A Car-Steering Model Based on an Adaptive Neuro-Fuzzy Controller

NASA Astrophysics Data System (ADS)

Amor, Mohamed Anis Ben; Oda, Takeshi; Watanabe, Shigeyoshi

This paper is concerned with the development of a car-steering model for traffic simulation. Our focus in this paper is to propose a model of the steering behavior of a human driver for different driving scenarios. These scenarios are modeled in a unified framework using the idea of target position. The proposed approach deals with the driver’s approximation and decision-making mechanisms in tracking a target position by means of fuzzy set theory. The main novelty in this paper lies in the development of a learning algorithm that has the intention to imitate the driver’s self-learning from his driving experience and to mimic his maneuvers on the steering wheel, using linear networks as local approximators in the corresponding fuzzy areas. Results obtained from the simulation of an obstacle avoidance scenario show the capability of the model to carry out a human-like behavior with emphasis on learned skills.

Performance consequences of alternating directional control-response compatibility: evidence from a coal mine shuttle car simulator.

PubMed

Zupanc, Christine M; Burgess-Limerick, Robin J; Wallis, Guy

2007-08-01

To investigate error and reaction time consequences of alternating compatible and incompatible steering arrangements during a simulated obstacle avoidance task. Underground coal mine shuttle cars provide an example of a vehicle in which operators are required to alternate between compatible and incompatible steering configurations. This experiment examines the performance of 48 novice participants in a virtual analogy of an underground coal mine shuttle car. Participants were randomly assigned to a compatible condition, an incompatible condition, an alternating condition in which compatibility alternated within and between hands, or an alternating condition in which compatibility alternated between hands. Participants made fewer steering direction errors and made correct steering responses more quickly in the compatible condition. Error rate decreased over time in the incompatible condition. A compatibility effect for both errors and reaction time was also found when the control-response relationship alternated; however, performance improvements over time were not consistent. Isolating compatibility to a hand resulted in reduced error rate and faster reaction time than when compatibility alternated within and between hands. The consequences of alternating control-response relationships are higher error rates and slower responses, at least in the early stages of learning. This research highlights the importance of ensuring consistently compatible human-machine directional control-response relationships.

78 FR 65761 - General Motors, LLC, Receipt of Petition for Decision of Inconsequential Noncompliance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-01

... vehicles does not fully comply with paragraph S9.1.1 of FMVSS No. 108, which requires an active turn signal to cancel when the steering wheel is rotated. On some of the vehicles, the turn signal may... The turn signal operating unit installed on passenger cars, multipurpose passenger vehicles, trucks...

Using the centre of percussion to design a steering controller for an autonomous race car

NASA Astrophysics Data System (ADS)

Kritayakirana, Krisada; Gerdes, J. Christian

2012-01-01

Understanding how a race car driver controls a vehicle at its friction limits can provide insights into the development of vehicle safety systems. In this paper, a race car driver's behaviour inspires the design of an autonomous racing controller. The resulting controller uses the vehicle's centre of percussion (COP) to design feedforward and feedback steering. At the COP, the effects of rotation and translation from the rear tire force cancel each other out; consequently, the feedforward steering command is robust to the disturbances from the rear tire force. Using the COP also simplifies the equations of motion, as the vehicle's lateral motion is decoupled from the vehicle's yaw motion and highlights the challenge of controlling a vehicle when the rear tires are highly saturated. The resulting dynamics can be controlled with a linear state feedback based on a lane-keeping system with additional yaw damping. Utilising Lyapunov theory, the closed-loop system is shown to remain stable even when the rear tires are highly saturated. The experimental results demonstrate that an autonomous vehicle can operate at its limits while maintaining a minimal lateral error.

Simplified planar model of a car steering system with rack and pinion and McPherson suspension

NASA Astrophysics Data System (ADS)

Knapczyk, J.; Kucybała, P.

2016-09-01

The paper presents the analysis and optimization of steering system with rack and pinion and McPherson suspension using spatial model and equivalent simplified planar model. The dimension of the steering linkage that give minimum steering error can be estimated using planar model. The steering error is defined as the difference between the actual angle made by the outer front wheel during steering manoeuvers and the calculated angle for the same wheel based on the Ackerman principle. For a given linear rack displacement, a specified steering arms angular displacements are determined while simultaneously ensuring best transmission angle characteristics (i) without and (ii) with imposing linear correlation between input and output. Numerical examples are used to illustrate the proposed method.

49 CFR 661.11 - Rolling stock procurements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Devices; (21) Car Axle Counters; (22) Communication Based Train Control (CBTC). (u) Communication... components of a bus. This list is not all-inclusive. Car body shells, egines, transmissions, front axle... assemblies, air compressor and pneumatic systems, generator/alternator and electrical systems, steering...

49 CFR 661.11 - Rolling stock procurements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Devices; (21) Car Axle Counters; (22) Communication Based Train Control (CBTC). (u) Communication... components of a bus. This list is not all-inclusive. Car body shells, egines, transmissions, front axle... assemblies, air compressor and pneumatic systems, generator/alternator and electrical systems, steering...

Modelling Accuracy of a Car Steering Mechanism with Rack and Pinion and McPherson Suspension

NASA Astrophysics Data System (ADS)

Knapczyk, J.; Kucybała, P.

2016-08-01

Modelling accuracy of a car steering mechanism with a rack and pinion and McPherson suspension is analyzed. Geometrical parameters of the model are described by using the coordinates of centers of spherical joints, directional unit vectors and axis points of revolute, cylindrical and prismatic joints. Modelling accuracy is assumed as the differences between the values of the wheel knuckle position and orientation coordinates obtained using a simulation model and the corresponding measured values. The sensitivity analysis of the parameters on the model accuracy is illustrated by two numerical examples.

Experimental study of the vehicle dynamics behavior during lane changing in different speeds

NASA Astrophysics Data System (ADS)

Heerwan, P. M.; Asyraf, S. M.; Efistein, A. N.; Seah, C. H.; Zikri, J. M.; Syawahieda, J. N.

2017-10-01

During lane changing, the speed of the vehicle is related to the stability of the vehicle. If the driver changes the lane at a high speed, the vehicle will lose its stability and it can increase the possibility of an accident. In this study, the experiment has been developed to analyse how the speed of the vehicle can affect the vehicle dynamics behavior. To achieve this objective, the UMP Test Car which employed with global positioning system (GPS), steering torque and angle sensor, displacement sensor and gyro sensor is used in the experiment. The experiment is run at the UMP test track and the track has 2 lanes which can allows the vehicle to change the position from the left to the right. In the experiment, when the GPS monitor shows 30 km/h, the driver will maintain the speed and start to turn the steering just after the test car reaches to the first skittle. Then, the driver will turn again the steering when the test car reaches to the second skittle. This method is repeated two times and the same methods is used for the speed 50 km/h. The data from the sensors is recorded in the Dewetron software and the graph is plotted. From the experimental results, the steering angle, steering torque, yaw rate and displacement for the speed 30 km/h is smaller than 50 km/h. It means that during lane changing, the speed 30 km/h is more stable compared with 50 km/h.

Electronic differential control of 2WD electric vehicle considering steering stability

NASA Astrophysics Data System (ADS)

Hua, Yiding; Jiang, Haobin; Geng, Guoqing

2017-03-01

Aiming at the steering wheel differential steering control technology of rear wheel independent driving electric wheel, considering the assisting effect of electronic differential control on vehicle steering, based on the high speed steering characteristic of electric wheel car, the electronic differential speed of auxiliary wheel steering is also studied. A yaw moment control strategy is applied to the vehicle at high speed. Based on the vehicle stability reference value, yaw rate is used to design the fuzzy controller to distribute the driving wheel torque. The simulation results show that the basic electronic differential speed function is realized based on the yaw moment control strategy, while the vehicle stability control is improved and the driving safety is enhanced. On the other hand, the torque control strategy can also assist steering of vehicle.

Optimized coordination of brakes and active steering for a 4WS passenger car.

PubMed

Tavasoli, Ali; Naraghi, Mahyar; Shakeri, Heman

2012-09-01

Optimum coordination of individual brakes and front/rear steering subsystems is presented. The integrated control strategy consists of three modules. A coordinated high-level control determines the body forces/moment required to achieve vehicle motion objectives. The body forces/moment are allocated to braking and steering subsystems through an intermediate unit, which integrates available subsystems based on phase plane notion in an optimal manner. To this end, an optimization problem including several equality and inequality constraints is defined and solved analytically, such that a real-time implementation can be realized without the use of numeric optimization software. A low-level slip-ratio controller works to generate the desired longitudinal forces at small longitudinal slip-ratios, while averting wheel locking at large slip-ratios. The efficiency of the suggested approach is demonstrated through computer simulations. Copyright © 2012 ISA. Published by Elsevier Ltd. All rights reserved.

Asymptotic sideslip angle and yaw rate decoupling control in four-wheel steering vehicles

NASA Astrophysics Data System (ADS)

Marino, Riccardo; Scalzi, Stefano

2010-09-01

This paper shows that, for a four-wheel steering vehicle, a proportional-integral (PI) active front steering control and a PI active rear steering control from the yaw rate error together with an additive feedforward reference signal for the vehicle sideslip angle can asymptotically decouple the lateral velocity and the yaw rate dynamics; that is the control can set arbitrary steady state values for lateral speed and yaw rate at any longitudinal speed. Moreover, the PI controls can suppress oscillatory behaviours by assigning real stable eigenvalues to a widely used linearised model of the vehicle steering dynamics for any value of longitudinal speed in understeering vehicles. In particular, the four PI control parameters are explicitly expressed in terms of the three real eigenvalues to be assigned. No lateral acceleration and no lateral speed measurements are required. The controlled system maintains the well-known advantages of both front and rear active steering controls: higher controllability, enlarged bandwidth for the yaw rate dynamics, suppressed resonances, new stable cornering manoeuvres and improved manoeuvrability. In particular, zero lateral speed may be asymptotically achieved while controlling the yaw rate: in this case comfort is improved since the phase lag between lateral acceleration and yaw rate is reduced. Also zero yaw rate can be asymptotically achieved: in this case additional stable manoeuvres are obtained in obstacle avoidance. Several simulations, including step references and moose tests, are carried out on a standard small SUV CarSim model to explore the robustness with respect to unmodelled effects such as combined lateral and longitudinal tyre forces, pitch, roll and driver dynamics. The simulations confirm the decoupling between the lateral velocity and the yaw rate and show the advantages obtained by the proposed control: reduced lateral speed or reduced yaw rate, suppressed oscillations and new stable manoeuvres.

Evaluation of steering control devices in adapted cars using sled deceleration tests

NASA Astrophysics Data System (ADS)

Eixerés, B.; Masiá, J.; Dols, J. F.; Esquerdo, T. V.

2009-11-01

Steering control devices used by disabled drivers can reduce passive safety, interfering with the existing systems of safety in the vehicle or causing injury to the occupants [1]. In this article, the results obtained in different dynamic tests carried out in a crash test simulator are presented. These tests were carried out on the steering devices which interfere the most with the deployment of the driver's airbag and also with the knee airbag in a Citroen C5.

National Beef Quality Audit-2011: In-plant survey of targeted carcass characteristics related to quality, quantity, value, and marketing of fed steers and heifers

USDA-ARS?s Scientific Manuscript database

The National Beef Quality Audit – 2011 (NBQA-2011) assessed the current status of quality and consistency of fed steers and heifers. Beef carcasses (n = 9,802), representing approximately 10 percent of each production lot in 28 beef processing facilities, were selected randomly for the survey. Car...

Minimalistic optic flow sensors applied to indoor and outdoor visual guidance and odometry on a car-like robot.

PubMed

Mafrica, Stefano; Servel, Alain; Ruffier, Franck

2016-11-10

Here we present a novel bio-inspired optic flow (OF) sensor and its application to visual  guidance and odometry on a low-cost car-like robot called BioCarBot. The minimalistic OF sensor was robust to high-dynamic-range lighting conditions and to various visual patterns encountered thanks to its M 2 APIX auto-adaptive pixels and the new cross-correlation OF algorithm implemented. The low-cost car-like robot estimated its velocity and steering angle, and therefore its position and orientation, via an extended Kalman filter (EKF) using only two downward-facing OF sensors and the Ackerman steering model. Indoor and outdoor experiments were carried out in which the robot was driven in the closed-loop mode based on the velocity and steering angle estimates. The experimental results obtained show that our novel OF sensor can deliver high-frequency measurements ([Formula: see text]) in a wide OF range (1.5-[Formula: see text]) and in a 7-decade high-dynamic light level range. The OF resolution was constant and could be adjusted as required (up to [Formula: see text]), and the OF precision obtained was relatively high (standard deviation of [Formula: see text] with an average OF of [Formula: see text], under the most demanding lighting conditions). An EKF-based algorithm gave the robot's position and orientation with a relatively high accuracy (maximum errors outdoors at a very low light level: [Formula: see text] and [Formula: see text] over about [Formula: see text] and [Formula: see text]) despite the low-resolution control systems of the steering servo and the DC motor, as well as a simplified model identification and calibration. Finally, the minimalistic OF-based odometry results were compared to those obtained using measurements based on an inertial measurement unit (IMU) and a motor's speed sensor.

Objectification of steering feel around straight-line driving for vehicle/tyre design

NASA Astrophysics Data System (ADS)

Kim, Jungsik; Yoon, Yong-San

2015-02-01

This paper presents the objectification techniques for the assessment of steering feel including {on-centre} feel and steering response by measurement data. Here, new objective parameters are developed by considering not only the process by which the steering feel is evaluated subjectively but also by the ergonomic perceptive sensitivity of the driver. In order to validate such objective parameters, subjective tests are carried out by professional drivers. Objective measurements are also performed for several cars at a proving ground. The linear correlation coefficients between the subjective ratings and the objective parameters are calculated. As one of new objective parameters, steering wheel angle defined by ergonomic perception sensitivity shows high correlation with the subjective questionnaires of on-center responses. Newly defined steering torque curvature also shows high correlation with the subjective questionnaires of on-center effort. These correlation results conclude that the subjective assessment of steering feel can be successfully explained and objectified by means of the suggested objective parameters.

49 CFR 571.203 - Standard No. 203; Impact protection for the driver from the steering control system.

Code of Federal Regulations, 2014 CFR

2014-10-01

... a result of impact. S2. Application. This standard applies to passenger cars and to multipurpose... does not apply to vehicles that conform to the frontal barrier crash requirements (S5.1) of Standard No... impact. S4. Requirements. Each passenger car and each multipurpose passenger vehicle, truck and bus with...

49 CFR 571.203 - Standard No. 203; Impact protection for the driver from the steering control system.

Code of Federal Regulations, 2012 CFR

2012-10-01

... a result of impact. S2. Application. This standard applies to passenger cars and to multipurpose... does not apply to vehicles that conform to the frontal barrier crash requirements (S5.1) of Standard No... impact. S4. Requirements. Each passenger car and each multipurpose passenger vehicle, truck and bus with...

49 CFR 571.203 - Standard No. 203; Impact protection for the driver from the steering control system.

Code of Federal Regulations, 2013 CFR

2013-10-01

... a result of impact. S2. Application. This standard applies to passenger cars and to multipurpose... does not apply to vehicles that conform to the frontal barrier crash requirements (S5.1) of Standard No... impact. S4. Requirements. Each passenger car and each multipurpose passenger vehicle, truck and bus with...

Automated Steering Control Design by Visual Feedback Approach —System Identification and Control Experiments with a Radio-Controlled Car—

NASA Astrophysics Data System (ADS)

Fujiwara, Yukihiro; Yoshii, Masakazu; Arai, Yasuhito; Adachi, Shuichi

Advanced safety vehicle(ASV)assists drivers’ manipulation to avoid trafic accidents. A variety of researches on automatic driving systems are necessary as an element of ASV. Among them, we focus on visual feedback approach in which the automatic driving system is realized by recognizing road trajectory using image information. The purpose of this paper is to examine the validity of this approach by experiments using a radio-controlled car. First, a practical image processing algorithm to recognize white lines on the road is proposed. Second, a model of the radio-controlled car is built by system identication experiments. Third, an automatic steering control system is designed based on H∞ control theory. Finally, the effectiveness of the designed control system is examined via traveling experiments.

Simplified bionic solutions: a simple bio-inspired vehicle collision detection system.

PubMed

Hartbauer, Manfred

2017-02-15

Modern cars are equipped with both active and passive sensor systems that can detect potential collisions. In contrast, locusts avoid collisions solely by responding to certain visual cues that are associated with object looming. In neurophysiological experiments, I investigated the possibility that the 'collision-detector neurons' of locusts respond to impending collisions in films recorded with dashboard cameras of fast driving cars. In a complementary modelling approach, I developed a simple algorithm to reproduce the neuronal response that was recorded during object approach. Instead of applying elaborate algorithms that factored in object recognition and optic flow discrimination, I tested the hypothesis that motion detection restricted to a 'danger zone', in which frontal collisions on the motorways are most likely, is sufficient to estimate the risk of a collision. Furthermore, I investigated whether local motion vectors, obtained from the differential excitation of simulated direction-selective networks, could be used to predict evasive steering maneuvers and prevent undesired responses to motion artifacts. The results of the study demonstrate that the risk of impending collisions in real traffic scenes is mirrored in the excitation of the collision-detecting neuron (DCMD) of locusts. The modelling approach was able to reproduce this neuronal response even when the vehicle was driving at high speeds and image resolution was low (about 200  ×  100 pixels). Furthermore, evasive maneuvers that involved changing the steering direction and steering force could be planned by comparing the differences in the overall excitation levels of the simulated right and left direction-selective networks. Additionally, it was possible to suppress undesired responses of the algorithm to translatory movements, camera shake and ground shadows by evaluating local motion vectors. These estimated collision risk values and evasive steering vectors could be used as input for a driving assistant, converting the first into braking force and the latter into steering responses to avoid collisions. Since many processing steps were computed on the level of pixels and involved elements of direction-selective networks, this algorithm can be implemented in hardware so that parallel computations enhance the processing speed significantly.

Simplified bionic solutions: a simple bio-inspired vehicle collision detection system

PubMed Central

Hartbauer, Manfred

2018-01-01

Modern cars are equipped with both active and passive sensor systems that can detect potential collisions. In contrast, locusts avoid collisions solely by responding to certain visual cues that are associated with object looming. In neurophysiological experiments, I investigated the possibility that the ‘collision-detector neurons’ of locusts respond to impending collisions in films recorded with dashboard cameras of fast driving cars. In a complementary modelling approach, I developed a simple algorithm to reproduce the neuronal response that was recorded during object approach. Instead of applying elaborate algorithms that factored in object recognition and optic flow discrimination, I tested the hypothesis that motion detection restricted to a ‘danger zone’, in which frontal collisions on the motorways are most likely, is sufficient to estimate the risk of a collision. Furthermore, I investigated whether local motion vectors, obtained from the differential excitation of simulated direction-selective networks, could be used to predict evasive steering maneuvers and prevent undesired responses to motion artifacts. The results of the study demonstrate that the risk of impending collisions in real traffic scenes is mirrored in the excitation of the collision-detecting neuron (DCMD) of locusts. The modelling approach was able to reproduce this neuronal response even when the vehicle was driving at high speeds and image resolution was low (about 200 × 100 pixels). Furthermore, evasive maneuvers that involved changing the steering direction and steering force could be planned by comparing the differences in the overall excitation levels of the simulated right and left direction-selective networks. Additionally, it was possible to suppress undesired responses of the algorithm to translatory movements, camera shake and ground shadows by evaluating local motion vectors. These estimated collision risk values and evasive steering vectors could be used as input for a driving assistant, converting the first into braking force and the latter into steering responses to avoid collisions. Since many processing steps were computed on the level of pixels and involved elements of direction-selective networks, this algorithm can be implemented in hardware so that parallel computations enhance the processing speed significantly. PMID:28091394

? observer-based decentralised fuzzy control design for nonlinear interconnected systems: an application to vehicle dynamics

NASA Astrophysics Data System (ADS)

Latrach, Chedia; Kchaou, Mourad; Guéguen, Hervé

2017-05-01

In this study, a decentralised output learning control strategy for a class of nonlinear interconnected systems is studied. Based on Takagi-Sugeno fuzzy (TS) model to approximate the considered interconnected nonlinear systems, a decentralised observer-based control scheme is designed to override the external disturbances such that the ? performance is achieved. The appealing attributes of this approach include: (1) the closed-loop system exhibits a robustness against nonlinear interconnections and external disturbance, (2) by one-step procedure, the gain matrices of observer and controller are obtained on a single step. In simulation results, the controller design is evaluated on the steering stability of a car where the nonlinear model describes the side slip, roll and yaw motions of the automotive vehicle equipped with four-wheel-steering and active suspension.

Risk management algorithm for rear-side collision avoidance using a combined steering torque overlay and differential braking

NASA Astrophysics Data System (ADS)

Lee, Junyung; Yi, Kyongsu; Yoo, Hyunjae; Chong, Hyokjin; Ko, Bongchul

2015-06-01

This paper describes a risk management algorithm for rear-side collision avoidance. The proposed risk management algorithm consists of a supervisor and a coordinator. The supervisor is designed to monitor collision risks between the subject vehicle and approaching vehicle in the adjacent lane. An appropriate criterion of intervention, which satisfies high acceptance to drivers through the consideration of a realistic traffic, has been determined based on the analysis of the kinematics of the vehicles in longitudinal and lateral directions. In order to assist the driver actively and increase driver's safety, a coordinator is designed to combine lateral control using a steering torque overlay by motor-driven power steering and differential braking by vehicle stability control. In order to prevent the collision while limiting actuator's control inputs and vehicle dynamics to safe values for the assurance of the driver's comfort, the Lyapunov theory and linear matrix inequalities based optimisation methods have been used. The proposed risk management algorithm has been evaluated via simulation using CarSim and MATLAB/Simulink.

The effects of studded tires on fatal crashes with passenger cars and the benefits of electronic stability control (ESC) in Swedish winter driving.

PubMed

Strandroth, Johan; Rizzi, Matteo; Olai, Maria; Lie, Anders; Tingvall, Claes

2012-03-01

This study set out to examine the effects of studded tires on fatal crashes on roads covered with ice or snow in Sweden and also to investigate the extra benefits of electronic stability control (ESC) during the winter months. Two different studies are presented in this paper. Both studies used an induced exposure approach. In the main study, 369 in-depth studies of fatal crashes with passenger cars were analyzed to determine whether loss-of-control (LOC) had been a major component or not. Only crashes involving cars without ESC and equipped with approved studded or non-studded winter tires were analyzed. The additional study used police-reported crashes that occurred during the winter seasons 2003-2010, involving passenger cars with and without ESC. While police records in Sweden do not include any tire information, it was assumed that most cars involved in crashes during the winter period would be equipped with studded tires. Findings in the main study showed that in 64% of the fatal crashes on roads covered with ice or snow LOC had been a major component. Furthermore, in 82% of LOC crashes, the passenger car over-steered prior to collision. Studded tires were found to have a statistically significant effect of 42% in terms of fatal crash reduction on roads covered with ice or snow, compared to non-studded winter tires. The effect on dry or wet roads in the winter was negative, although statistically non-significant. In the additional study, it was found that ESC further reduced crashes with injuries by 29%. The benefits on severe and fatal crashes were slightly greater (32%), although the lower 95% confidence limit was lower. Although studded tires were shown to reduce the risk of fatal crash involvement, compared to non-studded winter tires, the proportion of LOC and over-steering among cars with studded tires was large (59% and 49%, respectively). It was therefore concluded that studded tires do not prevent all LOC crashes, while ESC has benefits in those crashes since this technology mostly addresses over-steering. This is also supported by the fact that the share of LOC fatal crashes is considerably lower for ESC-equipped cars. This study recommends that non-ESC cars should be fitted with studded tires if they are to be driven on roads covered by ice or snow. If the proportion of studded tires is to be decreased on Swedish roads to reduce the about of hazardous particulates especially in built up areas, from a road safety point of view it is recommended that this should be done in phase with the implementation of ESC on all passenger cars. Copyright © 2011 Elsevier Ltd. All rights reserved.

Casting Molding of PDCPD Material for Purpose of Car’s Power Steering Body

NASA Astrophysics Data System (ADS)

Grabowski, L.; Baier, A.; Sobek, M.

2018-01-01

The growing industry of polymer and composite materials is facing new challenges posed by the automotive industry. In this industry, traditional materials such as steel and aluminum are widely replaced with plastic materials, including polymers. In the past, such behavior concerned design and interior elements, but more and more often plastics are used in the case of load-bearing elements, i.e. those that require high strength and durability nowadays. This kind of materials are also often used in safety systems or driver assistance systems. Therefore, the aim of the activities described in this article are to carry out an innovative process of injection of cold polymeric material, PDCPD (Polidicyclopentadiene), polymerizing with the use of Metathesis reaction, which in 2005 was awarded the Nobel Prize. This injection applies to the worm gear components of the system, supports the power steering system of the passenger car. Also the process of selecting the appropriate parameters to carry out this process, guaranteeing the best quality of the obtained elements is necessary. The aim of the activities was to achieve a fully useful power steering support system, using a polymer body, which is replacing the aluminum. These activities were aimed at reducing the costs and weight of the final product. The injection process and the way to achieve the finished product were carried out in an innovative way, never used in industry before.

Influence of different shoulder-elbow configurations on steering precision and steering velocity in automotive context.

PubMed

Schmidt, Susanne; Seiberl, Wolfgang; Schwirtz, Ansgar

2015-01-01

Ergonomic design requirements are needed to develop optimum vehicle interfaces for the driver. The majority of the current specifications consider only anthropometric conditions and subjective evaluations of comfort. This paper examines specific biomechanical aspects to improve the current ergonomic requirements. Therefore, a research which involved 40 subjects was carried out to obtain more knowledge in the field of steering movement while driving a car. Five different shoulder-elbow joint configurations were analyzed using a driving simulator to find optimum posture for driving in respect of steering precision and steering velocity. Therefore, a 20 s precision test and a test to assess maximum steering velocity over a range of 90° steering motion have been conducted. The results show that driving precision, as well as maximum steering velocity, are significantly increased in mid-positions (elbow angles of 95° and 120°) compared to more flexed (70°) or extended (145° and 160°) postures. We conclude that driver safety can be enhanced by implementing these data in the automotive design process because faster and highly precise steering can be important during evasive actions and in accident situations. In addition, subjective comfort rating, analyzed with questionnaires, confirmed experimental results. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Influence of Steering Control Devices Mounted in Cars for the Disabled on Passive Safety

NASA Astrophysics Data System (ADS)

Masiá, J.; Eixerés, B.; Dols, J. F.; Colomina, F. J.

2009-11-01

The purpose of this research is to analyze the influence of steering control devices for disabled people on passive safety. It is based on the advances made in the modelling and simulation of the driver position and in the suit verification test. The influence of these devices is studied through airbag deployment and/or its influence on driver safety. We characterize the different adaptations that are used in adapted cars that can be found mounted in vehicles in order to generating models that are verified by experimental test. A three dimensional design software package was used to develop the model. The simulations were generated using a dynamic simulation program employing LSDYNA finite elements. This program plots the geometry and assigns materials. The airbag is shaped, meshed and folded just as it is mounted in current vehicles. The thermodynamic model of expansion of gases is assigned and the contact interfaces are defined. Static tests were carried out on deployment of the airbag to contrast with and to validate the computational models and to measure the behaviour of the airbag when there are steering adaptations mounted in the vehicle.

Analysis of vehicle dynamics under sadden cross wind

NASA Astrophysics Data System (ADS)

Walczak, S.

2016-09-01

In this paper, the way of calculating aerodynamic forces acting on a vehicle passing in the region of sadden cross wind was presented. The CarDyn, a vehicle dynamics simulation program, developed by the author was used. The effects of the cross wind were studied with a fixed steering wheel simulation. On the base of computer simulations the car cross wind sensitivity were determined, and vehicle responses such as lateral offset, side acceleration and yaw angular velocity are presented.

Azulene-to-naphthalene rearrangement: the Car-Parrinello metadynamics method explores various reaction mechanisms.

PubMed

Stirling, András; Iannuzzi, Marcella; Laio, Alessandro; Parrinello, Michele

2004-10-18

We studied the thermal intramolecular and radical rearrangement of azulene to naphthalene by employing a novel metadynamics method based on Car-Parrinello molecular dynamics. We demonstrate that relatively short simulations can provide us with several possible reaction mechanisms for the rearrangement. We show that different choices of the collective coordinates can steer the reaction along different pathways, thus offering the possibility of choosing the most probable mechanism. We consider herein three intramolecular mechanisms and two radical pathways. We found the norcaradiene pathway to be the preferable intramolecular mechanism, whereas the spiran mechanism is the favored radical route. We obtained high activation energies for all the intramolecular pathways (81.5-98.6 kcal mol(-1)), whereas the radical routes have activation energies of 24-39 kcal mol(-1). The calculations have also resulted in elementary steps and intermediates not yet considered. A few attractive features of the metadynamics method in studying chemical reactions are pointed out.

A Diagonal-Steering-Based Binaural Beamforming Algorithm Incorporating a Diagonal Speech Localizer for Persons With Bilateral Hearing Impairment.

PubMed

Lee, Jun Chang; Nam, Kyoung Won; Jang, Dong Pyo; Kim, In Young

2015-12-01

Previously suggested diagonal-steering algorithms for binaural hearing support devices have commonly assumed that the direction of the speech signal is known in advance, which is not always the case in many real circumstances. In this study, a new diagonal-steering-based binaural speech localization (BSL) algorithm is proposed, and the performances of the BSL algorithm and the binaural beamforming algorithm, which integrates the BSL and diagonal-steering algorithms, were evaluated using actual speech-in-noise signals in several simulated listening scenarios. Testing sounds were recorded in a KEMAR mannequin setup and two objective indices, improvements in signal-to-noise ratio (SNRi ) and segmental SNR (segSNRi ), were utilized for performance evaluation. Experimental results demonstrated that the accuracy of the BSL was in the 90-100% range when input SNR was -10 to +5 dB range. The average differences between the γ-adjusted and γ-fixed diagonal-steering algorithms (for -15 to +5 dB input SNR) in the talking in the restaurant scenario were 0.203-0.937 dB for SNRi and 0.052-0.437 dB for segSNRi , and in the listening while car driving scenario, the differences were 0.387-0.835 dB for SNRi and 0.259-1.175 dB for segSNRi . In addition, the average difference between the BSL-turned-on and the BSL-turned-off cases for the binaural beamforming algorithm in the listening while car driving scenario was 1.631-4.246 dB for SNRi and 0.574-2.784 dB for segSNRi . In all testing conditions, the γ-adjusted diagonal-steering and BSL algorithm improved the values of the indices more than the conventional algorithms. The binaural beamforming algorithm, which integrates the proposed BSL and diagonal-steering algorithm, is expected to improve the performance of the binaural hearing support devices in noisy situations. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

An MPC Algorithm with Combined Speed and Steering Control for Obstacle Avoidance in Autonomous Ground Vehicles

DTIC Science & Technology

2015-04-24

from this line to the upper left side is caused by aerodynamic drag. The data for estimating the lateral load transfer coefficients is generated by...2013. [13] J. H. Jeon, R. V. Cowlagi, S. C. Peters, S. Karaman, E. Frazzoli, P. Tsiotras, and K. Iagnemma, “Optimal motion planning with the half- car ...Elsevier, 2005. [21] A. Rucco, G. Notarstefano, and J. Hauser, “Optimal control based dynamics exploration of a rigid car with longitudinal load

Apparent mass of the human body in the vertical direction: Effect of a footrest and a steering wheel

NASA Astrophysics Data System (ADS)

Toward, M. G. R.; Griffin, M. J.

2010-04-01

The apparent mass of the seated human body influences the vibration transmitted through a car seat. The apparent mass of the body is known to be influenced by sitting posture but the influence of the position of the hands and the feet is not well understood. This study was designed to quantify the influence of steering wheel location and the position of a footrest on the vertical apparent mass of the human body. The influences of the forces applied by the hands to a steering wheel and by the feet to a footrest were also investigated. Twelve subjects were exposed to whole-body vertical random vibration (1.0 m s -2 rms over the frequency range 0.13-40.0 Hz) while supported by a rigid seat with a backrest reclined to 15°. The apparent mass of the body was measured with five horizontal positions and three vertical positions of a steering wheel and also with hands in the lap, and with five horizontal positions of a footrest. The influence of five forward forces (0, 50, 100, 150, 200 N) applied separately to the 'steering wheel' and the footrest were also investigated as well as a 'no backrest' condition. With their hands in their laps, subjects exhibited a resonance around 6.7 Hz, compared to 4.8 Hz when sitting upright with no backrest. In the same posture holding a steering wheel, the mass supported on the seat surface decreased and there was an additional resonance at 4 Hz. Moving the steering wheel away from the body reduced the apparent mass at the primary resonance frequency and increased the apparent mass around the 4 Hz resonance. As the feet moved forward, the mass supported on the seat surface decreased, indicating that the backrest and footrest supported a greater proportion of the subject weight. Applying force to either the steering wheel or the footrest reduced the apparent mass at resonance and decreased the mass supported on the seat surface. It is concluded that the positions and contact conditions of the hands and the feet affect the biodynamic response of the body in a car driving posture. As the biodynamic response influences the vibration transmitted through seats, these factors should be considered in dynamic models of vehicle seating.

Designation and verification of road markings detection and guidance method

NASA Astrophysics Data System (ADS)

Wang, Runze; Jian, Yabin; Li, Xiyuan; Shang, Yonghong; Wang, Jing; Zhang, JingChuan

2018-01-01

With the rapid development of China's space industry, digitization and intelligent is the tendency of the future. This report is present a foundation research about guidance system which based on the HSV color space. With the help of these research which will help to design the automatic navigation and parking system for the frock transport car and the infrared lamp homogeneity intelligent test equipment. The drive mode, steer mode as well as the navigation method was selected. In consideration of the practicability, it was determined to use the front-wheel-steering chassis. The steering mechanism was controlled by the stepping motors, and it is guided by Machine Vision. The optimization and calibration of the steering mechanism was made. A mathematical model was built and the objective functions was constructed for the steering mechanism. The extraction method of the steering line was studied and the motion controller was designed and optimized. The theory of HSV, RGB color space and analysis of the testing result will be discussed Using the function library OPENCV on the Linux system to fulfill the camera calibration. Based on the HSV color space to design the guidance algorithm.

Implementation of quick clearance in Michigan.

DOT National Transportation Integrated Search

2012-09-01

The subject of this research effort is the If You Can Steer It, Clear It law, passed by the Michigan legislature in : 2010. This legislation requires motorists to move disabled or wrecked vehicles to the side of the road if: 1) the car is : ope...

A design study for a simple-to-fly, constant attitude light aircraft

NASA Technical Reports Server (NTRS)

Smetana, F. O.; Humphreys, D. E.; Montoya, R. J.; Rickard, W. W.; Wilkinson, I. E.

1973-01-01

The activities during a four-year study by doctoral students to evolve in detail a design for a simple-to-fly, constant attitude light airplane are described. The study indicated that such aircraft could materially reduce the hazards to light airplane occupants which arise from the high pilot work load and poor visibility that occur during landing. Preliminary cost studies indicate that in volume production this system would increase the cost of the aircraft in roughly the same fashion that automatic transmission, power steering, power brakes, and cruise control increase the cost of a compact car.

Radial microstrip slotline feed network for circular mobile communications array

NASA Technical Reports Server (NTRS)

Simons, Rainee N.; Kelly, Eron S.; Lee, Richard Q.; Taub, Susan R.

1994-01-01

In mobile and satellite communications there is a need for low cost and low profile antennas which have a toroidal pattern. Antennas that have been developed for mobile communications include a L-Band electronically steered stripline phased array, a Ka-Band mechanically steered elliptical reflector antenna and a Ka-Band printed dipole. In addition, a L-Band mechanically steered microstrip array, a L-Band microstrip phased array tracking antenna for mounting on a car roof and an X-Band radial line slotted waveguide antenna have been demonstrated. In the above electronically scanned printed arrays, the individual element radiates normally to the plane of the array and hence require a phase shifter to scan the beam towards the horizon. Scanning in the azimuth is by mechanical or electronic steering. An alternate approach is to mount microstrip patch radiators on the surface of a cone to achieve the required elevation angle. The array then scans in the azimuth by beam switching.

Beam Steering Devices Reduce Payload Weight

NASA Technical Reports Server (NTRS)

2012-01-01

Scientists have long been able to shift the direction of a laser beam, steering it toward a target, but often the strength and focus of the light is altered. For precision applications, where the quality of the beam cannot be compromised, scientists have typically turned to mechanical steering methods, redirecting the source of the beam by swinging the entire laser apparatus toward the target. Just as the mechanical methods used for turning cars has evolved into simpler, lighter, power steering methods, so has the means by which researchers can direct lasers. Some of the typical contraptions used to redirect lasers are large and bulky, relying on steering gimbals pivoted, rotating supports to shift the device toward its intended target. These devices, some as large and awkward as a piece of heavy luggage, are subject to the same issues confronted by mechanical parts: Components rub, wear out, and get stuck. The poor reliability and bulk not to mention the power requirements to run one of the machines have made mechanical beam steering components less than ideal for use in applications where weight, bulk, and maneuverability are prime concerns, such as on an unmanned aerial vehicle (UAV) or a microscope. The solution to developing reliable, lighter weight, nonmechanical steering methods to replace the hefty steering boxes was to think outside the box, and a NASA research partner did just that by developing a new beam steering method that bends and redirects the beam, as opposed to shifting the entire apparatus. The benefits include lower power requirements, a smaller footprint, reduced weight, and better control and flexibility in steering capabilities. Such benefits are realized without sacrificing aperture size, efficiency, or scanning range, and can be applied to myriad uses: propulsion systems, structures, radiation protection systems, and landing systems.

Advanced vehicle dynamics of heavy trucks with the perspective of road safety

NASA Astrophysics Data System (ADS)

Trigell, Annika Stensson; Rothhämel, Malte; Pauwelussen, Joop; Kural, Karel

2017-10-01

This paper presents state-of-the art within advanced vehicle dynamics of heavy trucks with the perspective of road safety. The most common accidents with heavy trucks involved are truck against passenger cars. Safety critical situations are for example loss of control (such as rollover and lateral stability) and a majority of these occur during speed when cornering. Other critical situations are avoidance manoeuvre and road edge recovery. The dynamic behaviour of heavy trucks have significant differences compared to passenger cars and as a consequence, successful application of vehicle dynamic functions for enhanced safety of trucks might differ from the functions in passenger cars. Here, the differences between vehicle dynamics of heavy trucks and passenger cars are clarified. Advanced vehicle dynamics solutions with the perspective of road safety of trucks are presented, beginning with the topic vehicle stability, followed by the steering system, the braking system and driver assistance systems that differ in some way from that of passenger cars as well.

Nonintrusive biological signal monitoring in a car to evaluate a driver's stress and health state.

PubMed

Baek, Hyun Jae; Lee, Haet Bit; Kim, Jung Soo; Choi, Jong Min; Kim, Ko Keun; Park, Kwang Suk

2009-03-01

Nonintrusive monitoring of a driver's physiological signals was introduced and evaluated in a car as a test of extending the concept of ubiquitous healthcare to vehicles. Electrocardiogram, photoplethysmogram, galvanic skin response, and respiration were measured in the ubiquitous healthcare car (U-car) using nonintrusively installed sensors on the steering wheel, driver's seat, and seat belt. Measured signals were transmitted to the embedded computer via Bluetooth(R) communication and processed. We collected and analyzed physiological signals during driving in order to estimate a driver's stress state while using this system. In order to compare the effect of stress on physical and mental conditions, two categories of stresses were defined. Experimental results show that a driver's physiological signals were measured with acceptable quality for analysis without interrupting driving, and they were changed meaningfully due to elicited stress. This nonintrusive monitoring can be used to evaluate a driver's state of health and stress.

Modeling of Steer-by-Wire System Used in New Braking Handwheel Concept

NASA Astrophysics Data System (ADS)

Messaoudène, K.; Oufroukh, N. Ait; Mammar, S.

2008-06-01

The handwheel is one of the primary control mechanisms of automobile thus interaction between the handwheel and the driver is critical to safety. The driver applies forces that direct the vehicle while the handwheel communicates feedback information to the driver of the forces experience by the car within its environment. The handwheel also provides a predictable mechanical feel to the driver to allow smooth and safe control. Many researchers tried to reproduce this feeling by creating steer-by-wire systems. This paper explores this new concept of handwheel and it describes the modeling steps of the components including the restitution mechanism for force feedback and its various links with the vehicle lateral dynamics and the pneumatic contacts. The aim is to explore the possibility to combine a braking device within the steer-by-wire system in order to provide a more suitable and ergonomic device to the driver.

New approaches to enhance active steering system functionalities: preliminary results

NASA Astrophysics Data System (ADS)

Serarslan, Benan

2014-09-01

An important development of the steering systems in general is active steering systems like active front steering and steer-by-wire systems. In this paper the current functional possibilities in application of active steering systems are explored. A new approach and additional functionalities are presented that can be implemented to the active steering systems without additional hardware such as new sensors and electronic control units. Commercial active steering systems are controlling the steering angle depending on the driving situation only. This paper introduce methods for enhancing active steering system functionalities depending not only on the driving situation but also vehicle parameters like vehicle mass, tyre and road condition. In this regard, adaptation of the steering ratio as a function of above mentioned vehicle parameters is presented with examples. With some selected vehicle parameter changes, the reduction of the undesired influences on vehicle dynamics of these parameter changes has been demonstrated theoretically with simulations and with real-time driving measurements.

Driving Skills of Young Adults with Developmental Coordination Disorder: Regulating Speed and Coping with Distraction

ERIC Educational Resources Information Center

de Oliveira, Rita F.; Wann, John P.

2011-01-01

In two experiments, we used an automatic car simulator to examine the steering control, speed regulation and response to hazards of young adults with developmental coordination disorder (DCD) and limited driving experience. In Experiment 1 participants either used the accelerator pedal to regulate their speed, or used the brake pedal when they…

49 CFR 571.104 - Standard No. 104; Windshield wiping and washing systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... difference between one-half of the shoulder room dimension and the steering wheel centerline-to-car... frequency or speed shall be at least 45 cycles per minute regardless of engine load and engine speed. S4.1.1.3Regardless of engine speed and engine load, the highest and one lower frequency or speed shall differ by at...

Detecting lane departures from steering wheel signal.

PubMed

Sandström, Max; Lampsijärvi, Eetu; Holmström, Axi; Maconi, Göran; Ahmadzai, Shabana; Meriläinen, Antti; Hæggström, Edward; Forsman, Pia

2017-02-01

Current lane departure warning systems are video-based and lose data when road- and weather conditions are bad. This study sought to develop a lane departure warning algorithm based on the signal drawn from the steering wheel. The rationale is that a car-based lane departure warning system should be robust regardless of road- and weather conditions. N=34 professional driver students drove in a high-fidelity driving simulator at 80km/h for 55min every third hour during 36h of sustained wakefulness. During each driving session we logged the steering wheel- and lane position signals at 60Hz. To derive the lane position signal, we quantified the transfer function of the simulated vehicle and used it to derive the absolute lane position signal from the steering wheel signal. The Pearson correlation between the derived- and actual lane position signals was r=0.48 (based on 12,000km). Next we designed an algorithm that alerted, up to three seconds before they occurred, about upcoming lane deviations that exceeded 0.2m. The sensitivity of the algorithm was 47% and the specificity was 71%. To our knowledge this exceeds the performance of the current video-based systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dual-Pump CARS Development and Application to Supersonic Combustion

NASA Technical Reports Server (NTRS)

Magnotti, Gaetano; Cutler, Andrew D.

2012-01-01

A dual-pump Coherent Anti-Stokes Raman Spectroscopy (CARS) instrument has been developed to obtain simultaneous measurements of temperature and absolute mole fractions of N2, O2 and H2 in supersonic combustion and generate databases for validation and development of CFD codes. Issues that compromised previous attempts, such as beam steering and high irradiance perturbation effects, have been alleviated or avoided. Improvements in instrument precision and accuracy have been achieved. An axis-symmetric supersonic combusting coaxial jet facility has been developed to provide a simple, yet suitable flow to CFD modelers. Approximately one million dual-pump CARS single shots have been collected in the supersonic jet for varying values of flight and exit Mach numbers at several locations. Data have been acquired with a H2 co-flow (combustion case) or a N2 co-flow (mixing case). Results are presented and the effects of the compressibility and of the heat release are discussed.

Integrating engineering principles into the medico-legal investigation of a rare fatal rollover car accident involving complex dynamics.

PubMed

Grassi, Vincenzo M; Castagnola, Flaminia; Miscusi, Massimo; De-Giorgio, Fabio

2016-09-01

Rollover car accidents can be the result of forceful steering or hitting an obstacle that acts like a ramp. Mortality from this type of car accident is particularly high, especially when occupants are thrown out of the vehicle. We report a case of a 67-year-old man who died after a rollover accident that occurred when he was driving a car equipped with a glass moonroof. He was found inside his car with his safety belt correctly fastened and the roof shattered. At autopsy, a wide avulsion injury of the head was observed, which was associated with an atlanto-axial dislocation and full-thickness fracture of the cervical body and posterior facet joints of the seventh cervical vertebra. The data collected at the scene of the accident were integrated with the autopsy results to yield a forensic engineering reconstruction. This reconstruction elucidated the dynamics of the event and correctly ascribed the lesions observed at autopsy to the phases of the rollover. Afterward, an analysis of the scientific literature concerning rollover crash tests was conducted to understand why the driver sustained fatal injuries even though his seatbelt was properly fastened.

Steering Control in a Low-Cost Driving Simulator: A Case for the Role of Virtual Vehicle Cab.

PubMed

Mecheri, Sami; Lobjois, Régis

2018-04-01

The aim of this study was to investigate steering control in a low-cost driving simulator with and without a virtual vehicle cab. In low-cost simulators, the lack of a vehicle cab denies driver access to vehicle width, which could affect steering control, insofar as locomotor adjustments are known to be based on action-scaled visual judgments of the environment. Two experiments were conducted in which steering control with and without a virtual vehicle cab was investigated in a within-subject design, using cornering and straight-lane-keeping tasks. Driving around curves without vehicle cab information made drivers deviate more from the lane center toward the inner edge in right (virtual cab = 4 ± 19 cm; no cab = 42 ± 28 cm; at the apex of the curve, p < .001) but not in left curves. More lateral deviation from the lane center toward the edge line was also found in driving without the virtual cab on straight roads (virtual cab = 21 ± 28 cm; no cab = 36 ± 27 cm; p < .001), whereas driving stability and presence ratings were not affected. In both experiments, the greater lateral deviation in the no-cab condition led to significantly more time driving off the lane. The findings strongly suggest that without cab information, participants underestimate the distance to the right edge of the car (in contrast to the left edge) and thus vehicle width. This produces considerable differences in the steering trajectory. Providing a virtual vehicle cab must be encouraged for more effectively capturing drivers' steering control in low-cost simulators.

Sternal fractures occur most often in old cars to seat-belted drivers without any airbag often with concomitant spinal injuries: clinical findings and technical collision variables among 42,055 crash victims.

PubMed

Knobloch, Karsten; Wagner, Sebastian; Haasper, Carl; Probst, Christian; Krettek, Christian; Otte, Dietmar; Richter, Martinus

2006-08-01

The incidence and treatment of sternal fractures caused by traffic accidents is of increasing importance to ensure best possible outcomes. Analysis of technical indicators of the collision, preclinical, and clinical data of patients with sternal fractures from 1985 to 2004 among 42,055 injured patients was assessed by an Accident Research Unit. Two time groups were categorized: 1985 to 1994 (group A) versus 1995 to 2004 (group B). Of 42,055 patients, 267 (0.64%) suffered a sternal fracture. Regarding the vehicle type, the majority occurred after car accidents in 0.81% (251 of 31,183 patients), followed by 0.19% (5 of 2,633 patients) driving motorbike, and 0.11% (4 of 3,258 patients) driving a truck. Ninety-one percent wore a safety belt. Only 13% of all passengers suffering a sternal fracture had an airbag on board (33 of 255 car/trucks), with an airbag malfunction in 18%. The steering column was deformed in 39%, the steering wheel in 36%. Cars in the recent years were significantly older (group B, 7.67 +/- 5 years, versus group A, 5.88 +/- 5 years; p = 0.003). Cervical spine injuries are frequent (23% versus 22%), followed by multiple rib fractures (14% versus 12%) and lung contusions (12% versus 11%). We found 9 of 146 (6%) and 3 of 121 patients (3%) with heart contusion among the 267 sternal fractures. Maximal abbreviated injury scale score was 2.56 +/- 1.3 versus 2.62 +/- 1.3 (group A versus B, p = 0.349). Eighteen percent of patients were polytraumatized, with 11.2% dying at the scene, 2.3% in the hospital. Sternal fractures occur most often in old cars to seat-belted drivers often without any airbag. Severe multiple rib fractures and lung contusion are concomitant injuries in more than 10% each, indicating the severity of the crash. Over a 20-year period, the injury severity encountered was not different, with 18% polytrauma patients suffering sternal fractures.

Effect of driving experience on anticipatory look-ahead fixations in real curve driving.

PubMed

Lehtonen, Esko; Lappi, Otto; Koirikivi, Iivo; Summala, Heikki

2014-09-01

Anticipatory skills are a potential factor for novice drivers' curve accidents. Behavioural data show that steering and speed regulation are affected by forward planning of the trajectory. When approaching a curve, the relevant visual information for online steering control and for planning is located at different eccentricities, creating a need to disengage the gaze from the guidance of steering to anticipatory look-ahead fixations over curves. With experience, peripheral vision can be increasingly used in the visual guidance of steering. This could leave experienced drivers more gaze time to invest on look-ahead fixations over curves, facilitating the trajectory planning. Eighteen drivers (nine novices, nine experienced) drove an instrumented vehicle on a rural road four times in both directions. Their eye movements were analyzed in six curves. The trajectory of the car was modelled and divided to approach, entry and exit phases. Experienced drivers spent less time on the road-ahead and more time on the look-ahead fixations over the curves. Look-ahead fixations were also more common in the approach than in the entry phase of the curve. The results suggest that with experience drivers allocate greater part of their visual attention to trajectory planning. Copyright © 2014 Elsevier Ltd. All rights reserved.

Investigation of an alleged mechanism of finger injury in an automobile crash.

PubMed

Stacey, Stephen; Kent, Richard

2006-07-01

This investigation centers on the case of an adult male whose finger was allegedly amputated by the steering wheel of his car during a crash. The subject claimed to have been driving with his left index finger inserted through a hole in the spoke of his steering wheel and was subsequently involved in an offset frontal collision with a tree. The finger was found to be cleanly severed at the mid-shaft of the proximal phalanx after the crash. This injury was alleged to have been caused by inertial loading from the rotation of the steering wheel during the crash. To determine whether this injury mechanism was plausible, three laboratory tests representing distinct loading scenarios were carried out with postmortem human surrogates loaded dynamically by the subject's steering wheel. It was found that the inertial loads generated in this loading scenario are insufficient to amputate the finger. Additionally, artificially constraining the finger to force an amputation to occur revealed that a separation at the proximal interphalangeal joint occurs rather than a bony fracture of the proximal phalanx. Based on these biomechanical tests, it can be concluded that the subject's injury did not occur during the automobile crash in question. Furthermore, it can be shown that the injury was self-inflicted to fraudulently claim on an insurance policy.

VTI Driving Simulator: Mathematical Model of a Four-wheeled Vehicle for Simulation in Real Time. VTI Rapport 267A.

ERIC Educational Resources Information Center

Nordmark, Staffan

1984-01-01

This report contains a theoretical model for describing the motion of a passenger car. The simulation program based on this model is used in conjunction with an advanced driving simulator and run in real time. The mathematical model is complete in the sense that the dynamics of the engine, transmission and steering system is described in some…

Mind over motor mapping: Driver response to changing vehicle dynamics.

PubMed

Bruno, Jennifer L; Baker, Joseph M; Gundran, Andrew; Harbott, Lene K; Stuart, Zachary; Piccirilli, Aaron M; Hosseini, S M Hadi; Gerdes, J Christian; Reiss, Allan L

2018-06-08

Improvements in vehicle safety require understanding of the neural systems that support the complex, dynamic task of real-world driving. We used functional near infrared spectroscopy (fNIRS) and pupilometry to quantify cortical and physiological responses during a realistic, simulated driving task in which vehicle dynamics were manipulated. Our results elucidate compensatory changes in driver behavior in response to changes in vehicle handling. We also describe associated neural and physiological responses under different levels of mental workload. The increased cortical activation we observed during the late phase of the experiment may indicate motor learning in prefrontal-parietal networks. Finally, relationships among cortical activation, steering control, and individual personality traits suggest that individual brain states and traits may be useful in predicting a driver's response to changes in vehicle dynamics. Results such as these will be useful for informing the design of automated safety systems that facilitate safe and supportive driver-car communication. © 2018 Wiley Periodicals, Inc.

Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers.

PubMed

Russell, J R; Sexten, W J; Kerley, M S; Hansen, S L

2016-07-01

Feed efficiency (FE) can vary between individuals but sources of variation are not well characterized. Oxidative stress is among the biological mechanisms believed to contribute to variation. The objective of this study was to evaluate the relationship between FE, antioxidant activity, and oxidative stress in feedlot steers representing phenotypic extremes for FE. Crossbred beef steers ( = 181) fed 70-d growing phase (GP) whole-shell corn-based (G-Corn) or rye baleage and soybean hull-based (G-Rough) diets in GrowSafe bunks at the University of Missouri were shipped to Iowa State University where the 12 most feed efficient (HFE) and 12 least feed efficient (LFE) steers from each diet (n = 48; 467 kg [SD 51]) were selected for evaluation. Steers received diets similar to GP diets, and 3 d after arrival, blood was sampled to evaluate antioxidant activity and oxidative stress markers for the GP following transit. Steers were transitioned to finishing phase (FP) cracked corn-based (F-Corn) or dried distillers' grains and soybean hull-based (F-Byp) diets, and on FP d 97, blood samples for the FP were collected. Data for the GP were analyzed as a 2 × 2 factorial, and data for the FP were analyzed as a 2 × 2 × 2 factorial using PROC MIXED of SAS. No GP diet × FP diet, FP diet × FE group, or 3-way interactions were noted ( ≥ 0.11) for FP measures. Steers fed the G-Rough diet had greater ( = 0.04) GP plasma protein carbonyl concentrations. During the GP, HFE steers had greater ( ≤ 0.04) protein carbonyl and ratio of oxidized:reduced blood lysate glutathione concentrations than LFE steers. There were GP diet × FE group interactions ( ≤ 0.03) during the GP and FP. During the GP, total blood lysate superoxide dismutase (SOD) activity was greater ( ≤ 0.03) in G-Rough/LFE steers than in G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The G-Rough/LFE steers had greater ( < 0.04) glutathione peroxidase (GPX) activity than other groups and greater ( = 0.03) plasma malondialdehyde concentrations than G-Corn/LFE steers. During the FP, the G-Rough/LFE steers had greater ( ≤ 0.04) GPX activity than G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The F-Byp diet had greater ( < 0.01) protein carbonyl than the F-Corn diet, and no other FP diet effects were noted ( ≥ 0.3) for any FP measures. The GP diet and FE groups had stronger relationships with antioxidant activity and oxidative stress markers measured for the GP than for the FP. Overall, antioxidant activity may play a role in FE as LFE steers, driven largely by G-Rough/LFE steers, had greater SOD activity and GPX activity than HFE steers, potentially using a greater proportion of energy otherwise available for tissue accretion.

Self-driving carsickness.

PubMed

Diels, Cyriel; Bos, Jelte E

2016-03-01

This paper discusses the predicted increase in the occurrence and severity of motion sickness in self-driving cars. Self-driving cars have the potential to lead to significant benefits. From the driver's perspective, the direct benefits of this technology are considered increased comfort and productivity. However, we here show that the envisaged scenarios all lead to an increased risk of motion sickness. As such, the benefits this technology is assumed to bring may not be capitalised on, in particular by those already susceptible to motion sickness. This can negatively affect user acceptance and uptake and, in turn, limit the potential socioeconomic benefits that this emerging technology may provide. Following a discussion on the causes of motion sickness in the context of self-driving cars, we present guidelines to steer the design and development of automated vehicle technologies. The aim is to limit or avoid the impact of motion sickness and ultimately promote the uptake of self-driving cars. Attention is also given to less well known consequences of motion sickness, in particular negative aftereffects such as postural instability, and detrimental effects on task performance and how this may impact the use and design of self-driving cars. We conclude that basic perceptual mechanisms need to be considered in the design process whereby self-driving cars cannot simply be thought of as living rooms, offices, or entertainment venues on wheels. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Effects of enactment in episodic memory: a pilot virtual reality study with young and elderly adults.

PubMed

Jebara, Najate; Orriols, Eric; Zaoui, Mohamed; Berthoz, Alain; Piolino, Pascale

2014-01-01

None of the previous studies on aging have tested the influence of action with respect to the degree of interaction with the environment (active or passive navigation) and the source of itinerary choice (self or externally imposed), on episodic memory (EM) encoding. The aim of this pilot study was to explore the influence of these factors on feature binding (the association between what, where, and when) in EM and on the subjective sense of remembering. Navigation in a virtual city was performed by 64 young and 64 older adults in one of four modes of exploration: (1) passive condition where participants were immersed as passengers of a virtual car [no interaction, no itinerary control (IC)], (2) IC (the subject chose the itinerary, but did not drive the car), (3) low, or (4) high navigation control (the subject just moved the car on rails or drove the car with a steering-wheel and a gas pedal on a fixed itinerary, respectively). The task was to memorize as many events encountered in the virtual environment as possible along with their factual (what), spatial (where), and temporal (when) details, and then to perform immediate and delayed memory tests. An age-related decline was evidenced for immediate and delayed feature binding. Compared to passive and high navigation conditions, and regardless of age-groups, feature binding was enhanced by low navigation and IC conditions. The subjective sense of remembering was boosted by the IC in older adults. Memory performance following high navigation was specifically linked to variability in executive functions. The present findings suggest that the decision of the itinerary is beneficial to boost EM in aging, although it does not eliminate age-related deficits. Active navigation can also enhance EM when it is not too demanding for subjects' cognitive resources.

Effects of Enactment in Episodic Memory: A Pilot Virtual Reality Study with Young and Elderly Adults

PubMed Central

Jebara, Najate; Orriols, Eric; Zaoui, Mohamed; Berthoz, Alain; Piolino, Pascale

2014-01-01

None of the previous studies on aging have tested the influence of action with respect to the degree of interaction with the environment (active or passive navigation) and the source of itinerary choice (self or externally imposed), on episodic memory (EM) encoding. The aim of this pilot study was to explore the influence of these factors on feature binding (the association between what, where, and when) in EM and on the subjective sense of remembering. Navigation in a virtual city was performed by 64 young and 64 older adults in one of four modes of exploration: (1) passive condition where participants were immersed as passengers of a virtual car [no interaction, no itinerary control (IC)], (2) IC (the subject chose the itinerary, but did not drive the car), (3) low, or (4) high navigation control (the subject just moved the car on rails or drove the car with a steering-wheel and a gas pedal on a fixed itinerary, respectively). The task was to memorize as many events encountered in the virtual environment as possible along with their factual (what), spatial (where), and temporal (when) details, and then to perform immediate and delayed memory tests. An age-related decline was evidenced for immediate and delayed feature binding. Compared to passive and high navigation conditions, and regardless of age-groups, feature binding was enhanced by low navigation and IC conditions. The subjective sense of remembering was boosted by the IC in older adults. Memory performance following high navigation was specifically linked to variability in executive functions. The present findings suggest that the decision of the itinerary is beneficial to boost EM in aging, although it does not eliminate age-related deficits. Active navigation can also enhance EM when it is not too demanding for subjects’ cognitive resources. PMID:25566069

Implementation of object-oriented programming in study of electrical race car

NASA Astrophysics Data System (ADS)

Nowak, M.; Baier, M.

2016-08-01

The paper covers issue of conducting advanced research of electrical race car participating in international competition called Sileverline Corporate Challenge. Process of designing race cars in Silesian Greenpower team is aided by a professional engine test stand built particularly in purpose of this research. Phase of testing and simulation is an important part of the implementation of new technologies. Properly developed solutions and test procedures are able to significantly shorten development time and reduce design costs. Testing process must be controlled by a modular and flexible application, easy to modify and ensuring safety. This paper describes the concept of object-oriented programming in LabVIEW and exemplary architecture of object-oriented control application designed to control engine test stand of the electrical race car. Eventually, the task of application will be to steer the electromagnetic brake and the engine load torque to perform according to data from the actual race track. During the designing process of the car, minimizing energy losses and maximizing powertrain efficiency are the main aspects taken into consideration. One of the crucial issues to accomplish these goals is to maintain optimal performance of the motor by applying effective cooling. The paper covers the research verifying the effectiveness of the cooling system.

Noise, vibration and harshness (NVH) criteria as functions of vehicle design and consumer expectations

NASA Astrophysics Data System (ADS)

Raichel, Daniel R.

2005-09-01

The criteria for NVH design are to a large degree determined by the types of vehicles and the perceived desires of the purchasers of vehicles, as well as the cost of incorporating NVH measures. Vehicles may be classified into specific types, e.g., economy car, midsize passenger, near-luxury and luxury passenger cars, sports cars, vans, minivans, and sports utility vehicles of varying sizes. The owner of a luxury sedan would expect a quiet ride with minimal vibration and harshness-however, if that sedan is to display sporting characteristics, some aspects of NVH may actually have to be increased in order to enhance a feeling of driver exhilaration. A discussion of the requirements for specific types of vehicles is provided, with due regard for effects on the usability of installed sound/video systems, driver and passenger fatigue, feel of steering mechanisms and other mechanical components, consumer market research, etc. A number of examples of vehicles on the market are cited.

Eye Carduino: A Car Control System using Eye Movements

NASA Astrophysics Data System (ADS)

Kumar, Arjun; Nagaraj, Disha; Louzardo, Joel; Hegde, Rajeshwari

2011-12-01

Modern automotive systems are rapidly becoming highly of transportation, but can be a web integrated media centre. This paper explains the implementation of a vehicle control defined and characterized by embedded electronics and software. With new technologies, the vehicle industry is facing new opportunities and also new challenges. Electronics have improved the performance of vehicles and at the same time, new more complex applications are introduced. Examples of high level applications include adaptive cruise control and electronic stability programs (ESP). Further, a modern vehicle does not have to be merely a means using only eye movements. The EyeWriter's native hardware and software work to return the co-ordinates of where the user is looking. These co-ordinates are then used to control the car. A centre-point is defined on the screen. The higher on the screen the user's gaze is, the faster the car will accelerate. Braking is done by looking below centre. Steering is done by looking left and right on the screen.

Torque vectoring for improving stability of small electric vehicles

NASA Astrophysics Data System (ADS)

Grzegożek, W.; Weigel-Milleret, K.

2016-09-01

The electric vehicles solutions based on the individually controlled electric motors propel a single wheel allow to improve the dynamic properties of the vehicle by varying the distribution of the driving torque. Most of the literature refer to the vehicles with a track typical for passenger cars. This paper examines whether the narrow vehicle (with a very small track) torque vectoring bring a noticeable change of the understeer characteristics and whether torque vectoring is possible to use in securing a narrow vehicle from roll over (roll mitigation). The paper contains road tests of the steering characteristics (steady state understeer characteristic quasi-static acceleration with a fixed steering wheel (SH = const) and on the constant radius track (R = const)) of the narrow vehicle. The vehicle understeer characteristic as a function of a power distribution is presented.

Design of intelligent vehicle control system based on single chip microcomputer

NASA Astrophysics Data System (ADS)

Zhang, Congwei

2018-06-01

The smart car microprocessor uses the KL25ZV128VLK4 in the Freescale series of single-chip microcomputers. The image sampling sensor uses the CMOS digital camera OV7725. The obtained track data is processed by the corresponding algorithm to obtain track sideline information. At the same time, the pulse width modulation control (PWM) is used to control the motor and servo movements, and based on the digital incremental PID algorithm, the motor speed control and servo steering control are realized. In the project design, IAR Embedded Workbench IDE is used as the software development platform to program and debug the micro-control module, camera image processing module, hardware power distribution module, motor drive and servo control module, and then complete the design of the intelligent car control system.

An Invitation to Imitation

DTIC Science & Technology

2015-03-15

Super Mario Bros, 2010b. URL http://www.youtube.com/watch?v=anOI0xZ3kGM. S. Ross and J. A. Bagnell. Efficient reductions for imitation learning. In...learning to drive a car in a video game by performing a direct mapping from screen shots to steering angles. Figure 4 illustrates the classic super - an...same distribution and thus the super - vised learning assumption of independent and identically distributed (i.i.d.) data is badly violated. A natural

Vision-Based Steering Control, Speed Assistance and Localization for Inner-City Vehicles

PubMed Central

Olivares-Mendez, Miguel Angel; Sanchez-Lopez, Jose Luis; Jimenez, Felipe; Campoy, Pascual; Sajadi-Alamdari, Seyed Amin; Voos, Holger

2016-01-01

Autonomous route following with road vehicles has gained popularity in the last few decades. In order to provide highly automated driver assistance systems, different types and combinations of sensors have been presented in the literature. However, most of these approaches apply quite sophisticated and expensive sensors, and hence, the development of a cost-efficient solution still remains a challenging problem. This work proposes the use of a single monocular camera sensor for an automatic steering control, speed assistance for the driver and localization of the vehicle on a road. Herein, we assume that the vehicle is mainly traveling along a predefined path, such as in public transport. A computer vision approach is presented to detect a line painted on the road, which defines the path to follow. Visual markers with a special design painted on the road provide information to localize the vehicle and to assist in its speed control. Furthermore, a vision-based control system, which keeps the vehicle on the predefined path under inner-city speed constraints, is also presented. Real driving tests with a commercial car on a closed circuit finally prove the applicability of the derived approach. In these tests, the car reached a maximum speed of 48 km/h and successfully traveled a distance of 7 km without the intervention of a human driver and any interruption. PMID:26978365

Vision-Based Steering Control, Speed Assistance and Localization for Inner-City Vehicles.

PubMed

Olivares-Mendez, Miguel Angel; Sanchez-Lopez, Jose Luis; Jimenez, Felipe; Campoy, Pascual; Sajadi-Alamdari, Seyed Amin; Voos, Holger

2016-03-11

Autonomous route following with road vehicles has gained popularity in the last few decades. In order to provide highly automated driver assistance systems, different types and combinations of sensors have been presented in the literature. However, most of these approaches apply quite sophisticated and expensive sensors, and hence, the development of a cost-efficient solution still remains a challenging problem. This work proposes the use of a single monocular camera sensor for an automatic steering control, speed assistance for the driver and localization of the vehicle on a road. Herein, we assume that the vehicle is mainly traveling along a predefined path, such as in public transport. A computer vision approach is presented to detect a line painted on the road, which defines the path to follow. Visual markers with a special design painted on the road provide information to localize the vehicle and to assist in its speed control. Furthermore, a vision-based control system, which keeps the vehicle on the predefined path under inner-city speed constraints, is also presented. Real driving tests with a commercial car on a closed circuit finally prove the applicability of the derived approach. In these tests, the car reached a maximum speed of 48 km/h and successfully traveled a distance of 7 km without the intervention of a human driver and any interruption.

Elucidation of bacteria found in car interiors and strategies to reduce the presence of potential pathogens.

PubMed

Stephenson, Rachel E; Gutierrez, Daniel; Peters, Cindy; Nichols, Mark; Boles, Blaise R

2014-01-01

The human microbiome is influenced by a number of factors, including environmental exposure to microbes. Because many humans spend a large amount of time in built environments, it can be expected that the microbial ecology of these environments will influence the human microbiome. In an attempt to further understand the microbial ecology of built environments, the microbiota of car interiors was analyzed using culture dependent and culture independent methods. While it was found that the number and type of bacteria varied widely among the cars and sites tested, Staphylococcus and Propionibacterium were nearly always the dominant genera found at the locations sampled. Because Staphylococcus is of particular concern to human health, the characteristics of this genus found in car interiors were investigated. Staphylococcus epidermidis, S. aureus, and S. warnerii were the most prevalent staphylococcal species found, and 22.6% of S. aureus strains isolated from shared community vehicles were resistant to methicillin. The reduction in the prevalence of pathogenic bacteria in cars by using silver-based antimicrobial surface coatings was also evaluated. Coatings containing 5% silver ion additives were applied to steering wheels, placed in cars for five months and were found to eliminate the presence of culturable pathogenic bacteria recovered from these sites relative to controls. Together, these results provide new insight into the microbiota found in an important built environment, the automobile, and potential strategies for controlling the presence of human pathogens.

Elucidation of bacteria found in car interiors and strategies to reduce the presence of potential pathogens

PubMed Central

Stephenson, Rachel E.; Gutierrez, Daniel; Peters, Cindy; Nichols, Mark; Boles, Blaise R.

2014-01-01

The human microbiome is influenced by a number of factors, including environmental exposure to microbes. Because many humans spend a large amount of time in built environments, it can be expected that the microbial ecology of these environments will influence the human microbiome. In an attempt to further understand the microbial ecology of built environments, the microbiota of car interiors was analyzed using culture dependent and culture independent methods. While it was found that the number and type of bacteria varied widely among the cars and sites tested, Staphylococcus and Propionibacterium were nearly always the dominant genera found at the locations sampled. Because Staphylococcus is of particular concern to human health, the characteristics of this genus found in car interiors were investigated. Staphylococcus epidermidis, S. aureus, and S. warnerii were the most prevalent staphylococcal species found, and 22.6% of S. aureus strains isolated from shared community vehicles were resistant to methicillin. The reduction in the prevalence of pathogenic bacteria in cars by using silver-based antimicrobial surface coatings was also evaluated. Coatings containing 5% silver ion additives were applied to steering wheels, placed in cars for five months and were found to eliminate the presence of culturable pathogenic bacteria recovered from these sites relative to controls. Together, these results provide new insight into the microbiota found in an important built environment, the automobile, and potential strategies for controlling the presence of human pathogens. PMID:24564823

Take-over again: Investigating multimodal and directional TORs to get the driver back into the loop.

PubMed

Petermeijer, Sebastiaan; Bazilinskyy, Pavlo; Bengler, Klaus; de Winter, Joost

2017-07-01

When a highly automated car reaches its operational limits, it needs to provide a take-over request (TOR) in order for the driver to resume control. The aim of this simulator-based study was to investigate the effects of TOR modality and left/right directionality on drivers' steering behaviour when facing a head-on collision without having received specific instructions regarding the directional nature of the TORs. Twenty-four participants drove three sessions in a highly automated car, each session with a different TOR modality (auditory, vibrotactile, and auditory-vibrotactile). Six TORs were provided per session, warning the participants about a stationary vehicle that had to be avoided by changing lane left or right. Two TORs were issued from the left, two from the right, and two from both the left and the right (i.e., nondirectional). The auditory stimuli were presented via speakers in the simulator (left, right, or both), and the vibrotactile stimuli via a tactile seat (with tactors activated at the left side, right side, or both). The results showed that the multimodal TORs yielded statistically significantly faster steer-touch times than the unimodal vibrotactile TOR, while no statistically significant differences were observed for brake times and lane change times. The unimodal auditory TOR yielded relatively low self-reported usefulness and satisfaction ratings. Almost all drivers overtook the stationary vehicle on the left regardless of the directionality of the TOR, and a post-experiment questionnaire revealed that most participants had not realized that some of the TORs were directional. We conclude that between the three TOR modalities tested, the multimodal approach is preferred. Moreover, our results show that directional auditory and vibrotactile stimuli do not evoke a directional response in uninstructed drivers. More salient and semantically congruent cues, as well as explicit instructions, may be needed to guide a driver into a specific direction during a take-over scenario. Copyright © 2017 Elsevier Ltd. All rights reserved.

Volunteers Oriented Interface Design for the Remote Navigation of Rescue Robots at Large-Scale Disaster Sites

NASA Astrophysics Data System (ADS)

Yang, Zhixiao; Ito, Kazuyuki; Saijo, Kazuhiko; Hirotsune, Kazuyuki; Gofuku, Akio; Matsuno, Fumitoshi

This paper aims at constructing an efficient interface being similar to those widely used in human daily life, to fulfill the need of many volunteer rescuers operating rescue robots at large-scale disaster sites. The developed system includes a force feedback steering wheel interface and an artificial neural network (ANN) based mouse-screen interface. The former consists of a force feedback steering control and a six monitors’ wall. It provides a manual operation like driving cars to navigate a rescue robot. The latter consists of a mouse and a camera’s view displayed in a monitor. It provides a semi-autonomous operation by mouse clicking to navigate a rescue robot. Results of experiments show that a novice volunteer can skillfully navigate a tank rescue robot through both interfaces after 20 to 30 minutes of learning their operation respectively. The steering wheel interface has high navigating speed in open areas, without restriction of terrains and surface conditions of a disaster site. The mouse-screen interface is good at exact navigation in complex structures, while bringing little tension to operators. The two interfaces are designed to switch into each other at any time to provide a combined efficient navigation method.

Processing and filtrating of driver fatigue characteristic parameters based on rough set

NASA Astrophysics Data System (ADS)

Ye, Wenwu; Zhao, Xuyang

2018-05-01

With the rapid development of economy, people become increasingly rich, and cars have become a common means of transportation in daily life. However, the problem of traffic safety is becoming more and more serious. And fatigue driving is one of the main causes of traffic accidents. Therefore, it is of great importance for us to study the detection of fatigue driving to improve traffic safety. In the cause of determining whether the driver is tired, the characteristic quantity related to the steering angle of the steering wheel and the characteristic quantity of the driver's pulse are all important indicators. The fuzzy c-means clustering is used to discretize the above indexes. Because the characteristic parameters are too miscellaneous, rough set is used to filtrate these characteristics. Finally, this paper finds out the highest correlation with fatigue driving. It is proved that these selected characteristics are of great significance to the evaluation of fatigue driving.

Commercial-off-the-Shelf Vehicles for Towed Array Magnetometry

DTIC Science & Technology

2009-09-01

dump bed on the back, has upright seating for two adults, has the seats oriented side-by-side, and has a steering wheel and brake and accelerator... pedals like a car. By way of example, a ubiquitous side-by-side UTV is the John Deere Gator. The objective of this project was to test a number of...different angle , and one set of biases will not be able to take out all of the streaks. This raises the second issue. Because the bidirectional

Commercial-Off-The-Shelf Vehicles for Towed Array Magnetometry

DTIC Science & Technology

2009-09-01

a steering wheel, and brake and accelerator pedals like a car. By way of example, a ubiquitous side-by- side UTV is the John Deere Gator. The...tire tracks are imperfectly 42 followed. These new tracks will be at a slightly different angle , and one set of biases will not be able to take...tracks at an angle relative to the north-south traverses that we ran. In addition, we surveyed into the muddy wet section at the western end of the site

Nardo Ring, Italy

NASA Technical Reports Server (NTRS)

2008-01-01

The Nardo Ring is a striking visual feature from space, and astronauts have photographed it several times. The Ring is a race car test track; it is 12.5 kilometers long and steeply banked to reduce the amount of active steering needed by drivers. The Nardo Ring lies in a remote area on the heel of Italy's 'boot,' 50 kilometers east of the naval port of Taranto. The Ring encompasses a number of active (green) and fallow (brown to dark brown) agricultural fields. In this zone of intensive agriculture, farmers gain access to their fields through the Ring via a series of underpasses. Winding features within the southern section of the Ring appear to be smaller, unused race tracks.

The image covers an area of 18.8 x 16.4 km, was acquired on August 17. 2007, and is located at 49.3 degrees north latitude, 17.8 degrees east longitude.

The U.S. science team is located at NASA's Jet Propulsion Laboratory, Pasadena, Calif. The Terra mission is part of NASA's Science Mission Directorate.

Does haptic steering guidance instigate speeding? A driving simulator study into causes and remedies.

PubMed

Melman, T; de Winter, J C F; Abbink, D A

2017-01-01

An important issue in road traffic safety is that drivers show adverse behavioral adaptation (BA) to driver assistance systems. Haptic steering guidance is an upcoming assistance system which facilitates lane-keeping performance while keeping drivers in the loop, and which may be particularly prone to BA. Thus far, experiments on haptic steering guidance have measured driver performance while the vehicle speed was kept constant. The aim of the present driving simulator study was to examine whether haptic steering guidance causes BA in the form of speeding, and to evaluate two types of haptic steering guidance designed not to suffer from BA. Twenty-four participants drove a 1.8m wide car for 13.9km on a curved road, with cones demarcating a single 2.2m narrow lane. Participants completed four conditions in a counterbalanced design: no guidance (Manual), continuous haptic guidance (Cont), continuous guidance that linearly reduced feedback gains from full guidance at 125km/h towards manual control at 130km/h and above (ContRF), and haptic guidance provided only when the predicted lateral position was outside a lateral bandwidth (Band). Participants were familiarized with each condition prior to the experimental runs and were instructed to drive as they normally would while minimizing the number of cone hits. Compared to Manual, the Cont condition yielded a significantly higher driving speed (on average by 7km/h), whereas ContRF and Band did not. All three guidance conditions yielded better lane-keeping performance than Manual, whereas Cont and ContRF yielded lower self-reported workload than Manual. In conclusion, continuous steering guidance entices drivers to increase their speed, thereby diminishing its potential safety benefits. It is possible to prevent BA while retaining safety benefits by making a design adjustment either in lateral (Band) or in longitudinal (ContRF) direction. Copyright © 2016. Published by Elsevier Ltd.

Assessing the thermo-mechanical TaMeTirE model in offline vehicle simulation and driving simulator tests

NASA Astrophysics Data System (ADS)

Durand-Gasselin, Benoit; Dailliez, Thibault; Mössner-Beigel, Monika; Knorr, Stephanie; Rauh, Jochen

2010-12-01

This paper presents the experiences using Michelin's thermo-mechanical TaMeTirE tyre model for real-time handling applications in the field of advanced passenger car simulation. Passenger car handling simulations were performed using the tyre model in a full-vehicle real-time environment in order to assess TaMeTirE's level of consistency with real on-track handling behaviour. To achieve this goal, a first offline comparison with a state-of-the-art handling tyre model was carried out on three handling manoeuvres. Then, online real-time simulations of steering wheel steps and slaloms in straight line were run on Daimler's driving simulator by skilled and unskilled drivers. Two analytical tyre temperature effects and two inflation pressure effects were carried out in order to feel their impact on the handling behaviour of the vehicle. This paper underlines the realism of the handling simulation results performed with TaMeTirE, and shows the significant impact of a pressure or a temperature effect on the handling behaviour of a car.

Pursuit Eye-Movements in Curve Driving Differentiate between Future Path and Tangent Point Models

PubMed Central

Lappi, Otto; Pekkanen, Jami; Itkonen, Teemu H.

2013-01-01

For nearly 20 years, looking at the tangent point on the road edge has been prominent in models of visual orientation in curve driving. It is the most common interpretation of the commonly observed pattern of car drivers looking through a bend, or at the apex of the curve. Indeed, in the visual science literature, visual orientation towards the inside of a bend has become known as “tangent point orientation”. Yet, it remains to be empirically established whether it is the tangent point the drivers are looking at, or whether some other reference point on the road surface, or several reference points, are being targeted in addition to, or instead of, the tangent point. Recently discovered optokinetic pursuit eye-movements during curve driving can provide complementary evidence over and above traditional gaze-position measures. This paper presents the first detailed quantitative analysis of pursuit eye movements elicited by curvilinear optic flow in real driving. The data implicates the far zone beyond the tangent point as an important gaze target area during steady-state cornering. This is in line with the future path steering models, but difficult to reconcile with any pure tangent point steering model. We conclude that the tangent point steering models do not provide a general explanation of eye movement and steering during a curve driving sequence and cannot be considered uncritically as the default interpretation when the gaze position distribution is observed to be situated in the region of the curve apex. PMID:23894300

Driving a Semiautonomous Mobile Robotic Car Controlled by an SSVEP-Based BCI.

PubMed

Stawicki, Piotr; Gembler, Felix; Volosyak, Ivan

2016-01-01

Brain-computer interfaces represent a range of acknowledged technologies that translate brain activity into computer commands. The aim of our research is to develop and evaluate a BCI control application for certain assistive technologies that can be used for remote telepresence or remote driving. The communication channel to the target device is based on the steady-state visual evoked potentials. In order to test the control application, a mobile robotic car (MRC) was introduced and a four-class BCI graphical user interface (with live video feedback and stimulation boxes on the same screen) for piloting the MRC was designed. For the purpose of evaluating a potential real-life scenario for such assistive technology, we present a study where 61 subjects steered the MRC through a predetermined route. All 61 subjects were able to control the MRC and finish the experiment (mean time 207.08 s, SD 50.25) with a mean (SD) accuracy and ITR of 93.03% (5.73) and 14.07 bits/min (4.44), respectively. The results show that our proposed SSVEP-based BCI control application is suitable for mobile robots with a shared-control approach. We also did not observe any negative influence of the simultaneous live video feedback and SSVEP stimulation on the performance of the BCI system.

Driving a Semiautonomous Mobile Robotic Car Controlled by an SSVEP-Based BCI

PubMed Central

2016-01-01

Brain-computer interfaces represent a range of acknowledged technologies that translate brain activity into computer commands. The aim of our research is to develop and evaluate a BCI control application for certain assistive technologies that can be used for remote telepresence or remote driving. The communication channel to the target device is based on the steady-state visual evoked potentials. In order to test the control application, a mobile robotic car (MRC) was introduced and a four-class BCI graphical user interface (with live video feedback and stimulation boxes on the same screen) for piloting the MRC was designed. For the purpose of evaluating a potential real-life scenario for such assistive technology, we present a study where 61 subjects steered the MRC through a predetermined route. All 61 subjects were able to control the MRC and finish the experiment (mean time 207.08 s, SD 50.25) with a mean (SD) accuracy and ITR of 93.03% (5.73) and 14.07 bits/min (4.44), respectively. The results show that our proposed SSVEP-based BCI control application is suitable for mobile robots with a shared-control approach. We also did not observe any negative influence of the simultaneous live video feedback and SSVEP stimulation on the performance of the BCI system. PMID:27528864

Obstacle Avoidance, Visual Detection Performance, and Eye-Scanning Behavior of Glaucoma Patients in a Driving Simulator: A Preliminary Study

PubMed Central

Prado Vega, Rocío; van Leeuwen, Peter M.; Rendón Vélez, Elizabeth; Lemij, Hans G.; de Winter, Joost C. F.

2013-01-01

The objective of this study was to evaluate differences in driving performance, visual detection performance, and eye-scanning behavior between glaucoma patients and control participants without glaucoma. Glaucoma patients (n = 23) and control participants (n = 12) completed four 5-min driving sessions in a simulator. The participants were instructed to maintain the car in the right lane of a two-lane highway while their speed was automatically maintained at 100 km/h. Additional tasks per session were: Session 1: none, Session 2: verbalization of projected letters, Session 3: avoidance of static obstacles, and Session 4: combined letter verbalization and avoidance of static obstacles. Eye-scanning behavior was recorded with an eye-tracker. Results showed no statistically significant differences between patients and control participants for lane keeping, obstacle avoidance, and eye-scanning behavior. Steering activity, number of missed letters, and letter reaction time were significantly higher for glaucoma patients than for control participants. In conclusion, glaucoma patients were able to avoid objects and maintain a nominal lane keeping performance, but applied more steering input than control participants, and were more likely than control participants to miss peripherally projected stimuli. The eye-tracking results suggest that glaucoma patients did not use extra visual search to compensate for their visual field loss. Limitations of the study, such as small sample size, are discussed. PMID:24146975

Comparing and validating models of driver steering behaviour in collision avoidance and vehicle stabilisation

NASA Astrophysics Data System (ADS)

Markkula, G.; Benderius, O.; Wahde, M.

2014-12-01

A number of driver models were fitted to a large data set of human truck driving, from a simulated near-crash, low-friction scenario, yielding two main insights: steering to avoid a collision was best described as an open-loop manoeuvre of predetermined duration, but with situation-adapted amplitude, and subsequent vehicle stabilisation could to a large extent be accounted for by a simple yaw rate nulling control law. These two phenomena, which could be hypothesised to generalise to passenger car driving, were found to determine the ability of four driver models adopted from the literature to fit the human data. Based on the obtained results, it is argued that the concept of internal vehicle models may be less valuable when modelling driver behaviour in non-routine situations such as near-crashes, where behaviour may be better described as direct responses to salient perceptual cues. Some methodological issues in comparing and validating driver models are also discussed.

A parametric study of golf car and personal transport vehicle braking stability and their deficiencies.

PubMed

Seluga, Kristopher J; Baker, Lowell L; Ojalvo, Irving U

2009-07-01

This paper describes research and parametric analyses of braking effectiveness and directional stability for golf cars, personal transport vehicles (PTVs) and low speed vehicles (LSVs). It is shown that current designs, which employ brakes on only the rear wheels, can lead to rollovers if the brakes are applied while traveling downhill. After summarizing the current state of existing safety standards and brake system designs, both of which appear deficient from a safety perspective, a previously developed dynamic simulation model is used to identify which parameters have the greatest influence on the vehicles' yaw stability. The simulation results are then used to parametrically quantify which combination of these factors can lead to yaw induced rollover during hard braking. Vehicle velocity, steering input, path slope and tire friction are all identified as important parameters in determining braking stability, the effects of which on rollover propensity are presented graphically. The results further show that when vehicles are equipped with front brakes or four-wheel brakes, the probability of a yaw induced rollover is almost entirely eliminated. Furthermore, the parametric charts provided may be used as an aid in developing guidelines for golf car and PTV path design if rear brake vehicles are used.

[Steady car engine noise does not affect the cognitive abilities of sleep apnea syndrome patients].

PubMed

Mayoralas, L R; Barbé, F; Muñoz, A; Agustí, A G N

2003-09-01

Traffic accidents are more frequent for sleep apnea syndrome (SAS) patients than in the population at large. The mechanisms that underlie this observation are poorly defined. Our working hypothesis was that in SAS patients the steady noise of a car engine might alter cognitive capacities that may be involved in driving, thus increasing the risk of traffic accidents. To test this hypothesis we designed a prospective randomized controlled trial. Eighteen SAS patients (apnea-hypopnea index [SEM] 62 [6] h1) and 18 healthy controls were studied. All the participants were evaluated in random order both in basal conditions and after exposure to the steady noise of a car engine recorded on a compact disc. Their level of vigilance was evaluated (Steer-Clear) as well as their reaction time (PVT 192). Attention, coordination, and memory were measured using the following tests: Wechsler Memory Scale (digit span), the Wechsler Intelligence Scale (digit symbol), and Lezack's Trail Making tests A and B. The SAS patients were slightly younger than the control group (mean 50 [7] vs 57 [11] years, respectively; P=.05). The patients showed a lower level of vigilance than the controls both in basal and engine noise conditions (P<.05). No differences between groups were found for the other variables studied. Exposure to steady car engine noise had no effect on the tests of either group. In conclusion, the results of our study do not support the hypothesis that steady car engine noise significantly alters the cognitive ability of SAS patients.

Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium

PubMed Central

Oshida, Keiyu; Vasani, Naresh; Jones, Carlton; Moore, Tanya; Hester, Susan; Nesnow, Stephen; Auerbach, Scott; Geter, David R.; Aleksunes, Lauren M.; Thomas, Russell S.; Applegate, Dawn; Klaassen, Curtis D.; Corton, J. Christopher

2015-01-01

The nuclear receptor family member constitutive activated receptor (CAR) is activated by structurally diverse drugs and environmentally-relevant chemicals leading to transcriptional regulation of genes involved in xenobiotic metabolism and transport. Chronic activation of CAR increases liver cancer incidence in rodents, whereas suppression of CAR can lead to steatosis and insulin insensitivity. Here, analytical methods were developed to screen for chemical treatments in a gene expression compendium that lead to alteration of CAR activity. A gene expression biomarker signature of 83 CAR-dependent genes was identified using microarray profiles from the livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators (CITCO, phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher’s algorithm (p-value ≤ 10-4)) was used to evaluate the similarity between the CAR biomarker signature and a test set of 28 and 32 comparisons positive or negative, respectively, for CAR activation; the test resulted in a balanced accuracy of 97%. The biomarker signature was used to identify chemicals that activate or suppress CAR in an annotated mouse liver/primary hepatocyte gene expression database of ~1850 comparisons. CAR was activated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-type but not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type and to lesser extents in PXR-null mice, and 3) activators of PPARα in wild-type and PPARα-null mice. CAR was consistently activated by five conazole fungicides and four perfluorinated compounds. Comparison of effects in wild-type and CAR-null mice showed that the fungicide propiconazole increased liver weight and hepatocyte proliferation in a CAR-dependent manner, whereas the perfluorinated compound perfluorooctanoic acid (PFOA) increased these endpoints in a CAR-independent manner. A number of compounds suppressed CAR coincident with increases in markers of inflammation including acetaminophen, concanavalin A, lipopolysaccharide, and 300 nm silica particles. In conclusion, we have shown that a CAR biomarker signature coupled with a rank-based similarity method accurately predicts CAR activation. This analytical approach, when applied to a gene expression compendium, increased the universe of known chemicals that directly or indirectly activate CAR, highlighting the promiscuous nature of CAR activation and signaling through activation of other xenobiotic-activated receptors. PMID:25949234

A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3.

PubMed

Chen, Tao; Tompkins, Leslie M; Li, Linhao; Li, Haishan; Kim, Gregory; Zheng, Yuxin; Wang, Hongbing

2010-01-01

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pull-down assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators.

A Single Amino Acid Controls the Functional Switch of Human Constitutive Androstane Receptor (CAR) 1 to the Xenobiotic-Sensitive Splicing Variant CAR3

PubMed Central

Chen, Tao; Tompkins, Leslie M.; Li, Linhao; Li, Haishan; Kim, Gregory; Zheng, Yuxin

2010-01-01

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pull-down assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators. PMID:19820207

Development of A New Automotive Active Suspension System

NASA Astrophysics Data System (ADS)

Yousef Abdulhammed, Eng.; Eng. Hisham Elsherif, Dr, Prof.

2017-12-01

The main objective was to develop a smart new vehicle suspension system that minimizes the road irregularities impact on the driver, also to increase performance and stability of the vehicle at high speeds. The central idea is based on modifying the normal passive suspension system into a computer controller hydraulic actuated active suspension system simply by adding a new component such as a hydraulic cylinder on a normal passive system. The new suspension system is economical to be wildly used in consumer’s cars with low prices. The new added components was analytically tested and modeled according to different parameters. A new test rig was implemented to simulate a real quarter suspension system. The new suspension model was controlled by feedback controller according to the road conditions; the controller output controls the cylinder actuator to compensate the road oscillations and increases the vehicle stability for the passenger. Finally, to maximize the aerodynamics coefficients of the vehicle during high speeds by controlling the vehicle clearance level from the ground to achieve full stability, steering and fuel economy.

Transactivation potencies of Baikal seal constitutive active/androstane receptor by persistent organic pollutants and brominated flame retardants.

PubMed

Sakai, Hiroki; Kim, Eun-Young; Petrov, Evgeny A; Tanabe, Shinsuke; Iwata, Hisato

2009-08-15

To characterize ligand-dependent transcriptional activation of constitutive active/androstane receptor (CAR) in aquatic mammals, transactivation potentials of the Baikal seal (Pusa sibirica) CAR (bsCAR) by environmental pollutants, including persistent organic pollutants (POPs) and brominated flame retardants (BFRs), were investigated using an in vitro reporter gene assay, and compared with those of the mouse CAR (mCAR). Measurement of luciferase reporter gene activities demonstrated that the seal CAR was activated by POPs, including a technical mixture of PCBs (Kanechlor-500), certain individual PCB congeners, DDT compounds, and trans-nonachlor. No or slight bsCAR-dependent activity was detected in experiments with PBDE congeners and HBCDs. The interspecies comparison of lowest observed effect concentration (LOEC) for CAR transactivation byeach compound revealed that bsCAR responds more sensitively to PCBs than mCAR. In addition, bsCAR was weakly deactivated by PBDE99, whereas mCAR transcriptional activity decreased weakly by PBDE100, PBDE154, and PBDE187. Comparison of reporter gene activities by the congeners with the same IUPAC numbers among PCBs and PBDEs revealed that both bsCAR and mCAR were not activated by PBDE99 and PBDE153, but were activated by PCB99 and PCB153. The small ligand-binding pocket in CAR may contribute to difference in response between PCBs and PBDEs. Given that ethical rationale prevents dosing studies with such organohalogens in aquatic mammals, our in vitro assay system constructed with CAR cDNA from a species of interest provides a useful and realistic alternative approach in ecotoxicology.

Analysis of Motorcycle Weave Mode by using Energy Flow Method

NASA Astrophysics Data System (ADS)

Marumo, Yoshitaka; Katayama, Tsuyoshi

The activation mechanism of motorcycle weave mode is clarified within the framework of the energy flow method, which calculates energy flow of mechanical forces in each motion. It is demonstrated that only a few mechanical forces affect the stability of the weave mode from among a total of about 40 mechanical forces. The activation of the lateral, yawing and rolling motions destabilize the weave mode, while activation of the steering motion stabilizes the weave mode. A detailed investigation of the energy flow of the steering motion reveals that the steering motion plays an important role in clarifying the characteristics of the weave mode. As activation of the steering motion progresses the phase of the front tire side force, and the weave mode is consequently stabilized. This paper provides a design guide for stabilizing the weave mode and the wobble mode compatibility.

A novel estimating method for steering efficiency of the driver with electromyography signals

NASA Astrophysics Data System (ADS)

Liu, Yahui; Ji, Xuewu; Hayama, Ryouhei; Mizuno, Takahiro

2014-05-01

The existing research of steering efficiency mainly focuses on the mechanism efficiency of steering system, aiming at designing and optimizing the mechanism of steering system. In the development of assist steering system especially the evaluation of its comfort, the steering efficiency of driver physiological output usually are not considered, because this physiological output is difficult to measure or to estimate, and the objective evaluation of steering comfort therefore cannot be conducted with movement efficiency perspective. In order to take a further step to the objective evaluation of steering comfort, an estimating method for the steering efficiency of the driver was developed based on the research of the relationship between the steering force and muscle activity. First, the steering forces in the steering wheel plane and the electromyography (EMG) signals of the primary muscles were measured. These primary muscles are the muscles in shoulder and upper arm which mainly produced the steering torque, and their functions in steering maneuver were identified previously. Next, based on the multiple regressions of the steering force and EMG signals, both the effective steering force and the total force capacity of driver in steering maneuver were calculated. Finally, the steering efficiency of driver was estimated by means of the estimated effective force and the total force capacity, which represented the information of driver physiological output of the primary muscles. This research develops a novel estimating method for driver steering efficiency of driver physiological output, including the estimation of both steering force and the force capacity of primary muscles with EMG signals, and will benefit to evaluate the steering comfort with an objective perspective.

Optimal design for slip deceleration control in anti-lock braking system

NASA Astrophysics Data System (ADS)

Mishra, Sheelam; Kumar, Pankaj; Rahman, Mohd. Saifur

2018-05-01

ABS (Anti-lock Braking System) is the most advanced braking system implemented in modern cars to avoid the slipping or skidding of the vehicle on the road. Moreover, it reduces the stopping distance of the vehicle because it avoids the locking of the wheel during braking. It enables the driver to steer the vehicle during braking. But every system has its downsides and likewise ABS too, it is not efficient during normal braking or snowy conditions. Our aim is to overcome these downsides and optimize Anti-lock Braking System to make it even better.

Design of an actively controlled steerable needle with tendon actuation and FBG-based shape sensing.

PubMed

van de Berg, Nick J; Dankelman, Jenny; van den Dobbelsteen, John J

2015-06-01

This work presents a new steerable needle to facilitate active steering toward predefined target locations. It focuses on mechanical aspects and design choices in relation to the observed response in a tissue phantom. Tip steering with two rotational degrees of freedom was achieved by a tendon actuated ball joint mechanism. During insertion, the flexible cannula bends as a result of asymmetric tip-tissue interaction forces. The stylet was equipped with fiber Bragg gratings to measure the needle shape and tip position during use. A PI-controller was implemented to facilitate steering to predefined targets. During the validation study, nine targets were defined at a depth of 100 mm below the gelatin surface. One was located below the insertion point, the others at a radial offset of 30 mm in each of the eight principle steering directions. Per location, six repetitions were performed. The targeting accuracy was 6.2 ± 1.4 mm (mean ± std). The steering precision was 2.6 ± 1.1 mm. The ability to steer with this new needle steering approach is presented and the mechanical characteristics are discussed for this representative subset of steering directions. Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.

Advancements in Dual-Pump Broadband CARS for Supersonic Combustion Measurements

NASA Technical Reports Server (NTRS)

Tedder, Sarah Augusta Umberger

2010-01-01

Space- and time-resolved measurements of temperature and species mole fractions of nitrogen, oxygen, and hydrogen were obtained with a dual-pump coherent anti-Stokes Raman spectroscopy (CARS) system in hydrogen-fueled supersonic combustion free jet flows. These measurements were taken to provide time-resolved fluid properties of turbulent supersonic combustion for use in the creation and verification of computational fluid dynamic (CFD) models. CFD models of turbulent supersonic combustion flow currently facilitate the design of air-breathing supersonic combustion ramjet (scramjet) engines. Measurements were made in supersonic axi-symmetric free jets of two scales. First, the measurement system was tested in a laboratory environment using a laboratory-scale burner (approx.10 mm at nozzle exit). The flow structures of the laboratory-burner were too small to be resolved with the CARS measurements volume, but the composition and temperature of the jet allowed the performance of the system to be evaluated. Subsequently, the system was tested in a burner that was approximately 6 times larger, whose length scales are better resolved by the CARS measurement volume. During both these measurements, weaknesses of the CARS system, such as sensitivity to vibrations and beam steering and inability to measure temperature or species concentrations in hydrogen fuel injection regions were indentified. Solutions were then implemented in improved CARS systems. One of these improved systems is a dual-pump broadband CARS technique called, Width Increased Dual-pump Enhanced CARS (WIDECARS). The two lowest rotational energy levels of hydrogen detectable by WIDECARS are H2 S(3) and H2 S(4). The detection of these lines gives the system the capability to measure temperature and species concentrations in regions of the flow containing pure hydrogen fuel at room temperature. WIDECARS is also designed for measurements of all the major species (except water) in supersonic combustion flows fueled with hydrogen and hydrogen/ethylene mixtures (N2, O2, H2, C2H4, CO, and CO2). This instrument can characterize supersonic combustion fueled with surrogate fuel mixtures of hydrogen and ethylene. This information can lead to a better understanding of the chemistry and performance of supersonic combustion fueled with cracked jet propulsion (JP)-type fuel.

Phosphorylated Nuclear Receptor CAR Forms a Homodimer To Repress Its Constitutive Activity for Ligand Activation

PubMed Central

Shizu, Ryota; Osabe, Makoto; Perera, Lalith; Moore, Rick; Sueyoshi, Tatsuya

2017-01-01

ABSTRACT The nuclear receptor CAR (NR1I3) regulates hepatic drug and energy metabolism as well as cell fate. Its activation can be a critical factor in drug-induced toxicity and the development of diseases, including diabetes and tumors. CAR inactivates its constitutive activity by phosphorylation at threonine 38. Utilizing receptor for protein kinase 1 (RACK1) as the regulatory subunit, protein phosphatase 2A (PP2A) dephosphorylates threonine 38 to activate CAR. Here we demonstrate that CAR undergoes homodimer-monomer conversion to regulate this dephosphorylation. By coexpression of two differently tagged CAR proteins in Huh-7 cells, mouse primary hepatocytes, and mouse livers, coimmunoprecipitation and two-dimensional gel electrophoresis revealed that CAR can form a homodimer in a configuration in which the PP2A/RACK1 binding site is buried within its dimer interface. Epidermal growth factor (EGF) was found to stimulate CAR homodimerization, thus constraining CAR in its inactive form. The agonistic ligand CITCO binds directly to the CAR homodimer and dissociates phosphorylated CAR into its monomers, exposing the PP2A/RACK1 binding site for dephosphorylation. Phenobarbital, which is not a CAR ligand, binds the EGF receptor, reversing the EGF signal to monomerize CAR for its indirect activation. Thus, the homodimer-monomer conversion is the underlying molecular mechanism that regulates CAR activation, by placing phosphorylated threonine 38 as the common target for both direct and indirect activation of CAR. PMID:28265001

Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design

PubMed Central

Poels, Renée; Mulders, Manon J.; van de Donk, Niels W. C. J.; Themeli, Maria; Lokhorst, Henk M.; Mutis, Tuna

2018-01-01

Recent clinical advances with chimeric antigen receptor (CAR) T cells have led to the accelerated clinical approval of CD19-CARs to treat acute lymphoblastic leukemia. The CAR T cell therapy is nevertheless associated with toxicities, especially if the CARs are not entirely tumor-specific. Therefore, strategies for controlling the CAR T cell activity are required to improve their safety profile. Here, by using the multiple myeloma (MM)-associated CD38 molecule as target molecule, we tested the feasibility and utility of a doxycycline (DOX) inducible Tet-on CD38-CAR design to control the off-target toxicities of CAR T cells. Using CARs with high affinity to CD38, we demonstrate that this strategy allows the proper induction of CD38-CARs and CAR-mediated T cell cytotoxicity in a DOX-dose dependent manner. Especially when the DOX dose was limited to 10ng/ml, its removal resulted in a relatively rapid decay of CAR- related off-tumor effects within 24 hours, indicating the active controllability of undesired CAR activity. This Tet-on CAR design also allowed us to induce the maximal anti-MM cytotoxic activity of affinity-optimized CD38-CAR T cells, which already display a low toxicity profile, hereby adding a second level of safety to these cells. Collectively, these results indicate the possibility to utilize this DOX inducible CAR-design to actively regulate the CAR-mediated activities of therapeutic T cells. We therefore conclude that the Tet-on system may be more advantageous above suicide-genes to control the potential toxicities of CAR T cells without the need to destroy them permanently. PMID:29847570

Development of formula varsity race car chassis

NASA Astrophysics Data System (ADS)

Abdullah, M. A.; Mansur, M. R.; Tamaldin, N.; Thanaraj, K.

2013-12-01

Three chassis designs have been developed using commercial computer aided design (CAD) software. The design is based on the specifications of UTeM Formula VarsityTM 2012 (FV2012). The selection of the design is derived from weighted matrix which consists of reliability, cost, time consumption and weight. The score of the matrix is formulated based on relative weighted factor among the selections. All three designs are then fabricated using selected materials available. The actual cost, time consumption and weight of the chassis's are compared with the theoretical weighted scores. Standard processes of cuttings, fittings and welding are performed in chassis mock up and fabrication. The chassis is later assembled together with suspension systems, steering linkages, brake systems, engine system, and drive shaft systems. Once the chassis is assembled, the studies of driver's ergonomic and part accessibility are performed. The completion in final fittings and assembly of the race car and its reliability demonstrate an outstanding design for manufacturing (DFM) practices of the chassis.

Ventilation and Heart Rate Monitoring in Drivers using a Contactless Electrical Bioimpedance System

NASA Astrophysics Data System (ADS)

Macías, R.; García, M. A.; Ramos, J.; Bragós, R.; Fernández, M.

2013-04-01

Nowadays, the road safety is one of the most important priorities in the automotive industry. Many times, this safety is jeopardized because of driving under inappropriate states, e.g. drowsiness, drugs and/or alcohol. Therefore several systems for monitoring the behavior of subjects during driving are researched. In this paper, a device based on a contactless electrical bioimpedance system is shown. Using the four-wire technique, this system is capable of obtaining the heart rate and the ventilation of the driver through multiple textile electrodes. These textile electrodes are placed on the car seat and the steering wheel. Moreover, it is also reported several measurements done in a controlled environment, i.e. a test room where there are no artifacts due to the car vibrations or the road state. In the mentioned measurements, the system response can be observed depending on several parameters such as the placement of the electrodes or the number of clothing layers worn by the driver.

Fetal bovine serum and human constitutive androstane receptor: Evidence for activation of the SV23 splice variant by artemisinin, artemether, and arteether in a serum-free cell culture system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lau, Aik Jiang; Chang, Thomas K.H., E-mail: thomas.chang@ubc.ca

The naturally occurring SV23 splice variant of human constitutive androstane receptor (hCAR-SV23) is activated by di-(2-ethylhexyl)phthalate (DEHP), which is detected as a contaminant in fetal bovine serum (FBS). In our initial experiment, we compared the effect of dialyzed FBS, charcoal-stripped, dextran-treated FBS (CS-FBS), and regular FBS on the basal activity and ligand-activation of hCAR-SV23 in a cell-based reporter gene assay. In transfected HepG2 cells cultured in medium supplemented with 10% FBS, basal hCAR-SV23 activity varied with the type of FBS (regular > dialyzed > CS). DEHP increased hCAR-SV23 activity when 10% CS-FBS, but not regular FBS or dialyzed FBS, wasmore » used. With increasing concentrations (1–10%) of regular FBS or CS-FBS, hCAR-SV23 basal activity increased, whereas in DEHP-treated cells, hCAR-SV23 activity remained similar (regular FBS) or slightly increased (CS-FBS). Subsequent experiments identified a serum-free culture condition to detect DEHP activation of hCAR-SV23. Under this condition, artemisinin, artemether, and arteether increased hCAR-SV23 activity, whereas they decreased it in cells cultured in medium supplemented with 10% regular FBS. By comparison, FBS increased the basal activity of the wild-type isoform of hCAR (hCAR-WT), whereas it did not affect the basal activity of the SV24 splice variant (hCAR-SV24) or ligand activation of hCAR-SV24 and hCAR-WT by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The use of serum-free culture condition was suitable for detecting CITCO activation of hCAR-WT and hCAR-SV24. In conclusion, FBS leads to erroneous classification of pharmacological ligands of hCAR-SV23 in cell-based assays, but investigations on functional ligands of hCAR isoforms can be conducted in serum-free culture condition. - Highlights: • FBS leads to erroneous pharmacological classification of hCAR-SV23 ligands. • Artemisinin, artemether, and arteether activate hCAR-SV23 in the absence of FBS. • Serum-free culture condition can be used for identifying ligands of hCAR isoforms.« less

A multimodal dataset for various forms of distracted driving

PubMed Central

Taamneh, Salah; Tsiamyrtzis, Panagiotis; Dcosta, Malcolm; Buddharaju, Pradeep; Khatri, Ashik; Manser, Michael; Ferris, Thomas; Wunderlich, Robert; Pavlidis, Ioannis

2017-01-01

We describe a multimodal dataset acquired in a controlled experiment on a driving simulator. The set includes data for n=68 volunteers that drove the same highway under four different conditions: No distraction, cognitive distraction, emotional distraction, and sensorimotor distraction. The experiment closed with a special driving session, where all subjects experienced a startle stimulus in the form of unintended acceleration—half of them under a mixed distraction, and the other half in the absence of a distraction. During the experimental drives key response variables and several explanatory variables were continuously recorded. The response variables included speed, acceleration, brake force, steering, and lane position signals, while the explanatory variables included perinasal electrodermal activity (EDA), palm EDA, heart rate, breathing rate, and facial expression signals; biographical and psychometric covariates as well as eye tracking data were also obtained. This dataset enables research into driving behaviors under neatly abstracted distracting stressors, which account for many car crashes. The set can also be used in physiological channel benchmarking and multispectral face recognition. PMID:28809848

The effect of concurrent bandwidth feedback on learning the lane-keeping task in a driving simulator.

PubMed

de Groot, Stefan; de Winter, Joost C F; López García, José Manuel; Mulder, Max; Wieringa, Peter A

2011-02-01

The aim of this study was to investigate whether concurrent bandwidth feedback improves learning of the lane-keeping task in a driving simulator. Previous research suggests that bandwidth feedback improves learning and that off-target feedback is superior to on-target feedback. This study aimed to extend these findings for the lane-keeping task. Participants without a driver's license drove five 8-min lane-keeping sessions in a driver training simulator: three practice sessions, an immediate retention session, and a delayed retention session I day later. There were four experimental groups (n=15 per group): (a) on-target, receiving seat vibrations when the center of the car was within 0.5 m of the lane center; (b) off-target, receiving seat vibrations when the center of the car was more than 0.5 m away from the lane center; (c) control, receiving no vibrations; and (d) realistic, receiving seat vibrations depending on engine speed. During retention, all groups were provided with the realistic vibrations. During practice, on-target and off-target groups had better lane-keeping performance than the nonaugmented groups, but this difference diminished in the retention phase. Furthermore, during late practice and retention, the off-target group outperformed the on-target group.The off-target group had a higher rate of steering reversal and higher steering entropy than the nonaugmented groups, whereas no clear group differences were found regarding mean speed, mental workload, or self-reported measures. Off-target feedback is superior to on-target feedback for learning the lane-keeping task. This research provides knowledge to researchers and designers of training systems about the value of feedback in simulator-based training of vehicular control.

Hepatic glutamate transport and glutamine synthesis capacities are decreased in finished vs. growing beef steers, concomitant with increased GTRAP3-18 content.

PubMed

Huang, J; Jia, Y; Li, Q; Burris, W R; Bridges, P J; Matthews, J C

2018-05-01

Hepatic glutamate uptake and conversion to glutamine is critical for whole-body N metabolism, but how this process is regulated during growth is poorly described. The hepatic glutamate uptake activities, protein content of system [Formula: see text] transporters (EAAC1, GLT-1) and regulatory proteins (GTRAP3-18, ARL6IP1), glutamine synthetase (GS) activity and content, and glutathione (GSH) content, were compared in liver tissue of weaned Angus steers randomly assigned (n = 8) to predominantly lean (growing) or predominantly lipid (finished) growth regimens. Steers were fed a cotton seed hull-based diet to achieve final body weights of 301 or 576 kg, respectively, at a constant rate of growth. Liver tissue was collected at slaughter and hepatic membranes fractionated. Total (75%), Na + -dependent (90%), system [Formula: see text]-dependent (abolished) glutamate uptake activity, and EAAC1 content (36%) in canalicular membrane-enriched vesicles decreased as steers developed from growing (n = 6) to finished (n = 4) stages, whereas Na + -independent uptake did not change. In basolateral membrane-enriched vesicles, total (60%), Na + -dependent (60%), and Na + -independent (56%) activities decreased, whereas neither system [Formula: see text]-dependent uptake nor protein content changed. EAAC1 protein content in liver homogenates (n = 8) decreased in finished vs. growing steers, whereas GTRAP3-18 and ARL6IP1 content increased and GLT-1 content did not change. Concomitantly, hepatic GS activity decreased (32%) as steers fattened, whereas GS and GSH contents did not differ. We conclude that hepatic glutamate uptake and GS synthesis capacities are reduced in livers of finished versus growing beef steers, and that hepatic system [Formula: see text] transporter activity/EAAC1 content is inversely proportional to GTRAP3-18 content.

Tasco-Forage: I. Influence of a seaweed extract on antioxidant activity in tall fescue and in ruminants.

PubMed

Fike, J H; Allen, V G; Schmidt, R E; Zhang, X; Fontenot, J P; Bagley, C P; Ivy, R L; Evans, R R; Coelho, R W; Wester, D B

2001-04-01

Seaweed (Ascophyllum nodosum) is a known source of plant growth regulators, and application to turfgrasses has increased activity of the antioxidant superoxide dismutase (SOD) and specific vitamin precursors. Increased antioxidant activity in both plants and animals diminishes oxidative stress. Two pasture experiments investigated effects of Tasco-Forage (a proprietary seaweed-based product) applied to tall fescue (Festuca arundinacea) on antioxidant activity in plants and in ruminants that grazed the forage. In Exp. 1, fescue was 70 to 100% infected with the endophyte fungus Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin). Twenty-four wether lambs (initial BW 41 kg; SD = 5) grazed fescue treated with 0, 1.7, or 3.4 kg Tasco/ha applied in April and July, 1994, with four replications per treatment. Grazing occurred for 26 d beginning April 21 and for 22 d beginning July 19. In July, there was a linear increase in daily gains (P < 0.05), and serum vitamin A (P < 0.13) and whole-blood Se (P < 0.10) tended to increase in lambs grazing Tasco-treated fescue. In Exp. 2,48 Angus and Angus x Hereford steers (initial BW 245 kg; SD = 20) grazed infected or uninfected tall fescue in Virginia that was treated (3.4 kg/ ha) or untreated with Tasco in April and July, 1995. Steers that grazed infected tall fescue had lower (P < 0.02) serum vitamin A and E and tended (P < 0.07) to have lower whole-blood Se in September compared with steers that grazed uninfected tall fescue. Tasco decreased (P < 0.06) serum vitamin E but tended to increase whole-blood Se (P < 0.10) in September and serum vitamin A in July (P < 0.12). During 1996 and 1997, the experiment was repeated in Virginia with Angus steers and was replicated at Prairie, MS, where 1/4 Brahman x 3/4 Angus steers were used. Forty-eight steers were included at each location in each year (n = 192 total steers for 1996 and 1997). Steers that grazed infected tall fescue in Mississippi had lower (P < 0.05) serum vitamin E by the end of the grazing season. At both locations Tasco increased (P < 0.05) activity of superoxide dismutase in both infected and uninfected fescue. The endophyte in tall fescue seemed to decrease antioxidant activity in grazing steers, whereas Tasco seemed to increase antioxidant activity in both the forage and the grazing ruminant. Tasco may provide opportunities to reduce oxidative stress in plants and animals.

Rational Quantitative Structure-Activity Relationship (RQSAR) Screen for PXR and CAR Isoform-Specific Nuclear Receptor Ligands

PubMed Central

Dring, Ann M.; Anderson, Linnea E.; Qamar, Saima; Stoner, Matthew A.

2010-01-01

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes.

PubMed

Rondini, Elizabeth A; Duniec-Dmuchowski, Zofia; Kocarek, Thomas A

2016-04-01

Our laboratory previously reported that accumulation of nonsterol isoprenoids following treatment with the squalene synthase inhibitor, squalestatin 1 (SQ1) markedly induced cytochrome P450 (CYP)2B1 mRNA and reporter activity in primary cultured rat hepatocytes, which was dependent on activation of the constitutive androstane receptor (CAR). The objective of the current study was to evaluate whether isoprenoids likewise activate murine CAR (mCAR) or one or more isoforms of human CAR (hCAR) produced by alternative splicing (SPTV, hCAR2; APYLT, hCAR3). We found that SQ1 significantly induced Cyp2b10 mRNA (∼3.5-fold) in primary hepatocytes isolated from both CAR-wild-type and humanized CAR transgenic mice, whereas the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin had no effect. In the absence of CAR, basal Cyp2b10 mRNA levels were reduced by 28-fold and the effect of SQ1 on Cyp2b10 induction was attenuated. Cotransfection with an expression plasmid for hCAR1, but not hCAR2 or hCAR3, mediated SQ1-induced CYP2B1 and CYP2B6 reporter activation in hepatocytes isolated from CAR-knockout mice. This effect was also observed following treatment with the isoprenoid trans,trans-farnesol. The direct agonist CITCO increased interaction of hCAR1, hCAR2, and hCAR3 with steroid receptor coactivator-1. However, no significant effect on coactivator recruitment was observed with SQ1, suggesting an indirect activation mechanism. Further results from an in vitro ligand binding assay demonstrated that neither farnesol nor other isoprenoids are direct ligands for hCAR1. Collectively, our findings demonstrate that SQ1 activates CYP2B transcriptional responses through farnesol metabolism in an hCAR1-dependent manner. Further, this effect probably occurs through an indirect mechanism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Transactivation Assays that Identify Indirect and Direct Activators of Human Pregnane X Receptor (PXR, NR1I2) and Constitutive Androstane Receptor (CAR, NR1I3).

PubMed

Pinne, Marija; Ponce, Elsa; Raucy, Judy L

2017-01-01

Nuclear Receptors (NRs), including PXR and CAR, are presumed to be ligand-dependent transcription factors, but ligand binding is not an absolute requirement for activation. Indeed, many compounds activate PXR and CAR by indirect mechanisms. Detecting these indirect activators of specific nuclear receptors in vitro has been difficult. As NR activation of either or both PXR and CAR can lead to drug-drug interactions and adverse drug effects, false negatives obtained with screening tools incapable of detecting indirect activators could present liabilities. The aim of this study was to establish assays that identify indirect activators of human PXR and CAR. Commercially available human PXR and CAR transactivation assays were used for analyses. We show that transactivation assays containing full-length nuclear receptors with native promoters can identify indirect activators of human CAR and PXRwhen compared to those of commercially available assays containing only the LBD of PXR and CAR. Of these two assay systems, only human PXR and CAR1 assays with full-length receptors and native promoters are capable of detecting indirect and ligand activators. With this capability, several kinase inhibitors were identified that activate PXR and CAR by indirect mechanisms. Furthermore by using both the LBD and full-length receptors, phenobarbital and midostaurin were found to be direct and indirect activators of PXR while human CAR activation by phenobarbital occurs by indirect mechanisms only. Cell based transactivation assays employing the full-length receptors and native promoters identify both direct and indirect activators of either or both human PXR and CAR. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes

PubMed Central

Rondini, Elizabeth A.; Duniec-Dmuchowski, Zofia

2016-01-01

Our laboratory previously reported that accumulation of nonsterol isoprenoids following treatment with the squalene synthase inhibitor, squalestatin 1 (SQ1) markedly induced cytochrome P450 (CYP)2B1 mRNA and reporter activity in primary cultured rat hepatocytes, which was dependent on activation of the constitutive androstane receptor (CAR). The objective of the current study was to evaluate whether isoprenoids likewise activate murine CAR (mCAR) or one or more isoforms of human CAR (hCAR) produced by alternative splicing (SPTV, hCAR2; APYLT, hCAR3). We found that SQ1 significantly induced Cyp2b10 mRNA (∼3.5-fold) in primary hepatocytes isolated from both CAR–wild-type and humanized CAR transgenic mice, whereas the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin had no effect. In the absence of CAR, basal Cyp2b10 mRNA levels were reduced by 28-fold and the effect of SQ1 on Cyp2b10 induction was attenuated. Cotransfection with an expression plasmid for hCAR1, but not hCAR2 or hCAR3, mediated SQ1-induced CYP2B1 and CYP2B6 reporter activation in hepatocytes isolated from CAR-knockout mice. This effect was also observed following treatment with the isoprenoid trans,trans-farnesol. The direct agonist CITCO increased interaction of hCAR1, hCAR2, and hCAR3 with steroid receptor coactivator-1. However, no significant effect on coactivator recruitment was observed with SQ1, suggesting an indirect activation mechanism. Further results from an in vitro ligand binding assay demonstrated that neither farnesol nor other isoprenoids are direct ligands for hCAR1. Collectively, our findings demonstrate that SQ1 activates CYP2B transcriptional responses through farnesol metabolism in an hCAR1-dependent manner. Further, this effect probably occurs through an indirect mechanism. PMID:26798158

Sustained sensorimotor control as intermittent decisions about prediction errors: computational framework and application to ground vehicle steering.

PubMed

Markkula, Gustav; Boer, Erwin; Romano, Richard; Merat, Natasha

2018-06-01

A conceptual and computational framework is proposed for modelling of human sensorimotor control and is exemplified for the sensorimotor task of steering a car. The framework emphasises control intermittency and extends on existing models by suggesting that the nervous system implements intermittent control using a combination of (1) motor primitives, (2) prediction of sensory outcomes of motor actions, and (3) evidence accumulation of prediction errors. It is shown that approximate but useful sensory predictions in the intermittent control context can be constructed without detailed forward models, as a superposition of simple prediction primitives, resembling neurobiologically observed corollary discharges. The proposed mathematical framework allows straightforward extension to intermittent behaviour from existing one-dimensional continuous models in the linear control and ecological psychology traditions. Empirical data from a driving simulator are used in model-fitting analyses to test some of the framework's main theoretical predictions: it is shown that human steering control, in routine lane-keeping and in a demanding near-limit task, is better described as a sequence of discrete stepwise control adjustments, than as continuous control. Results on the possible roles of sensory prediction in control adjustment amplitudes, and of evidence accumulation mechanisms in control onset timing, show trends that match the theoretical predictions; these warrant further investigation. The results for the accumulation-based model align with other recent literature, in a possibly converging case against the type of threshold mechanisms that are often assumed in existing models of intermittent control.

Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state.

PubMed

Shiraki, Takuma; Sakai, Noriko; Kanaya, Eiko; Jingami, Hisato

2003-03-28

In contrast to the classical nuclear receptors, the constitutive androstane receptor (CAR) is transcriptionally active in the absence of ligand. In the course of searching for the mediator of CAR activation, we found that ligand-independent activation of CAR was achieved in cooperation with the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). PGC-1 beta, a PGC-1 alpha homologue, also activated CAR to less of an extent than PGC-1 alpha. Coexpression of the ligand-binding domain of a heterodimerization partner, retinoid X receptor alpha, enhanced the PGC-1 alpha-mediated activation of CAR, although it had a weak effect on the basal activity of CAR in the absence of PGC-1 alpha. Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1 alpha were required for full activation of CAR. Pull-down experiments using recombinant proteins revealed that CAR directly interacted with both the LXXLL motif and the RS domain. Furthermore, we demonstrated that the RS domain of PGC-1 alpha was required for CAR localization at nuclear speckles. These results indicate that PGC-1 alpha mediates the ligand-independent activation of CAR by means of subnuclear targeting through the RS domain of PGC-1 alpha.

The Environmental Estrogen, Nonylphenol, Activates the Constitutive Androstane Receptor

PubMed Central

Hernandez, Juan P.; Huang, Wendong; Chapman, Laura M.; Chua, Steven; Moore, David D.; Baldwin, William S.

2007-01-01

Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription–PCR of Cyp2b10 transcript levels. CAR-null (CAR −/−) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models. PMID:17483497

Representing and Learning Complex Object Interactions

PubMed Central

Zhou, Yilun; Konidaris, George

2017-01-01

We present a framework for representing scenarios with complex object interactions, in which a robot cannot directly interact with the object it wishes to control, but must instead do so via intermediate objects. For example, a robot learning to drive a car can only indirectly change its pose, by rotating the steering wheel. We formalize such complex interactions as chains of Markov decision processes and show how they can be learned and used for control. We describe two systems in which a robot uses learning from demonstration to achieve indirect control: playing a computer game, and using a hot water dispenser to heat a cup of water. PMID:28593181

In vitro anti-MRSA activity of carvone with gentamicin.

PubMed

Mun, Su-Hyun; Kang, Ok-Hwa; Joung, Dae-Ki; Kim, Sung-Bae; Choi, Jang-Gi; Shin, Dong-Won; Kwon, Dong-Yeul

2014-04-01

Carvone is one of the naturally occurring monoterpenes, the largest class of secondary metabolites in plants, and exists in two enantiomers, R-carvone (R-car) and S-car. The objective of this study was to investigate the antimicrobial activity of R-car and S-car with gentamicin (GET) against methicillin-resistant Staphylococcus aureus (MRSA). MRSA is a major human pathogen that causes serious problems, including hospital-acquired pneumonia, abscesses and surgical wound infections. Nosocomial MRSA infections often exhibit multidrug resistance. In the present study, antimicrobial susceptibility testing was performed with R-car, S-car and GET using the broth microdilution method. Minimal inhibitory concentration values for R- and S-car against six different strains of S. aureus ranged between 500 and 1,000 μg/ml. Anti-MRSA activity was evaluated using the checkerboard and time-kill assays to investigate the potential synergistic effects of different combinations of the carvone enantiomers and GET. R-car plus S-car, R-car plus GET and S-car plus GET exhibited significant synergistic activity against MRSA. These findings suggest that the single-agent anti-MRSA activities of R-car, S-car and GET are effectively increased through combination therapy. This study showed that carvone may be a potential adjuvant antimicrobial agent.

In vitro anti-MRSA activity of carvone with gentamicin

PubMed Central

MUN, SU-HYUN; KANG, OK-HWA; JOUNG, DAE-KI; KIM, SUNG-BAE; CHOI, JANG-GI; SHIN, DONG-WON; KWON, DONG-YEUL

2014-01-01

Carvone is one of the naturally occurring monoterpenes, the largest class of secondary metabolites in plants, and exists in two enantiomers, R-carvone (R-car) and S-car. The objective of this study was to investigate the antimicrobial activity of R-car and S-car with gentamicin (GET) against methicillin-resistant Staphylococcus aureus (MRSA). MRSA is a major human pathogen that causes serious problems, including hospital-acquired pneumonia, abscesses and surgical wound infections. Nosocomial MRSA infections often exhibit multidrug resistance. In the present study, antimicrobial susceptibility testing was performed with R-car, S-car and GET using the broth microdilution method. Minimal inhibitory concentration values for R- and S-car against six different strains of S. aureus ranged between 500 and 1,000 μg/ml. Anti-MRSA activity was evaluated using the checkerboard and time-kill assays to investigate the potential synergistic effects of different combinations of the carvone enantiomers and GET. R-car plus S-car, R-car plus GET and S-car plus GET exhibited significant synergistic activity against MRSA. These findings suggest that the single-agent anti-MRSA activities of R-car, S-car and GET are effectively increased through combination therapy. This study showed that carvone may be a potential adjuvant antimicrobial agent. PMID:24669246

A Global Genomic Screening Strategy Reveals Diverse Activators of Constitutive Activated Receptor (CAR)

EPA Science Inventory

A comprehensive survey of conditions that activate CAR in the mouse liver has not been carried out but would be useful in understanding their impact on CAR-dependent liver tumor induction. A gene signature dependent on CAR activation was identified by comparing the transcript pr...

Strength Training to Enhance Early Recovery after Hematopoietic Stem Cell Transplantation.

PubMed

Hacker, Eileen Danaher; Collins, Eileen; Park, Chang; Peters, Tara; Patel, Pritesh; Rondelli, Damiano

2017-04-01

Intensive cancer treatment followed by hematopoietic stem cell transplantation (HCT) results in moderate to severe fatigue and physical inactivity, leading to diminished functional ability. The purpose of this study was to determine the efficacy of an exercise intervention, strength training to enhance early recovery (STEER), on physical activity, fatigue, muscle strength, functional ability, and quality of life after HCT. This single-blind, randomized clinical trial compared strength training (n = 33) to usual care plus attention control with health education (UC + AC with HE) (n = 34). Subjects were stratified by type of transplantation and age. STEER consisted of a comprehensive program of progressive resistance introduced during hospitalization and continued for 6 weeks after hospital discharge. Fatigue, physical activity, muscle strength, functional ability, and quality of life were assessed before HCT hospital admission and after intervention completion. Data were analyzed using split-plot analysis of variance. Significant time × group interactions effects were noted for fatigue (P = .04). The STEER group reported improvement in fatigue from baseline to after intervention whereas the UC + AC with HE group reported worsened fatigue from baseline to after intervention. Time (P < .001) and group effects (P = .05) were observed for physical activity. Physical activity declined from baseline to 6 weeks after hospitalization. The STEER group was more physically active. Functional ability tests (timed stair climb and timed up and go) resulted in a significant interaction effect (P = .03 and P = .05, respectively). Subjects in the UC + AC with HE group were significantly slower on both tests baseline to after intervention, whereas the STEER group's time remained stable. The STEER group completed both tests faster than the UC + AC with HE group after intervention. Study findings support the use of STEER after intensive cancer treatment and HCT. Strength training demonstrated positive effects on fatigue, physical activity, muscle strength, and functional ability. The exact recovery patterns between groups and over time varied; the STEER group either improved or maintained their status from baseline to after intervention (6 weeks after hospital discharge) whereas the health education group generally declined over time or did not change. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lynch, Caitlin; Pan, Yongmei; Li, Linhao

Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluatedmore » in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role of hCAR in hepatic energy metabolism was examined. • hCAR activators repress gluconeogenesis but not lipogenesis and fatty acid synthesis. • Human and mouse CAR exhibit differential effects on energy metabolism.« less

Reliability of Heart Rate Variability Analysis by Using Electrocardiogram Recorded Unrestrainedly from an Automobile Steering-Wheel

NASA Astrophysics Data System (ADS)

Osaka, Motohisa; Murata, Hiroshige; Tateoka, Katsuhiko; Katoh, Takao

2007-07-01

Some cases of traffic accidents are assumed to be due to the occurrences of cardiac events during driving, which are thought to be induced by imbalance of autonomic nervous activities. These can be measured by analyzing heart rate variability. Therefore, we developed a new system of steering-wheel electrocardiogram with a soft-ware to remove noises. We compared the trends of sympathetic and parasympathetic nerve activities measured from the steering-wheel electrocardiograms with those recorded simultaneously from chest leads. For each parameter of instantaneous heart rate, low- or high-frequency component of heart rate variability in all the cases, the trend from the steering-wheel electrocardiogram resembled that from the chest-lead electrocardiogram. In 3 of 7 subjects, the trend of LF/HF showed a strong relationship between the steering-wheel electrocardiogram and the chest-lead electrocardiogram. Our system will open doors to a new strategy to keep a driver out of a risk by notifying it while driving.

Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes.

PubMed

Abe, Taiki; Amaike, Yuto; Shizu, Ryota; Takahashi, Miki; Kano, Makoto; Hosaka, Takuomi; Sasaki, Takamitsu; Kodama, Susumu; Matsuzawa, Atsushi; Yoshinari, Kouichi

2018-06-08

Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEAD. In mouse livers, TCPOBOP (a mouse CAR activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared to mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mouse CAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.

Displacement and force coupling control design for automotive active front steering system

NASA Astrophysics Data System (ADS)

Zhao, Wanzhong; Zhang, Han; Li, Yijun

2018-06-01

A displacement and force coupling control design for active front steering (AFS) system of vehicle is proposed in this paper. In order to investigate the displacement and force characteristics of the AFS system of the vehicle, the models of AFS system, vehicle, tire as well as the driver model are introduced. Then, considering the nonlinear characteristics of the tire force and external disturbance, a robust yaw rate control method is designed by applying a steering motor to generate an active steering angle to adjust the yaw stability of the vehicle. Based on mixed H2/H∞ control, the system robustness and yaw rate tracking performance are enforced by H∞ norm constraint and the control effort is captured through H2 norm. In addition, based on the AFS system, a planetary gear set and an assist motor are both added to realize the road feeling control in this paper to dismiss the influence of extra steering angle through a compensating method. Evaluation of the overall system is accomplished by simulations and experiments under various driving condition. The simulation and experiment results show the proposed control system has excellent tracking performance and road feeling performance, which can improve the cornering stability and maneuverability of vehicle.

Laser Beam Steering/shaping for Free Space Optical Communication

NASA Technical Reports Server (NTRS)

Wang, Xinghua; Wang, Bin; Bos, Philip J.; Anderson, James E.; Pouch, John; Miranda, Felix; McManamon, Paul F.

2004-01-01

The 2-D Optical Phased Array (OPA) antenna based on a Liquid Crystal On Silicon (LCoS) device can be considered for use in free space optical communication as an active beam controlling device. Several examples of the functionality of the device include: beam steering in the horizontal and elevation direction; high resolution wavefront compensation in a large telescope; and beam shaping with the computer generated kinoform. Various issues related to the diffraction efficiency, steering range, steering accuracy as well as the magnitude of wavefront compensation are discussed.

Mapping automotive like controls to a general aviation aircraft

NASA Astrophysics Data System (ADS)

Carvalho, Christopher G.

The purpose of this thesis was to develop fly-by-wire control laws enabling a general aviation aircraft to be flown with automotive controls, i.e. a steering wheel and gas/brake pedals. There was a six speed shifter used to change the flight mode of the aircraft. This essentially allows the pilot to have control over different aspects of the flight profile such as climb/descend or cruise. A highway in the sky was used to aid in the navigation since it is not intuitive to people without flight experience how to navigate from the sky or when to climb and descend. Many believe that general aviation could become as widespread as the automobile. Every person could have a personal aircraft at their disposal and it would be as easy to operate as driving an automobile. The goal of this thesis is to fuse the ease of drivability of a car with flight of a small general aviation aircraft. A standard automotive control hardware setup coupled with variably autonomous control laws will allow new pilots to fly a plane as easily as driving a car. The idea is that new pilots will require very little training to become proficient with these controls. Pilots with little time to stay current can maintain their skills simply by driving a car which is typically a daily activity. A human factors study was conducted to determine the feasibility of the applied control techniques. Pilot performance metrics were developed to compare candidates with no aviation background and experienced pilots. After analyzing the relative performance between pilots and non-pilots, it has been determined that the control system is robust and easy to learn. Candidates with no aviation experience whatsoever can learn to fly an aircraft as safely and efficiently as someone with hundreds of hours of flight experience using these controls.

Relationships among Ergot Alkaloids, Cytochrome P450 Activity, and Beef Steer Growth

NASA Astrophysics Data System (ADS)

Rosenkrans, Charles; Ezell, Nicholas

2015-03-01

Determining a grazing animal’s susceptibility to ergot alkaloids has been a research topic for decades. Our objective was to determine if the Promega™ P450-Glo assay could be used to indirectly detect ergot alkaloids or their metabolites in urine of steers. The first experiment validated the effects of ergot alkaloids [0, 20, and 40 μM of ergotamine (ET), dihydroergotamine (DHET), and ergonovine (EN)] on human CYP3A4 using the P450-Glo assay (Promega™ V9800). With this assay, luminescence is directly proportional to CYP450 activity. Relative inhibition of in vitro cytochrome P450 activity was affected (P < 0.001) by an interaction between alkaloids and concentration. That interaction resulted in no concentration effect of EN, but within ET and DHET 20 and 40 µM concentrations inhibited CYP450 activity when compared with controls. In experiment 2, urine was collected from Angus-sired crossbred steers (n = 39; 216 ± 2.6 d of age; 203 ± 1.7 kg) after grazing tall fescue pastures for 105 d. Non-diluted urine was added to the Promega™ P450-Glo assay, and observed inhibition (3.7 % ± 2.7 of control). Urine content of total ergot alkaloids (331.1 ng/mg of creatinine ± 325.7) was determined using enzyme linked immunosorbent assay. Urine inhibition of CYP450 activity and total alkaloids were correlated (r = -0.31; P < 0.05). Steers were genotyped at CYP450 single nucleotide polymorphism, C994G. Steer genotype affected (P < 0.03) inhibition of CYP450 activity by urine; heterozygous steers had the least amount of CYP450 inhibition suggesting that genotyping cattle may be a method of identifying animals that are susceptible to ergot alkaloids. Although, additional research is needed, we demonstrate that the Promega™ P450-Glo assay is sensitive to ergot alkaloids and urine from steers grazing tall fescue. With some refinement the P450-Glo assay has potential as a tool for screening cattle for their exposure to fescue toxins.

Steering Dynamics of Tilting Narrow Track Vehicle with Passive Front Wheel Design

NASA Astrophysics Data System (ADS)

TAN, Jeffrey Too Chuan; ARAKAWA, Hiroki; SUDA, Yoshihiro

2016-09-01

In recent years, narrow track vehicle has been emerged as a potential candidate for the next generation of urban transportation system, which is greener and space effective. Vehicle body tilting has been a symbolic characteristic of such vehicle, with the purpose to maintain its stability with the narrow track body. However, the coordination between active steering and vehicle tilting requires considerable driving skill in order to achieve effective stability. In this work, we propose an alternative steering method with a passive front wheel that mechanically follows the vehicle body tilting. The objective of this paper is to investigate the steering dynamics of the vehicle under various design parameters of the passive front wheel. Modeling of a three-wheel tilting narrow track vehicle and multibody dynamics simulations were conducted to study the effects of two important front wheel design parameters, i.e. caster angle and trail toward the vehicle steering dynamics in steering response time, turning radius, steering stability and resiliency towards external disturbance. From the results of the simulation studies, we have verified the relationships of these two front wheel design parameters toward the vehicle steering dynamics.

CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

PubMed Central

Cherian, Milu T; Lin, Wenwei; Wu, Jing

2015-01-01

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function. PMID:25762023

Commuting by car: weight gain among physically active adults.

PubMed

Sugiyama, Takemi; Ding, Ding; Owen, Neville

2013-02-01

Prolonged sitting, including time spent sitting in cars, is detrimentally associated with health outcomes. This study examined whether commuting by car was associated with adults' weight gain over 4 years. Among 822 adult residents of Adelaide, Australia, weight change was ascertained from self-reported weight at baseline (2003-2004) and at follow-up (2007-2008). Using time spent for car commuting and work status at baseline, participants were categorized as non-car commuters, occasional car commuters, and daily car commuters. Multilevel linear regression (conducted in 2012) examined associations of weight change with car-commuting category, adjusting for potential confounding variables, for the whole sample, and among those who were physically inactive or active (≥150 minutes/week) in their leisure time. For the overall sample, adjusted mean weight gain (95% CI) over 4 years was 1.26 (0.64, 1.89) kg for non-car commuters; 1.53 (0.69, 2.37) kg for occasional car commuters; and 2.18 (1.44, 2.92) kg for daily car commuters (p for trend=0.090). Stratified analyses found a stronger association for those with sufficient leisure-time physical activity. For non-car commuters with sufficient leisure-time physical activity, the adjusted mean weight gain was 0.46 (-0.43, 1.35) kg, which was not significantly greater than 0. Over 4 years, those who used cars daily for commuting tended to gain more weight than those who did not commute by car. This relationship was pronounced among those who were physically active during leisure time. Reducing sedentary time may prevent weight gain among physically active adults. Copyright © 2013 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Fuzzy Logic Based Autonomous Parallel Parking System with Kalman Filtering

NASA Astrophysics Data System (ADS)

Panomruttanarug, Benjamas; Higuchi, Kohji

This paper presents an emulation of fuzzy logic control schemes for an autonomous parallel parking system in a backward maneuver. There are four infrared sensors sending the distance data to a microcontroller for generating an obstacle-free parking path. Two of them mounted on the front and rear wheels on the parking side are used as the inputs to the fuzzy rules to calculate a proper steering angle while backing. The other two attached to the front and rear ends serve for avoiding collision with other cars along the parking space. At the end of parking processes, the vehicle will be in line with other parked cars and positioned in the middle of the free space. Fuzzy rules are designed based upon a wall following process. Performance of the infrared sensors is improved using Kalman filtering. The design method needs extra information from ultrasonic sensors. Starting from modeling the ultrasonic sensor in 1-D state space forms, one makes use of the infrared sensor as a measurement to update the predicted values. Experimental results demonstrate the effectiveness of sensor improvement.

Feasible Path Generation Using Bezier Curves for Car-Like Vehicle

NASA Astrophysics Data System (ADS)

Latip, Nor Badariyah Abdul; Omar, Rosli

2017-08-01

When planning a collision-free path for an autonomous vehicle, the main criteria that have to be considered are the shortest distance, lower computation time and completeness, i.e. a path can be found if one exists. Besides that, a feasible path for the autonomous vehicle is also crucial to guarantee that the vehicle can reach the target destination considering its kinematic constraints such as non-holonomic and minimum turning radius. In order to address these constraints, Bezier curves is applied. In this paper, Bezier curves are modeled and simulated using Matlab software and the feasibility of the resulting path is analyzed. Bezier curve is derived from a piece-wise linear pre-planned path. It is found that the Bezier curves has the capability of making the planned path feasible and could be embedded in a path planning algorithm for an autonomous vehicle with kinematic constraints. It is concluded that the length of segments of the pre-planned path have to be greater than a nominal value, derived from the vehicle wheelbase, maximum steering angle and maximum speed to ensure the path for the autonomous car is feasible.

CCCT - NCTN Steering Committees - Clinical Imaging

Cancer.gov

The Clinical Imaging Steering Committee serves as a forum for the extramural imaging and oncology communities to provide strategic input to the NCI regarding its significant investment in imaging activities in clinical trials.

Different enzymatic antioxidative pathways operate within the sheep caruncular and intercaruncular endometrium throughout the estrous cycle and early pregnancy.

PubMed

Al-Gubory, K H; Faure, P; Garrel, C

2017-09-01

There has been a growing interest in the role played by antioxidant enzymes in the regulation of endometrial function in mammals. However, little is known about enzymatic antioxidative pathways involved in conditioning the cyclic and early pregnant endometrium for conceptus attachment and implantation in domestic ruminants. We aimed to investigate changes in activities of superoxide dismutase 1 and 2 (SOD1, SOD2), glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT) in sheep caruncles (CAR) and intercaruncles (ICAR) endometrial tissues of cyclic and early pregnant ewes. Irrespective of day of cycle or pregnancy, CAR demonstrated higher activities of SOD1 and SOD2 than in ICAR. On day 12 of the estrous cycle, ICAR demonstrated higher activity of GPX and GR than in CAR tissues. On days 12 and 16 the estrous cycle, ICAR demonstrated higher activity of CAT than in CAR. CAR demonstrated higher activity of GPX on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. CAR demonstrated higher activity of CAT on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. ICAR demonstrated higher activity of CAT on day 18 than on days 4, 8, and 16 of the estrous cycle. The activity of CAT in ICAR increased from days 4 and 8 to day 12 of the estrous cycle. The activity of SOD2 in CAR increased from day 16 to day 18 of pregnancy. On day 12 of pregnancy, CAR demonstrated higher activity of GPX than in ICAR. On day 16 of pregnancy, ICAR demonstrated higher activity of GPX than in CAR. The activity of GPX in ICAR increased from day 12 to day 16 of pregnancy. The activity of GPX in CAR increased from day 16 to day 18 of pregnancy. The activity of GR in CAR and ICAR increased from days 12 and 16 to day 18 of pregnancy. On days 16 and 18 of pregnancy, ICAR demonstrated higher activity of CAT than in CAR. The activity of CAT in CAR decreased from day 12 to days 16 and 18 of pregnancy. The activity of CAT in ICAR decreased from day 12 to day 16 of pregnancy and then increased from day 16 to day 18 of pregnancy. In conclusion, different antioxidant mechanisms operate within CAR and ICAR endometrium throughout the estrous cycle and during early pregnancy. This might be related to the different but important roles of CAR and ICAR endometrial tissues for the establishment of pregnancy. Copyright © 2017. Published by Elsevier Inc.

Aortic ruptures in seat belt wearers.

PubMed

Arajärvi, E; Santavirta, S; Tolonen, J

1989-09-01

Several investigations have indicated that rupture of the thoracic aorta is one of the leading causes of immediate death in victims of road traffic accidents. In Finland in 1983, 92% of front-seat passengers were seat belt wearers on highways and 82% in build-up areas. The mechanisms of rupture of the aorta have been intensively investigated, but the relationship between seat belt wearing and injury mechanisms leading to aortic rupture is still largely unknown. This study comprises 4169 fatally injured victims investigated by the Boards of Traffic Accident Investigation of Insurance Companies during the period 1972 to 1985. Chest injuries were recorded as the main cause of death in 1121 (26.9%) victims, 207 (5.0%) of those victims having worn a seat belt. Aortic ruptures were found at autopsy in 98 victims and the exact information of the location of the aortic tears was available in 68. For a control group, we analyzed 72 randomly chosen unbelted victims who had a fatal aortic rupture in similar accidents. The location of the aortic rupture in unbelted victims was more often in the ascending aorta, especially in drivers, whereas in seat belt wearers the distal descending aorta was statistically more often ruptured, especially in right-front passengers (p less than 0.05). The steering wheel predominated statistically as the part of the car estimated to have caused the injury in unbelted victims (37/72), and some interior part of the car was the most common cause of fatal thoracic impacts in seat belt wearers (48/68) (p less than 0.001). The mechanism of rupture of the aorta in the classic site just distal to the subclavian artery seems to be rapid deceleration, although complex body movements are also responsible in side impact collisions. The main mechanism leading to rupture of the ascending aorta seems to be severe blow to the bony thorax. This also often causes associated thoracic injuries, such as heart rupture and sternal fracture. Injuries in the ascending aorta were mostly found in unbelted victims and were sustained in frontal impact collisions, the injury-causing part of the car being the steering wheel. Ruptures of the distal descending part of the aorta were frequently associated with fractures of the thoracic vertebra.

Effects of isobutyrate supplementation on ruminal microflora, rumen enzyme activities and methane emissions in Simmental steers.

PubMed

Wang, C; Liu, Q; Zhang, Y L; Pei, C X; Zhang, S L; Wang, Y X; Yang, W Z; Bai, Y S; Shi, Z G; Liu, X N

2015-02-01

The objective of this study was to evaluate the effects of isobutyrate supplementation on rumen microflora, enzyme activities and methane emissions in Simmental steers consuming a corn stover-based diet. Eight ruminally cannulated Simmental steers were used in a replicated 4 × 4 Latin square experiment. The treatments were control (without isobutyrate), low isobutyrate (LIB), moderate isobutyrate (MIB) and high isobutyrate (HIB) with 8.4, 16.8 and 25.2 g isobutyrate per steer per day respectively. Isobutyrate was hand-mixed into the concentrate portion. Diet consisted of 60% corn stover and 40% concentrate [dry matter (DM) basis]. Dry matter intake (averaged 9 kg/day) was restricted to a maximum of 90% of ad libitum intake. Population of total bacteria, cellulolytic bacteria and anaerobic fungi were linearly increased, whereas that of protozoa and total methanogens was linearly reduced with increasing isobutyrate supplementation. Real-time PCR quantification of population of Ruminococcus albus, Ruminococcus flavefaciens, Butyrivibrio fibrisolvens and Fibrobacter succinogenes was linearly increased with increasing isobutyrate supplementation. Activities of carboxymethyl cellulase, xylanase and β-glucosidase were linearly increased, whereas that of protease was linearly reduced. Methane production was linearly decreased with increasing isobutyrate supplementation. Effective degradabilities of cellulose and hemicellulose of corn stover were linearly increased, whereas that of crude protein in diet was linearly decreased with increasing isobutyrate supplementation. The present results indicate that isobutyrate supplemented improved microflora, rumen enzyme activities and methane emissions in steers. It was suggested that the isobutyrate stimulated the digestive micro-organisms or enzymes in a dose-dependent manner. In the experimental conditions of this trial, the optimum isobutyrate dose was approximately 16.8 g isobutyrate per steer per day. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

Robust gaze-steering of an active vision system against errors in the estimated parameters

NASA Astrophysics Data System (ADS)

Han, Youngmo

2015-01-01

Gaze-steering is often used to broaden the viewing range of an active vision system. Gaze-steering procedures are usually based on estimated parameters such as image position, image velocity, depth and camera calibration parameters. However, there may be uncertainties in these estimated parameters because of measurement noise and estimation errors. In this case, robust gaze-steering cannot be guaranteed. To compensate for such problems, this paper proposes a gaze-steering method based on a linear matrix inequality (LMI). In this method, we first propose a proportional derivative (PD) control scheme on the unit sphere that does not use depth parameters. This proposed PD control scheme can avoid uncertainties in the estimated depth and camera calibration parameters, as well as inconveniences in their estimation process, including the use of auxiliary feature points and highly non-linear computation. Furthermore, the control gain of the proposed PD control scheme on the unit sphere is designed using LMI such that the designed control is robust in the presence of uncertainties in the other estimated parameters, such as image position and velocity. Simulation results demonstrate that the proposed method provides a better compensation for uncertainties in the estimated parameters than the contemporary linear method and steers the gaze of the camera more steadily over time than the contemporary non-linear method.

Highly integrated optical phased arrays: photonic integrated circuits for optical beam shaping and beam steering

NASA Astrophysics Data System (ADS)

Heck, Martijn J. R.

2017-01-01

Technologies for efficient generation and fast scanning of narrow free-space laser beams find major applications in three-dimensional (3D) imaging and mapping, like Lidar for remote sensing and navigation, and secure free-space optical communications. The ultimate goal for such a system is to reduce its size, weight, and power consumption, so that it can be mounted on, e.g. drones and autonomous cars. Moreover, beam scanning should ideally be done at video frame rates, something that is beyond the capabilities of current opto-mechanical systems. Photonic integrated circuit (PIC) technology holds the promise of achieving low-cost, compact, robust and energy-efficient complex optical systems. PICs integrate, for example, lasers, modulators, detectors, and filters on a single piece of semiconductor, typically silicon or indium phosphide, much like electronic integrated circuits. This technology is maturing fast, driven by high-bandwidth communications applications, and mature fabrication facilities. State-of-the-art commercial PICs integrate hundreds of elements, and the integration of thousands of elements has been shown in the laboratory. Over the last few years, there has been a considerable research effort to integrate beam steering systems on a PIC, and various beam steering demonstrators based on optical phased arrays have been realized. Arrays of up to thousands of coherent emitters, including their phase and amplitude control, have been integrated, and various applications have been explored. In this review paper, I will present an overview of the state of the art of this technology and its opportunities, illustrated by recent breakthroughs.

Activation of the Constitutive Androstane Receptor Inhibits Gluconeogenesis without Affecting Lipogenesis or Fatty Acid Synthesis in Human Hepatocytes

PubMed Central

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Heyward, Scott; Moeller, Timothy; Swaan, Peter W.; Wang, Hongbing

2014-01-01

Objective Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods Ligand-based structure-activity models were used for virtual screening of the Specs database (www.specs.net) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. PMID:24878338

Optimal control of Formula One car energy recovery systems

NASA Astrophysics Data System (ADS)

Limebeer, D. J. N.; Perantoni, G.; Rao, A. V.

2014-10-01

The utility of orthogonal collocation methods in the solution of optimal control problems relating to Formula One racing is demonstrated. These methods can be used to optimise driver controls such as the steering, braking and throttle usage, and to optimise vehicle parameters such as the aerodynamic down force and mass distributions. Of particular interest is the optimal usage of energy recovery systems (ERSs). Contemporary kinetic energy recovery systems are studied and compared with future hybrid kinetic and thermal/heat ERSs known as ERS-K and ERS-H, respectively. It is demonstrated that these systems, when properly controlled, can produce contemporary lap time using approximately two-thirds of the fuel required by earlier generation (2013 and prior) vehicles.

Constitutive androstane receptor activation evokes the expression of glycolytic genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yarushkin, Andrei A.; Kazantseva, Yuliya A.; Prokopyeva, Elena A.

It is well-known that constitutive androstane receptor (CAR) activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases the liver-to-body weight ratio. CAR-mediated liver growth is correlated with increased expression of the pleiotropic transcription factor cMyc, which stimulates cell cycle regulatory genes and drives proliferating cells into S phase. Because glycolysis supports cell proliferation and cMyc is essential for the activation of glycolytic genes, we hypothesized that CAR-mediated up-regulation of cMyc in mouse livers might play a role in inducing the expression of glycolytic genes. The aim of the present study was to examine the effect of long-term CAR activation on glycolytic genes in amore » mouse model not subjected to metabolic stress. We demonstrated that long-term CAR activation by TCPOBOP increases expression of cMyc, which was correlated with reduced expression of gluconeogenic genes and up-regulation of glucose transporter, glycolytic and mitochondrial pyruvate metabolising genes. These changes in gene expression after TCPOBOP treatment were strongly correlated with changes in levels of glycolytic intermediates in mouse livers. Moreover, we demonstrated a significant positive regulatory effect of TCPOBOP-activated CAR on both mRNA and protein levels of Pkm2, a master regulator of glucose metabolism and cell proliferation. Thus, our findings provide evidence to support the conclusion that CAR activation initiates a transcriptional program that facilitates the coordinated metabolic activities required for cell proliferation. - Highlights: • CAR-mediated liver growth is correlated with increased expression of cMyc. • CAR activation increased the expression of glycolytic genes in mouse livers. • CAR activation increased the level of Pkm2 in mouse livers.« less

Masked Chimeric Antigen Receptor for Tumor-Specific Activation.

PubMed

Han, Xiaolu; Bryson, Paul D; Zhao, Yifan; Cinay, Gunce E; Li, Si; Guo, Yunfei; Siriwon, Natnaree; Wang, Pin

2017-01-04

Adoptive cellular therapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a powerful form of cancer immunotherapy. CAR-T cells can be redirected to specifically recognize tumor-associated antigens (TAAs) and induce high levels of antitumor activity. However, they may also display "on-target off-tumor" toxicities, resulting from low-level expression of TAAs in healthy tissues. These adverse effects have raised considerable safety concerns and limited the clinical application of this otherwise promising therapeutic modality. To minimize such side effects, we have designed an epidermal growth factor receptor (EGFR)-specific masked CAR (mCAR), which consists of a masking peptide that blocks the antigen-binding site and a protease-sensitive linker. Proteases commonly active in the tumor microenvironment can cleave the linker and disengage the masking peptide, thereby enabling CAR-T cells to recognize target antigens only at the tumor site. In vitro mCAR showed dramatically reduced antigen binding and antigen-specific activation in the absence of proteases, but normal levels of binding and activity upon treatment with certain proteases. Masked CAR-T cells also showed antitumor efficacy in vivo comparable to that of unmasked CAR. Our study demonstrates the feasibility of improving the safety profile of conventional CARs and may also inspire future design of CAR molecules targeting broadly expressed TAAs. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Dual-Pump CARS Development and Application to Supersonic Combustion

NASA Astrophysics Data System (ADS)

Magnotti, Gaetano

Successful design of hypersonic air-breathing engines requires new computational fluid dynamics (CFD) models for turbulence and turbulence-chemistry interaction in supersonic combustion. Unfortunately, not enough data are available to the modelers to develop and validate their codes, due to difficulties in taking measurements in such a harsh environment. Dual-pump coherent anti-Stokes Raman spectroscopy (CARS) is a non-intrusive, non-linear, laser-based technique that provides temporally and spatially resolved measurements of temperature and absolute mole fractions of N2, O2 and H2 in H2-air flames. A dual-pump CARS instrument has been developed to obtain measurements in supersonic combustion and generate databases for the CFD community. Issues that compromised previous attempts, such as beam steering and high irradiance perturbation effects, have been alleviated or avoided. Improvements in instrument precision and accuracy have been achieved. An axis-symmetric supersonic combusting coaxial jet facility has been developed to provide a simple, yet suitable flow to CFD modelers. The facility provides a central jet of hot "vitiated air" simulating the hot air entering the engine of a hypersonic vehicle flying at Mach numbers between 5 and 7. Three different silicon carbide nozzles, with exit Mach number 1, 1.6 and 2, are used to provide flows with the effects of varying compressibility. H2 co-flow is available in order to generate a supersonic combusting free jet. Dual-pump CARS measurements have been obtained for varying values of flight and exit Mach numbers at several locations. Approximately one million Dual-pump CARS single shots have been collected in the supersonic jet for varying values of flight and exit Mach numbers at several locations. Data have been acquired with a H2 co-flow (combustion case) or a N 2 co-flow (mixing case). Results are presented and the effects of the compressibility and of the heat release are discussed.

Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion MetabolismS⃞

PubMed Central

Mota, Linda C.; Hernandez, Juan P.

2010-01-01

Constitutive androgen receptor (CAR) is activated by several chemicals and in turn regulates multiple detoxification genes. Our research demonstrates that parathion is one of the most potent, environmentally relevant CAR activators with an EC50 of 1.43 μM. Therefore, animal studies were conducted to determine whether CAR was activated by parathion in vivo. Surprisingly, CAR-null mice, but not wild-type (WT) mice, showed significant parathion-induced toxicity. However, parathion did not induce Cyp2b expression, suggesting that parathion is not a CAR activator in vivo, presumably because of its short half-life. CAR expression is also associated with the expression of several drug-metabolizing cytochromes P450 (P450). CAR-null mice demonstrate lower expression of Cyp2b9, Cyp2b10, Cyp2c29, and Cyp3a11 primarily, but not exclusively in males. Therefore, we incubated microsomes from untreated WT and CAR-null mice with parathion in the presence of esterase inhibitors to determine whether CAR-null mice show perturbed P450-mediated parathion metabolism compared with that in WT mice. The metabolism of parathion to paraoxon and p-nitrophenol (PNP) was reduced in CAR-null mice with male CAR-null mice showing reduced production of both paraoxon and PNP, and female CAR-null mice showing reduced production of only PNP. Overall, the data indicate that CAR-null mice metabolize parathion slower than WT mice. These results provide a potential mechanism for increased sensitivity of individuals with lower CAR activity such as newborns to parathion and potentially other chemicals due to decreased metabolic capacity. PMID:20573718

Occupant Protection during Orion Crew Exploration Vehicle Landings

NASA Technical Reports Server (NTRS)

Gernhardt, Michael L.; Jones, J. A.; Granderson, B. K.; Somers, J. T.

2009-01-01

The constellation program is evaluating current vehicle design capabilities for nominal water landings and contingency land landings of the Orion Crew Exploration vehicle. The Orion Landing Strategy tiger team was formed to lead the technical effort for which associated activities include the current vehicle design, susceptibility to roll control and tip over, reviewing methods for assessing occupant injury during ascent / aborts /landings, developing an alternate seat/attenuation design solution which improves occupant protection and operability, and testing the seat/attenuation system designs to ensure valid results. The EVA physiology, systems and Performance (EPSP) project is leading the effort under the authority of the Tiger Team Steering committee to develop, verify, validate and accredit biodynamics models using a variety of crash and injury databases including NASCAR, Indy Car and military aircraft. The validated biodynamics models will be used by the Constellation program to evaluate a variety of vehicle, seat and restraint designs in the context of multiple nominal and off-nominal landing scenarios. The models will be used in conjunction with Acceptable Injury Risk definitions to provide new occupant protection requirements for the Constellation Program.

Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor

PubMed Central

Chen, Tao; Laurenzana, Elizabeth M.; Coslo, Denise M.; Chen, Fengming; Omiecinski, Curtis J.

2014-01-01

The CAR (constitutive androstane receptor; NR1I3) is a critical xenobiotic sensor that regulates xenobiotic metabolism, drug clearance, energy and lipid homoeostasis, cell proliferation and development. Although constitutively active, in hepatocytes CAR is normally held quiescent through a tethering mechanism in the cytosol, anchored to a protein complex that includes several components, including heat-shock protein 90. Release and subsequent nuclear translocation of CAR is triggered through either direct binding to ligand activators such as CITCO {6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime} or through indirect chemical activation, such as with PB (phenobarbital). In the present study, we demonstrate that proteasomal inhibition markedly disrupts CAR function, repressing CAR nuclear trafficking, disrupting CAR’s interaction with nuclear co-activators and inhibiting induction of CAR target gene responses in human primary hepatocytes following treatment with either PB or CITCO. Paradoxically, these effects occur following accumulation of ubiquitinated hCAR (human CAR). Furthermore, a non-proteolytic function was indicated by its interaction with a SUG1 (suppressor for Gal1), a subunit of the 26S proteasome. Taken together, these data demonstrate that the proteasome complex functions at multiple levels to regulate the functional biology of hCAR activity. PMID:24224465

Multi-Objective Sliding Mode Control on Vehicle Cornering Stability with Variable Gear Ratio Actuator-Based Active Front Steering Systems.

PubMed

Ma, Xinbo; Wong, Pak Kin; Zhao, Jing; Xie, Zhengchao

2016-12-28

Active front steering (AFS) is an emerging technology to improve the vehicle cornering stability by introducing an additional small steering angle to the driver's input. This paper proposes an AFS system with a variable gear ratio steering (VGRS) actuator which is controlled by using the sliding mode control (SMC) strategy to improve the cornering stability of vehicles. In the design of an AFS system, different sensors are considered to measure the vehicle state, and the mechanism of the AFS system is also modelled in detail. Moreover, in order to improve the cornering stability of vehicles, two dependent objectives, namely sideslip angle and yaw rate, are considered together in the design of SMC strategy. By evaluating the cornering performance, Sine with Dwell and accident avoidance tests are conducted, and the simulation results indicate that the proposed SMC strategy is capable of improving the cornering stability of vehicles in practice.

Identification of Novel Activators of Constitutive Androstane Receptor from FDA-approved Drugs by Integrated Computational and Biological Approaches

PubMed Central

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Ferguson, Stephen S.; Xia, Menghang; Swaan, Peter W.; Wang, Hongbing

2012-01-01

Purpose The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest. Methods Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6. Results Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation. Conclusion These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules. PMID:23090669

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

PubMed Central

Mukherjee, Malini; Grada, Zakaria; Pignata, Antonella; Landi, Daniel; Navai, Shoba A.; Wakefield, Amanda; Bielamowicz, Kevin; Chow, Kevin K.H.; Brawley, Vita S.; Byrd, Tiara T.; Krebs, Simone; Gottschalk, Stephen; Wels, Winfried S.; Baker, Matthew L.; Dotti, Gianpietro; Mamonkin, Maksim; Brenner, Malcolm K.

2016-01-01

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape. PMID:27427982

Is improved lane keeping during cognitive load caused by increased physical arousal or gaze concentration toward the road center?

PubMed

Li, Penghui; Markkula, Gustav; Li, Yibing; Merat, Natasha

2018-08-01

Driver distraction is one of the main causes of motor-vehicle accidents. However, the impact on traffic safety of tasks that impose cognitive (non-visual) distraction remains debated. One particularly intriguing finding is that cognitive load seems to improve lane keeping performance, most often quantified as reduced standard deviation of lateral position (SDLP). The main competing hypotheses, supported by current empirical evidence, suggest that cognitive load improves lane keeping via either increased physical arousal, or higher gaze concentration toward the road center, but views are mixed regarding if, and how, these possible mediators influence lane keeping performance. Hence, a simulator study was conducted, with participants driving on a straight city road section whilst completing a cognitive task at different levels of difficulty. In line with previous studies, cognitive load led to increased physical arousal, higher gaze concentration toward the road center, and higher levels of micro-steering activity, accompanied by improved lane keeping performance. More importantly, during the high cognitive task, both physical arousal and gaze concentration changed earlier in time than micro-steering activity, which in turn changed earlier than lane keeping performance. In addition, our results did not show a significant correlation between gaze concentration and physical arousal on the level of individual task recordings. Based on these findings, various multilevel models for micro-steering activity and lane keeping performance were conducted and compared, and the results suggest that all of the mechanisms proposed by existing hypotheses could be simultaneously involved. In other words, it is suggested that cognitive load leads to: (i) an increase in arousal, causing increased micro-steering activity, which in turn improves lane keeping performance, and (ii) an increase in gaze concentration, causing lane keeping improvement through both (a) further increased micro-steering activity and (b) a tendency to steer toward the gaze target. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development of an electric, battery powered, skid-steer loader

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alcock, R.; Froehlich, D.P.; Christianson, L.L.

1985-01-01

A battery powered, skid-steer loader was developed for farm chore routines and materials handling activities. Outlined are details on drive train, hydraulics, loader, frame, cab, controls, battery and controller. Preliminary performance characteristics of the hydraulics are presented.

Influence of rice whole-crop silage diet on growth performance, carcass and meat characteristics and muscle-related gene expression in Japanese Black steers.

PubMed

Shibata, Masahiro; Hikino, Yasuko; Imanari, Mai; Matsumoto, Kazunori; Yamamoto, Naoyuki

2016-07-01

The present study investigated the influence of a diet largely comprising rice whole-crop silage (rWCS) on growth performance, carcass and meat characteristics, and expression of genes involved in muscle growth of Japanese Black steers. Steers were randomly separated into rWCS-fed (rWCS ad libitum and restricted feeding of concentrate) and concentrate-fed groups. Total digestible nutrient intake and daily gain (DG) decreased in rWCS-fed steers in comparison with concentrate-fed steers, whereas dressed carcass weight and final body weight did not significantly differ between the groups. Decreases in drip loss in the muscle of rWCS-fed steers may be caused by α-tocopherol and β-carotene in muscle. Feeding large amounts of rWCS to steers may maintain quantitative productivity of beef steers equally to a concentrate-based diet, and improve the qualitative productivity. Results of gene expression suggest that activation of skeletal muscle growth in rWCS-fed steers may occur at the late fattening period owing to a decrease in myostatin and increase in myosin heavy chain gene expression. Preadipocyte factor-1 and myostatin genes may be strongly involved in the control of lipid accumulation. This rearing system would allow beef production to switch to rWCS-based diets from concentrate-based diets. © 2015 Japanese Society of Animal Science.

Quantitative High-throughput Luciferase Screening in Identifying CAR Modulators

PubMed Central

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2017-01-01

Summary The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR. PMID:27518621

Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators.

PubMed

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2016-01-01

The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the high basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR.

Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marmugi, Alice; Lukowicz, Céline; Lasserre, Freder

The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenicmore » genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases. - Highlights: • Induction of hepatic glycolytic and lipogenic genes upon CAR activation by TCPOBOP. • These effects are not mediated by the nuclear receptor LXR. • CAR activation resulted in hepatic lipid accumulation. • Pnpla3 expression is regulated by CAR in mouse liver and human hepatocytes.« less

Evidence for triclosan-induced activation of human and rodent xenobiotic nuclear receptors.

PubMed

Paul, Katie B; Thompson, Jerry T; Simmons, Steven O; Vanden Heuvel, John P; Crofton, Kevin M

2013-10-01

The bacteriostat triclosan (2,4,4'-trichloro-2'-hydroxydiphenylether) (TCS) decreases rat serum thyroxine via putative nuclear receptor (NR) interaction(s) and subsequent transcriptional up-regulation of hepatic catabolism and clearance. However, due to the evolutionary divergence of the constitutive androstane and pregnane-X receptors (CAR, PXR), TCS-mediated downstream effects may be species-dependent. To test the hypothesis that TCS activates xenobiotic NRs across species, cell-based NR reporter assays were employed to assess potential activation of rat, mouse, and human PXR, and rat, mouse, and three splice variants of human CAR. TCS activated hPXR, acted as an inverse agonist of hCAR1, and as a weak agonist of hCAR3. TCS failed to activate rPXR in full-length receptor reporter assays, and instead acted as a modest inverse agonist of rCAR. Consistent with the rat data, TCS also failed to activate mPXR and was a modest inverse agonist of mCAR. These data suggest that TCS may interact with multiple NRs, including hPXR, hCAR1, hCAR3, and rCAR in order to potentially affect hepatic catabolism. Overall these data support the conclusion that TCS may interact with NRs to regulate hepatic catabolism and downstream thyroid hormone homeostasis in both rat and human models, though perhaps by divergent mechanisms. Published by Elsevier Ltd.

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Salman, Fadheela; Plant, Nick, E-mail: N.Plant@Surrey.ac.uk

The polychlorinated biphenyl group possesses high environmental persistence, leading to bioaccumulation and a number of adverse effects in mammals. Whilst coplanar PCBs elicit their toxic effects through agonism of the aryl hydrocarbon receptor; however, non-coplanar PCBs are not ligands for AhR, but may be ligands for members of the nuclear receptor family of proteins. To better understand the biological actions of non-coplanar PCBs, we have undertaken a systematic analysis of their ability to activate PXR and CAR-mediated effects. Cells were exposed to a range of non-coplanar PCBs (99, 138, 153, 180 and 194), or the coplanar PCB77: Direct activation ofmore » PXR and CAR was measured using a mammalian receptor activation assay in human liver cells, with rifampicin and CITCO used as positive controls ligands for PXR and CAR, respectively; activation of target gene expression was examined using reporter gene plasmids for CYP3A4 and MDR1 transfected into liver, intestine and lung cell lines. Several of the non-coplanar PCBs directly activated PXR and CAR, whilst the coplanar PCB77 did not. Non-coplanar PCBs were also able to activate PXR/CAR target gene expression in a substitution- and tissue-specific manner. Non-coplanar PCBs act as direct activators for the nuclear receptors PXR and CAR, and are able to elicit transcriptional activation of target genes in a substitution- and tissue-dependent manner. Chronic activation of PXR/CAR is linked to adverse effects and must be included in any risk assessment of PCBs. -- Highlights: ► Several Non-coplanar PCBs are able to directly activate both PXR and CAR in vitro. ► PCB153 is the most potent direct activator of PXR and CAR nuclear receptors. ► Non-coplanar PCB activation of CYP3A4/MDR1 reporter genes is structure-dependent. ► Non-coplanar PCB activate CYP3A4/MDR1 reporter genes in a tissue-dependent. ► PCB153 is the most potent activator of PXR/CAR target gene in all tissues.« less

Coordinated Regulation of Nuclear Receptor CAR by CCRP/DNAJC7, HSP70 and the Ubiquitin-Proteasome System

PubMed Central

Timsit, Yoav E.; Negishi, Masahiko

2014-01-01

The constitutive active/androstane receptor (CAR) plays an important role as a coordinate transcription factor in the regulation of various hepatic metabolic pathways for chemicals such as drugs, glucose, fatty acids, bilirubin, and bile acids. Currently, it is known that in its inactive state, CAR is retained in the cytoplasm in a protein complex with HSP90 and the tetratricopeptide repeat protein cytosoplasmic CAR retention protein (CCRP). Upon activation by phenobarbital (PB) or the PB-like inducer 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP), CAR translocates into the nucleus. We have identified two new components to the cytoplasmic regulation of CAR: ubiquitin-dependent degradation of CCRP and protein-protein interaction with HSP70. Treatment with the proteasome inhibitor MG132 (5 µM) causes CAR to accumulate in the cytoplasm of transfected HepG2 cells. In the presence of MG132, TCPOBOP increases CCRP ubiquitination in HepG2 cells co-expressing CAR, while CAR ubiquitination was not detected. MG132 treatment of HepG2 also attenuated of TCPOBOP-induced CAR transcriptional activation on reporter constructs which contain CAR-binding DNA elements derived from the human CYP2B6 gene. The elevation of cytoplasmic CAR protein with MG132 correlated with an increase of HSP70, and to a lesser extent HSP60. Both CCRP and CAR were found to interact with endogenous HSP70 in HepG2 cells by immunoprecipitation analysis. Induction of HSP70 levels by heat shock also increased cytoplasmic CAR levels, similar to the effect of MG132. Lastly, heat shock attenuated TCPOBOP-induced CAR transcriptional activation, also similar to the effect of MG132. Collectively, these data suggest that ubiquitin-proteasomal regulation of CCRP and HSP70 are important contributors to the regulation of cytoplasmic CAR levels, and hence the ability of CAR to respond to PB or PB-like inducers. PMID:24789201

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

PubMed

Prinzing, Brooke L; Gottschalk, Stephen M; Krenciute, Giedre

2018-05-01

The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.

Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling

PubMed Central

Mutoh, Shingo; Sobhany, Mack; Moore, Rick; Perera, Lalith; Pedersen, Lee; Sueyoshi, Tatsuya; Negishi, Masahiko

2017-01-01

Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr52, which then promoted the dephosphorylation of CAR at Thr38 by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR. PMID:23652203

Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling.

PubMed

Mutoh, Shingo; Sobhany, Mack; Moore, Rick; Perera, Lalith; Pedersen, Lee; Sueyoshi, Tatsuya; Negishi, Masahiko

2013-05-07

Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.

Biologic and epigenetic impact of commuting to work by car or using public transportation: a case-control study.

PubMed

Morabia, Alfredo; Zhang, Fang Fang; Kappil, Maya A; Flory, Janine; Mirer, Frank E; Santella, Regina M; Wolff, Mary; Markowitz, Steven B

2012-01-01

Commuting by public transportation (PT) entails more physical activity and energy expenditure than by cars, but its biologic consequences are unknown. In 2009-2010, we randomly sampled New York adults, usually commuting either by car (n=79) or PT (n=101). Measures comprised diet and physical activity questionnaires, weight and height, white blood cell (WBC) count, C reactive protein, (CRP) gene-specific methylation (IL-6), and global genomic DNA methylation (LINE-1 methylation). Compared to the 101 PT commuters, the 79 car drivers were about 9 years older, 2 kg/m(2) heavier, more often non-Hispanic whites, and ate more fruits and more meats. The 2005 guidelines for physical activity were met by more car drivers than PT users (78.5% vs. 65.0%). There were no differences in median levels of CRP (car vs. PT: 0.6 vs. 0.5mg/dl), mean levels of WBC (car vs. PT: 6.7 vs. 6.5 cells/mm(3)), LINE-1 methylation (car vs. PT: 78.0% vs. 78.3%), and promoter methylation of IL-6 (car vs. PT: 56.1% vs. 58.0%). PT users were younger and lighter than car drivers, but their commute mode did not translate into a lower inflammatory response or a higher DNA methylation, maybe because, overall, car drivers were more physically active. Copyright © 2012 Elsevier Inc. All rights reserved.

GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade

PubMed Central

Gargett, Tessa; Yu, Wenbo; Dotti, Gianpietro; Yvon, Eric S; Christo, Susan N; Hayball, John D; Lewis, Ian D; Brenner, Malcolm K; Brown, Michael P

2016-01-01

Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological “space”, functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1+ tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients. PMID:27019998

BIOLOGIC AND EPIGENETIC IMPACT OF COMMUTING TO WORK BY CAR OR USING PUBLIC TRANSPORTATION: A CASE-CONTROL STUDY

PubMed Central

Morabia, Alfredo; Zhang, Fang Fang; Kappil, Maya A.; Flory, Janine; Mirer, Frank E; Santella, Regina M.; Wolff, Mary; Markowitz, Steven B

2013-01-01

Background and Aims Commuting by public transportation (PT) entails more physical activity and energy expenditure than by cars, but its biologic consequences are unknown. Methods In 2009-2010, we randomly sampled New York adults, usually commuting either by car (n=79) or PT (n=101). Measures comprised diet and physical activity questionnaires, weight and height, white blood cell (WBC) count, C reactive protein, (CRP) gene-specific methylation (IL-6), and global genomic DNA methylation (LINE-1 methylation). Results Compared to the 101 PT commuters, the 79 car drivers were about 9 years older, 2 kg/m2 heavier, more often non-Hispanic whites, and ate more fruits and more meats. The 2005 guidelines for physical activity were met by more car drivers than PT users (78.5% vs. 65.0%). There were no differences in median levels of CRP (car vs. PT: 0.6 vs. 0.5 mg/dl), mean levels of WBC (car vs. PT: 6.7 vs. 6.5 cells/mm3), LINE-1 methylation (car vs. PT: 78.0% vs. 78.3%), and promoter methylation of IL-6 (car vs. PT: 56.1% vs. 58.0%). Conclusions PT users were younger and lighter than car drivers, but their commute mode did not translate into a lower inflammatory response or a higher DNA methylation, maybe because, overall, car drivers were more physically active. PMID:22313796

DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Serikawa, Takafumi; Inajima, Jun

Highlights: Black-Right-Pointing-Pointer DP97 interacts with nuclear receptor CAR. Black-Right-Pointing-Pointer DP97 enhances CAR-mediated transcriptional activation. Black-Right-Pointing-Pointer DP97 synergistically enhances transactivity of CAR by the co-expression of SRC-1 or PGC1{alpha}. Black-Right-Pointing-Pointer DP97 is a gene-selective co-activator for hCAR. -- Abstract: The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with smallmore » interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Thus, DP97 was found to be a gene (or promoter)-selective co-activator for hCAR. DP97-mediated CAR transactivation was synergistically enhanced by the co-expression of SRC-1 or PGC1{alpha}, therefore it might act as mediator between hCAR and appropriate co-activators.« less

CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α

PubMed Central

Gao, Jie; Yan, Jiong; Xu, Meishu; Ren, Songrong

2015-01-01

The constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) are master regulators of drug metabolism and gluconeogenesis, respectively. In supporting the cross talk between drug metabolism and energy metabolism, activation of CAR has been shown to suppress hepatic gluconeogenesis and ameliorate hyperglycemia in vivo, but the underlying molecular mechanism remains elusive. In this study, we demonstrated that CAR suppressed hepatic gluconeogenic gene expression through posttranslational regulation of the subcellular localization and degradation of PGC1α. Activated CAR translocated into the nucleus and served as an adaptor protein to recruit PGC1α to the Cullin1 E3 ligase complex for ubiquitination. The interaction between CAR and PGC1α also led to their sequestration within the promyelocytic leukemia protein-nuclear bodies, where PGC1α and CAR subsequently underwent proteasomal degradation. Taken together, our findings revealed an unexpected function of CAR in recruiting an E3 ligase and targeting the gluconeogenic activity of PGC1α. Both drug metabolism and gluconeogenesis are energy-demanding processes. The negative regulation of PGC1α by CAR may represent a cellular adaptive mechanism to accommodate energy-restricted conditions. PMID:26407237

CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α.

PubMed

Gao, Jie; Yan, Jiong; Xu, Meishu; Ren, Songrong; Xie, Wen

2015-11-01

The constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) are master regulators of drug metabolism and gluconeogenesis, respectively. In supporting the cross talk between drug metabolism and energy metabolism, activation of CAR has been shown to suppress hepatic gluconeogenesis and ameliorate hyperglycemia in vivo, but the underlying molecular mechanism remains elusive. In this study, we demonstrated that CAR suppressed hepatic gluconeogenic gene expression through posttranslational regulation of the subcellular localization and degradation of PGC1α. Activated CAR translocated into the nucleus and served as an adaptor protein to recruit PGC1α to the Cullin1 E3 ligase complex for ubiquitination. The interaction between CAR and PGC1α also led to their sequestration within the promyelocytic leukemia protein-nuclear bodies, where PGC1α and CAR subsequently underwent proteasomal degradation. Taken together, our findings revealed an unexpected function of CAR in recruiting an E3 ligase and targeting the gluconeogenic activity of PGC1α. Both drug metabolism and gluconeogenesis are energy-demanding processes. The negative regulation of PGC1α by CAR may represent a cellular adaptive mechanism to accommodate energy-restricted conditions.

Determination of total chromium in tanned leather samples used in car industry.

PubMed

Zeiner, Michaela; Rezić, Iva; Ujević, Darko; Steffan, Ilse

2011-03-01

Despite the high competition of synthetic fibers leather is nowadays still widely used for many applications. In order to ensure a sufficient stability of the skin matrix against many factors, such as microbial degradation, heat and sweat, a tanning process is indispensable. Using chromium (III) for this purpose offers a multitude of advantages, thus this way of tanning is widely applied. During the use of chromium tanned leather as clothing material as well as for decoration/covering purposes, chromium is extracted from the leather and may then cause nocuous effects to human skin, e.g. allergic reactions. Thus the knowledge of the total chromium content of leather samples expected to come into prolonged touch with human skin is very important. In car industry leather is used as cover for seats, steering wheel and gearshift lever The chromium contents often chromium tanned leather samples used in car industry were determined. First all samples were dried at 65 degrees C overnight and then cut in small pieces using a ceramic knife, weighed and analyzed by inductively coupled plasma--optical emission spectrometry (ICP-OES) after acidic microwave assisted digestion. The total chromium amounts found were in the range from 19 mg/g up to 32 mg/g. The extraction yield of chromium from leather samples in sweat is approximately 2-7%. Thus especially during long journeys in summer chromium can be extracted in amounts which may cause nocuous effects for example on the palm of the hands or on the back.

Alternative splicing within the ligand binding domain of the human constitutive androstane receptor.

PubMed

Savkur, Rajesh S; Wu, Yifei; Bramlett, Kelli S; Wang, Minmin; Yao, Sufang; Perkins, Douglas; Totten, Michelle; Searfoss, George; Ryan, Timothy P; Su, Eric W; Burris, Thomas P

2003-01-01

The human constitutive androstane receptor (hCAR; NR1I3) is a member of the nuclear receptor superfamily. The activity of hCAR is regulated by a variety of xenobiotics including clotrimazole and acetaminophen metabolites. hCAR, in turn, regulates a number of genes responsible for xenobiotic metabolism and transport including several cytochrome P450s (CYP 2B5, 2C9, and 3A4) and the multidrug resistance-associated protein 2 (MRP2, ABCC2). Thus, hCAR is believed to be a mediator of drug-drug interactions. We identified two novel hCAR splice variants: hCAR2 encodes a receptor in which alternative splice acceptor sites are utilized resulting in a 4 amino acid insert between exons 6 and 7, and a 5 amino acid insert between 7 and 8, and hCAR3 encodes a receptor with exon 7 completely deleted resulting in a 39 amino acid deletion. Both hCAR2 and hCAR3 mRNAs are expressed in a pattern similar to the initially described MB67 (hCAR1) with some key distinctions. Although the levels of expression vary depending on the tissue examined, hCAR2 and hCAR3 contribute 6-8% of total hCAR mRNA in liver. Analysis of the activity of these variants indicates that both hCAR2 and hCAR3 lose the ability to heterodimerize with RXR and lack transactivation activity in cotransfection experiments where either full-length receptor or GAL4 DNA-binding domain/CAR ligand binding domain chimeras were utilized. Although the role of hCAR2 and hCAR3 is currently unclear, these additional splice variants may provide for increased diversity in terms of responsiveness to xenobiotics.

Increased recovery of touch DNA evidence using FTA paper compared to conventional collection methods.

PubMed

Kirgiz, Irina A; Calloway, Cassandra

2017-04-01

Tape lifting and FTA paper scraping methods were directly compared to traditional double swabbing for collecting touch DNA from car steering wheels (n = 70 cars). Touch DNA was collected from the left or right side of each steering wheel (randomized) using two sterile cotton swabs, while the other side was sampled using water-soluble tape or FTA paper cards. DNA was extracted and quantified in duplicate using qPCR. Quantifiable amounts of DNA were detected for 100% of the samples (n = 140) collected independent of the method. However, the DNA collection yield was dependent on the collection method. A statistically significant difference in DNA yield was observed between FTA scraping and double swabbing methods (p = 0.0051), with FTA paper collecting a two-fold higher amount. Statistical analysis showed no significant difference in DNA yields between the double swabbing and tape lifting techniques (p = 0.21). Based on the DNA concentration required for 1 ng input, 47% of the samples collected using FTA paper would be expected to yield a short tandem repeat (STR) profile compared to 30% and 23% using double swabbing or tape, respectively. Further, 55% and 77% of the samples collected using double swabbing or tape, respectively, did not yield a high enough DNA concentration for the 0.5 ng of DNA input recommended for conventional STR kits and would be expected to result in a partial or no profile compared to 35% of the samples collected using FTA paper. STR analysis was conducted for a subset of the higher concentrated samples to confirm that the DNA collected from the steering wheel was from the driver. 32 samples were selected with DNA amounts of at least 1 ng total DNA (100 pg/μl when concentrated if required). A mixed STR profile was observed for 26 samples (88%) and the last driver was the major DNA contributor for 29 samples (94%). For one sample, the last driver was the minor DNA contributor. A full STR profile of the last driver was observed for 21 samples (69%) and a partial profile was observed for nine samples (25%); STR analysis failed for two samples collected using tape (6%). In conclusion, we show that the FTA paper scraping method has the potential to collect higher DNA yields from touch DNA evidence deposited on non-porous surfaces often encountered in criminal cases compared to conventional methods. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Daidzein enhances intramuscular fat deposition and improves meat quality in finishing steers

PubMed Central

Zhao, Xiang-Hui; Yang, Zhu-Qing; Bao, Lin-Bin; Wang, Can-Yu; -Zhou, Shan; Gong, Jian-Ming; Fu, Chuan-Bian; Xu, Lan-Jiao; Liu, Chan-Juan

2015-01-01

An experiment was conducted to determine the effects of soy isoflavone daidzein on carcass characteristics, fat deposition, meat quality, and blood metabolites in finishing steers. Fourteen crossbred steers were used in a 120-d finishing study. These steers were stratified by weight into groups and randomly allotted by group to one of two dietary treatments: (1) control and (2) daidzein (500 mg/kg concentrate). The steers were fed a 90% concentrate diet. Supplemental daidzein did not affect slaughter weight, hot carcass weight, and dressing percentage, but tended to reduce fat proportion (not including intramuscular fat) in carcass and backfat thickness of steers. The carcass bone proportion was greater in steers fed daidzein diets than those fed control diets. Daidzein supplementation reduced pH at 24 h after slaughtered and moisture content and increased isocitrate dehydrogenase activity, fat content (16.28% and 7.94%), marbling score (5.29 and 3.36), redness (a*), and chroma (C*) values in longissimus muscle relative to control treatment. The concentrations of blood metabolites including glucose, blood urea nitrogen, triglyceride, total cholesterol, non-esterified fatty acid, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were all lower in steers fed daidzein diets than those fed control diets. Current results suggest that supplemental daidzein can affect lipid metabolism, increase intramuscular fat content and marbling score, and improve meat quality in finishing steers. Daidzein should be a promising feed additive for production of high-quality beef meat. PMID:25526906

Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors

PubMed Central

Karlsson, Hannah; Svensson, Emma; Gigg, Camilla; Jarvius, Malin; Olsson-Strömberg, Ulla; Savoldo, Barbara; Dotti, Gianpietro; Loskog, Angelica

2015-01-01

CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs. PMID:26700307

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

NASA Technical Reports Server (NTRS)

Ye, C. P.; Yamaguchi, T.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

2000-01-01

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

Opportunities and limitations for intersection collision intervention-A study of real world 'left turn across path' accidents.

PubMed

Sander, Ulrich

2017-02-01

Turning across the path of oncoming vehicle accidents are frequent and dangerous. To date not many car manufacturers have introduced Automated Emergency Braking (AEB) systems addressing this type of conflict situation, but it is foreseeable that these scenarios will be part of the Euro NCAP 2020 rating. Nine out of ten collisions are caused by the driver of the turning vehicle. An AEB system evaluating the ego and conflict vehicle driver's possibilities to avoid a pending crash by either braking or steering was specified for application in various constellations of vehicle collisions. In virtual simulation, AEB system parameters were varied, covering parameters that are relevant for driver comfort such as longitudinal and lateral acceleration (to define avoidance possibilities), expected steering maneuvers to avoid conflict, and intervention response characteristics (brake delay and ramp up) to assess the safety benefit. The reference simulation showed a potential of the AEB system in the turning vehicle to avoid approximately half of the collisions. An AEB system of the straight going vehicle was less effective. The effectiveness of the turning vehicle's AEB system increases if spatial limitations for the collision-avoidance steering maneuver are known. Such information could be provided by sensors detecting free space in or around the road environment or geographical information shared via vehicle to cloud communication. AEB interventions rarely result in collision avoidance for turning vehicles with speeds above 40km/h or for straight going vehicles with speeds above 60km/h. State of the art field-of-views of forward looking sensing systems designed for AEB rear-end interventions are capable of addressing turning across path situations. Copyright © 2016 Elsevier Ltd. All rights reserved.

A control theoretic model of driver steering behavior

NASA Technical Reports Server (NTRS)

Donges, E.

1977-01-01

A quantitative description of driver steering behavior such as a mathematical model is presented. The steering task is divided into two levels: (1) the guidance level involving the perception of the instantaneous and future course of the forcing function provided by the forward view of the road, and the response to it in an anticipatory open-loop control mode; (2) the stabilization level whereby any occuring deviations from the forcing function are compensated for in a closed-loop control mode. This concept of the duality of the driver's steering activity led to a newly developed two-level model of driver steering behavior. Its parameters are identified on the basis of data measured in driving simulator experiments. The parameter estimates of both levels of the model show significant dependence on the experimental situation which can be characterized by variables such as vehicle speed and desired path curvature.

UAVSAR Active Electronically-Scanned Array

NASA Technical Reports Server (NTRS)

Sadowy, Gregory; Brown, Kyle; Chamberlain, Neil; Figueroa, Harry; Fisher, Charlie; Grando, Maurio; Hamilton, Gary; Vorperian, Vatche; Zawadzki, Mark

2010-01-01

The Uninhabited Airborne Vehicle Synthetic Aperture Radar (UAVSAR) L-band (1.2-1.3 GHz) repeat pass, interferometric synthetic aperture radar (InSAR) used for Earth science applications. Using complex radar images collected during separate passes on time scales of hours to years, changes in surface topography can be measured. The repeat-pass InSAR technique requires that the radar look angle be approximately the same on successive passes. Due to variations in aircraft attitude between passes, antenna beam steering is required to replicate the radar look angle. This paper describes an active, electronically steered array (AESA) that provides beam steering capability in the antenna azimuth plane. The array contains 24 transmit/receive modules generating 2800 W of radiated power and is capable of pulse-to-pulse beam steering and polarization agility. Designed for high reliability as well as serviceability, all array electronics are contained in single 178cm x 62cm x 12 cm air-cooled panel suitable for operation up 60,000 ft altitude.

Multi-Objective Sliding Mode Control on Vehicle Cornering Stability with Variable Gear Ratio Actuator-Based Active Front Steering Systems

PubMed Central

Ma, Xinbo; Wong, Pak Kin; Zhao, Jing; Xie, Zhengchao

2016-01-01

Active front steering (AFS) is an emerging technology to improve the vehicle cornering stability by introducing an additional small steering angle to the driver’s input. This paper proposes an AFS system with a variable gear ratio steering (VGRS) actuator which is controlled by using the sliding mode control (SMC) strategy to improve the cornering stability of vehicles. In the design of an AFS system, different sensors are considered to measure the vehicle state, and the mechanism of the AFS system is also modelled in detail. Moreover, in order to improve the cornering stability of vehicles, two dependent objectives, namely sideslip angle and yaw rate, are considered together in the design of SMC strategy. By evaluating the cornering performance, Sine with Dwell and accident avoidance tests are conducted, and the simulation results indicate that the proposed SMC strategy is capable of improving the cornering stability of vehicles in practice. PMID:28036037

Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Inajima, Jun; Kato, Sayaka

The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6more » but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.« less

Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent anti-tumor activity

PubMed Central

Caruso, Hillary G.; Hurton, Lenka V.; Najjar, Amer; Rushworth, David; Ang, Sonny; Olivares, Simon; Mi, Tiejuan; Switzer, Kirsten; Singh, Harjeet; Huls, Helen; Lee, Dean A.; Heimberger, Amy B.; Champlin, Richard E.; Cooper, Laurence J. N.

2015-01-01

Many tumors over express tumor-associated antigens relative to normal tissue, such as epidermal growth factor receptor (EGFR). This limits targeting by human T cells modified to express chimeric antigen receptors (CARs) due to potential for deleterious recognition of normal cells. We sought to generate CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate density of EGFR expression by generating two CARs from monoclonal antibodies which differ in affinity. T cells with low affinity Nimo-CAR selectively targeted cells over-expressing EGFR, but exhibited diminished effector function as the density of EGFR decreased. In contrast, the activation of T cells bearing high affinity Cetux-CAR was not impacted by the density of EGFR. In summary, we describe the generation of CARs able to tune T-cell activity to the level of EGFR expression in which a CAR with reduced affinity enabled T cells to distinguish malignant from non-malignant cells. PMID:26330164

Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes.

PubMed

Haines, Corinne; Elcombe, Barbara M; Chatham, Lynsey R; Vardy, Audrey; Higgins, Larry G; Elcombe, Clifford R; Lake, Brian G

2018-03-01

Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes. The treatment of WT and hCAR/hPXR mice with 186-984 ppm NaPB in the diet for 7 days resulted in increased relative liver weight, hypertrophy and induction of cytochrome P450 (CYP) enzyme activities. Treatment with NaPB also produced dose-dependent increases in hepatocyte replicative DNA synthesis (RDS), with the effect being more marked in WT than in hCAR/hPXR mice. While the treatment of cultured C57BL/6J and CD-1 mouse, Sprague-Dawley rat and human hepatocytes with 100 and/or 1000 μM NaPB for 4 days induced CYP enzyme activities, increased RDS was only observed in mouse and rat hepatocytes. However, as a positive control, epidermal growth factor increased RDS in hepatocytes from all three species. In summary, although human hepatocytes are refractory to the mitogenic effects of NaPB, treatment with NaPB induced RDS in vivo in hCAR/hPXR mice, which is presumably due to the human CAR and PXR receptors operating in a mouse hepatocyte regulatory environment. As the response of the hCAR/hPXR mouse to the CAR activator NaPB differs markedly from that of human hepatocytes, the hCAR/hPXR mouse is thus not a suitable animal model for studies on the hepatic effects of nongenotoxic rodent CAR activators. Copyright © 2018 Elsevier B.V. All rights reserved.

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma

PubMed Central

Quintarelli, Concetta; Orlando, Domenico; Boffa, Iolanda; Guercio, Marika; Petretto, Andrea; Lavarello, Chiara; Sinibaldi, Matilde; Weber, Gerrit; Del Bufalo, Francesca; Giorda, Ezio; Scarsella, Marco; Petrini, Stefania; Pagliara, Daria; Locatelli, Franco

2018-01-01

ABSTRACT Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB. PMID:29872565

Tasco-Forage: III. Influence of a seaweed extract on performance, monocyte immune cell response, and carcass characteristics in feedlot-finished steers.

PubMed

Allen, V G; Pond, K R; Saker, K E; Fontenot, J P; Bagley, C P; Ivy, R L; Evans, R R; Brown, C P; Miller, M F; Montgomery, J L; Dettle, T M; Wester, D B

2001-04-01

Tall fescue (Festuca arundinacea Schreb.) infected with the endophyte Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin) causes fescue toxicosis in cattle grazing the forage, but effects of the endophyte were considered to be abated soon after removal of the animals from pastures. Tasco-Forage, a proprietary extract from the brown seaweed Ascophyllum nodosum, is a known source of cytokinins and has increased antioxidant activity in both plants and the animals that graze the forage. Tasco was applied at 0 and 3.4 kg/ha to infected and uninfected tall fescue pastures in Virginia and Mississippi. Forty-eight steers grazed the pastures at each location during each of 2 yr (n = 192) before being transported to Texas for feedlot finishing. On arrival at the feedlot, steers from Tasco-treated pastures had higher (P < 0.01) monocyte phagocytic activity and tended (P < 0.07) to have higher major histocompatibility complex class II expression than steers that grazed the untreated pastures. A depression (P < 0.05) in monocyte immune cell function due to grazing infected fescue was detected throughout the feedlot finishing period but was reversed by Tasco. Rectal temperatures were elevated (P < 0.07) in steers that had grazed the infected tall fescue when they arrived in Texas, but by d 14 no difference was detected. However, by d 28 the temperature effects of infected tall fescue were reversed. Steers that had grazed infected fescue had lower (P < 0.01) rectal temperatures on d 112 of the feedlot period, demonstrating a much longer-lasting effect of the endophyte on thermoregulatory mechanisms than previously thought. Steers that had grazed Tasco-treated pastures had higher (P < 0.01) rectal temperatures on d 56 than steers that had grazed untreated fescue. Steers that had grazed the Tasco-treated pastures had higher marbling scores (P < 0.05) regardless of the endophyte, but no effect of Tasco or endophyte on gain was measured. Our data suggest that Tasco application to tall fescue pastures alleviated some of the negative effects of tall fescue toxicity.

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smetanina, Mariya A., E-mail: maria.smetanina@gmail.com; Laboratory of Gene Expression Control, Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, prospekt Lavrentyeva 10, Novosibirsk 630090; Group of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, prospekt Lavrentyeva 8, Novosibirsk 630090

2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepaticmore » mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car{sup -/-}) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car{sup -/-} livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor. - Highlights: > The azo dye and mouse carcinogen OAT is a very effective mCAR activator. > OAT increases mCAR transactivation in a dose-dependent manner. > OAT CAR-dependently increases the expression of a specific subset of CAR target genes. > OAT induces an unexpectedly deferred, but CAR-dependent hepatocyte proliferation.« less

The use of hazard road signs to improve the perception of severe bends.

PubMed

Milleville-Pennel, Isabelle; Jean-Michel, Hoc; Elise, Jolly

2007-07-01

Collision analysis indicates that many car accidents occur when negotiating a bend. Excessive speed and steering wheel errors are often given by way of explanation. Nevertheless, the underlying origin of these dramatic errors could be, at least in part, a poor estimation of bend curvature. The aim of this study was to investigate both the assessment of bend curvature by drivers and the impact of symbolic road signs that indicate a hazardous bend on this assessment. Thus, participants first viewed a video recording showing approaching bends of different curvature before being asked to assess the curvature of these bends. This assessment could either be a verbal (symbolic control) estimation of the bend's curvature and risk, or a sensorimotor (subsymbolic control) estimation of the bend's curvature (participants were asked to turn a steering wheel to mimic the position that would be necessary to accurately negotiate the bend). Results show that very severe bends (with a radius of less than 80 m) were actually underestimated. This was associated with an underestimation of risk corresponding to these bends and a poor sensorimotor anticipation of bend curvature. Road signs, which indicate risk significantly improve bend assessment, but this was of no use for sensorimotor anticipation. Thus, other indicators need to be envisaged in order to also improve this level of control.

CarD uses a minor groove wedge mechanism to stabilize the RNA polymerase open promoter complex.

PubMed

Bae, Brian; Chen, James; Davis, Elizabeth; Leon, Katherine; Darst, Seth A; Campbell, Elizabeth A

2015-09-08

A key point to regulate gene expression is at transcription initiation, and activators play a major role. CarD, an essential activator in Mycobacterium tuberculosis, is found in many bacteria, including Thermus species, but absent in Escherichia coli. To delineate the molecular mechanism of CarD, we determined crystal structures of Thermus transcription initiation complexes containing CarD. The structures show CarD interacts with the unique DNA topology presented by the upstream double-stranded/single-stranded DNA junction of the transcription bubble. We confirm that our structures correspond to functional activation complexes, and extend our understanding of the role of a conserved CarD Trp residue that serves as a minor groove wedge, preventing collapse of the transcription bubble to stabilize the transcription initiation complex. Unlike E. coli RNAP, many bacterial RNAPs form unstable promoter complexes, explaining the need for CarD.

A novel technique for optimal integration of active steering and differential braking with estimation to improve vehicle directional stability.

PubMed

Mirzaeinejad, Hossein; Mirzaei, Mehdi; Rafatnia, Sadra

2018-06-11

This study deals with the enhancement of directional stability of vehicle which turns with high speeds on various road conditions using integrated active steering and differential braking systems. In this respect, the minimum usage of intentional asymmetric braking force to compensate the drawbacks of active steering control with small reduction of vehicle longitudinal speed is desired. To this aim, a new optimal multivariable controller is analytically developed for integrated steering and braking systems based on the prediction of vehicle nonlinear responses. A fuzzy programming extracted from the nonlinear phase plane analysis is also used for managing the two control inputs in various driving conditions. With the proposed fuzzy programming, the weight factors of the control inputs are automatically tuned and softly changed. In order to simulate a real-world control system, some required information about the system states and parameters which cannot be directly measured, are estimated using the Unscented Kalman Filter (UKF). Finally, simulations studies are carried out using a validated vehicle model to show the effectiveness of the proposed integrated control system in the presence of model uncertainties and estimation errors. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Are cars the new tobacco?

PubMed

Douglas, Margaret J; Watkins, Stephen J; Gorman, Dermot R; Higgins, Martin

2011-06-01

Public health must continually respond to new threats reflecting wider societal changes. Ecological public health recognizes the links between human health and global sustainability. We argue that these links are typified by the harms caused by dependence on private cars. We present routine data and literature on the health impacts of private car use; the activities of the 'car lobby' and factors underpinning car dependence. We compare these with experience of tobacco. Private cars cause significant health harm. The impacts include physical inactivity, obesity, death and injury from crashes, cardio-respiratory disease from air pollution, noise, community severance and climate change. The car lobby resists measures that would restrict car use, using tactics similar to the tobacco industry. Decisions about location and design of neighbourhoods have created environments that reinforce and reflect car dependence. Car ownership and use has greatly increased in recent decades and there is little public support for measures that would reduce this. Car dependence is a potent example of an issue that ecological public health should address. The public health community should advocate strongly for effective policies that reduce car use and increase active travel.

Enhancing older driver safety: A driving survey and evaluation of the CarFit program.

PubMed

Gaines, Jean M; Burke, Kasey L; Marx, Katherine A; Wagner, Mary; Parrish, John M

2011-10-01

To evaluate CarFit, an educational program designed to promote optimal alignment of driver with vehicle. A driving activity survey was sent to 727 randomly selected participants living in retirement communities. Drivers (n=195) were assigned randomly to CarFit intervention (n=83, M age=78.1) or Comparison (n=112, M age=79.6) groups. After 6months, participants completed a post-test of driving activity and CarFit recommendations. Nonconsenting drivers were older and participated in fewer driving activities. CarFit participation was moderate (71%) with 86% of the participants receiving recommendations. 60% followed the recommendations at the 6-month re-evaluation). The CarFit (67.6%) and Comparison (59.3%) groups reported at least one type of self-regulation of driving activity at baseline. There was no significant change in the driving behaviors at the six-month follow-up. CarFit was able to detect addressable opportunities that may contribute to the safety of older drivers. CarFit recommendations may need stronger reinforcement in order to be enacted by a participant. Copyright © 2011 National Safety Council and Elsevier Ltd. All rights reserved.

Effects of a Saccharomyces cerevisiae fermentation product in receiving diets of newly weaned beef steers II: Digestibility and response to a vaccination challenge.

PubMed

Deters, E L; Stokes, R S; Genther-Schroeder, O N; Hansen, S L

2018-06-15

Thirty-six newly weaned, crossbred beef steers (323 ± 12 kg; SD) from a single-source were used in a 56-d study to examine the effects of a Saccharomyces cerevisiae fermentation product (SCFP; Original XPC, Diamond V, Cedar Rapids, IA) on total tract nutrient digestibility and response to a vaccination challenge. Twelve d after arrival, steers were blocked by body weight (BW) and randomly assigned to treatments: SCFP at 0 (CON), 14 (SCFP14), or 28 (SCFP28) g·steer-1·d-1. Steers were fed via bunks that measured individual intake and received ear tags (CowManager, Select Sires, Plain City, OH) that recorded rumination and activity. Body weights were collected on d -1, 0, 14, 28, 42, 55, and 56. Titanium dioxide was fed as an indigestible marker to all steers from d 12 to 27, followed by consecutive d fecal samples, for determination of total tract nutrient digestibility. On d 34, steers received a Mannheimia haemolytica vaccination (One Shot, Zoetis, Kalamazoo, MI) to induce an acute phase protein (APP) response. Blood was collected from all steers on d 34 (prior to vaccination) and 3, 6, 9, 11, and 14 d post-vaccination. Data were analyzed using Proc Mixed of SAS (experimental unit = steer; n = 12/treatment); the model included the fixed effect of treatment and block and the random effect of steer. Blood measures, ear tag, and dry matter intake (DMI) data for the 15-d vaccination period were analyzed as repeated measures. Contrast statements (CON vs. SCFP14; SCFP14 vs. SCFP28) were used to compare treatment means. Digestibility of dry matter and organic matter was greater for SCFP14 vs. SCFP28 (P ≤ 0.03). Steers fed SCFP14 exhibited greater crude protein digestibility compared to CON (P < 0.01). Steers fed SCFP14 exhibited greater DMI for 15 d post-vaccination (P = 0.02) and greater ADG from d 28 to 56 (P = 0.05) vs. SCFP28-fed steers. Post-vaccination, steers fed SCFP14 spent less time ruminating per kg of dry matter, neutral detergent fiber (NDF), and physically effective NDF consumed than CON or SCFP28 (P ≤ 0.07). Serum IL-8 and haptoglobin concentrations tended to be lesser for steers fed SCFP14 vs. SCFP28 (P ≤ 0.08). Ceruloplasmin concentrations were lesser on d 14 post-vaccination for steers fed SCFP14 vs. CON or SCFP28 (treatment × d; P = 0.004); there were no differences on other sampling days due to treatment. Although no overall performance benefit was noted, steers fed SCFP14 responded better to a vaccination challenge vs. SCFP28-fed steers.

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.

PubMed

Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

2011-11-01

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.

Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.

PubMed

Ghosh, Arnab; Smith, Melody; James, Scott E; Davila, Marco L; Velardi, Enrico; Argyropoulos, Kimon V; Gunset, Gertrude; Perna, Fabiana; Kreines, Fabiana M; Levy, Emily R; Lieberman, Sophie; Jay, Hillary V; Tuckett, Andrea Z; Zakrzewski, Johannes L; Tan, Lisa; Young, Lauren F; Takvorian, Kate; Dudakov, Jarrod A; Jenq, Robert R; Hanash, Alan M; Motta, Ana Carolina F; Murphy, George F; Liu, Chen; Schietinger, Andrea; Sadelain, Michel; van den Brink, Marcel R M

2017-02-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.

Driving with Intuition: A Preregistered Study about the EEG Anticipation of Simulated Random Car Accidents

PubMed Central

Duma, Gian Marco; Mento, Giovanni; Manari, Tommaso; Martinelli, Massimiliano

2017-01-01

The study of neural pre-stimulus or “anticipatory” activity opened a new window for understanding how the brain actively constructs the forthcoming reality. Usually, experimental paradigms designed to study anticipatory activity make use of stimuli. The purpose of the present study is to expand the study of neural anticipatory activity upon the temporal occurrence of dichotomic, statistically unpredictable (random) stimuli within an ecological experimental paradigm. To this purpose, we used a simplified driving simulation including two possible, randomly-presented trial types: a car crash end trial and a no car crash end trial. Event Related Potentials (ERP) were extracted -3,000 ms before stimulus onset. We identified a fronto-central negativity starting around 1,000 ms before car crash presentation. By contrast, a whole-scalp distributed positivity characterized the anticipatory activity observed before the end of the trial in the no car crash end condition. The present data are in line with the hypothesis that the brain may also anticipate dichotomic, statistically unpredictable stimuli, relaying onto different pre-stimulus ERP activity. Possible integration with car-smart-systems is also suggested. PMID:28103303

Identifying cognitive distraction using steering wheel reversal rates.

PubMed

Kountouriotis, Georgios K; Spyridakos, Panagiotis; Carsten, Oliver M J; Merat, Natasha

2016-11-01

The influence of driver distraction on driving performance is not yet well understood, but it can have detrimental effects on road safety. In this study, we examined the effects of visual and non-visual distractions during driving, using a high-fidelity driving simulator. The visual task was presented either at an offset angle on an in-vehicle screen, or on the back of a moving lead vehicle. Similar to results from previous studies in this area, non-visual (cognitive) distraction resulted in improved lane keeping performance and increased gaze concentration towards the centre of the road, compared to baseline driving, and further examination of the steering control metrics indicated an increase in steering wheel reversal rates, steering wheel acceleration, and steering entropy. We show, for the first time, that when the visual task is presented centrally, drivers' lane deviation reduces (similar to non-visual distraction), whilst measures of steering control, overall, indicated more steering activity, compared to baseline. When using a visual task that required the diversion of gaze to an in-vehicle display, but without a manual element, lane keeping performance was similar to baseline driving. Steering wheel reversal rates were found to adequately tease apart the effects of non-visual distraction (increase of 0.5° reversals) and visual distraction with offset gaze direction (increase of 2.5° reversals). These findings are discussed in terms of steering control during different types of in-vehicle distraction, and the possible role of manual interference by distracting secondary tasks. Copyright © 2016 Elsevier Ltd. All rights reserved.

General Education: A Curriculum Cornerstone.

ERIC Educational Resources Information Center

Bunker Hill Community Coll., Boston, MA.

Prepared by the General Education (GE) Review Steering Committee of Massachusetts' Bunker Hill Community College in 1991, this guide presents the Committee's GE curiculum Cornerstone model. Following a short preface which discusses the goals and activities of the Steering Committee, chapter 1 presents a rationale for the model and describes its…

Temperament and dominance relate to feeding behaviour and activity in beef cattle: implications for performance and methane emissions.

PubMed

Llonch, P; Somarriba, M; Duthie, C A; Troy, S; Roehe, R; Rooke, J; Haskell, M J; Turner, S P

2018-04-02

In beef cattle, feeding behaviour and activity are associated with feed efficiency and methane (CH4) emissions. This study aimed to understand the underlying traits responsible for the contribution of cattle behaviour to individual differences in feed efficiency, performance and CH4 emissions. A total of 84 steers (530±114 kg BW) of two different breeds (crossbreed Charolais and Luing) were used. The experiment was a 2×2×3 factorial design with breed, basal diets (concentrate v. mixed) and dietary treatments (no additive, calcium nitrate or rapeseed cake) as the main factors. The individual dry matter intake (DMI; kg) was recorded daily and the BW was measured weekly over a 56-day period. Ultrasound fat depth was measured on day 56. Based on the previous data, the indexes average daily gain, food conversion and residual feed intake (RFI) were calculated. The frequency of meals, the duration per visit and the time spent feeding per day were taken as feeding behaviour measures. Daily activity was measured using the number of steps, the number of standing bouts and the time standing per day. Agonistic interactions (including the number of contacts, aggressive interactions, and displacements per day) between steers at the feeders were assessed as indicators of dominance. Temperament was assessed using the crush score test (which measures restlessness when restrained) and the flight speed on release from restraint. Statistical analysis was performed using multivariate regression models. Steers that spent more time eating showed better feed efficiency (P=0.039), which can be due to greater secretion of saliva. Feeding time was longer with the mixed diet (P<0.001), Luings (P=0.009) and dominant steers (P=0.032). Higher activity (more steps) in the pen was associated with poorer RFI, possibly because of higher energy expenditure for muscle activity. Frequent meals contributed to a reduction in CH4 emissions per kg DMI. The meal frequency was higher with a mixed diet (P<0.001) and increased in more temperamental (P=0.003) and dominant (P=0.017) steers. In addition, feed intake was lower (P=0.032) in more temperamental steers. This study reveals that efficiency increases with a longer feeding time and CH4 emissions decrease with more frequent meals. As dominant steers eat more frequently and for longer, a reduction in competition at the feeder would improve both feed efficiency and CH4 emissions. Feed efficiency can also be improved through a reduction in activity. Selection for calmer cattle would reduce activity and increase feed intake, which may improve feed efficiency and promote growth, respectively.

Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase.

PubMed

Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

2016-11-01

Inward rectifier K + channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP 2 ). Stimulation of the Ca 2+ -sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G q/11 , which decreases PIP 2 , and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP 2 . How membrane PIP 2 levels are regulated by CaR activation and whether these changes modulate inward rectifier K + are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K + current (I K1 ) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP 2 reporter tubby-R332H-cYFP to monitor PIP 2 levels, we found that CaR activation in HEK293T cells increased membrane PIP 2 concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP 2 and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K + channels by accelerating PIP 2 synthesis. The regulation of I K1 plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.

Walk, Bicycle, and Transit Trips of Transit-Dependent and Choice Riders in the 2009 United States National Household Travel Survey.

PubMed

Lachapelle, Ugo

2015-08-01

Previous research has shown that public transit use may be associated with active transportation. Access to a car may influence active transportation of transit riders. Using the 2009 United States National Household Travel Survey (NHTS), transit users ≥ 16 years old (n = 25,550) were categorized according to driver status and number of cars and drivers in the household. This typology ranged from choice transit riders (ie, "fully motorized drivers") to transit-dependent riders (ie, "unmotorized nondriver"). Transit trips, walking trips, and bicycling trips of transit users are estimated in negative binomial models against the car availability typology. Sixteen percent of participants took transit in the past month; most (86%) lived in car-owning households. As income increased, car availability also increased. Transit user groups with lower car availability were generally more likely than fully motorized drivers to take more public transit, walking, and bicycle trips. Transit riders have varying levels of vehicle access; their use of combinations of alternative modes of transportation fluctuates accordingly. Transit-dependent individuals without cars or sharing cars used active transportation more frequently than car owners. Policies to reduce vehicle ownership in households may enable increases in the use of alternative modes of transportation for transit users, even when cars are still owned.

Development of CAR T cells designed to improve antitumor efficacy and safety

PubMed Central

Jaspers, Janneke E.; Brentjens, Renier J.

2017-01-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are ‘on-target, off-tumor’ toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. PMID:28342824

Development of CAR T cells designed to improve antitumor efficacy and safety.

PubMed

Jaspers, Janneke E; Brentjens, Renier J

2017-10-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. Published by Elsevier Inc.

Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A.

MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation ofmore » miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR decreases the miR-122 level through the suppression of HNF4α transcriptional activity. • CAR activation increases the cMyc level through the repression of miR-122.« less

Clofibric acid induces hepatic CYP 2B1/2 via constitutive androstane receptor not via peroxisome proliferator activated receptor alpha in rat.

PubMed

Ibrahim, Zein Shaban; Ahmed, Mohamed Mohamed; El-Shazly, Samir Ahmed; Ishizuka, Mayumi; Fujita, Shoichi

2014-01-01

Peroxisome proliferator activated receptor α (PPARα) ligands, fibrates used to control hyperlipidemia. We demonstrated CYP2B induction by clofibric acid (CFA) however, the mechanism was not clear. In this study, HepG2 cells transfected with expression plasmid of mouse constitutive androstane receptor (CAR) or PPARα were treated with CFA, phenobarbital (PB) or TCPOBOP. Luciferase assays showed that CFA increased CYP2B1 transcription to the same level as PB, or TCPOBOP in HepG2 transfected with mouse CAR But failed to induce it in PPARα transfected cells. CYP2B expressions were increased with PB or CFA in Wistar female rats (having normal levels of CAR) but not in Wistar Kyoto female rats (having low levels of CAR). The induction of CYP2B by PB or CFA was comparable to nuclear CAR levels. CAR nuclear translocation was induced by CFA in both rat strains. This indicates that fibrates can activate CAR and that fibrates-insulin sensitization effect may occur through CAR, while hypolipidemic effect may operate through PPARα.

Current steering to activate targeted neural pathways during deep brain stimulation of the subthalamic region

PubMed Central

Chaturvedi, Ashutosh; Foutz, Thomas J.; McIntyre, Cameron C.

2012-01-01

Deep brain stimulation (DBS) has steadily evolved into an established surgical therapy for numerous neurological disorders, most notably Parkinson’s disease (PD). Traditional DBS technology relies on voltage-controlled stimulation with a single source; however, recent engineering advances are providing current-controlled devices with multiple independent sources. These new stimulators deliver constant current to the brain tissue, irrespective of impedance changes that occur around the electrode, and enable more specific steering of current towards targeted regions of interest. In this study, we examined the impact of current steering between multiple electrode contacts to directly activate three distinct neural populations in the subthalamic region commonly stimulated for the treatment of PD: projection neurons of the subthalamic nucleus (STN), globus pallidus internus (GPi) fibers of the lenticular fasiculus, and internal capsule (IC) fibers of passage. We used three-dimensional finite element electric field models, along with detailed multi-compartment cable models of the three neural populations to determine their activations using a wide range of stimulation parameter settings. Our results indicate that selective activation of neural populations largely depends on the location of the active electrode(s). Greater activation of the GPi and STN populations (without activating any side-effect related IC fibers) was achieved by current steering with multiple independent sources, compared to a single current source. Despite this potential advantage, it remains to be seen if these theoretical predictions result in a measurable clinical effect that outweighs the added complexity of the expanded stimulation parameter search space generated by the more flexible technology. PMID:22277548

Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.

PubMed

Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew; Klaassen, Curtis D

2016-06-01

Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver

PubMed Central

Lickteig, Andrew J.; Csanaky, Iván L.; Pratt-Hyatt, Matthew

2016-01-01

Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver. PMID:26984780

Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment.

PubMed

Wang, Zhenguang; Guo, Yelei; Han, Weidong

2017-12-01

Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.

CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

PubMed Central

Bridgeman, J S; Ladell, K; Sheard, V E; Miners, K; Hawkins, R E; Price, D A; Gilham, D E

2014-01-01

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions. PMID:24116999

Eclipse SteerTech liquid lenslet beam steering technology

NASA Astrophysics Data System (ADS)

Westfall, Raymond T.; Rogers, Stanley; Shannon, Kenneth C., III

2007-09-01

Eclipse SteerTech TM transmissive fluid state electrowetting technology has successfully demonstrated the ability to control the shape and position of a fluid lenslet. In its final form, the technology will incorporate a dual fluid lenslet approach capable of operating in extremely high acceleration environments. The beam steering system works on the principle of electro-wetting. A substrate is covered with a closely spaced array of, independently addressable, transparent, electrically conductive pixels utilizing Eclipse's proprietary EclipseTEC TM technology. By activating and deactivating selected EclipseTEC TM pixels in the proper sequence, the shape and position of fluid lenslets or arrays of lenslets can be dynamically changed at will. The position and shape of individual fluid lenslets may be accurately controlled on any flat, simply curved, or complex curved, transparent or reflective surface. The smaller the pixels the better control of the position and shape of the fluid lenslets. Information on the successful testing of the Eclipse SteerTech TM lenslet and discussion of its use in a de-centered lenslet array will be presented.

Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy.

PubMed

Urak, Ryan; Walter, Miriam; Lim, Laura; Wong, ChingLam W; Budde, Lihua E; Thomas, Sandra; Forman, Stephen J; Wang, Xiuli

2017-01-01

Insufficient persistence and effector function of chimeric antigen receptor (CAR)-redirected T cells have been challenging issues for adoptive T cell therapy. Generating potent CAR T cells is of increasing importance in the field. Studies have demonstrated the importance of the Akt pathway in the regulation of T cell differentiation and memory formation. We now investigate whether inhibition of Akt signaling during ex vivo expansion of CAR T cells can promote the generation of CAR T cells with enhanced antitumor activity following adoptive therapy in a murine leukemia xenograft model. Various T cell subsets including CD8+ T cells, bulk T cells, central memory T cells and naïve/memory T cells were isolated from PBMC of healthy donors, activated with CD3/CD28 beads, and transduced with a lentiviral vector encoding a second-generation CD19CAR containing a CD28 co-stimulatory domain. The transduced CD19CAR T cells were expanded in the presence of IL-2 (50U/mL) and Akt inhibitor (Akti) (1 μM) that were supplemented every other day. Proliferative/expansion potential, phenotypical characteristics and functionality of the propagated CD19CAR T cells were analyzed in vitro and in vivo after 17-21 day ex vivo expansion. Anti-tumor activity was evaluated after adoptive transfer of the CD19CAR T cells into CD19+ tumor-bearing immunodeficient mice. Tumor signals were monitored with biophotonic imaging, and survival rates were analyzed by the end of the experiments. We found that Akt inhibition did not compromise CD19CAR T cell proliferation and expansion in vitro, independent of the T cell subsets, as comparable CD19CAR T cell expansion was observed after culturing in the presence or absence of Akt inhibitor. Functionally, Akt inhibition did not dampen cell-mediated effector function, while Th1 cytokine production increased. With respect to phenotype, Akti-treated CD19CAR T cells expressed higher levels of CD62L and CD28 as compared to untreated CD19CAR T cells. Once adoptively transferred into CD19+ tumor-bearing mice, Akti treated CD19CAR T cells exhibited more antitumor activity than did untreated CD19CAR T cells. Inhibition of Akt signaling during ex vivo priming and expansion gives rise to CD19CAR T cell populations that display comparatively higher antitumor activity.

Braking, steering, and wear performance of radial-belted and bias-ply aircraft tires

NASA Technical Reports Server (NTRS)

Yager, Thomas J.; Davis, Pamela A.; Stubbs, Sandy M.; Martinson, Veloria J.

1992-01-01

Preliminary steering, braking, and tread wear performance results from testing of radial-belted and bias-ply aircraft tires at NASA Langley are described. An overview of the joint NASA/FAA/industry START program is presented. Attention is given to the Langley Test Facility, equipment and future activities.

Enhanced expression of extracellular calcium sensing receptor in monocyte-differentiated versus undifferentiated HL-60 cells: potential role in regulation of a nonselective cation channel

NASA Technical Reports Server (NTRS)

Yamaguchi, T.; Ye, C.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

2000-01-01

Human promyelocytic leukemia cells (HL-60) have been used widely as a model for studying the differentiation of hematopoietic progenitor cells in vitro. After treatment with phorbol-12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], HL-60 cells differentiate into cells with the phenotype of monocytes/macrophages. We previously showed that peripheral blood monocytes and the murine J774 monocytic cell line express the CaR, and myeloid progenitors in the bone marrow and myeloid cells in peripheral blood other than monocytes express lower levels of the CaR. Therefore, we investigated whether undifferentiated HL-60 cells express a functional G protein-coupled, extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) and if the expression of the CaR increases as these cells differentiate along the monocytic lineage. The use of reverse transcription-polymerase chain reaction (RT-PCR) with CaR-specific primers, followed by sequencing of the amplified products, identified an authentic CaR transcript in undifferentiated HL-60 cells. Both immunocytochemistry and Western blot analysis using a CaR-specific antiserum detected low levels of CaR protein expression in undifferentiated HL-60 cells. The levels of CaR protein increased considerably following treatment of the cells with PMA (50 nM) or 1,25(OH)(2)D(3) (100 nM) for 5 days. Northern analysis using a CaR-specific riboprobe identified CaR transcripts in undifferentiated HL-60 cells, but CaR mRNA levels did not change appreciably after treatment with either agent, suggesting that upregulation of CaR protein occurs at a translational level. PMA-treated HL-60 cells expressed a nonselective cation channel (NCC), and the calcimimetic CaR activator, NPS R-467, but not its less active stereoisomer, NPS S-467, as well as the polycationic CaR agonist, neomycin, activated this NCC, demonstrating that the CaR expressed in these cells is functionally active. Therefore, HL-60 cells exhibit an increase in CaR protein expression, occurring at a translational level during their differentiation into cells with a monocyte/macrophage phenotype in response to treatment with PMA or 1, 25(OH)(2)D(3), which is functionally linked to activation of a nonselective cation channel.

Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation

PubMed Central

Hernandez, J.P.; Mota, L.C.; Baldwin, W.S.

2010-01-01

The constitutive androstane receptor (CAR) and the pregnane × receptor (PXR) are activated by a variety of endogenous and exogenous ligands, such as steroid hormones, bile acids, pharmaceuticals, and environmental, dietary, and occupational chemicals. In turn, they induce phase I–III detoxification enzymes and transporters that help eliminate these chemicals. Because many of the chemicals that activate CAR and PXR are environmentally-relevant (dietary and anthropogenic), studies need to address whether these chemicals or mixtures of these chemicals may increase the susceptibility to adverse drug interactions. In addition, CAR and PXR are involved in hepatic proliferation, intermediary metabolism, and protection from cholestasis. Therefore, activation of CAR and PXR may have a wide variety of implications for personalized medicine through physiological effects on metabolism and cell proliferation; some beneficial and others adverse. Identifying the chemicals that activate these promiscuous nuclear receptors and understanding how these chemicals may act in concert will help us predict adverse drug reactions (ADRs), predict cholestasis and steatosis, and regulate intermediary metabolism. This review summarizes the available data on CAR and PXR, including the environmental chemicals that activate these receptors, the genes they control, and the physiological processes that are perturbed or depend on CAR and PXR action. This knowledge contributes to a foundation that will be necessary to discern interindividual differences in the downstream biological pathways regulated by these key nuclear receptors. PMID:20871735

Getting More Mileage out of Mousetrap Cars

ERIC Educational Resources Information Center

Rutherford, Sandra; Wylo, Bonnie

2004-01-01

Building and racing mousetrap cars is a common activity in many eighth- and ninth-grade physical science classrooms. However, once students have raced their cars, most mousetrap assignments come to an end. In this article, the authors developed a project to help teachers get more mileage out of mousetrap cars. The Mousetrap Car Project addresses…

Cloning and characterization of a novel NAC family gene CarNAC1 from chickpea (Cicer arietinum L.).

PubMed

Peng, Hui; Yu, Xingwang; Cheng, Huiying; Shi, Qinghua; Zhang, Hua; Li, Jiangui; Ma, Hao

2010-01-01

The plant-specific NAC (for NAM, ATAF1,2 and CUC2) proteins have been found to play important roles in plant development and stress responses. In this study, a NAC gene CarNAC1 (for Cicer arietinum L. NAC gene 1) was isolated from a cDNA library constructed with chickpea seedling leaves treated by polyethylene glycol. CarNAC1 encoded a putative protein with 239 amino acids and contained 3 exons and 2 introns within genomic DNA sequence. CarNAC1 had a conserved NAC domain in the N-terminus and the CarNAC1:GFP (green fluorescent protein) fusion protein was localized in the nucleus of onion epidermal cells. Additionally, CarNAC1 exhibited the trans-activation activity which was mapped to the C-terminus. The CarNAC1 transcript was detected in many chickpea organs including seedling leaves, stems, roots, flowers, and young pods, but less accumulated in young seeds. CarNAC1 was induced by leaf age and showed changes in expression during seed development and germination. Furthermore, the expression of CarNAC1 was strongly induced by drought, salt, cold, wounding, H(2)O(2), ethephon, salicylic acid, indole-3-acetic acid, and gibberellin. Our results suggest that CarNAC1 encodes a novel NAC-domain protein and may be a transcriptional activator involved in plant development and various stress responses.

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy.

PubMed

Fry, Terry J; Shah, Nirali N; Orentas, Rimas J; Stetler-Stevenson, Maryalice; Yuan, Constance M; Ramakrishna, Sneha; Wolters, Pamela; Martin, Staci; Delbrook, Cindy; Yates, Bonnie; Shalabi, Haneen; Fountaine, Thomas J; Shern, Jack F; Majzner, Robbie G; Stroncek, David F; Sabatino, Marianna; Feng, Yang; Dimitrov, Dimiter S; Zhang, Ling; Nguyen, Sang; Qin, Haiying; Dropulic, Boro; Lee, Daniel W; Mackall, Crystal L

2018-01-01

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 10 6 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19 dim or CD19 - B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22 + cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

PubMed

Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

2018-01-01

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.

An interactive driving simulation for driver control and decision-making research

NASA Technical Reports Server (NTRS)

Allen, R. W.; Hogge, J. R.; Schwartz, S. H.

1975-01-01

Display techniques and equations of motion for a relatively simple fixed base car simulation are described. The vehicle dynamics include simplified lateral (steering) and longitudinal (speed) degrees of freedom. Several simulator tasks are described which require a combination of operator control and decision making, including response to wind gust inputs, curved roads, traffic signal lights, and obstacles. Logic circuits are used to detect speeding, running red lights, and crashes. A variety of visual and auditory cues are used to give the driver appropriate performance feedback. The simulated equations of motion are reviewed and the technique for generating the line drawing CRT roadway display is discussed. On-line measurement capabilities and experimenter control features are presented, along with previous and current research results demonstrating simulation capabilities and applications.

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

PubMed Central

Kumar, Ramiya; Mota, Linda C.; Litoff, Elizabeth J.; Rooney, John P.; Boswell, W. Tyler; Courter, Elliott; Henderson, Charles M.; Hernandez, Juan P.; Corton, J. Christopher; Moore, David D.

2017-01-01

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice. PMID:28350814

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.

PubMed

Kumar, Ramiya; Mota, Linda C; Litoff, Elizabeth J; Rooney, John P; Boswell, W Tyler; Courter, Elliott; Henderson, Charles M; Hernandez, Juan P; Corton, J Christopher; Moore, David D; Baldwin, William S

2017-01-01

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

PubMed Central

Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina; Weber, Gerrit; Liu, Hao; Kim, Eugene S.; Ittmann, Michael M.; Marchetti, Dario; Dotti, Gianpietro

2015-01-01

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors1–3 than in lymphoid malignancies4, 5. Although active tumor-mediated immunosuppression may play a role in limiting efficacy6, functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors. PMID:25849134

Car Transfer and Wheelchair Loading Techniques in Independent Drivers with Paraplegia

PubMed Central

Haubert, Lisa Lighthall; Mulroy, Sara J.; Hatchett, Patricia E.; Eberly, Valerie J.; Maneekobkunwong, Somboon; Gronley, Joanne K.; Requejo, Philip S.

2015-01-01

Car transfers and wheelchair (WC) loading are crucial for independent community participation in persons with complete paraplegia from spinal cord injury, but are complex, physically demanding, and known to provoke shoulder pain. This study aimed to describe techniques and factors influencing car transfer and WC loading for individuals with paraplegia driving their own vehicles and using their personal WCs. Sedans were the most common vehicle driven (59%). Just over half (52%) of drivers place their right leg only into the vehicle prior to transfer. Overall, the leading hand was most frequently placed on the driver’s seat (66%) prior to transfer and the trailing hand was most often place on the WC seat (48%). Vehicle height influenced leading hand placement but not leg placement such that drivers of higher profile vehicles were more likely to place their hand on the driver’s seat than those who drove sedans. Body lift time was negatively correlated with level of injury and age and positively correlated with vehicle height and shoulder abduction strength. Drivers who transferred with their leading hand on the steering wheel had significantly higher levels of shoulder pain than those who placed their hand on the driver’s seat or overhead. The majority of participants used both hands (62%) to load their WC frame, and overall, most loaded their frame into the back (62%) vs. the front seat. Sedan drivers were more likely to load their frame into the front seat than drivers of higher profile vehicles (53 vs. 17%). Average time to load the WC frame (10.7 s) was 20% of the total WC loading time and was not related to shoulder strength, frame weight, or demographic characteristics. Those who loaded their WC frame into the back seat had significantly weaker right shoulder internal rotators. Understanding car transfers and WC loading in independent drivers is crucial to prevent shoulder pain and injury and preserve community participation. PMID:26442253

Increased actin polymerization reduces the inhibition of serum response factor activity by Yin Yang 1.

PubMed Central

Ellis, Peter D; Martin, Karen M; Rickman, Colin; Metcalfe, James C; Kemp, Paul R

2002-01-01

Recent evidence has implicated CC(A/T(richG))GG (CArG) boxes, binding sites for serum response factor (SRF), in the regulation of expression of a number of genes in response to changes in the actin cytoskeleton. In many cases, the activity of SRF at CArG boxes is modulated by transcription factors binding to overlapping (e.g. Yin Yang 1, YY1) or adjacent (e.g. ets) binding sites. However, the mechanisms by which SRF activity is regulated by the cytoskeleton have not been determined. To investigate these mechanisms, we screened for cells that did or did not increase the activity of a fragment of the promoter for a smooth-muscle (SM)-specific gene SM22alpha, in response to changes in actin cytoskeletal polymerization induced by LIM kinase. These experiments showed that vascular SM cells (VSMCs) and C2C12 cells increased the activity of promoters containing at least one of the SM22alpha CArG boxes (CArG near) in response to LIM kinase, whereas P19 cells did not. Bandshift assays using a probe to CArG near showed that P19 cells lacked detectable YY1 DNA binding to the CArG box in contrast with the other two cell types. Expression of YY1 in P19 cells inhibited SM22alpha promoter activity and conferred responsiveness to LIM kinase. Mutation of the CArG box to inhibit YY1 or SRF binding indicated that both factors were required for the LIM kinase response in VSMCs and C2C12 cells. The data indicate that changes in the actin cytoskeletal organization modify SRF activity at CArG boxes by modulating YY1-dependent inhibition. PMID:12023898

Quantitative High-Throughput Identification of Drugs as Modulators of Human Constitutive Androstane Receptor

PubMed Central

Lynch, Caitlin; Zhao, Jinghua; Huang, Ruili; Xiao, Jingwei; Li, Linhao; Heyward, Scott; Xia, Menghang; Wang, Hongbing

2015-01-01

The constitutive androstane receptor (CAR, NR1I3) plays a key role in governing the transcription of numerous hepatic genes that involve xenobiotic metabolism/clearance, energy homeostasis, and cell proliferation. Thus, identification of novel human CAR (hCAR) modulators may not only enhance early prediction of drug-drug interactions but also offer potentially novel therapeutics for diseases such as metabolic disorders and cancer. In this study, we have generated a double stable cell line expressing both hCAR and a CYP2B6-driven luciferase reporter for quantitative high-throughput screening (qHTS) of hCAR modulators. Approximately 2800 compounds from the NIH Chemical Genomics Center Pharmaceutical Collection were screened employing both the activation and deactivation modes of the qHTS. Activators (115) and deactivators (152) of hCAR were identified from the primary qHTS, among which 10 agonists and 10 antagonists were further validated in the physiologically relevant human primary hepatocytes for compound-mediated hCAR nuclear translocation and target gene expression. Collectively, our results reveal that hCAR modulators can be efficiently identified through this newly established qHTS assay. Profiling drug collections for hCAR activity would facilitate the prediction of metabolism-based drug-drug interactions, and may lead to the identification of potential novel therapeutics. PMID:25993555

Effect of protein supplementation on ruminal parameters and microbial community fingerprint of Nellore steers fed tropical forages.

PubMed

Bento, C B P; Azevedo, A C; Gomes, D I; Batista, E D; Rufino, L M A; Detmann, E; Mantovani, H C

2016-01-01

In tropical regions, protein supplementation is a common practice in dairy and beef farming. However, the effect of highly degradable protein in ruminal fermentation and microbial community composition has not yet been investigated in a systematic manner. In this work, we aimed to investigate the impact of casein supplementation on volatile fatty acids (VFA) production, specific activity of deamination (SAD), ammonia concentration and bacterial and archaeal community composition. The experimental design was a 4×4 Latin square balanced for residual effects, with four animals (average initial weight of 280±10 kg) and four experimental periods, each with duration of 29 days. The diet comprised Tifton 85 (Cynodon sp.) hay with an average CP content of 9.8%, on a dry matter basis. Animals received basal forage (control) or infusions of pure casein (230 g) administered direct into the rumen, abomasum or divided (50 : 50 ratio) in the rumen/abomasum. There was no differences (P>0.05) in ruminal pH and microbial protein concentration between supplemented v. non-supplemented animals. However, in steers receiving ruminal infusion of casein the SAD and ruminal ammonia concentration increased 33% and 76%, respectively, compared with the control. The total concentration of VFA increased (P0.05) in species richness and diversity of γ-proteobacteria, firmicutes and archaea between non-supplemented Nellore steers and steers receiving casein supplementation in the rumen. However, species richness and the Shannon-Wiener index were lower (P<0.05) for the phylum bacteroidetes in steers supplemented with casein in the rumen compared with non-supplemented animals. Venn diagrams indicated that the number of unique bands varied considerably among individual animals and was usually higher in number for non-supplemented steers compared with supplemented animals. These results add new knowledge about the effects of ruminal and postruminal protein supplementation on metabolic activities of rumen microbes and the composition of bacterial and archaeal communities in the rumen of steers.

Expression of extracellular calcium-sensing receptor in human osteoblastic MG-63 cell line

NASA Technical Reports Server (NTRS)

Yamaguchi, T.; Chattopadhyay, N.; Kifor, O.; Ye, C.; Vassilev, P. M.; Sanders, J. L.; Brown, E. M.

2001-01-01

We have previously shown the expression of the extracellular calcium (Ca2+o)-sensing receptor (CaR) in osteoblast-like cell lines, and others have documented its expression in sections of murine, bovine, and rat bone. The existence of the CaR in osteoblasts remains controversial, however, since some studies have failed to document its expression in the same osteoblast-like cell lines. The goals of the present study were twofold. 1) We sought to determine whether the CaR is expressed in the human osteoblast-like cell line, MG-63, which has recently been reported by others not to express this receptor. 2) We investigated whether the CaR, if present in MG-63 cells, is functionally active, since most previous studies have not proven the role of the CaR in mediating known actions of Ca2+o on osteoblast-like cells. We used immunocytochemistry and Western blotting with the specific, affinity-purified anti-CaR antiserum 4637 as well as Northern blot analysis and RT-PCR using a riboprobe and PCR primers specific for the human CaR, respectively, to show readily detectable CaR protein and mRNA expression in MG-63 cells. Finally, we employed the patch-clamp technique to show that an elevation in Ca2+o as well as the specific, allosteric CaR activator NPS R-467 (0.5 microM), but not its less active stereoisomer NPS S-467 (0.5 microM), activate an outward K+ channel in MG-63 cells, strongly suggesting that the CaR in MG-63 cells is not only expressed but is functionally active.

Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms

PubMed Central

Burk, O; Piedade, R; Ghebreghiorghis, L; Fait, JT; Nussler, AK; Gil, JP; Windshügel, B; Schwab, M

2012-01-01

BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug–drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug–drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered. PMID:22577882

Controlled Structures Technology Steering Committee Workshop

NASA Technical Reports Server (NTRS)

1992-01-01

Viewgraphs on controlled structures technology presented at the steering committee workshop on 22-23 Jan. 1992 are included. Topics addressed include: interferometer testbed; middeck 0-gravity dynamics experiment; middeck active control experiment; multivariable identification for control; strain actuated aeroelastic control; sensor/actuator technology development; input command shaping; and other research projects. A description of the organization and committee are included.

Sensorimotor Integration for Decision Making: How the Worm Steers.

PubMed

Kaplan, Harris S; Zimmer, Manuel

2018-01-17

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu et al. (2018) show how C. elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals. Copyright © 2017 Elsevier Inc. All rights reserved.

Multi-Level Steering and Institution Building: The European Union's Approach to Research Policy

ERIC Educational Resources Information Center

Young, Mitchell

2012-01-01

Adopting the conception of the university as a primary driver of innovation and economic growth has brought increased pressure for the European Union (EU) to actively steer university-based research policy, despite its being outside of the EU's direct jurisdiction. While the open method of coordination (OMC) was developed for such situations, the…

Effects of castration on eating pattern and physical activity of Holstein bulls fed high-concentrate rations under commercial conditions.

PubMed

Devant, M; Marti, S; Bach, A

2012-12-01

A total of 132 animals (initial BW = 220 ± 22 kg and age = 166 ± 0.4 d) were used to study the effect of castration on eating behavior and physical activity. Animals were randomly allocated to 6 pens with 2 pens for each of the 3 treatment groups: 44 intact bulls, 44 steers castrated (3 mo of age) before the study began, and 44 bulls castrated (CAS) at 8 mo of age (at d 69 of the study). The study finished when animals reached 292 d of age. Each pen held 22 animals, and had 1 computerized concentrate feeder (GEA WestfaliaSurge, Germany), 1 feed trough for straw, and 1 water source. Concentrate and straw were offered ad libitum. Animals were weighed every 14 d and eating pattern at which animals consumed concentrate was averaged for each 14-d period. A pedometer was placed on the left hind leg of 86 animals randomly distributed among treatments to estimate physical activity from d -5 to 10 relative to surgical castration (d 65 to 79 of study). The statistical model included initial BW as a covariate, treatment, period, and the interaction between treatment and time (14-d), as fixed effects, and pen and animal as random effects. For physical activity data, day was the repeated measure. The CAS animals exhibited reduced ADG and concentrate DMI (P < 0.001) during the first 2 wk after castration than bulls or steers. Eating behavior throughout the study differed among treatments. Meal size (1.3 ± 0.05 kg) and meal duration (12.4 ± 0.47 min) were greater (P < 0.001) in bulls during the 2 wk after castration than in steers (1.0 ± 0.05 kg and 9.7 ± 0.46 min, respectively) and CAS animals (0.8 ± 0.05 kg and 7.8 ± 0.47 min, respectively). In contrast, bulls visited the feeders less frequently (5.3 ± 0.34/d) during these 2 wk than did steers (6.7 ± 0.34/d) and CAS animals (7.7 ± 0.34/d). In addition, daily intake, meal size, and eating rate increased (P < 0.001) with time. Lying time in CAS animals was reduced (P < 0.001) for the 5 d after castration compared with bulls and steers. Bulls were more active (steps/h) than steers, and activity of recently castrated animals decreased (P < 0.001) for at least 10 d after castration. Although 2 wk after castration differences in eating pattern across treatments were observed, the long-term effects of castration and gender (bull vs. steer) on eating behavior were difficult to interpret. Castration effects on total feed intake and lying time are temporary, whereas castration has a lasting reduction on physical activity.

Stable Overexpression of the Constitutive Androstane Receptor Reduces the Requirement for Culture with Dimethyl Sulfoxide for High Drug Metabolism in HepaRG Cells.

PubMed

van der Mark, Vincent A; Rudi de Waart, D; Shevchenko, Valery; Elferink, Ronald P J Oude; Chamuleau, Robert A F M; Hoekstra, Ruurdtje

2017-01-01

Dimethylsulfoxide (DMSO) induces cellular differentiation and expression of drug metabolic enzymes in the human liver cell line HepaRG; however, DMSO also induces cell death and interferes with cellular activities. The aim of this study was to examine whether overexpression of the constitutive androstane receptor (CAR, NR1I3), the nuclear receptor controlling various drug metabolism genes, would sufficiently promote differentiation and drug metabolism in HepaRG cells, optionally without using DMSO. By stable lentiviral overexpression of CAR, HepaRG cultures were less affected by DMSO in total protein content and obtained increased resistance to acetaminophen- and amiodarone-induced cell death. Transcript levels of CAR target genes were significantly increased in HepaRG-CAR cultures without DMSO, resulting in increased activities of cytochrome P450 (P450) enzymes and bilirubin conjugation to levels equal or surpassing those of HepaRG cells cultured with DMSO. Unexpectedly, CAR overexpression also increased the activities of non-CAR target P450s, as well as albumin production. In combination with DMSO treatment, CAR overexpression further increased transcript levels and activities of CAR targets. Induction of CYP1A2 and CYP2B6 remained unchanged, whereas CYP3A4 was reduced. Moreover, the metabolism of low-clearance compounds warfarin and prednisolone was increased. In conclusion, CAR overexpression creates a more physiologically relevant environment for studies on hepatic (drug) metabolism and differentiation in HepaRG cells without the utilization of DMSO. DMSO still may be applied to accomplish higher drug metabolism, required for sensitive assays, such as low-clearance studies and identification of (rare) metabolites, whereas reduced total protein content after DMSO culture is diminished by CAR overexpression. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way.

PubMed

Marmugi, Alice; Lukowicz, Céline; Lasserre, Frederic; Montagner, Alexandra; Polizzi, Arnaud; Ducheix, Simon; Goron, Adeline; Gamet-Payrastre, Laurence; Gerbal-Chaloin, Sabine; Pascussi, Jean Marc; Moldes, Marthe; Pineau, Thierry; Guillou, Hervé; Mselli-Lakhal, Laila

2016-07-15

The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenic genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver

PubMed Central

Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

2014-01-01

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car +/+ mice. After being fed the DDC diet, Car +/+, but not Car−/− mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car +/+, but not Car−/− mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car +/+ mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma. PMID:21826054

Light-induced carotenogenesis in Myxococcus xanthus: evidence that CarS acts as an anti-repressor of CarA.

PubMed

Whitworth, D E; Hodgson, D A

2001-11-01

In the bacterium Myxococcus xanthus, carotenoids are produced in response to illumination, as a result of expression of the crt carotenoid biosynthesis genes. The majority of crt genes are clustered in the crtEBDC operon, which is repressed in the dark by CarA. Genetic data suggest that, in the light, CarS is synthesized and achieves activation of the crtEBDC operon by removing the repressive action of CarA. As CarS contains no known DNA-binding motif, the relief of CarA-mediated repression was postulated to result from a direct interaction between these two proteins. Use of the yeast two-hybrid system demonstrated direct interaction between CarA and CarS. The two-hybrid system also implied that CarA and, possibly, CarS are capable of homodimerization. Direct evidence for CarS anti-repressor action was provided in vitro. A glutathione S-transferase (GST)-CarA protein fusion was shown to bind specifically to a palindromic operator sequence within the crtEBDC promoter. CarA was prevented from binding to its operator, and prebound CarA was removed by the addition of purified CarS. CarS is therefore an anti-repressor.

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants.

PubMed

Krenciute, Giedre; Prinzing, Brooke L; Yi, Zhongzhen; Wu, Meng-Fen; Liu, Hao; Dotti, Gianpietro; Balyasnikova, Irina V; Gottschalk, Stephen

2017-07-01

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo , IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens. Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss variants highlights the need to target multiple tumor antigens. Cancer Immunol Res; 5(7); 571-81. ©2017 AACR . ©2017 American Association for Cancer Research.

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18.

PubMed

Hu, Biliang; Ren, Jiangtao; Luo, Yanping; Keith, Brian; Young, Regina M; Scholler, John; Zhao, Yangbing; June, Carl H

2017-09-26

The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors. Copyright © 2017. Published by Elsevier Inc.

Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity

PubMed Central

Wang, Liang-Chuan S; Lo, Albert; Scholler, John; Sun, Jing; Majumdar, Rajrupa S; Kapoor, Veena; Antzis, Michael; Cotner, Cody E.; Johnson, Laura A; Durham, Amy C; Solomides, Charalambos C.; June, Carl H; Puré, Ellen; Albelda, Steven M

2013-01-01

The majority of chimeric antigen receptor (CAR) T cell research has focused on attacking cancer cells. Here we show that targeting the tumor-promoting, non-transformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single chain Fv FAP (mAb 73.3) with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective suggesting that further clinical development of anti-human FAP-CAR is warranted. PMID:24778279

76 FR 9775 - Agency Information Collection Activities; Submission to OMB for Review and Approval; Comment...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-22

... Activities; Submission to OMB for Review and Approval; Comment Request; The Consolidated Air Rule (CAR) for... (CAR) for the Synthetic Organic Chemical Manufacturing Industry (SOCMI) (Renewal). ICR Numbers: EPA ICR... with the above standards under the Consolidated Air Rule (CAR) at 40 CFR part 65, as promulgated on...

Handling and safety enhancement of race cars using active aerodynamic systems

NASA Astrophysics Data System (ADS)

Diba, Fereydoon; Barari, Ahmad; Esmailzadeh, Ebrahim

2014-09-01

A methodology is presented in this work that employs the active inverted wings to enhance the road holding by increasing the downward force on the tyres. In the proposed active system, the angles of attack of the vehicle's wings are adjusted by using a real-time controller to increase the road holding and hence improve the vehicle handling. The handling of the race car and safety of the driver are two important concerns in the design of race cars. The handling of a vehicle depends on the dynamic capabilities of the vehicle and also the pneumatic tyres' limitations. The vehicle side-slip angle, as a measure of the vehicle dynamic safety, should be narrowed into an acceptable range. This paper demonstrates that active inverted wings can provide noteworthy dynamic capabilities and enhance the safety features of race cars. Detailed analytical study and formulations of the race car nonlinear model with the airfoils are presented. Computer simulations are carried out to evaluate the performance of the proposed active aerodynamic system.

Glycolytic potential and activity of adenosine monophosphate kinase (AMPK), glycogen phosphorylase (GP) and glycogen debranching enzyme (GDE) in steer carcasses with normal (<5.8) or high (>5.9) 24h pH determined in M. longissimus dorsi.

PubMed

Apaoblaza, A; Galaz, A; Strobel, P; Ramírez-Reveco, A; Jeréz-Timaure, N; Gallo, C

2015-03-01

Muscle glycogen concentration (MGC) and lactate (LA), activity of glycogen debranching enzyme (GDE), glycogen phosphorylase (GP) and adenosine monophosphate kinase (AMPK) were determined at 0.5h (T0) and 24h (T24) post-mortem in Longissimus dorsi samples from 38 steers that produced high pH (>5.9) and normal pH (<5.8) carcasses at 24h postmortem. MGC, LA and glycolytic potential were higher (P<0.05) in normal pH carcasses. GDE activity was similar (P>0.05) in both pH categories. GP activity increased between T0 and T24 only in normal pH carcasses. AMPK activity was four times higher in normal pH v/s high pH carcasses, without changing its activity over time. Results reinforce the idea that differences in postmortem glycogenolytic/glycolytic flow in L. dorsi of steers showing normal v/s high muscle pH at 24h, could be explained not only by the higher initial MGC in normal pH carcasses, but also by a high and sustained activity of AMPK and an increased GP activity at 24h postmortem. Copyright © 2014 Elsevier Ltd. All rights reserved.

Novel activating mutation of human calcium-sensing receptor in a family with autosomal dominant hypocalcaemia.

PubMed

Baran, Natalia; ter Braak, Michael; Saffrich, Rainer; Woelfle, Joachim; Schmitz, Udo

2015-05-15

Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium sensing receptor gene (CaR) and characterised by mostly asymptomatic mild to moderate hypocalcaemia with low, inappropriately serum concentration of PTH. The purpose of the present study was to biochemically and functionally characterise a novel mutation of CaR. A female proband presenting with hypocalcaemia was diagnosed to have "idiopathic hypoparathyroidism" at the age of 10 with a history of muscle pain and cramps. Further examinations demonstrated hypocalcaemia in nine additional family members, affecting three generations. P136L CaR mutation was predicted to cause gain of function of CaR. Affected family members showed relevant hypocalcaemia (mean ± SD; 1.9 ± 0.1 mmol/l). Patient history included mild seizures and recurrent nephrolithiasis. Genetic analysis confirmed that hypocalcaemia cosegregated with a heterozygous mutation at codon 136 (CCC → CTC/Pro → Leu) in exon 3 of CaR confirming the diagnosis of ADH. For in vitro studies P136L mutant CaR was generated by site-directed mutagenesis and examined in transiently transfected HEK293 cells. Extracellular calcium stimulation of transiently transfected HEK293 cells showed significantly increased intracellular Ca(2+) mobilisation and MAPK activity for mutant P136L CaR compared to wild type CaR. The present study gives insight about a novel activating mutation of CaR and confirms that the novel P136L-CaR mutation is responsible for ADH in this family. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparing spatially static and dynamic vibrotactile take-over requests in the driver seat.

PubMed

Petermeijer, S M; Cieler, S; de Winter, J C F

2017-02-01

Vibrotactile stimuli can be effective as warning signals, but their effectiveness as directional take-over requests in automated driving is yet unknown. This study aimed to investigate the correct response rate, reaction times, and eye and head orientation for static versus dynamic directional take-over requests presented via vibrating motors in the driver seat. In a driving simulator, eighteen participants performed three sessions: 1) a session involving no driving (Baseline), 2) driving a highly automated car without additional task (HAD), and 3) driving a highly automated car while performing a mentally demanding task (N-Back). Per session, participants received four directional static (in the left or right part of the seat) and four dynamic (moving from one side towards the opposite left or right of the seat) take-over requests via two 6×4 motor matrices embedded in the seat back and bottom. In the Baseline condition, participants reported whether the cue was left or right, and in the HAD and N-Back conditions participants had to change lanes to the left or to the right according to the directional cue. The correct response rate was operationalized as the accuracy of the self-reported direction (Baseline session) and the accuracy of the lane change direction (HAD & N-Back sessions). The results showed that the correct response rate ranged between 94% for static patterns in the Baseline session and 74% for dynamic patterns in the N-Back session, although these effects were not statistically significant. Steering wheel touch and steering input reaction times were approximately 200ms faster for static patterns than for dynamic ones. Eye tracking results revealed a correspondence between head/eye-gaze direction and lane change direction, and showed that head and eye-gaze movements where initiated faster for static vibrations than for dynamic ones. In conclusion, vibrotactile stimuli presented via the driver seat are effective as warnings, but their effectiveness as directional take-over requests may be limited. The present study may encourage further investigation into how to get drivers safely back into the loop. Copyright © 2016 Elsevier Ltd. All rights reserved.

Garlic Extract Diallyl Sulfide (DAS) Activates Nuclear Receptor CAR to Induce the Sult1e1 Gene in Mouse Liver

PubMed Central

Sueyoshi, Tatsuya; Green, William D.; Vinal, Kellie; Woodrum, Tyler S.; Moore, Rick; Negishi, Masahiko

2011-01-01

Constituent chemicals in garlic extract are known to induce phase I and phase II enzymes in rodent livers. Here we have utilized Car +/+ and Car −/− mice to demonstrate that the nuclear xenobiotic receptor CAR regulated the induction of the estrogen sulfotransferase Sult1e1 gene by diallyl sulfide (DAS) treatment in mouse liver. DAS treatment caused CAR accumulation in the nucleus, resulting in a remarkable increase of SULT1E1 mRNA (3,200 fold) and protein in the livers of Car +/+ females but not of Car −/− female mice. DAS also induced other CAR-regulated genes such as Cyp2b10, Cyp3a11 and Gadd45β. Compared with the rapid increase of these mRNA levels, which began as early as 6 hourrs after DAS treatment, the levels of SULT1E1 mRNA began increasing after 24 hours. This slow response to DAS suggested that CAR required an additional factor to activate the Sult1e1 gene or that this activation was indirect. Despite the remarkable induction of SULT1E1, there was no decrease in the serum levels of endogenous E2 or increase of estrone sulfate while the clearance of exogenously administrated E2 was accelerated in DAS treated mice. PMID:21698271

Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors.

PubMed

Kochenderfer, James N; Rosenberg, Steven A

2013-05-01

Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19(+) B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies.

Garlic extract diallyl sulfide (DAS) activates nuclear receptor CAR to induce the Sult1e1 gene in mouse liver.

PubMed

Sueyoshi, Tatsuya; Green, William D; Vinal, Kellie; Woodrum, Tyler S; Moore, Rick; Negishi, Masahiko

2011-01-01

Constituent chemicals in garlic extract are known to induce phase I and phase II enzymes in rodent livers. Here we have utilized Car(+/+) and Car(-/-) mice to demonstrate that the nuclear xenobiotic receptor CAR regulated the induction of the estrogen sulfotransferase Sult1e1 gene by diallyl sulfide (DAS) treatment in mouse liver. DAS treatment caused CAR accumulation in the nucleus, resulting in a remarkable increase of SULT1E1 mRNA (3,200 fold) and protein in the livers of Car(+/+) females but not of Car(-/-) female mice. DAS also induced other CAR-regulated genes such as Cyp2b10, Cyp3a11 and Gadd45β. Compared with the rapid increase of these mRNA levels, which began as early as 6 hours after DAS treatment, the levels of SULT1E1 mRNA began increasing after 24 hours. This slow response to DAS suggested that CAR required an additional factor to activate the Sult1e1 gene or that this activation was indirect. Despite the remarkable induction of SULT1E1, there was no decrease in the serum levels of endogenous E2 or increase of estrone sulfate while the clearance of exogenously administrated E2 was accelerated in DAS treated mice.

Steer by ear: Myoelectric auricular control of powered wheelchairs for individuals with spinal cord injury.

PubMed

Schmalfuß, L; Rupp, R; Tuga, M R; Kogut, A; Hewitt, M; Meincke, J; Klinker, F; Duttenhoefer, W; Eck, U; Mikut, R; Reischl, M; Liebetanz, D

2015-01-01

Providing mobility solutions for individuals with tetraplegia remains challenging. Existing control devices have shortcomings such as varying or poor signal quality or interference with communication. To overcome these limitations, we present a novel myoelectric auricular control system (ACS) based on bilateral activation of the posterior auricular muscles (PAMs). Ten able-bodied subjects and two individuals with tetraplegia practiced PAM activation over 4 days using visual feedback and software-based training for 1 h/day. Initially, half of these subjects were not able to voluntarily activate their PAMs. This ability was tested with regard to 8 parameters such as contraction rate, lateralized activation, wheelchair speed and path length in a virtual obstacle course. In session 5, all subjects steered an electric wheelchair with the ACS. Performance of all subjects in controlling their PAMs improved steadily over the training period. By day 5, all subjects successfully generated basic steering commands using the ACS in a powered wheelchair, and subjects with tetraplegia completed a complex real-world obstacle course. This study demonstrates that the ability to activate PAM on both sides together or unilaterally can be learned and used intuitively to steer a wheelchair. With the ACS we can exploit the untapped potential of the PAMs by assigning them a new, complex function. The inherent advantages of the ACS, such as not interfering with oral communication, robustness, stability over time and proportional and continuous signal generation, meet the specific needs of wheelchair users and render it a realistic alternative to currently available assistive technologies.

Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability

DOE PAGES

Tsutakawa, Susan E.; Thompson, Mark J.; Arvai, Andrew S.; ...

2017-06-27

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA formore » catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.« less

Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsutakawa, Susan E.; Thompson, Mark J.; Arvai, Andrew S.

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA formore » catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.« less

Steering disturbance rejection using a physics-based neuromusculoskeletal driver model

NASA Astrophysics Data System (ADS)

Mehrabi, Naser; Sharif Razavian, Reza; McPhee, John

2015-10-01

The aim of this work is to develop a comprehensive yet practical driver model to be used in studying driver-vehicle interactions. Drivers interact with their vehicle and the road through the steering wheel. This interaction forms a closed-loop coupled human-machine system, which influences the driver's steering feel and control performance. A hierarchical approach is proposed here to capture the complexity of the driver's neuromuscular dynamics and the central nervous system in the coordination of the driver's upper extremity activities, especially in the presence of external disturbance. The proposed motor control framework has three layers: the first (or the path planning) plans a desired vehicle trajectory and the required steering angles to perform the desired trajectory; the second (or the musculoskeletal controller) actuates the musculoskeletal arm to rotate the steering wheel accordingly; and the final layer ensures the precision control and disturbance rejection of the motor control units. The physics-based driver model presented here can also provide insights into vehicle control in relaxed and tensed driving conditions, which are simulated by adjusting the driver model parameters such as cognition delay and muscle co-contraction dynamics.

Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T

PubMed Central

Yoon, Dok Hyun; Osborn, Mark J.; Tolar, Jakub; Kim, Chong Jai

2018-01-01

Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade. PMID:29364163

Relationships between inflammation- and immunity-related transcript abundance in the rumen and jejunum of beef steers with divergent average daily gain

USDA-ARS?s Scientific Manuscript database

The bovine rumen papillae are in contact with a wide array of microorganisms and the metabolites they produce, which may activate an inflammatory and/or immune response. Cytokines, chemokines and their receptor genes were tested for differential expression in the rumen and jejunum of beef steers wit...

Is this car looking at you? How anthropomorphism predicts fusiform face area activation when seeing cars.

PubMed

Kühn, Simone; Brick, Timothy R; Müller, Barbara C N; Gallinat, Jürgen

2014-01-01

Anthropomorphism encompasses the attribution of human characteristics to non-living objects. In particular the human tendency to see faces in cars has long been noticed, yet its neural correlates are unknown. We set out to investigate whether the fusiform face area (FFA) is associated with seeing human features in car fronts, or whether, the higher-level theory of mind network (ToM), namely temporoparietal junction (TPJ) and medial prefrontal cortex (MPFC) show a link to anthropomorphism. Twenty participants underwent fMRI scanning during a passive car-front viewing task. We extracted brain activity from FFA, TPJ and MPFC. After the fMRI session participants were asked to spontaneously list adjectives that characterize each car front. Five raters judged the degree to which each adjective can be applied as a characteristic of human beings. By means of linear mixed models we found that the implicit tendency to anthropomorphize individual car fronts predicts FFA, but not TPJ or MPFC activity. The results point to an important role of FFA in the phenomenon of ascribing human attributes to non-living objects. Interestingly, brain regions that have been associated with thinking about beliefs and mental states of others (TPJ, MPFC) do not seem to be related to anthropomorphism of car fronts.

Is This Car Looking at You? How Anthropomorphism Predicts Fusiform Face Area Activation when Seeing Cars

PubMed Central

Kühn, Simone; Brick, Timothy R.; Müller, Barbara C. N.; Gallinat, Jürgen

2014-01-01

Anthropomorphism encompasses the attribution of human characteristics to non-living objects. In particular the human tendency to see faces in cars has long been noticed, yet its neural correlates are unknown. We set out to investigate whether the fusiform face area (FFA) is associated with seeing human features in car fronts, or whether, the higher-level theory of mind network (ToM), namely temporoparietal junction (TPJ) and medial prefrontal cortex (MPFC) show a link to anthropomorphism. Twenty participants underwent fMRI scanning during a passive car-front viewing task. We extracted brain activity from FFA, TPJ and MPFC. After the fMRI session participants were asked to spontaneously list adjectives that characterize each car front. Five raters judged the degree to which each adjective can be applied as a characteristic of human beings. By means of linear mixed models we found that the implicit tendency to anthropomorphize individual car fronts predicts FFA, but not TPJ or MPFC activity. The results point to an important role of FFA in the phenomenon of ascribing human attributes to non-living objects. Interestingly, brain regions that have been associated with thinking about beliefs and mental states of others (TPJ, MPFC) do not seem to be related to anthropomorphism of car fronts. PMID:25517511

An Insulin-Like Growth Factor 1 Receptor Inhibitor Induces CYP3A4 Expression through a Pregnane X Receptor-Independent, Noncanonical Constitutive Androstane Receptor-Related Mechanism

PubMed Central

Li, Linhao; Sinz, Michael W.; Zimmermann, Kurt

2012-01-01

Inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling represents an attractive therapeutic strategy for cancer treatment. A first-generation IGF-1R inhibitor (R)-4-(3-(3-chlorophenyl)-3-hydroxypropyl)-3-(4-methyl-6-morpholino-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-536924), however, was associated with potent CYP3A4 induction mediated by pregnane X receptor (PXR; NR1I2) transactivation. Structural activity-based modification led to the synthesis of 4-(1-(2-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-1H-benzo[d]imidazol-6-yl)piperidin-4-yl) piperazine-1-carboxylate (BMS-665351) with no PXR activity while maintaining its ability to inhibit IGF-1R. However, BMS-665351 significantly induces CYP3A4 expression in human primary hepatocytes (HPHs). Here, we report a novel nonclassical constitutive androstane receptor (CAR; NR1I3)-related pathway of BMS-665351-mediated CYP3A4 induction. BMS-665351 treatment resulted in the significant induction of CYP3A4 in HPHs and HepG2 cells, but failed to activate either PXR or CAR in cell-based reporter assays. Moreover, BMS-665351 at concentrations that induce CYP3A4 expression was unable to translocate human CAR from the cytoplasm to the nucleus of HPHs, which represents the initial step of CAR activation. Nevertheless, quantitative polymerase chain reaction analysis demonstrated that BMS-665351 significantly enhanced the expression of CYP3A4 in CAR- but not PXR-transfected HepG2 and Huh7 cells. It is noteworthy that BMS-665351 selectively induced the expression of CAR but not PXR in all tested hepatic cell systems. Synergistic induction of CYP3A4 was observed in HPHs cotreated with BMS-665351 and prototypical activators of CAR but not PXR. In summary, our results indicate that BMS-665351-mediated induction of CYP3A4 is CAR-dependent, but BMS-665351 itself is not a typical activator of either CAR or PXR, rather it functions as a selective inducer of CAR expression and increases CYP3A4 through a noncanonical CAR-related mechanism. PMID:22171088

Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells

PubMed Central

Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S.; Mok, Pooi Ling

2017-01-01

Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non–transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. PMID:28885562

Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells.

PubMed

Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S; Mok, Pooi Ling

2017-09-08

Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours.

78 FR 59032 - Agency Information Collection Activities; Proposed Collection; Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-25

... information collection requirements in its regulation ``Used Motor Vehicle Trade Regulation Rule'' (``Used Car... INFORMATION section below. Write ``Used Car Rule, PRA Comment, P137606'' on your comment and file your comment.... SUPPLEMENTARY INFORMATION: The Used Car Rule promotes informed purchasing decisions by requiring used car...

Full-Scale Field Test of Wake Steering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleming, Paul; Annoni, Jennifer; Scholbrock, Andrew

Wind farm control, in which turbine controllers are coordinated to improve farmwide performance, is an active field of research. One form of wind farm control is wake steering, in which a turbine is yawed to the inflow to redirect its wake away from downstream turbines. Wake steering has been studied in depth in simulations as well as in wind tunnels and scaled test facilities. This work performs a field test of wake steering on a full-scale turbine. In the campaign, the yaw controller of the turbine has been set to track different yaw misalignment set points while a nacelle-mounted lidarmore » scans the wake at several ranges downwind. The lidar measurements are combined with turbine data, as well as measurements of the inflow made by a highly instrumented meteorological mast. In conclusion, these measurements are then compared to the predictions of a wind farm control-oriented model of wakes.« less

Adaptive beam tracking and steering via electrowetting-controlled liquid prism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, JT; Chen, CL

2011-11-07

We report an electrowetting-controlled optofluidic system for adaptive beam tracking and agile steering. With two immiscible fluids in a transparent cell, we can actively control the contact angle along the fluid-fluid-solid tri-junction line and hence the orientation of the fluid-fluid interface via electrowetting. The naturally formed meniscus between the two liquids can function as an optical prism. We have fabricated a liquid prism module with an aperture size of 10 mm -10mm. With 1 wt.% KCl and 1 wt.% Sodium Dodecyl Sulfate added into deionized water, the orientation of the water-silicone oil interface has been modulated between -26 degrees andmore » 26 degrees that can deflect and steer beam within the incidence angle of 0 degrees-15 degrees. The wide-range beam tracking and steering enables the liquid prism work as an electrowetting solar cell. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3660578]« less

Adaptive beam tracking and steering via electrowetting-controlled liquid prism

NASA Astrophysics Data System (ADS)

Cheng, Jiangtao; Chen, Chung-Lung

2011-11-01

We report an electrowetting-controlled optofluidic system for adaptive beam tracking and agile steering. With two immiscible fluids in a transparent cell, we can actively control the contact angle along the fluid-fluid-solid tri-junction line and hence the orientation of the fluid-fluid interface via electrowetting. The naturally formed meniscus between the two liquids can function as an optical prism. We have fabricated a liquid prism module with an aperture size of 10 mm × 10mm. With 1 wt. % KCl and 1 wt. % Sodium Dodecyl Sulfate added into deionized water, the orientation of the water-silicone oil interface has been modulated between -26° and 26° that can deflect and steer beam within the incidence angle of 0°-15°. The wide-range beam tracking and steering enables the liquid prism work as an electrowetting solar cell.

Full-Scale Field Test of Wake Steering

DOE PAGES

Fleming, Paul; Annoni, Jennifer; Scholbrock, Andrew; ...

2017-06-13

Wind farm control, in which turbine controllers are coordinated to improve farmwide performance, is an active field of research. One form of wind farm control is wake steering, in which a turbine is yawed to the inflow to redirect its wake away from downstream turbines. Wake steering has been studied in depth in simulations as well as in wind tunnels and scaled test facilities. This work performs a field test of wake steering on a full-scale turbine. In the campaign, the yaw controller of the turbine has been set to track different yaw misalignment set points while a nacelle-mounted lidarmore » scans the wake at several ranges downwind. The lidar measurements are combined with turbine data, as well as measurements of the inflow made by a highly instrumented meteorological mast. In conclusion, these measurements are then compared to the predictions of a wind farm control-oriented model of wakes.« less

Association of car ownership and physical activity across the spectrum of human development: Modeling the Epidemiologic Transition Study (METS).

PubMed

Shoham, David A; Dugas, Lara R; Bovet, Pascal; Forrester, Terrence E; Lambert, Estelle V; Plange-Rhule, Jacob; Schoeller, Dale A; Brage, Soren; Ekelund, Ulf; Durazo-Arvizu, Ramon A; Cooper, Richard S; Luke, Amy

2015-02-21

Variations in physical activity (PA) across nations may be driven by socioeconomic position. As national incomes increase, car ownership becomes within reach of more individuals. This report characterizes associations between car ownership and PA in African-origin populations across 5 sites at different levels of economic development and with different transportation infrastructures: US, Seychelles, Jamaica, South Africa, and Ghana. Twenty-five hundred adults, ages 25-45, were enrolled in the study. A total of 2,101 subjects had valid accelerometer-based PA measures (reported as average daily duration of moderate to vigorous PA, MVPA) and complete socioeconomic information. Our primary exposure of interest was whether the household owned a car. We adjusted for socioeconomic position using household income and ownership of common goods. Overall, PA levels did not vary largely between sites, with highest levels in South Africa, lowest in the US. Across all sites, greater PA was consistently associated with male gender, fewer years of education, manual occupations, lower income, and owning fewer material goods. We found heterogeneity across sites in car ownership: after adjustment for confounders, car owners in the US had 24.3 fewer minutes of MVPA compared to non-car owners in the US (20.7 vs. 45.1 minutes/day of MVPA); in the non-US sites, car-owners had an average of 9.7 fewer minutes of MVPA than non-car owners (24.9 vs. 34.6 minutes/day of MVPA). PA levels are similar across all study sites except Jamaica, despite very different levels of socioeconomic development. Not owning a car in the US is associated with especially high levels of MVPA. As car ownership becomes prevalent in the developing world, strategies to promote alternative forms of active transit may become important.

Engineering Chimeric Antigen Receptors

PubMed Central

Kulemzin, S. V.; Kuznetsova, V. V.; Mamonkin, M.; Taranin, A. V.; Gorchakov, A. A.

2017-01-01

Chimeric antigen receptors (CARs) are recombinant protein molecules that redirect cytotoxic lymphocytes toward malignant and other target cells. The high feasibility of manufacturing CAR-modified lymphocytes for the therapy of cancer has spurred the development and optimization of new CAR T cells directed against a broad range of target antigens. In this review, we describe the main structural and functional elements constituting a CAR, discuss the roles of these elements in modulating the anti-tumor activity of CAR T cells, and highlight alternative approaches to CAR engineering. PMID:28461969

Analysis of car-to-bicycle approach patterns for developing active safety devices.

PubMed

Matsui, Yasuhiro; Oikawa, Shoko; Hitosugi, Masahito

2016-05-18

To reduce the severity of injuries and the number of cyclist deaths in traffic accidents, active safety devices providing cyclist detection are considered to be effective countermeasures. The features of car-to-bicycle collisions need to be known in detail to develop such safety devices. The study investigated near-miss situations captured by drive recorders installed in passenger cars. Because similarities in the approach patterns between near-miss incidents and real-world fatal cyclist accidents in Japan were confirmed, we analyzed the 229 near-miss incident data via video capturing bicycles crossing the road in front of forward-moving cars. Using a video frame captured by a drive recorder, the time to collision (TTC) was calculated from the car's velocity and the distance between the car and bicycle at the moment when the bicycle initially appeared. The average TTC in the cases where bicycles emerged from behind obstructions was shorter than that in the cases where drivers had unobstructed views of the bicycles. In comparing the TTC of car-to-bicycle near-miss incidents to the previously obtained results of car-to-pedestrian near-miss incidents, it was determined that the average TTC in car-to-bicycle near-miss incidents was significantly longer than that in car-to-pedestrian near-miss incidents. When considering the TTC in the test protocol of evaluation for safety performance of active safety devices, we propose individual TTCs for evaluation of cyclist and pedestrian detections, respectively. In the test protocols, the following 2 scenarios should be employed: bicycle emerging from behind an unobstructed view and bicycle emerging from behind obstructions.

A multielement trace mineral injection improves liver copper and selenium concentrations and manganese superoxide dismutase activity in beef steers.

PubMed

Genther, O N; Hansen, S L

2014-02-01

Trace minerals (TM) are vital to health and growth of livestock, but low dietary concentrations and dietary antagonists may reduce mineral status and feeder cattle TM status is usually unknown at arrival. The objective of this study was to examine the effect of TM status on response to mineral injection in beef cattle. Forty steers were equally assigned to diets for an 84-d depletion period: control (CON; supplemental Cu, Mn, Se, and Zn) or deficient (DEF; no supplemental Cu, Mn, Se, or Zn plus Fe and Mo as TM antagonists). Lesser liver Cu and Se concentrations (79.0 ± 11.60 and 1.66 ± 0.080 mg/kg DM, respectively) in DEF steers compared with CON steers (228.8 ± 11.60 and 2.41 ± 0.080 mg/kg DM, respectively) on d 71 of depletion indicated mild deficiencies of these TM (P < 0.001). On d 1 of the 85-d repletion period, 10 steers within each dietary treatment were injected with sterilized saline (SAL) or Multimin90 (MM), containing 15, 10, 5, and 60 mg/mL of Cu, Mn, Se, and Zn, respectively, at a dose of 1 mL/68 kg BW. All steers were fed the same repletion diet supplemented with Cu, Mn, Se, and Zn to meet or exceed NRC recommendations. Blood was collected on d 0 and 1, and blood and liver biopsies were collected on d 8, 15, 29, 57, and 85 postinjection. Red blood cell lysate manganese-superoxide dismutase activity was greater in MM (P = 0.02), suggesting incorporation of injectable TM into a biological process. The increase in liver Se in response to MM was greater in CON vs. DEF (P = 0.02), suggesting TM from injection were used rather than stored in DEF steers. Liver Se and Cu (P < 0.05) were elevated through at least d 30 by MM. Dietary TM deficiency decreased neutrophil bacteria killing ability and increased myeloperoxidase (MPO) degranulation (P < 0.04) as measured on d 0, 1, 13, and 14 during the repletion period while injection had no impact. Within CON animals, total MPO was greater in animals that received TM injection, but injection did not affect MPO within DEF steers (P = 0.007). Overall, TM from an injectable mineral were used differently between TM adequate and mildly deficient steers.

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study.

PubMed

Cruz, Conrad Russell Y; Micklethwaite, Kenneth P; Savoldo, Barbara; Ramos, Carlos A; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A John; Ito, Sawa; Shpall, Elizabeth J; Krance, Robert A; Kamble, Rammurti T; Carrum, George; Hosing, Chitra M; Gee, Adrian P; Mei, Zhuyong; Grilley, Bambi J; Heslop, Helen E; Rooney, Cliona M; Brenner, Malcolm K; Bollard, Catherine M; Dotti, Gianpietro

2013-10-24

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control.

High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model

PubMed Central

Richman, Sarah A.; Nunez-Cruz, Selene; Moghimi, Babak; Li, Lucy Z.; Gershenson, Zachary T.; Mourelatos, Zissimos; Barrett, David M.; Grupp, Stephan A.; Milone, Michael C.

2018-01-01

The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)–modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are under way. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR and compared their properties in vivo. We included the E101K mutation of GD2 scFv (GD2-E101K) that has enhanced antitumor activity against a GD2+ human neuroblastoma xenograft in vivo. However, this enhanced antitumor efficacy in vivo was concomitantly associated with lethal central nervous system (CNS) toxicity comprised of extensive CAR T-cell infiltration and proliferation within the brain and neuronal destruction. The encephalitis was localized to the cerebellum and basal regions of the brain that display low amounts of GD2. Our results highlight the challenges associated with target antigens that exhibit shared expression on critical normal tissues. Despite the success of GD2-specific antibody therapies in the treatment of neuroblastoma, the fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in our studies suggests that GD2 may be a difficult target antigen for CAR T-cell therapy without additional strategies that can control CAR T-cell function within the CNS. PMID:29180536

Pregnant women in vehicles: Driving habits, position and risk of injury.

PubMed

Auriault, F; Brandt, C; Chopin, A; Gadegbeku, B; Ndiaye, A; Balzing, M-P; Thollon, L; Behr, M

2016-04-01

This study proposed to broadly examine vehicle use by pregnant women in order to improve realism of accident simulations involving these particular occupants. Three research pathways were developed: the first consisted in a questionnaire survey examining the driving habits of 135 pregnant women, the second obtained measurements of 15 pregnant women driving position in their own vehicle from the 6th to the 9th month of pregnancy by measuring distances between body parts and vehicle parts, and the third examined car accidents involving pregnant occupants. Results obtained indicate that between 90% and 100% of pregnant women wore their seat belts whatever their stage of pregnancy, although nearly one third of subjects considered the seat belt was dangerous for their unborn child. The measurements obtained also showed that the position of the pregnant woman in her vehicle, in relation to the various elements of the passenger compartment, changed significantly during pregnancy. In the studied accidents, no correlation was found between the conditions of the accident and the resulting fetal injury. Results reveal that pregnant women do not modify significantly the seat setting as a function of pregnancy stage. Only the distance between maternal abdomen and steering wheel change significantly, from 16 cm to 12 cm at 6 and 9 month respectively. Pregnant women are mainly drivers before 8 months of pregnancy, passengers after that. Car use frequency falls down rapidly from 6 to 9 months of pregnancy. Real crashes investigations indicate a low rate of casualties, i.e. 342 car accidents involving pregnant women for a period of 9 years in an approximately 1.7 million inhabitants area. No specific injury was found as a function of stage of pregnancy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation.

PubMed

Lemmen, Julia; Tozakidis, Iasson E P; Bele, Prachee; Galla, Hans-Joachim

2013-03-21

ATP-driven efflux transporters are considered to be the major hurdle in the treatment of central nervous system (CNS) diseases. Abcb1 (P-glycoprotein) and Abcg2 (breast cancer resistance protein/brain multidrug resistance protein) belong to the best known ABC-transporters. These ABC-transporters limit the permeability of the blood-brain barrier and protect the brain against toxic compounds in the blood but on the other hand they also reduce the efficacy of CNS pharmacotherapy. Even after 40 years of extensive research, the regulatory mechanisms of these efflux transporters are still not completely understood. To unravel the efflux transporter regulation, we analyzed the effect of the nuclear receptor CAR (constitutive androstane receptor) on the expression of Abcb1 and Abcg2 in primary cultures of porcine brain capillary endothelial cells (PBCEC). CAR is a xenobiotic-activated transcription factor, which is, like the other important nuclear receptor pregnane X receptor (PXR), highly expressed in barrier tissue and known to be a positive regulator of ABC-transporters. We demonstrate that activation of porcine CAR by the human CAR (hCAR) ligand CITCO (6-(4-chlorophenyl)-imidazo[2,1-b]thiazole-5-carbaldehyde) leads to an up-regulation of both transporters, whereas the mouse-specific CAR ligand TCPOBOP (1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene) had no effect on transporter expression. The stimulation of PBCEC with CITCO caused a significant up-regulation of both efflux-transporters on RNA-level, protein level and transport level. Furthermore the additional application of a CAR inhibitor significantly decreased the transporter expression to control niveau. In conclusion our data prove CAR activation only by the human ligand CITCO leading to an increased ABC-transporter expression and transport activity. Copyright © 2013 Elsevier B.V. All rights reserved.

Statistical analyses of influence of solar and geomagnetic activities on car accident events

NASA Astrophysics Data System (ADS)

Alania, M. V.; Gil, A.; Wieliczuk, R.

2001-01-01

Statistical analyses of the influence of Solar and geomagnetic activity, sector structure of the interplanetary magnetic field and galactic cosmic ray Forbush effects on car accident events in Poland for the period of 1990-1999 have been carried out. Using auto-correlation, cross-correlation, spectral analyses and superposition epochs methods it has been shown that there are separate periods when car accident events have direct correlation with Ap index of the geomagnetic activity, sector structure of the interplanetary magnetic field and Forbush decreases of galactic cosmic rays. Nevertheless, the single-valued direct correlation is not possible to reveal for the whole period of 1990-1999. Periodicity of 7 days and its second harmonic (3.5 days) has been reliably revealed in the car accident events data in Poland for the each year of the period 1990-1999. It is shown that the maximum car accident events take place in Poland on Friday and practically does not depend on the level of solar and geomagnetic activities.

A dual chain chimeric antigen receptor (CAR) in the native antibody format for targeting immune cells towards cancer cells without the need of an scFv.

PubMed

Faitschuk, E; Nagy, V; Hombach, A A; Abken, H

2016-10-01

Adoptive cell therapy with chimeric antigen receptor (CAR)-modified T cells showed remarkable therapeutic efficacy in the treatment of leukaemia/lymphoma. However, the application to a variety of cancer entities is often constricted by the non-availability of a single chain antibody (scFv), which is usually the targeting domain in a CAR, while antibodies in the natural format are often available. To overcome the limitation, we designed a CAR that uses an antibody in its natural configuration for binding. Such CAR consists of two chains, the immunoglobulin light and heavy chain with their constant regions, whereby the heavy chain is anchored to the membrane and linked to an intracellular signalling domain for T-cell activation. The two chains form a stable heterodimer, a so-called dual chain CAR (dcCAR), and bind with high affinity and in a specific manner to their cognate antigen. By specific binding, the dcCAR activates engineered T cells for the release of pro-inflammatory cytokines and for target cell lysis. We provide evidence by three examples that the dcCAR format is universally applicable and thereby broadens the CAR cell therapy towards a larger variety of targets for which an scFv antibody is not available.

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

PubMed Central

Rodgers, David T.; Mazagova, Magdalena; Hampton, Eric N.; Cao, Yu; Ramadoss, Nitya S.; Hardy, Ian R.; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K.; Wright, Timothy M.; Schultz, Peter G.; Kim, Chan Hyuk; Young, Travis S.

2016-01-01

Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level.

PubMed

Song, De-Gang; Ye, Qunrui; Poussin, Mathilde; Chacon, Jessica A; Figini, Mariangela; Powell, Daniel J

2016-07-20

The poor prognosis and the limited efficacy of targeted therapy in patients with triple-negative breast cancer (TNBC) have raised the need for alternative therapies. Recent studies have demonstrated that folate receptor-alpha (FRα) may represent an ideal tumor-associated marker for immunotherapy for TNBC. The aim of the present study was to apply a chimeric antigen receptor (CAR) approach for the targeting of FRα expressed on TNBC cells and evaluate the antitumor activity of CAR-engineered T cells in vitro and in vivo. We found that human T cells expressing a FRα-specific CAR were potent and specific killers of TNBC cells that express moderate levels of FRα in vitro and significantly inhibited tumor outgrowth following infusion into immunodeficient mice bearing an MDA-MB-231 tumor xenograft. However, the antitumor activity of the FRα CAR T cells was modest when compared to the same CAR T cells applied in an ovarian tumor xenograft model where FRα expression is more abundant. Notably, FRα CAR T cells induced superior tumor regression in vivo against MDA-MB-231 that was engineered for overexpression of FRα. Taken together, our results show that FRα CAR T cells can mediate antitumor activity against established TNBC tumor, particularly when FRα is expressed at higher levels. These results have significant implications for the pre-selection of patients with high antigen expression levels when utilizing CAR-based adoptive T cell therapies of cancer in future clinical trials.

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

PubMed Central

Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

2018-01-01

ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

Effects of dietary protein levels and 2-methylbutyrate on ruminal fermentation, nutrient degradability, bacterial populations and urinary purine derivatives in Simmental steers.

PubMed

Wang, C; Liu, Q; Guo, G; Huo, W J; Pei, C X; Zhang, S L; Yang, W Z

2018-06-01

The objective of this study was to evaluate the effects of dietary crude protein (CP) levels and 2-methylbutyrate (MB) supplementation on ruminal fermentation, bacterial populations, microbial enzyme activity and urinary excretion of purine derivatives (PD) in Simmental steers. Eight ruminally cannulated Simmental steers, averaging 18 months of age and 465 ± 8.6 kg of body weight (BW), were used in a replicated 4 × 4 Latin square design by a 2 × 2 factorial arrangement. Low protein (98.5 g CP/kg dry matter [LP] or high protein (128.7 g CP/kg dry matter [HP]) diets were fed with MB supplementation (0 g [MB-] or 16.8 g steer -1  day -1 [MB+]). Steers were fed a total mixed ration with dietary corn straw to concentrate ratio of 50:50 (dry matter [DM] basis). The CP × MB interaction was observed for ruminal total VFA, molar proportions of acetate and propionate, acetate to propionate ratio, ammonia-N, effective degradability of neutral detergent fibre (NDF) and CP, microbial enzyme activity, bacterial populations and total PD excretion (p < .05). Ruminal pH decreased (p < .05), but ruminal total VFA concentration increased (p < .05) with increasing dietary CP level or MB supplementation. Acetate molar proportion increased (p = .043) with MB supplementation, but was not affected by dietary CP level. Propionate molar proportion decreased (p < .05) with increasing dietary CP level or MB supplementation. Consequently, acetate-to-propionate ratio increased (p = .001) with MB supplementation, but was not affected by dietary CP level. Ruminal ammonia-N content increased (p = .034) with increasing dietary CP level, but decreased (p = .012) with MB supplementation. The effective degradability of NDF and CP increased (p < .05) with increasing dietary CP level or MB supplementation. Microbial enzyme activity, bacterial populations and total PD excretion also increased (p < .05) with increasing dietary CP level or MB supplementation. The results indicated that ruminal fermentation, nutrient degradability, microbial enzyme activity, ruminal bacterial populations and microbial protein synthesis improved with increasing dietary CP level or MB supplementation in steers. © 2017 Blackwell Verlag GmbH.

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

PubMed Central

Beavis, Paul A.; Henderson, Melissa A.; Giuffrida, Lauren; Mills, Jane K.; Sek, Kevin; Cross, Ryan S.; Davenport, Alexander J.; John, Liza B.; Mardiana, Sherly; Slaney, Clare Y.; Johnstone, Ricky W.; Trapani, Joseph A.; Stagg, John; Loi, Sherene; Kats, Lev; Gyorki, David; Kershaw, Michael H.; Darcy, Phillip K.

2017-01-01

Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types. PMID:28165340

Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.

PubMed

Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Hu, Haihong; Chen, Baian; Lu, Jing; Xie, Wen; Zeng, Su

2016-09-01

The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2015 Elsevier B.V. All rights reserved.

Most Do, but Some Do Not: CD4+CD25− T Cells, but Not CD4+CD25+ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR)

PubMed Central

Hombach, Andreas A.; Abken, Hinrich

2017-01-01

Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ T cells. However, the cytolytic capacity of redirected CD4+CD25− T cells, in comparison with CD4+CD25+ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28­CD3ζ signalling for redirecting CD4+CD25− T cells and CD4+CD25+ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4+CD25− CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4+CD25− T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4+ cells and Treg cells imply their use for different purposes in cell therapy. PMID:28850063

Vehicle Technologies Program Educational Activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2011-12-13

Description of educational activities including: EcoCAR2: Plugging In to the Future, EcoCAR: The NeXt Challenge, Green Racing, Automotive X Prize, Graduate Technology Automotive Education (GATE), and Hydrogen Education.

MicroRNA-122 Down-Regulation Is Involved in Phenobarbital-Mediated Activation of the Constitutive Androstane Receptor

PubMed Central

Shizu, Ryota; Shindo, Sawako; Yoshida, Takemi; Numazawa, Satoshi

2012-01-01

Constitutive androstane receptor (CAR) is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK)-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes. PMID:22815988

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize.

PubMed

Elolimy, Ahmed A; Moisá, Sonia J; Brennan, Kristen M; Smith, Allison C; Graugnard, Daniel; Shike, Daniel W; Loor, Juan J

2018-05-29

Our main objective was to evaluate the effects of feeding α-amylase (Amaize, Alltech Inc., Nicholasville, KY, USA) for 140 days on skeletal muscle and liver gene transcription in beef steers. Steers fed Amaize had lower average daily gain (p = .03) and gain:feed ratio (p = .05). No differences (p > .10) in serum metabolites or carcass traits were detected between the two groups but Amaize steers tended (p < .15) to have increased 12th rib fat depth. Microarray analysis of skeletal muscle revealed 21 differentially expressed genes (DEG), where 14 were up-regulated and seven were down-regulated in Amaize-fed steers. The bioinformatics analysis indicated that metabolic pathways involved in fat formation and deposition, stress response, and muscle function were activated, while myogenesis was inhibited in Amaize-fed steers. The quantitative PCR results for liver revealed a decrease (p < .01) in expression of fatty acid binding protein 1 (FABP1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) with Amaize. Because these genes are key for intracellular fatty acid transport, oxidation and ketone body production, data suggest a reduction in hepatic lipid catabolism. Future work to investigate potential positive effects of Amaize on cellular stress response, muscle function, and liver function in beef cattle appears warranted. © 2018 Japanese Society of Animal Science.

Carbonaceous material production from vegetable residue and their use in the removal of textile dyes present in wastewater

NASA Astrophysics Data System (ADS)

Peláez-Cid, A. A.; Tlalpa-Galán, M. A.; Herrera-González, A. M.

2013-06-01

This paper presents the adsorption results of acid, basic, direct, vat, and reactive-type dyes on carbonaceous adsorbent materials prepared starting off vegetable residue such as Opuntia ficus indica and Casimiroa edulis fruit wastes. The adsorbents prepared from Opuntia ficus indica waste were designated: TunaAsh, CarTunaT, and CarTunaQ. The materials obtained from Casimiroa edulis waste were named: CenZAP, CarZAPT, and CarZAPQ. TunaAsh and CenZAP consist of ashes obtained at 550 °C CarTunaT and CarZAPT consist of the materials carbonized at 400 °C lastly, CarTunaQ and CarZAPQ consist of chemically activated carbons using H3PO4 at 400 °C. Only the chemically activated materials were washed with distilled water until a neutral pH was obtained after their carbonization. All materials were ground and sieved to obtain a particle size ranging from 0.25 to 0.84 mm. The static adsorption results showed that both ashes and chemically activated carbon are more efficient at dye removal for both vegetable residues. For TunaAsh and CarTunaQ, removal rates of up to 100% in the cases of basic, acid, and direct dyes were achieved. Regarding wastewater containing reactive dyes, the efficiency ranged from 60 to 100%. For vat effluents, it ranged from 42 to 52%. In the case of CenZAP and CarZAPQ, it was possible to treat reactive effluents with rates ranging between 63 and 91%. Regarding vat effluents, it ranged from 57 to 68%. The process of characterization for all materials was done using scanning electron microscopy and infrared spectroscopy.

Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

PubMed Central

Cherian, Milu T.; Yang, Lei; Chai, Sergio C.; Lin, Wenwei

2016-01-01

The constitutive androstane receptor (CAR) regulates the expression of genes involved in drug metabolism and other processes. A specific inhibitor of CAR is critical for modulating constitutive CAR activity. We recently described a specific small-molecule inhibitor of CAR, CINPA1 (ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate), which is capable of reducing CAR-mediated transcription by changing the coregulator recruitment pattern and reducing CAR occupancy at the promoter regions of its target genes. In this study, we showed that CINPA1 is converted to two main metabolites in human liver microsomes. By using cell-based reporter gene and biochemical coregulator recruitment assays, we showed that although metabolite 1 was very weak in inhibiting CAR function and disrupting CAR-coactivator interaction, metabolite 2 was inactive in this regard. Docking studies using the CAR ligand-binding domain structure showed that although CINPA1 and metabolite 1 can bind in the CAR ligand-binding pocket, metabolite 2 may be incapable of the molecular interactions required for binding. These results indicate that the metabolites of CINPA1 may not interfere with the action of CINPA1. We also used in vitro enzyme assays to identify the cytochrome P450 enzymes responsible for metabolizing CINPA1 in human liver microsomes and showed that CINPA1 was first converted to metabolite 1 by CYP3A4 and then further metabolized by CYP2D6 to metabolite 2. Identification and characterization of the metabolites of CINPA1 enabled structure-activity relationship studies of this family of small molecules and provided information to guide in vivo pharmacological studies. PMID:27519550

A longitudinal analysis of cars, transit, and employment outcomes.

DOT National Transportation Integrated Search

2015-09-01

Access to cars and transit can influence individuals ability to reach opportunities such as jobs, health care, and other important : activities. While access to cars and public transit varies considerably across time, space, and across populations...

Alterations in serotonin receptor-induced contractility of bovine lateral saphenous vein in cattle grazing endophyte-infected tall fescue.

PubMed

Klotz, J L; Brown, K R; Xue, Y; Matthews, J C; Boling, J A; Burris, W R; Bush, L P; Strickland, J R

2012-02-01

As part of a 2-yr study documenting the physiologic impact of grazing endophyte-infected tall fescue on growing cattle, 2 experiments were conducted to characterize and evaluate effects of grazing 2 levels of toxic endophyte-infected tall fescue pastures on vascular contractility and serotonin receptors. Experiment 1 examined vasoconstrictive activities of 5-hydroxytryptamine (5HT), α-methylserotonin (ME5HT; a 5HT(2) receptor agonist), d-lysergic acid (LSA), and ergovaline (ERV) on lateral saphenous veins collected from steers immediately removed from a high-endophyte-infected tall fescue pasture (HE) or a low-endophyte-infected mixed-grass (LE) pasture. Using the same pastures, Exp. 2 evaluated effects of grazing 2 levels of toxic endophyte-infected tall fescue on vasoconstrictive activities of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), BW 723C86 (BW7), CGS-12066A (CGS), and 5-carboxamidotryptamine hemiethanolate maleate (5CT), agonists for 5HT(2A),( 2B), 5HT(1B), and 5HT(7) receptors, respectively. One-half of the steers in Exp. 2 were slaughtered immediately after removal from pasture, and the other one-half were fed finishing diets for >91 d before slaughter. For Exp. 1, maximal contractile intensities were greater (P < 0.05) for steers grazing LE pastures than HE pastures for 5HT (73.3 vs. 48.9 ± 2.1%), ME5HT (52.7 vs. 24.9 ± 1.5%), and ERV (65.7 vs. 49.1 ± 2.6%). Onset of contractile response did not differ for 5HT (P = 0.26) and ERV (P = 0.93), but onset of ME5HT contraction was not initiated (P < 0.05) in HE steers until 10(-4) compared with 10(-5) M in LE-grazing steers. For Exp. 2, maximal contractile intensities achieved with DOI were 35% less (P < 0.05), whereas those achieved with 5CT were 37% greater (P < 0.05), in steers grazing HE pastures. Contractile response to CGS did not differ between pasture groups, and there was an absence of contractile response to BW7 in both groups. There were no differences between endophyte content in contractile responses after animals were finished for >91 d. Experiment 1 demonstrated that grazing of HE pastures for 89 to 105 d induces functional alterations in blood vessels, as evidenced by reduced contractile capacity and altered serotonergic receptor activity. Experiment 2 demonstrated that grazing HE pastures alters vascular responses, which may be mediated through altered serotonin receptor activities, and these alterations may be ameliorated by the removal of ergot alkaloid exposure as demonstrated by the absence of differences in finished steers.

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study

PubMed Central

Cruz, Conrad Russell Y.; Micklethwaite, Kenneth P.; Savoldo, Barbara; Ramos, Carlos A.; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A. John; Ito, Sawa; Shpall, Elizabeth J.; Krance, Robert A.; Kamble, Rammurti T.; Carrum, George; Hosing, Chitra M.; Gee, Adrian P.; Mei, Zhuyong; Grilley, Bambi J.; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Bollard, Catherine M.

2013-01-01

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control. This study is registered at clinicaltrials.gov as #NCT00840853. PMID:24030379

Optimization of vehicle-trailer connection systems

NASA Astrophysics Data System (ADS)

Sorge, F.

2016-09-01

The three main requirements of a vehicle-trailer connection system are: en route stability, over- or under-steering restraint, minimum off-tracking along curved path. Linking the two units by four-bar trapeziums, wider stability margins may be attained in comparison with the conventional pintle-hitch for both instability types, divergent or oscillating. The stability maps are traced applying the Hurwitz method or the direct analysis of the characteristic equation at the instability threshold. Several types of four-bar linkages may be quickly tested, with the drawbars converging towards the trailer or the towing unit. The latter configuration appears preferable in terms of self-stability and may yield high critical speeds by optimising the geometrical and physical properties. Nevertheless, the system stability may be improved in general by additional vibration dampers in parallel with the connection linkage. Moreover, the four-bar connection may produce significant corrections of the under-steering or over-steering behaviour of the vehicle-train after a steering command from the driver. The off- tracking along the curved paths may be also optimized or kept inside prefixed margins of acceptableness. Activating electronic stability systems if necessary, fair results are obtainable for both the steering conduct and the off-tracking.

4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

PubMed Central

Long, Adrienne H.; Haso, Waleed M.; Shern, Jack F.; Wanhainen, Kelsey M.; Murgai, Meera; Ingaramo, Maria; Smith, Jillian P.; Walker, Alec J.; Kohler, M. Eric; Venkateshwara, Vikas R.; Kaplan, Rosandra N.; Patterson, George H.; Fry, Terry J.; Orentas, Rimas J.; Mackall, Crystal L.

2015-01-01

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3ζ phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation ameliorates, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19.BBz CAR T cells are more persistent than CD19.28z CAR T cells in clinical trials. PMID:25939063

Dose-response approaches for nuclear receptor-mediated ...

EPA Pesticide Factsheets

A public workshop, organized by a Steering Committee of scientists from government, industry, universities, and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose-response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of subthreshold doses for a number of receptor-mediated MOPs. The workshop explored the development of dose-response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance framework (HRF). Case studies addressed activation of the AHR; the CAR/PXR, and the PPARa. This paper describes the workshop process, key issues discussed, and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose-response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the

Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.

PubMed

Boardman, D A; Philippeos, C; Fruhwirth, G O; Ibrahim, M A A; Hannen, R F; Cooper, D; Marelli-Berg, F M; Watt, F M; Lechler, R I; Maher, J; Smyth, L A; Lombardi, G

2017-04-01

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

DNA polymorphisms and transcript abundance of PRKAG2 and phosphorylated AMP-activated protein kinase in the rumen are associated with gain and feed intake in beef steers

USDA-ARS?s Scientific Manuscript database

Beef steers with variation in feed efficiency phenotypes were evaluated previously on a high density SNP panel. Ten markers from rs110125325-rs41652818 on bovine chromosome 4 were associated with average daily gain (ADG). To identify the gene(s) in this 1.2Mb region responsible for variation in AD...

An assessment of chemical contaminants in sediments from the St. Thomas East End Reserves, St. Thomas, USVI.

PubMed

Pait, Anthony S; Hartwell, S Ian; Mason, Andrew L; Warner, Robert A; Jeffrey, Christopher F G; Hoffman, Anne M; Apeti, Dennis A; Pittman, Simon J

2014-08-01

The St. Thomas East End Reserves or STEER is located on the southeastern end of the island of St. Thomas, USVI. The STEER contains extensive mangroves and seagrass beds, along with coral reefs, lagoons, and cays. Within the watershed, however, are a large active landfill, numerous marinas, resorts, various commercial activities, an EPA Superfund Site, and residential areas, all of which have the potential to contribute pollutants to the STEER. As part of a project to develop an integrated assessment for the STEER, 185 chemical contaminants were analyzed in sediments from 24 sites. Higher levels of chemical contaminants were found in Mangrove Lagoon and Benner Bay in the western portion of the study area. The concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), zinc, copper, lead, and mercury were above a NOAA Effects Range-Low (ERL) sediment quality guideline at one or more sites, indicating impacts may be present in more sensitive species or life stages. Copper at one site in Benner Bay was above a NOAA Effects Range-Median (ERM) guideline indicating effects on benthic organisms were likely. The antifoulant boat hull ingredient tributyltin (TBT) was found at the third highest concentration in the history of NOAA's National Status and Trends (NS&T) Program, which monitors the nation's coastal and estuarine waters for chemical contaminants and bioeffects. The results from this project will provide resource managers with key information needed to make effective decisions affecting coral reef ecosystem health and gauge the efficacy of restoration activities.

Integrating Norm Activation Model and Theory of Planned Behavior to Understand Sustainable Transport Behavior: Evidence from China.

PubMed

Liu, Yuwei; Sheng, Hong; Mundorf, Norbert; Redding, Colleen; Ye, Yinjiao

2017-12-18

With increasing urbanization in China, many cities are facing serious environmental problems due to continuous and substantial increase in automobile transportation. It is becoming imperative to examine effective ways to reduce individual automobile use to facilitate sustainable transportation behavior. Empirical, theory-based research on sustainable transportation in China is limited. In this research, we propose an integrated model based on the norm activation model and the theory of planned behavior by combining normative and rational factors to predict individuals' intention to reduce car use. Data from a survey of 600 car drivers in China's three metropolitan areas was used to test the proposed model and hypotheses. Results showed that three variables, perceived norm of car-transport reduction, attitude towards reduction, and perceived behavior control over car-transport reduction, significantly affected the intention to reduce car-transport. Personal norms mediated the relationship between awareness of consequences of car-transport, ascription of responsibility of car-transport, perceived subjective norm for car-transport reduction, and intention to reduce car-transport. The results of this research not only contribute to theory development in the area of sustainable transportation behavior, but also provide a theoretical frame of reference for relevant policy-makers in urban transport management.

Integrating Norm Activation Model and Theory of Planned Behavior to Understand Sustainable Transport Behavior: Evidence from China

PubMed Central

Liu, Yuwei; Sheng, Hong; Mundorf, Norbert; Redding, Colleen

2017-01-01

With increasing urbanization in China, many cities are facing serious environmental problems due to continuous and substantial increase in automobile transportation. It is becoming imperative to examine effective ways to reduce individual automobile use to facilitate sustainable transportation behavior. Empirical, theory-based research on sustainable transportation in China is limited. In this research, we propose an integrated model based on the norm activation model and the theory of planned behavior by combining normative and rational factors to predict individuals’ intention to reduce car use. Data from a survey of 600 car drivers in China’s three metropolitan areas was used to test the proposed model and hypotheses. Results showed that three variables, perceived norm of car-transport reduction, attitude towards reduction, and perceived behavior control over car-transport reduction, significantly affected the intention to reduce car-transport. Personal norms mediated the relationship between awareness of consequences of car-transport, ascription of responsibility of car-transport, perceived subjective norm for car-transport reduction, and intention to reduce car-transport. The results of this research not only contribute to theory development in the area of sustainable transportation behavior, but also provide a theoretical frame of reference for relevant policy-makers in urban transport management. PMID:29258245

Postweaning performance and carcass merit of F1 steers sired by Brahman and alternative subtropically adapted breeds.

PubMed

Franke, D E

1997-10-01

Comparisons were made among F1 steers sired by Brahman and alternative subtropically adapted breeds of bulls for feedlot and carcass traits when steers were produced from Angus- and Hereford-type dams. Brahman-derivative breeds included Brangus, Beefmaster, and Santa Gertrudis. Brangus- and Beefmaster-sired steers weighed less at slaughter, whereas carcasses of Brangus- and Santa Gertrudis-sired steers had more marbling than those of Brahman-sired steers. Brahman-sired steer carcasses had greater longissimus muscle area than carcasses of Santa Gertrudis-sired steers. Other Zebu breeds compared to Brahman were Boran, Gir, Indu-Brazil, Nellore, Red Brahman, and Sahiwal. Steers by Brahman sires had higher slaughter weights than steers by Boran, Gir, Nellore, or Sahiwal sires. Hot carcass weights of Brahman-sired steers were also higher than those of Boran- and Sahiwal-sired steers. Steer carcasses by Brahman sires had greater longissimus muscle area than those of steers by Sahiwal sires. Non-Zebu breeds included Tuli and Senepol. Steers by Tuli sires grew slower, had lower slaughter weights, and their carcasses weighed less than those of Brahman-sired steers. Brahman-sired steer carcasses had greater longissimus muscle area but less marbling than carcasses of Tuli-sired steers. These data suggest that steers by Brahman sires have an advantage for slaughter weight over steers by Brangus, Beefmaster, Boran, Gir, Nellore, Sahiwal, and Tuli sires, but their carcasses are at a disadvantage for marbling score compared with those by Brangus, Boran, Nellore, and Tuli sires.

A new model to compute the desired steering torque for steer-by-wire vehicles and driving simulators

NASA Astrophysics Data System (ADS)

Fankem, Steve; Müller, Steffen

2014-05-01

This paper deals with the control of the hand wheel actuator in steer-by-wire (SbW) vehicles and driving simulators (DSs). A novel model for the computation of the desired steering torque is presented. The introduced steering torque computation does not only aim to generate a realistic steering feel, which means that the driver should not miss the basic steering functionality of a modern conventional steering system such as an electric power steering (EPS) or hydraulic power steering (HPS), and this in every driving situation. In addition, the modular structure of the steering torque computation combined with suitably selected tuning parameters has the objective to offer a high degree of customisability of the steering feel and thus to provide each driver with his preferred steering feel in a very intuitive manner. The task and the tuning of each module are firstly described. Then, the steering torque computation is parameterised such that the steering feel of a series EPS system is reproduced. For this purpose, experiments are conducted in a hardware-in-the-loop environment where a test EPS is mounted on a steering test bench coupled with a vehicle simulator and parameter identification techniques are applied. Subsequently, how appropriate the steering torque computation mimics the test EPS system is objectively evaluated with respect to criteria concerning the steering torque level and gradient, the feedback behaviour and the steering return ability. Finally, the intuitive tuning of the modular steering torque computation is demonstrated for deriving a sportier steering feel configuration.

The weal and woe of costimulation in the adoptive therapy of cancer with chimeric antigen receptor (CAR)-redirected T cells.

PubMed

Hombach, A A; Holzinger, A; Abken, H

2013-08-01

Adoptive cell therapy has shown impressive efficacy to combat cancer in early phase clinical trials, in particular when T cells engineered to specifically target tumor cells were applied. The patient's T cells are genetically equipped with a chimeric antigen receptor (CAR) which allows them to be redirected in a predefined manner towards virtually any target; by using an antibody-derived domain for binding, CAR T cells can be redirected in a major histocompatibility complex (MHC) dependent and independent fashion. The CAR also provides the stimuli required to induce and maintain T cell activation. Recent clinical data sustain the notion that strong costimulation in conjunction with the primary activation signal is crucial for lasting therapeutic efficacy of CAR T cells. However, costimulation is a double-edged sword and the impact of the individual costimuli to optimize T cell activation is still under debate; some general rules are emerging. The review summarizes how costimulation modulates, improves and prolongs the redirected anti-tumor T cell response and how the same costimulatory signals may contribute to unintended side effects including "cytokine storm" and T cell repression. Upcoming strategies to break the activation/repression circle by using CAR's with modified costimulatory signals are also discussed.

Production systems comparing early weaning to normal weaning with or without creep feeding for beef steers.

PubMed

Myers, S E; Faulkner, D B; Ireland, F A; Berger, L L; Parrett, D F

1999-02-01

A 2-yr study was conducted to determine the effects of three weaning management systems on cow and steer performance. Cow-calf pairs were randomly assigned to one of three treatments, in which the steer calves were 1) early-weaned (yr 1, 177 +/- 9 d; yr 2, 158 +/- 21 d of age) and placed on a finishing diet (EW), 2) supplemented with grain for 55 d on pasture (yr 1, 177 to 231 d; yr 2, 158 to 213 d of age) while nursing their dams and then placed on a finishing diet (NWC), and 3) on pasture for 55 d while nursing their dams (yr 1, 177 to 231 d; yr 2, 158 to 213 d of age) and then placed on a finishing diet (NW). In yr 2, potential breed differences were evaluated using steers of three breed types: 1) Angus x Hereford (BRI); 2) Angus x Simmental (CON); and 3) Angus x Wagyu (WAG). In yr 1, EW steers gained 100% faster (P = .0001) than the average of NWC and NW steers, and NWC steers gained 32% faster (P = .02) than NW steers before weaning. In the feedlot, EW steers had lower intakes (7.70 vs 8.16 kg/d, P = .008) and better feed conversions (.170 vs .153, P = .002) than the average of NWC and NW steers. Marbling score was improved for EW steers compared with the average of NWC and NW steers (P = .003). In yr 2, EW steers had higher gains (P = .0006) during the entire study than the average of NWC and NW steers, and NWC steers had higher gains (P = .003) than NW steers. The EW steers had lower intakes (7.29 vs 7.68 kg/d, P = .0008) and better feed conversions (.160 vs .141, P = .0001) than the average of NWC and NW steers. The CON steers were heavier at slaughter than BRI steers (P = .01), and BRI steers were heavier than WAG steers (P =.0004). Early weaning improved the percentage of steers grading Average Choice or higher by 40%. The percentage of BRI steers grading Choice or greater was 21% higher and percentage of steers grading Average Choice or greater was 33% higher than CON. Cows with EW steers had higher ADG than cows with NW steers (.38 vs -.17 kg/d, P = .0001) before weaning. Cows with EW steers gained in body condition score (.23 vs .00, P = .04), and cows with NW steers did not change. Early weaning improved feed efficiency and quality grades of beef steers.

CD28z CARs and Armored CARs

PubMed Central

Pegram, Hollie J.; Park, Jae H.; Brentjens, Renier J.

2015-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whilst promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate “armored CAR T cells” which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors or monoclonal antibodies are aimed at improving the anti-tumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include utilizing dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel “armored CAR T cell” approaches for improving anti-tumor efficacy therapy. PMID:24667958

CD28z CARs and armored CARs.

PubMed

Pegram, Hollie J; Park, Jae H; Brentjens, Renier J

2014-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whereas promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate "armored CAR T cells," which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors, or monoclonal antibodies, are aimed at improving the antitumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include using dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel armored CAR T cell approaches for improving antitumor efficacy therapy.

How Chimeric Antigen Receptor Design Affects Adoptive T Cell Therapy.

PubMed

Gacerez, Albert T; Arellano, Benjamine; Sentman, Charles L

2016-12-01

Chimeric antigen receptor (CAR) T cells have been developed to treat tumors and have shown great success against B cell malignancies. Exploiting modular designs and swappable domains, CARs can target an array of cell surface antigens and, upon receptor-ligand interactions, direct signaling cascades, thereby driving T cell effector functions. CARs have been designed using receptors, ligands, or scFv binding domains. Different regions of a CAR have each been found to play a role in determining the overall efficacy of CAR T cells. Therefore, this review provides an overview of CAR construction and common designs. Each CAR region is discussed in the context of its importance to a CAR's function. Additionally, the review explores how various engineering strategies have been applied to CAR T cells in order to regulate CAR T cell function and activity. J. Cell. Physiol. 231: 2590-2598, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Problem of the Used Cars Import on the Territory of the Russian Federation

NASA Astrophysics Data System (ADS)

Taskaev, Vladimir; Taskaeva, Natalia

2017-10-01

Authors completed the analysis of the accepted practice of classification of the sawn car bodies in Russia. They conclude that the tools of the Product Range of Foreign Economic Activity do not allow to classify the front and rear parts of the car as goods. Nowadays the participants of foreign economic activity sent the efforts to search for any new way to cut the customs payments. Meanwhile that is not incidental, that during car sale, the sellers specify in their offers not only purely technical characteristics but also the fact that “It is not a Sawn Car”. Thereby the sellers of cars agree that the car, obtained by joint of the sawn parts in the handicraft conditions, have an uncertainty of such important characteristic as safety, and that reduces the consumer properties of the purchase. Many buyers consider unsafe and even impossible to use the car in which such fundamental characteristic as safety is not provided. Therefore, the attempts of customs to carry out any classification of goods in the commodity position 8703 for the increase in collectable customs payments have a negative side as the matters of health and life of future owner of the car are concerned.

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease.

PubMed

Wang, Xiuyan; Zheng, Liyu; Wu, Jinming; Tang, Binbin; Zhang, Mengqin; Zhu, Debin; Lin, Xianfan

2017-06-01

Increased plasma levels of bilirubin have been reported in rat models and patients with alcoholic liver disease (ALD). The constitutive androstane receptor (CAR) is a known xenobiotic receptor, which induces the detoxification and transport of bilirubin. In the present study, the bilirubin transport regulatory mechanisms, and the role of CAR activation in hepatic and extrahepatic bilirubin clearance were investigated in a murine model of ALD. The mice were fed a Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks, followed by the administration of CAR agonists, 1,4-bis-[2‑(3,5-dichlorpyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB), and their vehicles to examine the effect of the pharmacological activation of CAR on serum levels of bilirubin and on the bilirubin clearance pathway in ALD by serological survey, western blotting and reverse transcription‑quantitative polymerase chain reaction. The results showed that chronic ethanol ingestion impaired the nuclear translocation of CAR, which was accompanied by elevated serum levels of bilirubin, suppression of the expression of hepatic and renal organic anion transporting polypeptide (OATP) 1A1 and hepatic multidrug resistance‑associated protein 2 (MRP2), and induction of the expression of UDP-glucuronosyltransferase (UGT) 1A1. The activation of CAR by TCPOBOP and PB resulted in downregulation of the serum levels of bilirubin followed by selective upregulation of the expression levels of OATP1A1, OATP1A4, UGT1A1 and MRP2 in ALD. These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.

Surface localization of the nuclear receptor CAR in influenza A virus-infected cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Tadanobu; Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, CREST, JST, and COE Program in the 21st Century, Shizuoka 422-8526; Moriyama, Yusuke

Constitutive active/androstane receptor CAR is a member of the nuclear receptors which regulate transcription of xenobiotic metabolism enzymes. CAR is usually localized in the cytosol and nucleus. Here, we found that CAR was localized at the cell surface of influenza A virus (IAV)-infected cells. Additionally, we demonstrated that expression of a viral envelope glycoprotein, either hemagglutinin (HA) or neuraminidase (NA), but not viral nucleoprotein (NP), was responsible for this localization. This report is the first demonstration of CAR at the surface of tissue culture cells, and suggests that CAR may exert the IAV infection mechanism.

[Compounds modulating parathyroid hormone (PTH) secretion].

PubMed

Nagano, N; Iijima, H

2001-08-01

The control of parathyroid hormone (PTH) secretion is strictly regulated by the parathyroid Ca receptor (CaR). Calcimimetics and calcilytics selectively act on the parathyroid CaR to inhibit and enhance PTH secretion, respectively. According to the recent pharmacological two-state model, calcimimetics act on the CaR as allosteric agonists to stabilize an active conformation of CaR. Conversely, calcilytics act on the CaR as allosteric inverse agonists to stabilize an inactive conformation of CaR. These compounds that can alter circulating levels of PTH and bone turnover might provide novel treatments for adynamic bone disease in patients with chronic renal failure.

How chimeric antigen receptor design affects adoptive T cell therapy

PubMed Central

Gacerez, Albert T.; Arellano, Benjamine; Sentman, Charles L.

2016-01-01

Chimeric antigen receptor (CAR) T cells have been developed to treat tumors and have shown great success against B cell malignancies. Exploiting modular designs and swappable domains, CARs can target an array of cell surface antigens and, upon receptor-ligand interactions, direct signaling cascades, thereby driving T cell effector functions. CARs have been designed using receptors, ligands, or scFv binding domains. Different regions of a CAR have each been found to play a role in determining the overall efficacy of CAR T cells. Therefore, this review provides an overview of CAR construction and common designs. Each CAR region is discussed in the context of its importance to a CAR’s function. Additionally, the review explores how various engineering strategies have been applied to CAR T cells in order to regulate CAR T cell function and activity. PMID:27163336

Quantum steering in cascaded four-wave mixing processes.

PubMed

Wang, Li; Lv, Shuchao; Jing, Jietai

2017-07-24

Quantum steering is used to describe the "spooky action-at-a-distance" nonlocality raised in the Einstein-Podolsky-Rosen (EPR) paradox, which is important for understanding entanglement distribution and constructing quantum networks. Here, in this paper, we study an experimentally feasible scheme for generating quantum steering based on cascaded four-wave-mixing (FWM) processes in hot rubidium (Rb) vapor. Quantum steering, including bipartite steering and genuine tripartite steering among the output light fields, is theoretically analyzed. We find the corresponding gain regions in which the bipartite and tripartite steering exist. The results of bipartite steering can be used to establish a hierarchical steering model in which one beam can steer the other two beams in the whole gain region; however, the other two beams cannot steer the first beam simultaneously. Moreover, the other two beams cannot steer with each other in the whole gain region. More importantly, we investigate the gain dependence of the existence of the genuine tripartite steering and we find that the genuine tripartite steering exists in most of the whole gain region in the ideal case. Also we discuss the effect of losses on the genuine tripartite steering. Our results pave the way to experimental demonstration of quantum steering in cascaded FWM process.

Coxsackievirus and adenovirus receptor (CAR) mediates trafficking of acid sensing ion channel 3 (ASIC3) via PSD-95.

PubMed

Excoffon, Katherine J D A; Kolawole, Abimbola O; Kusama, Nobuyoshi; Gansemer, Nicholas D; Sharma, Priyanka; Hruska-Hageman, Alesia M; Petroff, Elena; Benson, Christopher J

2012-08-17

We have previously shown that the Coxsackievirus and adenovirus receptor (CAR) can interact with post-synaptic density 95 (PSD-95) and localize PSD-95 to cell-cell junctions. We have also shown that activity of the acid sensing ion channel (ASIC3), a H(+)-gated cation channel that plays a role in mechanosensation and pain signaling, is negatively modulated by PSD-95 through a PDZ-based interaction. We asked whether CAR and ASIC3 simultaneously interact with PSD-95, and if so, whether co-expression of these proteins alters their cellular distribution and localization. Results indicate that CAR and ASIC3 co-immunoprecipitate only when co-expressed with PSD-95. CAR also brings both PSD-95 and ASIC3 to the junctions of heterologous cells. Moreover, CAR rescues PSD-95-mediated inhibition of ASIC3 currents. These data suggest that, in addition to activity as a viral receptor and adhesion molecule, CAR can play a role in trafficking proteins, including ion channels, in a PDZ-based scaffolding complex. Copyright © 2012 Elsevier Inc. All rights reserved.

Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation

PubMed Central

Kittayaruksakul, Suticha; Zhao, Wenchen; Xu, Meishu; Ren, Songrong; Lu, Jing; Wang, Ju; Downes, Michael; Evans, Ronald M.; Venkataramanan, Raman; Chatsudthipong, Varanuj; Xie, Wen

2013-01-01

The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been known to play a role in xenobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters. In addition, PXR agonists were found to exert therapeutic effects through multiple mechanisms, such as detoxification of bile acids and inhibition of inflammation. In this study, we first investigated the effects of three natural product compounds, carapin, santonin and isokobusone, on the activity of PXR and CAR. These compounds activated both PXR and CAR in transient transfection and luciferase reporter gene assays. Mutagenesis studies showed that two amino acid residues, Phe305 of the rodent PXR and Leu308 of the human PXR, are critical for the recognition of these compounds by PXR. Importantly, the activation of PXR and CAR by these compounds induced the expression of drug-metabolizing enzymes in primary human and mouse hepatocytes. Furthermore, activation of PXR by these compounds inhibited the expression of inflammatory mediators in response to lipopolysaccharide (LPS). The effects of these natural compounds on drug metabolism and inflammation were abolished in PXR−/− hepatocytes. These natural compounds can be explored for their potential in the treatment of diseases where the PXR activation has been shown to be beneficial, such as inflammatory bowel disease, cholestasis, and hyperbilirubinemia. PMID:23896737

Creating virtual electrodes with 2D current steering

NASA Astrophysics Data System (ADS)

Spencer, Thomas C.; Fallon, James B.; Shivdasani, Mohit N.

2018-06-01

Objective. Current steering techniques have shown promise in retinal prostheses as a way to increase the number of distinct percepts elicitable without increasing the number of implanted electrodes. Previously, it has been shown that ‘virtual’ electrodes can be created between simultaneously stimulated electrode pairs, producing unique cortical response patterns. This study investigated whether virtual electrodes could be created using 2D current steering, and whether these virtual electrodes can produce cortical responses with predictable spatial characteristics. Approach. Normally-sighted eyes of seven adult anaesthetised cats were implanted with a 42-channel electrode array in the suprachoroidal space and multi-unit neural activity was recorded from the visual cortex. Stimuli were delivered to individual physical electrodes, or electrodes grouped into triangular, rectangular, and hexagonal arrangements. Varying proportions of charge were applied to each electrode in a group to ‘steer’ current and create virtual electrodes. The centroids of cortical responses to stimulation of virtual electrodes were compared to those evoked by stimulation of single physical electrodes. Main results. Responses to stimulation of groups of up to six electrodes with equal ratios of charge on each electrode resulted in cortical activation patterns that were similar to those elicited by the central physical electrode (centroids: RM ANOVA on ranks, p  >  0.05 neural spread: one-way ANOVA on Ranks, p  >  0.05). We were also able to steer the centroid of activation towards the direction of any of the electrodes of the group by applying a greater charge to that electrode, but the movement in the centroid was not found to be significant. Significance. The results suggest that current steering is possible in two dimensions between up to at least six electrodes, indicating it may be possible to increase the number of percepts in patients without increasing the number of physical electrodes. Being able to reproduce spatial characteristics of responses to individual physical electrodes suggests that this technique could also be used to compensate for faulty electrodes.

Where We Look When We Drive with or without Active Steering Wheel Control

PubMed Central

Mars, Franck; Navarro, Jordan

2012-01-01

Current theories on the role of visuomotor coordination in driving agree that active sampling of the road by the driver informs the arm-motor system in charge of performing actions on the steering wheel. Still under debate, however, is the nature of visual cues and gaze strategies used by drivers. In particular, the tangent point hypothesis, which states that drivers look at a specific point on the inside edge line, has recently become the object of controversy. An alternative hypothesis proposes that drivers orient gaze toward the desired future path, which happens to be often situated in the vicinity of the tangent point. The present study contributed to this debate through the analyses of the distribution of gaze orientation with respect to the tangent point. The results revealed that drivers sampled the roadway in the close vicinity of the tangent point rather than the tangent point proper. This supports the idea that drivers look at the boundary of a safe trajectory envelop near the inside edge line. Furthermore, the study investigated for the first time the reciprocal influence of manual control on gaze control in the context of driving. This was achieved through the comparison of gaze behavior when drivers actively steered the vehicle or when steering was performed by an automatic controller. The results showed an increase in look-ahead fixations in the direction of the bend exit and a small but consistent reduction in the time spent looking in the area of the tangent point when steering was passive. This may be the consequence of a change in the balance between cognitive and sensorimotor anticipatory gaze strategies. It might also reflect bidirectional coordination control between the eye and arm-motor systems, which goes beyond the common assumption that the eyes lead the hands when driving. PMID:22928043

Integrated Chassis Control of Active Front Steering and Yaw Stability Control Based on Improved Inverse Nyquist Array Method

PubMed Central

2014-01-01

An integrated chassis control (ICC) system with active front steering (AFS) and yaw stability control (YSC) is introduced in this paper. The proposed ICC algorithm uses the improved Inverse Nyquist Array (INA) method based on a 2-degree-of-freedom (DOF) planar vehicle reference model to decouple the plant dynamics under different frequency bands, and the change of velocity and cornering stiffness were considered to calculate the analytical solution in the precompensator design so that the INA based algorithm runs well and fast on the nonlinear vehicle system. The stability of the system is guaranteed by dynamic compensator together with a proposed PI feedback controller. After the response analysis of the system on frequency domain and time domain, simulations under step steering maneuver were carried out using a 2-DOF vehicle model and a 14-DOF vehicle model by Matlab/Simulink. The results show that the system is decoupled and the vehicle handling and stability performance are significantly improved by the proposed method. PMID:24782676

Integrated chassis control of active front steering and yaw stability control based on improved inverse nyquist array method.

PubMed

Zhu, Bing; Chen, Yizhou; Zhao, Jian

2014-01-01

An integrated chassis control (ICC) system with active front steering (AFS) and yaw stability control (YSC) is introduced in this paper. The proposed ICC algorithm uses the improved Inverse Nyquist Array (INA) method based on a 2-degree-of-freedom (DOF) planar vehicle reference model to decouple the plant dynamics under different frequency bands, and the change of velocity and cornering stiffness were considered to calculate the analytical solution in the precompensator design so that the INA based algorithm runs well and fast on the nonlinear vehicle system. The stability of the system is guaranteed by dynamic compensator together with a proposed PI feedback controller. After the response analysis of the system on frequency domain and time domain, simulations under step steering maneuver were carried out using a 2-DOF vehicle model and a 14-DOF vehicle model by Matlab/Simulink. The results show that the system is decoupled and the vehicle handling and stability performance are significantly improved by the proposed method.

Field relevance of a suite of rollover tests to real-world crashes and injuries.

PubMed

Parenteau, Chantal S; Viano, David C; Shah, Minoo; Gopal, Madana; Davies, John; Nichols, David; Broden, Johan

2003-01-01

The objective of this study was to assess the distribution of rollover accidents occurring in the field and to compare the vehicle kinematics in the predominant field crash modes with available laboratory tests. For this purpose, US accident data were analyzed to identify types and circumstances for vehicle rollovers. Rollovers were most commonly induced when the lateral motion of the vehicle was suddenly slowed or stopped. This type of rollover mechanism is referred to as "trip-over". Trip-overs accounted for 57% of passenger car and 51% of light truck vehicle (LTV) rollovers. More than 90% of trip-overs were initiated by ground contact. Fall-overs were the second most common rollover type, accounting for 13% of passenger car and 15% of LTV rollovers. Bounce-overs only accounted for 8% of both passenger car and LTV rollovers. The FMVSS 208 dolly and the ADAC corkscrew rollover tests are well-known laboratory tests, but do not simulate many of the real-world rollovers. Three additional tests have been devised to more fully address the field relevant conditions identified in this study. To do so, assumptions were made and adding the new laboratory tests (soil-trip, curb-trip and ditch fall-over) increases representativeness to 83% of passenger car and 75% of LTV rollovers reported in the field. Accident data were also used to identify injuries in belted drivers so the information could later be used to better understand occupant kinematics in various roll conditions. The injury distribution for belted/non-ejected drivers was assessed for trip-over, fall-over and bounce-over accidents. Serious injuries (AIS 3+) were most common to the head and thorax, in particular for bounce-overs. Head injuries occurred from contact with the roof, pillar and the interior, while thoracic injuries resulted from contact with the interior and steering wheel assembly. Field data are useful in the development of laboratory test conditions for rollovers as it provides insights on the significance of various rollover types, understanding of injury biomechanics, guidance for future testing and inputs for mathematical modeling.

49 CFR 570.7 - Steering systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 6 2011-10-01 2011-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

49 CFR 570.7 - Steering systems.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 6 2012-10-01 2012-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

49 CFR 570.7 - Steering systems.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 6 2014-10-01 2014-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

49 CFR 570.7 - Steering systems.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 6 2010-10-01 2010-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

N-acyl homoserine lactone binding to the CarR receptor determines quorum-sensing specificity in Erwinia.

PubMed

Welch, M; Todd, D E; Whitehead, N A; McGowan, S J; Bycroft, B W; Salmond, G P

2000-02-15

Quorum sensing via an N-acyl homoserine lactone (HSL) pheromone controls the biosynthesis of a carbapenem antibiotic in Erwinia carotovora. Transcription of the carbapenem biosynthetic genes is dependent on the LuxR-type activator protein, CarR. Equilibrium binding of a range of HSL molecules, which are thought to activate CarR to bind to its DNA target sequence, was examined using fluorescence quenching, DNA bandshift analysis, limited proteolysis and reporter gene assays. CarR bound the most physiologically relevant ligand, N-(3-oxohexanoyl)-L-homoserine lactone, with a stoichiometry of two molecules of ligand per dimer of protein and a dissociation constant of 1.8 microM, in good agreement with the concentration of HSL required to activate carbapenem production in vivo. In the presence of HSL, CarR formed a very high molecular weight complex with its target DNA, indicating that the ligand causes the protein to multimerize. Chemical cross-linking analysis supported this interpretation. Our data show that the ability of a given HSL to facilitate CarR binding to its target DNA sequence is directly proportional to the affinity of the HSL for the protein.

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

PubMed Central

Kumaresan, Pappanaicken R.; Manuri, Pallavi R.; Albert, Nathaniel D.; Maiti, Sourindra; Singh, Harjeet; Mi, Tiejuan; Roszik, Jason; Rabinovich, Brian; Olivares, Simon; Krishnamurthy, Janani; Zhang, Ling; Najjar, Amer M.; Huls, M. Helen; Lee, Dean A.; Champlin, Richard E.; Kontoyiannis, Dimitrios P.; Cooper, Laurence J. N.

2014-01-01

Clinical-grade T cells are genetically modified ex vivo to express chimeric antigen receptors (CARs) to redirect their specificity to target tumor-associated antigens in vivo. We now have developed this molecular strategy to render cytotoxic T cells specific for fungi. We adapted the pattern-recognition receptor Dectin-1 to activate T cells via chimeric CD28 and CD3-ζ (designated “D-CAR”) upon binding with carbohydrate in the cell wall of Aspergillus germlings. T cells genetically modified with the Sleeping Beauty system to express D-CAR stably were propagated selectively on artificial activating and propagating cells using an approach similar to that approved by the Food and Drug Administration for manufacturing CD19-specific CAR+ T cells for clinical trials. The D-CAR+ T cells exhibited specificity for β-glucan which led to damage and inhibition of hyphal growth of Aspergillus in vitro and in vivo. Treatment of D-CAR+ T cells with steroids did not compromise antifungal activity significantly. These data support the targeting of carbohydrate antigens by CAR+ T cells and provide a clinically appealing strategy to enhance immunity for opportunistic fungal infections using T-cell gene therapy. PMID:25002471

Emissions and Noise Pervasive Panel

NASA Technical Reports Server (NTRS)

Henderson, Brenda; Lee, Chi

2008-01-01

Objectives include: Provide interagency coordination of technology development, aimed at engine noise reduction. a) Provide recommendations to the Steering Committee on potential areas of interagency technology collaboration to maximize the use of government investments in noise reduction. b) Serve as a forum for information and technology exchange in order to coordinate gas turbine engine environmental strategies and policies among the member agencies and industry; c) Coordinate activities across panel representatives; and d) Communicate progress to VAATE steering committee.

Study of car-sharing diffusion criticality conditions based on human traveling network

NASA Astrophysics Data System (ADS)

Xu, Yan; Ji, Xuehong

Car-sharing program, like Car2go, is an innovative urban transportation mode where the car-sharing company provides a car fleet to offer people with the short-term access of car traveling. As a new traveling service, car-sharing platforms have been struggling hard to trigger initial users and speed up their diffusion process. Unlike new product spreading via geographical proximity people, car-sharing users usually drive sharing cars to different destinations and influence people there, and potential user decision also depends on previous user activity at all their destinations. Car-sharing user connections are mainly affected by their traveling behaviors. The influence of user traveling network on new service/product spreading process has been rarely studied before. Here, we find that the infective rate between users with the same destination is critical to the minimum user base of car-sharing diffusion. Moreover, a city with central user network is more appropriate for car-sharing. It leads to a small critical infective rate for diffusion, and a large stable market size of car-sharing service. Our study can impact car-sharing market strategies ranging from market expansion in one city to optimal market selection among different cities.

Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy.

PubMed

Yeku, Oladapo O; Brentjens, Renier J

2016-04-15

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the 'armor' agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms. © 2016 Authors; published by Portland Press Limited.

Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy

PubMed Central

Yeku, Oladapo O.; Brentjens, Renier J.

2017-01-01

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the ‘armor’ agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms. PMID:27068948

RSV (Research Safety Vehicle) test monitoring and data publication-results of European performance and handling test on the Calspan RSV. Final report, Apr-May 79

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, N.; Davis, S.

1979-07-01

Performance and handling tests on the Calspan RSV were performed in Italy by the Istituto Sperimentale Auto E Motori (ISAM) and in West Germany by Volkswagenwerk AG Wolfsburg. The ISAM tests evaluated the Calspan RSV in the areas of fuel economy, vehicle response, braking and handling, and driver environment. The Volkswagen tests evaluated the Calspan RSV in the areas of braking, steering, handling, and overturning immunity. The ISAM tests are unlike any previously used to evaluate American vehicles. Therefore, the Calspan RSV results are compared to those of ten European cars which had undergone identical tests. The Volkswagen test proceduresmore » were identical to those specified in the Research Safety Vehicle program. The Calspan RSV results are compared to the RSV specifications for these tests.« less

Structural Optimization of a Knuckle with Consideration of Stiffness and Durability Requirements

PubMed Central

Kim, Geun-Yeon

2014-01-01

The automobile's knuckle is connected to the parts of the steering system and the suspension system and it is used for adjusting the direction of a rotation through its attachment to the wheel. This study changes the existing material made of GCD45 to Al6082M and recommends the lightweight design of the knuckle as the optimal design technique to be installed in small cars. Six shape design variables were selected for the optimization of the knuckle and the criteria relevant to stiffness and durability were considered as the design requirements during the optimization process. The metamodel-based optimization method that uses the kriging interpolation method as the optimization technique was applied. The result shows that all constraints for stiffness and durability are satisfied using A16082M, while reducing the weight of the knuckle by 60% compared to that of the existing GCD450. PMID:24995359

Nonintrusive biosignal measurement system in a vehicle.

PubMed

Lee, Haet Bit; Choi, Jong Min; Kim, Jung Soo; Kim, Yun Seong; Baek, Hyun Jae; Ryu, Myung Suk; Sohn, Ryang Hee; Park, Kwang Suk

2007-01-01

Measurement of driver's state is important in both daily healthcare and prevention of car accidents. Existing measurement methods, however, are too complex and uncomfortable to measure for everyday. A nonintrusive biosignal monitoring system is demanded for increasing the accessibility. In this paper, we proposed a nonintrusive measurement system integrated in a vehicle for recording electrocardiographic (ECG) signals and tested the performance of the system. The system consists of dry electrodes attached to the steering wheel and a wireless communication module using a Bluetooth device. ECG signals measured by our system were compared with those by a conventional system employing wet electrodes during real city road driving. Various parameters used for HRV analysis in time and frequency domain showed no significant differences between the two simultaneously measured ECG signals. The result implies the possibility that developed system could have a potential to monitor health information in a vehicle instead of commercial equipments.

49 CFR 570.60 - Steering system.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 6 2014-10-01 2014-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

49 CFR 570.60 - Steering system.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 6 2012-10-01 2012-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

49 CFR 570.60 - Steering system.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 6 2011-10-01 2011-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

49 CFR 570.60 - Steering system.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 6 2010-10-01 2010-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

Protein Activity of the Fusarium fujikuroi Rhodopsins CarO and OpsA and Their Relation to Fungus–Plant Interaction

PubMed Central

Adam, Alexander; Deimel, Stephan; Pardo-Medina, Javier; García-Martínez, Jorge; Konte, Tilen; Limón, M. Carmen; Avalos, Javier

2018-01-01

Fungi possess diverse photosensory proteins that allow them to perceive different light wavelengths and to adapt to changing light conditions in their environment. The biological and physiological roles of the green light-sensing rhodopsins in fungi are not yet resolved. The rice plant pathogen Fusarium fujikuroi exhibits two different rhodopsins, CarO and OpsA. CarO was previously characterized as a light-driven proton pump. We further analyzed the pumping behavior of CarO by patch-clamp experiments. Our data show that CarO pumping activity is strongly augmented in the presence of the plant hormone indole-3-acetic acid and in sodium acetate, in a dose-dependent manner under slightly acidic conditions. By contrast, under these and other tested conditions, the Neurospora rhodopsin (NR)-like rhodopsin OpsA did not exhibit any pump activity. Basic local alignment search tool (BLAST) searches in the genomes of ascomycetes revealed the occurrence of rhodopsin-encoding genes mainly in phyto-associated or phytopathogenic fungi, suggesting a possible correlation of the presence of rhodopsins with fungal ecology. In accordance, rice plants infected with a CarO-deficient F. fujikuroi strain showed more severe bakanae symptoms than the reference strain, indicating a potential role of the CarO rhodopsin in the regulation of plant infection by this fungus. PMID:29324661

40 CFR 201.10 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Standards § 201.10 Applicability. The provisions of this subpart apply to all rail cars and all locomotives... level emitted by rail cars and locomotives operated under the conditions specified, including the sound... provisions of this subpart apply to all active retarders, all car coupling operations, all switcher...

40 CFR 201.10 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Standards § 201.10 Applicability. The provisions of this subpart apply to all rail cars and all locomotives... level emitted by rail cars and locomotives operated under the conditions specified, including the sound... provisions of this subpart apply to all active retarders, all car coupling operations, all switcher...

40 CFR 201.10 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Standards § 201.10 Applicability. The provisions of this subpart apply to all rail cars and all locomotives... level emitted by rail cars and locomotives operated under the conditions specified, including the sound... provisions of this subpart apply to all active retarders, all car coupling operations, all switcher...

40 CFR 201.10 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Standards § 201.10 Applicability. The provisions of this subpart apply to all rail cars and all locomotives... level emitted by rail cars and locomotives operated under the conditions specified, including the sound... provisions of this subpart apply to all active retarders, all car coupling operations, all switcher...

40 CFR 201.10 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Standards § 201.10 Applicability. The provisions of this subpart apply to all rail cars and all locomotives... level emitted by rail cars and locomotives operated under the conditions specified, including the sound... provisions of this subpart apply to all active retarders, all car coupling operations, all switcher...

A chimeric switch-receptor targeting PD1 augments the efficacy of second generation CAR T-Cells in advanced solid tumors

PubMed Central

Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang; Fang, Chongyun; Sun, Jing; Kim, Soyeon; Newick, Kheng; Lo, Albert; June, Carl H.; Zhao, Yangbing; Moon, Edmund K.

2015-01-01

Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy (ATC) has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally-occurring and genetically-modified tumor infiltrating lymphocytes (TILs) by inhibitory receptors (IRs), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T cell activity against solid tumors. To address this possibility, we introduced a genetically-engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T-cells. We tested the effect of this supplement, “PD1CD28”, on human CAR T-cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T-cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared to treatments with CAR T-cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality. PMID:26979791

A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

PubMed Central

Song, De-Gang; Ye, Qunrui; Poussin, Mathilde; Liu, Lin; Figini, Mariangela; Powell, Daniel J.

2015-01-01

Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate “on-target” toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and “on-target off-tumor” toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs. PMID:26101914

Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects.

PubMed

Shi, Huan; Sun, Meili; Liu, Lin; Wang, Zhehai

2014-09-21

Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell's activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.

Auditory orientation in crickets: Pattern recognition controls reactive steering

NASA Astrophysics Data System (ADS)

Poulet, James F. A.; Hedwig, Berthold

2005-10-01

Many groups of insects are specialists in exploiting sensory cues to locate food resources or conspecifics. To achieve orientation, bees and ants analyze the polarization pattern of the sky, male moths orient along the females' odor plume, and cicadas, grasshoppers, and crickets use acoustic signals to locate singing conspecifics. In comparison with olfactory and visual orientation, where learning is involved, auditory processing underlying orientation in insects appears to be more hardwired and genetically determined. In each of these examples, however, orientation requires a recognition process identifying the crucial sensory pattern to interact with a localization process directing the animal's locomotor activity. Here, we characterize this interaction. Using a sensitive trackball system, we show that, during cricket auditory behavior, the recognition process that is tuned toward the species-specific song pattern controls the amplitude of auditory evoked steering responses. Females perform small reactive steering movements toward any sound patterns. Hearing the male's calling song increases the gain of auditory steering within 2-5 s, and the animals even steer toward nonattractive sound patterns inserted into the speciesspecific pattern. This gain control mechanism in the auditory-to-motor pathway allows crickets to pursue species-specific sound patterns temporarily corrupted by environmental factors and may reflect the organization of recognition and localization networks in insects. localization | phonotaxis

Within- and between-session reliability of the maximal voluntary knee extension torque and activation.

PubMed

Park, Jihong; Hopkins, J Ty

2013-01-01

A ratio between the torque generated by maximal voluntary isometric contraction (MVIC) and exogenous electrical stimulus, central activation ratio (CAR), has been widely used to assess quadriceps function. To date, no data exist regarding between-session reliability of this measurement. Thirteen neurologically sound volunteers underwent three testing sessions (three trials per session) with 48 hours between-session. Subjects performed MVICs of the quadriceps with the knee locked at 90° flexion and the hip at 85°. Once the MVIC reached a plateau, an electrical stimulation from superimposed burst technique (SIB: 125 V with peak output current 450 mA) was manually delivered and transmitted directly to the quadriceps via stimulating electrodes. CAR was calculated by using the following equation: CAR = MVIC torque/MVIC + SIB torque. Intraclass correlation coefficients (ICC) were calculated within- (ICC((2,1))) and between-session (ICC((2,k))) for MVIC torques and CAR values. Our data show that quadriceps MVIC and CAR are very reliable both within- (ICC((2,1)) = 0.99 for MVIC; 0.94 for CAR) and between-measurement sessions (ICC((2,k)) = 0.92 for MVIC; 0.86 for CAR) in healthy young adults. For clinical research, more data of the patients with pathological conditions are required to ensure reproducibility of calculation of CAR.

75 FR 62538 - Agency Information Collection Activities; Proposed Collection; Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-12

... information collection requirements contained in its Used Motor Vehicle Trade Regulation Rule (``Used Car Rule...-5634. SUPPLEMENTARY INFORMATION: The Used Car Rule facilitates informed purchasing decisions by requiring used car dealers to disclose information about warranty coverage, if any, and the mechanical...

49 CFR 37.3 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., painting or wallpapering, asbestos removal, or changes to mechanical or electrical systems are not... vehicles or multi-car trains. Service may be on a fixed schedule or in response to a passenger-activated... to another mode of transportation. Commuter rail car means a rail passenger car obtained by a...

Air pollution and activity during transportation by car, subway, and walking.

PubMed

Morabia, Alfredo; Amstislavski, Philippe N; Mirer, Franklin E; Amstislavski, Tashia M; Eisl, Holger; Wolff, Mary S; Markowitz, Steven B

2009-07-01

Little evidence exists about the health risks and benefits associated with using public buses and subways rather than cars. The objective of the current study was to assess the magnitude and variance of personal exposure to particulate matter 2.5 microns or smaller (PM(2.5)) and concomitant physical activity energy expenditure (PAEE) for transportation by car, subway, or walking. Twenty nonsmoking volunteers from New York City traveled on predetermined routes by car, subway, and walking, for up to 8 hours on 3 different days, between October 2007 and February 2008. Outfitted with a personal monitor with PM(2.5) aerosol inlet, and a GPS receiver, they completed a detailed physical activity diary for each route. Both metabolic equivalent (MET) and PAEE rates (Kcal/min) were computed from GPS-derived activity durations and speeds, activity-specific METs, and measured body weight. Total PM(2.5) exposures did not differ among car, subway, and walking arms (respectively, 21.4, 30.6, and 26.5 microg/m(3) x min, p=0.19); but average MET values (respectively, 1.51, 2.03, and 2.60 Kcal/kg x hr, p<0.0001) and PAEE rates (1.74, 2.35, and 3.04 Kcal/min, p<0.0001) did. After correction for the humidity factor, exposure to PM(2.5) appeared to be lower for the car arm (13.1 microg/m(3) x min) than for the subway (19.6 microg/m(3) x min) or walking (23.9 microg/m(3) x min, p=0.004) arms. Driving cars was associated with less physical activity but not necessarily less exposure to PM(2.5) than riding subways or walking in an urban environment. These effect sizes and variances can be used to design larger experiments assessing the health effects of urban transportation.

Integrated chassis control for a three-axle electric bus with distributed driving motors and active rear steering system

NASA Astrophysics Data System (ADS)

Liu, Wei; He, Hongwen; Sun, Fengchun; Lv, Jiangyi

2017-05-01

This paper describes an integrated chassis control framework for a novel three-axle electric bus with active rear steering (ARS) axle and four motors at the middle and rear wheels. The proposed integrated framework consists of four parts: (1) an active speed limiting controller is designed for anti-body slip control and rollover prevention; (2) an ARS controller is designed for coordinating the tyre wear between the driving wheels; (3) an inter-axle torque distribution controller is designed for optimal torque distribution between the axles, considering anti-wheel slip and battery power limitations and (4) a data acquisition and estimation module for collecting the measured and estimated vehicle states. To verify the performances, a simulation platform is established in Trucksim software combined with Simulink. Three test cases are particularly designed to show the performances. The proposed algorithm is compared with a simple even control algorithm. The test results show satisfactory lateral stability and rollover prevention performances under severe steering conditions. The desired tyre wear coordinating performance is also realised, and the wheel slip ratios are restricted within stable region during intensive driving and emergency braking with complicated road conditions.

Effects of two hospital bed design features on physical demands and usability during brake engagement and patient transportation: a repeated measures experimental study.

PubMed

Kim, Sunwook; Barker, Linsey M; Jia, Bochen; Agnew, Michael J; Nussbaum, Maury A

2009-03-01

Work-related musculoskeletal disorders (WMSDs) are prevalent among healthcare workers worldwide. While existing research has focused on patient-handling techniques during activities which require direct patient contact (e.g., patient transfer), nursing tasks also involve other patient-handling activities, such as engaging bed brakes and transporting patients in beds, which could render healthcare workers at risk of developing WMSDs. Effectiveness of hospital bed design features (brake pedal location and steering-assistance) was evaluated in terms of physical demands and usability during brake engagement and patient transportation tasks. Two laboratory-based studies were conducted. In simulated brake engagement tasks, three brake pedal locations (head-end vs. foot-end vs. side of a bed) and two hands conditions (hands-free vs. hands-occupied) were manipulated. Additionally, both in-room and corridor patient transportation tasks were simulated, in which activation of steering-assistance features (5th wheel and/or front wheel caster lock) and two patient masses were manipulated. Nine novice participants were recruited from the local student population and community for each study. During brake engagement, trunk flexion angle, task completion time, and questionnaires were used to quantify postural comfort and usability. For patient transportation, dependent measures were hand forces and questionnaire responses. Brake pedal locations and steering-assistance features in hospital beds had significant effects on physical demands and usability during brake engagement and patient transportation tasks. Specifically, a brake pedal at the head-end of a bed increased trunk flexion by 74-224% and completion time by 53-74%, compared to other pedal locations. Participants reported greater overall perceived difficulty and less postural comfort with the brake pedal at the head-end. During in-room transportation, participants generally reported "Neither Low nor High" physical demands with the 5th wheel activated, compared to "Moderately High" physical demands when the 5th wheel was deactivated. Corridor transportation was similarly reported to be easier when a steering-assistance feature (the 5th wheel or front caster lock) was activated. Braking and steering-assistance features of hospital beds can have important effects on task efficiency and physical demands placed on healthcare workers. Selection of specific designs may thus be able to improve productivity and contribute to a reduction in WMSDs risk among healthcare workers.

Wideband plasmonic beam steering in metal gratings.

PubMed

de Ceglia, Domenico; Vincenti, Maria Antonietta; Scalora, Michael

2012-01-15

We demonstrate controllable light deflection in thick metal gratings with periodic subwavelength slits filled with an active material. Under specific illumination conditions, the grating becomes nearly transparent and acts as a uniform optical phased-array antenna where the phase of the radiating elements is controlled by modifying the index of refraction of the material that fills each slit. The beam-steering operational regime occurs in a wide wavelength band, and it is relatively insensitive to the input angle.

The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.

PubMed

Okegawa, T; Pong, R C; Li, Y; Bergelson, J M; Sagalowsky, A I; Hsieh, J T

2001-09-01

The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.

Experimental verification of multidimensional quantum steering

NASA Astrophysics Data System (ADS)

Li, Che-Ming; Lo, Hsin-Pin; Chen, Liang-Yu; Yabushita, Atsushi

2018-03-01

Quantum steering enables one party to communicate with another remote party even if the sender is untrusted. Such characteristics of quantum systems not only provide direct applications to quantum information science, but are also conceptually important for distinguishing between quantum and classical resources. While concrete illustrations of steering have been shown in several experiments, quantum steering has not been certified for higher dimensional systems. Here, we introduce a simple method to experimentally certify two different kinds of quantum steering: Einstein-Podolsky-Rosen (EPR) steering and single-system (SS) steering (i.e., temporal steering), for dimensionality (d) up to d = 16. The former reveals the steerability among bipartite systems, whereas the latter manifests itself in single quantum objects. We use multidimensional steering witnesses to verify EPR steering of polarization-entangled pairs and SS steering of single photons. The ratios between the measured witnesses and the maximum values achieved by classical mimicries are observed to increase with d for both EPR and SS steering. The designed scenario offers a new method to study further the genuine multipartite steering of large dimensionality and potential uses in quantum information processing.

A Hierarchical Model Predictive Tracking Control for Independent Four-Wheel Driving/Steering Vehicles with Coaxial Steering Mechanism

NASA Astrophysics Data System (ADS)

Itoh, Masato; Hagimori, Yuki; Nonaka, Kenichiro; Sekiguchi, Kazuma

2016-09-01

In this study, we apply a hierarchical model predictive control to omni-directional mobile vehicle, and improve the tracking performance. We deal with an independent four-wheel driving/steering vehicle (IFWDS) equipped with four coaxial steering mechanisms (CSM). The coaxial steering mechanism is a special one composed of two steering joints on the same axis. In our previous study with respect to IFWDS with ideal steering, we proposed a model predictive tracking control. However, this method did not consider constraints of the coaxial steering mechanism which causes delay of steering. We also proposed a model predictive steering control considering constraints of this mechanism. In this study, we propose a hierarchical system combining above two control methods for IFWDS. An upper controller, which deals with vehicle kinematics, runs a model predictive tracking control, and a lower controller, which considers constraints of coaxial steering mechanism, runs a model predictive steering control which tracks the predicted steering angle optimized an upper controller. We verify the superiority of this method by comparing this method with the previous method.

Neurological injuries from car surfing.

PubMed

Wang, Arthur; Cohen, Alan R; Robinson, Shenandoah

2009-11-01

Trauma secondary to car surfing is a unique mechanism of head and spinal injury in children and adolescents. In this study, the authors present their experience with neurological injuries resulting from car surfing and describe the growing national trend of car-surfing injuries and the increasing portrayal of this activity in the media. A retrospective study of the Rainbow Babies and Children's Hospital trauma database was conducted to identify all cases of neurological injuries secondary to car surfing. Between January 1995 and December 2008, 7 patients

Particulates and noise exposure during bicycle, bus and car commuting: A study in three European cities.

PubMed

Okokon, Enembe O; Yli-Tuomi, Tarja; Turunen, Anu W; Taimisto, Pekka; Pennanen, Arto; Vouitsis, Ilias; Samaras, Zissis; Voogt, Marita; Keuken, Menno; Lanki, Timo

2017-04-01

In order to curb traffic-related air pollution and its impact on the physical environment, contemporary city commuters are encouraged to shift from private car use to active or public transport modes. However, personal exposures to particulate matter (PM), black carbon and noise during commuting may be substantial. Therefore, studies comparing exposures during recommended modes of transport versus car trips are needed. We measured personal exposure to various-sized particulates, soot, and noise during commuting by bicycle, bus and car in three European cities: Helsinki in Finland, Rotterdam in the Netherlands and Thessaloniki in Greece using portable monitoring devices. We monitored commonly travelled routes in these cities. The total number of one-way trips yielding data on any of the measured parameters were 84, 72, 94 and 69 for bicycle, bus, closed-window car and open-window car modes, respectively. The highest mean PM 2.5 (85µg/m 3 ), PM 10 (131µg/m 3 ), black carbon (10.9µg/m 3 ) and noise (75dBA) levels were recorded on the bus, bus (again), open-window car and bicycle modes, respectively, all in Thessaloniki, PM and soot concentrations were generally higher during biking and taking a bus than during a drive in a a car with closed windows. Ratios of bike:car PM 10 ranged from 1.1 in Thessaloniki to 2.6 in Helsinki, while bus:car ratios ranged from in 1.0 in Rotterdam to 5.6 in Thessaloniki. Higher noise levels were mostly recorded during bicycle rides. Based on our study, active- and public-transport commuters are often at risk of higher air pollution and noise exposure than private car users. This should be taken into account in urban transportation planning. Copyright © 2017 Elsevier Inc. All rights reserved.

[Modern foreign car safety systems and their forensic-medical significance].

PubMed

Iakunin, S A

2007-01-01

The author gives a characteristic of active and passive security systems installed in cars of foreign production. These security systems significantly modify the classic car trauma character decreasing frequency of occurrence and dimensions of specific and typical injuries. A new approach based on the theory of probability to estimate these injuries is required. The most common active and passive security systems are described in the article; their principles of operation and influence on the trauma character are estimated.

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

PubMed

Sampson, John H; Choi, Bryan D; Sanchez-Perez, Luis; Suryadevara, Carter M; Snyder, David J; Flores, Catherine T; Schmittling, Robert J; Nair, Smita K; Reap, Elizabeth A; Norberg, Pamela K; Herndon, James E; Kuan, Chien-Tsun; Morgan, Richard A; Rosenberg, Steven A; Johnson, Laura A

2014-02-15

Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. ©2013 AACR

Generation of Potent T-cell Immunotherapy for Cancer using DAP12-based, Multichain, Chimeric Immunoreceptors

PubMed Central

Wang, Enxiu; Wang, Liang-Chuan; Tsai, Ching-Yi; Bhoj, Vijay; Gershenson, Zack; Moon, Edmund; Newick, Kheng; Sun, Jing; Lo, Albert; Baradet, Timothy; Feldman, Michael D.; Barrett, David; Puré, Ellen; Albelda, Steven; Milone, Michael C.

2015-01-01

Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity towards B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs (ITAM)-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared to standard first and second generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. PMID:25941351

46 CFR 58.25-80 - Automatic pilots and ancillary steering gear.

Code of Federal Regulations, 2010 CFR

2010-10-01

... AND AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-80 Automatic pilots and ancillary steering gear. (a) Automatic pilots and ancillary steering gear, and steering-gear control systems, must be arranged to allow immediate resumption of manual operation of the steering-gear control system required in...

46 CFR 58.25-80 - Automatic pilots and ancillary steering gear.

Code of Federal Regulations, 2011 CFR

2011-10-01

... AND AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-80 Automatic pilots and ancillary steering gear. (a) Automatic pilots and ancillary steering gear, and steering-gear control systems, must be arranged to allow immediate resumption of manual operation of the steering-gear control system required in...

No damage to rail cars or SRB segments in derailment

NASA Technical Reports Server (NTRS)

2000-01-01

One of two solid rocket booster rail cars is off the track after being involved in a minor derailment incident during a routine movement on the tracks. The rail cars were being moved as part of a standard operation to '''order''' the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area.

No damage to rail cars or SRB segments in derailment

NASA Technical Reports Server (NTRS)

2000-01-01

After being involved in a minor derailment incident during a routine movement on the tracks, rail cars carrying solid rocket booster segments sit idle. The rail cars were being moved as part of a standard operation to '''order''' the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area.

Highly efficient gene transfer using a retroviral vector into murine T cells for preclinical chimeric antigen receptor-expressing T cell therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kusabuka, Hotaka; Fujiwara, Kento; Tokunaga, Yusuke

Adoptive immunotherapy using chimeric antigen receptor-expressing T (CAR-T) cells has attracted attention as an efficacious strategy for cancer treatment. To prove the efficacy and safety of CAR-T cell therapy, the elucidation of immunological mechanisms underlying it in mice is required. Although a retroviral vector (Rv) is mainly used for the introduction of CAR to murine T cells, gene transduction efficiency is generally less than 50%. The low transduction efficiency causes poor precision in the functional analysis of CAR-T cells. We attempted to improve the Rv gene transduction protocol to more efficiently generate functional CAR-T cells by optimizing the period ofmore » pre-cultivation and antibody stimulation. In the improved protocol, gene transduction efficiency to murine T cells was more than 90%. In addition, almost all of the prepared murine T cells expressed CAR after puromycin selection. These CAR-T cells had antigen-specific cytotoxic activity and secreted multiple cytokines by antigen stimulation. We believe that our optimized gene transduction protocol for murine T cells contributes to the advancement of T cell biology and development of immunotherapy using genetically engineered T cells. - Highlights: • We established highly efficient gene transduction protocols for murine T cells. • CD8{sup +} CAR-T cells had antigen-specific cytotoxic activity. • CD4{sup +} CAR-T cells secreted multiple cytokines by antigen stimulation. • This finding can contribute to the development of T-cell biology and immunotherapy.« less

Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells.

PubMed

Fraietta, Joseph A; Nobles, Christopher L; Sammons, Morgan A; Lundh, Stefan; Carty, Shannon A; Reich, Tyler J; Cogdill, Alexandria P; Morrissette, Jennifer J D; DeNizio, Jamie E; Reddy, Shantan; Hwang, Young; Gohil, Mercy; Kulikovskaya, Irina; Nazimuddin, Farzana; Gupta, Minnal; Chen, Fang; Everett, John K; Alexander, Katherine A; Lin-Shiao, Enrique; Gee, Marvin H; Liu, Xiaojun; Young, Regina M; Ambrose, David; Wang, Yan; Xu, Jun; Jordan, Martha S; Marcucci, Katherine T; Levine, Bruce L; Garcia, K Christopher; Zhao, Yangbing; Kalos, Michael; Porter, David L; Kohli, Rahul M; Lacey, Simon F; Berger, Shelley L; Bushman, Frederic D; June, Carl H; Melenhorst, J Joseph

2018-06-01

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies 1-3 . In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells 4,5 . Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.

Towards immunotherapy with redirected T cells in a large animal model: Ex vivo activation, expansion, and genetic modification of canine T cells

PubMed Central

Mata, Melinda; Vera, Juan; Gerken, Claudia; Rooney, Cliona M.; Miller, Tasha; Pfent, Catherine; Wang, Lisa L.; Wilson-Robles, Heather M.; Gottschalk, Stephen

2014-01-01

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising anti-tumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells we targeted HER2-positive OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2-positive canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy prior to conducting studies in humans. PMID:25198528

Characterization and functional analysis of a carboxylesterase gene associated with chlorpyrifos resistance in Nilaparvata lugens (Stål).

PubMed

Lu, Kai; Wang, Ying; Chen, Xia; Zhang, Zhichao; Li, Yue; Li, Wenru; Zhou, Qiang

2017-12-01

The widespread and extensive application of insecticides have promoted the development of resistance in the brown planthopper Nilaparvata lugens (Stål), one of the most important rice pests in Asia. To better understand the underlying molecular mechanisms of metabolic resistance to insecticides, a chlorpyrifos-resistant (CR) strain of N. lugens was selected and its possible resistance mechanism was investigated. Synergistic tests using carboxylesterases (CarEs) inhibitor triphenyl phosphate (TPP) decreased the resistance of N. lugens to chlorpyrifos, and CarE activities could be induced by low concentrations of chlorpyrifos. Subsequently, a gene putatively encoding CarE, namely NlCarE, predominant in the midgut and ovary was isolated and characterized. The expression levels of NlCarE were detected and compared between the CR and a susceptible (SS) strain of N. lugens. Consistent with the increased CarE activity, this gene was overexpressed in the CR strain compared to the SS strain. The transcript levels of NlCarE were up-regulated by chlorpyrifos exposure, showing dose- and time-dependent expression patterns. Furthermore, RNA interference (RNAi)-mediated knockdown of NlCarE followed by insecticide application significantly increased the susceptibility of N. lugens to chlorpyrifos. These results demonstrate that NlCarE plays an important role in chlorpyrifos detoxification and its overexpression may be involved in chlorpyrifos resistance in N. lugens. Copyright © 2017 Elsevier Inc. All rights reserved.

Country watch: Central African Republic (CAR).

PubMed

Aubel, J; Sobela, F; Voga, P

1997-01-01

This article describes the activities of the Community Peer AIDS Education Project, initiated in 1995 in the Central African Republic (CAR). The CAR project was created by the National AIDS Committee (NAC) and the US Peace Corps. A 4-day workshop was held at the onset for project staff and consultants. Staff developed a simple monitoring and evaluation (M&E) system that emphasizes "learning." M&E schemes measure project outputs, expenditures, and other measures of program implementation in order to help staff gradually improve implementation. M&E helps staff document activities, share information, and learn from the implementation process. Project activities are documented by maintaining community logbooks, taking photos of significant aspects of the educational activities, and leading informal discussion groups. The CAR project engaged in sharing and learning activities by holding meetings with peer leaders, team meetings, meetings with project managers, and meetings with the NAC. Once a month, peer field coordinators conducted a structured exercise with peer leaders. One aim was to gain their feedback on the successes and constraints of activities. Another was to make suggestions on how to improve activities. These structured exercises are recorded as lessons learned in a project book. Team meetings are held periodically. During meetings, staff review project books and photos and discuss successes and problems encountered. Project manager meetings provide time to share lessons learned and to suggest project strengthening options. NAC meetings between the project manager and field coordinators allow for a bottom-up learning process. CAR project staff were receptive to M&E efforts.

The Role of Constitutive Androstane Receptor in Oxazaphosphorine-mediated Induction of Drug-metabolizing Enzymes in Human Hepatocytes

PubMed Central

Wang, Duan; Li, Linhao; Fuhrman, Jennifer; Ferguson, Stephen; Wang, Hongbing

2013-01-01

Purpose The objective of this study was to investigate the roles of the constitutive androstane receptor (CAR) in cyclophosphamide (CPA)- and ifosfamide (IFO)-mediated induction of hepatic drug-metabolizing enzymes (DME). Methods Induction of DMEs was evaluated using real-time RT-PCR and Western blotting analysis in human primary hepatocyte (HPH) cultures. Activation of CAR, pregnane X receptor (PXR), and aryl hydrocarbon receptor by CPA and IFO was assessed in cell-based reporter assays in HepG2 cells and/or nuclear translocation assays in HPHs. Results CYP2B6 reporter activity was significantly enhanced by CPA and IFO in HepG2 cells co-transfected with CYP2B6 reporter plasmid and a chemical-responsive human CAR variant (CAR1+A) construct. Real-time RT-PCR and Western blotting analysis in HPHs showed that both CPA and IFO induced the expressions of CYP2B6 and CYP3A4. Notably, treatment of HPHs with CPA but not IFO resulted in significant nuclear accumulation of CAR, which represents the initial step of CAR activation. Further studies in HPHs demonstrated that selective inhibition of PXR by sulforaphane preferentially repressed IFO- over CPA-mediated induction of CYP2B6. Conclusion These results provide novel insights into the differential roles of CAR in the regulation of CPA- and IFO-induced DME expression and potential drug-drug interactions. PMID:21487929

High-frequency transformation of a methylotrophic yeast, Candida boidinii, with autonomously replicating plasmids which are also functional in Saccharomyces cerevisiae.

PubMed

Sakai, Y; Goh, T K; Tani, Y

1993-06-01

We have developed a transformation system which uses autonomous replicating plasmids for a methylotrophic yeast, Candida boidinii. Two autonomous replication sequences, CARS1 and CARS2, were newly cloned from the genome of C. boidinii. Plasmids having both a CARS fragment and the C. boidinii URA3 gene transformed C. boidinii ura3 cells to Ura+ phenotype at frequencies of up to 10(4) CFU/micrograms of DNA. From Southern blot analysis, CARS plasmids seemed to exist in polymeric forms as well as in monomeric forms in C. boidinii cells. The C. boidinii URA3 gene was overexpressed in C. boidinii on these CARS vectors. CARS1 and CARS2 were found to function as an autonomous replicating element in Saccharomyces cerevisiae as well. Different portions of the CARS1 sequence were needed for autonomous replicating activity in C. boidinii and S. cerevisiae. C. boidinii could also be transformed with vectors harboring a CARS fragment and the S. cerevisiae URA3 gene.

46 CFR 182.610 - Main steering gear.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Main steering gear. 182.610 Section 182.610 Shipping...) MACHINERY INSTALLATION Steering Systems § 182.610 Main steering gear. (a) A vessel must be provided with a main steering gear that is: (1) Of adequate strength and capable of steering the vessel at all service...

46 CFR 108.641 - Instructions for changing steering gear.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Instructions for changing steering gear. 108.641 Section... steering gear. Instructions stating, in order, the different steps to be taken for changing to emergency and secondary steering gear must be posted in the steering gear room and at each secondary steering...

Steering and Suspension Systems. Auto Mechanics Curriculum Guide. Module 5. Instructor's Guide.

ERIC Educational Resources Information Center

Rains, Larry

This module is the fifth of nine modules in the competency-based Missouri Auto Mechanics Curriculum Guide. Seventeen units cover: steering system design; diagnosing steering systems problems; inspecting and replacing steering linkage components; manual and power steering gear service; manual and power rack and pinion steering gear service; power…

46 CFR 131.845 - Instructions for shift of steering gear.

Code of Federal Regulations, 2013 CFR

2013-10-01

... alternative steering stations must be on water-resistant material and posted at each steering station and in... gear or steering stations. (d) Each clutch, gear, wheel, lever, valve, or switch used during any shift of steering gear or steering stations must be numbered or lettered on a metal plate or painted so...

Shaping Social Activity by Incentivizing Users

PubMed Central

Farajtabar, Mehrdad; Du, Nan; Rodriguez, Manuel Gomez; Valera, Isabel; Zha, Hongyuan; Song, Le

2015-01-01

Events in an online social network can be categorized roughly into endogenous events, where users just respond to the actions of their neighbors within the network, or exogenous events, where users take actions due to drives external to the network. How much external drive should be provided to each user, such that the network activity can be steered towards a target state? In this paper, we model social events using multivariate Hawkes processes, which can capture both endogenous and exogenous event intensities, and derive a time dependent linear relation between the intensity of exogenous events and the overall network activity. Exploiting this connection, we develop a convex optimization framework for determining the required level of external drive in order for the network to reach a desired activity level. We experimented with event data gathered from Twitter, and show that our method can steer the activity of the network more accurately than alternatives. PMID:26005312

Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital

EPA Science Inventory

Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...

49 CFR 1220.0 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... companies Electric railway companies Express companies Persons furnishing cars to railroads Ratemaking... associations, demurrage and car service bureaus, weighing and inspection bureaus, and other joint activities...

49 CFR 1220.0 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... companies Electric railway companies Express companies Persons furnishing cars to railroads Ratemaking... associations, demurrage and car service bureaus, weighing and inspection bureaus, and other joint activities...

49 CFR 1220.0 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... companies Electric railway companies Express companies Persons furnishing cars to railroads Ratemaking... associations, demurrage and car service bureaus, weighing and inspection bureaus, and other joint activities...

49 CFR 1220.0 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... companies Electric railway companies Express companies Persons furnishing cars to railroads Ratemaking... associations, demurrage and car service bureaus, weighing and inspection bureaus, and other joint activities...

49 CFR 1220.0 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... companies Electric railway companies Express companies Persons furnishing cars to railroads Ratemaking... associations, demurrage and car service bureaus, weighing and inspection bureaus, and other joint activities...

Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats.

PubMed

Kumral, A; Giriş, M; Soluk-Tekkeşin, M; Olgaç, V; Doğru-Abbasoğlu, S; Türkoğlu, Ü; Uysal, M

2016-06-01

Oxidative stress plays an important role in doxorubicin (DOX)-induced toxicity. Carnosine (CAR) is a dipeptide with antioxidant properties. The aim of this study was to evaluate the decreasing or preventive effect of CAR alone or combination with vitamin E (CAR + Vit E) on DOX-induced toxicity in heart, liver, and brain of rats. Rats were treated with CAR (250 mg kg(-1) day(-1); intraperitoneally (i.p.)) or CAR + Vit E (equals 200 mg kg(-1) α-tocopherol; once every 3 days; intramuscularly) for 12 consecutive days. On the 8th day of treatment, rats were injected with a single dose of DOX (30 mg kg(-1), i.p.). Serum cardiac troponin I (cTnI), urea, and creatinine levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities; and oxidative stress parameters in tissues were measured. We also determined thiobarbituric acid reactive substances, diene conjugate, protein carbonyl (PC), and glutathione levels and antioxidant enzyme activities. DOX resulted in increased serum cTnI, ALT, AST, urea, and creatinine levels and increased lipid peroxide and PC levels in tissues. CAR or CAR + Vit E treatments led to decreases in serum cTnI levels and ALT and AST activities. These treatments reduced prooxidant status and ameloriated histopathologic findings in the examined tissues. Our results may indicate that CAR alone, especially in combination with Vit E, protect against DOX-induced toxicity in heart, liver, and kidney tissues of rats. This was evidenced by improved cardiac, hepatic, and renal markers and restoration of the prooxidant state and amelioration of histopathologic changes. © The Author(s) 2015.

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

PubMed Central

Adusumilli, Prasad S.; Cherkassky, Leonid; Villena-Vargas, Jonathan; Colovos, Christos; Servais, Elliot; Plotkin, Jason; Jones, David R.; Sadelain, Michel

2015-01-01

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication or persistence. The remarkable ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” Based on these results, we are opening a phase I clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies. PMID:25378643

BEAMLINE-CONTROLLED STEERING OF SOURCE-POINT ANGLE AT THE ADVANCED PHOTON SOURCE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Emery, L.; Fystro, G.; Shang, H.

An EPICS-based steering software system has been implemented for beamline personnel to directly steer the angle of the synchrotron radiation sources at the Advanced Photon Source. A script running on a workstation monitors "start steering" beamline EPICS records, and effects a steering given by the value of the "angle request" EPICS record. The new system makes the steering process much faster than before, although the older steering protocols can still be used. The robustness features of the original steering remain. Feedback messages are provided to the beamlines and the accelerator operators. Underpinning this new steering protocol is the recent refinementmore » of the global orbit feedback process whereby feedforward of dipole corrector set points and orbit set points are used to create a local steering bump in a rapid and seamless way.« less

78 FR 77684 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-24

... Rule'' (``Used Car Rule'' or ``Rule''), which applies to used vehicle dealers. That clearance expires... part of the SUPPLEMENTARY INFORMATION section below. Write ``Used Car Rule, PRA Comment, P137606'' on... comment on the information collection requirements associated with the Used Car Rule (September 25, 2013...

Rev Your Engines!

ERIC Educational Resources Information Center

Blanchard, Margaret; Sharp, Jennifer; Grable, Lisa

2009-01-01

As part of the "Car Lab Project," students constructed rubber band cars, raced them, and worked through a number of automotive activities. The students engaged in this project certainly had fun, but they also used high-tech gear such as motion sensors and graphing calculators to gather data on the distance and time cars traveled and to generate…

76 FR 57103 - Reports, Forms and Recordkeeping Requirements Agency Information Collection Activity Under OMB...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-15

... Federal Motor Vehicle Theft Prevention Standard was extended to include all passenger cars and... Vehicle Theft Prevention Standard (Part 541), all passenger cars, and multipurpose passenger vehicles with..., 565 and 567. Part 541 The Motor Vehicle Information and Cost Savings Act was amended by the Anti-Car...

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

PubMed

Peffer, Richard C; LeBaron, Matthew J; Battalora, Michael; Bomann, Werner H; Werner, Christoph; Aggarwal, Manoj; Rowe, Rocky R; Tinwell, Helen

2018-04-16

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

The CAR agonist TCPOBOP inhibits lipogenesis and promotes fibrosis in the mammary gland of adolescent female mice.

PubMed

Xu, Pengfei; Hong, Fan; Wang, Jing; Dai, Shu; Wang, Jialin; Zhai, Yonggong

2018-06-15

Constitutive androstane receptor (CAR) is a nuclear receptor that not only regulates drug-metabolizing enzymes but also influences energy metabolism. TC, 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene (TCPOBOP) has been shown to inhibit lipogenesis in the liver and adipose tissues. The mammary gland is mainly composed of fat pads and duct systems in adolescent female mice. Here, activation of CAR by TC reduces the mammary gland weight, blocks lipid accumulation by inhibiting lipogenesis and gluconeogenesis, and accelerates collagen formation and fibrosis in the mammary fat pad of adolescent female mice. This information provides a reference for CAR activation, which may affect mammary gland development in adolescent females. Copyright © 2018 Elsevier B.V. All rights reserved.

Cost of Einstein-Podolsky-Rosen steering in the context of extremal boxes

NASA Astrophysics Data System (ADS)

Das, Debarshi; Datta, Shounak; Jebaratnam, C.; Majumdar, A. S.

2018-02-01

Einstein-Podolsky-Rosen steering is a form of quantum nonlocality, which is weaker than Bell nonlocality, but stronger than entanglement. Here we present a method to check Einstein-Podolsky-Rosen steering in the scenario where the steering party performs two black-box measurements and the trusted party performs projective qubit measurements corresponding to two arbitrary mutually unbiased bases. This method is based on decomposing the measurement correlations in terms of extremal boxes of the steering scenario. In this context, we propose a measure of steerability called steering cost. We show that our steering cost is a convex steering monotone. We illustrate our method to check steerability with two families of measurement correlations and find out their steering cost.

Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells.

PubMed

Li, Daochuan; Mackowiak, Bryan; Brayman, Timothy G; Mitchell, Michael; Zhang, Lei; Huang, Shiew-Mei; Wang, Hongbing

2015-11-01

The constitutive androstane receptor (CAR) modulates the transcription of numerous genes involving drug metabolism, energy homeostasis, and cell proliferation. Most functions of CAR however were defined from animal studies. Given the known species difference of CAR and the significant cross-talk between CAR and the pregnane X receptor (PXR), it is extremely difficult to decipher the exact role of human CAR (hCAR) in gene regulation, relying predominantly on pharmacological manipulations. Here, utilizing a newly generated hCAR-knockout (KO) HepaRG cell line, we carried out RNA-seq analysis of the global transcriptomes in wild-type (WT) and hCAR-KO HepaRG cells treated with CITCO, a selective hCAR agonist, phenobarbital (PB), a dual activator of hCAR and hPXR, or vehicle control. Real-time PCR assays in separate experiments were used to validate RNA-seq findings. Our results indicate that genes encoding drug-metabolizing enzymes are among the main clusters altered by both CITCO and PB. Specifically, CITCO significantly changed the expression of 135 genes in an hCAR-dependent manner, while PB altered the expression of 227 genes in WT cells of which 94 were simultaneously modulated in both cell lines reflecting dual effects of PB on hCAR/PXR. Notably, we found that many genes promoting cell proliferation and tumorigenesis were up-regulated in hCAR-KO cells, suggesting that hCAR may play an important role in cell growth that differs from mouse CAR. Together, our results reveal both novel and known targets of hCAR and support the role of hCAR in maintaining the homeostasis of metabolism and cell proliferation in the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of preshipping management on measures of stress and performance of beef steers during feedlot receiving.

PubMed

Arthington, J D; Qiu, X; Cooke, R F; Vendramini, J M B; Araujo, D B; Chase, C C; Coleman, S W

2008-08-01

Over 2 yr, a total of 96 steers (approximately 7 mo of age) were allocated to 1 of 4 weaning management strategies: 1) control: weaned on the day of shipping; 2) creep-fed: allowed free-choice access to concentrate before weaning and shipping; 3) preweaned: weaned and provided supplemental concentrate on pasture before shipping; and 4) early-weaned: weaned at 70 to 90 d of age and kept on pasture. On the day of shipping, steers were loaded together onto a commercial livestock trailer and transported 1,600 km over 24 h before being received into the feedlot. At the feedlot, steers were penned by treatment (4 pens/treatment) and provided access to free-choice hay and concentrate in separate feeding spaces. Samples of blood were collected on d 0, 1, 4, 8, 15, 22, and 29 relative to shipping. Steer performance was assessed over the receiving period, including DMI of hay and concentrate, ADG, and G:F. Predetermined contrasts included control vs. early-weaned, creep-fed vs. preweaned, and control vs. creep-fed and preweaned. Overall ADG was greater (P < 0.01) for early-weaned vs. control steers (1.39 vs. 0.88 kg). In wk 1, early-weaned steers consumed more concentrate and less hay compared with control steers (P < 0.03), and preweaned steers consumed more concentrate (P < 0.01) but a similar amount of hay (P = 0.75) compared with creep-fed steers. Average DMI was greater for preweaned compared with creep-fed steers (2.84 vs. 2.50% of BW; P = 0.01) and tended to be greater for early-weaned compared with control steers (2.76 vs. 2.50% of BW; P = 0.06). Feed efficiency of early-weaned steers was greater than that of control steers (G:F = 0.17 vs. 0.12; P < 0.01) but similar for preweaned compared with creep-fed steers (P = 0.72). Plasma ceruloplasmin concentrations were less (P < 0.05) in control vs. early-weaned steers on d 0, but increased sharply after shipping and were greater in control vs. early-weaned steers on d 15 and 22 (P < 0.05). Creep-fed steers also experienced greater (P < 0.05) plasma ceruloplasmin concentrations than preweaned steers on d 29. These data suggest that early-weaned steers have improved performance in the feedlot compared with steers weaned directly before transport and feedlot entry. Differences in preshipping management appear to significantly affect measures of the acute phase protein response in steers.

The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies

PubMed Central

Wang, Duan; Li, Linhao; Yang, Hui; Ferguson, Stephen S.; Baer, Maria R.; Gartenhaus, Ronald B.

2013-01-01

Cyclophosphamide (CPA) is one of the most widely used chemotherapeutic prodrugs that undergoes hepatic bioactivation mediated predominantly by cytochrome P450 (CYP) 2B6. Given that the CYP2B6 gene is primarily regulated by the constitutive androstane receptor (CAR, NR1I3), we hypothesize that selective activation of CAR can enhance systemic exposure of the pharmacologically active 4-hydroxycyclophosamide (4-OH-CPA), with improved efficacy of CPA-based chemotherapy. In this study, we have developed a unique human primary hepatocyte (HPH)–leukemia cell coculture model; the chemotherapeutic effects of CPA on leukemia cells can be directly investigated in vitro in a cellular environment where hepatic metabolism was well maintained. Our results demonstrated that activation of CAR preferentially induces the expression of CYP2B6 over CYP3A4 in HPHs, although endogenous expression of these enzymes in leukemia cells remains negligible. Importantly, coadministration of CPA with a human CAR activator led to significantly enhanced cytotoxicity in leukemia cells by inducing the apoptosis pathways, without concomitant increase in the off-target hepatotoxicity. Associated with the enhanced antitumor activity, a time and concentration-dependent increase in 4-OH-CPA formation was observed in the coculture system. Together, our findings offer proof of concept that CAR as a novel molecular target can facilitate CPA-based chemotherapy by selectively promoting its bioactivation. PMID:23160467

Simple control-theoretic models of human steering activity in visually guided vehicle control

NASA Technical Reports Server (NTRS)

Hess, Ronald A.

1991-01-01

A simple control theoretic model of human steering or control activity in the lateral-directional control of vehicles such as automobiles and rotorcraft is discussed. The term 'control theoretic' is used to emphasize the fact that the model is derived from a consideration of well-known control system design principles as opposed to psychological theories regarding egomotion, etc. The model is employed to emphasize the 'closed-loop' nature of tasks involving the visually guided control of vehicles upon, or in close proximity to, the earth and to hypothesize how changes in vehicle dynamics can significantly alter the nature of the visual cues which a human might use in such tasks.

Behavioral characteristics of Hanwoo (Bos taurus coreanae) steers at different growth stages and seasons.

PubMed

Kim, Na Yeon; Kim, Seong Jin; Jang, Se Young; Oh, Mi Rae; Tang, Yu Jiao; Seong, Hye Jin; Yun, Yeong Sik; Moon, Sang Ho

2017-10-01

This research analyzed behavioral characteristics of Hanwoo ( Bos taurus coreanae ) steers during each season and growth stage to enable measurement of the animals' welfare level for precision livestock farming. A hundred-eight beef steers were divided into three equal groups at a Hanwoo farm according to their growth stage: growing stage (GS), 8 months; early-fattening stage (EFS), 19 months; and late-fattening stage (LFS), 30 months. Twelve behavioral categories were continuously recorded for 13 day-time hours in each four seasons with three replications. Time spent standing was found to be significantly longer in summer at all growth stages (p<0.05). Hanwoos at the GS spent significantly longer standing time in spring and summer than those at the EFS and LFS (p<0.05). Lying time in summer was the shortest for all growth stages (p<0.05). Steers at the LFS spent significantly longer lying time than that at the GS (p<0.05) in summer. For GS and EFS, time spent eating in spring and autumn were longer than in summer and winter (p<0.05). Eating time was the longest for the GS in spring, autumn, and winter, excluding for the LFS in winter (p<0.05). Regarding ruminating, steers at the LFS spent significantly shorter time than those at other stages in all seasons (p<0.05). GS and EFS steers showed the longest walking time in summer compared with other seasons (p<0.05). At GS and LFS, drinking time in summer was the longest of all seasons (p<0.05). Sleeping time was significantly shorter in summer compared with the other seasons (p<0.05). Self-grooming time was the longest in winter for all growth stages (p<0.05). Steers were found to have more variable behavioral patterns during summer and the GS and less active behaviors during the LFS, thus extra care seems necessary during the GS, LFS, and summer period.

KSC00pp0939

NASA Image and Video Library

2000-07-20

After being involved in a minor derailment incident during a routine movement on the tracks, rail cars carrying solid rocket booster segments sit idle. The rail cars were being moved as part of a standard operation to “order” the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area

KSC-00pp0939

NASA Image and Video Library

2000-07-20

After being involved in a minor derailment incident during a routine movement on the tracks, rail cars carrying solid rocket booster segments sit idle. The rail cars were being moved as part of a standard operation to “order” the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area

Versatile CAR T-cells for cancer immunotherapy

PubMed Central

Cao, Jingjing; Neelalpu, Sattva S

2018-01-01

Chimeric antigen receptor (CAR) T-cell therapy has been clinically proven to efficiently combat haematological malignancies. However, continuous efforts are required to increase the specificity of CAR T-cells against tumour versus normal tissues, and are essential to improve their antitumour activity in solid tumours. This review summarises the structure of major CAR designs, and strategies to overcome immunosuppressive tumour microenvironment, and reduce toxicities. Along with reviewing currently available techniques that allow the elimination of CAR T-cells after they fulfil their desired functions, using suicide genes, drug elimination strategies are also introduced. A better understanding of the strengths and pitfalls of CAR T-cell therapy will provide fundamental knowledge for the improvement of engineered T-cell therapy in the near future. PMID:29628798

Study concerning the loads over driver's chests in car crashes with cars of the same or different generation

NASA Astrophysics Data System (ADS)

Ispas, N.; Năstăsoiu, M.

2016-08-01

Reducing occupant injuries for cars involves in traffic accidents is a main target of today cars designers. Known as active or passive safety, many technological solutions were developing over the time for an actual better car's occupant safety. In the real world, in traffic accidents are often involved cars from different generations with various safety historical solutions. The main aim of these papers are to quantify the influences over the car driver chest loads in cases of same or different generation of cars involved in side car crashes. Both same and different cars generations were used for the study. Other goal of the paper was the study of in time loads conformity for diver's chests from both cars involved in crash. The paper's experimental results were obtained by support of DSD, Dr. Steffan Datentechnik GmbH - Linz, Austria. The described tests were performed in full test facility of DSD Linz, in “Easter 2015 PC-Crash Seminar”. In all crashes we obtaining results from both dummy placed in impacted and hits car. The novelty of the paper are the comparisons of data set from each of driver (dummy) of two cars involved in each of six experimental crashes. Another novelty of this paper consists in possibilities to analyse the influences of structural historical cars solutions over deformation and loads in cases of traffic accidents involved. Paper's conclusions can be future used for car passive safety improvement.

Walking the tightrope-perspectives on local politicians' role in implementing a national social care policy on evidence-based practice.

PubMed

Bäck, A; Ståhl, C; von Thiele Schwarz, U; Richter, A; Hasson, H

2016-01-01

Despite national policy recommending evidence-based practice (EBP), its application in social care has been limited. While local politicians can affect the process, little is known about their knowledge, attitudes and roles regarding EBP. The aim here is twofold: to explore the role of local politicians in the implementation of EBP in social care from both their own and a management perspective; and to examine factors politicians perceive as affecting their decisions and actions concerning the implementation of EBP policy. Local politicians (N = 13) and managers (N = 22) in social care were interviewed. Qualitative thematic analysis with both inductive and deductive codes was used. Politicians were rather uninformed regarding EBP and national policy. The factors limiting their actions were, beside the lack of awareness, lack of ability to question existing working methods, and a need for support in the steering of EBP. Thus, personal interest played a significant part in what role the politicians assumed. This resulted in some politicians taking a more active role in steering EBP while others were not involved. From the managers' perspective, a more active steering by politicians was desired. Setting budget and objectives, as well as active follow-up of work processes and outcomes, were identified as means to affect the implementation of EBP. However, the politicians seemed unaware of the facilitating effects of these actions. Local politicians had a possibility to facilitate the implementation of EBP, but their role was unclear. Personal interest played a big part in determining what role was taken. The results imply that social care politicians might need support in the development of their steering of EBP. Moving the responsibility for EBP facilitation upwards in the political structure could be an important step in developing EBP in social care.

A GMP-compliant protocol to expand and transfect cancer patient T cells with mRNA encoding a tumor-specific chimeric antigen receptor.

PubMed

Krug, Christian; Wiesinger, Manuel; Abken, Hinrich; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Schaft, Niels

2014-10-01

Chimeric antigen receptors (CARs), which combine an antibody-derived binding domain (single chain fragment variable) with T-cell-activating signaling domains, have become a promising tool in the adoptive cellular therapy of cancer. Retro- and lenti-viral transductions are currently the standard methods to equip T cells with a CAR; permanent CAR expression, however, harbors several risks like uncontrolled auto-reactivity. Modification of T cells by electroporation with CAR-encoding RNA to achieve transient expression likely circumvents these difficulties. We here present a GMP-compliant protocol to activate and expand T cells for clinical application. The protocol is optimized in particular to produce CAR-modified T cells in clinically sufficient numbers under full GMP-compliance from late-stage cancer patients. This protocol allows the generation of 6.7 × 10(8) CAR-expressing T cells from one patient leukapheresis. The CAR-engineered T cells produced pro-inflammatory cytokines after stimulation with antigen-bearing tumor cells and lysed tumor cells in an antigen-specific manner. This functional capacity was maintained after cryopreservation. Taken together, we provide a clinically applicable protocol to transiently engineer sufficient numbers of antigen-specific patient T cells for use in adoptive cell therapy of cancer.

Suppression of Murine Colitis and its Associated Cancer by Carcinoembryonic Antigen-Specific Regulatory T Cells

PubMed Central

Blat, Dan; Zigmond, Ehud; Alteber, Zoya; Waks, Tova; Eshhar, Zelig

2014-01-01

The adoptive transfer of regulatory T cells (Tregs) offers a promising strategy to combat pathologies that are characterized by aberrant immune activation, including graft rejection and autoinflammatory diseases. Expression of a chimeric antigen receptor (CAR) gene in Tregs redirects them to the site of autoimmune activity, thereby increasing their suppressive efficiency while avoiding systemic immunosuppression. Since carcinoembryonic antigen (CEA) has been shown to be overexpressed in both human colitis and colorectal cancer, we treated CEA-transgenic mice that were induced to develop colitis with CEA-specific CAR Tregs. Two disease models were employed: T-cell-transfer colitis as well as the azoxymethane–dextran sodium sulfate model for colitis-associated colorectal cancer. Systemically administered CEA-specific (but not control) CAR Tregs accumulated in the colons of diseased mice. In both model systems, CEA-specific CAR Tregs suppressed the severity of colitis compared to control Tregs. Moreover, in the azoxymethane–dextran sodium sulfate model, CEA-specific CAR Tregs significantly decreased the subsequent colorectal tumor burden. Our data demonstrate that CEA-specific CAR Tregs exhibit a promising potential in ameliorating ulcerative colitis and in hindering colorectal cancer development. Collectively, this study provides a proof of concept for the therapeutic potential of CAR Tregs in colitis patients as well as in other autoimmune inflammatory disorders. PMID:24686242

Teaching Science: Seat Belt Science.

ERIC Educational Resources Information Center

Leyden, Michael B.

1994-01-01

Describes activities that will help students understand how car seat belts work, the limited reaction time available to passengers in an automobile accident, and the force of impact in a car collision. These activities will provide students with hands-on experiences that demonstrate the importance of always wearing seat belts while in an…

Tin Can Racer Derby.

ERIC Educational Resources Information Center

Milson, James L.

1986-01-01

Describes directions for constructing "racing" cars out of simple materials like spools and coffee cans. Discusses procedures for students to build cars, then to test and race them. Stresses that the activity allows for self-discovery of problem solving techniques and opportunities to discuss the scientific concepts related to the activity. (TW)

Detection of quantum steering in multipartite continuous-variable Greenberger-Horne-Zeilinger-like states

NASA Astrophysics Data System (ADS)

Wang, Meng; Xiang, Yu; He, Qiongyi; Gong, Qihuang

2015-01-01

The multipartite entangled state has drawn broad attention for both foundations of quantum mechanics and applications in quantum information processing. Here, we study the spatially separated N -partite continuous-variable Greenberger-Horne-Zeilinger-like states, which can be produced by a linear optical network with squeezed light and N -1 beamsplitters. We investigate the properties of multipartite Einstein-Podolsky-Rosen steering possessed by those states, and find that the steering of a given quantum mode is allowed when not less than half of the modes within the states take part in the steering group. This is certified by the detection of the correlation between position and momentum quadratures of the steered mode and a combination of quadratures of other modes inside the steering group. The steering is evidenced by the high correlation where the steering group can infer the quadratures of the steered mode to high precision, i.e., below the quantum limit for the position and momentum quadratures of the steered quantum mode. We also examine the influence of inefficiency on the multipartite steering, and derive the threshold of the loss tolerance. Furthermore, we discuss the collective N -partite steering induced by the asymmetric loss on beams, which exists when a given quantum mode can only be steered by all the remaining N -1 modes collaboratively. The present multipartite steering correlation may have potential applications in certain quantum information tasks where the issue of trust is important, such as one-sided device-independent quantum secret sharing.

Three-bead steering microswimmers

NASA Astrophysics Data System (ADS)

Rizvi, Mohd Suhail; Farutin, Alexander; Misbah, Chaouqi

2018-02-01

The self-propelled microswimmers have recently attracted considerable attention as model systems for biological cell migration as well as artificial micromachines. A simple and well-studied microswimmer model consists of three identical spherical beads joined by two springs in a linear fashion with active oscillatory forces being applied on the beads to generate self-propulsion. We have extended this linear microswimmer configuration to a triangular geometry where the three beads are connected by three identical springs in an equilateral triangular manner. The active forces acting on each spring can lead to autonomous steering motion; i.e., allowing the swimmer to move along arbitrary paths. We explore the microswimmer dynamics analytically and pinpoint its rich character depending on the nature of the active forces. The microswimmers can translate along a straight trajectory, rotate at a fixed location, as well as perform a simultaneous translation and rotation resulting in complex curved trajectories. The sinusoidal active forces on the three springs of the microswimmer contain naturally four operating parameters which are more than required for the steering motion. We identify the minimal operating parameters which are essential for the motion of the microswimmer along any given arbitrary trajectory. Therefore, along with providing insights into the mechanics of the complex motion of the natural and artificial microswimmers, the triangular three-bead microswimmer can be utilized as a model for targeted drug delivery systems and autonomous underwater vehicles where intricate trajectories are involved.

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity

PubMed Central

Li, Wenpeng; Guo, Linjie; Rathi, Purva; Marinova, Ekaterina; Gao, Xiuhua; Wu, Meng-Feng; Liu, Hao; Dotti, Gianpietro; Gottschalk, Stephen; Metelitsa, Leonid S.; Heczey, Andras

2017-01-01

T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3ζ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors. PMID:27530312

A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction

PubMed Central

Shindo, Sawako; Numazawa, Satoshi; Yoshida, Takemi

2006-01-01

CAR (constitutive androstane receptor) is a nuclear receptor that regulates the transcription of target genes, including CYP (cytochrome P450) 2B and 3A. The transactivation by CAR is regulated by its subcellular localization; however, the mechanism that governs nuclear translocation has yet to be clarified. It has been reported recently that AMPK (AMP-activated protein kinase) is involved in phenobarbital-mediated CYP2B induction in a particular culture system. We therefore investigated in vivo whether AMPK is involved in the activation of CAR-dependent gene expression. Immunoblot analysis using an antibody which recognizes Thr-172-phosphorylated AMPKα1/2 revealed phenobarbital-induced AMPK activation in rat and mouse livers as well. Phenobarbital, however, failed to increase the liver phospho-AMPK level of tumour-bearing rats in which CAR nuclear translocation had been impaired. In in vivo reporter gene assays employing PBREM (phenobarbital-responsive enhancer module) from CYP2B1, an AMPK inhibitor 8-bromo-AMP abolished phenobarbital-induced transactivation. In addition, Cyp2b10 gene expression was attenuated by 8-bromo-AMP. Forced expression of a dominant-negative mutant and the wild-type of AMPKα2 in the mouse liver suppressed and further enhanced phenobarbital-induced PBREM-reporter activity respectively. Moreover, the AMPK activator AICAR (5-amino-4-imidazolecarboxamide riboside) induced PBREM transactivation and an accumulation of CAR in the nuclear fraction of the mouse liver. However, AICAR and metformin, another AMPK activator, failed to induce hepatic CYP2B in mice and rats. These observations suggest that AMPK is at least partly involved in phenobarbital-originated signalling, but the kinase activation by itself is not sufficient for CYP2B induction in vivo. PMID:17032173

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Young Joo; Seoul National University Bundang Hospital, Seoul; Lee, Eun Kyung

Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR{sup −/−} mice, but not in hypothyroid PXR{sup −/−} mice. In contrast, expression of Cyp2b10 was inducedmore » in both WT and PXR{sup −/−} hypothyroid mice, and this induction was abolished in CAR{sup −/−} mice and in and CAR{sup −/−} PXR{sup −/−} double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR{sup −/−} mice and lowest in WT and PXR{sup −/−} mice. Hypothyroid WT or PXR{sup −/−} mice survived chronic CBZ treatment, but all hypothyroid CAR{sup −/−} and CAR{sup −/−} PXR{sup −/−} mice died, with CAR{sup −/−}PXR{sup −/−} mice surviving longer than CAR{sup −/−} mice (12.3 ± 3.3 days vs. 6.3 ± 2.1 days, p = 0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge. -- Highlights: ► Hypothyroid status activates CAR in mice and induces Cyp2b10 expression. ► Hypothyroid status suppresses PXR activity in mice and represses Cyp3a11 expression. ► These responses balance each other out in normal mice. ► Hypothyroidism sensitizes CAR null mice to toxic effects of carbamazepine.« less

Optimal control of directional deep brain stimulation in the parkinsonian neuronal network

NASA Astrophysics Data System (ADS)

Fan, Denggui; Wang, Zhihui; Wang, Qingyun

2016-07-01

The effect of conventional deep brain stimulation (DBS) on debilitating symptoms of Parkinson's disease can be limited because it can only yield the spherical field. And, some side effects are clearly induced with influencing their adjacent ganglia. Recent experimental evidence for patients with Parkinson's disease has shown that a novel DBS electrode with 32 independent stimulation source contacts can effectively optimize the clinical therapy by enlarging the therapeutic windows, when it is applied on the subthalamic nucleus (STN). This is due to the selective activation in clusters of various stimulation contacts which can be steered directionally and accurately on the targeted regions of interest. In addition, because of the serious damage to the neural tissues, the charge-unbalanced stimulation is not typically indicated and the real DBS utilizes charge-balanced bi-phasic (CBBP) pulses. Inspired by this, we computationally investigate the optimal control of directional CBBP-DBS from the proposed parkinsonian neuronal network of basal ganglia-thalamocortical circuit. By appropriately tuning stimulation for different neuronal populations, it can be found that directional steering CBBP-DBS paradigms are superior to the spherical case in improving parkinsonian dynamical properties including the synchronization of neuronal populations and the reliability of thalamus relaying the information from cortex, which is in a good agreement with the physiological experiments. Furthermore, it can be found that directional steering stimulations can increase the optimal stimulation intensity of desynchronization by more than 1 mA compared to the spherical case. This is consistent with the experimental result with showing that there exists at least one steering direction that can allow increasing the threshold of side effects by 1 mA. In addition, we also simulate the local field potential (LFP) and dominant frequency (DF) of the STN neuronal population induced by the activation of 32 different contacts with optimal stimulation intensity and immediately after the stimulation, respectively. These can reveal regional differences in pathological activity within STN nucleus. It is shown that in line with the experimental results directional steering stimulation can induce the low-amplitude LFP which implies the occurrence of desynchronizing regime, as well as the distribution of DF can locate at the 13-40 Hz of beta frequency range. Hopefully, the obtained results can provide theoretical evidences in exploring pathophysiologic activity of brain.

Car surfing: case studies of a growing dangerous phenomenon.

PubMed

Clark, Steven; Mangram, Alicia; Dunn, Ernest

2008-03-01

Car surfing is a dangerous new pastime for American youth. Car surfing is an activity that is defined as standing (or lying) on a vehicle while it is being driven. This activity frequently results in severe injuries that often require significant surgical intervention. Despite its destructive nature, however, there are many Internet sites that encourage this behavior and view it as amusing. As a result, car surfing is becoming increasingly popular. We conducted a retrospective chart review of all patients injured as a result of car surfing over the last 4 years at our Urban Level II trauma center. Data collected included Injury Severity Score (ISS), Revised Trauma Score (RTS), age, gender, injury pattern, surgical intervention, and length of stay. Eight car surfers were identified. The average age was 17. The average Revised Trauma Score was 6.8 with an average Injury Severity Score of 16.9. Five patients were admitted to the intensive care unit. Four of these five patients needed to be intubated for ventilatory support. Five of the eight patients had significant intracranial injuries. Two patients had epidural hematomas that required evacuation. Two other patients had subdural hematomas that were treated nonoperatively, and one patient had a subarachnoid hemorrhage that was also treated nonoperatively. Four of the eight patients required surgical intervention. There were no deaths in this study. Car surfing leads to severe injuries that can result in significant morbidity. American youth have access to Internet sites that project this activity as an acceptable behavior. Five of our eight patients had a significant intracranial injury. Trauma surgeons need to be more aware of this injury phenomenon.

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

PubMed

Wang, Dongrui; Aguilar, Brenda; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R; Forman, Stephen J; Brown, Christine E

2018-05-17

Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity

PubMed Central

Wang, Dongrui; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R.; Forman, Stephen J.; Brown, Christine E.

2018-01-01

Chimeric antigen receptor–modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy. PMID:29769444

Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor

PubMed Central

Hoffart, E; Ghebreghiorghis, L; Nussler, AK; Thasler, WE; Weiss, TS; Schwab, M; Burk, O

2012-01-01

BACKGROUND AND PURPOSE Atorvastatin metabolites differ in their potential for drug interaction because of differential inhibition of drug-metabolizing enzymes and transporters. We here investigate whether they exert differential effects on the induction of these genes via activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). EXPERIMENTAL APPROACH Ligand binding to PXR or CAR was analysed by mammalian two-hybrid assembly and promoter/reporter gene assays. Additionally, surface plasmon resonance was used to analyse ligand binding to CAR. Primary human hepatocytes were treated with atorvastatin metabolites, and mRNA and protein expression of PXR-regulated genes was measured. Two-hybrid co-activator interaction and co-repressor release assays were utilized to elucidate the molecular mechanism of PXR activation. KEY RESULTS All atorvastatin metabolites induced the assembly of PXR and activated CYP3A4 promoter activity. Ligand binding to CAR could not be proven. In primary human hepatocytes, the para-hydroxy metabolite markedly reduced or abolished induction of cytochrome P450 and transporter genes. While significant differences in co-activator recruitment were not observed, para-hydroxy atorvastatin demonstrated only 50% release of co-repressors. CONCLUSIONS AND IMPLICATIONS Atorvastatin metabolites are ligands of PXR but not of CAR. Atorvastatin metabolites demonstrate differential induction of PXR target genes, which results from impaired release of co-repressors. Consequently, the properties of drug metabolites have to be taken into account when analysing PXR-dependent induction of drug metabolism and transport. The drug interaction potential of the active metabolite, para-hydroxy atorvastatin, might be lower than that of the parent compound. PMID:21913896

The power of product integrity.

PubMed

Clark, K B; Fujimoto, T

1990-01-01

In the dictionary, integrity means wholeness, completeness, soundness. In products, integrity is the source of sustainable competitive advantage. Products with integrity perform superbly, provide good value, and satisfy customers' expectations in every respect, including such intangibles as their look and feel. Consider this example from the auto industry. In 1987, Mazda put a racy four-wheel steering system in a five-door family hatchback. Honda introduced a comparable system in the Prelude, a sporty, two-door coupe. Most of Honda's customers installed the new technology; Mazda's system sold poorly. Potential customers felt the fit--or misfit--between the car and the new component, and they responded accordingly. Companies that consistently develop products with integrity are coherent, integrated organizations. This internal integrity is visible at the level of strategy and structure, in management and organization, and in the skills, attitudes, and behavior of individual designers, engineers, and operators. Moreover, these companies are integrated externally: customers become part of the development organization. Integrity starts with a product concept that describes the new product from the potential customer's perspective--"pocket rocket" for a sporty, subcompact car, for example. Whether the final product has integrity will depend on two things: how well the concept satisfies potential customers' wants and needs and how completely the concept has been embodied in the product's details. In the most successful development organizations, "heavyweight" product managers are responsible for leading both tasks, as well as for guiding the creation of a strong product concept.

Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects.

PubMed

Di, Shengmeng; Li, Zonghai

2016-04-01

Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed.

Intelligent vehicle safety control strategy in various driving situations

NASA Astrophysics Data System (ADS)

Moon, Seungwuk; Cho, Wanki; Yi, Kyongsu

2010-12-01

This paper describes a safety control strategy for intelligent vehicles with the objective of optimally coordinating the throttle, brake, and active front steering actuator inputs to obtain both lateral stability and longitudinal safety. The control system consists of a supervisor, control algorithms, and a coordinator. From the measurement and estimation signals, the supervisor determines the active control modes among normal driving, longitudinal safety, lateral stability, and integrated safety control mode. The control algorithms consist of longitudinal and lateral stability controllers. The longitudinal controller is designed to improve the driver's comfort during normal, safe-driving situations, and to avoid rear-end collision in vehicle-following situations. The lateral stability controller is designed to obtain the required manoeuvrability and to limit the vehicle body's side-slip angle. To obtain both longitudinal safety and lateral stability control in various driving situations, the coordinator optimally determines the throttle, brake, and active front steering inputs based on the current status of the subject vehicle. Closed-loop simulations with the driver-vehicle-controller system are conducted to investigate the performance of the proposed control strategy. From these simulation results, it is shown that the proposed control algorithm assists the driver in combined severe braking/large steering manoeuvring so that the driver can maintain good manoeuvrability and prevent the vehicle from crashing in vehicle-following situations.

Monogamy of Einstein-Podolsky-Rosen Steering in the Background of an Asymptotically Flat Black Hole

NASA Astrophysics Data System (ADS)

Wang, Jieci; Jing, Jiliang; Fan, Heng

2018-03-01

We study the behavior of monogamy deficit and monogamy asymmetry for Einstein-Podolsky-Rosen steering of Gaussian states under the influence of the Hawking effect. We demonstrate that the monogamy of quantum steering shows an extreme scenario in the curved spacetime: the first part of a tripartite system cannot individually steer two other parties, but it can steer the collectivity of the remaining two parties. We also find that the monogamy deficit of Gaussian steering, a quantifier of genuine tripartite steering, are generated due to the influence of the Hawking thermal bath. Our results elucidate the structure of quantum steering in tripartite quantum systems in curved spacetime.

Antimicrobial, antioxidant and sensory features of eugenol, carvacrol and trans-anethole in active packaging for organic ready-to-eat iceberg lettuce.

PubMed

Wieczyńska, Justyna; Cavoski, Ivana

2018-09-01

In this study, bio-based emitting sachets containing eugenol (EUG), carvacrol (CAR) and trans-anethole (ANT) were inserted into cellulose (CE) and polypropylene (PP) pillow packages of organic ready-to-eat (RTE) iceberg lettuce to investigate their functional features. EUG, CAR and ANT sachets in CE; and CAR in PP packages showed antimicrobial activities against coliforms (Δlog CFU g -1 of -1.38, -0.91, -0.93 and -0.93, respectively). EUG and ANT sachets in both packages reduced discoloration (ΔE of 9.5, 1.8, 9.4 and 5.6, respectively). ANT in both, and EUG only in PP packages induced biosynthesis of caffeoyl derivatives (C a T A , D i C a T A , D i C a Q A ), total phenolics and antioxidant activity (FRAP). Also, ANT and EUG in both packages improved overall freshness and odor. Principal component analysis separated ANT and EUG from CAR in both packages. The Pearson correlation confirmed that overall quality improvements were more pronounced by ANT inside the packages in comparison to EUG and CAR. Copyright © 2018 Elsevier Ltd. All rights reserved.

Demonstration of Multisetting One-Way Einstein-Podolsky-Rosen Steering in Two-Qubit Systems

NASA Astrophysics Data System (ADS)

Xiao, Ya; Ye, Xiang-Jun; Sun, Kai; Xu, Jin-Shi; Li, Chuan-Feng; Guo, Guang-Can

2017-04-01

Einstein-Podolsky-Rosen (EPR) steering describes the ability of one party to remotely affect another's state through local measurements. One of the most distinguishable properties of EPR steering is its asymmetric aspect. Steering can work in one direction but fail in the opposite direction. This type of one-way steering, which is different from the symmetry concepts of entanglement and Bell nonlocality, has garnered much interest. However, an experimental demonstration of genuine one-way EPR steering in the simplest scenario, i.e., one that employs two-qubit systems, is still lacking. In this Letter, we experimentally demonstrate one-way EPR steering with multimeasurement settings for a class of two-qubit states, which are still one-way steerable even with infinite settings. The steerability is quantified by the steering radius, which represents a necessary and sufficient steering criterion. The demonstrated one-way steering in the simplest bipartite quantum system is of fundamental interest and may provide potential applications in one-way quantum information tasks.

Efficient discovery of bioactive scaffolds by activity-directed synthesis

NASA Astrophysics Data System (ADS)

Karageorgis, George; Warriner, Stuart; Nelson, Adam

2014-10-01

The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach—which we term activity-directed synthesis—in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.

Advanced Smart Structures Flight Experiments for Precision Spacecraft

NASA Astrophysics Data System (ADS)

Denoyer, Keith K.; Erwin, R. Scott; Ninneman, R. Rory

2000-07-01

This paper presents an overview as well as data from four smart structures flight experiments directed by the U.S. Air Force Research Laboratory's Space Vehicles Directorate in Albuquerque, New Mexico. The Middeck Active Control Experiment $¯Flight II (MACE II) is a space shuttle flight experiment designed to investigate modeling and control issues for achieving high precision pointing and vibration control of future spacecraft. The Advanced Controls Technology Experiment (ACTEX-I) is an experiment that has demonstrated active vibration suppression using smart composite structures with embedded piezoelectric sensors and actuators. The Satellite Ultraquiet Isolation Technology Experiment (SUITE) is an isolation platform that uses active piezoelectric actuators as well as damped mechanical flexures to achieve hybrid passive/active isolation. The Vibration Isolation, Suppression, and Steering Experiment (VISS) is another isolation platform that uses viscous dampers in conjunction with electromagnetic voice coil actuators to achieve isolation as well as a steering capability for an infra-red telescope.

Fatty acid profiles, meat quality, and sensory attributes of organic versus conventional dairy beef steers.

PubMed

Bjorklund, E A; Heins, B J; Dicostanzo, A; Chester-Jones, H

2014-03-01

Meat from Holstein and crossbred organic and conventional dairy steers were evaluated and compared for fatty acid profiles, meat quality, sensory attributes, and consumer acceptance. Bull calves (n=49) were randomly assigned to 1 of 3 replicated groups: conventional (CONV), organic (ORG, pasture + concentrate), or grass-fed organic (GRS) and were born at the University of Minnesota West Central Research and Outreach Center (Morris, MN) between March and May 2011. The CONV steers (n=16) were fed a diet that contained 80% concentrate and 20% forage, and ORG steers (n=16) were fed a diet of organic corn, organic corn silage, and organic protein supplement. Furthermore, ORG steers consumed at least 30% of diet dry matter of high-quality organic pasture during the grazing season. The GRS steers (n=17) consumed 100% forage from pasture during the grazing season and high-quality hay or hay silage during the nongrazing season. The ORG steers had fat that was greater in oleic acid (C18:1) than the GRS and CONV steers (47.1, 36.1, and 39.9%, respectively). The GRS steers (21.9%) were lower for monounsaturated fat than the ORG (42.1%) and CONV (40.4%) steers. Furthermore, the GRS steers tended to have greater n-3 fat and had lower n-6 fat than the ORG and CONV steers. Consequently, the GRS (1.4%) steers had a lower n-6-to-n-3 fat ratio than the ORG (12.9%) and CONV (10.0%) steers. The GRS (2.6 kg) steers had steaks that were not different for Warner-Bratzler shear force than ORG (2.3 kg) steaks; however, the GRS steaks tended to have greater shear force than the CONV (2.0 kg) steaks. The 3 steer group had steaks that were not different for color brightness (L*; 0 = black and 100 = white) and yellowness/blueness (b*; positive values = yellow and negative values = blue) values; however, the GRS (10.5) steaks had lower redness/greenness (a*; positive values = red and negative values = green) values than CONV (14.5) steaks. For sensory attributes (0- to 120-point scale), no differences were observed for ORG (71.3) and CONV (69.2) steers for overall consumer liking of the beef; however, the GRS (56.3) steers had the lowest overall liking among beef consumers. The ORG (73.3) steers had greater flavor liking than the GRS (56.8) and CONV (69.2) steers. Conversely, the GRS (6.3) steers had the highest scores for off-flavor (0- to 20-point scale) compared with the ORG (3.9) and CONV (4.1) steers. The results of the current study suggest that a potential market may exist for organic grass-fed dairy steers in the United States, but quality and consistency of the beef needs to be improved. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A compound chimeric antigen receptor strategy for targeting multiple myeloma.

PubMed

Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

2018-02-01

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

Optimisation of active suspension control inputs for improved vehicle handling performance

NASA Astrophysics Data System (ADS)

Čorić, Mirko; Deur, Joško; Kasać, Josip; Tseng, H. Eric; Hrovat, Davor

2016-11-01

Active suspension is commonly considered under the framework of vertical vehicle dynamics control aimed at improvements in ride comfort. This paper uses a collocation-type control variable optimisation tool to investigate to which extent the fully active suspension (FAS) application can be broaden to the task of vehicle handling/cornering control. The optimisation approach is firstly applied to solely FAS actuator configurations and three types of double lane-change manoeuvres. The obtained optimisation results are used to gain insights into different control mechanisms that are used by FAS to improve the handling performance in terms of path following error reduction. For the same manoeuvres the FAS performance is compared with the performance of different active steering and active differential actuators. The optimisation study is finally extended to combined FAS and active front- and/or rear-steering configurations to investigate if they can use their complementary control authorities (over the vertical and lateral vehicle dynamics, respectively) to further improve the handling performance.

Contributions of neural excitability and voluntary activation to quadriceps muscle strength following anterior cruciate ligament reconstruction.

PubMed

Lepley, Adam S; Ericksen, Hayley M; Sohn, David H; Pietrosimone, Brian G

2014-06-01

Persistent quadriceps weakness is common following anterior cruciate ligament reconstruction (ACLr). Alterations in spinal-reflexive excitability, corticospinal excitability and voluntary activation have been hypothesized as underlying mechanisms contributing to quadriceps weakness. The aim of this study was to evaluate the predictive capabilities of spinal-reflexive excitability, corticospinal excitability and voluntary activation on quadriceps strength in healthy and ACLr participants. Quadriceps strength was measured using maximal voluntary isometric contractions (MVIC). Voluntary activation was quantified via the central activation ratio (CAR). Corticospinal and spinal-reflexive excitability were measured using active motor thresholds (AMT) and Hoffmann reflexes normalized to maximal muscle responses (H:M), respectively. ACLr individuals were also split into high and low strength subsets based on MVIC. CAR was the only significant predictor in the healthy group. In the ACLr group, CAR and H:M significantly predicted 47% of the variance in MVIC. ACLr individuals in the high strength subset demonstrated significantly higher CAR and H:M than those in the low strength subset. Increased quadriceps voluntary activation, spinal-reflexive excitability and corticospinal excitability relates to increased quadriceps strength in participants following ACLr. Rehabilitation strategies used to target neural alterations may be beneficial for the restoration of muscle strength following ACLr. Copyright © 2014 Elsevier B.V. All rights reserved.

The neural substrates of driving at a safe distance: a functional MRI study.

PubMed

Uchiyama, Yuji; Ebe, Kazutoshi; Kozato, Akio; Okada, Tomohisa; Sadato, Norihiro

2003-12-11

An important driving skill is the ability to maintain a safe distance from a preceding car. To determine the neural substrates of this skill we performed functional magnetic resonance imaging of simulated driving in 21 subjects. Subjects used a joystick to adjust their own driving speed in order to maintain a constant distance from a preceding car traveling at varying speeds. The task activated multiple brain regions. Activation of the cerebellum may reflect visual feedback during smooth tracking of the preceding car. Co-activation of the basal ganglia, thalamus and premotor cortex is related to movement selection. Activation of a premotor-parietal network is related to visuo-motor co-ordination. Task performance was negatively correlated with anterior cingulate activity, consistent with the role of this region in error detection and response selection.

Fine-tuning the CAR spacer improves T-cell potency

PubMed Central

Watanabe, Norihiro; Bajgain, Pradip; Sukumaran, Sujita; Ansari, Salma; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Leen, Ann M.; Vera, Juan F.

2016-01-01

ABSTRACT The adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs) has emerged as a transformative cancer therapy with curative potential, precipitating a wave of preclinical and clinical studies in academic centers and the private sector. Indeed, significant effort has been devoted to improving clinical benefit by incorporating accessory genes/CAR endodomains designed to enhance cellular migration, promote in vivo expansion/persistence or enhance safety by genetic programming to enable the recognition of a tumor signature. However, our efforts centered on exploring whether CAR T-cell potency could be enhanced by modifying pre-existing CAR components. We now demonstrate how molecular refinements to the CAR spacer can impact multiple biological processes including tonic signaling, cell aging, tumor localization, and antigen recognition, culminating in superior in vivo antitumor activity. PMID:28180032

KSC-00pp0934

NASA Image and Video Library

2000-07-20

One of two solid rocket booster rail cars is off the track after being involved in a minor derailment incident during a routine movement on the tracks. The rail cars were being moved as part of a standard operation to “order” the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area

KSC00pp0934

NASA Image and Video Library

2000-07-20

One of two solid rocket booster rail cars is off the track after being involved in a minor derailment incident during a routine movement on the tracks. The rail cars were being moved as part of a standard operation to “order” the cars, placing them into a proper sequence for upcoming segment processing activities. The rear wheels of one car and the front wheels of the car behind it slid off the tracks while passing through a railway switch onto a siding. They were traveling approximately 3 miles per hour at the time, about normal walking speed. No damage occurred to the SRB segments, or to the devices that secure the segments to the rail cars. The incident occurred on KSC property, just north of the NASA Causeway in the KSC Industrial Area

[Novel therapy for malignant lymphoma: adoptive immuno-gene therapy using chimeric antigen receptor(CAR)-expressing T lymphocytes].

PubMed

Ozawa, Keiya

2014-03-01

Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this review article, CD19-CAR-T gene therapy for refractory B-cell non-Hodgkin lymphoma is discussed.

Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells.

PubMed

Kochenderfer, James N; Yu, Zhiya; Frasheri, Dorina; Restifo, Nicholas P; Rosenberg, Steven A

2010-11-11

Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)-expressing T cells is a new approach for treating advanced B-cell malignancies. To evaluate anti-CD19-CAR-transduced T cells in a murine model of adoptive T-cell therapy, we developed a CAR that specifically recognized murine CD19. We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19. One infusion of anti-CD19-CAR-transduced T cells completely eliminated normal B cells from mice for at least 143 days. Anti-CD19-CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses. The antilymphoma efficacy of anti-CD19-CAR-transduced T cells was critically dependent on irradiation of mice before anti-CD19-CAR-transduced T-cell infusion. Anti-CD19-CAR-transduced T cells had superior antilymphoma efficacy compared with the anti-CD19 monoclonal antibody from which the anti-CD19 CAR was derived. Our results demonstrated impressive antilymphoma activity and profound destruction of normal B cells caused by anti-CD19-CAR-transduced T cells in a clinically relevant murine model.

46 CFR 169.623 - Power-driven steering systems.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Power-driven steering systems. 169.623 Section 169.623 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Machinery and Electrical Steering Systems § 169.623 Power-driven steering systems. (a) Power-driven steering...

46 CFR 169.623 - Power-driven steering systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Power-driven steering systems. 169.623 Section 169.623 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Machinery and Electrical Steering Systems § 169.623 Power-driven steering systems. (a) Power-driven steering...

Large angle nonmechanical laser beam steering at 4.6 μm using a digital micromirror device

NASA Astrophysics Data System (ADS)

Lindle, James Ryan; Watnik, Abbie T.

2018-02-01

Large angle, nonmechanical beam steering is demonstrated at 4.62 μm using the digital light processing technology. A 42-deg steering range is demonstrated, limited by the field-of-view of the recollimating lens. The measured diffraction efficiency is 8.1% on-axis and falls-off with a sin2 dependence with the steering angle. However, within the 42-deg steering range, the power varied less than 25%. The profile of the steered laser beam is Gaussian with a divergence of 5.2 mrad. Multibeam, randomly addressable beam steering, is also demonstrated.

Relative entropy of steering: on its definition and properties

NASA Astrophysics Data System (ADS)

Kaur, Eneet; Wilde, Mark M.

2017-11-01

In Gallego and Aolita (2015 Phys. Rev. X 5 041008), the authors proposed a definition for the relative entropy of steering and showed that the resulting quantity is a convex steering monotone. Here we advocate for a different definition for relative entropy of steering, based on well grounded concerns coming from quantum Shannon theory. We prove that this modified relative entropy of steering is a convex steering monotone. Furthermore, we establish that it is uniformly continuous and faithful, in both cases giving quantitative bounds that should be useful in applications. We also consider a restricted relative entropy of steering which is relevant for the case in which the free operations in the resource theory of steering have a more restricted form (the restricted operations could be more relevant in practical scenarios). The restricted relative entropy of steering is convex, monotone with respect to these restricted operations, uniformly continuous, and faithful.

Is car use related with successful aging of older adults? Results from the multinational Mediterranean islands study.

PubMed

Tyrovolas, Stefanos; Polychronopoulos, Evangelos; Morena, Marianthi; Mariolis, Anargiros; Piscopo, Suzanne; Valacchi, Giuseppe; Bountziouka, Vassiliki; Anastasiou, Foteini; Zeimbekis, Akis; Tyrovola, Dimitra; Foscolou, Alexandra; Gotsis, Efthimios; Metallinos, George; Soulis, George; Tur, Josep-Antoni; Matalas, Antonia; Lionis, Christos; Sidossis, Labros S; Panagiotakos, Demosthenes

2017-03-01

The aim of the present work was to evaluate the relation between car use and the level of successful aging of a random sample of older adults living in the Mediterranean basin. During 2005-2011, 2749 older (aged 65-100 years) from 22 islands and the rural Mani region (Peloponnesus) of Greece were voluntarily enrolled in the Mediterranean islands cross-sectional study. Sociodemographics, medical conditions, and dietary and lifestyle habits were derived throughout standard procedures. Car use was recorded with a standard binary question. A successful aging index ranging from 0-10 was used. Older adults who used a car on regular basis had significantly higher levels of successful aging, as well as less prevalence of obesity and hypertension while were more physically active (P < .001). After adjusting for several confounders car use was still positively related with elderly islander's successful aging level (beta coefficient [95% confidence interval]: 0.65 [0.54-0.77]). In conclusion, the activity of car use seems to be an indicator of quality of life among older adults, as measured through successful aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of supplementing zinc or chromium to finishing steers fed ractopamine hydrochloride on growth performance, carcass characteristics, and meat quality.

PubMed

Edenburn, B M; Kneeskern, S G; Bohrer, B M; Rounds, W; Boler, D D; Dilger, A C; Felix, T L

2016-02-01

Objectives were to determine the effects of feeding ractopamine hydrochloride (RAC) with zinc (Zn) and chromium (Cr) on feedlot growth performance, carcass characteristics, and meat quality. Steers ( = 179; initial BW = 533 ± 94 kg) were blocked by BW and allotted to 30 pens, and pens were randomly assigned 1 of 5 treatments: (1) control (CONT), (2) RAC only (RO), (3) RAC + Zn (RZ), (4) RAC + Cr (RC), or (5) RAC + Zn + Cr (RZC). Trace minerals were fed from d 0 to 63 to target 1 g of Zn/steer·d (KemTRACE Zn; Kemin Industries, Inc., Des Moines, IA) and 3 mg Cr/steer·d (KemTRACE Chromium; Kemin Industries, Inc.) for Zn and Cr treatments, respectively. Dry-rolled corn, 0.605 kg/steer, was removed from the diet and 400 mg RAC, per 0.605 kg of ground corn carrier, was top dressed per steer immediately following feed delivery to pens fed RAC. There were no effects ( ≥ 0.45) of trace mineral supplementation on DMI, ADG, or G:F before RAC feeding. There were also no treatment effects ( ≥ 0.46) over all 63 d of the trial on DMI, ADG, or G:F. Despite the lack of differences in live performance, steers fed RO and RC averaged 0.10 kg/d greater ( = 0.10) carcass ADG than steers fed RZC and CONT, while steers fed RZ were intermediate and not different. Steers fed RO had the greatest ( = 0.09) carcass G:F, while steers fed CONT had the least carcass G:F, 0.0875 and 0.0774, respectively. Steers fed RO and RC averaged 5.5 kg heavier ( = 0.09) HCW than steers fed RZC and CONT, while steers fed RZ were intermediate and not different. There were no treatment effects ( ≥ 0.32) on LM area, 12th rib fat, marbling score, KPH, carcass yield, or USDA yield grade and distribution. However, carcasses from steers fed RC had the greatest ( = 0.10) percentage grading USDA Select. There were no treatment effects ( ≥ 0.20) on shear force, intramuscular fat, pH, a*, and b*. Steaks from steers fed RO and RC had 11.4% greater ( = 0.08) cook loss than steaks from steers fed CONT and RZC, whereas steaks from steers fed RZ were intermediate and not different. Also, steaks from steers fed RC had 2.11 units greater ( = 0.03) L* values (i.e., were lighter) than steaks from steers fed RZ; steaks from steers fed CONT, RO, and RZC were intermediate. In feedlot steers, the addition of both Cr and Zn supplementation did not improve growth performance or meat quality when fed in combination with 28 d of RAC supplementation; however, RAC, fed alone or in combination with Cr, did increase HCW.

Active travel to work in NSW: trends over time and the effect of social advantage.

PubMed

Zander, Alexis; Rissel, Chris; Rogers, Kris; Bauman, Adrian

2014-12-01

Active travel can increase population levels of physical activity, but should be promoted equitably. Socio-economic advantage, housing location and/or car ownership influence walking and cycling (active travel) for transport. We examined active commuting over time in the Sydney Greater Metropolitan Region, and associations between active commuting and socioeconomic advantage, urban/rural location and car ownership at a Local Government Area (LGA) level across New South Wales (NSW). Journey to work data from the 2001, 2006 and 2011 Australian Census were examined. Associations between levels of active commuting in each LGA in NSW and the Socio-Economic Index for Areas (SEIFA), Accessibility/Remoteness Index of Australia (ARIA) and car ownership were examined using negative binomial regression modelling. Between 2001 and 2011, active commuting increased in inner Sydney (relative increase of 24%), decreased slightly in outer Sydney (declined 5.1%) and declined in the Greater Metropolitan Region (down 15%). Overall, active commuting increased slightly (6.8% relative increase). After adjusting for the LGA age and sex profile and all other LGA variables, people living in NSW LGAs with high socioeconomic status, more rural areas and low car ownership were more likely to cycle or walk to work. More needs to be done in NSW to increase levels of active commuting consistently across regions and socio-demographic groups. SO WHAT?: Despite small increases in active travel in the Sydney region, active travel patterns are not evenly distributed across locations or populations.

Central Role of the PPARγ Gene Network in Coordinating Beef Cattle Intramuscular Adipogenesis in Response to Weaning Age and Nutrition

PubMed Central

Moisá, Sonia J.; Shike, Daniel W.; Faulkner, Dan B.; Meteer, William T.; Keisler, Duane; Loor, Juan J.

2014-01-01

Adipogenic/lipogenic transcriptional networks regulating intramuscular fat deposition (IMF) in response to weaning age and dietary starch level were studied. The longissimus muscle (LM) of beef steers on an early weaning (141 days age) plus high-starch diet (EWS) or a normal weaning (NW, 222 days age) plus starch creep-feed diet (CFS) was biopsied at 0 (EW), 25, 50, 96 (NW), 167, and 222 (pre-slaughter) days. Expression patterns of 35 target genes were studied. From NW through slaughter, all steers received the same high-starch diet. In EWS steers the expression of PPARG, other adipogenic (CEBPA, ZFP423) and lipogenic (THRSP, SREBF1, INSIG1) activators, and several enzymes (FASN, SCD, ELOVL6, PCK1, DGAT2) that participate in the process of IMF increased gradually to a peak between 96 and 167 days on treatment. Steers in NW did not achieve similar expression levels even by 222 days on treatment, suggesting a blunted response even when fed a high-starch diet after weaning. High-starch feeding at an early age (EWS) triggers precocious and sustained adipogenesis, resulting in greater marbling. PMID:24516329

Program for Editing Spacecraft Command Sequences

NASA Technical Reports Server (NTRS)

Gladden, Roy; Waggoner, Bruce; Kordon, Mark; Hashemi, Mahnaz; Hanks, David; Salcedo, Jose

2006-01-01

Sequence Translator, Editor, and Expander Resource (STEER) is a computer program that facilitates construction of sequences and blocks of sequences (hereafter denoted generally as sequence products) for commanding a spacecraft. STEER also provides mechanisms for translating among various sequence product types and quickly expanding activities of a given sequence in chronological order for review and analysis of the sequence. To date, construction of sequence products has generally been done by use of such clumsy mechanisms as text-editor programs, translating among sequence product types has been challenging, and expanding sequences to time-ordered lists has involved arduous processes of converting sequence products to "real" sequences and running them through Class-A software (defined, loosely, as flight and ground software critical to a spacecraft mission). Also, heretofore, generating sequence products in standard formats has been troublesome because precise formatting and syntax are required. STEER alleviates these issues by providing a graphical user interface containing intuitive fields in which the user can enter the necessary information. The STEER expansion function provides a "quick and dirty" means of seeing how a sequence and sequence block would expand into a chronological list, without need to use of Class-A software.

Central Role of the PPARγ Gene Network in Coordinating Beef Cattle Intramuscular Adipogenesis in Response to Weaning Age and Nutrition.

PubMed

Moisá, Sonia J; Shike, Daniel W; Faulkner, Dan B; Meteer, William T; Keisler, Duane; Loor, Juan J

2014-01-01

Adipogenic/lipogenic transcriptional networks regulating intramuscular fat deposition (IMF) in response to weaning age and dietary starch level were studied. The longissimus muscle (LM) of beef steers on an early weaning (141 days age) plus high-starch diet (EWS) or a normal weaning (NW, 222 days age) plus starch creep-feed diet (CFS) was biopsied at 0 (EW), 25, 50, 96 (NW), 167, and 222 (pre-slaughter) days. Expression patterns of 35 target genes were studied. From NW through slaughter, all steers received the same high-starch diet. In EWS steers the expression of PPARG, other adipogenic (CEBPA, ZFP423) and lipogenic (THRSP, SREBF1, INSIG1) activators, and several enzymes (FASN, SCD, ELOVL6, PCK1, DGAT2) that participate in the process of IMF increased gradually to a peak between 96 and 167 days on treatment. Steers in NW did not achieve similar expression levels even by 222 days on treatment, suggesting a blunted response even when fed a high-starch diet after weaning. High-starch feeding at an early age (EWS) triggers precocious and sustained adipogenesis, resulting in greater marbling.

Time-course comparison of xenobiotic activators of CAR and PPAR{alpha} in mouse liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ross, Pamela K.; Woods, Courtney G.; ExxonMobil Biomedical Sciences, Annandale, NJ

Constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor (PPAR){alpha} are transcription factors known to be primary mediators of liver effects, including carcinogenesis, by phenobarbital-like compounds and peroxisome proliferators, respectively, in rodents. Many similarities exist in the phenotypes elicited by these two classes of agents in rodent liver, and we hypothesized that the initial transcriptional responses to the xenobiotic activators of CAR and PPAR{alpha} will exhibit distinct patterns, but at later time-points these biological pathways will converge. In order to capture the global transcriptional changes that result from activation of these nuclear receptors over a time-course in the mouse liver,more » microarray technology was used. First, differences in basal expression of liver genes between C57Bl/6J wild-type and Car-null mice were examined and 14 significantly differentially expressed genes were identified. Next, mice were treated with phenobarbital (100 mg/kg by gavage for 24 h, or 0.085% w/w diet for 7 or 28 days), and liver gene expression changes with regards to both time and treatment were identified. While several pathways related to cellular proliferation and metabolism were affected by phenobarbital in wild-type mice, no significant changes in gene expression were found over time in the Car-nulls. Next, we determined commonalities and differences in the temporal response to phenobarbital and WY-14,643, a prototypical activator of PPAR {alpha}. Gene expression signatures from livers of wild-type mice C57Bl6/J mice treated with PB or WY-14,643 were compared. Similar pathways were affected by both compounds; however, considerable time-related differences were present. This study establishes common gene expression fingerprints of exposure to activators of CAR and PPAR{alpha} in rodent liver and demonstrates that despite similar phenotypic changes, molecular pathways differ between classes of chemical carcinogens.« less

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.

PubMed

Gust, Juliane; Hay, Kevin A; Hanafi, Laïla-Aïcha; Li, Daniel; Myerson, David; Gonzalez-Cuyar, Luis F; Yeung, Cecilia; Liles, W Conrad; Wurfel, Mark; Lopez, Jose A; Chen, Junmei; Chung, Dominic; Harju-Baker, Susanna; Özpolat, Tahsin; Fink, Kathleen R; Riddell, Stanley R; Maloney, David G; Turtle, Cameron J

2017-12-01

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19 + cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity. Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR. See related commentary by Mackall and Miklos, p. 1371 This article is highlighted in the In This Issue feature, p. 1355 . ©2017 American Association for Cancer Research.

Geraniol dehydrogenase, the key enzyme in biosynthesis of the alarm pheromone, from the astigmatid mite Carpoglyphus lactis (Acari: Carpoglyphidae).

PubMed

Noge, Koji; Kato, Makiko; Mori, Naoki; Kataoka, Michihiko; Tanaka, Chihiro; Yamasue, Yuji; Nishida, Ritsuo; Kuwahara, Yasumasa

2008-06-01

Geraniol dehydrogenase (GeDH), which plays an important role in the biosynthesis of neral, an alarm pheromone, was purified from the astigmatid mite Carpoglyphus lactis. The enzyme was obtained in an apparently homogeneous and active form after 1879-fold purification through seven steps of chromatography. Car. lactis GeDH was determined to be a monomer in its active form with a relative molecular mass of 42 800, which is a unique subunit structure in comparison with already established alcohol dehydrogenases. Car. lactis GeDH oxidized geraniol into geranial in the presence of NAD+. NADP+ was ineffective as a cofactor, suggesting that Car. lactis GeDH is an NAD+-dependent alcohol dehydrogenase. The optimal pH and temperature for geraniol oxidation were determined to be pH 9.0 and 25 degrees C, respectively. The Km values for geraniol and NAD+ were 51.0 microm and 59.5 microm, respectively. Car. lactis GeDH was shown to selectively oxidize geraniol, whereas its geometrical isomer, nerol, was inert as a substrate. The high specificity for geraniol suggests that Car. lactis GeDH specializes in the alarm pheromone biosynthesis of Car. lactis. Car. lactis GeDH is composed of 378 amino acids. Structurally, Car. lactis GeDH showed homology with zinc-dependent alcohol dehydrogenases found in mammals and a mosquito (36.6-37.6% identical), and the enzyme was considered to be a member of the medium-chain dehydrogenase/reductase family, in view of the highly conserved sequences of zinc-binding and NAD+-binding sites. Phylogenetic analyses indicate that Car. lactis GeDH could be categorized as a new class, different from other established alcohol dehydrogenases.

Dose- and tissue-specific interaction of monoterpenes with the gibberellin-mediated release of potato tuber bud dormancy, sprout growth and induction of α-amylases and β-amylases.

PubMed

Rentzsch, Sonja; Podzimska, Dagmara; Voegele, Antje; Imbeck, Madeleine; Müller, Kerstin; Linkies, Ada; Leubner-Metzger, Gerhard

2012-01-01

Gibberellins (GA) are involved in bud dormancy release in several species. We show here that GA-treatment released bud dormancy, initiated bud sprouting and promoted sprout growth of excised potato tuber bud discs ('eyes'). Monoterpenes from peppermint oil (PMO) and S-(+)-carvone (CAR) interact with the GA-mediated bud dormancy release in a hormesis-type response: low monoterpene concentrations enhance dormancy release and the initiation of bud sprouting, whereas high concentrations inhibit it. PMO and CAR did, however, not affect sprout growth rate after its onset. We further show that GA-induced dormancy release is associated with tissue-specific regulation of α- and β-amylases. Molecular phylogenetic analysis shows that potato α-amylases cluster into two distinct groups: α-AMY1 and α-AMY2. GA-treatment induced transcript accumulation of members of both α-amylase groups, as well as α- and β-amylase enzyme activity in sprout and 'sub-eye' tissues. In sprouts, CAR interacts with the GA-mediated accumulation of α-amylase transcripts in an α-AMY2-specific and dose-dependent manner. Low CAR concentrations enhance the accumulation of α-AMY2-type α-amylase transcripts, but do not affect the α-AMY1-type transcripts. Low CAR concentrations also enhance the accumulation of α- and β-amylase enzyme activity in sprouts, but not in 'sub-eye' tissues. In contrast, high CAR concentrations have no appreciable effect in sprouts on the enzyme activities and the α-amylase transcript abundances of either group. The dose-dependent effects on the enzyme activities and the α-AMY2-type α-amylase transcripts in sprouts are specific for CAR but not for PMO. Different monoterpenes therefore may have specific targets for their interaction with hormone signalling pathways.

Causation mechanisms in car-to-vulnerable road user crashes: implications for active safety systems.

PubMed

Habibovic, Azra; Davidsson, Johan

2012-11-01

Vulnerable road users (VRUs), such as pedestrians and bicyclists, are often involved in crashes with passenger cars. One way to prevent these crashes is to deploy active safety systems that support the car drivers and/or VRUs. However, to develop such systems, a thorough understanding of crash causation mechanisms is required. The aim of this study is to identify crash causation mechanisms from the perspective of the VRUs, and to explore the implications of these mechanisms for the development of active safety systems. Data originate from the European project SafetyNet, where 995 crashes were in-depth investigated using the SafetyNet Accident Causation System (SNACS). To limit the scope, this study analyzed only intersection crashes involving VRUs. A total of 56 VRU crashes were aggregated. Results suggest that, while 30% of the VRUs did not see the conflict car due to visual obstructions in the traffic environment, 70% of the VRUs saw the car before the collision, but still misunderstood the traffic situation and/or made an inadequate plan of action. An important implication that follows from this is that, while detection of cars is clearly an issue that needs to be addressed, it is even more important to help the VRUs to correctly understand traffic situation (e.g., does the driver intend to slow down, and if s/he does, is it to let the VRU cross or for some other reason?). The former issue suggests a role for various cooperative active safety systems, as the obstacles are generally impenetrable with regular sensors. The latter issue is less straightforward. While various systems can be proposed, such as providing gap size estimation and reducing the car speed variability, the functional merits of each such a system need to be further investigated. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protective effects of L-carnosine on CCl4 -induced hepatic injury in rats.

PubMed

Alsheblak, Mehyar Mohammad; Elsherbiny, Nehal M; El-Karef, Amro; El-Shishtawy, Mamdouh M

2016-03-01

The present study was undertaken to investigate the possible protective effect of L-carnosine (CAR), an endogenous dipeptide of alanine and histidine, on carbon tetrachloride (CCl4)-induced hepatic injury. Liver injury was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injections of CCl4, twice weekly for six weeks. CAR was administered to rats daily, at dose of 250 mg/kg, i.p. At the end of six weeks, blood and liver tissue specimens were collected. Results show that CAR treatment attenuated the hepatic morphological changes, necroinflammation and fibrosis induced by CCl4, as indicated by hepatic histopathology scoring. In addition, CAR treatment significantly reduced the CCl4-induced elevation of liver-injury parameters in serum. CAR treatment also combatted oxidative stress; possibly by restoring hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) levels. Moreover, CAR treatment prevented the activation of hepatic stellate cells (HSCs), as indicated by reduced α-smooth muscle actin (α-SMA) expression in the liver, and decreased hepatic inflammation as demonstrated by a reduction in hepatic tumor necrosis factor-α (TNF-α) and restoration of interleukin-10 (IL-10) levels. In conclusion, CCl4-induced hepatic injury was alleviated by CAR treatment. The results suggest that these beneficial, protective effects are due, at least in part, to its anti-oxidant, anti-inflammatory and anti-fibrotic activities.

UAVSAR Active Electronically Scanned Array

NASA Technical Reports Server (NTRS)

Sadowy, Gregory, A.; Chamberlain, Neil F.; Zawadzki, Mark S.; Brown, Kyle M.; Fisher, Charles D.; Figueroa, Harry S.; Hamilton, Gary A.; Jones, Cathleen E.; Vorperian, Vatche; Grando, Maurio B.

2011-01-01

The Uninhabited Airborne Vehicle Synthetic Aperture Radar (UAVSAR) is a pod-based, L-band (1.26 GHz), repeatpass, interferometric, synthetic aperture radar (InSAR) used for Earth science applications. Repeat-pass interferometric radar measurements from an airborne platform require an antenna that can be steered to maintain the same angle with respect to the flight track over a wide range of aircraft yaw angles. In order to be able to collect repeat-pass InSAR data over a wide range of wind conditions, UAVSAR employs an active electronically scanned array (AESA). During data collection, the UAVSAR flight software continuously reads the aircraft attitude state measured by the Embedded GPS/INS system (EGI) and electronically steers the beam so that it remains perpendicular to the flight track throughout the data collection

Steering system for a train of rail-less vehicles

DOEpatents

Voight, Edward T.

1983-01-01

A steering system for use with a multiple vehicle train permits tracking without rails of one vehicle after another. This system is particularly useful for moving conveyor systems into and out of curved paths of room and pillar underground mine installations. The steering system features an elongated steering bar pivotally connected to each of adjacent vehicles at end portions of the bar permitting angular orientation of each vehicle in respect to the steering bar and other vehicles. Each end portion of the steering bar is linked to the near pair of vehicle wheels through wheel yoke pivot arms about king pin type pivots. Movement of the steering bar about its pivotal connection provides proportional turning of the wheels to effect steering and tracking of one vehicle following another in both forward and reverse directions.

Influence of feed efficiency classification on diet digestibility and growth performance of beef steers.

PubMed

Russell, J R; Minton, N O; Sexten, W J; Kerley, M S; Hansen, S L

2016-04-01

The diet digestibility and feed efficiency (FE) relationship is not well characterized in cattle. The study objective was to determine effects of growing phase FE and diet as well as finishing phase diet on diet digestibility and finishing phase FE. Two groups, totaling 373 crossbred steers, were fed for 70 d at the University of Missouri for the growing phase and then shipped to Iowa State University (ISU) for finishing. GrowSafe feed bunks were used during both the growing and the finishing phases. Steers were fed either growing phase whole shell corn (G-Corn) or growing phase roughage-based (G-Rough) diets. Within each group, the 12 greatest and 12 least feed efficient steers from each growing diet ( = 96 total; 48 steers/group; 488 ± 5 kg) were selected for further evaluation. At ISU, steers were fed an average of 10 g TiO/steer daily in receiving phase diets similar to growing diets for 15 d, with fecal grab samples collected on d 14 and 15 to determine diet DM digestibility during receiving (GDMdig). For finishing, steers were transitioned to byproduct-based diets (F-Byp) or corn-based diets (F-Corn) with 12 steers per growing-finishing diet combination per group. Optaflexx (200 mg/d) was fed for 28 d before harvest, and the TiO protocol was repeated immediately before introducing Optaflexx to determine diet DM digestibility during finishing (FDMdig). Data from the 2 groups (96 steers) were pooled, and steers were ranked by growing phase G:F and then classified as the 24 greatest feed efficient (HFE) or 24 least feed efficient (LFE) steers from each growing diet. Data were analyzed using PROC MIXED of SAS with group applied as a fixed effect. There was a positive correlation between GDMdig and FDMdig for steers fed nutritionally similar diets during both feeding phases, G-Rough/F-Byp steers ( = 0.68, < 0.01) and G-Corn/F-Corn steers ( = 0.49, = 0.02), but a negative correlation for G:F between phases in G-Rough/F-Corn steers ( = -0.57, < 0.01). Finishing G:F was greater in HFE steers versus LFE steers ( = 0.04), but there was no difference ( ≥ 0.5) in GDMdig or FDMdig due to FE classification. There was a positive correlation for DM digestibility between feeding phases when steers were grown and finished on similar diets. Overall, FE was repeatable but was negatively correlated between phases when steers were roughage grown and corn finished, reinforcing the idea that cattle should be FE tested using diet types similar to the production environment of interest.

Performance, insulin sensitivity, carcass characteristics, and fatty acid profile of beef from steers fed microalgae.

PubMed

Carvalho, J R R; Brennan, K M; Ladeira, M M; Schoonmaker, J P

2018-05-25

Heterotrophic production of microalgae biomass provides a consistent, high quality source of docosahexaenoic acid (DHA; C22:6 n-3) in triglyceride oils that could be used as a ration supplement for feedlot steers to improve nutritional qualities of beef. Sixty Angus × Simmental steers (438 ± 6.4 kg) were allotted to 2 treatments (30 steers each, 6 pens, 5 steers/pen) to determine the effects of ForPLUS (DHA-rich microalgae Aurantiochytrium limacinum; 63.6 % fat; 17.9% DHA; 30 mg/kg Sel-Plex; Alltech Inc.) on performance, insulin sensitivity, LM fatty acid composition, and meat quality. Steers were fed basal diets containing 45% corn, 30% distillers dried grains with solubles, 20% corn silage, and 5% supplement. Basal diets were formulated to contain 16.1% CP and 1.32 Mcal/kg NEg. Treatments were delivered to steers in a ground corn based top-dress (454 g total/steer) and contained no microalgae for control steers or 100 g/steer daily of ForPLUS for microalgae steers. A glucose tolerance test (GTT) was performed 10 d prior to slaughter. Steers were slaughtered when a target pen BW of 621 kg was achieved. Fatty acid oxidation potential was determined by measuring thiobarbituric acid reactive substances (TBARS) on LM samples collected 24 h after slaughter and aged for 48 h or 21 d. Weight and BW gain did not differ during the study (P ≥ 0.13); however, steers fed microalgae remained in the feedlot 7 more d compared to steers fed the control diet (111 vs. 104 d; P = 0.04). Overall DMI decreased (P = 0.002) and G:F increased during the second half of the study (P = 0.04) in steers fed microalgae compared to steers fed the control diet. Steers fed microalgae secreted less insulin (P = 0.01) and took longer to clear glucose (P = 0.01) during a 2 h GTT. Carcass traits did not differ between treatments (P ≥ 0.23). Microalgae had no effect on n-6 content (P = 0.67), but more than doubled the n-3 fatty acid percentage and the n3:n6 ratio of the LM (P < 0.0001). The percentage of n-3 fatty acids C20:5 and C22:6 were increased (P < 0.0001) 4-fold and 6.25-fold, respectively, by microalgae supplementation. Concentration of TBARS did not differ in LM aged for 48 h (P = 0.91); however, when aged for 21 d, steers fed microalgae tended to produce LM with greater TBARS concentration compared to steers fed the control diet (P = 0.08). In conclusion, DHA-rich microalgae decreased DMI of steers, and increased n-3 fatty acids and beef oxidation in steaks aged for 21 d.

Investigation of insecticide-resistance status of Cydia pomonella in Chinese populations.

PubMed

Yang, X-Q; Zhang, Y-L

2015-06-01

The codling moth Cydia pomonella (L.) is an economically important fruit pest and it has been directly targeted by insecticides worldwide. Serious resistance to insecticides has been reported in many countries. As one of the most serious invasive pest, the codling moth has populated several areas in China. However, resistance to insecticides has not been reported in China. We investigated the insecticide-resistance status of four field populations from Northwestern China by applying bioassays, enzyme activities, and mutation detections. Diagnostic concentrations of lambda-cyhalothrin, chlorpyrifos-ethyl, carbaryl, and imidacloprid were determined and used in bioassays. Field populations were less susceptible to chlorpyrifos-ethyl and carbaryl than laboratory strain. Insensitive populations displayed an elevated glutathione S-transferases (GSTs) activity. Reduced carboxylesterase (CarE) activity was observed in some insecticide insensitive populations and reduced acetylcholinesterase activity was observed only in the Wuw population. The cytochrome P450 polysubstrate monooxygenases activities in four field populations were not found to be different from susceptible strains. Neither the known-resistance mutation F399V in the acetylcholinesterase (AChE) gene, ace1, nor mutations in CarE gene CpCE-1 were found in adult individuals from our field populations. Native-PAGE revealed that various CarE isozymes and AChE insensitivity were occurring among Chinese populations. Our results indicate that codling moth populations from Northwestern China were insensitivity to chlorpyrifos-ethyl and carbaryl. Increased GST activity was responsible for insecticides insensitivity. Decreased CarE activity, as well as the presence of CarE and AChE polymorphisms might also be involved in insecticides insensitivity. New management strategies for managing this pest are discussed.

One-way EPR steering and genuine multipartite EPR steering

NASA Astrophysics Data System (ADS)

He, Qiongyi; Reid, Margaret D.

2012-11-01

We propose criteria and experimental strategies to realise the Einstein-Podolsky-Rosen (EPR) steering nonlocality. One-way steering can be obtained where there is asymmetry of thermal noise on each system. We also present EPR steering inequalities that act as signatures and suggest how to optimise EPR correlations in specific schemes so that the genuine multipartite EPR steering nonlocality (EPR paradox) can also possibly be realised. The results presented here also apply to the spatially separated macroscopic atomic ensembles.

The Electric Car Challenge.

ERIC Educational Resources Information Center

Diehl, Brian E.

1997-01-01

Describes the Electric Car Challenge during which students applied methods of construction to build lightweight, strong vehicles that were powered by electricity. The activity required problem solving, sheet metal work, electricity, design, and construction skills. (JOW)

46 CFR 58.25-10 - Main and auxiliary steering gear.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 2 2010-10-01 2010-10-01 false Main and auxiliary steering gear. 58.25-10 Section 58.25... AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-10 Main and auxiliary steering gear. (a) Power-operated main and auxiliary steering gear must be separate systems that are independent throughout their...

46 CFR 196.37-33 - Instructions for changing steering gear.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Instructions for changing steering gear. 196.37-33... steering gear. (a) Instructions in at least 1/2 inch letters and figures shall be posted in the steering engineroom, relating in order, the different steps to be taken in changing to the emergency steering gear...

Effects of feeding dry or modified wet distillers grains with solubles with or without supplemental calcium oxide on ruminal metabolism and microbial enzymatic activity of beef cattle.

PubMed

Schroeder, A R; Iakiviak, M; Felix, T L

2014-09-01

The objectives of this study were to determine the interaction of feeding dry (DDGS) or modified wet (MDGS) distillers grains with solubles (DGS) with or without supplemental CaO on in situ DM and NDF disappearance; ruminal pH, VFA, and methane concentration; and cellulase and xylanase activity. Fistulated steers (n = 8; average initial BW = 540 ± 250 kg) were used in a replicated 4 × 4 Latin square design. Treatments were arranged in a 2 × 2 factorial, and steers were randomly allotted to 1 of 4 dietary treatments: 1) 50% DDGS with 0% CaO, 2) 48.8% DDGS supplemented with 1.2% CaO, 3) 50% MDGS with 0% CaO, or 4) 48.8% MDGS supplemented with 1.2% CaO (DM basis). The remainder of the diet was husklage, dry-rolled corn, and vitamin and mineral supplement. There were no interactions (P ≥ 0.12) of DGS type and CaO addition on any parameters measured. Steers fed DDGS had a 17% increase (P < 0.01) in DMI compared to steers fed MDGS; however, CaO supplementation reduced (P = 0.03) DMI by 12%, regardless of DGS type. As expected, addition of CaO increased the pH of the diet by 1.82 pH units. This caused a time by CaO interaction (P = 0.05) for ruminal pH. Regardless of DGS type, steers supplemented with CaO tended to have increased (P = 0.09) ruminal pH at 1.5 h and had increased (P = 0.03) ruminal pH at 3 h postfeeding; however, ruminal pH did not differ (P ≥ 0.24) for the remainder of the day. There was no difference (P = 0.46) in ruminal cellulase activity when comparing type of DGS fed. However, there was a time by CaO interaction (P < 0.01); cattle fed 1.2% CaO diets had 28% greater ruminal cellulase activity only at 0 h postfeeding when compared to cattle fed 0% CaO. Furthermore, feeding supplemental CaO increased (P = 0.04) acetate to propionate ratio (A:P) regardless of type of DGS fed. Increased initial ruminal pH and cellulase activity from supplemental CaO did not increase (P = 0.48) in situ NDF disappearance. No differences (P ≥ 0.48) in ruminal methane concentration were found when comparing DGS type or supplemental CaO. In conclusion, the type of DGS fed had little effect on ruminal metabolism. Even though CaO increased ruminal pH and cellulase activity at some times postfeeding, it was not enough to affect in situ fiber disappearance.

49 CFR 571.114 - Standard No. 114; Theft protection and rollaway prevention.

Code of Federal Regulations, 2013 CFR

2013-10-01

... key to activate the engine or motor. Vehicle type, as used in S5.1.2, refers to passenger car, truck... motion. S3. Application. This standard applies to all passenger cars, and to trucks and multipurpose... (by physical or electronic means), enables the vehicle operator to activate the engine or motor. Open...

49 CFR 571.114 - Standard No. 114; Theft protection and rollaway prevention.

Code of Federal Regulations, 2014 CFR

2014-10-01

... key to activate the engine or motor. Vehicle type, as used in S5.1.2, refers to passenger car, truck... motion. S3. Application. This standard applies to all passenger cars, and to trucks and multipurpose... (by physical or electronic means), enables the vehicle operator to activate the engine or motor. Open...

49 CFR 571.114 - Standard No. 114; Theft protection and rollaway prevention.

Code of Federal Regulations, 2012 CFR

2012-10-01

... key to activate the engine or motor. Vehicle type, as used in S5.1.2, refers to passenger car, truck... motion. S3. Application. This standard applies to all passenger cars, and to trucks and multipurpose... (by physical or electronic means), enables the vehicle operator to activate the engine or motor. Open...

The pharmacology of second-generation chimeric antigen receptors.

PubMed

van der Stegen, Sjoukje J C; Hamieh, Mohamad; Sadelain, Michel

2015-07-01

Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

The influence of Unruh effect on quantum steering for accelerated two-level detectors with different measurements

NASA Astrophysics Data System (ADS)

Liu, Tonghua; Wang, Jieci; Jing, Jiliang; Fan, Heng

2018-03-01

We propose a tight measure of quantum steering and study the dynamics of steering in a relativistic setting via different quantifiers. We present the dynamics of steering between two correlated Unruh-Dewitt detectors when one of them locally interacts with external scalar field. We find that the quantum steering, either measured by the entropic steering inequality or the Cavalcanti-Jones-Wiseman-Reid inequality, is fragile under the influence of Unruh thermal noise. The quantum steering is found always asymmetric and the asymmetry is extremely sensitive to the initial state parameter. In addition, the steering-type quantum correlations experience "sudden death" for some accelerations, which are quite different from the behaviors of other quantum correlations in the same system. It is worth noting that the domination value of the tight quantum steering exists a transformation point with increasing acceleration. We also find that the robustness of quantum steerability under the Unruh thermal noise can be realized by choosing the smallest energy gap in the detectors.

Tasco-Forage: II. Monocyte immune cell response and performance of beef steers grazing tall fescue treated with a seaweed extract.

PubMed

Saker, K E; Allen, V G; Fontenot, J P; Bagley, C P; Ivy, R L; Evans, R R; Wester, D B

2001-04-01

Effects of applying Tasco-Forage, an Ascophyllum nodosum seaweed-based product prepared by a proprietary process, to endophyte (Neotyphodium coenophialum [Morgan-Jones and Gams] Glenn, Bacon, and Hanlin)-infected and endophyte-free tall fescue (Festuca arundinacea Schreb.) were studied in each of 3 yr (1995, 1996, and 1997) in Virginia and in 1996 and 1997 in Mississippi. There were 48 steers at each location in each year (n = 240) in a 2 x 2 x 2 factorial arrangement with two replications at each location. Steers in Virginia were Angus and Angus x Hereford with initial weights of 245 kg (SD = 20), 234 kg (SD = 9), and 265 kg (SD = 5) in yr 1, 2, and 3, respectively. Steers in Mississippi were 3/4 Angus and 1/4 Brahman and weighed 230 kg (SD = 8) and 250 kg (SD = 2) in yr 2 and 3, respectively. Tasco (3.4 kg/ha) was dissolved in water and applied to pastures in April before grazing was begun and again in July at the same rate. The grazing period was from mid-April to late September or mid-October. Total gains were higher (P < 0.05) for steers grazing uninfected than for those grazing endophyte-infected tall fescue. Rectal temperatures were increased (P < 0.05) due to endophyte infection at both locations; Tasco application decreased temperature of steers grazing infected fescue in Virginia (interaction, P < 0.07) but increased temperatures of steers grazing infected fescue in Mississippi (interaction, P < 0.05). Presence of the endophyte resulted in rough hair coats and loss of hair color, but the effect was partially offset (P < 0.05) by Tasco application in Virginia in 1995. Both monocyte phagocytic activity (all years and locations) and major histocompatibility complex class II expression (1995 only) were decreased (P < 0.05) in steers due to endophyte infection, but this effect was reversed (P < 0.05) by application of Tasco to pastures. Application of the extract from A. nodosum seems to have use in alleviating adverse effects of endophyte on immune function and may improve hair coat condition in cattle grazing infected fescue, but effects on rectal temperature varied due to location.

Selection for increased muscling in Angus cattle did not increase the glycolytic potential or negatively impact pH decline, retail colour stability or mineral content.

PubMed

McGilchrist, P; Greenwood, P L; Pethick, D W; Gardner, G E

2016-04-01

This study determined the impact of selection for greater muscling in Angus cattle on myofibre characteristics, muscle enzymatics, retail colour stability, pH decline and mineral content of the semimembranosus (SM), semitendinosus (ST) and longissimus thoracis (LT). Muscle from 10 low muscled (low) and 11 high muscled (high) steers were analysed. The high steers had myofibres 22% and 24% larger in cross-sectional area in the SM and ST (P<0.05), and 8.6% less type IIX myofibres in the LT than the low steers (P<0.05). The highs had 4.9% lower lactate dehydrogenase activity, 10.2% and 12.3% higher citrate synthase and isocitrate dehydrogenase activity than lows (P<0.05). The highs had 27% more iron in the LT (P<0.05). The results indicate that the oxidative capacity of muscle can be maintained in more muscular cattle with no detrimental effects to mineral content, pH decline or retail colour stability. Myofibre hypertrophy is one mechanism leading to greater muscle mass of these high muscled cattle. Copyright © 2015 Elsevier Ltd. All rights reserved.

The influence of oscillating dietary protein concentrations on finishing cattle. I. Feedlot performance and odorous compound production.

PubMed

Archibeque, S L; Miller, D N; Freetly, H C; Berry, E D; Ferrell, C L

2007-06-01

We hypothesized that oscillation of the dietary CP concentration, which may improve N retention of finishing beef steers, would reduce production of manure odor compounds and total N inputs while yielding comparable performance. Charolais-sired steers (n = 144; 303 +/- 5 kg of initial BW) were used in a completely randomized block design (6 pens/treatment). The steers were fed to 567 kg of BW on the following finishing diets, which were based on dry-rolled corn: 1) low (9.1% CP), 2) medium (11.8% CP), 3) high (14.9% CP), or 4) low and high oscillated on a 48-h interval for each feed (oscillating). Steers fed low tended (P = 0.08) to have less DMI (7.80 kg/d) than steers fed medium (8.60 kg/d) or oscillating (8.67 kg/d), but not less than steers fed high (8.12 kg/d). Daily N intake was greatest (P < 0.01) for steers fed high (189 g), intermediate for medium (160 g) and oscillating (164 g), and least for low (113 g). The ADG was lower (P < 0.01) for steers fed low (1.03 kg) than for those fed medium (1.45 kg), high (1.45 kg), or oscillating (1.43 kg). Similarly, steers fed low had a lower adjusted fat thickness (P < 0.01) and yield grade (P = 0.05) and tended (P = 0.10) to have less marbling than steers fed the other 3 diets. In slurries with feces, urine, soil, and water, incubated for 35 d, nonsoluble CP was similar among slurries from steers fed medium, high, or oscillating, but was less (P < 0.01) in slurries from steers fed low. However, throughout the incubation period, slurries from steers fed high or oscillating had greater (P < 0.01) concentrations of total aromatics and ammonia than those from steers fed low or medium. Also, the slurries from steers fed oscillating had greater (P < 0.01) concentrations of branched-chain VFA than manure slurries from steers fed any of the other diets. These data indicate that although there is no apparent alteration in the performance of finishing steers fed diets with oscillation of the dietary protein, there may be undesirable increases in the production of compounds associated with malodor.

Basic Fibroblast Growth Factor Activates Serum Response Factor Gene Expression by Multiple Distinct Signaling Mechanisms

PubMed Central

Spencer, Jeffrey A.; Major, Michael L.; Misra, Ravi P.

1999-01-01

Serum response factor (SRF) plays a central role in the transcriptional response of mammalian cells to a variety of extracellular signals. It is a key regulator of many cellular early response genes which are believed to be involved in cell growth and differentiation. The mechanism by which SRF activates transcription in response to mitogenic agents has been extensively studied; however, significantly less is known about regulation of the SRF gene itself. Previously, we identified distinct regulatory elements in the SRF promoter that play a role in activation, including a consensus ETS domain binding site, a consensus overlapping Sp/Egr-1 binding site, and two SRF binding sites. We further showed that serum induces SRF by a mechanism that requires an intact SRF binding site, also termed a CArG box. In the present study we demonstrate that in response to stimulation of cells by a purified growth factor, basic fibroblast growth factor (bFGF), the SRF promoter is upregulated by a complex pathway that involves at least two independent mechanisms: a CArG box-independent mechanism that is mediated by an ETS binding site, and a novel CArG box-dependent mechanism that requires both an Sp factor binding site and the CArG motifs for maximal stimulation. Our analysis indicates that the CArG/Sp element activation mechanism is mediated by distinct signaling pathways. The CArG box-dependent component is targeted by a Rho-mediated pathway, and the Sp binding site-dependent component is targeted by a Ras-mediated pathway. Both SRF and bFGF have been implicated in playing an important role in mediating cardiogenesis during development. The implications of our findings for SRF expression during development are discussed. PMID:10330138

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.

PubMed

Brown, Christine E; Aguilar, Brenda; Starr, Renate; Yang, Xin; Chang, Wen-Chung; Weng, Lihong; Chang, Brenda; Sarkissian, Aniee; Brito, Alfonso; Sanchez, James F; Ostberg, Julie R; D'Apuzzo, Massimo; Badie, Behnam; Barish, Michael E; Forman, Stephen J

2018-01-03

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8 + T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Optimisation of driver actions in RWD race car including tyre thermodynamics

NASA Astrophysics Data System (ADS)

Maniowski, Michal

2016-04-01

The paper presents an innovative method for a lap time minimisation by using genetic algorithms for a multi objective optimisation of a race driver-vehicle model. The decision variables consist of 16 parameters responsible for actions of a professional driver (e.g. time traces for brake, accelerator and steering wheel) on a race track part with RH corner. Purpose-built, high fidelity, multibody vehicle model (called 'miMa') is described by 30 generalised coordinates and 440 parameters, crucial in motorsport. Focus is put on modelling of the tyre tread thermodynamics and its influence on race vehicle dynamics. Numerical example considers a Rear Wheel Drive BMW E36 prepared for track day events. In order to improve the section lap time (by 5%) and corner exit velocity (by 4%) a few different driving strategies are found depending on thermal conditions of semi-slick tyres. The process of the race driver adaptation to initially cold or hot tyres is explained.

Driving experience and special skills reflected in eye movements

NASA Astrophysics Data System (ADS)

Paeglis, Roberts; Bluss, Kristaps; Atvars, Aigars

2011-10-01

When driving a vehicle, people use the central vision both to plan ahead and monitor their performance feedback (research by Donges, 1978 [1], and after). Discussion is ongoing if making eye movements do more than gathering information. Moving eyes may also prepare the following body movements like steering. Different paradigms exist to explore vision in driving. Our perspective was to quantify eye movements and fixation patterns of different proficiency individuals, a driving learner, a novice, an experienced driver and a European level car racer. Thus for safety reasons we started by asking them to follow a video tour through a known city, remote from an infrared eye tracker sampling at 250 Hz. We report that gaze strategy of an experienced driver differs qualitatively from that of an automobile sports master. Quantitative differences only were found between the latter and a driving learner or a novice driver. Experience in a motor action provides skills different from sports training. We are aiming at testing this finding in real world driving.

Auto Mechanics I. Learning Activity Packets (LAPs). Section D--Suspension.

ERIC Educational Resources Information Center

Oklahoma State Board of Vocational and Technical Education, Stillwater. Curriculum and Instructional Materials Center.

This document contains six learning activity packets (LAPs) that outline the study activities for the "suspension" instructional area for an Auto Mechanics I course. The six LAPs cover the following topics: wheel bearings, tires and wheels, wheel balancing, suspension system, steering system, and wheel alignment. Each LAP contains a…

Carotenoid Biosynthesis in Fusarium

PubMed Central

Avalos, Javier; Pardo-Medina, Javier; Parra-Rivero, Obdulia; Ruger-Herreros, Macarena; Rodríguez-Ortiz, Roberto; Hornero-Méndez, Dámaso; Limón, María Carmen

2017-01-01

Many fungi of the genus Fusarium stand out for the complexity of their secondary metabolism. Individual species may differ in their metabolic capacities, but they usually share the ability to synthesize carotenoids, a family of hydrophobic terpenoid pigments widely distributed in nature. Early studies on carotenoid biosynthesis in Fusarium aquaeductuum have been recently extended in Fusarium fujikuroi and Fusarium oxysporum, well-known biotechnological and phytopathogenic models, respectively. The major Fusarium carotenoid is neurosporaxanthin, a carboxylic xanthophyll synthesized from geranylgeranyl pyrophosphate through the activity of four enzymes, encoded by the genes carRA, carB, carT and carD. These fungi produce also minor amounts of β-carotene, which may be cleaved by the CarX oxygenase to produce retinal, the rhodopsin’s chromophore. The genes needed to produce retinal are organized in a gene cluster with a rhodopsin gene, while other carotenoid genes are not linked. In the investigated Fusarium species, the synthesis of carotenoids is induced by light through the transcriptional induction of the structural genes. In some species, deep-pigmented mutants with up-regulated expression of these genes are affected in the regulatory gene carS. The molecular mechanisms underlying the control by light and by the CarS protein are currently under investigation. PMID:29371556

The Coxsackievirus and Adenovirus Receptor: a new adhesion protein in cochlear development.

PubMed

Excoffon, Katherine J D A; Avenarius, Matthew R; Hansen, Marlan R; Kimberling, William J; Najmabadi, Hossein; Smith, Richard J H; Zabner, Joseph

2006-05-01

The Coxsackievirus and Adenovirus Receptor (CAR) is an essential regulator of cell growth and adhesion during development. The gene for CAR, CXADR, is located within the genomic locus for Usher syndrome type 1E (USH1E). Based on this and a physical interaction with harmonin, the protein responsible for USH1C, we hypothesized that CAR may be involved in cochlear development and that mutations in CXADR may be responsible for USH1E. The expression of CAR in the cochlea was determined by PCR and immunofluorescence microscopy. We found that CAR expression is highly regulated during development. In neonatal mice, CAR is localized to the junctions of most cochlear cell types but is restricted to the supporting and strial cells in adult cochlea. A screen of two populations consisting of non-syndromic deaf and Usher 1 patients for mutations in CXADR revealed one haploid mutation (P356S). Cell surface expression, viral receptor activity, and localization of the mutant form of CAR were indistinguishable from wild-type CAR. Although we were unable to confirm a role for CAR in autosomal recessive, non-syndromic deafness, or Usher syndrome type 1, based on its regulation, localization, and molecular interactions, CAR remains an attractive candidate for genetic deafness.

Allogeneic chimeric antigen receptor-modified cells for adoptive cell therapy of cancer.

PubMed

Marcus, Assaf; Eshhar, Zelig

2014-07-01

Chimeric antigen (or antibody) receptors (CAR) are fusion proteins typically combining an antibody-derived targeting fragment with signaling domains capable of activating immune cells. Recent clinical trials have shown the tremendous potential of adoptive cell transfer (ACT) of autologous T cells engineered to express a CD19-specific CAR targeting B-cell malignancies. Building on this approach, ACT therapies employing allogeneic CAR-expressing cytotoxic cells are now being explored. The basic principles of CAR-ACT are introduced. The potential benefits as well as problems of using allogeneic CAR-modified cells against tumor antigens are discussed. Various approaches to allogeneic CAR therapy are presented, including donor leukocyte infusion, CAR-redirected γδ T cells and natural killer cells, strategies to avoid graft-versus-host disease, modulation of lymphocyte migration, and exploitation of graft-versus-host reactivity. CAR-modified allogeneic cells have the potential to act as universal effector cells, which can be administered to any patient regardless of MHC type. Such universal effector cells could be used as an 'off-the-shelf' cell-mediated treatment for cancer.

Analysis of hydraulic steering system of tracked all-terrain vehicles' articulated mechanism

NASA Astrophysics Data System (ADS)

Meng, Zhongliang; Zang, Hao

2018-04-01

As for the researches on the dynamic characteristics of tracked all-terrain vehicles' articulated mechanism, the hydraulic feature of their steering system needs researching more, apart from the study on mechanical models. According to the maximum pressure required by the steering system of tracked all-terrain vehicle and the principle of the steering system, this paper conducts an analysis of the hydraulic steering system of the articulated mechanism. Based on the structure principle of the steering gear, a simulation model of the tracked all-terrain vehicle turning left is built. When building the simulation model of the steering gear, it makes a simulation analysis, taking the tracked all-terrain vehicle turning left as an example.

Acceleration control system for semi-active in-car crib with joint application of regular and inverted pendulum mechanisms

NASA Astrophysics Data System (ADS)

Kawashima, T.

2016-09-01

To reduce the risk of injury to an infant in an in-car crib (or in a child safety bed) collision shock during a car crash, it is necessary to maintain a constant force acting on the crib below a certain allowable value. To realize this objective, we propose a semi-active in-car crib system with the joint application of regular and inverted pendulum mechanisms. The arms of the proposed crib system support the crib like a pendulum while the pendulum system itself is supported like an inverted pendulum by the arms. In addition, the friction torque of each arm is controlled using a brake mechanism that enables the proposed in-car crib to decrease the acceleration of the crib gradually and maintain it around the target value. This system not only reduces the impulsive force but also transfers the force to the infant's back using a spin control system, i.e., the impulse force acts is made to act perpendicularly on the crib. The spin control system was developed in our previous work. This work focuses on the acceleration control system. A semi-active control law with acceleration feedback is introduced, and the effectiveness of the system is demonstrated using numerical simulation and model experiment.

Race Car Rally.

ERIC Educational Resources Information Center

Anthony, Joan L.

1994-01-01

Describes an activity where teams of parents and children work together to solve problems involving matchbox-sized race cars. The teams collect, record, and analyze data; measure distances in metric; and explore concepts related to mass, friction, and force. (PR)

52. Patent steering gear, hatch and steering compass binnacle, view ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

52. Patent steering gear, hatch and steering compass binnacle, view from starboard looking aft. Photograph by Jet Lowe, April 1988. - Ship BALCLUTHA, 2905 Hyde Street Pier, San Francisco, San Francisco County, CA

Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies.

PubMed

Nakabo, Shuichiro; Hashimoto, Motomu; Ito, Shinji; Furu, Moritoshi; Ito, Hiromu; Fujii, Takao; Yoshifuji, Hajime; Imura, Yoshitaka; Nakashima, Ran; Murakami, Kosaku; Kuramoto, Nobuo; Tanaka, Masao; Satoh, Junko; Ishigami, Akihito; Morita, Satoshi; Mimori, Tsuneyo; Ohmura, Koichiro

2017-07-01

Anti-carbamylated protein (anti-CarP) antibodies are detected in RA patients. Fetal calf serum is used as an antigen source in anti-CarP ELISA, and the precise target antigens have not been found. We aimed to identify the target antigens of anti-CarP antibodies. Western blotting of anti-CarP antibodies was conducted. Anti-carbamylated human albumin (CarALB) antibody was detected by in-house ELISA for 493 RA patients and 144 healthy controls (HCs). An inhibition ELISA of anti-CarP antibodies by CarALB and citrullinated albumin (citALB) was performed using eight RA patients' sera. Serum CarALB was detected by liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the serum MPO concentration was measured by ELISA. We focused on carbamylated albumin because it corresponded to the size of the thickest band detected by western blotting of anti-CarP antibodies. Anti-CarALB antibody was detected in 31.4% of RA patients, and the correlation of the titres between anti-CarALB and anti-CarP was much closer than that between anti-citALB and anti-CCP antibodies (ρ = 0.59 and ρ = 0.16, respectively). The inhibition ELISA showed that anti-CarP antibodies were inhibited by CarALB, but not by citALB. CarALB was detected in sera from RA patients by LC/MS/MS. The serum MPO concentration was correlated with disease activity and was higher in RA patients with anti-CarALB antibody than in those without. We found that carbamylated albumin is a novel target antigen of anti-CarP antibodies, and it is the first reported target antigen that has not been reported as the target of ACPA. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy.

PubMed

Zhang, Erhao; Xu, Hanmei

2017-01-03

Adoptive cell therapy using chimeric antigen receptor (CAR)-engineered T cells has emerged as a very promising approach to combating cancer. Despite its ability to eliminate tumors shown in some clinical trials, CAR-T cell therapy involves some significant safety challenges, such as cytokine release syndrome (CRS) and "on-target, off-tumor" toxicity, which is related to poor control of the dose, location, and timing of T cell activity. In the past few years, some strategies to avoid the side effects of CAR-T cell therapy have been reported, including suicide gene, inhibitory CAR, dual-antigen receptor, and the use of exogenous molecules as switches to control the CAR-T cell functions. Because of the advances of the CAR paradigm and other forms of cancer immunotherapy, the most effective means of defeating the cancer has become the integration therapy with the combinatorial control system of switchable dual-receptor CAR-T cell and immune checkpoint blockade.

Peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) but not PPAR-interacting protein (PRIP) is required for nuclear translocation of constitutive androstane receptor in mouse liver.

PubMed

Guo, Dongsheng; Sarkar, Joy; Ahmed, Mohamed R; Viswakarma, Navin; Jia, Yuzhi; Yu, Songtao; Sambasiva Rao, M; Reddy, Janardan K

2006-08-25

The constitutive androstane receptor (CAR) regulates transcription of phenobarbital-inducible genes that encode xenobiotic-metabolizing enzymes in liver. CAR is localized to the hepatocyte cytoplasm but to be functional, it translocates into the nucleus in the presence of phenobarbital-like CAR ligands. We now demonstrate that adenovirally driven EGFP-CAR, as expected, translocates into the nucleus of normal wild-type hepatocytes following phenobarbital treatment under both in vivo and in vitro conditions. Using this approach we investigated the role of transcription coactivators PBP and PRIP in the translocation of EGFP-CAR into the nucleus of PBP and PRIP liver conditional null mouse hepatocytes. We show that coactivator PBP is essential for nuclear translocation of CAR but not PRIP. Adenoviral expression of both PBP and EGFP-CAR restored phenobarbital-mediated nuclear translocation of exogenously expressed CAR in PBP null livers in vivo and in PBP null primary hepatocytes in vitro. CAR translocation into the nucleus of PRIP null livers resulted in the induction of CAR target genes such as CYP2B10, necessary for the conversion of acetaminophen to its hepatotoxic intermediate metabolite, N-acetyl-p-benzoquinone imine. As a consequence, PRIP-deficiency in liver did not protect from acetaminophen-induced hepatic necrosis, unlike that exerted by PBP deficiency. These results establish that transcription coactivator PBP plays a pivotal role in nuclear localization of CAR, that it is likely that PBP either enhances nuclear import or nuclear retention of CAR in hepatocytes, and that PRIP is redundant for CAR function.

49 CFR 393.209 - Steering wheel systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

49 CFR 393.209 - Steering wheel systems.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

49 CFR 393.209 - Steering wheel systems.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

49 CFR 393.209 - Steering wheel systems.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

49 CFR 393.209 - Steering wheel systems.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

Method of Controlling Steering of a Ground Vehicle

NASA Technical Reports Server (NTRS)

Guo, Raymond (Inventor); Atluri, Venkata Prasad (Inventor); Bluethmann, William J. (Inventor); Lee, Chunhao J. (Inventor); Vitale, Robert L. (Inventor); Dawson, Andrew D. (Inventor)

2016-01-01

A method of controlling steering of a vehicle through setting wheel angles of a plurality of modular electronic corner assemblies (eModules) is provided. The method includes receiving a driving mode selected from a mode selection menu. A position of a steering input device is determined in a master controller. A velocity of the vehicle is determined, in the master controller, when the determined position of the steering input device is near center. A drive mode request corresponding to the selected driving mode to the plurality of steering controllers is transmitted to the master controller. A required steering angle of each of the plurality of eModules is determined, in the master controller, as a function of the determined position of the steering input device, the determined velocity of the vehicle, and the selected first driving mode. The eModules are set to the respective determined steering angles.

Monogamy of quantum steering

NASA Astrophysics Data System (ADS)

Milne, Antony; Jennings, David; Jevtic, Sania; Rudolph, Terry; Wiseman, Howard

The quantum steering ellipsoid formalism naturally extends the Bloch vector picture for qubits to provide a visualisation of two-qubit systems. If Alice and Bob share a correlated state then a local measurement by Bob steers Alice's qubit inside the Bloch sphere; given all possible measurements by Bob, the set of states to which Alice can be steered form her steering ellipsoid. We apply the formalism to a three-party scenario and find that steering ellipsoid volumes obey a simple monogamy relation. This gives us a novel derivation of the well-known CKW (Coffman-Kundu-Wootters) inequality for entanglement monogamy. The geometric perspective also identifies a new measure of quantum correlation, `obesity', and a set of `maximally obese' states that saturate the steering monogamy bound. These states are found to have extremal quantum correlation properties that are significant in the steering ellipsoid picture and for the study of two-qubit states in general.

Vehicle active steering control research based on two-DOF robust internal model control

NASA Astrophysics Data System (ADS)

Wu, Jian; Liu, Yahui; Wang, Fengbo; Bao, Chunjiang; Sun, Qun; Zhao, Youqun

2016-07-01

Because of vehicle's external disturbances and model uncertainties, robust control algorithms have obtained popularity in vehicle stability control. The robust control usually gives up performance in order to guarantee the robustness of the control algorithm, therefore an improved robust internal model control(IMC) algorithm blending model tracking and internal model control is put forward for active steering system in order to reach high performance of yaw rate tracking with certain robustness. The proposed algorithm inherits the good model tracking ability of the IMC control and guarantees robustness to model uncertainties. In order to separate the design process of model tracking from the robustness design process, the improved 2 degree of freedom(DOF) robust internal model controller structure is given from the standard Youla parameterization. Simulations of double lane change maneuver and those of crosswind disturbances are conducted for evaluating the robust control algorithm, on the basis of a nonlinear vehicle simulation model with a magic tyre model. Results show that the established 2-DOF robust IMC method has better model tracking ability and a guaranteed level of robustness and robust performance, which can enhance the vehicle stability and handling, regardless of variations of the vehicle model parameters and the external crosswind interferences. Contradiction between performance and robustness of active steering control algorithm is solved and higher control performance with certain robustness to model uncertainties is obtained.

Electrostatic steering and ionic tethering in enzyme-ligand binding: insights from simulations.

PubMed

Wade, R C; Gabdoulline, R R; Lüdemann, S K; Lounnas, V

1998-05-26

To bind at an enzyme's active site, a ligand must diffuse or be transported to the enzyme's surface, and, if the binding site is buried, the ligand must diffuse through the protein to reach it. Although the driving force for ligand binding is often ascribed to the hydrophobic effect, electrostatic interactions also influence the binding process of both charged and nonpolar ligands. First, electrostatic steering of charged substrates into enzyme active sites is discussed. This is of particular relevance for diffusion-influenced enzymes. By comparing the results of Brownian dynamics simulations and electrostatic potential similarity analysis for triose-phosphate isomerases, superoxide dismutases, and beta-lactamases from different species, we identify the conserved features responsible for the electrostatic substrate-steering fields. The conserved potentials are localized at the active sites and are the primary determinants of the bimolecular association rates. Then we focus on a more subtle effect, which we will refer to as "ionic tethering." We explore, by means of molecular and Brownian dynamics simulations and electrostatic continuum calculations, how salt links can act as tethers between structural elements of an enzyme that undergo conformational change upon substrate binding, and thereby regulate or modulate substrate binding. This is illustrated for the lipase and cytochrome P450 enzymes. Ionic tethering can provide a control mechanism for substrate binding that is sensitive to the electrostatic properties of the enzyme's surroundings even when the substrate is nonpolar.

Effect of the mileage of a passenger car on changes in its body geometry

NASA Astrophysics Data System (ADS)

Gonera, Jarosław; Napiórkowski, Jerzy

2018-04-01

This study analyses the effect of the mileage of a passenger car on changes in its body geometry in regards to its safety. Ninety-six passenger cars used in similar environmental conditions were examined. The required position of twelve base points was compared to their actual position. Those were the points responsible for the active and passive safety of a car on the left and right side of the floor panel. The geometry of the floor panel was measured with a GYSMETER device manufactured by GYS and Allvis Light software. Increasing mileage was found to result in increasing changes in the floor panel geometry, which take place mainly on the right side of a car and at points affecting passive safety.