatie. Het twee-mutatie-carcinogenese model is gebaseerd op een gemodificeerd twee-stappen model van

  10. Characterization of various types of mast cells derived from model mice of familial gastrointestinal stromal tumors with KIT-Asp818Tyr mutation.

    Science.gov (United States)

    Kajimoto, Noriko; Nakai, Norihiro; Ohkouchi, Mizuka; Hashikura, Yuka; Liu-Kimura, Ning-Ning; Isozaki, Koji; Hirota, Seiichi

    2015-01-01

    Sporadic mast cell neoplasms and gastrointestinal stromal tumors (GISTs) often have various types of somatic gain-of-function mutations of the c-kit gene which encodes a receptor tyrosine kinase, KIT. Several types of germline gain-of-function mutations of the c-kit gene have been detected in families with multiple GISTs. All three types of model mice for the familial GISTs with germline c-kit gene mutations at exon 11, 13 or 17 show development of GIST, while they are different from each other in skin mast cell number. Skin mast cell number in the model mice with exon 17 mutation was unchanged compared to the corresponding wild-type mice. In the present study, we characterized various types of mast cells derived from the model mice with exon 17 mutation (KIT-Asp818Tyr) corresponding to human familial GIST case with human KIT-Asp820Tyr to clarify the role of the c-kit gene mutation in mast cells. Bone marrow-derived cultured mast cells (BMMCs) derived from wild-type mice, heterozygotes and homozygotes were used for the experiments. Immortalized BMMCs, designated as IMC-G4 cells, derived from BMMCs of a homozygote during long-term culture were also used. Ultrastructure, histamine contents, proliferation profiles and phosphorylation of various signaling molecules in those cells were examined. In IMC-G4 cells, presence of additional mutation(s) of the c-kit gene and effect of KIT inhibitors on both KIT autophosphorylation and cell proliferation were also analyzed. We demonstrated that KIT-Asp818Tyr did not affect ultrastructure and proliferation profiles but did histamine contents in BMMCs. IMC-G4 cells had an additional novel c-kit gene mutation of KIT-Tyr421Cys which is considered to induce neoplastic transformation of mouse mast cells and the mutation appeared to be resistant to a KIT inhibitor of imatinib but sensitive to another KIT inhibitor of nilotinib. IMC-G4 cells might be a useful mast cell line to investigate mast cell biology.

  11. Investigation Of Tribologic Processes in Bearing Nodes with the Use of the Fam-C And Fdm-A Methods – The Model With Elevated Passive Resistance

    National Research Council Canada - National Science Library

    Andrzej Gębura

    2014-01-01

    The paper discloses selected results of application of the FAM-C (a.c. generator) and FDM-A (d.c. generator) methods for comprehensive troubleshooting of bearing nodes in single-spool turbojet engines...

  12. Investigation Of Tribologic Processes in Bearing Nodes with the Use of the Fam-C And Fdm-A Methods – The Model With Elevated Passive Resistance

    Directory of Open Access Journals (Sweden)

    Gębura Andrzej

    2014-12-01

    Full Text Available The paper discloses selected results of application of the FAM-C (a.c. generator and FDM-A (d.c. generator methods for comprehensive troubleshooting of bearing nodes in single-spool turbojet engines.

  13. Transposon-mediated Generation of Cellular and Mouse Models of Splicing Mutations to Assess the Efficacy of snRNA-based Therapeutics

    Directory of Open Access Journals (Sweden)

    Elena Barbon

    2016-01-01

    Full Text Available Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs. However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X to integrate human factor IX (hFIX minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt or mutated (SChFIXex5-2C. In both models the SChFIXex5-2C variant, found in patients affected by Hemophilia B, displayed an aberrant splicing pattern characterized by exon 5 skipping. This allowed us to test, for the first time in a genomic DNA context, the efficacy of the snRNA U1-fix9, delivered with an adeno-associated virus (AAV vector. With this approach, we showed rescue of the correct splicing pattern of hFIX mRNA, leading to hFIX protein expression. These data validate the SB100X as a versatile tool to quickly generate models of human genetic mutations, to study their effect in a stable DNA context and to assess mutation-targeted therapeutic strategies.

  14. Transposon-mediated Generation of Cellular and Mouse Models of Splicing Mutations to Assess the Efficacy of snRNA-based Therapeutics.

    Science.gov (United States)

    Barbon, Elena; Ferrarese, Mattia; van Wittenberghe, Laetitia; Sanatine, Peggy; Ronzitti, Giuseppe; Collaud, Fanny; Colella, Pasqualina; Pinotti, Mirko; Mingozzi, Federico

    2016-11-29

    Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs). However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X) to integrate human factor IX (hFIX) minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt) or mutated (SChFIXex5-2C). In both models the SChFIXex5-2C variant, found in patients affected by Hemophilia B, displayed an aberrant splicing pattern characterized by exon 5 skipping. This allowed us to test, for the first time in a genomic DNA context, the efficacy of the snRNA U1-fix9, delivered with an adeno-associated virus (AAV) vector. With this approach, we showed rescue of the correct splicing pattern of hFIX mRNA, leading to hFIX protein expression. These data validate the SB100X as a versatile tool to quickly generate models of human genetic mutations, to study their effect in a stable DNA context and to assess mutation-targeted therapeutic strategies.

  15. Mutations in the exon 7 of Trp53 gene and the level of p53 protein in double transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Dorszewska, Jolanta; Oczkowska, Anna; Suwalska, Monika; Rozycka, Agata; Florczak-Wyspianska, Jolanta; Dezor, Mateusz; Lianeri, Margarita; Jagodzinski, Paweł P; Kowalczyk, Michal J; Prendecki, Michal; Kozubski, Wojciech

    2014-01-01

    Alzheimer's disease (AD) leads to generation of β-amyloid (Aβ) in the brain. Alzheimer's disease model PS/APP mice show a markedly accelerated accumulation of Aβ, which may lead to apoptosis induction e.g. in cells expressing wild-type p53. The TP53 gene is found to be the most frequently mutated gene in human tumour cells. There is accumulating evidence pointing out to the contribution of oxidative stress and chronic inflammation in both AD and cancer. The purpose of this study was to analyze exon 7 mutations of the murine Trp53 gene and Aβ/A4 and p53 protein levels in PS/APP and control mice. The studies were performed on female double transgenic PS/APP mice and young adults (8-12 weeks old) and age-matched control mice. The Trp53 mutation analysis was carried out with the use of PCR and DNA sequencing. The Aβ/A4 and p53 levels were analyzed by Western blotting. The frequency of mutations was almost quadrupled in PS/APP mice (44%), compared to controls (14%). PS/APP mice with the A929T and A857G mutations had a similar p53 level. In cerebral gray matter of PS/APP mice the level of p53 positive correlated with the level of Aβ protein (RS = +0.700, p p53 down-regulation, while in aging ones, G859A substitution was most likely associated with over-expression of p53. In silico protein analysis revealed a possibly substantial impact of all four mutations on p53 activity. Three mutations were in close proximity to zinc-coordinating cysteine residues. It seems that in PS/APP mice missense Trp53 exon 7 mutations may be associated with the degenerative process by changes of p53 protein function.

  16. Eastern slopes grizzly bear project : project update

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2002-01-01

    This report updates a study to examine the cumulative effects of human activities on the grizzly bears in the central Canadian Rockies. The project was initiated in 1994 to acquire accurate scientific information on the habitat and populations of grizzly bears in the area of the Banff National Park and Kananaskis Country. This area is probably the most heavily used and developed area where the grizzly still survives. The information gathered throughout the course of the study is used to better protect and manage the bears and other sensitive carnivores in the region. Using telemetry, researchers monitored 25 grizzly bears which were radio-collared in a 22,000 square-kilometer area in the upper Bow Valley drainage of the eastern Alberta slopes. The researchers worked with representatives from Husky Oil and Rigel Energy on the development of the Moose Mountain oil and gas field without adversely affecting the grizzly bear population. Information collected over eight years indicates that the grizzly bears have few and infrequent offspring. Using the information gathered thus far, the location of the Moose Mountain to Jumping Pound pipeline was carefully selected, since the bears suffer from high mortality, and the food and cover had already been compromised by the high number of roads, trails and other human activities in the area. The research concluded in November 2001 provides sufficient information to accurately asses the status of the grizzly bear population and habitat. The data will be analyzed and integrated in 2002 into models that reflect the variables affecting grizzly bears and a final report will be published.

  17. Tribology of alternative bearings.

    Science.gov (United States)

    Fisher, John; Jin, Zhongmin; Tipper, Joanne; Stone, Martin; Ingham, Eileen

    2006-12-01

    The tribological performance and biological activity of the wear debris produced has been compared for highly cross-linked polyethylene, ceramic-on-ceramic, metal-on-metal, and modified metal bearings in a series of in vitro studies from a single laboratory. The functional lifetime demand of young and active patients is 10-fold greater than the estimated functional lifetime of traditional polyethylene. There is considerable interest in using larger diameter heads in these high demand patients. Highly cross-linked polyethylene show a four-fold reduction in functional biological activity. Ceramic-on-ceramic bearings have the lowest wear rates and least reactive wear debris. The functional biological activity is 20-fold lower than with highly cross-linked polyethylene. Hence, ceramic-on-ceramic bearings address the tribological lifetime demand of highly active patients. Metal-on-metal bearings have substantially lower wear rates than highly cross-linked polyethylene and wear decreases with head diameter. Bedding in wear is also lower with reduced radial clearance. Differential hardness ceramic-on-metal bearings and the application of ceramic-like coatings reduce metal wear and ion levels.

  18. Kinematic Analysis of Healthy Hips during Weight-Bearing Activities by 3D-to-2D Model-to-Image Registration Technique

    Directory of Open Access Journals (Sweden)

    Daisuke Hara

    2014-01-01

    Full Text Available Dynamic hip kinematics during weight-bearing activities were analyzed for six healthy subjects. Continuous X-ray images of gait, chair-rising, squatting, and twisting were taken using a flat panel X-ray detector. Digitally reconstructed radiographic images were used for 3D-to-2D model-to-image registration technique. The root-mean-square errors associated with tracking the pelvis and femur were less than 0.3 mm and 0.3° for translations and rotations. For gait, chair-rising, and squatting, the maximum hip flexion angles averaged 29.6°, 81.3°, and 102.4°, respectively. The pelvis was tilted anteriorly around 4.4° on average during full gait cycle. For chair-rising and squatting, the maximum absolute value of anterior/posterior pelvic tilt averaged 12.4°/11.7° and 10.7°/10.8°, respectively. Hip flexion peaked on the way of movement due to further anterior pelvic tilt during both chair-rising and squatting. For twisting, the maximum absolute value of hip internal/external rotation averaged 29.2°/30.7°. This study revealed activity dependent kinematics of healthy hip joints with coordinated pelvic and femoral dynamic movements. Kinematics’ data during activities of daily living may provide important insight as to the evaluating kinematics of pathological and reconstructed hips.

  19. Effects of Oral Administration of Fucoidan Extracted from Cladosiphon okamuranus on Tumor Growth and Survival Time in a Tumor-Bearing Mouse Model

    Directory of Open Access Journals (Sweden)

    Yoshiharu Okamoto

    2012-10-01

    Full Text Available We evaluated the anti-tumor activities of the oral administration of fucoidan extracted from Cladosiphon okamuranus using a tumor (colon 26-bearing mouse model. The materials used included low-molecular-weight fucoidan (LMWF: 6.5–40 kDa, intermediate-molecular-weight fucoidan (IMWF: 110–138 kDa and high-molecular-weight fucoidan (HMWF: 300–330 kDa. The IMWF group showed significantly suppressed tumor growth. The LMWF and HMWF groups showed significantly increased survival times compared with that observed in the control group (mice fed a fucoidan-free diet. The median survival times in the control, LMWF, IMWF and HMWF groups were 23, 46, 40 and 43 days, respectively. It was also found that oral administration of fucoidan increased the population of natural killer cells in the spleen. Furthermore, from the results of the experiment using Myd-88 knockout mice, it was found that these effects are related to gut immunity. These results suggest that fucoidan is a candidate anti-tumor functional food.

  20. Preappointment testing for BRAF/KIT mutation in advanced melanoma: a model in molecular data delivery for individualized medicine.

    Science.gov (United States)

    Mounajjed, Taofic; Brown, Char L; Stern, Therese K; Bjorheim, Annette M; Bridgeman, Andrew J; Rumilla, Kandelaria M; McWilliams, Robert R; Flotte, Thomas J

    2014-11-01

    The emergence of individualized medicine is driven by developments in precision diagnostics, epitomized by molecular testing. Because treatment decisions are being made based on such molecular data, data management is gaining major importance. Among data management challenges, creating workflow solutions for timely delivery of molecular data has become pivotal. This study aims to design and implement a scalable process that permits preappointment BRAF/KIT mutation analysis in melanoma patients, allowing molecular results necessary for treatment plans to be available before the patient's appointment. Process implementation aims to provide a model for efficient molecular data delivery for individualized medicine. We examined the existing process of BRAF/KIT testing in melanoma patients visiting our institution for oncology consultation. We created 5 working groups, each designing a specific segment of an alternative process that would allow preappointment BRAF/KIT testing and delivery of results. Data were captured and analyzed to evaluate the success of the alternative process. For 1 year, 35 (59%) of 55 patients had prior BRAF/KIT testing. The remaining 20 patients went through the new process of preappointment testing; results were available at the time of appointment for 12 patients (overall preappointment results availability, 85.5%). The overall process averaged 13.4 ± 4.7 days. In conclusion, we describe the successful implementation of a scalable workflow solution that permits preappointment BRAF/KIT mutation analysis and result delivery in melanoma patients. This sets the stage for further applications of this model to other conditions, answering an increasing demand for robust delivery of molecular data for individualized medicine. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Monitoring tumor response with [18F]FMAU in a sarcoma-bearing mouse model after liposomal vinorelbine treatment.

    Science.gov (United States)

    Chan, Pei-Chia; Wu, Chun-Yi; Chang, Wei-Ting; Lin, Chih-Yuan; Tseng, Yun-Long; Liu, Ren-Shyan; Alauddin, Mian M; Lin, Wuu-Jyh; Wang, Hsin-Ell

    2013-11-01

    Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2'-deoxy-2'-[(18)F]fluoro-β-d-arabinofuranosyluracil ([(18)F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150 ± 50 mm(3) (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [(18)F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [(18)F]FDG/[(18)F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. A significant inhibition (plipo-VNB-treated group declined from 2.33 ± 0.16 to 1.26 ± 0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [(18)F]FDG and [(18)F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [(18)F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB. © 2013.

  2. RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

    Directory of Open Access Journals (Sweden)

    Li eJiang

    2014-04-01

    Full Text Available RNA interference (RNAi knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F producing a slowly progressing cone/rod dystrophy (CORD. The late onset GCAP1(L151F-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection. In both allele-specific (GCAP1(Y99C-RP and nonallele-specific (GCAP1(L151F-CORD models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a proof of concept toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.

  3. 弹性滑板复合隔震模型振动台试验研究%Study on shaking table test model in composite isolation with elastic sliding bearings

    Institute of Scientific and Technical Information of China (English)

    贾剑辉; 辛晓鹏; 杨树标

    2012-01-01

    进行了复合隔震模型振动台试验,通过调整隔震层中弹性滑板支座数量,研究隔震层摩擦承压比的变化对结构基底剪力系数、位移反应及频谱特性的影响。试验结果表明,弹性滑板数量适中的复合隔震结构,在合理摩擦承压比范围内时,是一种隔震性能良好的隔震体系。%Shaking table tests on a model of composite isolation structure were performed.By adjusting the number of the elastic sliding bearings in the isolation layer,the influences of the change of friction bearing ratio on the shear coefficient of the model,displacement response and frequency spectrum characteristics were studied.The experimental results show that the composite isolation system has good performance when the number of elastic sliding bearings is moderate and the friction bearing ratio is reasonable.

  4. Parasites and mutational load: an experimental test of a pluralistic theory for the evolution of sex

    Science.gov (United States)

    Cooper, Tim F.; Lenski, Richard E.; Elena, Santiago F.

    2005-01-01

    Ecological and mutational explanations for the evolution of sexual reproduction have usually been considered independently. Although many of these explanations have yielded promising theoretical results, experimental support for their ability to overcome a twofold cost of sex has been limited. For this reason, it has recently been argued that a pluralistic approach, combining effects from multiple models, may be necessary to explain the apparent advantage of sex. One such pluralistic model proposes that parasite load and synergistic epistasis between deleterious mutations might interact to create an advantage for recombination. Here, we test this proposal by comparing the fitness functions of parasitized and parasite-free genotypes of Escherichia coli bearing known numbers of transposon-insertion mutations. In both classes, we failed to detect any evidence for synergistic epistasis. However, the average effect of deleterious mutations was greater in parasitized than parasite-free genotypes. This effect might broaden the conditions under which another proposed model combining parasite–host coevolutionary dynamics and mutation accumulation can explain the maintenance of sex. These results suggest that, on average, deleterious mutations act multiplicatively with each other but in synergy with infection in determining fitness. PMID:15705557

  5. Radial Halbach Magnetic Bearings

    Science.gov (United States)

    Eichenberg, Dennis J.; Gallo, Christopher A.; Thompson, William K.

    2009-01-01

    Radial Halbach magnetic bearings have been investigated as part of an effort to develop increasingly reliable noncontact bearings for future high-speed rotary machines that may be used in such applications as aircraft, industrial, and land-vehicle power systems and in some medical and scientific instrumentation systems. Radial Halbach magnetic bearings are based on the same principle as that of axial Halbach magnetic bearings, differing in geometry as the names of these two types of bearings suggest. Both radial and axial Halbach magnetic bearings are passive in the sense that unlike most other magnetic bearings that have been developed in recent years, they effect stable magnetic levitation without need for complex active control. Axial Halbach magnetic bearings were described in Axial Halbach Magnetic Bearings (LEW-18066-1), NASA Tech Briefs, Vol. 32, No. 7 (July 2008), page 85. In the remainder of this article, the description of the principle of operation from the cited prior article is recapitulated and updated to incorporate the present radial geometry. In simplest terms, the basic principle of levitation in an axial or radial Halbach magnetic bearing is that of the repulsive electromagnetic force between (1) a moving permanent magnet and (2) an electric current induced in a stationary electrical conductor by the motion of the magnetic field. An axial or radial Halbach bearing includes multiple permanent magnets arranged in a Halbach array ("Halbach array" is defined below) in a rotor and multiple conductors in the form of wire coils in a stator, all arranged so the rotary motion produces an axial or radial repulsion that is sufficient to levitate the rotor. A basic Halbach array (see Figure 1) consists of a row of permanent magnets, each oriented so that its magnetic field is at a right angle to that of the adjacent magnet, and the right-angle turns are sequenced so as to maximize the magnitude of the magnetic flux density on one side of the row while

  6. Partial tooth gear bearings

    Science.gov (United States)

    Vranish, John M. (Inventor)

    2010-01-01

    A partial gear bearing including an upper half, comprising peak partial teeth, and a lower, or bottom, half, comprising valley partial teeth. The upper half also has an integrated roller section between each of the peak partial teeth with a radius equal to the gear pitch radius of the radially outwardly extending peak partial teeth. Conversely, the lower half has an integrated roller section between each of the valley half teeth with a radius also equal to the gear pitch radius of the peak partial teeth. The valley partial teeth extend radially inwardly from its roller section. The peak and valley partial teeth are exactly out of phase with each other, as are the roller sections of the upper and lower halves. Essentially, the end roller bearing of the typical gear bearing has been integrated into the normal gear tooth pattern.

  7. Mouse Models of Mutations and Variations in Autism Spectrum Disorder-Associated Genes: Mice Expressing Caps2/Cadps2 Copy Number and Alternative Splicing Variants

    Directory of Open Access Journals (Sweden)

    Tetsushi Sadakata

    2013-11-01

    Full Text Available Autism spectrum disorder (ASD is a neurodevelopmental disorder characterized by disturbances in interpersonal relationships and behavior. Although the prevalence of autism is high, effective treatments have not yet been identified. Recently, genome-wide association studies have identified many mutations or variations associated with ASD risk on many chromosome loci and genes. Identification of the biological roles of these mutations or variations is necessary to identify the mechanisms underlying ASD pathogenesis and to develop clinical treatments. At present, mice harboring genetic modifications of ASD-associated gene candidates are the best animal models to analyze hereditary factors involved in autism. In this report, the biological significance of ASD-associated genes is discussed by examining the phenotypes of mouse models with ASD-associated mutations or variations in mouse homologs, with a focus on mice harboring genetic modifications of the Caps2/Cadps2 (Ca2+-dependent activator protein for secretion 2 gene.

  8. The Little Bear

    Institute of Scientific and Technical Information of China (English)

    林战峰; 乐伟国

    2007-01-01

    @@ 一、故事内容 A little bear has a magic stick.It can make his wishes come true. One day,the little bear is walking in the forest.He sees a bird.It is flying in the sky.It has two beautiful wings."I want two beautiful wings.I wish I can fly like a bird,"he says to the magic stick.Two beautiful wings come out from his back and he can fly like a bird now.He is very happy.

  9. Modular gear bearings

    Science.gov (United States)

    Vranish, John M. (Inventor)

    2009-01-01

    A gearing system using modular gear bearing components. Each component is composed of a core, one or more modules attached to the core and two or more fastening modules rigidly attaching the modules to the core. The modules, which are attached to the core, may consist of gears, rollers or gear bearing components. The core orientation affects the orientation of the modules attached to the core. This is achieved via the keying arrangement of the core and the component modules that attach to the core. Such an arrangement will also facilitate the phase tuning of gear modules with respect to the core and other gear modules attached to the core.

  10. Structural insight with mutational impact on tyrosinase and PKC-β interaction from Homo sapiens: Molecular modeling and docking studies for melanogenesis, albinism and increased risk for melanoma.

    Science.gov (United States)

    Banerjee, Arundhati; Ray, Sujay

    2016-10-30

    Human tyrosinase, is an important protein for biosynthetic pathway of melanin. It was studied to be phosphorylated and activated by protein kinase-C, β-subunit (PKC-β) through earlier experimentations with in vivo evidences. Documentation documents that mutation in two essentially vital serine residues in C-terminal end of tyrosinase leads to albinism. Due to the deficiency of protective shield like enzyme; melanin, albinos are at an increased peril for melanoma and other skin cancers. So, computational and residue-level insight including a mutational exploration with evolutionary importance into this mechanism lies obligatory for future pathological and therapeutic developments. Therefore, functional tertiary models of the relevant proteins were analyzed after satisfying their stereo-chemical features. Evolutionarily paramount residues for the activation of tyrosinase were perceived via multiple sequence alignment phenomena. Mutant-type tyrosinase protein (S98A and S102A) was thereby modeled, maintaining the wild-type proteins' functionality. Furthermore, this present comparative study discloses the variation in the stable residual participation (for mutant-type and wild-type tyrosinase-PKCβ complex). Mainly, an increased number of polar negatively charged residues from the wild-type tyrosinase participated with PKC-β, predominantly. Fascinatingly supported by evaluation of statistical significances, mutation even led to a destabilizing impact in tyrosinase accompanied by conformational switches with a helix-to-coil transition in the mutated protein. Even the allosteric sites in the protein got poorly hampered upon mutation leading to weaker tendency for binding partners to interact.

  11. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...... mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely...... caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP...

  12. Programmable models of growth and mutation of cancer-cell populations

    CERN Document Server

    Bortolussi, Luca; 10.4204/EPTCS.67.4

    2011-01-01

    In this paper we propose a systematic approach to construct mathematical models describing populations of cancer-cells at different stages of disease development. The methodology we propose is based on stochastic Concurrent Constraint Programming, a flexible stochastic modelling language. The methodology is tested on (and partially motivated by) the study of prostate cancer. In particular, we prove how our method is suitable to systematically reconstruct different mathematical models of prostate cancer growth - together with interactions with different kinds of hormone therapy - at different levels of refinement.

  13. Mutational Analyses of HAMP Helices Suggest a Dynamic Bundle Model of Input-Output Signaling in Chemoreceptors

    Science.gov (United States)

    Zhou, Qin; Ames, Peter; Parkinson, John S.

    2009-01-01

    SUMMARY To test the gearbox model of HAMP signaling in the E. coli serine receptor, Tsr, we generated a series of amino acid replacements at each residue of the AS1 and AS2 helices. The residues most critical for Tsr function defined hydrophobic packing faces consistent with a 4-helix bundle. Suppression patterns of helix lesions conformed to the the predicted packing layers in the bundle. Although the properties and patterns of most AS1 and AS2 lesions were consistent with both proposed gearbox structures, some mutational features specifically indicate the functional importance of an x-da bundle over an alternative a-d bundle. These genetic data suggest that HAMP signaling could simply involve changes in the stability of its x-da bundle. We propose that Tsr HAMP controls output signals by modulating destabilizing phase clashes between the AS2 helices and the adjoining kinase control helices. Our model further proposes that chemoeffectors regulate HAMP bundle stability through a control cable connection between the transmembrane segments and AS1 helices. Attractant stimuli, which cause inward piston displacements in chemoreceptors, should reduce cable tension, thereby stabilizing the HAMP bundle. This study shows how transmembrane signaling and HAMP input-output control could occur without the helix rotations central to the gearbox model. PMID:19656294

  14. Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases.

    Directory of Open Access Journals (Sweden)

    Anshuman Dixit

    2011-10-01

    Full Text Available The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic aspects of long-range communications in ABL and EGFR kinases based on the results of multiscale simulations of regulatory complexes and computational modeling of signal propagation in proteins. These approaches have been systematically employed to elucidate organizing molecular principles of allosteric signaling in the ABL and EGFR multi-domain regulatory complexes and analyze allosteric signatures of the gate-keeper cancer mutations. We have presented evidence that mechanisms of allosteric activation may have universally evolved in the ABL and EGFR regulatory complexes as a product of a functional cross-talk between the organizing αF-helix and conformationally adaptive αI-helix and αC-helix. These structural elements form a dynamic network of efficiently communicated clusters that may control the long-range interdomain coupling and allosteric activation. The results of this study have unveiled a unifying effect of the gate-keeper cancer mutations as catalysts of kinase activation, leading to the enhanced long-range communication among allosterically coupled segments and stabilization of the active kinase form. The results of this study can reconcile recent experimental studies of allosteric inhibition and long-range cooperativity between binding sites in protein kinases. The presented study offers a novel molecular insight into mechanistic aspects of allosteric kinase signaling and provides a quantitative picture of activation mechanisms in protein kinases at the atomic level.

  15. Determining structure and function of steroid dehydrogenase enzymes by sequence analysis, homology modeling, and rational mutational analysis.

    Science.gov (United States)

    Duax, William L; Thomas, James; Pletnev, Vladimir; Addlagatta, Anthony; Huether, Robert; Habegger, Lukas; Weeks, Charles M

    2005-12-01

    The short-chain oxidoreductase (SCOR) family of enzymes includes over 6,000 members identified in sequenced genomes. Of these enzymes, approximately 300 have been characterized functionally, and the three-dimensional crystal structures of approximately 40 have been reported. Since some SCOR enzymes are steroid dehydrogenases involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown and to determine their three-dimensional structure and mechanism of action. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30-40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure-function features including cofactor preference, catalytic residues, and substrate specificity. Human type 1 3beta-hydroxysteroid dehydrogenase isomerase (3beta-HSDI) has 30% sequence identity with a human UDP galactose 4-epimerase (UDPGE), a SCOR family enzyme for which an X-ray structure has been reported. Both UDPGE and 3-HSDI appear to trace their origins back to bacterial 3alpha,20beta-HSD. Combining three-dimensional structural information and sequence data on the 3alpha,20beta-HSD, UDPGE, and 3beta-HSDI subfamilies with mutational analysis, we were able to identify the residues critical to the dehydrogenase function of 3-HSDI. We also identified the residues most probably responsible for the isomerase activity of 3beta-HSDI. We test our predictions by specific mutations based on sequence analysis and our structure-based model.

  16. Rotor Bearing System Analysis Using the Transfer Matrix Method with Thickness Assumption of Disk and Bearing

    CERN Document Server

    Ghasemalizadeh, Omid; Sadeghi, Hossein; Ahmadian, Mohammad Taghi

    2013-01-01

    One of the methods to find the natural frequencies of rotating systems is the application of the transfer matrix method. In this method the rotor is modeled as several elements along the shaft which have their own mass and moment of inertia. Using these elements, the entire continuous system is discretized and the corresponding differential equation can be stated in matrix form. The bearings at the end of the shaft are modeled as equivalent spring and dampers which are applied as boundary conditions to the discretized system. In this paper the dynamics of a rotor-bearing system is analyzed, considering the gyroscopic effect. The thickness of the disk and bearings is also taken into account. Cont