EEG-Based Detection of Braking Intention Under Different Car Driving Conditions

PubMed Central

Hernández, Luis G.; Mozos, Oscar Martinez; Ferrández, José M.; Antelis, Javier M.

2018-01-01

The anticipatory recognition of braking is essential to prevent traffic accidents. For instance, driving assistance systems can be useful to properly respond to emergency braking situations. Moreover, the response time to emergency braking situations can be affected and even increased by different driver's cognitive states caused by stress, fatigue, and extra workload. This work investigates the detection of emergency braking from driver's electroencephalographic (EEG) signals that precede the brake pedal actuation. Bioelectrical signals were recorded while participants were driving in a car simulator while avoiding potential collisions by performing emergency braking. In addition, participants were subjected to stress, workload, and fatigue. EEG signals were classified using support vector machines (SVM) and convolutional neural networks (CNN) in order to discriminate between braking intention and normal driving. Results showed significant recognition of emergency braking intention which was on average 71.1% for SVM and 71.8% CNN. In addition, the classification accuracy for the best participant was 80.1 and 88.1% for SVM and CNN, respectively. These results show the feasibility of incorporating recognizable driver's bioelectrical responses into advanced driver-assistance systems to carry out early detection of emergency braking situations which could be useful to reduce car accidents. PMID:29910722

Automatic license plate reader: a solution to avoiding vehicle pursuit

NASA Astrophysics Data System (ADS)

Jordan, Stanley K.

1997-01-01

The Massachusetts Governor's Auto Theft Strike Force has tested an automatic license plate reader (LPR) to recover stolen cars and catch car thieves, without vehicle pursuit. Experiments were conducted at the Sumner Tunnel in Boston, and proved the feasibility of a LPR for identifying stolen cars instantly. The same technology can be applied to other law-enforcement objectives.

Contribution of the central histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol.

PubMed

Jain, Nishant S; Tandi, Lakshyapati; Verma, Lokesh

2015-12-01

The antipsychotic properties of haloperidol are primarily attributed to its ability to block dopamine D2 receptors. Histaminergic transmission modulates some of the behavioral effects of haloperidol. Hence, the present study investigated the contribution of central histaminergic transmission in the cataleptic and neuroleptic effect of haloperidol respectively, using bar test and conditioned avoidance response (CAR) in a two-way shuttle box. The studies revealed that haloperidol (0.50 or 1 mg/kg, i.p.) exhibited cataleptic behavior and inhibited conditioned avoidance response (CAR) in the doses 0.25 or 0.50 mg in rats. The rats, pretreated centrally (i.c.v.) with histamine precursor, L-histidine (1, 2.5 μg) or histamine neuronal inducer (H3 receptor antagonist), thioperamide (20, 50 μg/rat), showed an enhanced cataleptic effect with sub-maximal dose of haloperidol (0.5 mg/kg, i.p.). Similarly, the neuroleptic effect of haloperidol (0.25 mg/kg, i.p.) in CAR was also potentiated in the rats pretreated with L-histidine (2.5 μg) or thioperamide (50 μg/rat). Further, the cataleptic effect of haloperidol (1 mg/kg, i.p.) was attenuated in rats pretreated with the H1 receptor antagonist, chlorpheniramine (60, 80 μg/rat, i.c.v.) or H2 receptor antagonist, ranitidine (60 μg/rat, i.c.v.). However, the neuroleptic effect of haloperidol (0.5 mg/kg, i.p.) was completely reversed by pretreatment with ranitidine (60 μg/rat, i.c.v.), and partially attenuated by chlorpheniramine (80 μg/rat, i.c.v.). These findings suggest the possible involvement of histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol probably via H1 or H2 receptor stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

Responsibility for crashes of autonomous vehicles: an ethical analysis.

PubMed

Hevelke, Alexander; Nida-Rümelin, Julian

2015-06-01

A number of companies including Google and BMW are currently working on the development of autonomous cars. But if fully autonomous cars are going to drive on our roads, it must be decided who is to be held responsible in case of accidents. This involves not only legal questions, but also moral ones. The first question discussed is whether we should try to design the tort liability for car manufacturers in a way that will help along the development and improvement of autonomous vehicles. In particular, Patrick Lin's concern that any security gain derived from the introduction of autonomous cars would constitute a trade-off in human lives will be addressed. The second question is whether it would be morally permissible to impose liability on the user based on a duty to pay attention to the road and traffic and to intervene when necessary to avoid accidents. Doubts about the moral legitimacy of such a scheme are based on the notion that it is a form of defamation if a person is held to blame for causing the death of another by his inattention if he never had a real chance to intervene. Therefore, the legitimacy of such an approach would depend on the user having an actual chance to do so. The last option discussed in this paper is a system in which a person using an autonomous vehicle has no duty (and possibly no way) of interfering, but is still held (financially, not criminally) responsible for possible accidents. Two ways of doing so are discussed, but only one is judged morally feasible.

Small car exposure data project. Phase 1 : methodology

DOT National Transportation Integrated Search

1985-10-01

The Small Car Exposure Data Project represents the first phase of an effort to build a data : base of exposure variables for crash-avoidance studies. Among these are: (1) vehicle make, : model, year, body style, wheel base, weight, and horsepower; (2...

Advanced Vehicle Control Systems Potential Tort Liability For Developers

DOT National Transportation Integrated Search

1993-12-01

AUTOMOBILE ACCIDENTS AVOIDED BECAUSE THE AUTOMATIC COLLISION AVOIDANCE SYSTEM APPLIES THE BRAKES, HIGHWAYS WHICH ACCOMMODATE MORE VEHICLES WITH FEWER ACCIDENTS, AND EVEN CARS WHICH ARE PILOTED ENTIRELY BY SOPHISTICATED ELECTRONIC SYSTEMS -- ALL OF TH...

Transporting Your Children Safely: Traffic Safety Tips

DOT National Transportation Integrated Search

1996-01-01

This fact sheet from NHTSA Facts: Summer 1996 discusses the use of child safety seats in cars. It describes the proper use of the seats, how to select one that fits both your child and the car, and lists problems to avoid. It mentions where to place ...

Mileage, car ownership, experience of punishment avoidance, and the risky driving of young drivers.

PubMed

Scott-Parker, B; Watson, B; King, M J; Hyde, M K

2011-12-01

Young drivers are at greatest risk of injury or death from a car crash in the first 6 months of independent driving. In Queensland, the graduated driver licensing (GDL) program was extensively modified in July 2007 in order to reduce this risk. Increased mileage and car ownership have been found to play a role in risky driving, offenses, and crashes; however, GDL programs typically do not consider these variables. In addition, young novice drivers' experiences of punishment avoidance have not previously been examined. This article explores the mileage (duration and distance), car ownership, and punishment avoidance behaviors of young newly licensed intermediate (provisional) drivers and their relationship to risky driving, crashes, and offenses. Drivers (n = 1032) aged 17 to 19 years recruited from across Queensland for longitudinal research completed survey 1 exploring prelicense and learner experiences and sociodemographic characteristics. survey 2 explored the same variables with a subset of these drivers (n = 341) after they had completed their first 6 months of independent driving. Most young drivers in survey 2 reported owning a vehicle and paying attention to police presence. Drivers who had their own cars reported significantly greater mileage and more risky driving. Novices who drove more kilometers, spent more hours each week driving, or avoided actual and anticipated police presence were more likely to report risky driving. These drivers were also more likely to report being detected by police for a driving-related offense. The media, parents, friends, and other drivers play a pivotal role in informing novices of on-road police enforcement operations. GDL programs should incorporate education for the parent and novice driver regarding the increased risks associated with greater driving, particularly when the novice driver owns a vehicle. Parents should be encouraged to delay exclusive access to a vehicle. Parents should also consider whether their young novices will deliberately avoid police if they are aware of their location. This may reinforce not only the risky behavior but also young novices' beliefs that their parents condone this behavior.

Crisis in Amateur Sports Organizations Viewed by Change Agent Research (CAR).

ERIC Educational Resources Information Center

Guilmette, Ann Marie; Moriarty, Dick

The Sports Institute for Research Through Change Agent Research (SIR/CAR) provides a service whereby organizations through an audit and feedback system prognosticate and identify problems in order to avoid situations discordant with their organizational goals and objectives. This document reports the organizational crisis that faced the Windsor…

Chimeric Antigen Receptor T cells for B Cell Neoplasms: Choose the Right CAR for You.

PubMed

Ruella, Marco; June, Carl H

2016-10-01

Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome. Several strategies are being implemented in order to solve the current open issues of CART19 therapy: (i) increasing efficacy against indolent B cell leukemias and lymphomas, (ii) avoiding or preventing antigen-loss relapses, (iii) reducing and managing toxicity, and (iv) bringing this CART therapy to routine clinical practice. The field of CART therapies is thriving, and exciting new avenues are opening for both scientists and patients.

Using Thermal Radiation in Detection of Negative Obstacles

NASA Technical Reports Server (NTRS)

Rankin, Arturo L.; Matthies, Larry H.

2009-01-01

A method of automated detection of negative obstacles (potholes, ditches, and the like) ahead of ground vehicles at night involves processing of imagery from thermal-infrared cameras aimed at the terrain ahead of the vehicles. The method is being developed as part of an overall obstacle-avoidance scheme for autonomous and semi-autonomous offroad robotic vehicles. The method could also be applied to help human drivers of cars and trucks avoid negative obstacles -- a development that may entail only modest additional cost inasmuch as some commercially available passenger cars are already equipped with infrared cameras as aids for nighttime operation.

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.

Local laser-strengthening: Customizing the forming behavior of car body steel sheets

NASA Astrophysics Data System (ADS)

Wagner, M.; Jahn, A.; Beyer, E.; Balzani, D.

2018-05-01

Future trends in designing lightweight components especially for automotive applications increasingly require complex and delicate structures with highest possible level of capacity [1]. The manufacturing of metallic car body components is primarily realized by deep or stretch drawing. The forming process of especially cold rolled and large-sized components is typically characterized by inhomogeneous stress and strain distributions. As a result, the avoidance of undesirable deep drawing effects like earing and local necking is among the greatest challenges in forming complex car body structures [2]. Hence, a novel local laser-treatment approach with the objective of customizing the forming behavior of car body steel sheets is currently explored.

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.

Health co-benefits in mortality avoidance from implementation of the mass rapid transit (MRT) system in Kuala Lumpur, Malaysia.

PubMed

Kwan, Soo Chen; Tainio, Marko; Woodcock, James; Hashim, Jamal Hisham

2016-03-01

The mass rapid transit (MRT) is the largest transport infrastructure project under the national key economic area (NKEA) in Malaysia. As urban rail is anticipated to be the future spine of public transport network in the Greater Kuala Lumpur city, it is important to mainstream climate change mitigation and public health benefits in the local transport development. This study quantifies the health co-benefits in terms of mortality among the urbanites when the first line of the 150 km MRT system in Kuala Lumpur commences by 2017. Using comparative health risk assessment, we estimated the potential health co-benefits from the establishment of the MRT system. We estimated the reduced CO2 emissions and air pollution (PM2.5) exposure reduction among the general population from the reduced use of motorized vehicles. Mortality avoided from traffic incidents involving motorcycles and passenger cars, and from increased physical activity from walking while using the MRT system was also estimated. A total of 363,130 tonnes of CO2 emissions could be reduced annually from the modal shift from cars and motorcycles to the MRT system. Atmospheric PM2.5 concentration could be reduced 0.61 μg/m3 annually (2%). This could avoid a total of 12 deaths, mostly from cardio-respiratory diseases among the city residents. For traffic injuries, 37 deaths could be avoided annually from motorcycle and passenger cars accidents especially among the younger age categories (aged 15-30). One additional death was attributed to pedestrian walking. The additional daily physical activity to access the MRT system could avoid 21 deaths among its riders. Most of the mortality avoided comes from cardiovascular diseases. Overall, a total of 70 deaths could be avoided annually among both the general population and the MRT users in the city. The implementation of the MRT system in Greater Kuala Lumpur could bring substantial health co-benefits to both the general population and the MRT users mainly from the avoidance of mortality from traffic injuries.

Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors.

PubMed

Luisier, Raphaëlle; Lempiäinen, Harri; Scherbichler, Nina; Braeuning, Albert; Geissler, Miriam; Dubost, Valerie; Müller, Arne; Scheer, Nico; Chibout, Salah-Dine; Hara, Hisanori; Picard, Frank; Theil, Diethilde; Couttet, Philippe; Vitobello, Antonio; Grenet, Olivier; Grasl-Kraupp, Bettina; Ellinger-Ziegelbauer, Heidrun; Thomson, John P; Meehan, Richard R; Elcombe, Clifford R; Henderson, Colin J; Wolf, C Roland; Schwarz, Michael; Moulin, Pierre; Terranova, Rémi; Moggs, Jonathan G

2014-06-01

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR(KO)-PXR(KO)), double humanized CAR and PXR (CAR(h)-PXR(h)), and wild-type C57BL/6 mice. Wild-type and CAR(h)-PXR(h) mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CAR(KO)-PXR(KO) mouse livers and largely reversible in wild-type and CAR(h)-PXR(h) mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR(h)-PXR(h) mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

Impact of excess NOx emissions from diesel cars on air quality, public health and eutrophication in Europe

NASA Astrophysics Data System (ADS)

Jonson, J. E.; Borken-Kleefeld, J.; Simpson, D.; Nyíri, A.; Posch, M.; Heyes, C.

2017-09-01

Diesel cars have been emitting four to seven times more NOx in on-road driving than in type approval tests. These ‘excess emissions’ are a consequence of deliberate design of the vehicle’s after-treatment system, as investigations during the ‘Dieselgate’ scandal have revealed. Here we calculate health and environmental impacts of these excess NOx emissions in all European countries for the year 2013. We use national emissions reported officially under the UNECE Convention for Long-range Transport of Atmospheric Pollutants and employ the EMEP MSC-W Chemistry Transport Model and the GAINS Integrated Assessment Model to determine atmospheric concentrations and resulting impacts. We compare with impacts from hypothetical emissions where light duty diesel vehicles are assumed to emit only as much as their respective type approval limit value or as little as petrol cars of the same age. Excess NO2 concentrations can also have direct health impacts, but these overlap with the impacts from particulate matter (PM) and are not included here. We estimate that almost 10 000 premature deaths from PM2.5 and ozone in the adult population (age >30 years) can be attributed to the NOx emissions from diesel cars and light commercial vehicles in EU28 plus Norway and Switzerland in 2013. About 50% of these could have been avoided if diesel limits had been achieved also in on-road driving; and had diesel cars emitted as little NOx as petrol cars, 80% of these premature deaths could have been avoided. Ecosystem eutrophication impacts (critical load exceedances) from the same diesel vehicles would also have been reduced at similar rates as for the health effects.

Directional control-response compatibility of joystick steered shuttle cars.

PubMed

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

2012-01-01

Shuttle cars are an unusual class of vehicle operated in underground coal mines, sometimes in close proximity to pedestrians and steering errors may have very serious consequences. A directional control-response incompatibility has previously been described in shuttle cars which are controlled using a steering wheel oriented perpendicular to the direction of travel. Some other shuttle car operators are seated perpendicular to the direction of travel and steer the car via a seat mounted joystick. A virtual simulation was utilised to determine whether the steering arrangement in these vehicles maintains directional control-response compatibility. Twenty-four participants were randomly assigned to either a condition corresponding to this design (consistent direction), or a condition in which the directional steering response was reversed while driving in-bye (visual field compatible). Significantly less accurate steering performance was exhibited by the consistent direction group during the in-bye trials only. Shuttle cars which provide the joystick steering mechanism described here require operators to accommodate alternating compatible and incompatible directional control-response relationships with each change of car direction. A virtual simulation of an underground coal shuttle car demonstrates that the design incorporates a directional control-response incompatibility when driving the vehicle in one direction. This design increases the probability of operator error, with potential adverse safety and productivity consequences.

Digital-Difference Processing For Collision Avoidance.

NASA Technical Reports Server (NTRS)

Shores, Paul; Lichtenberg, Chris; Kobayashi, Herbert S.; Cunningham, Allen R.

1988-01-01

Digital system for automotive crash avoidance measures and displays difference in frequency between two sinusoidal input signals of slightly different frequencies. Designed for use with Doppler radars. Characterized as digital mixer coupled to frequency counter measuring difference frequency in mixer output. Technique determines target path mathematically. Used for tracking cars, missiles, bullets, baseballs, and other fast-moving objects.

Torque coordinating robust control of shifting process for dry dual clutch transmission equipped in a hybrid car

NASA Astrophysics Data System (ADS)

Zhao, Z.-G.; Chen, H.-J.; Yang, Y.-Y.; He, L.

2015-09-01

For a hybrid car equipped with dual clutch transmission (DCT), the coordination control problems of clutches and power sources are investigated while taking full advantage of the integrated starter generator motor's fast response speed and high accuracy (speed and torque). First, a dynamic model of the shifting process is established, the vehicle acceleration is quantified according to the intentions of the driver, and the torque transmitted by clutches is calculated based on the designed disengaging principle during the torque phase. Next, a robust H∞ controller is designed to ensure speed synchronisation despite the existence of model uncertainties, measurement noise, and engine torque lag. The engine torque lag and measurement noise are used as external disturbances to initially modify the output torque of the power source. Additionally, during the torque switch phase, the torque of the power sources is smoothly transitioned to the driver's demanded torque. Finally, the torque of the power sources is further distributed based on the optimisation of system efficiency, and the throttle opening of the engine is constrained to avoid sharp torque variations. The simulation results verify that the proposed control strategies effectively address the problem of coordinating control of clutches and power sources, establishing a foundation for the application of DCT in hybrid cars.

Sector-Based Detection for Hands-Free Speech Enhancement in Cars

NASA Astrophysics Data System (ADS)

Lathoud, Guillaume; Bourgeois, Julien; Freudenberger, Jürgen

2006-12-01

Adaptation control of beamforming interference cancellation techniques is investigated for in-car speech acquisition. Two efficient adaptation control methods are proposed that avoid target cancellation. The "implicit" method varies the step-size continuously, based on the filtered output signal. The "explicit" method decides in a binary manner whether to adapt or not, based on a novel estimate of target and interference energies. It estimates the average delay-sum power within a volume of space, for the same cost as the classical delay-sum. Experiments on real in-car data validate both methods, including a case with[InlineEquation not available: see fulltext.] km/h background road noise.

Universal Artificial Antigen Presenting Cells to Selectively Propagate T Cells Expressing Chimeric Antigen Receptor Independent of Specificity

PubMed Central

Rushworth, David; Jena, Bipulendu; Olivares, Simon; Maiti, Sourindra; Briggs, Neima; Somanchi, Srinivas; Dai, Jianliang; Lee, Dean; Cooper, Laurence J. N.

2014-01-01

T cells genetically modified to stably express immunoreceptors are being assessed for therapeutic potential in clinical trials. T cells expressing a chimeric antigen receptor (CAR) are endowed with a new specificity to target tumor-associated antigen (TAA) independent of major histocompatibility complex. Our approach to non-viral gene transfer in T cells uses ex vivo numeric expansion of CAR+ T cells on irradiated artificial antigen presenting cells (aAPC) bearing the targeted TAA. The requirement for aAPC to express a desired TAA limits the human application of CARs with multiple specificities when selective expansion through co-culture with feeder cells is sought. As an alternative to expressing individual TAAs on aAPC, we expressed one ligand that could activate CAR+ T cells for sustained proliferation independent of specificity. We expressed a CAR ligand (designated CARL) that binds the conserved IgG4 extracellular domain of CAR and demonstrated CARL+ aAPC propagate CAR+ T cells of multiple specificities. CARL avoids technical issues and costs associated with deploying clinical-grade aAPC for each TAA targeted by a given CAR. Employing CARL enables one aAPC to numerically expand all CAR+ T cells containing the IgG4 domain, and simplifies expansion, testing, and clinical translation of CAR+ T cells of any specificity. PMID:24714354

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

Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

PubMed

Gao, Jun; Qin, Rongyin; Li, Ming

2015-04-01

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. © The Author(s) 2014.

Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function

PubMed Central

Gao, Jun; Qin, Rongyin; Li, Ming

2016-01-01

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. PMID:25586399

Dynamic responses of railroad car models to vertical and lateral rail inputs

NASA Technical Reports Server (NTRS)

Sewall, J. L.; Parrish, R. V.; Durling, B. J.

1971-01-01

Simplified dynamic models were applied in a study of vibration in a high-speed railroad car. The mathematical models used were a four-degree-of-freedom model for vertical responses to vertical rail inputs and a ten-degree-of-freedom model for lateral response to lateral or rolling (cross-level) inputs from the rails. Elastic properties of the passenger car body were represented by bending and torsion of a uniform beam. Rail-to-car (truck) suspensions were modeled as spring-mass-dashpot oscillators. Lateral spring nonlinearities approximating certain complicated truck mechanisms were introduced. The models were excited by displacement and, in some cases, velocity inputs from the rails by both deterministic (including sinusoidal) and random input functions. Results were obtained both in the frequency and time domains. Solutions in the time domain for the lateral model were obtained for a wide variety of transient and random inputs generated on-line by an analog computer. Variations in one of the damping properties of the lateral car suspension gave large fluctuations in response over a range of car speeds for a given input. This damping coefficient was significant in reducing lateral car responses that were higher for nonlinear springs for three different inputs.

Mechanisms underlying cognitive conspicuity in the detection of cyclists by car drivers.

PubMed

Rogé, Joceline; Ndiaye, Daniel; Aillerie, Isabelle; Aillerie, Stéphane; Navarro, Jordan; Vienne, Fabrice

2017-07-01

The aim of this study was to evaluate the visibility of cyclists for motorists in a simulated car driving task. In several cases involving collisions between cars and cyclists, car drivers failed to detect the latter in time to avoid collision because of their low conspicuity. 2 groups of motorists (29.2 years old), including 12 cyclist-motorists and 13 non-cyclist-motorists, performed a vulnerable road user detection task in a car-driving simulator. They had to detect cyclists and pedestrians in an urban setting and evaluate the realism of the cyclists, the traffic, the city, the infrastructure, the car driven and the situations. Cyclists appeared in critical situations derived from previous accounts given by injured cyclists and from cyclists' observations in real-life situations. Cyclist's levels of visibility for car drivers were either high or low in these situations according to the cyclists. Realism scores were similar and high in both groups. Cyclist-motorists had fewer collisions with cyclists and detected cyclists at a greater distance in all situations, irrespective of cyclist visibility. Several mechanisms underlying the cognitive conspicuity of cyclists for car drivers were considered. The attentional selection of a cyclist in the road environment during car driving depends on top-down processing. We consider the practical implications of these results for the safety of vulnerable road users and future directions of research. Copyright © 2017 Elsevier Ltd. All rights reserved.

Gaze movements and spatial working memory in collision avoidance: a traffic intersection task

PubMed Central

Hardiess, Gregor; Hansmann-Roth, Sabrina; Mallot, Hanspeter A.

2013-01-01

Street crossing under traffic is an everyday activity including collision detection as well as avoidance of objects in the path of motion. Such tasks demand extraction and representation of spatio-temporal information about relevant obstacles in an optimized format. Relevant task information is extracted visually by the use of gaze movements and represented in spatial working memory. In a virtual reality traffic intersection task, subjects are confronted with a two-lane intersection where cars are appearing with different frequencies, corresponding to high and low traffic densities. Under free observation and exploration of the scenery (using unrestricted eye and head movements) the overall task for the subjects was to predict the potential-of-collision (POC) of the cars or to adjust an adequate driving speed in order to cross the intersection without collision (i.e., to find the free space for crossing). In a series of experiments, gaze movement parameters, task performance, and the representation of car positions within working memory at distinct time points were assessed in normal subjects as well as in neurological patients suffering from homonymous hemianopia. In the following, we review the findings of these experiments together with other studies and provide a new perspective of the role of gaze behavior and spatial memory in collision detection and avoidance, focusing on the following questions: (1) which sensory variables can be identified supporting adequate collision detection? (2) How do gaze movements and working memory contribute to collision avoidance when multiple moving objects are present and (3) how do they correlate with task performance? (4) How do patients with homonymous visual field defects (HVFDs) use gaze movements and working memory to compensate for visual field loss? In conclusion, we extend the theory of collision detection and avoidance in the case of multiple moving objects and provide a new perspective on the combined operation of external (bottom-up) and internal (top-down) cues in a traffic intersection task. PMID:23760667

Effects of coupling between the vibrational modes on CARS signal

NASA Astrophysics Data System (ADS)

Patel, Vishesha; Malinovskaya, Svetlana

2007-06-01

CARS is well suited spectroscopy method for imaging specific molecules, e.g., proteins and live cells, diagnosis of cancerous cells, imaging dueterated compounds, etc. CARS imaging techniques avoid problems associated with photo bleaching and photo induced toxicity. The CARS signal is accompanied by a strong non resonant background which may overshadow the weak signal of interest. Two methods, using femtosecond chriped laser pulses and providing the Rabi oscillation and the adiabatic passage type of control [1], allow one to achieve sensitivity with high resolution and are known to efficiently suppress background. It has been previously shown that coupling between vibrational modes affects the sensitivity of the Raman signal and selective excitation of vibrational modes [2]. In this paper we will discuss simulation results on vibrational coupling between modes and its impact into control mechanisms of the CARS signal. [1] S.A.Malinovskaya, Physical.Rev.A 73, 033416(2006) [2] S.A. Malinovskaya,P.H. Bucksbaum, and P.R. Berman, J. Chem. Phys. 121, 3434 (2004).

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.

Impact self-excited vibrations of linear motor

NASA Astrophysics Data System (ADS)

Zhuravlev, V. Ph.

2010-08-01

Impact self-exciting vibration modes in a linear motor of a monorail car are studied. Existence and stability conditions of self-exciting vibrations are found. Ways of avoiding the vibrations are discussed.

Analysis of work zone rear-end crash risk for different vehicle-following patterns.

PubMed

Weng, Jinxian; Meng, Qiang; Yan, Xuedong

2014-11-01

This study evaluates rear-end crash risk associated with work zone operations for four different vehicle-following patterns: car-car, car-truck, truck-car and truck-truck. The deceleration rate to avoid the crash (DRAC) is adopted to measure work zone rear-end crash risk. Results show that the car-truck following pattern has the largest rear-end crash risk, followed by truck-truck, truck-car and car-car patterns. This implies that it is more likely for a car which is following a truck to be involved in a rear-end crash accident. The statistical test results further confirm that rear-end crash risk is statistically different between any two of the four patterns. We therefore develop a rear-end crash risk model for each vehicle-following pattern in order to examine the relationship between rear-end crash risk and its influencing factors, including lane position, the heavy vehicle percentage, lane traffic flow and work intensity which can be characterized by the number of lane reductions, the number of workers and the amount of equipment at the work zone site. The model results show that, for each pattern, there will be a greater rear-end crash risk in the following situations: (i) heavy work intensity; (ii) the lane adjacent to work zone; (iii) a higher proportion of heavy vehicles and (iv) greater traffic flow. However, the effects of these factors on rear-end crash risk are found to vary according to the vehicle-following patterns. Compared with the car-car pattern, lane position has less effect on rear-end crash risk in the car-truck pattern. The effect of work intensity on rear-end crash risk is also reduced in the truck-car pattern. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

Development of a computer model for prediction of collision response of a railroad passenger car

DOT National Transportation Integrated Search

2002-04-23

The paper describes the development of a detailed finite element model that is capable of predicting the response of a rail passenger car to collision conditions. This model was developed to predict the car crush, the three-dimensional gross motions ...

Significance of anti-CarLA salivary IgA antibody in first grazing season cattle naturally infected with gastrointestinal nematodes.

PubMed

Merlin, Aurélie; Shaw, Richard; Chauvin, Alain; Bareille, Nathalie; Chartier, Christophe

2017-08-30

A carbohydrate larval surface antigen (CarLA) present on infective larvae of all trichostrongylid nematodes is a target antigen for host immunoglobulins (Ig). Levels of anti-CarLA salivary IgA antibody (CarLA-IgA) have been shown to be correlated to the level of protective immunity to GIN in sheep and deer but no information is available in cattle. The first objective of this study was to assess the pattern of CarLA-IgA response in 7 groups (G1-G7) of first grazing season cattle (FGSC) naturally infected with gastrointestinal nematodes. The second objective was to assess the phenotypic correlations between CarLA-IgA level, 3 parasitological indicators (faecal egg count-FEC, pepsinogen level, serum anti-O. ostertagi IgG antibody level-OstertagiaIgG), a clinical indicator (diarrhea score) and average daily weight gain (ADWG). Overall, CarLA-IgA response gradually increased over grazing season and showed large variations in speed and magnitude both between and within groups. Based on the mean group CarLA-IgA response pattern, the 7 groups could be allocated to 3 different classes: (i) 'Late High' class characterized by a high response at housing (G1 and G2); (ii) 'Low' class with a low response over time (G3, G4 and G5); and (iii) 'Early' class with an high initial then stable response (G6 and G7). This classification was consistent with the grazing management practices. In the 'Late High' class, the mean CarLA-IgA at housing was 6.05units/mL and negatively correlated with FEC while no correlation was seen with the other indicators nor ADWG. In the 'Low' class, CarLA response at housing was low (1.95units/mL) and mainly positively correlated with OstertagiaIgG. In the 'Early' class, mean CarLA-IgA ranged from 1.32 to 1.86units/mL during the grazing season and positive correlations were seen with parasitological and clinical indicators. These results suggest that, according to the intensity of larval challenge occurring during the first grazing season, CarLA-IgA response in cattle could be either an indicator of the early manifestation of immunity (FEC decreases) or the reflection of exposure to GIN. Copyright © 2017 Elsevier B.V. All rights reserved.

The European New Car Assessment Programme: A historical review.

PubMed

van Ratingen, Michiel; Williams, Aled; Lie, Anders; Seeck, Andre; Castaing, Pierre; Kolke, Reinhard; Adriaenssens, Guido; Miller, Andrew

2016-04-01

Established in 1997, the European New Car Assessment Programme (Euro NCAP) provides consumers with a safety performance assessment for the majority of the most popular cars in Europe. Thanks to its rigorous crash tests, Euro NCAP has rapidly become an important driver safety improvement to new cars. After ten years of rating vehicles, Euro NCAP felt that a change was necessary to stay in tune with rapidly emerging driver assistance and crash avoidance systems and to respond to shifting priorities in road safety. A new overall rating system was introduced that combines the most important aspects of vehicle safety under a single star rating. The overall rating system has allowed Euro NCAP to continue to push for better fitment and higher performance for vehicles sold on the European market. In the coming years, the safety rating is expected to play an important role in the support of the roll-out of highly automated vehicles.

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

Analysis of accelerations measured during full-scale tank car impact tests

DOT National Transportation Integrated Search

2007-04-01

Tank car impact responses were investigated using accelerometers mounted at various locations on a tank car. Several tests were run with both a full and an empty tank car, and varying the tank car impact speed. The data from the accelerometers went t...

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

Drug Interactions: What You Should Know

MedlinePlus

... driving a car or operating machinery dangerous. Drug-food/beverage interactions result from drugs reacting with foods or ... it with other drugs? Should I avoid certain foods, beverages or other products? What are possible drug interaction ...

Low conspicuity of motorcycles for car drivers: dominant role of bottom-up control of visual attention or deficit of top-down control?

PubMed

Rogé, Joceline; Douissembekov, Evgueni; Vienne, Fabrice

2012-02-01

The aim of this study was to evaluate whether the low visibility of motorcycles is the result of their low cognitive conspicuity and/or their low sensory conspicuity for car drivers. In several cases of collision between a car and a motorcycle, the car driver failed to detect the motorcyclist in time to avoid the collision. To test the low cognitive conspicuity hypothesis, 42 car drivers (32.02 years old) including 21 motorcyclist motorists and 21 non-motorcyclist motorists carried out a motorcycle detection task in a car-driving simulator.To test the low sensory conspicuity hypothesis, the authors studied the effect of the color contrast between motorcycles and the road surface on the ability of car drivers to detect motorcycles when they appear from different parts of the road. A high level of color contrast enhanced the visibility of motorcycles when they appeared in front of the participants. Moreover, when motorcyclists appeared from behind the participants,the motorcyclist motorists detected oncoming motorcycles at a greater distance than did the non-motorcyclist motorists. Motorcyclist motorists carry out more saccades and rapidly capture information (on their rearview mirrors and on the road in front of them). The results related to the sensory conspicuity and cognitive conspicuity of motorcycles for car drivers are discussed from the viewpoint of visual attention theories. The practical implications of these results and future lines of research related to training methods for car drivers are considered.

[Behavioral pharmacological properties of nicergoline. Effects on gross-behavior in rats and monkeys and on DRL response, CER, and CAR in rats].

PubMed

Yamamura, M; Maeda, K; Nakagawa, H; Ishida, R

1986-02-01

Whether nicergoline has psychotropic-like pharmacological properties was examined through the gross-behavioral and operant behavioral observations in rats and monkeys. In gross-behavioral observations, slight decrement of spontaneous motor activity, lying on the abdomen and relaxation of abdominal tone were observed in rats when nicergoline was administered intravenously (1 mg/kg or more) and intraperitoneally (4 mg/kg or more). However, when it was administered orally, slight decrement of spontaneous motor activity was observed only at large doses of 32 and 128 mg/kg. In monkeys, nicergoline produced decrement of spontaneous motor activity, palpebral ptosis, and lacrimation when administered intraperitoneally at doses of 1 mg/kg or more. Under a differential reinforcement of low rate (DRL) schedule for food reinforcement in rats, nicergoline depressed the response at 4 mg/kg, i.p., or 128 mg/kg, orally. In conditioned emotional response (CER), nicergoline had no effect on the responses during both the alarm and safe periods at doses of 0.25, 1, and 4 mg/kg, i.p., or 8, 32, and 128 mg/kg, p.o. In Sidman continuous avoidance response (CAR), nicergoline (0.25, 1, and 4 mg/kg, i.p., or 8, 32, and 128 mg/kg, p.o.) slightly depressed the response and increased the total shock. These results were compared with those of chlorpromazine, chlordiazepoxide, pentobarbital, and methamphetamine and the following conclusion was drawn: Inhibitory effects of nicergoline on gross and operant behaviors seem to be non-specific, and its behavioral pharmacological properties are qualitatively different from those of anti-psychotics, anti-anxietics, hypnotics, and stimulants.

Toxicities of chimeric antigen receptor T cells: recognition and management

PubMed Central

Brudno, Jennifer N.

2016-01-01

Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy. PMID:27207799

Comparing car drivers' and motorcyclists' opinions about junction crashes.

PubMed

Robbins, Chloe J; Allen, Harriet A; Chapman, Peter

2018-08-01

Motorcyclists are involved in a disproportionate number of crashes given the distance they travel, with a high proportion of these crashes occurring at junctions. Despite car drivers being solely responsible for many road crashes involving a motorcycle, previous research has mostly focussed on understanding motorcyclists' attitudes towards their own safety. We compared car drivers' (n = 102) and motorcyclists' (n = 579) opinions about junction crashes using a web-based questionnaire. Motorcyclists and car drivers were recruited in similar ways so that responses could be directly compared, accessing respondents through driver/rider forums and on social media. Car drivers' and motorcyclists' opinions were compared in relation to who they believe to be blameworthy in situations which varied in specificity, ranging from what road user they believe is most likely to cause a motorcyclist to have a road crash, to what road user is at fault in four specific scenarios involving a car and motorcycle at a junction. Two of these scenarios represented typical 'Right of way' (ROW) crashes with a motorcycle approaching from the left and right, and two scenarios involved a motorcycle overtaking another vehicle at the junction, known as 'Motorcycle Manoeuvrability Accidents' (MMA). Qualitative responses were analysed using LIWC software to detect objective differences in car drivers' and motorcyclists' language. Car drivers' and motorcyclists' opinions about the blameworthiness of accidents changed depending on how specific the situation was that was being presented. When respondents were asked about the cause of motorcycle crashes in a general abstract sense, car drivers' and motorcyclists' responses significantly differed, with motorcyclists more likely to blame car drivers, demonstrating an in-group bias. However, this in-group favouritism was reduced when asked about specific scenarios, especially in MMA situations which involve motorcyclists manoeuvring their motorcycles around cars at a junction. In the four specific scenarios, car drivers were more likely to blame the car driver, and motorcyclists were more likely to blame the motorcyclist. In the typical ROW scenarios, the responses given by both road users, as analysed by the LIWC, show that the law is taken into account, as well as a large emphasis on the lack of observation given around junctions, especially from car drivers. It is concluded that the perception of blameworthiness in crashes is very much dependent on the details of the crash, with a more specific situation eliciting a fairer evaluation by both car drivers and motorcyclists. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

76 FR 67073 - Safety and Health Requirements Related to Camp Cars

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-31

...), a new compliance date would be necessary in order to avoid creating an unconstitutional, ex post facto law, and that is what Congress provided with the new statutory deadline for compliance of December...

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.

Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response.

PubMed

Xue, Qiong; Bettini, Emily; Paczkowski, Patrick; Ng, Colin; Kaiser, Alaina; McConnell, Timothy; Kodrasi, Olja; Quigley, Máire F; Heath, James; Fan, Rong; Mackay, Sean; Dudley, Mark E; Kassim, Sadik H; Zhou, Jing

2017-11-21

It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti-CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16-plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. We demonstrate a new method for single-cell profiling of CD19 CAR-T pre-infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-γ, MIP-1α, TNF-α), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL-17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high dimensional data requires new visualization methods to further define precise polyfunctional response differences in these products. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy.

49 CFR 238.313 - Class I brake test.

Code of Federal Regulations, 2013 CFR

2013-10-01

... occurs first, that the train remains in continuous passenger service. (c) Each passenger car and each... performed on the car within the previous calendar day and the car has not been disconnected from a source of... applied on each car in the train until a release of the brakes has been initiated on each car in response...

49 CFR 238.313 - Class I brake test.

Code of Federal Regulations, 2014 CFR

2014-10-01

... occurs first, that the train remains in continuous passenger service. (c) Each passenger car and each... performed on the car within the previous calendar day and the car has not been disconnected from a source of... applied on each car in the train until a release of the brakes has been initiated on each car in response...

49 CFR 238.313 - Class I brake test.

Code of Federal Regulations, 2012 CFR

2012-10-01

... occurs first, that the train remains in continuous passenger service. (c) Each passenger car and each... performed on the car within the previous calendar day and the car has not been disconnected from a source of... applied on each car in the train until a release of the brakes has been initiated on each car in response...

49 CFR 238.313 - Class I brake test.

Code of Federal Regulations, 2011 CFR

2011-10-01

... occurs first, that the train remains in continuous passenger service. (c) Each passenger car and each... performed on the car within the previous calendar day and the car has not been disconnected from a source of... applied on each car in the train until a release of the brakes has been initiated on each car in response...

49 CFR 238.313 - Class I brake test.

Code of Federal Regulations, 2010 CFR

2010-10-01

... occurs first, that the train remains in continuous passenger service. (c) Each passenger car and each... performed on the car within the previous calendar day and the car has not been disconnected from a source of... applied on each car in the train until a release of the brakes has been initiated on each car in response...

A role for multiple chimeric antigen receptor-expressing leukocytes in antigen-specific responses to cancer

PubMed Central

Yong, Carmen S.M.; John, Liza B.; Devaud, Christel; Prince, Miles H.; Johnstone, Ricky W.; Trapani, Joseph A.

2016-01-01

While adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells can induce remission of some tumors, the role of other CAR-modified leukocytes is not well characterized. In this study, we characterize the function of leukocytes including natural killer (NK) cells, macrophages and CAR T cells from transgenic mice expressing a CAR under the control of the pan-hematopoietic promoter, vav, and determine the ability of these mice to respond to ERB expressing tumors. We demonstrate the anti-tumor functions of leukocytes, including antigen specific cytotoxicity and cytokine secretion. The adoptive transfer of CAR T cells provided a greater survival advantage in the E0771ERB tumor model than their wildtype (WT) counterparts. In addition, CAR NK cells and CAR T cells also mediated increased survival in the RMAERB tumor model. When challenged with Her2 expressing tumors, F38 mice were shown to mount an effective immune response, resulting in tumor rejection and long-term survival. This was shown to be predominantly dependent on both CD8+ T cells and NK cells. However, macrophages and CD4+ T cells were also shown to contribute to this response. Overall, this study highlights the use of the vav-CAR mouse model as a unique tool to determine the anti-tumor function of various immune subsets, either alone or when acting alongside CAR T cells in adoptive immunotherapy. PMID:27153556

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.

Market penetration of intersection AEB: Characterizing avoided and residual straight crossing path accidents.

PubMed

Sander, Ulrich; Lubbe, Nils

2018-06-01

Car occupants account for one third of all junction fatalities in the European Union. Driver warning can reduce intersection accidents by up to 50 percent; adding Autonomous Emergency Braking (AEB) delivers a reduction of up to 70 percent. However, these findings are based on an assumed 100 percent equipment rate, which may take decades to achieve. Our study investigates the relationship between intersection AEB market penetration rates and avoidance of accidents and injuries in order to guide implementation strategies. Additionally, residual accident characteristics (impact configurations and severity) are analyzed to provide a basis for future in-crash protection requirements. We determined which accidents would have been avoided through the use of an Intersection AEB system with different sensor field-of-views (180° and 120°) by means of re-simulating the pre-crash phase of 792 straight crossing path (SCP) car-to-car accidents recorded in the German In-Depth Accident Study (GIDAS) and the associated Pre-Crash Matrix (PCM). Intersection AEB was activated when neither of the conflict opponents could avoid the crash through reasonable braking or steering reactions. For not-avoided accidents, we used the Kudlich-Slibar rigid body impulse model to calculate the change of velocity during the impact as a measure of impact severity and the principal direction of force. Accident avoidance over market penetration is not linear but exponential, with higher gains at low penetration rates and lower gains at higher rates. A wide field-of-view sensor (180°) substantially increased accident avoidance and injury mitigation rates compared to a 120° field-of-view sensor. For a 180° field-of-view sensor at 100 percent market penetration, about 80 percent of the accidents and 90 percent of the MAIS2 + F injuries could be avoided. For the remaining accidents, AEB intervention rarely affected side of impact. The median change of velocity (delta-V) of the remaining crashes reduces only marginally at low penetration rates but this reduction increases with higher penetration rates. With 100 percent market penetration, one quarter of the vehicles still involved in straight crossing path accidents will sustain a delta-V higher than 17 km/h. Intersection AEB is very effective. Enabling a fast initial implementation of systems with wide field-of-view sensor(s) and ensuring a high market penetration over the longer term is essential to achieve high crash avoidance and injury mitigation rates over time. The standards for in-crash protection must be high to mitigate injury in the unavoidable, residual accidents. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Approach for counting vehicles in congested traffic flow

NASA Astrophysics Data System (ADS)

Tan, Xiaojun; Li, Jun; Liu, Wei

2005-02-01

More and more image sensors are used in intelligent transportation systems. In practice, occlusion is always a problem when counting vehicles in congested traffic. This paper tries to present an approach to solve the problem. The proposed approach consists of three main procedures. Firstly, a new algorithm of background subtraction is performed. The aim is to segment moving objects from an illumination-variant background. Secondly, object tracking is performed, where the CONDENSATION algorithm is used. This can avoid the problem of matching vehicles in successive frames. Thirdly, an inspecting procedure is executed to count the vehicles. When a bus firstly occludes a car and then the bus moves away a few frames later, the car will appear in the scene. The inspecting procedure should find the "new" car and add it as a tracking object.

78 FR 39017 - Investigative Hearing

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

... emergency response operations, roles of the response teams, evacuations and communications, incident response protocols, hazmat training, oversight of Paulsboro emergency preparedness, roles of local, state... of 2 locomotives and 82 cars, derailed 7 cars near milepost 13.7 on the Conrail Penn's Grove...

Electric cars. Advantages and disadvantages

NASA Astrophysics Data System (ADS)

Gelmanova, Z. S.; Zhabalova, G. G.; Sivyakova, G. A.; Lelikova, O. N.; Onishchenko, O. N.; Smailova, A. A.; Kamarova, S. N.

2018-05-01

The article considers the positive and negative aspects of the use of electric vehicles. A rough calculation of the energy efficiency and average cost per month was made. Also priorities to avoid the existing problems in the market of electric vehicles were set.

49 CFR 1152.36 - Submission of revenue and cost data.

Code of Federal Regulations, 2014 CFR

2014-10-01

...-freight cars j. Revenue taxes k. Property taxes 6. Off-branch costs a. Off-branch costs (other than return.... Holding gain (loss) XXXX 16. Total return on value (line 14 minus 15) 3 XXXX 17. Avoidable loss from...

49 CFR 1152.36 - Submission of revenue and cost data.

Code of Federal Regulations, 2011 CFR

2011-10-01

...-freight cars j. Revenue taxes k. Property taxes 6. Off-branch costs a. Off-branch costs (other than return.... Holding gain (loss) XXXX 16. Total return on value (line 14 minus 15) 3 XXXX 17. Avoidable loss from...

49 CFR 1152.36 - Submission of revenue and cost data.

Code of Federal Regulations, 2010 CFR

2010-10-01

...-freight cars j. Revenue taxes k. Property taxes 6. Off-branch costs a. Off-branch costs (other than return.... Holding gain (loss) XXXX 16. Total return on value (line 14 minus 15) 3 XXXX 17. Avoidable loss from...

49 CFR 1152.36 - Submission of revenue and cost data.

Code of Federal Regulations, 2012 CFR

2012-10-01

...-freight cars j. Revenue taxes k. Property taxes 6. Off-branch costs a. Off-branch costs (other than return.... Holding gain (loss) XXXX 16. Total return on value (line 14 minus 15) 3 XXXX 17. Avoidable loss from...

49 CFR 1152.36 - Submission of revenue and cost data.

Code of Federal Regulations, 2013 CFR

2013-10-01

...-freight cars j. Revenue taxes k. Property taxes 6. Off-branch costs a. Off-branch costs (other than return.... Holding gain (loss) XXXX 16. Total return on value (line 14 minus 15) 3 XXXX 17. Avoidable loss from...

The cortisol awakening response and major depression: examining the evidence

PubMed Central

Dedovic, Katarina; Ngiam, Janice

2015-01-01

A vast body of literature has revealed that dysregulation of the hypothalamic–pituitary–adrenal (HPA) stress axis is associated with etiology of major depressive disorder (MDD). There are many ways that the dysregulation of the HPA axis can be assessed: by sampling diurnal basal secretion and/or in response to a stress task, pharmacological challenge, and awakening. Here, we focus on the association between cortisol awakening response (CAR), as one index of HPA axis function, and MDD, given that the nature of this association is particularly unclear. Indeed, in the following selective review, we attempt to reconcile sometimes-divergent evidence of the role of CAR in the pathway to depression. We first examine association of CAR with psychological factors that have been linked with increased vulnerability to develop depression. Then, we summarize the findings regarding the CAR profile in those with current depression, and evaluate evidence for the role of CAR following depression resolution and continued vulnerability. Finally, we showcase longitudinal studies showing the role of CAR in predicting depression onset and recurrence. Overall, the studies reveal an important, but complex, association between CAR and vulnerability to depression. PMID:25999722

Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist

PubMed Central

Levine, Bruce L.

2016-01-01

The field of cancer immunotherapy has rapidly progressed in the past decade as several therapeutic modalities have entered into the clinic. One such immunotherapy that has shown promise in the treatment of cancer is the use of chimeric antigen receptor (CAR)-modified T lymphocytes. CARs are engineered receptors constructed from antigen recognition regions of antibodies fused to T-cell signaling and costimulatory domains that can be used to reprogram a patient’s T cells to specifically target tumor cells. CAR T-cell therapy has demonstrated sustained complete responses for some patients with advanced leukemia, and a number of CAR therapies are being evaluated in clinical studies. CAR T-cell therapy-associated toxicities, including cytokine release syndrome, macrophage activation syndrome, and tumor lysis syndrome, have been observed and effectively managed in the clinic. In patients with significant clinical responses, sustained B-cell aplasia has also been observed and is a marker of CAR T-cell persistence that might provide long-term disease control. Education on CAR T-cell therapy efficacy and safety management is critical for clinicians and patients who are considering this novel type of treatment. In the present report, the current landscape of CAR T-cell therapy, the effective management of patients undergoing treatment, and which patients are the most suitable candidates for current trials are discussed. Implications for Practice: The present report describes the current status of chimeric antigen receptor (CAR) T lymphocytes as an immunotherapy for patients with relapsed or refractory B-cell malignancies. CAR T cells targeting CD19, a protein expressed on many B-cell malignancies, typically induce high complete response rates in patients with B-cell leukemia or lymphoma who have very limited therapeutic options. Recent clinical trial results of CD19 CAR T-cell therapies and the management of CAR T-cell-associated adverse events are discussed. The present report will therefore inform physicians regarding the efficacy and safety of CAR T cells as a therapy for B-cell malignancies. PMID:27009942

Overgeneral autobiographical memory in healthy young and older adults: Differential age effects on components of the capture and rumination, functional avoidance, and impaired executive control (CaRFAX) model.

PubMed

Ros, Laura; Latorre, Jose M; Serrano, Juan P; Ricarte, Jorge J

2017-08-01

The CaRFAX model (Williams et al., 2007) has been used to explain the causes of overgeneral autobiographical memory (OGM; the difficulty to retrieve specific autobiographical memories), a cognitive phenomenon generally related with different psychopathologies. This model proposes 3 different mechanisms to explain OGM: capture and rumination (CaR), functional avoidance (FA) and impaired executive functions (X). However, the complete CaRFAX model has not been tested in nonclinical populations. This study aims to assess the usefulness of the CaRFAX model to explain OGM in 2 healthy samples: a young sample and an older sample, to test for possible age-related differences in the underlying causes of OGM. A total of 175 young (age range: 19-36 years) and 175 older (age range: 53-88 years) participants completed measures of brooding rumination (CaR), functional avoidance (FA), and executive tasks (X). Using structural equation modeling, we found that memory specificity is mainly associated with lower functional avoidance and higher executive functions in the older group, but only with executive functions in young participants. We discuss the different roles of emotional regulation strategies used by young and older people and their relation to the CaRFAX model to explain OGM in healthy people. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

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.

Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

PubMed

Ikeda, Shinobu; Kurose, Kouichi; Jinno, Hideto; Sai, Kimie; Ozawa, Shogo; Hasegawa, Ryuichi; Komamura, Kazuo; Kotake, Takeshi; Morishita, Hideki; Kamakura, Shiro; Kitakaze, Masafumi; Tomoike, Hitonobu; Tamura, Tomohide; Yamamoto, Noboru; Kunitoh, Hideo; Yamada, Yasuhide; Ohe, Yuichiro; Shimada, Yasuhiro; Shirao, Kuniaki; Kubota, Kaoru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Saito, Yoshiro; Sawada, Jun-ichi

2005-01-01

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

Effectiveness and efficiency of safety belt and child restraint usage programs

DOT National Transportation Integrated Search

1982-03-01

Problem: Each year, approximately 34,000 persons are killed and 520,000 receive moderate to severe injuries as occupants of passenger cars, light trucks and vans. Approximately half ofthese deaths and injuries could be avoided if all such occupants w...

The maternal cortisol awakening response in human pregnancy is associated with the length of gestation.

PubMed

Buss, Claudia; Entringer, Sonja; Reyes, Jonazary F; Chicz-DeMet, Aleksandra; Sandman, Curt A; Waffarn, Feizal; Wadhwa, Pathik D

2009-10-01

The purpose of this study was to examine the relationship between intraindividual changes in cortisol responsiveness over pregnancy and the length of human gestation. Pregnancy-related changes in the cortisol awakening response (CAR), which is a measure of hypothalamic-pituitary-adrenal axis responsiveness, were assessed prospectively in 101 pregnant women at 16.8 +/- 1.4 weeks' and 31.4 +/- 1.3 weeks' (+/-SD) gestation. Cortisol was measured in saliva that was collected immediately and +30, +45 and +60 minutes after awakening. The CAR was significant in pregnancy and exhibited progressive attenuation over the course of gestation. A larger CAR in late pregnancy and reduced attenuation of the CAR from early to late gestation were associated significantly with shorter gestational length. The findings are the first to suggest that the hormonal (cortisol) response to a naturally occurring challenge (awakening) and the degree of attenuation of this response over the course of gestation may represent a novel biomarker of increased vulnerability for earlier birth.

Dissecting the impact of sleep and stress on the cortisol awakening response in young adults.

PubMed

Vargas, Ivan; Lopez-Duran, Nestor

2014-02-01

Cortisol rises precipitously upon awakening, in what has been called the cortisol awakening response (CAR). Atypical CARs have been linked to a number of negative health outcomes. Yet, our understanding of the possible mechanisms creating these associations remains unclear. Both stress and sleep can influence CAR, and may potentially explain its links to health. However, these factors also impact each other, and their influence on CAR has rarely been studied simultaneously. In order to differentiate their effects, this study examined the impact of daily life hassles, anticipatory stress, and subjectively reported sleep on CAR among 58 college students. Self-reported stress and sleep, as well as salivary cortisol (collected during the first hour after awakening) were obtained across two consecutive days. Total sleep time predicted CAR magnitude, but daily hassles and anticipatory stress did not after accounting for the effect of sleep. Lower total sleep time was associated with lower awakening cortisol and greater CAR. These results provide further evidence for the impact of sleep insufficiency on CAR, and suggest future efforts to use CAR as a stress biomarker should take the impact of sleep into consideration. Published by Elsevier Ltd.

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.

Does a tow-bar increase the risk of neck injury in rear-end collisions?

PubMed

Olesen, Anne Vingaard; Elvik, Rune; Andersen, Camilla Sloth; Lahrmann, Harry S

2018-06-01

Does a tow-bar increase the risk of neck injury in the struck car in a rear-end collision? The rear part of a modern car has collision zones that are rendered nonoperational when the car is equipped with a tow-bar. Past crash tests have shown that a car's acceleration was higher in a car equipped with a tow-bar and also that a dummy placed in a car with a tow-bar had higher peak acceleration in the lower neck area. This study aimed to investigate the association between the risk of neck injury in drivers and passengers, and the presence of a registered tow-bar on the struck car in a rear-end collision. We performed a merger of police reports, the National Hospital Discharge Registry, and the National Registry of Motor Vehicles in Denmark. We identified 9,370 drivers and passengers of whom 1,519 were diagnosed with neck injury within the first year after the collision. We found a statistically insignificant 5% decrease in the risk of neck injury in the occupants of the struck car when a tow-bar was fitted compared to when it was not fitted (hazard ratio=0.95; 95% confidence level=0.85-1.05; p=0.32). The result was controlled for gender, age, and the seat of the occupant. Several other collision and car characteristics and demographic information on the drivers and passengers were evaluated as confounders but were not statistically significant. The present study may serve as valuable input for a meta-analysis on the effect of a tow-bar because negative results are necessary in order to avoid publication bias. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Generation and communication of dynamic maps using light projection

NASA Astrophysics Data System (ADS)

Busch, Steffen; Schlichting, Alexander; Brenner, Claus

2018-05-01

Many accidents are caused by miscommunication between traffic participants. Much research is being conducted in the area of car to car and car to infrastructure communication in order to eliminate this cause of accidents. How-ever, less attention is paid to the question how the behavior of a car can be communicated to pedestrians. Especially considering automated traffic, there is a lack of communication between cars and pedestrians. In this paper, we address the question how an autonomously driving car can inform pedestrians about its intentions. Especially in case of highly automated driving, making eye contact with a driver will give no clue about his or her intensions. We developed a prototype which continuously informs pedestrians about the intentions of the vehicle by projecting visual patterns onto the ground. Furthermore, the system communicates its interpretation of the observed situation to the pedestrians to warn them or to encourage them to perform a certain action. In order to communicate adaptively, the vehicle needs to develop an understanding of the dynamics of a city to know what to expect in certain situations and what speed is appropriate. To support this, we created a dynamic map, which estimates the number of pedestrians and cyclists in a certain area, which is then used to determine how `hazardous' the area is. This dynamic map is obtained from measurement data from many time instances, in contrast to the static car navigation maps, which are prevalent today. Apart from being used for communication purposes, the dynamic map can also influence the speed of a car, be it manually or autonomously driven. Adapting the speed in hazardous areas will avoid accidents where a car drives too fast, so that neither a human nor a computer-operated system would be able to stop in time.

Chimeric antigen receptor T-cell therapy in AML: How close are we?

PubMed Central

Gill, Saar

2016-01-01

The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T-cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range. This is in part because the full power of T cells must be restrained in order to avoid lethal graft-versus-host disease (GVHD) and partly because only a sub-population of donor T cells are expected to be able to recognize AML cells via their T cell receptor. Chimeric antigen receptor (CAR) T cell therapy, most advanced in the treatment of patients with B-cell malignancies, may circumvent some of these limitations. However, major challenges remain to be overcome before CAR T cell therapy can be safely applied to AML. PMID:27890255

Autonomous collision avoidance system by combined control of steering and braking using geometrically optimised vehicular trajectory

NASA Astrophysics Data System (ADS)

Hayashi, Ryuzo; Isogai, Juzo; Raksincharoensak, Pongsathorn; Nagai, Masao

2012-01-01

This study proposes an autonomous obstacle avoidance system not only by braking but also by steering, as one of the active safety technologies to prevent traffic accidents. The proposed system prevents the vehicle from colliding with a moving obstacle like a pedestrian jumping out from the roadside. In the proposed system, to avoid the predicted colliding position based on constant-velocity obstacle motion assumption, the avoidance trajectory is derived as connected two identical arcs. The system then controls the vehicle autonomously by the combined control of the braking and steering systems. In this paper, the proposed system is examined by real car experiments and its effectiveness is shown from the results of the experiments.

Moulded infrared optics making night vision for cars within reach

NASA Astrophysics Data System (ADS)

Bourget, Antoine; Guimond, Yann; Franks, John; Van Den Bergh, Marleen

2005-02-01

Sustainable mobility is a major public concern, making increased safety one of the major challenges for the car of the future. About half of all serious traffic accidents occur at night, while only a minority of journeys is at night. Reduced visibility is one of the main reasons for these striking statistics and this explains the interest of the automobile industry in Enhanced Night Vision Systems. As an answer to the need for high volume, low cost optics for these applications, Umicore has developed GASIR. This material is transparent in the NEAR and FAR infrared, and is mouldable into high quality finished spherical, aspherical and diffractive lenses. Umicore's GASIR moulded lenses are an ideal solution for thermal imaging for cars (Night Vision) and for sensing systems like pedestrian detection, collision avoidance, occupation detection, intelligent airbag systems etc.

Role of kinin B1 and B2 receptors in memory consolidation during the aging process of mice.

PubMed

Lemos, Mayra Tolentino Resk; Amaral, Fabio Agostini; Dong, Karis Ester; Bittencourt, Maria Fernanda Queiroz Prado; Caetano, Ariadiny Lima; Pesquero, João Bosco; Viel, Tania Araujo; Buck, Hudson Sousa

2010-04-01

Under physiological conditions, elderly people present memory deficit associated with neuronal loss. This pattern is also associated with Alzheimer's disease but, in this case, in a dramatically intensified level. Kinin receptors have been involved in neurodegeneration and increase of amyloid-beta concentration, associated with Alzheimer's disease (AD). Considering these findings, this work evaluated the role of kinin receptors in memory consolidation during the aging process. Male C57Bl/6 (wt), knock-out B1 (koB1) or B2 (koB2) mice (3, 6, 12 and 18-month-old - mo; n=10 per group) were submitted to an acquisition session, reinforcement to learning (24h later: test 1) and final test (7days later: test 2), in an active avoidance apparatus, to evaluate memory. Conditioned avoidance responses (CAR, % of 50 trials) were registered. In acquisition sessions, similar CAR were obtained among age matched animals from all strains. However, a significant decrease in CAR was observed throughout the aging process (3mo: 8.8+/-2.3%; 6mo: 4.1+/-0.6%; 12mo: 2.2+/-0.6%, 18mo: 3.6+/-0.6%, P<0.01), indicating a reduction in the learning process. In test 1, as expected, memory retention increased significantly (P<0.05) in all 3- and 6-month-old animals as well as in 12-month-old-wt and 12-month-old-koB1 (P<0.01), compared to the training session. However, 12-month-old-koB2 and all 18-month-old animals did not show an increase in memory retention. In test 2, 3- and 6-month-old wt and koB1 mice of all ages showed a significant improvement in memory (P<0.05) compared to test 1. However, 12-month-old wt and koB2 mice of all ages showed no difference in memory retention. We suggest that, during the aging process, the B1 receptor could be involved in neurodegeneration and memory loss. Nevertheless, the B2 receptor is apparently acting as a neuroprotective factor. Copyright 2009 Elsevier Ltd. All rights reserved.

75 FR 66390 - Notice of Lodging of Settlement Agreement Under the Comprehensive Environmental Response...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-28

... & Luxury Car Clark Street Site in Michigan; 58. The Delta Engine Plant Site in Michigan; 59. The 1831... GMNA Car--Wilmington Site in Delaware; 2. The GMPT--Danville Landfill Site in Illinois; 3. The Former... Car (Fisher Body)--Lansing Site in Michigan; 21. The Midsize & Luxury Car--Willow Run Site in Michigan...

9 CFR 71.6 - Carrier responsible for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or...

Code of Federal Regulations, 2011 CFR

2011-01-01

... disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. 71.6 Section 71.6 Animals... for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. (a) Railroad cars, trucks, boats, aircraft, and other means of conveyance which have been used in the...

9 CFR 71.6 - Carrier responsible for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or...

Code of Federal Regulations, 2012 CFR

2012-01-01

... disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. 71.6 Section 71.6 Animals... for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. (a) Railroad cars, trucks, boats, aircraft, and other means of conveyance which have been used in the...

9 CFR 71.6 - Carrier responsible for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or...

Code of Federal Regulations, 2013 CFR

2013-01-01

... disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. 71.6 Section 71.6 Animals... for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. (a) Railroad cars, trucks, boats, aircraft, and other means of conveyance which have been used in the...

9 CFR 71.6 - Carrier responsible for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or...

Code of Federal Regulations, 2010 CFR

2010-01-01

... disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. 71.6 Section 71.6 Animals... for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. (a) Railroad cars, trucks, boats, aircraft, and other means of conveyance which have been used in the...

9 CFR 71.6 - Carrier responsible for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or...

Code of Federal Regulations, 2014 CFR

2014-01-01

... disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. 71.6 Section 71.6 Animals... for cleaning and disinfecting of railroad cars, trucks, boats, aircraft or other means of conveyance. (a) Railroad cars, trucks, boats, aircraft, and other means of conveyance which have been used in the...

Analysis of Vehicle-Following Heterogeneity Using Self-Organizing Feature Maps

PubMed Central

Cheu, Ruey Long; Guo, Xiucheng; Romo, Alicia

2014-01-01

A self-organizing feature map (SOM) was used to represent vehicle-following and to analyze the heterogeneities in vehicle-following behavior. The SOM was constructed in such a way that the prototype vectors represented vehicle-following stimuli (the follower's velocity, relative velocity, and gap) while the output signals represented the response (the follower's acceleration). Vehicle trajectories collected at a northbound segment of Interstate 80 Freeway at Emeryville, CA, were used to train the SOM. The trajectory information of two selected pairs of passenger cars was then fed into the trained SOM to identify similar stimuli experienced by the followers. The observed responses, when the stimuli were classified by the SOM into the same category, were compared to discover the interdriver heterogeneity. The acceleration profile of another passenger car was analyzed in the same fashion to observe the interdriver heterogeneity. The distribution of responses derived from data sets of car-following-car and car-following-truck, respectively, was compared to ascertain inter-vehicle-type heterogeneity. PMID:25538767

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

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.

Numerical Simulation of Unsteady Turbulent Flow Induced by Two-Dimensional Elevator Car and Counter Weight System

NASA Astrophysics Data System (ADS)

Shi, Li-qun; Liu, Ying-zheng; Jin, Si-yu; Cao, Zhao-min

2007-12-01

A two-dimensional model of unsteady turbulent flow induced by high-speed elevator system was established in the present study. The research was focused on the instantaneous variation of the aerodynamic force on the car structure during traversing motion of the counter weight in the hoistway. A dynamic meshing method was employed to treat the multi-body motion system to avoid poor distortion of meshes. A comprehensive understanding of this significant aspect was obtained by varying the horizontal gap (Δ = 0.1m, 0.2m, and 0.3m) between the elevator car and the counter weight, and the moving speed ( U 0 = 2m/s, 6m/s, and 10m/s) of the elevator system. A pulsed intensification of the aerodynamic force on the elevator car and subsequent appearance of large valley with negative aerodynamic force were clearly observed in the numerical results. In parameters studied (Δ = 0.1m, U 0 = 2m/s, 6m/s, 10m/s), the peaked horizontal and vertical forces are respectively 7-11 and 4.3-5.65 times of that when the counter weight is far from the car. These results demonstrated the prominent influence of the traversing counter weight on aerodynamic force on the elevator car, which is of great significance to designers of high-speed elevator system.

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.

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.

Order Up

ERIC Educational Resources Information Center

Gibeault, Michael

2005-01-01

Change orders. The words can turn the stomachs of administrators. Horror stories about change orders create fear and distrust among school officials, designers and builders. Can change orders be avoided? If car manufacturers can produce millions of intricately designed vehicles, why can't the same quality control be achieved on a construction…

78 FR 59866 - New Car Assessment Program (NCAP)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-30

... because ESC is now required for all light vehicles. For many years, NCAP has provided comparative... site, www.safercar.gov . NCAP provides comparative information on the safety performance and features... Features on www.safercar.gov are designed to assist drivers in avoiding backover crashes. After considering...

Particle Pollution

MedlinePlus

... of running) so you don't breathe as hard. Avoid busy roads and highways where PM is usually worse because of emissions from cars and trucks. For more tools to help you learn about air quality, visit Tracking Air Quality . Top of Page File Formats Help: How do I view different file formats ( ...

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy

PubMed Central

Maus, Marcela V.; June, Carl H.

2016-01-01

Chimeric antigen receptors (CARs) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprogram a patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of ≈90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into mechanisms regulating the persistence of CAR T cells. Additionally, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy. PMID:27084741

First stereo video dataset with ground truth for remote car pose estimation using satellite markers

NASA Astrophysics Data System (ADS)

Gil, Gustavo; Savino, Giovanni; Pierini, Marco

2018-04-01

Leading causes of PTW (Powered Two-Wheeler) crashes and near misses in urban areas are on the part of a failure or delayed prediction of the changing trajectories of other vehicles. Regrettably, misperception from both car drivers and motorcycle riders results in fatal or serious consequences for riders. Intelligent vehicles could provide early warning about possible collisions, helping to avoid the crash. There is evidence that stereo cameras can be used for estimating the heading angle of other vehicles, which is key to anticipate their imminent location, but there is limited heading ground truth data available in the public domain. Consequently, we employed a marker-based technique for creating ground truth of car pose and create a dataset∗ for computer vision benchmarking purposes. This dataset of a moving vehicle collected from a static mounted stereo camera is a simplification of a complex and dynamic reality, which serves as a test bed for car pose estimation algorithms. The dataset contains the accurate pose of the moving obstacle, and realistic imagery including texture-less and non-lambertian surfaces (e.g. reflectance and transparency).

An extended car-following model to describe connected traffic dynamics under cyberattacks

NASA Astrophysics Data System (ADS)

Wang, Pengcheng; Yu, Guizhen; Wu, Xinkai; Qin, Hongmao; Wang, Yunpeng

2018-04-01

In this paper, the impacts of the potential cyberattacks on vehicles are modeled through an extended car-following model. To better understand the mechanism of traffic disturbance under cyberattacks, the linear and nonlinear stability analysis are conducted respectively. Particularly, linear stability analysis is performed to obtain different neutral stability conditions with various parameters; and nonlinear stability analysis is carried out by using reductive perturbation method to derive the soliton solution of the modified Korteweg de Vries equation (mKdV) near the critical point, which is used to draw coexisting stability lines. Furthermore, by applying linear and nonlinear stability analysis, traffic flow state can be divided into three states, i.e., stable, metastable and unstable states which are useful to describe shockwave dynamics and driving behaviors under cyberattacks. The theoretical results show that the proposed car-following model is capable of successfully describing the car-following behavior of connected vehicles with cyberattacks. Finally, numerical simulation using real values has confirmed the validity of theoretical analysis. The results further demonstrate our model can be used to help avoid collisions and relieve traffic congestion with cybersecurity threats.

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.

An extended car-following model at un-signalized intersections under V2V communication environment

PubMed Central

Wang, Tao; Li, Peng

2018-01-01

An extended car-following model is proposed in this paper to analyze the impacts of V2V (vehicle to vehicle) communication on the micro driving behavior at the un-signalized intersection. A four-leg un-signalized intersection with twelve streams (left-turn, through movement, and right turn from each leg) is used. The effect of the guidance strategy on the reduction of the rate of stops and total delay is explored by comparing the proposed model and the traditional FVD car-following model. The numerical results illustrate that potential conflicts between vehicles can be predicted and some stops can be avoided by decelerating in advance. The driving comfort and traffic efficiency can be improved accordingly. More benefits could be obtained under the long communication range, low to medium traffic density, and simple traffic pattern conditions. PMID:29425243

Isolation and functional characterization of a methyl jasmonate-responsive 3-carene synthase from Lavandula x intermedia.

PubMed

Adal, Ayelign M; Sarker, Lukman S; Lemke, Ashley D; Mahmoud, Soheil S

2017-04-01

A methyl jasmonate responsive 3-carene synthase (Li3CARS) gene was isolated from Lavandula x intermedia and functionally characterized in vitro. Lavenders produce essential oils consisting mainly of monoterpenes, including the potent antimicrobial and insecticidal monoterpene 3-carene. In this study we isolated and functionally characterized a leaf-specific, methyl jasmonate (MeJA)-responsive monoterpene synthase (Li3CARS) from Lavandula x intermedia. The ORF excluding transit peptides encoded a 64.9 kDa protein that was expressed in E. coli, and purified with Ni-NTA agarose affinity chromatography. The recombinant Li3CARS converted GPP into 3-carene as the major product, with K m and k cat of 3.69 ± 1.17 µM and 2.01 s -1 respectively. Li3CARS also accepted NPP as a substrate to produce multiple products including a small amount of 3-carene. The catalytic efficiency of Li3CARS to produce 3-carene was over ten fold higher for GPP (k cat /K m = 0.56 µM -1 s -1 ) than NPP (k cat /K m = 0.044 µM -1 s -1 ). Production of distinct end product profiles from different substrates (GPP versus NPP) by Li3CARS indicates that monoterpene metabolism may be controlled in part through substrate availability. Li3CARS transcripts were found to be highly abundant in leaves (16-fold) as compared to flower tissues. The transcriptional activity of Li3CARS correlated with 3-carene production, and was up-regulated (1.18- to 3.8-fold) with MeJA 8-72 h post-treatment. The results suggest that Li3CARS may have a defensive role in Lavandula.

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.

Dynamic Vibrotactile Signals for Forward Collision Avoidance Warning Systems

PubMed Central

Meng, Fanxing; Gray, Rob; Ho, Cristy; Ahtamad, Mujthaba

2015-01-01

Objective: Four experiments were conducted in order to assess the effectiveness of dynamic vibrotactile collision-warning signals in potentially enhancing safe driving. Background: Auditory neuroscience research has demonstrated that auditory signals that move toward a person are more salient than those that move away. If this looming effect were found to extend to the tactile modality, then it could be utilized in the context of in-car warning signal design. Method: The effectiveness of various vibrotactile warning signals was assessed using a simulated car-following task. The vibrotactile warning signals consisted of dynamic toward-/away-from-torso cues (Experiment 1), dynamic versus static vibrotactile cues (Experiment 2), looming-intensity- and constant-intensity-toward-torso cues (Experiment 3), and static cues presented on the hands or on the waist, having either a low or high vibration intensity (Experiment 4). Results: Braking reaction times (BRTs) were significantly faster for toward-torso as compared to away-from-torso cues (Experiments 1 and 2) and static cues (Experiment 2). This difference could not have been attributed to differential responses to signals delivered to different body parts (i.e., the waist vs. hands; Experiment 4). Embedding a looming-intensity signal into the toward-torso signal did not result in any additional BRT benefits (Experiment 3). Conclusion: Dynamic vibrotactile cues that feel as though they are approaching the torso can be used to communicate information concerning external events, resulting in a significantly faster reaction time to potential collisions. Application: Dynamic vibrotactile warning signals that move toward the body offer great potential for the design of future in-car collision-warning system. PMID:25850161

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

Staying Motivated and Avoiding Burnout

ERIC Educational Resources Information Center

Malikow, Max

2007-01-01

Personal motivation is critical to effective teaching. This article explores the complexity of motivation and its application to teaching. It also discusses the nine principles for sustaining motivation and preempting burnout: (1) Respond to the symptoms; (2) Know the critical distinction; (3) Do not treat your car better than yourself; (4) Have a…

A Criminal Law Approach to Terrorism in Brazil

DTIC Science & Technology

2014-12-01

Israeli Embassy, killing 29 and hurting over 250; and the second, in 1994, when a suicide terrorist in a car bomb drove into AMIA (Argentina-Israel...requisite. The main concern regarding the law is the possibility of adversely affecting civil rights. In the model, we can avoid this temptation and

Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo

NASA Technical Reports Server (NTRS)

Olszak, I. T.; Poznansky, M. C.; Evans, R. H.; Olson, D.; Kos, C.; Pollak, M. R.; Brown, E. M.; Scadden, D. T.; O'Malley, B. W. (Principal Investigator)

2000-01-01

Recruitment of macrophages to sites of cell death is critical for induction of an immunologic response. Calcium concentrations in extracellular fluids vary markedly, and are particularly high at sites of injury or infection. We hypothesized that extracellular calcium participates in modulating the immune response, perhaps acting via the seven-transmembrane calcium-sensing receptor (CaR) on mature monocytes/macrophages. We observed a dose-dependent increase in monocyte chemotaxis in response to extracellular calcium or the selective allosteric CaR activator NPS R-467. In contrast, monocytes derived from mice deficient in CaR lacked the normal chemotactic response to a calcium gradient. Notably, CaR activation of monocytes bearing the receptor synergistically augmented the transmigration response of monocytes to the chemokine MCP-1 in association with increased cell-surface expression of its cognate receptor, CCR2. Conversely, stimulation of monocytes with MCP-1 or SDF-1alpha reciprocally increased CaR expression, suggesting a dual-enhancing interaction of Ca(2+) with chemokines in recruiting inflammatory cells. Subcutaneous administration in mice of Ca(2+), MCP-1, or (more potently) the combination of Ca(2+) and MCP-1, elicited an inflammatory infiltrate consisting of monocytes/macrophages. Thus extracellular calcium functions as an ionic chemokinetic agent capable of modulating the innate immune response in vivo and in vitro by direct and indirect actions on monocytic cells. Calcium deposition may be both consequence and cause of chronic inflammatory changes at sites of injury, infection, and atherosclerosis.

Carbonic anhydrase enzymes regulate mast cell–mediated inflammation

PubMed Central

Soteropoulos, Patricia

2016-01-01

Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine–mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2–associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy–like disease. Further, we used CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell–mediated inflammation. PMID:27526715

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

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

Development of turbocharger for improving passenger car acceleration

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

Watanabe, Tsuyoshi; Koike, Takaaki; Furukawa, Hiromu

1996-09-01

Recently, passenger cars require better acceleration from low engine speed including starting-up in order to decrease the amount of particulate matter (PM) of diesel engines or to improve the driver`s feeling. However, turbocharged cars generally have worse response than the non turbo cars because it takes a few seconds to get the turbocharger rotate up to high speed, usually called Turbo-lag. In order to solve this, various technologies have been developed for a turbocharger itself as well as for charging system such as the sequential system. Here in this paper, the authors focus on the development of the following turbochargermore » technology to reduce Turbo-lag and to achieve better transient response.« less

49 CFR 213.333 - Automated vehicle inspection systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... hours of the inspection, output reports that— (1) Provide a continuous plot, on a constant-distance axis... instrumented car having dynamic response characteristics that are representative of other equipment assigned to... instrumented car having dynamic response characteristics that are representative of other equipment assigned to...

49 CFR 213.333 - Automated vehicle inspection systems.

Code of Federal Regulations, 2010 CFR

2010-10-01

... hours of the inspection, output reports that— (1) Provide a continuous plot, on a constant-distance axis... instrumented car having dynamic response characteristics that are representative of other equipment assigned to... instrumented car having dynamic response characteristics that are representative of other equipment assigned to...

77 FR 27384 - Demurrage Liability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-10

... establishing that a person receiving rail cars from a rail carrier for loading or unloading who detains the cars beyond the ``free time'' provided in the carrier's governing tariff will generally be responsible for paying demurrage, if that person has actual notice, prior to rail car placement, of the demurrage...

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...

Identification and characterization of a LEA family gene CarLEA4 from chickpea (Cicer arietinum L.).

PubMed

Gu, Hanyan; Jia, Yuying; Wang, Xiansheng; Chen, Quanjia; Shi, Shubing; Ma, Lin; Zhang, Jusong; Zhang, Hua; Ma, Hao

2012-04-01

Late-embryogenesis abundant (LEA) proteins have been reported to be closely correlated with the acquisition of desiccation tolerance during seed development and response of plant to drought, salinity, and freezing, etc. In this study, a LEA gene, CarLEA4 (GenBank accession no. GU247511), was isolated from chickpea based on a cDNA library constructed with chickpea seedling leaves treated by polyethylene glycol (PEG). CarLEA4 contained two exons and one intron within genomic DNA sequence and encoded a putative polypeptide of 152 amino acids. CarLEA4 had a conserved pfam domain, and showed high similarity to the group 4 LEA proteins in secondary structure. It was localized in the nucleus. The transcripts of CarLEA4 were detected in many chickpea organs including seedling leaves, stems, roots, flowers, young pods, and young seeds. CarLEA4 was inhibited by leaf age and showed expression changes in expression during seed development, pod development and germination. Furthermore, the expression of CarLEA4 was strongly induced by drought, salt, heat, cold, ABA, IAA, GA(3) and MeJA. Our results suggest that CarLEA4 encodes a protein of LEA group 4 and may be involved in various plant developmental processes and abiotic stress responses.

TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

PubMed Central

Morton, Penny E.; Hicks, Alexander; Ortiz-Zapater, Elena; Raghavan, Swetavalli; Pike, Rosemary; Noble, Alistair; Woodfin, Abigail; Jenkins, Gisli; Rayner, Emma; Santis, George; Parsons, Maddy

2016-01-01

Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings. PMID:27193388

Responsibility Study: Main Illicit Psychoactive Substances Among Car Drivers Involved in Fatal Road Crashes

PubMed Central

Gadegbeku, Blandine; Amoros, Emmanuelle; Laumon, Bernard

2011-01-01

In 1999, in France, before considering modifications in drug legislation, the government requested a study of the effect of illicit drugs on the risk of road crashes. It implemented a systematic screening of illicit drugs for all drivers involved in fatal crashes between October 2001 and September 2003. Within the European DRUID project, the study was restricted to car drivers. The project reported here is a responsibility analysis and, as such, it belongs to the framework of case-control studies; the outcome of interest is “being responsible for a fatal crash”. It was assessed with a method adapted from Robertson and Drummer. Cases are the 4,946 car drivers who are responsible for the crash; controls are the 1,986 car drivers selected from the non-responsible car drivers, in a way that makes the control group similar to the general driving population. The effect of cannabis on fatal crash responsibility is significant after adjustment for age, sex and alcohol: adjusted odds ratio is 1.89 [1.43–2.51]. The dose-response effect is significant (p=0.0001). For alcohol (≥0.1 g/l), the adjusted odds ratio for responsibility is 8.39 [6.95–10.11]. No interaction was found between alcohol and cannabis. For amphetamine, cocaine and opiates, adjusted odds ratios were not significantly different from 1. However the statistical power is low. The study finds similar odds ratios for alcohol as previously published. For cannabis, the significant odds ratio together with the significant dose-response effect indicates a causal relationship between cannabis and road crashes. A multiplicative effect between cannabis and alcohol was noted. PMID:22105404

The Peptide Near the C Terminus Regulates Receptor CAR Nuclear Translocation Induced by Xenochemicals in Mouse Liver

PubMed Central

Zelko, Igor; Sueyoshi, Tatsuya; Kawamoto, Takeshi; Moore, Rick; Negishi, Masahiko

2001-01-01

In response to phenobarbital (PB) and other PB-type inducers, the nuclear receptor CAR translocates to the mouse liver nucleus (T. Kawamoto et al., Mol. Cell. Biol. 19:6318–6322, 1999). To define the translocation mechanism, fluorescent protein-tagged human CAR (hCAR) was expressed in the mouse livers using the in situ DNA injection and gene delivery systems. As in the wild-type hCAR, the truncated receptor lacking the C-terminal 10 residues (i.e., AF2 domain) translocated to the nucleus, indicating that the PB-inducible translocation is AF2 independent. Deletion of the 30 C-terminal residues abolished the receptor translocation, and subsequent site-directed mutagenesis delineated the PB-inducible translocation activity of the receptor to the peptide L313GLL316AEL319. Ala mutations of Leu313, Leu316, or Leu319 abrogated the translocation of CAR in the livers, while those of Leu312 or Leu315 did not affect the nuclear translocation. The leucine-rich peptide dictates the nuclear translocation of hCAR in response to various PB-type inducers and appears to be conserved in the mouse and rat receptors. PMID:11283262

It’s Not What You Think, It’s How You Relate to It: Dispositional Mindfulness Moderates the Relationship Between Psychological Distress and the Cortisol Awakening Response

PubMed Central

Daubenmier, Jennifer; Hayden, Dara; Chang, Vickie; Epel, Elissa

2014-01-01

Objective The cortisol awakening response (CAR) is a natural metabolic response that can be potentiated by negative cognitive-emotional processes, including stress appraisals, negative affect, and rumination. Psychological distress and the CAR are not consistently related, however. Individual differences in aspects of dispositional mindfulness which reflect how people relate to negative thoughts and emotions may help explain such inconsistencies. We tested whether the tendency to 1) label and describe inner experiences and 2) accept negative thoughts and feelings without judgment moderated the association between psychological distress and the CAR. Methods Self-reported dispositional mindfulness, perceived stress, anxiety, negative affect, and rumination, and the CAR were assessed among overweight/obese women. Regression analyses were conducted to examine whether dispositional mindfulness moderated the relationship between indicators of psychological distress and the CAR. Results While psychological distress was consistently positively related to the CAR, these associations were qualified by significant interactions with both components of dispositional mindfulness. Psychological distress was associated with the CAR at lower levels of dispositional mindfulness but not at higher levels. Conclusion These findings support the idea that the tendency to describe and accept distressing experiences may buffer the impact of psychological distress on physiological arousal. These metacognitive processes may be important moderators in unraveling the complex relationship between psychological distress and physiological stress reactivity. Further research is recommended to replicate this approach in other populations. PMID:24971591

The Confluence of Adverse Early Experience and Puberty on the Cortisol Awakening Response

ERIC Educational Resources Information Center

Quevedo, Karina; Johnson, Anna E.; Loman, Michelle L.; LaFavor, Theresa L.; Gunnar, Megan

2012-01-01

Associations between early deprivation/neglect in the form of institutional care with the cortisol awakening response (CAR) were examined as a function of pubertal status among 12- and 13-year-old postinstitutionalized youth. CARs indexed hypothalamic-pituitary-adrenocortical reactivity. Postinstitutionalized youth were compared to youth adopted…

Cortisol awakening response and emotion at extreme altitudes on Mount Kangchenjunga.

PubMed

Aguilar, Raúl; Martínez, Carlos; Alvero-Cruz, José R

2017-12-24

The cortisol awakening response (CAR) was examined over a 45days stay at extreme altitudes (above of about 5500m) on Mount Kangchenjunga. The CAR refers to a peak cortisol response during the waking period that is superimposed to the diurnal rhythmicity in cortisol secretion, whose function has been proposed to be the anticipation of demands of the upcoming day (the CAR anticipation hypothesis). According to this hypothesis, we distinguished between resting days on which the expedition team engaged in routine activities in the base camp, and ascent days on which it planned to climb up a very demanding track. We were also interested in examining the association of testosterone with emotional anticipation, given the role of this steroid hormone in reward-related processes in challenge situations. Results showed that the climber group had a bigger CAR on ascent days, relative to the Sherpa group at the same altitude and the non-climber group at sea level. Several methodological issues, however, made it difficult to interpret these group differences in terms of the CAR anticipation hypothesis (e.g. a seemingly influential covariate was awakening time). Although based on tentative results, correlational and regression analyses controlling for awakening time coherently showed that the CAR was associated with anticipation of a hard day and feelings of fear, and testosterone was associated with feelings of energy and positive affect. Whether or not the anticipation of a hard day played a key role in regulation of the CAR, the observation of an intact CAR in the climber group under hypobaric hypoxia conditions would require in-depth reflection from the perspective of human adaptive evolution. Copyright © 2017 Elsevier B.V. All rights reserved.

Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence

PubMed Central

Adam, Emma K.; Doane, Leah D.; Zinbarg, Richard E.; Mineka, Susan; Craske, Michelle G.; Griffith, James W.

2010-01-01

Levels of the stress-sensitive hormone cortisol increase dramatically in the first 30-40 minutes after waking, an effect known as the cortisol awakening response (CAR). There is considerable cross-sectional evidence that psychosocial stress is associated with an increased CAR, and the CAR has been found to be altered in the presence of stress-related diseases, including Major Depressive Disorder (MDD). To date, no prospective longitudinal studies have examined whether individual differences in the CAR serve as a premorbid risk factor for MDD. In a sample of 230 late adolescents, clinical diagnoses of MDD were predicted from the CAR as well as other indicators of basal cortisol functioning gathered one year earlier, including: waking cortisol levels, bedtime cortisol levels, the size of the CAR, average cortisol, and the slope of the diurnal cortisol rhythm across the waking day. Age and gender, health and health behaviors, baseline neuroticism, exposure to stressful life events and past episodes of mood and anxiety disorders were included as covariates, to help ensure effects are attributable to the CAR rather than related variables. A higher baseline CAR was associated with a significantly increased risk of developing MDD by follow-up, even when excluding individuals with baseline MDD. No other baseline cortisol measures were significant prospective predictors of MDD. In summary, the CAR is a significant prospective risk factor for the development of MDD in young adults, providing some support for the possibility that a heightened CAR may play a role in the etiology of Major Depressive Disorder. PMID:20079576

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

Argall, Brenna; Cheleshkin, Eugene; Greenberg, J.M.

Traffic flow on a unidirectional roadway in the presence of traffic lights is modeled. Individual car responses to green, yellow, and red lights are postulated and these result in rules governing the acceleration and deceleration of individual cars. The essence of the model is that only specific cars are directly affected by the lights. The other cars behave according to simple follow-the-leader rules which limit their speed by the spacing between it and the car directly ahead. The model has a number of desirable properties; namely cars do not run red lights, cars do not smash into one another, andmore » cars exhibit no velocity reversals. In a situation with multiple lights operating in-phase we get, after an initial startup period, a constant number of cars through each light during any green-yellow period. Moreover, this flux is less by one or two cars per period than the flux obtained in discretized versions of the idealized Lighthill, Whitham, Richards model which allows for infinite accelerations.« less

The Flavoproteins CryD and VvdA Cooperate with the White Collar Protein WcoA in the Control of Photocarotenogenesis in Fusarium fujikuroi

PubMed Central

Castrillo, Marta; Avalos, Javier

2015-01-01

Light stimulates carotenoid biosynthesis in the ascomycete fungus Fusarium fujikuroi through transcriptional activation of the structural genes of the pathway carRA, carB, and cart, but the molecular basis of this photoresponse is unknown. The F. fujikuroi genome contains genes for different predicted photoreceptors, including the WC protein WcoA, the DASH cryptochrome CryD and the Vivid-like flavoprotein VvdA. We formerly found that null mutants of wcoA, cryD or vvdA exhibit carotenoid photoinduction under continuous illumination. Here we show that the wild type exhibits a biphasic response in light induction kinetics experiments, with a rapid increase in carotenoid content in the first hours, a transient arrest and a subsequent slower increase. The mutants of the three photoreceptors show different kinetic responses: the wcoA mutants are defective in the rapid response, the cryD mutants are affected in the slower response, while the fast and slow responses were respectively enhanced and attenuated in the vvdA mutants. Transcriptional analyses of the car genes revealed a strong reduction of dark and light-induced transcript levels in the wcoA mutants, while minor or no reductions were found in the cryD mutants. Formerly, we found no change on carRA and carB photoinduction in vvdA mutants. Taken together, our data suggest a cooperative participation of WcoA and CryD in early and late stages of photoinduction of carotenoid biosynthesis in F. fujikuroi, and a possible modulation of WcoA activity by VvdA. An unexpected transcriptional induction by red light of vvdA, cryD and carRA genes suggest the participation of an additional red light-absorbing photoreceptor. PMID:25774802

Pro-environmental beach driving is uncommon and ineffective in reducing disturbance to beach-dwelling birds.

PubMed

Weston, Michael A; Schlacher, Thomas A; Lynn, David

2014-05-01

Vehicles on beaches cause numerous deleterious effects to coastal wildlife. These impacts may, hypothetically, be lessened if drivers act to reduce disturbance. Since it is unknown to what extent such behavior occurs, and whether it can reduce disturbance, we quantified the behavior of drivers who encountered birds on open-coast, sandy beaches in eastern Australia and the consequent bird responses. Drivers of commercial tourist buses never slowed or altered course ("evaded birds") to avoid disturbing birds; conversely, 34 % of drivers of private cars did evade birds. Drivers of vehicles with fishing rod holders tended (P = 0.09) to evade birds more frequently than non-fishing vehicles. Evasion, when it occurred, was modest, and did not significantly decrease the intensity of bird response or the probability of escapes on the wing. Voluntary behavioral adjustments to alleviate impacts on wildlife may be unworkable, suggesting that other solutions (e.g., beach closures) might be the only effective and feasible way to reduce disturbance to birds on ocean beaches.

Evaluation of an autonomous braking system in real-world PTW crashes.

PubMed

Savino, Giovanni; Pierini, Marco; Rizzi, Matteo; Frampton, Richard

2013-01-01

Powered 2-wheelers (PTWs) are becoming increasingly popular in Europe. They have the ability to get around traffic queues, thus lowering fuel consumption and increasing mobility. The risk of rider injury in a traffic crash is however much higher than that associated with car users. The European project, Powered Two Wheeler Integrated Safety (PISa), identified an autonomous braking system (AB) as a priority to reduce the injury consequences of a PTW crash. The aim of this study was to assess the potential effectiveness of the AB system developed in PISa, taking into account the specific system characteristics that emerged during the design, development and testing phases. Fifty-eight PTW cases representing European crash configurations were examined, in which 43 percent of riders sustained a Maximum Abbreviated Injury Scale (MAIS) 2+ injury. Two of the most common crash types were a PTW impacting a stationary object (car following scenario) 16% and an object pulling across the PTW path (crossing scenario) 54%. An expert team analysed the in-depth material of the sample crashes and determined a posteriori to what extent the AB would have affected the crash. For those cases where the AB was evaluated as applicable, a further quantitative evaluation of the benefits was conducted by considering a set of different possible rider reactions in addition to that exhibited in the actual crash. In 67 percent of cases, the application of AB could have mitigated the crash outcome. Analysis of those real crash cases showed the potential for an expert rider to avoid the collision. An early reaction of the rider, associated with a correct application of the brakes would have avoided 18 of the 37 car following/crossing scenarios. Conversely, according to the analysis, an expert rider would not have been able to avoid 19 of the 37 cases. In 14 of those 19 cases, the AB would have contributed to mitigating the crash outcome. This study demonstrated significant potential for application of the autonomous braking system in car following and crossing scenarios. In addition, the theoretical benefit curves for the AB globally, were able to provide good quantitative indications of its benefits in real cases where the AB was considered applicable. Further analysis with larger databases is suggested in order to confirm the magnitude of benefits in the PTW crash population.

A single gene for lycopene cyclase, phytoene synthase, and regulation of carotene biosynthesis in Phycomyces

PubMed Central

Arrach, Nabil; Fernández-Martín, Rafael; Cerdá-Olmedo, Enrique; Avalos, Javier

2001-01-01

Previous complementation and mapping of mutations that change the usual yellow color of the Zygomycete Phycomyces blakesleeanus to white or red led to the definition of two structural genes for carotene biosynthesis. We have cloned one of these genes, carRA, by taking advantage of its close linkage to the other, carB, responsible for phytoene dehydrogenase. The sequences of the wild type and six mutants have been established, compared with sequences in other organisms, and correlated with the mutant phenotypes. The carRA and carB coding sequences are separated by 1,381 untranslated nucleotides and are divergently transcribed. Gene carRA contains separate domains for two enzymes, lycopene cyclase and phytoene synthase, and regulates the overall activity of the pathway and its response to physical and chemical stimuli from the environment. The lycopene cyclase domain of carRA derived from a duplication of a gene from a common ancestor of fungi and Brevibacterium linens; the phytoene synthase domain is similar to the phytoene and squalene synthases of many organisms; but the regulatory functions appear to be specific to Phycomyces. PMID:11172012

Influence of long-wavelength track irregularities on the motion of a high-speed train

NASA Astrophysics Data System (ADS)

Hung, C. F.; Hsu, W. L.

2018-01-01

Vertical track irregularities over viaducts in high-speed rail systems could be possibly caused by concrete creep if pre-stressed concrete bridges are used. For bridge spans that are almost uniformly distributed, track irregularity exhibits a near-regular wave profile that excites car bodies as a high-speed train moves over the bridge system. A long-wavelength irregularity induces low-frequency excitation that may be close to the natural frequencies of the train suspension system, thereby causing significant vibration of the car body. This paper investigates the relationship between the levels of car vibration, bridge vibration, track irregularity, and the train speed. First, this study investigates the vibration levels of a high-speed train and bridge system using 3D finite-element (FE) transient dynamic analysis, before and after adjustment of vertical track irregularities by means of installing shimming plates under rail pads. The analysis models are validated by in situ measurements and on-board measurement. Parametric studies of car body vibration and bridge vibration under three different levels of track irregularity at five train speeds and over two bridge span lengths are conducted using the FE model. Finally, a discontinuous shimming pattern is proposed to avoid vehicle suspension resonance.

Non-CAR resists and advanced materials for Massively Parallel E-Beam Direct Write process integration

NASA Astrophysics Data System (ADS)

Pourteau, Marie-Line; Servin, Isabelle; Lepinay, Kévin; Essomba, Cyrille; Dal'Zotto, Bernard; Pradelles, Jonathan; Lattard, Ludovic; Brandt, Pieter; Wieland, Marco

2016-03-01

The emerging Massively Parallel-Electron Beam Direct Write (MP-EBDW) is an attractive high resolution high throughput lithography technology. As previously shown, Chemically Amplified Resists (CARs) meet process/integration specifications in terms of dose-to-size, resolution, contrast, and energy latitude. However, they are still limited by their line width roughness. To overcome this issue, we tested an alternative advanced non-CAR and showed it brings a substantial gain in sensitivity compared to CAR. We also implemented and assessed in-line post-lithographic treatments for roughness mitigation. For outgassing-reduction purpose, a top-coat layer is added to the total process stack. A new generation top-coat was tested and showed improved printing performances compared to the previous product, especially avoiding dark erosion: SEM cross-section showed a straight pattern profile. A spin-coatable charge dissipation layer based on conductive polyaniline has also been tested for conductivity and lithographic performances, and compatibility experiments revealed that the underlying resist type has to be carefully chosen when using this product. Finally, the Process Of Reference (POR) trilayer stack defined for 5 kV multi-e-beam lithography was successfully etched with well opened and straight patterns, and no lithography-etch bias.

Cortisol Awakening Response and Internalizing Symptoms across Childhood: Exploring the Role of Age and Externalizing Symptoms

ERIC Educational Resources Information Center

McGinnis, Ellen W.; Lopez-Duran, Nestor; Martinez-Torteya, Cecilia; Abelson, James L.; Muzik, Maria

2016-01-01

Efforts to identify biological correlates of internalizing symptoms in childhood have involved examinations of HPA-axis functioning, namely Cortisol Awakening Response (CAR). However, research has not assessed the relationship between CAR and internalizing problems among children younger than 8 years. Findings with older samples have been somewhat…

The Cortisol Awakening Response Mediates the Relationship Between Acculturative Stress and Self-Reported Health in Mexican Americans.

PubMed

Garcia, Antonio F; Wilborn, Kristin; Mangold, Deborah L

2017-12-01

The assessment of acculturative stress as synonymous with acculturation level overlooks the dynamic, interactive, and developmental nature of the acculturation process. An individual's unique perception and response to a range of stressors at each stage of the dynamic process of acculturation may be associated with stress-induced alterations in important biological response systems that mediate health outcomes. Evidence suggests the cortisol awakening response (CAR) is a promising pre-clinical biomarker of stress exposure that may link acculturative stress to self-reported health in Mexican Americans. The aim of the current study was to examine whether alterations in the CAR mediate the relationship between acculturative stress and self-reported health in Mexican Americans. Salivary cortisol samples were collected at awakening, 30, 45, and 60 min thereafter, on two consecutive weekdays from a sample of adult Mexican Americans. Acculturative stress and self-reported health were assessed. Data were aggregated and analyzed (n = 89) using a mixed effects regression model and path analysis. Poorer self-reported health was associated with attenuated CAR profiles (primarily due to a diminished post-awakening rise in cortisol) predicted by both moderate and high levels of exposure to acculturative stress. Stress-induced alterations in the CAR mediated the relationship between exposure to acculturative stressors and self-reported health. Findings demonstrate that different levels of acculturative stress are associated with distinct CAR profiles and suggest the CAR is one possible biological pathway through which exposure to culturally unique stressors may be linked to health disparities.

Chemical Computer Man: Chemical Agent Response Simulation (CARS). Technical report, January 1983-September 1985

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

Davis, E.G.; Mioduszewski, R.J.

The Chemical Computer Man: Chemical Agent Response Simulation (CARS) is a computer model and simulation program for estimating the dynamic changes in human physiological dysfunction resulting from exposures to chemical-threat nerve agents. The newly developed CARS methodology simulates agent exposure effects on the following five indices of human physiological function: mental, vision, cardio-respiratory, visceral, and limbs. Mathematical models and the application of basic pharmacokinetic principles were incorporated into the simulation so that for each chemical exposure, the relationship between exposure dosage, absorbed dosage (agent blood plasma concentration), and level of physiological response are computed as a function of time. CARS,more » as a simulation tool, is designed for the users with little or no computer-related experience. The model combines maximum flexibility with a comprehensive user-friendly interactive menu-driven system. Users define an exposure problem and obtain immediate results displayed in tabular, graphical, and image formats. CARS has broad scientific and engineering applications, not only in technology for the soldier in the area of Chemical Defense, but also in minimizing animal testing in biomedical and toxicological research and the development of a modeling system for human exposure to hazardous-waste chemicals.« less

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

PubMed Central

Smith, Tyrel T.; Moffett, Howell F.; Stephan, Sirkka B.; Opel, Cary F.; Dumigan, Amy G.; Jiang, Xiuyun; Pillarisetty, Venu G.; Pillai, Smitha P. S.; Wittrup, K. Dane; Stephan, Matthias T.

2017-01-01

Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants. PMID:28436934

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors.

PubMed

Smith, Tyrel T; Moffett, Howell F; Stephan, Sirkka B; Opel, Cary F; Dumigan, Amy G; Jiang, Xiuyun; Pillarisetty, Venu G; Pillai, Smitha P S; Wittrup, K Dane; Stephan, Matthias T

2017-06-01

Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants.

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.

The Effect of a Low-Speed Automatic Brake System Estimated From Real Life Data

PubMed Central

Isaksson-Hellman, Irene; Lindman, Magdalena

2012-01-01

A substantial part of all traffic accidents involving passenger cars are rear-end collisions and most of them occur at low speed. Auto Brake is a feature that has been launched in several passenger car models during the last few years. City Safety is a technology designed to help the driver mitigate, and in certain situations avoid, rear-end collisions at low speed by automatically braking the vehicle. Studies have been presented that predict promising benefits from these kinds of systems, but few attempts have been made to show the actual effect of Auto Brake. In this study, the effect of City Safety, a standard feature on the Volvo XC60 model, is calculated based on insurance claims data from cars in real traffic crashes in Sweden. The estimated claim frequency of rear-end frontal collisions measured in claims per 1,000 insured vehicle years was 23% lower for the City Safety equipped XC60 model than for other Volvo models without the system. PMID:23169133

A two-stage path planning approach for multiple car-like robots based on PH curves and a modified harmony search algorithm

NASA Astrophysics Data System (ADS)

Zeng, Wenhui; Yi, Jin; Rao, Xiao; Zheng, Yun

2017-11-01

In this article, collision-avoidance path planning for multiple car-like robots with variable motion is formulated as a two-stage objective optimization problem minimizing both the total length of all paths and the task's completion time. Accordingly, a new approach based on Pythagorean Hodograph (PH) curves and Modified Harmony Search algorithm is proposed to solve the two-stage path-planning problem subject to kinematic constraints such as velocity, acceleration, and minimum turning radius. First, a method of path planning based on PH curves for a single robot is proposed. Second, a mathematical model of the two-stage path-planning problem for multiple car-like robots with variable motion subject to kinematic constraints is constructed that the first-stage minimizes the total length of all paths and the second-stage minimizes the task's completion time. Finally, a modified harmony search algorithm is applied to solve the two-stage optimization problem. A set of experiments demonstrate the effectiveness of the proposed approach.

The effect of a low-speed automatic brake system estimated from real life data.

PubMed

Isaksson-Hellman, Irene; Lindman, Magdalena

2012-01-01

A substantial part of all traffic accidents involving passenger cars are rear-end collisions and most of them occur at low speed. Auto Brake is a feature that has been launched in several passenger car models during the last few years. City Safety is a technology designed to help the driver mitigate, and in certain situations avoid, rear-end collisions at low speed by automatically braking the vehicle.Studies have been presented that predict promising benefits from these kinds of systems, but few attempts have been made to show the actual effect of Auto Brake. In this study, the effect of City Safety, a standard feature on the Volvo XC60 model, is calculated based on insurance claims data from cars in real traffic crashes in Sweden. The estimated claim frequency of rear-end frontal collisions measured in claims per 1,000 insured vehicle years was 23% lower for the City Safety equipped XC60 model than for other Volvo models without the system.

The influence of ambient light on the driver

NASA Astrophysics Data System (ADS)

Klinger, Karsten D.; Lemmer, Uli

2008-04-01

Increasingly, cars are fitted with interior ambient lighting which is switched on while driving. This special kind of interior light emphasizes the interior design of the car, it makes a car look special and gives the buyers a new option to personalize their automobiles. But how does ambient interior light influence the driver? We conducted a series of over 50 tests to study the influence of interior ambient light on contrast perception under different illumination levels, colors and positions of the illuminated areas. Our tests show that in many cases the ambient lighting can improve the visual contrast for seeing objects in the headlamp beam. But the test persons mentioned that the tested brightness looked too bright and that they felt glared. The measured values instead proved that no disability glare exists. Therefore, provided that the drivers can adjust the intensity of the ambient light to avoid glare, the ambient light has no negative effect on the drivers' contrast perception.

Impact analysis of side door of a car and bullet proof vest with material ‘SAM2X5-630’ using finite element analysis

NASA Astrophysics Data System (ADS)

Dhode, Trushant; Patil, Girish; Rajkumar, E.

2017-11-01

The components which are bound to impact are subjected to deformation even though it may be for a small scale. The efforts are always on for finding the best material to take impact that has no failure or moreover, less plastic deformation. A newly found material which is glass matrix steel named as ‘SAM2X5-630’ has astounding high elastic limit of 12.5GPa. Thus it can take powerful impact & regain its original shape avoiding the deformation of component under impact. The paper is focused on performing the Finite element analysis to assess the behaviour of ‘SAM2X5-630’ steel under impact loading of side door of car as well as impact of bullet on bulletproof jacket on which the material is assigned. The displacement or deformation occurred during impact is found to be lesser than known materials like Kevlar in bulletproof vest and Aluminium alloy in car door.

Putting Up a Big Front: Car Design and Size Affect Road-Crossing Behaviour

PubMed Central

Klatt, Wilhelm K.; Chesham, Alvin; Lobmaier, Janek S.

2016-01-01

Previous research suggests that people tend to see faces in car fronts and that they attribute personality characteristics to car faces. In the present study we investigated whether car design influences pedestrian road-crossing behaviour. An immersive virtual reality environment with a zebra crossing scenario was used to determine a) whether the minimum accepted distance for crossing the street is larger for cars with a dominant appearance than for cars with a friendly appearance and b) whether the speed of dominant-looking cars is overestimated as compared to friendly-looking cars. Participants completed both tasks while either standing on the pavement or on the centre island. We found that people started to cross the road later in front of friendly-looking low-power cars compared to dominant-looking high-power cars, but only if the cars were relatively large in size. For small cars we found no effect of power. The speed of smaller cars was estimated to be higher compared to large cars (size-speed bias). Furthermore, there was an effect of starting position: From the centre island, participants entered the road significantly later (i. e. closer to the approaching car) and left the road later than when starting from the pavement. Similarly, the speed of the cars was estimated significantly lower when standing on the centre island compared to the pavement. To our knowledge, this is the first study to show that car fronts elicit responses on a behavioural level. PMID:27434187

Putting Up a Big Front: Car Design and Size Affect Road-Crossing Behaviour.

PubMed

Klatt, Wilhelm K; Chesham, Alvin; Lobmaier, Janek S

2016-01-01

Previous research suggests that people tend to see faces in car fronts and that they attribute personality characteristics to car faces. In the present study we investigated whether car design influences pedestrian road-crossing behaviour. An immersive virtual reality environment with a zebra crossing scenario was used to determine a) whether the minimum accepted distance for crossing the street is larger for cars with a dominant appearance than for cars with a friendly appearance and b) whether the speed of dominant-looking cars is overestimated as compared to friendly-looking cars. Participants completed both tasks while either standing on the pavement or on the centre island. We found that people started to cross the road later in front of friendly-looking low-power cars compared to dominant-looking high-power cars, but only if the cars were relatively large in size. For small cars we found no effect of power. The speed of smaller cars was estimated to be higher compared to large cars (size-speed bias). Furthermore, there was an effect of starting position: From the centre island, participants entered the road significantly later (i. e. closer to the approaching car) and left the road later than when starting from the pavement. Similarly, the speed of the cars was estimated significantly lower when standing on the centre island compared to the pavement. To our knowledge, this is the first study to show that car fronts elicit responses on a behavioural level.

Cars, corporations, and commodities: consequences for the social determinants of health.

PubMed

Woodcock, James; Aldred, Rachel

2008-02-21

Social epidemiologists have drawn attention to health inequalities as avoidable and inequitable, encouraging thinking beyond proximal risk factors to the causes of the causes. However, key debates remain unresolved including the contribution of material and psychosocial pathways to health inequalities. Tools to operationalise social factors have not developed in tandem with conceptual frameworks, and research has often remained focused on the disadvantaged rather than on forces shaping population health across the distribution. Using the example of transport, we argue that closer attention to social processes (capital accumulation and motorisation) and social forms (commodity, corporation, and car) offers a way forward. Corporations tied to the car, primarily oil and vehicle manufacturers, are central to the world economy. Key drivers in establishing this hegemony are the threat of violence from motor vehicles and the creation of distance through the restructuring of place. Transport matters for epidemiology because the growth of mass car ownership is environmentally unsustainable and affects population health through a myriad of pathways. Starting from social forms and processes, rather than their embodiment as individual health outcomes and inequalities, makes visible connections between road traffic injuries, obesity, climate change, underdevelopment of oil producing countries, and the huge opportunity cost of the car economy. Methodological implications include a movement-based understanding of how place affects health and a process-orientated integration of material and psychosocial explanations that, while materially based, contests assumptions of automatic benefits from economic growth. Finally, we identify car and oil corporations as anti-health forces and suggest collaboration with them creates conflicts of interest.

Cars, corporations, and commodities: Consequences for the social determinants of health

PubMed Central

Woodcock, James; Aldred, Rachel

2008-01-01

Social epidemiologists have drawn attention to health inequalities as avoidable and inequitable, encouraging thinking beyond proximal risk factors to the causes of the causes. However, key debates remain unresolved including the contribution of material and psychosocial pathways to health inequalities. Tools to operationalise social factors have not developed in tandem with conceptual frameworks, and research has often remained focused on the disadvantaged rather than on forces shaping population health across the distribution. Using the example of transport, we argue that closer attention to social processes (capital accumulation and motorisation) and social forms (commodity, corporation, and car) offers a way forward. Corporations tied to the car, primarily oil and vehicle manufacturers, are central to the world economy. Key drivers in establishing this hegemony are the threat of violence from motor vehicles and the creation of distance through the restructuring of place. Transport matters for epidemiology because the growth of mass car ownership is environmentally unsustainable and affects population health through a myriad of pathways. Starting from social forms and processes, rather than their embodiment as individual health outcomes and inequalities, makes visible connections between road traffic injuries, obesity, climate change, underdevelopment of oil producing countries, and the huge opportunity cost of the car economy. Methodological implications include a movement-based understanding of how place affects health and a process-orientated integration of material and psychosocial explanations that, while materially based, contests assumptions of automatic benefits from economic growth. Finally, we identify car and oil corporations as anti-health forces and suggest collaboration with them creates conflicts of interest. PMID:18291031

Factors related to the cortisol awakening response of children working on the streets and siblings, before and after 2 years of a psychosocial intervention.

PubMed

Mello, Andrea Feijo; Juruena, Mario Francisco; Maciel, Mariana Rangel; Cavalcante-Nobrega, Luciana Porto; Cividanes, Giuliana Claudia; Fossaluza, Victor; Calsavara, Vinicius; Mello, Marcelo Feijo; Cleare, Anthony James; Mari, Jair de Jesus

2015-02-28

The study objective was to observe the cortisol awakening response (CAR) pattern before and after a psychosocial intervention with children from dysfunctional families who had at least one child working on the streets, and to verify factors related to it. Two hundred and eleven children between 7 and 14 years old were selected and 191 were included, 178 were re-evaluated 2 years after, of whom 113 had cortisol measures completed. Besides cortisol, they were evaluated at baseline and at end point regarding: abuse/neglect, mental health symptoms, exposure to urban violence and family environment. There was no significant difference between the CAR area under the curve (AUC) before and after the intervention. Two regression analysis models were built to evaluate factors related to the CAR before and after intervention. Before the intervention, working on the streets (vs. not) was related to a greater cortisol increase after awakening, at follow-up, having suffered physical punishment (vs. not) was related to a flattened cortisol response. The intervention was not associated with changes in the magnitude of the CAR AUC, though the CAR was associated with psychosocial stressors pre- and post-intervention. Effective interventions for children at risk that might shape a physiological cortisol response are still needed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

49 CFR 1152.32 - Calculation of avoidable costs.

Code of Federal Regulations, 2012 CFR

2012-10-01

...—CR 40-13-20 Do. Purchased services 41-13-20 Do. Other expenses 61-13-20 Do. Electric power systems.... Shop buildings—freight cars Salaries and wages 11-13-25 Do. Materials 21-13-25 Do. Repairs by others—DR... and maintenance Salaries and wages 11-21-41 Road diesel and road electric locomotive gross ton miles...

49 CFR 1152.32 - Calculation of avoidable costs.

Code of Federal Regulations, 2013 CFR

2013-10-01

...—CR 40-13-20 Do. Purchased services 41-13-20 Do. Other expenses 61-13-20 Do. Electric power systems.... Shop buildings—freight cars Salaries and wages 11-13-25 Do. Materials 21-13-25 Do. Repairs by others—DR... and maintenance Salaries and wages 11-21-41 Road diesel and road electric locomotive gross ton miles...

49 CFR 1152.32 - Calculation of avoidable costs.

Code of Federal Regulations, 2014 CFR

2014-10-01

...—CR 40-13-20 Do. Purchased services 41-13-20 Do. Other expenses 61-13-20 Do. Electric power systems.... Shop buildings—freight cars Salaries and wages 11-13-25 Do. Materials 21-13-25 Do. Repairs by others—DR... and maintenance Salaries and wages 11-21-41 Road diesel and road electric locomotive gross ton miles...

49 CFR 1152.32 - Calculation of avoidable costs.

Code of Federal Regulations, 2010 CFR

2010-10-01

...—CR 40-13-20 Do. Purchased services 41-13-20 Do. Other expenses 61-13-20 Do. Electric power systems.... Shop buildings—freight cars Salaries and wages 11-13-25 Do. Materials 21-13-25 Do. Repairs by others—DR... and maintenance Salaries and wages 11-21-41 Road diesel and road electric locomotive gross ton miles...

49 CFR 1152.32 - Calculation of avoidable costs.

Code of Federal Regulations, 2011 CFR

2011-10-01

...—CR 40-13-20 Do. Purchased services 41-13-20 Do. Other expenses 61-13-20 Do. Electric power systems.... Shop buildings—freight cars Salaries and wages 11-13-25 Do. Materials 21-13-25 Do. Repairs by others—DR... and maintenance Salaries and wages 11-21-41 Road diesel and road electric locomotive gross ton miles...

Avoidance of crack inducement when laser welding hot-formed car body components - a variable analysis

NASA Astrophysics Data System (ADS)

Larsson, Johnny K.

The Volvo XC60 car body contains numerous parts in Ultra High Strength Steels (UHSS) in order to guarantee the structural integrity of the car in the event of a crash situation. Most of the parts are manufactured in a hot-forming process, so called presshardening, resulting in component tensile strength in the range of 1,500 MPa. As this type of material also presents fairly high carbon content (˜0.22%) it brings a challenge when it comes to welding. The Volvo XC60 car body is at the same time to a large extent assembled by laser welding technology. In early development stages of the project (Y413), it was observed that laser welding of hot-formed components presented a number of challenges due to the unique conditions offered by this welding method. The presentation will thoroughly describe the modes of procedure how to avoid crack inducement during the welding operation. A variable analysis approach was used based on the present circumstances at the production facility in the Gent plant. Crucial variables at laser welding such as gap between sheets, focal point position, welding speed and laser weld position relative to the flange edge were included in a test matrix and welding trials were carried out accordingly in the Pilot Plant in Gothenburg. The paper will discuss those welding results, the subsequent analysis and plausible theoretic explanations. From the lessons learnt in this research, the optimum laser welding parameters were then transferred to the laser welding stations in the Gent plant. There it has been proven, that also at high volume automotive manufacturing, it is possible to provide an outstanding weld quality also at such difficult pre-conditions. The presentation ends with some facts and figures and experiences from high volume series production, which also includes aspects on quality assurance.

Benefits of magnesium wheels for consumer cars

NASA Astrophysics Data System (ADS)

Frishfelds, Vilnis; Timuhins, Andrejs; Bethers, Uldis

2018-05-01

Advantages and disadvantages of magnesium wheels are considered based on a mechanical model of a car. Magnesium wheels are usually applied to racing cars as they provide slightly better strength/weight ratio than aluminum alloys. Do they provide notable benefits also for the everyday user when the car speeds do not exceed allowed speed limit? Distinct properties of magnesium rims are discussed. Apart from lighter weight of magnesium alloys, they are also good in dissipating the energy of vibrations. The role of energy dissipation in the rim of a wheel is estimated by a quarter car model. Improvements to safety by using the magnesium wheels are considered. Braking distance and responsiveness of the car is studied both with and without using an Anti Blocking System (ABS). Influence of rim weight on various handling parameters of the car is quantitatively tested.

Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.

PubMed

Campion, Katherine L; McCormick, Wanda D; Warwicker, Jim; Khayat, Mohd Ezuan Bin; Atkinson-Dell, Rebecca; Steward, Martin C; Delbridge, Leigh W; Mun, Hee-Chang; Conigrave, Arthur D; Ward, Donald T

2015-09-01

The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca(2+)i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca(2+)o). Similar pHo effects were observed for Ca(2+)o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca(2+)i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo. Copyright © 2015 by the American Society of Nephrology.

Operator design and mechanism for CarA repressor-mediated down-regulation of the photoinducible carB operon in Myxococcus xanthus.

PubMed

López-Rubio, José Juan; Padmanabhan, S; Lázaro, Jose María; Salas, Margarita; Murillo, Francisco José; Elías-Arnanz, Montserrat

2004-07-09

The carB operon encodes all except one of the enzymes involved in light-induced carotenogenesis in Myxococcus xanthus. Expression of its promoter (P(B)) is repressed in the dark by sequence-specific DNA binding of CarA to a palindrome (pI) located between positions -47 and -64 relative to the transcription start site. This promotes subsequent binding of CarA to additional sites that remain to be defined. CarS, produced in the light, interacts physically with CarA, abrogates CarA-DNA binding, and thereby derepresses P(B). In this study, we delineate the operator design that exists for CarA by precisely mapping out the second operator element. For this, we examined how stepwise deletions and site-directed mutagenesis in the region between the palindrome and the transcription start site affect CarA binding around P(B) in vitro and expression of P(B) in vivo. These revealed the second operator element to be an imperfect interrupted palindrome (pII) spanning positions -26 to -40. In vitro assays using purified M. xanthus RNA polymerase showed that CarA abolishes P(B)-RNA polymerase binding and runoff transcription and that both were restored by CarS, thus rationalizing the observations in vivo. CarA binding to pII (after association with pI) effectively occludes RNA polymerase from P(B) and so provides the operative mechanism for the repression of the carB operon by CarA. The bipartite operator design, whereby transcription is blocked by the low affinity CarA-pII binding and is readily restored by CarS, may have evolved to match the needs for a rapid and an effective response to light.

Freedom, Constraint, and Family Responsibility: Teens and Parents Collaboratively Negotiate around the Car, Class, Gender, and Culture

ERIC Educational Resources Information Center

Best, Amy L.

2006-01-01

This article examines kids' talk about cars, exploring what their talk reveals about the dynamics of family life among families with teenagers. Using in depth and focus group interviews with teens, this article identifies how the car serves as cultural object around which parents and kids collaboratively negotiate both kids' autonomy from the…

Combined effects of inversion and feature removal on N170 responses elicited by faces and car fronts

PubMed Central

Kloth, Nadine; Itier, Roxane J.; Schweinberger, Stefan R.

2014-01-01

The face-sensitive N170 is typically enhanced for inverted compared to upright faces. Itier, Alain, Sedore, and McIntosh (2007) recently suggested that this N170 inversion effect is mainly driven by the eye region which becomes salient when the face configuration is disrupted. Here we tested whether similar effects could be observed with non-face objects that are structurally similar to faces in terms of possessing a homogeneous within-class first-order feature configuration. We presented upright and inverted pictures of intact car fronts, car fronts without lights, and isolated lights, in addition to analogous face conditions. Upright cars elicited substantial N170 responses of similar amplitude to those evoked by upright faces. In strong contrast to face conditions however, the car-elicited N170 was mainly driven by the global shape rather than the presence or absence of lights, and was dramatically reduced for isolated lights. Overall, our data confirm a differential influence of the eye region in upright and inverted faces. Results for car fronts do not suggest similar interactive encoding of eye-like features and configuration for non-face objects, even when these objects possess a similar feature configuration as faces. PMID:23485023

Paving the road ahead for CD19 CAR T-cell therapy.

PubMed

Nellan, Anandani; Lee, Daniel W

2015-11-01

Modern immunotherapies, most notably in the form of anti-CD19 chimeric antigen receptor (CAR) T cells, have produced significant clinical responses in otherwise refractory pre-B-cell acute lymphoblastic leukemia patients. Several groups have simultaneously reported robust response rates in children and adults alike. These early studies indicate an impending shift in paradigm for the treatment of acute lymphoblastic leukemia. Incorporating CD19 CAR T-cell therapy into upfront or salvage regimens has its challenges and opportunities. Most CD19 CAR T-cell products in trial today are excellent at inducing minimal residual disease negative remissions, and most responding patients experience cytokine release syndrome and/or neurotoxicity. The challenges facing the CAR community involve how best to minimize the severity of cytokine release syndrome and neurotoxicity while maximizing antitumor efficacy, determining what role this therapy will play for the prophylaxis and treatment of central nervous system leukemia, and its implications on subsequent hematopoietic stem cell transplant given the emergence of CD19-negative relapses. CD19 CAR T-cell therapy is a powerful new tool in the oncologist's arsenal. How it is incorporated into standard practice and how it will shift survival curves are the exciting questions that are waiting to be answered.

Responses of the Q6/Q6s ATD Positioned in Booster Seats in the Far-Side Seat Location of Side Impact Passenger Car and Sled Tests.

PubMed

Tylko, Suzanne; Bohman, Katarina; Bussières, Alain

2015-11-01

Passenger car side impact crash tests and sled tests were conducted to investigate the influence of booster seats, near-side occupant characteristics and vehicle interiors on the responses of the Q6/Q6s child ATD positioned in the rear, far-side seating location. Data from nine side impact sled tests simulating a EuroNCAP AEMD barrier test were analyzed with data obtained from 44 side impact crash tests. The crash tests included: FMVSS 214 and IIHS MDB, moving car-to-stationary car and moving car-to-moving car. A Q6 or prototype Q6s ATD was seated on the far-side, using a variety of low and high back booster seats. Head and chest responses were recorded and ATD motions were tracked with high-speed videos. The vehicle lateral accelerations resulting from MDB tests were characterized by a much earlier and more rapid rise to peak than in tests where the bullet was another car. The near-side seating position was occupied by a Hybrid III 10-year-old ATD in the sled tests, and a rear or front facing child restraint or a 5th percentile side impact ATD in the crash tests. Head impacts occurred more frequently in vehicles where a forward facing child restraint was present behind the driver seat for both the low and high back booster seats. Pretensioners were found to reduce lateral head displacements in all sled test configurations but the greatest reduction in lateral excursion was obtained with a high back booster seat secured with LATCH and tested in combination with pretensioners.

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.

PubMed

Chan, Rosa; Wei, Chun-Yu; Chen, Yuan-Tsong; Benet, Leslie Z

2016-05-01

Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes.

Minimizing Heatstroke Incidents for Young Children Left inside Vehicle

NASA Astrophysics Data System (ADS)

Mahdin, Hairulnizam; Halim Omar, Abdul; Salwani Yaacob, Siti; Kasim, Shahreen; Fudzee, Mohd Farhan Md

2016-11-01

The number of children dying because of heatstroke after being left in the car is worrying. From 1998, there are about 618 children have died in the United State of America (USA) because of heatstroke. It was the leading cause of fatalities in non-crash incident in USA. The same situation also arises in other countries. Life stress is being identified as among the factor that lead to this incident. In this paper, we proposed the used of Android Apps with an Estimote Beacon, a bluetooth device, to warn parents or guardians about their children being left in the car. An alarm will be raised after the parent leaves their children at prespecified range to avoid any risk of heatstroke from occurring.

Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease.

PubMed

Brudno, Jennifer N; Somerville, Robert P T; Shi, Victoria; Rose, Jeremy J; Halverson, David C; Fowler, Daniel H; Gea-Banacloche, Juan C; Pavletic, Steven Z; Hickstein, Dennis D; Lu, Tangying L; Feldman, Steven A; Iwamoto, Alexander T; Kurlander, Roger; Maric, Irina; Goy, Andre; Hansen, Brenna G; Wilder, Jennifer S; Blacklock-Schuver, Bazetta; Hakim, Frances T; Rosenberg, Steven A; Gress, Ronald E; Kochenderfer, James N

2016-04-01

Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor. Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT. © 2016 by American Society of Clinical Oncology.

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.

A FPGA Implementation of the CAR-FAC Cochlear Model.

PubMed

Xu, Ying; Thakur, Chetan S; Singh, Ram K; Hamilton, Tara Julia; Wang, Runchun M; van Schaik, André

2018-01-01

This paper presents a digital implementation of the Cascade of Asymmetric Resonators with Fast-Acting Compression (CAR-FAC) cochlear model. The CAR part simulates the basilar membrane's (BM) response to sound. The FAC part models the outer hair cell (OHC), the inner hair cell (IHC), and the medial olivocochlear efferent system functions. The FAC feeds back to the CAR by moving the poles and zeros of the CAR resonators automatically. We have implemented a 70-section, 44.1 kHz sampling rate CAR-FAC system on an Altera Cyclone V Field Programmable Gate Array (FPGA) with 18% ALM utilization by using time-multiplexing and pipeline parallelizing techniques and present measurement results here. The fully digital reconfigurable CAR-FAC system is stable, scalable, easy to use, and provides an excellent input stage to more complex machine hearing tasks such as sound localization, sound segregation, speech recognition, and so on.

A FPGA Implementation of the CAR-FAC Cochlear Model

PubMed Central

Xu, Ying; Thakur, Chetan S.; Singh, Ram K.; Hamilton, Tara Julia; Wang, Runchun M.; van Schaik, André

2018-01-01

This paper presents a digital implementation of the Cascade of Asymmetric Resonators with Fast-Acting Compression (CAR-FAC) cochlear model. The CAR part simulates the basilar membrane's (BM) response to sound. The FAC part models the outer hair cell (OHC), the inner hair cell (IHC), and the medial olivocochlear efferent system functions. The FAC feeds back to the CAR by moving the poles and zeros of the CAR resonators automatically. We have implemented a 70-section, 44.1 kHz sampling rate CAR-FAC system on an Altera Cyclone V Field Programmable Gate Array (FPGA) with 18% ALM utilization by using time-multiplexing and pipeline parallelizing techniques and present measurement results here. The fully digital reconfigurable CAR-FAC system is stable, scalable, easy to use, and provides an excellent input stage to more complex machine hearing tasks such as sound localization, sound segregation, speech recognition, and so on. PMID:29692700

Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities

PubMed Central

Xia, An-Liang; Wang, Xiao-Chen; Lu, Yi-Jun; Lu, Xiao-Jie; Sun, Beicheng

2017-01-01

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possibl e solutions and future perspectives. PMID:29163850

Influence of unsteady aerodynamics on driving dynamics of passenger cars

NASA Astrophysics Data System (ADS)

Huemer, Jakob; Stickel, Thomas; Sagan, Erich; Schwarz, Martin; Wall, Wolfgang A.

2014-11-01

Recent approaches towards numerical investigations with computational fluid dynamics methods on unsteady aerodynamic loads of passenger cars identified major differences compared with steady-state aerodynamic excitations. Furthermore, innovative vehicle concepts such as electric-vehicles or hybrid drives further challenge the basic layout of passenger cars. Therefore, the relevance of unsteady aerodynamic loads on cross-wind stability of changing basic vehicle architectures should be analysed. In order to assure and improve handling and ride characteristics at high velocity of the actual range of vehicle layouts, the influence of unsteady excitations on the vehicle response was investigated. For this purpose, a simulation of the vehicle dynamics through multi-body simulation was used. The impact of certain unsteady aerodynamic load characteristics on the vehicle response was quantified and key factors were identified. Through a series of driving simulator tests, the identified differences in the vehicle response were evaluated regarding their significance on the subjective driver perception of cross-wind stability. Relevant criteria for the subjective driver assessment of the vehicle response were identified. As a consequence, a design method for the basic layout of passenger cars and chassis towards unsteady aerodynamic excitations was defined.

Development of a car-borne γ-ray survey system, KURAMA

NASA Astrophysics Data System (ADS)

Tanigaki, M.; Okumura, R.; Takamiya, K.; Sato, N.; Yoshino, H.; Yamana, H.

2013-10-01

A compact radiometric survey system, named KURAMA (Kyoto University RAdiation MApping system), has been developed as a response to the nuclear disaster of Fukushima Daiichi nuclear power plant. KURAMA is based on GPS (Global Positioning System) and network technology, and intended for the realtime data accumulation of multiple mobile monitoring stations, such as monitoring cars. KURAMA now serves for the car-borne surveys in Fukushima and surrounding prefectures by the Japanese Government and local authorities. An outline of KURAMA and discussions on car-borne γ-ray surveys using KURAMA are introduced.

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

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.

Structure of the Mtb CarD/RNAP β-lobes complex reveals the molecular basis of interaction and presents a distinct DNA-binding domain for Mtb CarD.

PubMed

Gulten, Gulcin; Sacchettini, James C

2013-10-08

CarD from Mycobacterium tuberculosis (Mtb) is an essential protein shown to be involved in stringent response through downregulation of rRNA and ribosomal protein genes. CarD interacts with the β-subunit of RNAP and this interaction is vital for Mtb's survival during the persistent infection state. We have determined the crystal structure of CarD in complex with the RNAP β-subunit β1 and β2 domains at 2.1 Å resolution. The structure reveals the molecular basis of CarD/RNAP interaction, providing a basis to further our understanding of RNAP regulation by CarD. The structural fold of the CarD N-terminal domain is conserved in RNAP interacting proteins such as TRCF-RID and CdnL, and displays similar interactions to the predicted homology model based on the TRCF/RNAP β1 structure. Interestingly, the structure of the C-terminal domain, which is required for complete CarD function in vivo, represents a distinct DNA-binding fold. Copyright © 2013 Elsevier Ltd. All rights reserved.

Automatic Car Identification - an Evaluation

DOT National Transportation Integrated Search

1972-03-01

In response to a Federal Railroad Administration request, the Transportation Systems Center evaluated the Automatic Car Identification System (ACI) used on the nation's railroads. The ACI scanner was found to be adequate for reliable data output whil...

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.

My School Makes Me Sick: Cheap Solutions to Environmental Problems in Schools.

ERIC Educational Resources Information Center

Wiley, Robert

This paper presents 19 solutions to problems within the school environment: (1) ventilation (e.g., keep the thermostat fan on whenever the room is occupied); (2) filters (e.g., get rid of 20 percent cheap filters); (3) clean the ductwork; (4) avoid car and bus fumes by keeping vehicles 50 feet from the building; (5) sewer vents (vents must…

Accidental strangulation in children by the automatic closing of a car window.

PubMed

Serena, Kailene; Piva, Jefferson Pedro; Andreolio, Cinara; Carvalho, Paulo Roberto Antonacci; Rocha, Tais Sica da

2018-03-01

Among the main causes of death in our country are car accidents, drowning and accidental burns. Strangulation is a potentially fatal injury and an important cause of homicide and suicide among adults and adolescents. In children, its occurrence is usually accidental. However, in recent years, several cases of accidental strangulation in children around the world have been reported. A 2-year-old male patient was strangled in a car window. The patient was admitted to the pediatric intensive care unit with a Glasgow Coma Scale score of 8 and presented with progressive worsening of respiratory dysfunction and torpor. The patient also presented acute respiratory distress syndrome, acute pulmonary edema and shock. He was managed with protective mechanical ventilation, vasoactive drugs and antibiotic therapy. He was discharged from the intensive care unit without neurological or pulmonary sequelae. After 12 days of hospitalization, he was discharged from the hospital, and his state was very good. The incidence of automobile window strangulation is rare but of high morbidity and mortality due to the resulting choking mechanism. Fortunately, newer cars have devices that stop the automatic closing of the windows if resistance is encountered. However, considering the severity of complications strangulated patients experience, the intensive neuro-ventilatory and hemodynamic management of the pathologies involved is important to reduce morbidity and mortality, as is the need to implement new campaigns for the education of parents and caregivers of children, aiming to avoid easily preventable accidents and to optimize safety mechanisms in cars with electric windows.

Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia

PubMed Central

Porter, David L.; Hwang, Wei-Ting; Frey, Noelle V.; Lacey, Simon F.; Shaw, Pamela A.; Loren, Alison W.; Bagg, Adam; Marcucci, Katherine T.; Shen, Angela; Gonzalez, Vanessa; Ambrose, David; Grupp, Stephan A.; Chew, Anne; Zheng, Zhaohui; Milone, Michael C.; Levine, Bruce L.; Melenhorst, Jan J.; June, Carl H.

2018-01-01

Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)–modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 108 to 11 × 108 CTL019 cells (median, 1.6 × 108 cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL. PMID:26333935

A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19

PubMed Central

Singh, Harjeet; Huls, Helen; Cooper, Laurence JN

2014-01-01

Summary The advent of efficient approaches to the genetic modification of T cells has provided investigators with clinically appealing approaches to improve the potency of tumor-specific clinical grade T cells. For example, gene therapy has been successfully used to enforce expression of chimeric antigen receptors (CAR) that provide T cells with ability to directly recognize tumor-associated antigens without the need for presentation by human leukocyte antigen. Gene transfer of CARs can be undertaken using viral-based and non-viral approaches. We have advanced DNA vectors derived from the Sleeping Beauty (SB) system to avoid the expense and manufacturing difficulty associated with transducing T cells with recombinant viral vectors. After electroporation, the transposon/transposase system improves the efficiency of integration of plasmids used to express CAR and other transgenes in T cells. The SB system combined with artificial antigen-presenting cells (aAPC) can selectively propagate and thus retrieve CAR+ T cells suitable for human application. This review describes the translation of the SB system and aAPC for use in clinical trials and highlights how a nimble and cost-effective approach to developing genetically modified T cells can be used to implement clinical trials infusing next-generation T cells with improved therapeutic potential. PMID:24329797

The Cortisol Awakening Response and Cognition across the Adult Lifespan

PubMed Central

Ennis, Gilda E.; Moffat, Scott D.; Hertzog, Christopher

2016-01-01

Although the hippocampus is thought to play a central role in the regulation of the cortisol awakening response (CAR), results from past studies examining the relationship between the CAR and hippocampally-mediated memory and cognition have been mixed. Inconsistent findings may be due to the use of cortisol samples collected on only 1 to 2 days since reduced sampling can permit unstable situational factors to bias results. We used cortisol assessments from 10 consecutive days to test the relationship of the CAR to episodic memory, working memory, and processing speed in a sample of healthy young, middle-aged, and older adults (age range: 23 – 79 years; N = 56). We tested if the relationship between the CAR and cognition would depend upon age and also tested if other cortisol measures, specifically waking cortisol, diurnal cortisol output (i.e., area under the curve) and diurnal cortisol slope (linear and quadratic), would be related to cognition. We found that a more positive CAR slope was related to better episodic memory and that this relationship did not depend upon age. The CAR was not significantly related to working memory. The relationship of the CAR to processing speed was not significant when using a CAR measure that corrected for non-compliant cortisol sampling. We also found that higher waking cortisol was significantly related to better working memory, but not episodic memory or processing speed. Neither diurnal cortisol output nor diurnal linear cortisol slope was significantly related to cognitive functioning. Future work should investigate the mechanisms underpinning the relationship of the cortisol awakening process to cognitive functioning. PMID:27105036

Redirecting T-Cell Specificity to EGFR Using mRNA to Self-limit Expression of Chimeric Antigen Receptor.

PubMed

Caruso, Hillary G; Torikai, Hiroki; Zhang, Ling; Maiti, Sourindra; Dai, Jianliang; Do, Kim-Anh; Singh, Harjeet; Huls, Helen; Lee, Dean A; Champlin, Richard E; Heimberger, Amy B; Cooper, Laurence J N

2016-06-01

Potential for on-target, but off-tissue toxicity limits therapeutic application of genetically modified T cells constitutively expressing chimeric antigen receptors (CARs) from tumor-associated antigens expressed in normal tissue, such as epidermal growth factor receptor (EGFR). Curtailing expression of CAR through modification of T cells by in vitro-transcribed mRNA species is one strategy to mitigate such toxicity. We evaluated expression of an EGFR-specific CAR coded from introduced mRNA in human T cells numerically expanded ex vivo to clinically significant numbers through coculture with activating and propagating cells (AaPC) derived from K562 preloaded with anti-CD3 antibody. The density of AaPC could be adjusted to affect phenotype of T cells such that reduced ratio of AaPC resulted in higher proportion of CD8 and central memory T cells that were more conducive to electrotransfer of mRNA than T cells expanded with high ratios of AaPC. RNA-modified CAR T cells produced less cytokine, but demonstrated similar cytolytic capacity as DNA-modified CAR T cells in response to EGFR-expressing glioblastoma cells. Expression of CAR by mRNA transfer was transient and accelerated by stimulation with cytokine and antigen. Loss of CAR abrogated T-cell function in response to tumor and normal cells expressing EGFR. We describe a clinically applicable method to propagate and modify T cells to transiently express EGFR-specific CAR to target EGFR-expressing tumor cells that may be used to limit on-target, off-tissue toxicity to normal tissue.

Behavior of amphibians on the road in response to car traffic

USGS Publications Warehouse

Mazerolle, M.J.; Huot, M.; Gravel, M.

2005-01-01

Nocturnal car traffic often results in amphibian casualties, especially during rainy nights. The behavior of amphibians presumably influences their vulnerability to mortality on the road, but this hypothesis remains untested. We investigated the behavioral response of individuals of six species of amphibians on roads when confronted by an approaching vehicle. We first conducted a field study consisting of 50 night-driving surveys over 4 yr during which we recorded the behavior (i.e., moving or immobile) of frogs, toads, tree frogs, and salamanders encountered on a 20-km stretch of road. In an effort to tease apart the effects of headlights and the sound of motors on amphibian behavior, we carried out a field experiment on a test road where we exposed individuals to different car-associated stimuli. Here, we tested the hypothesis that simultaneous exposure to headlights and the sound of a car motor would elicit a stronger response than exposure to a single stimulus or a control. Based on the observations of the 2767 individuals in the field survey, immobility was the most common response to the approach of a car (mean probability of 0.82 of remaining immobile); the response differed across species but depended on the season of the survey (May-June vs. July-September). Similarly, the 91 individuals included in the field experiment were more likely to move during the control treatment than during any of the car-associated treatments. The combined stimuli elicited the strongest response, followed by the headlights-only and the motor-only treatments. Spring peepers (Pseudacris crucifer) tended to move more often than the other species we tested in the field experiment, which suggests they spend less time on the road and are less vulnerable to traffic mortality than other species. Both the field survey and field experiment consistently indicated that amphibians tend to remain immobile at the approach of a vehicle. This behavior highlights the vulnerability of amphibians to road traffic and should be considered in measures to mitigate road impacts. ?? 2005 by The Herpetologists' League, Inc.

Combined effects of inversion and feature removal on N170 responses elicited by faces and car fronts.

PubMed

Kloth, Nadine; Itier, Roxane J; Schweinberger, Stefan R

2013-04-01

The face-sensitive N170 is typically enhanced for inverted compared to upright faces. Itier, Alain, Sedore, and McIntosh (2007) recently suggested that this N170 inversion effect is mainly driven by the eye region which becomes salient when the face configuration is disrupted. Here we tested whether similar effects could be observed with non-face objects that are structurally similar to faces in terms of possessing a homogeneous within-class first-order feature configuration. We presented upright and inverted pictures of intact car fronts, car fronts without lights, and isolated lights, in addition to analogous face conditions. Upright cars elicited substantial N170 responses of similar amplitude to those evoked by upright faces. In strong contrast to face conditions however, the car-elicited N170 was mainly driven by the global shape rather than the presence or absence of lights, and was dramatically reduced for isolated lights. Overall, our data confirm a differential influence of the eye region in upright and inverted faces. Results for car fronts do not suggest similar interactive encoding of eye-like features and configuration for non-face objects, even when these objects possess a similar feature configuration as faces. Copyright © 2013 Elsevier Inc. All rights reserved.

Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy.

PubMed

Bollino, Dominique; Webb, Tonya J

2017-09-01

Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

CAR T Cell Therapy for Glioblastoma: Recent Clinical Advances and Future Challenges.

PubMed

Bagley, Stephen J; Desai, Arati S; Linette, Gerald P; June, Carl H; O'Rourke, Donald M

2018-03-02

In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T cell therapy for glioblastoma. In addition, despite formidable barriers to T cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.

Chronic stress exposure decreases the cortisol awakening response in healthy young men.

PubMed

Duan, Hongxia; Yuan, Yiran; Zhang, Liang; Qin, Shaozheng; Zhang, Kan; Buchanan, Tony W; Wu, Jianhui

2013-11-01

Academic examination is a major stressor for students in China. Investigation of stress-sensitive endocrine responses to major examination stress serves as a good model of naturalistic chronic psychological stress in an otherwise healthy population. The cortisol awakening response (CAR) is an endocrine marker of the hypothalamic-pituitary-adrenocortical (HPA) axis in response to stress. However, it remains unknown how chronic examination stress impacts the CAR in a young healthy population To exclude the influence of sex effects on hormone level, the CAR and psychological stress responses were assessed on two consecutive workdays in 42 male participants during their preparations for the Chinese National Postgraduate Entrance Exam (NPEE) and 21 non-exam, age-matched male comparisons. On each day, four saliva samples were collected immediately after awakening, 15 minutes, 30 minutes and 60 minutes after awakening. The waking level (S1), the increase within 30 minutes after awakening (R30), the area under the curve with respect to ground (AUCg), and the area under the curve with respect to increase (AUCi) were used to quantify the CAR. Psychological stress and anxiety were assessed by the Perceived Stress Scale and the Spielberger State-Trait Anxiety Inventory, respectively. Male participants in the exam group had greater perceived stress and anxiety scores relatibe to the non-exam group. Both R30 and AUCi in the exam group were significantly lower than the comparison group and this effect was most pronounced for participants with high levels of perceived stress in the exam group. Perceived stress and anxiety levels were negatively correlated with both R30 and AUCi. Chronic examination stress can lead to the decrease of CAR in healthy young men, possibly due to reduced HPA axis activity under long-term sustained stress.

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

PubMed

Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L

2015-02-07

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

The cortisol awakening response predicts major depression: predictive stability over a 4-year follow-up and effect of depression history.

PubMed

Vrshek-Schallhorn, S; Doane, L D; Mineka, S; Zinbarg, R E; Craske, M G; Adam, E K

2013-03-01

The cortisol awakening response (CAR) has been shown to predict major depressive episodes (MDEs) over a 1-year period. It is unknown whether this effect: (a) is stable over longer periods of time; (b) is independent of prospective stressful life events; and (c) differentially predicts first onsets or recurrences of MDEs. A total of 270 older adolescents (mean age 17.06 years at cortisol measurement) from the larger prospective Northwestern-UCLA Youth Emotion Project completed baseline diagnostic and life stress interviews, questionnaires, and a 3-day cortisol sampling protocol measuring the CAR and diurnal rhythm, as well as up to four annual follow-up interviews of diagnoses and life stress. Non-proportional person-month survival analyses revealed that higher levels of the baseline CAR significantly predict MDEs for 2.5 years following cortisol measurement. However, the strength of prediction of depressive episodes significantly decays over time, with the CAR no longer significantly predicting MDEs after 2.5 years. Elevations in the CAR did not significantly increase vulnerability to prospective major stressful life events. They did, however, predict MDE recurrences more strongly than first onsets. These results suggest that a high CAR represents a time-limited risk factor for onsets of MDEs, which increases risk for depression independently of future major stressful life events. Possible explanations for the stronger effect of the CAR for predicting MDE recurrences than first onsets are discussed.

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.

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

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.

C2-domain abscisic acid-related proteins mediate the interaction of PYR/PYL/RCAR abscisic acid receptors with the plasma membrane and regulate abscisic acid sensitivity in Arabidopsis.

PubMed

Rodriguez, Lesia; Gonzalez-Guzman, Miguel; Diaz, Maira; Rodrigues, Americo; Izquierdo-Garcia, Ana C; Peirats-Llobet, Marta; Fernandez, Maria A; Antoni, Regina; Fernandez, Daniel; Marquez, Jose A; Mulet, Jose M; Albert, Armando; Rodriguez, Pedro L

2014-12-01

Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca(2+)-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling. © 2014 American Society of Plant Biologists. All rights reserved.

C2-Domain Abscisic Acid-Related Proteins Mediate the Interaction of PYR/PYL/RCAR Abscisic Acid Receptors with the Plasma Membrane and Regulate Abscisic Acid Sensitivity in Arabidopsis[C][W

PubMed Central

Rodriguez, Lesia; Diaz, Maira; Rodrigues, Americo; Izquierdo-Garcia, Ana C.; Peirats-Llobet, Marta; Fernandez, Maria A.; Antoni, Regina; Fernandez, Daniel; Marquez, Jose A.; Mulet, Jose M.; Albert, Armando; Rodriguez, Pedro L.

2014-01-01

Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca2+-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling. PMID:25465408

Physiological investigation of automobile driver's activation index using simulated monotonous driving.

PubMed

Yamakoshi, T; Yamakoshi, K; Tanaka, S; Nogawa, M; Kusakabe, M; Kusumi, M; Tanida, K

2004-01-01

Monotonous automobile operation in our daily life may cause the lowering of what might be termed an activation state of the human body, resulting in an increased risk of an accident. We therefore propose to create a more suitable environment in-car so as to allow active operation of the vehicle, hopefully thus avoiding potentially dangerous situations during driving. In order to develop such an activation method as a final goal, we have firstly focused on the acquisition of physiological variables, including cardiovascular parameters, during presentation to the driver of a monotonous screen image, simulating autonomous travel of constant-speed on a motorway. Subsequently, we investigated the derivation of a driver's activation index. During the screen image presentation, a momentary electrical stimulation of about 1 second duration was involuntarily applied to a subject's shoulder to obtain a physiological response. We have successfully monitored various physiological variables during the image presentation, and results suggest that a peculiar pattern in the beat-by-beat change of blood pressure in response to the involuntary stimulus may be an appropriate, and feasible, index relevant to activation state.

The Effect of Process Parameters and Tool Geometry on Thermal Field Development and Weld Formation in Friction Stir Welding of the Alloys AZ31 and AZ61

NASA Astrophysics Data System (ADS)

Zettler, R.; Blanco, A. C.; dos Santos, J. F.; Marya, S.

An increase in the use of magnesium (Mg) in the car manufacturing industry has raised questions concerning its weldability. Friction Stir Welding (FSW) has the advantage of achieving metallic bonding below that of the melting point of the base material thus avoiding many of the metallurgical problems associated with the solidification process. The present study presents the results of a development program carried out to investigate the response of Mg alloys AZ31 and AZ61 to different FSW tool geometries and process parameters. Temperature development across the weld zone was monitored and the produced welds have been subjected to microstructural analysis and mechanical testing. Defect free welds have been produced with optimised FSW-tool and parameters. The micro structure of the welded joint resulted in similar ductility and hardness levels as compared to that of the base material. The results also demonstrated that tool geometry plays a fundamental role in the response of the investigated alloys to the FSW process.

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.

Real life safety benefits of increasing brake deceleration in car-to-pedestrian accidents: Simulation of Vacuum Emergency Braking.

PubMed

Jeppsson, Hanna; Östling, Martin; Lubbe, Nils

2018-02-01

The objective of this study is to predict the real-life benefits, namely the number of injuries avoided rather than the reduction in impact speed, offered by a Vacuum Emergency Brake (VEB) added to a pedestrian automated emergency braking (AEB) system. We achieve this through the virtual simulation of simplified mathematical models of a system which incorporates expected future advances in technology, such as a wide sensor field of view, and reductions in the time needed for detection, classification, and brake pressure build up. The German In-Depth Accident Study database and the related Pre Crash Matrix, both released in the beginning of 2016, were used for this study and resulted in a final sample of 526 collisions between passenger car fronts and pedestrians. Weight factors were calculated for both simulation model and injury risk curves to make the data representative of Germany as a whole. The accident data was used with a hypothetical AEB system in a simulation model, and injury risk was calculated from the new impact speed using injury risk curves to generate new situations using real accidents. Adding a VEB to a car with pedestrian AEB decreased pedestrian casualties by an additional 8-22%, depending on system setting and injury level, over the AEB-only system. The overall decrease in fatalities was 80-87%, an improvement of 8%. Collision avoidance was improved by 14-28%. VEB with a maximum deceleration in the middle of the modelled performance range has an effectiveness similar to that of an "early activation" system, where the AEB is triggered as early as 2 s before collision. VEB may therefore offer a substantial increase in performance without increasing false positive rates, which earlier AEB activation does. Most collisions and injuries can be avoided when AEB is supplemented by the high performance VEB; remaining cases are characterised by high pedestrian walking speed and late visibility due to view obstructions. VEB is effective in all analysed accident scenarios. Copyright © 2017 Elsevier Ltd. All rights reserved.

Air Pollution Exposure in Relation to the Commute to School: A Bradford UK Case Study

PubMed Central

Dirks, Kim N.; Wang, Judith Y. T.; Khan, Amirul; Rushton, Christopher

2016-01-01

Walking School Buses (WSBs) provide a safe alternative to being driven to school. Children benefit from the contribution the exercise provides towards their daily exercise target, it gives children practical experience with respect to road safety and it helps to relieve traffic congestion around the entrance to their school. Walking routes are designed largely based in road safety considerations, catchment need and the availability of parent support. However, little attention is given to the air pollution exposure experienced by children during their journey to school, despite the commuting microenvironment being an important contributor to a child’s daily air pollution exposure. This study aims to quantify the air pollution exposure experienced by children walking to school and those being driven by car. A school was chosen in Bradford, UK. Three adult participants carried out the journey to and from school, each carrying a P-Trak ultrafine particle (UFP) count monitor. One participant travelled the journey to school by car while the other two walked, each on opposite sides of the road for the majority of the journey. Data collection was carried out over a period of two weeks, for a total of five journeys to school in the morning and five on the way home at the end of the school day. Results of the study suggest that car commuters experience lower levels of air pollution dose due to lower exposure and reduced commute times. The largest reductions in exposure for pedestrians can be achieved by avoiding close proximity to traffic queuing up at intersections, and, where possible, walking on the side of the road opposite the traffic, especially during the morning commuting period. Major intersections should also be avoided as they were associated with peak exposures. Steps to ensure that the phasing of lights is optimised to minimise pedestrian waiting time would also help reduce exposure. If possible, busy roads should be avoided altogether. By the careful design of WSB routes, taking into account air pollution, children will be able to experience the benefits that walking to school brings while minimizing their air pollution exposure during their commute to and from school. PMID:27801878

Air Pollution Exposure in Relation to the Commute to School: A Bradford UK Case Study.

PubMed

Dirks, Kim N; Wang, Judith Y T; Khan, Amirul; Rushton, Christopher

2016-10-29

Walking School Buses (WSBs) provide a safe alternative to being driven to school. Children benefit from the contribution the exercise provides towards their daily exercise target, it gives children practical experience with respect to road safety and it helps to relieve traffic congestion around the entrance to their school. Walking routes are designed largely based in road safety considerations, catchment need and the availability of parent support. However, little attention is given to the air pollution exposure experienced by children during their journey to school, despite the commuting microenvironment being an important contributor to a child's daily air pollution exposure. This study aims to quantify the air pollution exposure experienced by children walking to school and those being driven by car. A school was chosen in Bradford, UK. Three adult participants carried out the journey to and from school, each carrying a P-Trak ultrafine particle (UFP) count monitor. One participant travelled the journey to school by car while the other two walked, each on opposite sides of the road for the majority of the journey. Data collection was carried out over a period of two weeks, for a total of five journeys to school in the morning and five on the way home at the end of the school day. Results of the study suggest that car commuters experience lower levels of air pollution dose due to lower exposure and reduced commute times. The largest reductions in exposure for pedestrians can be achieved by avoiding close proximity to traffic queuing up at intersections, and, where possible, walking on the side of the road opposite the traffic, especially during the morning commuting period. Major intersections should also be avoided as they were associated with peak exposures. Steps to ensure that the phasing of lights is optimised to minimise pedestrian waiting time would also help reduce exposure. If possible, busy roads should be avoided altogether. By the careful design of WSB routes, taking into account air pollution, children will be able to experience the benefits that walking to school brings while minimizing their air pollution exposure during their commute to and from school.

The Influence of Depression on Cognitive Control: Disambiguating Approach and Avoidance Tendencies.

PubMed

Huang, He; Movellan, Javier; Paulus, Martin P; Harlé, Katia M

2015-01-01

Dysfunctions of approach and avoidance motivation play an important role in depression, which in turn may affect cognitive control, i.e., the ability to regulate thoughts and action to achieve internal goals. We use a novel experimental paradigm, i.e. a computer simulated driving-task, to study the impact of depression on cognitive control by measuring approach and avoidance actions in continuous time. In this task, 39 subjects with minimal to severe depression symptoms were instructed to use a joystick to move a virtual car as quickly as possible to a target point without crossing a stop-sign or crashing into a wall. We recorded their continuous actions on a joystick and found that depression 1) leads to further stopping distance to task target; and 2) increases the magnitude of late deceleration (avoidance) but not early acceleration (approach), which was only observed in the stop-sign condition. Taken together, these results are consistent with the hypothesis that depressed individuals have greater avoidance motivation near stopping target, but are minimally affected by approach motivation.

Review of BART "C" Car Fire Safety Characteristics

DOT National Transportation Integrated Search

1987-09-01

The report presents the results of a review of the fire safety characteristics of the prototype BART "C" Car. Initiated in response to a request from the Urban Mass Transportation Administration (UMTA) Region IX Administrator, the review has been str...

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.

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.

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

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

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

Modeling the number of car theft using Poisson regression

NASA Astrophysics Data System (ADS)

Zulkifli, Malina; Ling, Agnes Beh Yen; Kasim, Maznah Mat; Ismail, Noriszura

2016-10-01

Regression analysis is the most popular statistical methods used to express the relationship between the variables of response with the covariates. The aim of this paper is to evaluate the factors that influence the number of car theft using Poisson regression model. This paper will focus on the number of car thefts that occurred in districts in Peninsular Malaysia. There are two groups of factor that have been considered, namely district descriptive factors and socio and demographic factors. The result of the study showed that Bumiputera composition, Chinese composition, Other ethnic composition, foreign migration, number of residence with the age between 25 to 64, number of employed person and number of unemployed person are the most influence factors that affect the car theft cases. These information are very useful for the law enforcement department, insurance company and car owners in order to reduce and limiting the car theft cases in Peninsular Malaysia.

Cortisol Awakening Response and Walking Speed in Older People

PubMed Central

Pulopulos, Matias M.; Puig-Perez, Sara; Hidalgo, Vanesa; Villada, Carolina; Salvador, Alicia

2016-01-01

In older people, less diurnal variability in cortisol levels has been consistently related to worse physical performance, especially to slower walking speed (WS). The cortisol awakening response (CAR) is a discrete component of the hypothalamic-pituitary-adrenal axis that has been related to several health problems, such as cardiovascular disease and/or worse performance on executive function and memory. The relationship between the CAR and physical performance in older people is poorly understood. In this study, in 86 older people (mean age = 64.42, SD = 3.93), we investigated the relationship between the CAR and WS, a commonly used measure of physical performance in the older population that has also been related to health problems, such as cardiovascular disease and executive function performance in older people. Additionally, we studied whether the relationship between the CAR and WS was independent from cortisol levels on awakening and several possible confounders. Results showed that a CAR of reduced magnitude (measured with 3 samples each day, for two consecutive days, and calculated as the area under the curve with respect to the increase), but not cortisol levels on awakening, was related to slower WS. In addition, this relationship was independent from cortisol levels on awakening. It is possible that a CAR of reduced magnitude would contribute to less diurnal cortisol variability, affecting physical performance. Additionally, it is possible that a CAR of reduced magnitude affects WS through a possible negative effect on executive function, or that the association between the CAR and WS is due to the fact that both are related to similar health problems and to changes in cognitive performance in older people. PMID:27191847

Individual differences in the cortisol and salivary α-amylase awakening responses in early childhood: relations to age, sex, and sleep.

PubMed

Bright, Melissa A; Frick, Janet E; Out, Dorothee; Granger, Douglas A

2014-09-01

Recent studies have examined post-waking changes in cortisol as a marker of HPA functioning, but questions remain about the stability of this response, as well as its relation to sleep and other ANS markers. The purposes of this study were to a) examine the presence and developmental changes in the cortisol awakening response (CAR) and salivary α-amylase awakening (sAA-AR) in a toddler sample and b) determine whether and how sleep relates to these responses in this age group. We measured cortisol and sAA upon awakening (and 30 min post-waking) and sleep characteristics using actigraphy (e.g., total sleep time, sleep efficiency, number of awakenings) in toddlers (N = 47; 36% female, ages 12-24 months). Forty-six percent of toddlers demonstrated a CAR and 52% demonstrated a sAA-AR. Strength of either response did not change linearly with age. Additionally, likelihood of demonstrating the CAR and sAA-AR was unrelated to age, sex, awakening time, time between samples, and time since feeding. Higher waking cortisol levels were associated with a shorter total sleep time and an earlier awakening. No associations were observed between sleep characteristics and the sAA-AR, ps > .05. Our findings suggest that these awakening responses function independently of sleep in toddlers. Additionally, the lack of change in percentage of children showing a CAR or sAA-AR across these ages suggests that these responses are stable and not emerging reliably across the second year of life. © 2014 Wiley Periodicals, Inc.

The added economic and environmental value of plug-in electric vehicles connected to commercial building microgrids

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

Stadler, Michael; Momber, Ilan; Megel, Olivier

2010-08-25

Connection of electric storage technologies to smartgrids or microgrids will have substantial implications for building energy systems. In addition to potentially supplying ancillary services directly to the traditional centralized grid (or macrogrid), local storage will enable demand response. As an economically attractive option, mobile storage devices such as plug-in electric vehicles (EVs) are in direct competition with conventional stationary sources and storage at the building. In general, it is assumed that they can improve the financial as well as environmental attractiveness of renewable and fossil based on-site generation (e.g. PV, fuel cells, or microturbines operating with or without combined heatmore » and power). Also, mobile storage can directly contribute to tariff driven demand response in commercial buildings. In order to examine the impact of mobile storage on building energy costs and carbon dioxide (CO2) emissions, a microgrid/distributed-energy-resources (DER) adoption problem is formulated as a mixed-integer linear program with minimization of annual building energy costs applying CO2 taxes/CO2 pricing schemes. The problem is solved for a representative office building in the San Francisco Bay Area in 2020. By using employees' EVs for energy management, the office building can arbitrage its costs. But since the car battery lifetime is reduced, a business model that also reimburses car owners for the degradation will be required. In general, the link between a microgrid and an electric vehicle can create a win-win situation, wherein the microgrid can reduce utility costs by load shifting while the electric vehicle owner receives revenue that partially offsets his/her expensive mobile storage investment. For the California office building with EVs connected under a business model that distributes benefits, it is found that the economic impact is very limited relative to the costs of mobile storage for the site analyzed, i.e. cost reductions from electric vehicle connections are modest. Nonetheless, this example shows that some economic benefit is created because of avoided demand charges and on-peak energy. The strategy adopted by the office building is to avoid these high on-peak costs by using energy from the mobile storage in the business hours. CO2 emission reduction strategy results indicate that EVs' contribution at the selected office building are minor.« less

Why English Teachers Are Responsible for the X-Cars.

ERIC Educational Resources Information Center

Smith, Beverly J.

1985-01-01

The problems plaguing a frequently-recalled car provide satirical evidence that permitting students to get by with bad habits in school may enable them to continue their bad habits at work, forcing a wider public to suffer from the results. (PGD)

Smoking in cars: knowledge, behaviours and support for smokefree cars legislation among New Zealand smokers and recent quitters.

PubMed

Li, Judy; Nelson, Sarah; Newcombe, Rhiannon; Walton, Darren

2016-08-05

Exposure to second-hand smoke (SHS) poses serious health consequences to non-smokers, and normalises smoking. Currently, there is no legislation restricting smoking in private cars in New Zealand. This paper supplements previous New Zealand studies on exposure to SHS in cars by examining smokers and recent quitters' knowledge and behaviours towards smoking in cars, and their support for two possible smokefree cars policy options. The New Zealand Smoking Monitor is a fortnightly survey that uses a self-refreshing panel approach. The questionnaire contains smoking- and cessation-related questions, including eight non-core questions addressing smoking in homes or cars. These questions were answered by 364 respondents in 2014. Responses were compared by socio-demographic variables and recent quit attempt status. Smoking in cars was common among the respondents in our sample: 63% had recently smoked in a car when they were the only person in it, and 27% had done so when there were other people present. Some groups of respondents exhibited information gaps around the harms (eg, compared with males, females had reduced odds of agreeing with the false statement: "it's OK to smoke inside cars if there are windows open", OR=0.41, 0.21-0.78); however, support for banning smoking in cars if there are children in them was consistently high across different sub-groups (92% overall). Our data show the importance of providing specific information around the danger of smoking in cars, and strategies to enforce a complete smokefree rule in cars. Legislation may be required to further protect children from SHS exposure.

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

PubMed

Li-Tempel, Ting; Larra, Mauro F; Winnikes, Ulrike; Tempel, Tobias; DeRijk, Roel H; Schulz, André; Schächinger, Hartmut; Meyer, Jobst; Schote, Andrea B

2016-09-01

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Pedestrians' perception and response towards vehicles during road-crossing at nighttime.

PubMed

Balasubramanian, Venkatesh; Bhardwaj, Rahul

2018-01-01

Pedestrian being involved in road traffic accidents (RTA) is about 22% of all road traffic related deaths. In this study, we have estimated the pedestrian's response towards an approaching vehicle and the time taken to correctly recognize it while they crossed the road in dim-light nighttime conditions. This is also extendable to cycles and other low powered vehicles. Thirty volunteers participated in this study. A collection of six videos, which comprised of different vehicle scenarios were shown to each of the participants. It was observed that correct identification and time to recognize the vehicle was fastest when light emitting diode (LED) strip was fixed between headlights of a four-wheeler. Average time to recognize a low beam car and a high beam car with an LED strip was 7.62±2.39s and 11.23±2.94s respectively, whereas correct identification rates of the said low beam and high beam cars with LED strips were 93.33% and 86.67% respectively. Earlier when no LED was used, time to recognize low beam car and high beam car without LED strip were 20.55±3.50s and 25.57±4.14s respectively whereas correct identification of low beam car without LED strip and high beam car without LED strip were 90.00% and 56.67% respectively. Pedestrians are therefore less confused and can take right decision while crossing the road - particularly in a poor lighting environment - when there is a demarcating illumination between headlights of vehicle. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of impact speed on head and brain injury outcome in vulnerable road user impacts to the car hood.

PubMed

Fredriksson, Rikard; Zhang, Liying; Boström, Ola; Yang, King

2007-10-01

EuroNCAP and regulations in Europe and Japan evaluate the pedestrian protection performance of cars. The test methods are similar and they all have requirements for the passive protection of the hood area at a pedestrian to car impact speed of 40 km/h. In Europe, a proposal for a second phase of the regulation mandates a brake-assist system along with passive requirements. The system assists the driver in optimizing the braking performance during panic braking, resulting in activation only when the driver brakes sufficiently. In a European study this was estimated to occur in about 50% of pedestrian accidents. A future system for brake assistance will likely include automatic braking, in response to a pre-crash sensor, to avoid or mitigate injuries of vulnerable road users. An important question is whether these systems will provide sufficient protection, or if a parallel, passive pedestrian protection system will be necessary. This study investigated the influence of impact speed on head and brain injury risk, in impacts to the carhood. One car model was chosen and a rigid adjustable plate was mounted under the hood. Free-flying headform impacts were carried out at 20 and 30 km/h head impact velocities at different under-hood distances, 20 to 100 mm; and were compared to earlier tests at 40 km/h. The EEVC WG17 adult pedestrian headform was used for non-rotating tests and a Hybrid III adult 50th percentile head was used for rotational tests where linear and rotational acceleration was measured. Data from the rotational tests was used as input to a validated finite element model of the human head, the Wayne State University Head Injury Model (WSUHIM). The model was utilized to assess brain injury risk and potential injury mechanism in a pedestrian-hood impact. Although this study showed that it was not necessarily true that a lower HIC value reduced the risk for brain injury, it appeared, for the tested car model, under-hood distances of 60 mm in 20 km/h and 80 mm in 30 km/h reduced head injury values for both skull fractures and brain injuries. An earlier study showed that the corresponding value for a test speed of 40 km/h is 100 mm. A 10 km/h reduction in head impact velocity, as in automatic braking, allowed 20 mm less under-hood clearance with maintained head protection of the vulnerable road user.

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.

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

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

Effect of scattering on coherent anti-Stokes Raman scattering (CARS) signals.

PubMed

Ranasinghesagara, Janaka C; De Vito, Giuseppe; Piazza, Vincenzo; Potma, Eric O; Venugopalan, Vasan

2017-04-17

We develop a computational framework to examine the factors responsible for scattering-induced distortions of coherent anti-Stokes Raman scattering (CARS) signals in turbid samples. We apply the Huygens-Fresnel wave-based electric field superposition (HF-WEFS) method combined with the radiating dipole approximation to compute the effects of scattering-induced distortions of focal excitation fields on the far-field CARS signal. We analyze the effect of spherical scatterers, placed in the vicinity of the focal volume, on the CARS signal emitted by different objects (2μm diameter solid sphere, 2μm diameter myelin cylinder and 2μm diameter myelin tube). We find that distortions in the CARS signals arise not only from attenuation of the focal field but also from scattering-induced changes in the spatial phase that modifies the angular distribution of the CARS emission. Our simulations further show that CARS signal attenuation can be minimized by using a high numerical aperture condenser. Moreover, unlike the CARS intensity image, CARS images formed by taking the ratio of CARS signals obtained using x- and y-polarized input fields is relatively insensitive to the effects of spherical scatterers. Our computational framework provide a mechanistic approach to characterizing scattering-induced distortions in coherent imaging of turbid media and may inspire bottom-up approaches for adaptive optical methods for image correction.

Effect of scattering on coherent anti-Stokes Raman scattering (CARS) signals

PubMed Central

Ranasinghesagara, Janaka C.; De Vito, Giuseppe; Piazza, Vincenzo; Potma, Eric O.; Venugopalan, Vasan

2017-01-01

We develop a computational framework to examine the factors responsible for scattering-induced distortions of coherent anti-Stokes Raman scattering (CARS) signals in turbid samples. We apply the Huygens-Fresnel wave-based electric field superposition (HF-WEFS) method combined with the radiating dipole approximation to compute the effects of scattering-induced distortions of focal excitation fields on the far-field CARS signal. We analyze the effect of spherical scatterers, placed in the vicinity of the focal volume, on the CARS signal emitted by different objects (2μm diameter solid sphere, 2μm diameter myelin cylinder and 2μm diameter myelin tube). We find that distortions in the CARS signals arise not only from attenuation of the focal field but also from scattering-induced changes in the spatial phase that modifies the angular distribution of the CARS emission. Our simulations further show that CARS signal attenuation can be minimized by using a high numerical aperture condenser. Moreover, unlike the CARS intensity image, CARS images formed by taking the ratio of CARS signals obtained using x- and y-polarized input fields is relatively insensitive to the effects of spherical scatterers. Our computational framework provide a mechanistic approach to characterizing scattering-induced distortions in coherent imaging of turbid media and may inspire bottom-up approaches for adaptive optical methods for image correction. PMID:28437941

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.

Transcriptional activation of PPARalpha by phenobarbital in the absence of CAR and PXR.

PubMed

Tamasi, Viola; Juvan, Peter; Beer, Markus; Rozman, Damjana; Meyer, Urs A

2009-01-01

The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital on gene transcription. To investigate the relative contribution of these nuclear receptors to the expression of specific genes we studied the effect of phenobarbital in livers of wild type, CAR(-/-), PXR(-/-) and CAR/PXR(-/-) knockout mice. Spotted Steroltalk v1 cDNA arrays were applied containing probes for genes involved in drug metabolism, sterol biosynthesis, steroid synthesis/transport and heme synthesis. In the absence of CAR and PXR, phenobarbital unexpectedly induced mRNAs of several nuclear receptors, including PPARalpha and its target genes Cyp4a10 and Cyp4a14. Interestingly, in primary cultures of hepatocytes isolated from CAR/PXR(-/-) knockout mice, phenobarbital increased HNF-4alpha levels. In further experiments in these hepatocyte cultures we provide evidence that phenobarbital directly induces transcription of the PPARalpha gene via its HNF-4alpha response element, and indirectly by lack of inhibitory crosstalk of AMPK, CAR and PXR with HNF-4alpha. Our results provide further insight into CAR and PXR-independent effects of phenobarbital and the crosstalk between different nuclear receptor signaling pathways.

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

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

PubMed

Smith, Eric L; Staehr, Mette; Masakayan, Reed; Tatake, Ishan J; Purdon, Terence J; Wang, Xiuyan; Wang, Pei; Liu, Hong; Xu, Yiyang; Garrett-Thomson, Sarah C; Almo, Steven C; Riviere, Isabelle; Liu, Cheng; Brentjens, Renier J

2018-06-06

B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR T cell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR T cell therapy with properties, including rapid in vivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR T cell vectors stemming from this work are under clinical investigation. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Looming auditory collision warnings for driving.

PubMed

Gray, Rob

2011-02-01

A driving simulator was used to compare the effectiveness of increasing intensity (looming) auditory warning signals with other types of auditory warnings. Auditory warnings have been shown to speed driver reaction time in rear-end collision situations; however, it is not clear which type of signal is the most effective. Although verbal and symbolic (e.g., a car horn) warnings have faster response times than abstract warnings, they often lead to more response errors. Participants (N=20) experienced four nonlooming auditory warnings (constant intensity, pulsed, ramped, and car horn), three looming auditory warnings ("veridical," "early," and "late"), and a no-warning condition. In 80% of the trials, warnings were activated when a critical response was required, and in 20% of the trials, the warnings were false alarms. For the early (late) looming warnings, the rate of change of intensity signaled a time to collision (TTC) that was shorter (longer) than the actual TTC. Veridical looming and car horn warnings had significantly faster brake reaction times (BRT) compared with the other nonlooming warnings (by 80 to 160 ms). However, the number of braking responses in false alarm conditions was significantly greater for the car horn. BRT increased significantly and systematically as the TTC signaled by the looming warning was changed from early to veridical to late. Looming auditory warnings produce the best combination of response speed and accuracy. The results indicate that looming auditory warnings can be used to effectively warn a driver about an impending collision.

The Interaction of Childhood Maltreatment, Sex, and Borderline Personality Features in the Prediction of the Cortisol Awakening Response in Adolescents.

PubMed

Kaess, Michael; Whittle, Sarah; Simmons, Julian G; Jovev, Martina; Allen, Nicholas B; Chanen, Andrew M

2017-01-01

The study aimed to investigate childhood maltreatment, sex, and borderline personality disorder (BPD) symptoms as prospective predictors of adolescent hypothalamic-pituitary-adrenal (HPA) axis reactivity. A sample of 69 adolescents (30 female and 39 male) were selected from a larger longitudinal study of adolescent development and assessed at 3 time points. BPD symptoms were assessed at T1 (approx. 12.5 years), childhood maltreatment was assessed at T2 (approx. 14.9 years), and multiple assessments of salivary cortisol (cortisol awakening response; CAR) were undertaken at T3 (approx. 15.5 years). Multivariate linear regression analysis revealed a significant main effect for childhood maltreatment but not for early BPD symptoms as a predictor of lower CAR in adolescence (p = 0.047). The association between childhood maltreatment and attenuated CAR was moderated by both early BPD symptoms (p = 0.024; no childhood maltreatment-dependent attenuation of CAR in the presence of BPD symptoms) and sex (p = 0.012; childhood maltreatment-dependent attenuation of CAR in females only). Furthermore, a 3-way BPD × childhood maltreatment × sex interaction (p = 0.041) indicated that the moderating effect of BPD symptoms was present in females only. These findings indicate that attenuation of the HPA axis occurs as a response to early maltreatment rather than being related to the early occurrence of BPD pathology. Traumatized female individuals with BPD symptoms might bypass adaptive HPA axis attenuation. © 2017 S. Karger AG, Basel.

Carnosine Prevents Type 2 Diabetes-Induced Osteoarthritis Through the ROS/NF-κB Pathway.

PubMed

Yang, Yue; Wang, Yang; Kong, Yawei; Zhang, Xiaoning; Zhang, He; Gang, Yi; Bai, Lunhao

2018-01-01

Background: The anti-inflammatory and antioxidant capacity of carnosine (CAR) has been investigated in autoimmune diseases. The aim of this study was to evaluate the potential protective effects of oral CAR supplements to ameliorate type 2 diabetes mellitus (T2DM)-induced osteoarthritis (OA) in rats and its mechanism. Methods: Seventy male Sprague-Dawley rats were randomly divided into the control group (CG, n = 10) and the T2DM group ( n = 60). A rat model of T2DM was established using a high fat diet and streptozotocin (30 mg/kg, i.p.). The 41 rats that developed T2DM were chosen and randomly divided into four groups: T2DM-induced OA group (OAG, n = 11), and the T2DM-induced OA with low, moderate, and high-doses of CAR for 8 weeks group (CAR-L, CAR-M, and CAR-H, n = 10). After 13 weeks, all rats were evaluated by enzyme-linked immunosorbent assay (ELISA), histology, immunohistochemistry, and western blotting. Fibroblast-like synoviocytes (FLSs) were obtained from the knee joints of all rats. The effects of CAR on the inflammatory response in interleukin (IL)-1β-stimulated FLSs under a high glucose environment were evaluated by real-time quantitative polymerase chain reaction, western blotting, flow cytometry, and immunofluorescence. Results: The results of ELISA (IL-1β and tumor necrosis factor-α), the histological evaluation (Mankin and OARSI score), western blotting [COL2A1, matrix metalloproteinase (MMP)-3, MMP-13, IL-1β, and nuclear factor-kappaB (NF-κB) p65], and immunohistochemistry (COL2A1, MMP-3, and MMP-13) indicated that oral CAR attenuated the development of T2DM-induced OA and suppressed the inflammatory response. Moreover, CAR alleviated MMP-3 and MMP-13 expression levels by decreasing reactive oxygen species content and suppressing nuclear translocation of NF-κB p65 on IL-1β-induced FLSs in a high glucose environment. Conclusion: These findings indicate that oral CAR had chondroprotective effects on T2DM-induced OA through the reactive oxygen species (ROS)/NF-κB pathway.

The Effects of Multivitamin Supplementation on Diurnal Cortisol Secretion and Perceived Stress

PubMed Central

Camfield, David A.; Wetherell, Mark A.; Scholey, Andrew B.; Cox, Katherine H. M.; Fogg, Erin; White, David J.; Sarris, Jerome; Kras, Marni; Stough, Con; Sali, Avni; Pipingas, Andrew

2013-01-01

Recent evidence suggests that dietary intake of vitamins, in particular the B-vitamins including B6, B9 and B12 may have a number of positive effects on mood and stress. Given the effects of stress on a range of biological mechanisms including the endocrine system, it could be reasonably expected that multivitamin supplementation may also affect markers of these mechanisms such as diurnal cortisol secretion. In the current double-blind placebo-controlled study 138 adults (aged 20 to 50 years) were administered a multivitamin containing B-vitamins versus placebo over a 16-week period. Salivary cortisol measurements were taken at waking, 15-min, 30-min and at bedtime, at baseline, 8-weeks and 16-weeks. Perceived Stress (PSS) was measured at baseline, 8-weeks and 16-weeks, while blood serum measures of B6, B12 and homocysteine (HCy) as well as red cell folate (B9) were also collected at these time points. A significant interaction was found between treatment group and study visit for the Cortisol Awakening Response (CAR). Compared to placebo, at 16-weeks multivitamin supplementation was found to be associated with a near-significant trend towards an increased CAR. No significant differences in PSS were found between groups, with PSS increasing in both groups across the course of the study. Red cell folate was found to be significantly correlated with the CAR response at 16-weeks while HCy levels were not found to be associated with the CAR response, although HCy significantly correlated with waking cortisol levels at 8-weeks. A possible interpretation of the elevation in CAR associated with multivitamin supplementation is that this represents an adaptive response to everyday demands in healthy participants. PMID:24284609

Cloning of an ets-Related Transcription Factor Involved in a Novel Epigenetic Mechanism of Mammary Carcinogenesis

DTIC Science & Technology

2001-05-01

dystrophin gene promoter is regulated by YY1 and DPBF (33). Other studies showed that serum response factor (SRF) is required for muscle-specific...transcriptional activation through CArG boxes (68) and that SRF competes with YY1 for binding to wild-type CArG elements (51). CBF-A has significant...between SRF and YY1 proteins at CArG elements has been described in chicken skeletal muscle cells(36). Our previous study in a rat mammary carcinoma cell

Dose-response characteristics of Clematis triterpenoid saponins and clematichinenoside AR in rheumatoid arthritis rats by liquid chromatography/mass spectrometry-based serum and urine metabolomics.

PubMed

Li, Rui; Guo, Lin-Xiu; Li, Yi; Chang, Wen-Qi; Liu, Jian-Qun; Liu, Li-Fang; Xin, Gui-Zhong

2017-03-20

Clematidis Radix et Rhizoma is a traditional Chinese medicine widely used for treating arthritic disease. Clematis triterpenoid saponins (TS) and clematichinenoside AR (C-AR) have been considered to be responsible for its antiarthritic effects. However, the underling mechanism is still unclear because of their low bioavailability. To address of this issue, metabolomics tools were performed to determine metabolic variations associated with rheumatoid arthritis (RA) and responses to Clematis TS, C-AR and positive drug (Triptolide, TP) treatments. This metabolomics investigation of RA was conducted in collagen-induced arthritis (CIA) rats. Liquid chromatography/mass spectrometry and multivariate statistical tools were used to identify the alteration of serum and urine metabolites associated with RA and responses to drug treatment. As a result, 45 potential metabolites associated with RA were identified. After treatment, a total of 24 biomarkers were regulated to normal like levels. Among these, PC(18:0/20:4), 9,11-octadecadienoic acid, arachidonic acid, 1-methyladenosine, valine, hippuric acid and pantothenic acid etc, were reversed in Clematis TS and C-AR groups. Tetrahydrocortisol was regulated to normal levels in Clematis TS and TP groups, while 3,7,12-trihydroxycholan-24-oic acid was regulated in C-AR and TP groups. Biomarkers like citric acid, p-cresol glucuronide, creatinine, cortolone were reversed in TP group. Copyright © 2016 Elsevier B.V. All rights reserved.

Contributing Factors to Driver's Over-trust in a Driving Support System for Workload Reduction

NASA Astrophysics Data System (ADS)

Itoh, Makoto

Avoiding over-trust in machines is a vital issue in order to establish intelligent driver support systems. It is necessary to distinguish systems for workload reduction from systems for accident prevention/mitigation. This study focuses on over-trust in an Adaptive Cruise Control (ACC) system as a typical driving support system for workload reduction. By conducting an experiment, we obtained a case in which a driver trusted the ACC system too much. Concretely speaking, the driver just watched the ACC system crashing into a stopped car even though the ACC system was designed to ignore such stopped cars. This paper investigates possible contributing factors to the driver' s over-trust in the ACC system. The results suggest that emerging trust in the dimension of performance may cause over-trust in the dimension of method or purpose.

Monitoring the soot emissions of passing cars.

PubMed

Kurniawan, A; Schmidt-Ott, A

2006-03-15

We report on the first application of a novel fast on-road sensing method for measurement of particulate emissions of individual passing passenger cars. The studywas motivated by the shift of interest from gases to particles in connection with strong adverse health effects. The results correspond very much to findings by Beaton et al. (Science, May 19,1995) for gaseous hydrocarbon and CO emissions: A small percentage of "superpolluters" (here 5%) account for a high percentage (here 43%) of the pollution (here elemental carbon). We estimate that up to 50% of the particulate emissions of vehicles could be avoided on the basis of the present legislation, if on-road monitoring would be applied to enforce maintenance. Our fast sensing method for particles is based on photoelectron emission from the emitted airborne soot particles in combination with a CO2 sensor delivering a reference.

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy.

PubMed

Brown, Christine E; Alizadeh, Darya; Starr, Renate; Weng, Lihong; Wagner, Jamie R; Naranjo, Araceli; Ostberg, Julie R; Blanchard, M Suzette; Kilpatrick, Julie; Simpson, Jennifer; Kurien, Anita; Priceman, Saul J; Wang, Xiuli; Harshbarger, Todd L; D'Apuzzo, Massimo; Ressler, Julie A; Jensen, Michael C; Barish, Michael E; Chen, Mike; Portnow, Jana; Forman, Stephen J; Badie, Behnam

2016-12-29

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

PubMed Central

Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

2010-01-01

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer

PubMed Central

Cartellieri, Marc; Bachmann, Michael; Feldmann, Anja; Bippes, Claudia; Stamova, Slava; Wehner, Rebekka; Temme, Achim; Schmitz, Marc

2010-01-01

CD4+ and CD8+ T lymphocytes are powerful components of adaptive immunity, which essentially contribute to the elimination of tumors. Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors (CARs). First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients. However, further improvement is required, which may be achieved by second or third generation CAR-engrafted T cells. PMID:20467460

Category search speeds up face-selective fMRI responses in a non-hierarchical cortical face network.

PubMed

Jiang, Fang; Badler, Jeremy B; Righi, Giulia; Rossion, Bruno

2015-05-01

The human brain is extremely efficient at detecting faces in complex visual scenes, but the spatio-temporal dynamics of this remarkable ability, and how it is influenced by category-search, remain largely unknown. In the present study, human subjects were shown gradually-emerging images of faces or cars in visual scenes, while neural activity was recorded using functional magnetic resonance imaging (fMRI). Category search was manipulated by the instruction to indicate the presence of either a face or a car, in different blocks, as soon as an exemplar of the target category was detected in the visual scene. The category selectivity of most face-selective areas was enhanced when participants were instructed to report the presence of faces in gradually decreasing noise stimuli. Conversely, the same regions showed much less selectivity when participants were instructed instead to detect cars. When "face" was the target category, the fusiform face area (FFA) showed consistently earlier differentiation of face versus car stimuli than did the "occipital face area" (OFA). When "car" was the target category, only the FFA showed differentiation of face versus car stimuli. These observations provide further challenges for hierarchical models of cortical face processing and show that during gradual revealing of information, selective category-search may decrease the required amount of information, enhancing and speeding up category-selective responses in the human brain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epstein Barr virus–specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease

PubMed Central

Rooney, Cliona M.; Di Stasi, Antonio; Abken, Hinrich; Hombach, Andreas; Foster, Aaron E.; Zhang, Lan; Heslop, Helen E.; Brenner, Malcolm K.; Dotti, Gianpietro

2007-01-01

Adoptive transfer of Epstein Barr virus (EBV)–specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (± 11%) and 22% (± 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR+ CTLs killed both autologous EBV+ cells through their native receptor and EBV−/CD30+ targets through their major histocompatibility complex (MHC)–unrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR+ CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR+ EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBV−/CD30+ tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD. PMID:17507664

Development of wireless vehicle remote control for fuel lid operation

NASA Astrophysics Data System (ADS)

Sulaiman, N.; Jadin, M. S.; Najib, M. S.; Mustafa, M.; Azmi, S. N. F.

2018-04-01

Nowadays, the evolution of the vehicle technology had made the vehicle especially car to be equipped with a remote control to control the operation of the locking and unlocking system of the car’s door and rear’s bonnet. However, for the fuel or petrol lid, it merely can be opened from inside the car’s cabin by handling the fuel level inside the car’s cabin to open the fuel lid. The petrol lid can be closed by pushing the lid by hand. Due to the high usage of using fuel lever to open the fuel lid when refilling the fuel, the car driver might encounter the malfunction of fuel lid (fail to open) when pushing or pulling the fuel lever. Thus, the main aim of the research is to enhance the operation of an existing car remote control where the car fuel lid can be controlled using two techniques; remote control-based and smartphone-based. The remote control is constructed using Arduino microcontroller, wireless sensors and XCTU software to set the transmitting and receiving parameters. Meanwhile, the smartphone can control the operation of the fuel lid by communicating with Arduino microcontroller which is attached to the fuel lid using Bluetooth sensor to open the petrol lid. In order to avoid the conflict of instruction between wireless systems with the existing mechanical-based system, the servo motor will be employed to release the fuel lid merely after receiving the instruction from Arduino microcontroller and smartphone. As a conclusion, the prototype of the multipurpose vehicle remote control is successfully invented, constructed and tested. The car fuel lid can be opened either using remote control or smartphone in a sequential manner. Therefore, the outcome of the project can be used to serve as an alternative solution to solve the car fuel lid problem even though the problem rarely occurred.

The cortisol awakening response is associated with performance of a serial sequence reaction time task.

PubMed

Hodyl, Nicolette A; Schneider, Luke; Vallence, Ann-Maree; Clow, Angela; Ridding, Michael C; Pitcher, Julia B

2016-02-01

There is emerging evidence of a relationship between the cortisol awakening response (CAR) and the neural mechanisms underlying learning and memory. The aim of this study was to determine whether the CAR is associated with acquisition, retention and overnight consolidation or improvement of a serial sequence reaction time task. Salivary samples were collected at 0, 15, 30 and 45 min after awakening in 39 healthy adults on 2 consecutive days. The serial sequence reaction time task was repeated each afternoon. Participants completed the perceived stress scale and provided salivary samples prior to testing for cortisol assessment. While the magnitude of the CAR (Z score) was not associated with either baseline performance or the timed improvement during task acquisition of the serial sequence task, a positive correlation was observed with reaction times during the stable performance phase on day 1 (r=0.373, p=0.019). Residuals derived from the relationship between baseline and stable phase reaction times on day 1 were used as a surrogate for the degree of learning: these residuals were also correlated with the CAR mean increase on day 1 (r=0.357, p=0.048). Task performance on day 2 was not associated with the CAR obtained on this same day. No association was observed between the perceived stress score, cortisol at testing or task performance. These data indicate that a smaller CAR in healthy adults is associated with a greater degree of learning and faster performance of a serial sequence reaction time task. These results support recognition of the CAR as an important factor contributing to cognitive performance throughout the day. Copyright © 2015 Elsevier B.V. All rights reserved.

Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis.

PubMed

Powell, Daniel J H; Liossi, Christina; Moss-Morris, Rona; Schlotz, Wolff

2013-11-01

The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism. The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS). Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant. Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

PubMed Central

Fraietta, Joseph A.; Beckwith, Kyle A.; Patel, Prachi R.; Ruella, Marco; Zheng, Zhaohui; Barrett, David M.; Lacey, Simon F.; Melenhorst, Jan Joseph; McGettigan, Shannon E.; Cook, Danielle R.; Zhang, Changfeng; Xu, Jun; Do, Priscilla; Hulitt, Jessica; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Gill, Saar; Porter, David L.; Woyach, Jennifer A.; Long, Meixiao; Johnson, Amy J.; Maddocks, Kami; Muthusamy, Natarajan; Levine, Bruce L.; June, Carl H.; Byrd, John C.

2016-01-01

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749. PMID:26813675

Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.

PubMed

Fraietta, Joseph A; Beckwith, Kyle A; Patel, Prachi R; Ruella, Marco; Zheng, Zhaohui; Barrett, David M; Lacey, Simon F; Melenhorst, Jan Joseph; McGettigan, Shannon E; Cook, Danielle R; Zhang, Changfeng; Xu, Jun; Do, Priscilla; Hulitt, Jessica; Kudchodkar, Sagar B; Cogdill, Alexandria P; Gill, Saar; Porter, David L; Woyach, Jennifer A; Long, Meixiao; Johnson, Amy J; Maddocks, Kami; Muthusamy, Natarajan; Levine, Bruce L; June, Carl H; Byrd, John C; Maus, Marcela V

2016-03-03

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749. © 2016 by The American Society of Hematology.

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

Chimeric Antigen Receptor (CAR)-Specific Monoclonal Antibody to Detect CD19-Specific T Cells in Clinical Trials

PubMed Central

Jena, Bipulendu; Maiti, Sourindra; Huls, Helen; Singh, Harjeet; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

2013-01-01

Clinical trials targeting CD19 on B-cell malignancies are underway with encouraging anti-tumor responses. Most infuse T cells genetically modified to express a chimeric antigen receptor (CAR) with specificity derived from the scFv region of a CD19-specific mouse monoclonal antibody (mAb, clone FMC63). We describe a novel anti-idiotype monoclonal antibody (mAb) to detect CD19-specific CAR+ T cells before and after their adoptive transfer. This mouse mAb was generated by immunizing with a cellular vaccine expressing the antigen-recognition domain of FMC63. The specificity of the mAb (clone no. 136.20.1) was confined to the scFv region of the CAR as validated by inhibiting CAR-dependent lysis of CD19+ tumor targets. This clone can be used to detect CD19-specific CAR+ T cells in peripheral blood mononuclear cells at a sensitivity of 1∶1,000. In clinical settings the mAb is used to inform on the immunophenotype and persistence of administered CD19-specific T cells. Thus, our CD19-specific CAR mAb (clone no. 136.20.1) will be useful to investigators implementing CD19-specific CAR+ T cells to treat B-lineage malignancies. The methodology described to develop a CAR-specific anti-idiotypic mAb could be extended to other gene therapy trials targeting different tumor associated antigens in the context of CAR-based adoptive T-cell therapy. PMID:23469246

Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma.

PubMed

Chmielewski, Markus; Hombach, Andreas A; Abken, Hinrich

2014-01-01

Adoptive T-cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo-engineered patient T cells, which are redirected by a chimeric antigen receptor (CAR) and recognize a predefined target by an antibody-derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. However, given the tremendous phenotypic diversity in solid tumor lesions, a reasonable number of cancer cells are not recognized by a given CAR, considerably reducing the therapeutic success. This article reviews a recently described strategy for overcoming this shortcoming of the CAR T-cell therapy by modulating the tumor stroma by a CAR T-cell-secreted transgenic cytokine like interleukin-12 (IL-12). The basic process is that CAR T cells, when activated by their CAR, deposit IL-12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCKs, T cells redirected for universal cytokine-mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Vital Sign Monitoring and Mobile Phone Usage Detection Using IR-UWB Radar for Intended Use in Car Crash Prevention.

PubMed

Leem, Seong Kyu; Khan, Faheem; Cho, Sung Ho

2017-05-30

In order to avoid car crashes, active safety systems are becoming more and more important. Many crashes are caused due to driver drowsiness or mobile phone usage. Detecting the drowsiness of the driver is very important for the safety of a car. Monitoring of vital signs such as respiration rate and heart rate is important to determine the occurrence of driver drowsiness. In this paper, robust vital signs monitoring through impulse radio ultra-wideband (IR-UWB) radar is discussed. We propose a new algorithm that can estimate the vital signs even if there is motion caused by the driving activities. We analyzed the whole fast time vital detection region and found the signals at those fast time locations that have useful information related to the vital signals. We segmented those signals into sub-signals and then constructed the desired vital signal using the correlation method. In this way, the vital signs of the driver can be monitored noninvasively, which can be used by researchers to detect the drowsiness of the driver which is related to the vital signs i.e., respiration and heart rate. In addition, texting on a mobile phone during driving may cause visual, manual or cognitive distraction of the driver. In order to reduce accidents caused by a distracted driver, we proposed an algorithm that can detect perfectly a driver's mobile phone usage even if there are various motions of the driver in the car or changes in background objects. These novel techniques, which monitor vital signs associated with drowsiness and detect phone usage before a driver makes a mistake, may be very helpful in developing techniques for preventing a car crash.

Vital Sign Monitoring and Mobile Phone Usage Detection Using IR-UWB Radar for Intended Use in Car Crash Prevention

PubMed Central

Leem, Seong Kyu; Khan, Faheem; Cho, Sung Ho

2017-01-01

In order to avoid car crashes, active safety systems are becoming more and more important. Many crashes are caused due to driver drowsiness or mobile phone usage. Detecting the drowsiness of the driver is very important for the safety of a car. Monitoring of vital signs such as respiration rate and heart rate is important to determine the occurrence of driver drowsiness. In this paper, robust vital signs monitoring through impulse radio ultra-wideband (IR-UWB) radar is discussed. We propose a new algorithm that can estimate the vital signs even if there is motion caused by the driving activities. We analyzed the whole fast time vital detection region and found the signals at those fast time locations that have useful information related to the vital signals. We segmented those signals into sub-signals and then constructed the desired vital signal using the correlation method. In this way, the vital signs of the driver can be monitored noninvasively, which can be used by researchers to detect the drowsiness of the driver which is related to the vital signs i.e., respiration and heart rate. In addition, texting on a mobile phone during driving may cause visual, manual or cognitive distraction of the driver. In order to reduce accidents caused by a distracted driver, we proposed an algorithm that can detect perfectly a driver's mobile phone usage even if there are various motions of the driver in the car or changes in background objects. These novel techniques, which monitor vital signs associated with drowsiness and detect phone usage before a driver makes a mistake, may be very helpful in developing techniques for preventing a car crash. PMID:28556818

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.

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

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.

Fatigue based design and analysis of wheel hub for Student formula car by Simulation Approach

NASA Astrophysics Data System (ADS)

Gowtham, V.; Ranganathan, A. S.; Satish, S.; Alexis, S. John; Siva kumar, S.

2016-09-01

In the existing design of Wheel hub used for Student formula cars, the brake discs cannot be removed easily since the disc is mounted in between the knuckle and hub. In case of bend or any other damage to the disc, the replacement of the disc becomes difficult. Further using OEM hub and knuckle that are used for commercial vehicles will result in increase of unsprung mass, which should be avoided in Student formula cars for improving the performance. In this design the above mentioned difficulties have been overcome by redesigning the hub in such a way that the brake disc could be removed easily by just removing the wheel and the caliper and also it will have reduced weight when compared to existing OEM hub. A CAD Model was developed based on the required fatigue life cycles. The forces acting on the hub were calculated and linear static structural analysis was performed on the wheel hub for three different materials using ANSYS Finite Element code V 16.2. The theoretical fatigue strength was compared with the stress obtained from the structural analysis for each material.

Can new passenger cars reduce pedestrian lower extremity injury? A review of geometrical changes of front-end design before and after regulatory efforts.

PubMed

Nie, Bingbing; Zhou, Qing

2016-10-02

Pedestrian lower extremity represents the most frequently injured body region in car-to-pedestrian accidents. The European Directive concerning pedestrian safety was established in 2003 for evaluating pedestrian protection performance of car models. However, design changes have not been quantified since then. The goal of this study was to investigate front-end profiles of representative passenger car models and the potential influence on pedestrian lower extremity injury risk. The front-end styling of sedans and sport utility vehicles (SUV) released from 2008 to 2011 was characterized by the geometrical parameters related to pedestrian safety and compared to representative car models before 2003. The influence of geometrical design change on the resultant risk of injury to pedestrian lower extremity-that is, knee ligament rupture and long bone fracture-was estimated by a previously developed assessment tool assuming identical structural stiffness. Based on response surface generated from simulation results of a human body model (HBM), the tool provided kinematic and kinetic responses of pedestrian lower extremity resulted from a given car's front-end design. Newer passenger cars exhibited a "flatter" front-end design. The median value of the sedan models provided 87.5 mm less bottom depth, and the SUV models exhibited 94.7 mm less bottom depth. In the lateral impact configuration similar to that in the regulatory test methods, these geometrical changes tend to reduce the injury risk of human knee ligament rupture by 36.6 and 39.6% based on computational approximation. The geometrical changes did not significantly influence the long bone fracture risk. The present study reviewed the geometrical changes in car front-ends along with regulatory concerns regarding pedestrian safety. A preliminary quantitative benefit of the lower extremity injury reduction was estimated based on these geometrical features. Further investigation is recommended on the structural changes and inclusion of more accident scenarios.

An investigation into NVC characteristics of vehicle behaviour using modal analysis

NASA Astrophysics Data System (ADS)

Hanouf, Zahir; Faris, Waleed F.; Ahmad, Kartini

2017-03-01

NVC characterizations of vehicle behavior is one essential part of the development targets in automotive industries. Therefore understanding dynamic behavior of each structural part of the vehicle is a major requirement in improving the NVC characteristics of a vehicle. The main focus of this research is to investigate structural dynamic behavior of a passenger car using modal analysis part by part technique and apply this method to derive the interior noise sources. In the first part of this work computational modal analysis part by part tests were carried out to identify the dynamic parameters of the passenger car. Finite elements models of the different parts of the car are constructed using VPG 3.2 software. Ls-Dyna pre and post processing was used to identify and analyze the dynamic behavior of each car components panels. These tests had successfully produced natural frequencies and their associated mode shapes of such panels like trunk, hood, roof and door panels. In the second part of this research, experimental modal analysis part by part is performed on the selected car panels to extract modal parameters namely frequencies and mode shapes. The study establishes the step-by-step procedures to carry out experimental modal analysis on the car structures, using single input excitation and multi-output responses (SIMO) technique. To ensure the validity of the results obtained by the previous method an inverse method was done by fixing the response and moving the excitation and the results found were absolutely the same. Finally, comparison between results obtained from both analyses showed good similarity in both frequencies and mode shapes. Conclusion drawn from this part of study was that modal analysis part-by-part can be strongly used to establish the dynamic characteristics of the whole car. Furthermore, the developed method is also can be used to show the relationship between structural vibration of the car panels and the passengers’ noise comfort inside the cabin.

Coherent anti-Stokes Raman scattering enhancement of thymine adsorbed on graphene oxide

PubMed Central

2014-01-01

Coherent anti-Stokes Raman scattering (CARS) of carbon nanostructures, namely, highly oriented pyrolytic graphite, graphene nanoplatelets, graphene oxide, and multiwall carbon nanotubes as well CARS spectra of thymine (Thy) molecules adsorbed on graphene oxide were studied. The spectra of the samples were compared with spontaneous Raman scattering (RS) spectra. The CARS spectra of Thy adsorbed on graphene oxide are characterized by shifts of the main bands in comparison with RS. The CARS spectra of the initial nanocarbons are definitely different: for all investigated materials, there is a redistribution of D- and G-mode intensities, significant shift of their frequencies (more than 20 cm-1), and appearance of new modes about 1,400 and 1,500 cm-1. The D band in CARS spectra is less changed than the G band; there is an absence of 2D-mode at 2,600 cm-1 for graphene and appearance of intensive modes of the second order between 2,400 and 3,000 cm-1. Multiphonon processes in graphene under many photon excitations seem to be responsible for the features of the CARS spectra. We found an enhancement of the CARS signal from thymine adsorbed on graphene oxide with maximum enhancement factor about 105. The probable mechanism of CARS enhancement is discussed. PMID:24948887

In vivo lipid saturation study of C. elegans using quantitative broadband coherent anti-Stokes Raman imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Littleton, Bradley; Kavanagh, Thomas; Nie, Yu; Abbate, Vincenzo; Hylands, Peter; Sturzenbaum, Stephen; Richards, David

2016-03-01

In vivo lipid saturation maps of microscopic nematodes (Caenorhabditis elegans) have been produced using our novel Spectral Interferometric Polarisation Coherent anti-Stokes Raman Scattering (SIP-CARS) imaging technique. This technique employs simple passive polarisation optics and a balanced homodyne detection scheme to exploit symmetries in the CARS polarisation response resulting in the complete cancellation of the non-resonant background (NRB) and real component of the CARS signal (with no prior or post assumptions as regards to their form). The remaining imaginary component of the CARS response is linear with analyte concentration and directly relatable to the spontaneous Raman spectrum [1]. Furthermore, the resonant CARS signal is interferometrically amplified by the non-resonant response, a necessity for rapid imaging at biologically relevant powers [2]. This technique permits acquisition of a broad NRB-free spectrum, in excess of 1800cm-1, in a single exposure at each pixel. This allows simultaneous determination of lipid droplet saturation, from the fingerprint region, and lipid order, from the C-H stretch region from which maps can be readily constructed. Additionally exploiting the dispersive nature of our signal collection two-photon autofluorescence can be isolated and images subsequently produced. We have successfully applied this technique to identify differences in lipid saturation distributions in selective C. elegans mutants and demonstrated that the technique is sufficiently sensitive to detect the effects of lipid metabolism altering drugs on wild type C. elegans. [1] Littleton et al, Phys Rev Lett, 111, 103902 (2013) [2] Parekh et al, Biophys J, 99, 2695-2704 (2010)

Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle

PubMed Central

Hombach, Andreas A.; Abken, Hinrich

2013-01-01

Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed spectacular efficacy in the treatment of leukemia in recent early phase trials. Patient’s T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG1+ CD57+ CD7− CCR7− phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134) stimulation. We discuss the strategy with respect to prolong the anti-tumor response and to improve the over-all efficacy of adoptive cell therapy. PMID:23761793

Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle.

PubMed

Hombach, Andreas A; Abken, Hinrich

2013-01-01

Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed spectacular efficacy in the treatment of leukemia in recent early phase trials. Patient's T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG1(+) CD57(+) CD7(-) CCR7(-) phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134) stimulation. We discuss the strategy with respect to prolong the anti-tumor response and to improve the over-all efficacy of adoptive cell therapy.

Construction and evaluation of a novel humanized HER2-specific chimeric receptor

PubMed Central

2014-01-01

Introduction The human epidermal growth factor receptor 2 (HER2) represents one of the most studied tumor-associated antigens (TAAs) for cancer immunotherapy. The monoclonal antibody (mAb) trastuzumab has improved the outcomes of patients with HER2+ breast cancer. However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed. Methods HER2-specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR). Using a multistep overlap extension PCR method, we constructed a novel, humanized HER2 CAR-containing, chA21 single-chain variable fragment (scFv) region of antigen-specific mAb and T-cell intracellular signaling chains made up of CD28 and CD3ζ. An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells. Furthermore, SKBR3 tumor–bearing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were treated with HER2 CAR T cells to evaluate antitumor activity. Human CD3+ T cell accumulation in tumor xenograft was detected by immunohistochemistry. Results chA21-28z CAR was successfully constructed, and both CD4+ and CD8+ T cells were transduced. The expanded HER2 CAR T cells expressed a central memory phenotype and specifically reacted against HER2+ tumor cell lines. Furthermore, the SKBR3 tumor xenograft model revealed that HER2 CAR T cells significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed robust accumulation of human CD3+ T cells in regressing SKBR3 lesions. Conclusions The results of this study show that novel chA21 scFv-based, HER2-specific CAR T cells not only recognized and killed HER2+ breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo. Our data support further exploration of the HER2 CAR T-cell therapy for HER2-expressing cancers. PMID:24919843

Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race.

PubMed

Harrer, Dennis C; Dörrie, Jan; Schaft, Niels

2018-05-01

Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against acute lymphoblastic leukemia, and resulted in a very recent United States Food and Drug Administration approval of the first CAR-T-cell therapy. In most studies CARs are transferred to conventional αβT cells. Nevertheless, transferring a CAR into different cell types, such as γδT cells, natural killer cells, natural killer T cells, and myeloid cells has yet received relatively little attention, although these cell types possess unique features that may aid in surmounting some of the hurdles CAR-T-cell therapy currently faces. This review focuses on CAR therapy using effectors beyond conventional αβT cells and discusses those strategies against the backdrop of developing a safe, powerful, and durable cancer therapy.

Cortisol responses to naturalistic and laboratory stress in student teachers: comparison with a non-stress control day.

PubMed

Wolfram, Maren; Bellingrath, Silja; Feuerhahn, Nicolas; Kudielka, Brigitte M

2013-04-01

Ambulatory assessments of hypothalamus-pituitary-adrenal axis responses to acute natural stressors yield evidence on stress regulation with high ecological validity. Sampling of salivary cortisol is a standard technique in this field. In 21 healthy student teachers, we assessed cortisol responses to a demonstration lesson. On a control day, sampling was repeated at analogous times. Additionally, the cortisol awakening response (CAR) was assessed on both days. Participants were also exposed to a laboratory stressor, the Trier Social Stress Test, and rated their individual levels of chronic work stress. In pre-to-post-stress assessment, cortisol levels declined after the lesson. However, post-stress cortisol levels were significantly higher compared with those on the control day. Also, the Trier Social Stress Test yielded higher cortisol responses when using the control day as reference baseline. Associations between the CAR and chronic stress measures were observed solely on the control day. There were no significant associations between cortisol responses to the natural and laboratory stressors. Our results indicate that a control day might be an important complement in laboratory but especially in ambulatory stress research. Furthermore, associations between chronic stress measures and the CAR might be obscured by acute stress exposure. Finally, responses to the laboratory stressor do not seem to mirror natural stress responses. Copyright © 2012 John Wiley & Sons, Ltd.

Challenges and prospects of chimeric antigen receptor T cell therapy in solid tumors.

PubMed

Jindal, Vishal; Arora, Ena; Gupta, Sorab

2018-05-05

Chimeric antigen receptor (CAR) T cell therapy is a novel and innovative immunotherapy. CAR-T cells are genetically engineered T cells, carrying MHC independent specific antigen receptor and co-stimulatory molecule which can activate an immune response to a cancer specific antigen. This therapy showed great results in hematological malignancies but were unable to prove their worth in solid tumors. Likely reasons for their failure are lack of antigens, poor trafficking, and hostile tumor microenvironment. Excessive amount of research is going on to improve the efficacy of CAR T cell therapy in solid tumors. In this article, we will discuss the challenges faced in improving the outcome of CAR T cell therapy in solid tumors and various strategies adopted to curb them.

Finite element prediction on the chassis design of UniART4 racing car

NASA Astrophysics Data System (ADS)

Zaman, Z. I.; Basaruddin, K. S.; Basha, M. H.; Rahman, M. T. Abd; Daud, R.

2017-09-01

This paper presents the analysis and evaluation of the chassis design for University Automotive Racing Team No. 4 (UniART4) car based on finite element analysis. The existing UniART4 car chassis was measured and modelled geometrically using Solidwork before analysed in FEA software (ANSYS). Four types of static structural analysis were used to predict the chassis design capability under four different loading conditions; vertical bending, lateral bending, lateral torsion and horizontal lozenging. The results showed the chassis subjected to the highest stress and strain under horizontal lozenging, whereas the minimum stress and strain response was obtained under lateral bending. The present analysis result could provide valuable information in predicting the sustainability of the current UniART car chassis design.

Vertical and pitching resonance of train cars moving over a series of simple beams

NASA Astrophysics Data System (ADS)

Yang, Y. B.; Yau, J. D.

2015-02-01

The resonant response, including both vertical and pitching motions, of an undamped sprung mass unit moving over a series of simple beams is studied by a semi-analytical approach. For a sprung mass that is very small compared with the beam, we first simplify the sprung mass as a constant moving force and obtain the response of the beam in closed form. With this, we then solve for the response of the sprung mass passing over a series of simple beams, and validate the solution by an independent finite element analysis. To evaluate the pitching resonance, we consider the cases of a two-axle model and a coach model traveling over rough rails supported by a series of simple beams. The resonance of a train car is characterized by the fact that its response continues to build up, as it travels over more and more beams. For train cars with long axle intervals, the vertical acceleration induced by pitching resonance dominates the peak response of the train traveling over a series of simple beams. The present semi-analytical study allows us to grasp the key parameters involved in the primary/sub-resonant responses. Other phenomena of resonance are also discussed in the exemplar study.

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.

Attenuation of maternal psychophysiological stress responses and the maternal cortisol awakening response over the course of human pregnancy.

PubMed

Entringer, Sonja; Buss, Claudia; Shirtcliff, Elizabeth A; Cammack, Alison L; Yim, Ilona S; Chicz-DeMet, Aleksandra; Sandman, Curt A; Wadhwa, Pathik D

2010-05-01

The effects of maternal stress during pregnancy may depend, in part, on the timing in gestation of the occurrence of stress. The aim of the present study was to examine the effect of stage of gestation on maternal psychophysiological responses to stress using a standardized laboratory paradigm and on the cortisol response to awakening (CAR). A longitudinal design was employed to quantify maternal psychophysiological stress reactivity [changes in heart rate (HR), blood pressure, salivary cortisol, and psychological distress in response to the trier social stress test (TSST)] and the CAR at approximately 17 and 31 weeks gestation in a sample of 148 women. To account for the possible effects of habituation when being exposed to the same stress protocol twice, a non-pregnant comparison group (CG, N = 36) also underwent these assessments at two time points, with a comparable time interval between the assessments. In both groups, the TSST elicited significant changes in maternal HR, mean arterial pressure, and psychological distress levels but not a significant increase in cortisol levels. Among the pregnant women (pregnant group(PG)), the stressor-induced increases in HR, blood pressure, and psychological distress were significantly lower at the second (31 weeks gestation) compared to the first (17 weeks gestation) assessment of pregnancy (all p < 0.01). The maternal CAR was also significantly attenuated in later compared to earlier gestation (p = 0.003). In the CG, there were no significant differences in psychophysiological stress responses and in the CAR across the two assessments. Among pregnant women there is a progressive attenuation of psychophysiological stress responses with advancing gestation. This attenuation is unlikely to be attributable to habituation. Individual differences in the degree of attenuation of stress responses over gestation may represent a novel marker of stress susceptibility in human pregnancy.

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

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case-control study in the Chinese population.

PubMed

Tian, Tian; Xiao, Ling; Du, Jiangbo; Zhu, Xun; Gu, Yayun; Qin, Na; Yan, Caiwang; Liu, Li; Ma, Hongxia; Jiang, Yue; Chen, Jiaping; Yu, Hao; Dai, Juncheng

2017-11-01

The cysteinyl transfer RNA synthetase gene (CARS) is located on chromosome band 11p15.5, which is an important tumor-suppressor gene region. Mutations in CARS have been identified in many kinds of cancers; however, evidence for a relationship between genetic variants in CARS and gastric cancer at the population level is still lacking. Thus, we explored the association of variants in CARS with gastric cancer using a two-stage case-control strategy in Chinese. We undertook a two-stage case-control study to investigate the association between polymorphisms in CARS and risk of gastric cancer with use of an Illumina Infinium ® BeadChip and an ABI 7900 system. Four single nucleotide polymorphisms (SNPs) were significantly associated with gastric cancer risk in both the discovery stage and the validation stage after adjustment for age and sex. In addition, the combined results of the two stages showed these SNPs were related to gastric cancer risk (P false discovery rate  ≤ 0.001 for rs384,490, rs729662, rs2071101, and rs7394702). In silico analyses revealed that rs384490 and rs7394702 could affect transcription factor response elements or DNA methylation of CARS, and rs729662 was associated with the prognosis of gastric cancer. Additionally, expression quantitative trait loci analysis showed rs384490 and rs729662 might alter expression of CARS-related genes. The potential functional SNPs in CARS might influence the biological functions of CARS or CARS-related genes and ultimately modify the occurrence and development of gastric cancer in Chinese. Further large-scale population-based studies or biological functional assays are warranted to validate our findings.

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

Cortisol Awakening Response in Elite Military Men: Summary Parameters, Stability Measurement, and Effect of Compliance.

PubMed

Taylor, Marcus K; Hernández, Lisa M; Fuller, Shiloah A; Sargent, Paul; Padilla, Genieleah A; Harris, Erica

2016-11-01

The cortisol awakening response (CAR) holds promise as a clinically important marker of health status. However, CAR research is routinely challenged by its innate complexity, sensitivity to confounds, and methodological inconsistencies. In this unprecedented characterization of CAR in elite military men (N = 58), we established summary parameters, evaluated sampling stability across two consecutive days, and explored the effect of subject compliance. Average salivary cortisol concentrations increased nearly 60% within 30 minutes of waking, followed by a swift recovery to waking values at 60 minutes. Approximately one in six were classified as negative responders (i.e., <0% change from waking to 30-minute postawakening). Three summary parameters of magnitude, as well as three summary parameters of pattern, were computed. Consistent with our hypothesis, summary parameters of magnitude displayed superior stability compared with summary parameters of pattern in the total sample. As expected, compliance with target sampling times was relatively good; average deviations of self-reported morning sampling times in relation to actigraph-derived wake times across both days were within ±5 minutes, and nearly two-thirds of the sample was classified as CAR compliant across both days. Although compliance had equivocal effects on some measures of magnitude, it substantially improved the stability of summary parameters of pattern. The first of its kind, this study established the foundation for a program of CAR research in a profoundly resilient yet chronically stressed population. Building from this, our forthcoming research will evaluate demographic, biobehavioral, and clinical determinants of CAR in this unique population. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

Driving CAR-Based T-Cell Therapy to Success

PubMed Central

Jena, Bipulendu; Moyes, Judy S; Huls, Helen; Cooper, Laurence JN

2014-01-01

T-cells that have been genetically modified, activated, and propagated ex vivo can be infused to control tumor progression in patients who are refractory to conventional treatments. Early-phase clinical trials demonstrate that the tumor-associated antigen (TAA) CD19 can be therapeutically engaged through the enforced expression of a chimeric antigen receptor (CAR) on clinical-grade T-cells. Advances in vector design, the architecture of the CAR molecule especially as associated with T-cell co-stimulatory pathways, and understanding of the tumor microenvironment, play significant roles in the successful treatment of medically fragile patients. However, some recipients of CAR+ T-cells demonstrate incomplete responses. Understanding the potential for treatment failure provides a pathway to improve the potency of adoptive transfer of CAR+ T-cells. High throughput single-cell analyses to understand the complexity of the inoculum coupled with animal models may provide insight into the therapeutic potential of genetically modified T-cells. This review focusses on recent advances regarding the human application of C19-specific CAR+ T-cells and explores how their success for hematologic cancers can provide a framework for investigational treatment of solid tumor malignancies. PMID:24488441

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.

Insulation detection of electric vehicle batteries

NASA Astrophysics Data System (ADS)

Dai, Qiqi; Zhu, Zhongwen; Huang, Denggao; Du, Mingxing; Wei, Kexin

2018-06-01

In this paper, an electric vehicle insulation detection method with single side switching fixed resistance is designed, and the hardware and software design of the system are given. The experiment proves that the insulation detection system can detect the insulation resistance in a wide range of resistance values, and accurately report the fault level. This system can effectively monitor the insulation fault between the car body and the high voltage line and avoid the passengers from being injured.

Mode of Action and Human Relevance Analysis for Nuclear Receptor-Mediated Liver Toxicity: A Case Study with Phenobarbital as a Model Constitutive Androstane Receptor (CAR) Activator

EPA Science Inventory

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key nuclear receptors involved in the regulation of cellular responses. to exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non­ genotoxic i...

The Effect of Automobile Safety on Vehicle Type Choice: An Empirical Study.

ERIC Educational Resources Information Center

McCarthy, Patrick S.

An analysis was made of the extent to which the safety characteristics of new vehicles affect consumer purchase decisions. Using an extensive data set that combines vehicle data collected by the Automobile Club of Southern California Target Car Program with the responses from a national household survey of new car buyers, a statistical model of…

Pavlovian drug-sickness pairings result in the conditioning of an antisickness response.

PubMed

Lett, B T

1983-10-01

After a drug conditioned stimulus (CS) has been injected prior to lithium chloride as the unconditioned stimulus (US) on five occasions, the drug CS becomes able to evoke a conditioned antisickness response (CAR). This CAR is implied by the finding that the CS drug mitigates the conditioned saccharin aversion produced by lithium when it is administered in the interval between saccharin consumption and lithium injection. The following drugs were tested and are listed in approximate order of their effectiveness in producing a conditioned antisickness effect: pentobarbital, ethanol, morphine, amphetamine, and chlordiazepoxide.

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

Community knowledge, attitudes and behaviours about environmental tobacco smoke in homes and cars.

PubMed

Dunn, Jeff; Greenbank, Susan; McDowell, Michelle; Mahoney, Catherine; Mazerolle, Paul; Occhipinti, Stefano; Steginga, Suzanne

2008-08-01

to assess knowledge, attitudes and behaviours about environmental tobacco smoke (ETS) in cars and homes in Queensland. 1,026 randomly selected Queensland residents (84% response) participated in a computer assisted telephone survey to assess knowledge, attitudes and behaviours about ETS in cars and homes; and attitudes towards restrictions on smoking in a range of contexts. Most respondents are aware of the negative health effects of ETS and have smoking bans in their cars (75.8%) and homes (76.8%), however bans are less prevalent for smokers (cars: 37.9%; homes: 51%; p=0.000). For cars/homes, most smokers who did not have smoking bans would not smoke at all around pregnant women (67.7%/53.7%); fewer would refrain for childrenor=2 years (p=0.000) compared to non-parent smokers. Most respondents support car/ home smoking bans for children

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.

Prenatal Stress and the Cortisol Awakening Response in African-American and Caucasian Women in the Third Trimester of Pregnancy.

PubMed

Simon, Clarissa D; Adam, Emma K; Holl, Jane L; Wolfe, Kaitlin A; Grobman, William A; Borders, Ann E B

2016-10-01

Objectives Prior studies have shown significant racial disparities in psychosocial stressors for pregnant women. One physiological mechanism by which prenatal stress is expressed is via the stress-sensitive hormone cortisol, which itself differs by race. In this study, we examine differences in cortisol awakening response (CAR) for African-American and Caucasian pregnant women during late pregnancy, particularly whether racial disparities are evident after accounting for measures of psychosocial stress. Methods During their third trimester of pregnancy (32-40 weeks of gestation), we asked women to self-collect salivary samples at home over 2 days. We then measured salivary cortisol across the day for 30 pregnant women (18 Caucasian; 12 African-American) to examine the CAR by race and by multiple measures of self-reported psychosocial stress, including perceived discrimination. Results Although the women in our sample showed normative cortisol diurnal rhythms (high on waking, peak 30 min post-waking, lowest at bedtime), we found that African-American women had blunted (smaller) awakening responses compared to Caucasian women (p < 0.05). The CAR was significantly larger in Caucasian women compared to African-American women even after accounting for covariates in a multivariate equation. However, when we added measures of psychosocial stress to the multivariate equation, higher levels of stress were significantly associated with a smaller CAR (p < 0.05), and the association between maternal race and CAR was no longer significant. Conclusions Our results add to a growing body of evidence that racial differences in the activity of the hypothalamic-pituitary-adrenal axis are associated with psychosocial stress during pregnancy.

Changes in the transcriptional profile in response to overexpression of the osteopontin-c splice isoform in ovarian (OvCar-3) and prostate (PC-3) cancer cell lines

PubMed Central

2014-01-01

Background Especially in human tumor cells, the osteopontin (OPN) primary transcript is subject to alternative splicing, generating three isoforms termed OPNa, OPNb and OPNc. We previously demonstrated that the OPNc splice variant activates several aspects of the progression of ovarian and prostate cancers. The goal of the present study was to develop cell line models to determine the impact of OPNc overexpression on main cancer signaling pathways and thus obtain insights into the mechanisms of OPNc pro-tumorigenic roles. Methods Human ovarian and prostate cancer cell lines, OvCar-3 and PC-3 cells, respectively, were stably transfected to overexpress OPNc. Transcriptomic profiling was performed on these cells and compared to controls, to identify OPNc overexpression-dependent changes in gene expression levels and pathways by qRT-PCR analyses. Results Among 84 genes tested by using a multiplex real-time PCR Cancer Pathway Array approach, 34 and 16, respectively, were differentially expressed between OvCar-3 and PC-3 OPNc-overexpressing cells in relation to control clones. Differentially expressed genes are included in all main hallmarks of cancer, and several interacting proteins have been identified using an interactome network analysis. Based on marked up-regulation of Vegfa transcript in response to OPNc overexpression, we partially validated the array data by demonstrating that conditioned medium (CM) secreted from OvCar-3 and PC-3 OPNc-overexpressing cells significantly induced endothelial cell adhesion, proliferation and migration, compared to CM secreted from control cells. Conclusions Overall, the present study elucidated transcriptional changes of OvCar-3 and PC-3 cancer cell lines in response to OPNc overexpression, which provides an assessment for predicting the molecular mechanisms by which this splice variant promotes tumor progression features. PMID:24928374

Learning to avoid spiders: fear predicts performance, not competence.

PubMed

Luo, Xijia; Becker, Eni S; Rinck, Mike

2018-01-05

We used an immersive virtual environment to examine avoidance learning in spider-fearful participants. In 3 experiments, participants were asked to repeatedly lift one of 3 virtual boxes, under which either a toy car or a spider appeared and then approached the participant. Participants were not told that the probability of encountering a spider differed across boxes. When the difference was large (Exps. 1 and 2), spider-fearfuls learned to avoid spiders by lifting the few-spiders-box more often and the many-spiders-box less often than non-fearful controls did. However, they hardly managed to do so when the probability differences were small (Exp. 3), and they did not escape from threat more quickly (Exp. 2). In contrast to the observed performance differences, spider-fearfuls and non-fearfuls showed equal competence, that is comparable post-experimental knowledge about the probability to encounter spiders under the 3 boxes. The limitations and implications of the present study are discussed.

Stochastic Car-Following Model for Explaining Nonlinear Traffic Phenomena

NASA Astrophysics Data System (ADS)

Meng, Jianping; Song, Tao; Dong, Liyun; Dai, Shiqiang

There is a common time parameter for representing the sensitivity or the lag (response) time of drivers in many car-following models. In the viewpoint of traffic psychology, this parameter could be considered as the perception-response time (PRT). Generally, this parameter is set to be a constant in previous models. However, PRT is actually not a constant but a random variable described by the lognormal distribution. Thus the probability can be naturally introduced into car-following models by recovering the probability of PRT. For demonstrating this idea, a specific stochastic model is constructed based on the optimal velocity model. By conducting simulations under periodic boundary conditions, it is found that some important traffic phenomena, such as the hysteresis and phantom traffic jams phenomena, can be reproduced more realistically. Especially, an interesting experimental feature of traffic jams, i.e., two moving jams propagating in parallel with constant speed stably and sustainably, is successfully captured by the present model.

Embedding perseverative interest of a child with autism in text may result in improved reading comprehension: A pilot study.

PubMed

El Zein, Farah; Solis, Michael; Lang, Russell; Kim, Min Kyung

2016-06-01

We investigated the effects of embedding the perseverative interest (PI) of a child with autism (i.e. cars) within texts on reading comprehension. A PI text condition (text altered to include cars) was compared with a non-PI text condition (same story without cars inserted) in an alternating treatment design. Dependent variables were responses to reading comprehension questions and number of words uttered during an oral retell (i.e. curriculum-based measures [CBMs]). The reading level, instructional routines, and therapist where held constant across the randomly alternated conditions. Both CBMs suggested that reading comprehension was enhanced when the story included the child's PI. These preliminary findings suggest that embedding the PIs of students with autism spectrum disorder within readings may result in more accurate responses to reading comprehension questions and more detailed oral retelling. These findings are discussed in terms of potential directions for future research.

Differences Between the Childhood Autism Rating Scale and the Social Responsiveness Scale in Assessing Symptoms of Children with Autistic Spectrum Disorder.

PubMed

Chen, Kuan-Lin; Lin, Chien-Ho; Yu, Tzu-Ying; Huang, Chien-Yu; Chen, Ying-Dar

2018-04-25

This study aimed to compare symptoms of autism spectrum disorder using the Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS™-2) and to investigate their influencing factors. The diagnostic agreement was 92.7%, but with a fair Kappa value (0.247). Children's verbal comprehension was related to the CARS scores, and no variables were related to the SRS™-2 scores. Generally, significant small correlations were found between the two measures in children with normal or borderline to below average verbal comprehension (rs = 0.32 ~ 0.49, p < .005), but not in those with impaired verbal comprehension. The CARS and the SRS™-2 may contain different explicit behaviors and collect different perspectives (i.e., those of caregivers and professionals). Therefore, they appear to complement each other.

Basic-level categorization of intermediate complexity fragments reveals top-down effects of expertise in visual perception.

PubMed

Harel, Assaf; Ullman, Shimon; Harari, Danny; Bentin, Shlomo

2011-07-28

Visual expertise is usually defined as the superior ability to distinguish between exemplars of a homogeneous category. Here, we ask how real-world expertise manifests at basic-level categorization and assess the contribution of stimulus-driven and top-down knowledge-based factors to this manifestation. Car experts and novices categorized computer-selected image fragments of cars, airplanes, and faces. Within each category, the fragments varied in their mutual information (MI), an objective quantifiable measure of feature diagnosticity. Categorization of face and airplane fragments was similar within and between groups, showing better performance with increasing MI levels. Novices categorized car fragments more slowly than face and airplane fragments, while experts categorized car fragments as fast as face and airplane fragments. The experts' advantage with car fragments was similar across MI levels, with similar functions relating RT with MI level for both groups. Accuracy was equal between groups for cars as well as faces and airplanes, but experts' response criteria were biased toward cars. These findings suggest that expertise does not entail only specific perceptual strategies. Rather, at the basic level, expertise manifests as a general processing advantage arguably involving application of top-down mechanisms, such as knowledge and attention, which helps experts to distinguish between object categories. © ARVO

Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

PubMed Central

Erle, David J.

2016-01-01

Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID:27463381

Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

PubMed

Tchou, Julia; Zhao, Yangbing; Levine, Bruce L; Zhang, Paul J; Davis, Megan M; Melenhorst, Jan Joseph; Kulikovskaya, Irina; Brennan, Andrea L; Liu, Xiaojun; Lacey, Simon F; Posey, Avery D; Williams, Austin D; So, Alycia; Conejo-Garcia, Jose R; Plesa, Gabriela; Young, Regina M; McGettigan, Shannon; Campbell, Jean; Pierce, Robert H; Matro, Jennifer M; DeMichele, Angela M; Clark, Amy S; Cooper, Laurence J; Schuchter, Lynn M; Vonderheide, Robert H; June, Carl H

2017-12-01

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 7 or 3 × 10 8 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR . ©2017 American Association for Cancer Research.

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

Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.

PubMed

Liu, Hong; Xu, Yiyang; Xiang, Jingyi; Long, Li; Green, Shon; Yang, Zhiyuan; Zimdahl, Bryan; Lu, Jingwei; Cheng, Neal; Horan, Lucas H; Liu, Bin; Yan, Su; Wang, Pei; Diaz, Juan; Jin, Lu; Nakano, Yoko; Morales, Javier F; Zhang, Pengbo; Liu, Lian-Xing; Staley, Binnaz K; Priceman, Saul J; Brown, Christine E; Forman, Stephen J; Chan, Vivien W; Liu, Cheng

2017-01-15

The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors. We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP 158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01 + /AFP + while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP 158 -expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478-88. ©2016 AACR. ©2016 American Association for Cancer Research.

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells.

PubMed

Zhang, Yajing; Zhang, Wenying; Dai, Hanren; Wang, Yao; Shi, Fengxia; Wang, Chunmeng; Guo, Yelei; Liu, Yang; Chen, Meixia; Feng, Kaichao; Zhang, Yan; Liu, Chuanjie; Yang, Qingming; Li, Suxia; Han, Weidong

2016-04-01

Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.

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

Fall Protection Procedures for Sealing Bulk Waste Shipments by Rail Cars at Formerly Utilized Sites Remedial Action Program (FUSRAP) Sites - 13509

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

Boyle, J.D.; Fort, E. Joseph; Lorenz, William

2013-07-01

Rail-cars loaded with radioactive materials must be closed and fastened to comply with United States Department of Transportation (DOT) requirements before they shipped. Securing waste shipments in a manner that meets these regulations typically results in the use of a sealable rail-car liner. Workers accessing the tops of the 2.74 m high rail-cars to seal and inspect liners for compliance prior to shipment may be exposed to a fall hazard. Relatively recent revisions to the Fall Protection requirements in the Safety and Health Requirements Manual (EM385-1-1, U.S. Army Corps of Engineers) have necessitated modifications to the fall protection systems previouslymore » employed for rail-car loading at Formerly Utilized Sites Remedial Action Program (FUSRAP) sites. In response these projects have developed site-specific procedures to protect workers and maintain compliance with the improved fall protection regulations. (authors)« less

Self-Driving Cars and Engineering Ethics: The Need for a System Level Analysis.

PubMed

Borenstein, Jason; Herkert, Joseph R; Miller, Keith W

2017-11-13

The literature on self-driving cars and ethics continues to grow. Yet much of it focuses on ethical complexities emerging from an individual vehicle. That is an important but insufficient step towards determining how the technology will impact human lives and society more generally. What must complement ongoing discussions is a broader, system level of analysis that engages with the interactions and effects that these cars will have on one another and on the socio-technical systems in which they are embedded. To bring the conversation of self-driving cars to the system level, we make use of two traffic scenarios which highlight some of the complexities that designers, policymakers, and others should consider related to the technology. We then describe three approaches that could be used to address such complexities and their associated shortcomings. We conclude by bringing attention to the "Moral Responsibility for Computing Artifacts: The Rules", a framework that can provide insight into how to approach ethical issues related to self-driving cars.

Robust Multivariable Estimation of the Relevant Information Coming from a Wheel Speed Sensor and an Accelerometer Embedded in a Car under Performance Tests

PubMed Central

Hernandez, Wilmar

2005-01-01

In the present paper, in order to estimate the response of both a wheel speed sensor and an accelerometer placed in a car under performance tests, robust and optimal multivariable estimation techniques are used. In this case, the disturbances and noises corrupting the relevant information coming from the sensors' outputs are so dangerous that their negative influence on the electrical systems impoverish the general performance of the car. In short, the solution to this problem is a safety related problem that deserves our full attention. Therefore, in order to diminish the negative effects of the disturbances and noises on the car's electrical and electromechanical systems, an optimum observer is used. The experimental results show a satisfactory improvement in the signal-to-noise ratio of the relevant signals and demonstrate the importance of the fusion of several intelligent sensor design techniques when designing the intelligent sensors that today's cars need.

Immunotherapy for B-Cell Neoplasms using T Cells expressing Chimeric Antigen Receptors

PubMed Central

Boulassel, Mohamed-Rachid; Galal, Ahmed

2012-01-01

Immunotherapy with T cells expressing chimeric antigen receptors (CAR) is being evaluated as a potential treatment for B-cell neoplasms. In recent clinical trials it has shown promising results. As the number of potential candidate antigens expands, the choice of suitable target antigens becomes more challenging to design studies and to assess optimal efficacy of CAR. Careful evaluation of candidate target antigens is required to ensure that T cells expressing CAR will preferentially kill malignant cells with a minimal toxicity against normal tissues. B cells express specific surface antigens that can theoretically act as targets for CAR design. Although many of these antigens can stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a challenge. Only targeted B-cell antigens CD19 and CD20 have been tested in clinical trials. This article reviews exploitable B cell surface antigens for CAR design and examines obstacles that could interfere with the identification of potentially useful cellular targets. PMID:23269948

Different profiles of decision making and physiology under varying levels of stress in trained military personnel.

PubMed

Gamble, Katherine R; Vettel, Jean M; Patton, Debra J; Eddy, Marianna D; Caroline Davis, F; Garcia, Javier O; Spangler, Derek P; Thayer, Julian F; Brooks, Justin R

2018-03-23

Decision making is one of the most vital processes we use every day, ranging from mundane decisions about what to eat to life-threatening choices such as how to avoid a car collision. Thus, the context in which our decisions are made is critical, and our physiology enables adaptive responses that account for how environmental stress influences our performance. The relationship between stress and decision making can additionally be affected by one's expertise in making decisions in high-threat environments, where experts can develop an adaptive response that mitigates the negative impacts of stress. In the present study, 26 male military personnel made friend/foe discriminations in an environment where we manipulated the level of stress. In the high-stress condition, participants received a shock when they incorrectly shot a friend or missed shooting a foe; in the low-stress condition, participants received a vibration for an incorrect decision. We characterized performance using signal detection theory to investigate whether a participant changed their decision criterion to avoid making an error. Results showed that under high-stress, participants made more false alarms, mistaking friends as foes, and this co-occurred with increased high frequency heart rate variability. Finally, we examined the relationship between decision making and physiology, and found that participants exhibited adaptive behavioral and physiological profiles under different stress levels. We interpret this adaptive profile as a marker of an expert's ingrained training that does not require top down control, suggesting a way that expert training in high-stress environments helps to buffer negative impacts of stress on performance. Published by Elsevier B.V.

Developmental origins of infant emotion regulation: Mediation by temperamental negativity and moderation by maternal sensitivity.

PubMed

Thomas, Jenna C; Letourneau, Nicole; Campbell, Tavis S; Tomfohr-Madsen, Lianne; Giesbrecht, Gerald F

2017-04-01

Emotion regulation is essential to cognitive, social, and emotional development and difficulties with emotion regulation portend future socioemotional, academic, and behavioral difficulties. There is growing awareness that many developmental outcomes previously thought to begin their development in the postnatal period have their origins in the prenatal period. Thus, there is a need to integrate evidence of prenatal influences within established postnatal factors, such as infant temperament and maternal sensitivity. In the current study, prenatal depression, pregnancy anxiety, and diurnal cortisol patterns (i.e., the cortisol awakening response (CAR) and diurnal slope) were assessed in 254 relatively low-risk mother-infant pairs (primarily White, middle-class) in early (M = 15 weeks) and late pregnancy (M = 33 weeks). Mothers reported on infant temperamental negativity (Infant Behavior Questionnaire-Revised) at 3 months. At 6 months, maternal sensitivity (Parent Child Interaction Teaching Scale) and infant emotion regulation behavior (Laboratory Temperament Assessment Battery) were assessed. Greater pregnancy anxiety in early pregnancy and a blunted CAR in late pregnancy predicted higher infant temperamental negativity at 3 months, and those infants with higher temperamental negativity used fewer attentional regulation strategies and more avoidance (i.e., escape behavior) at 6 months. Furthermore, this indirect effect was moderated by maternal sensitivity whereby infants with elevated negativity demonstrated maladaptive emotion regulation at below average levels of maternal sensitivity. These findings suggest that the development of infant emotion regulation is influenced by the ways that prenatal exposures shape infant temperament and is further modified by postnatal caregiving. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

EMERGENCY BRAKING IN ADULTS VERSUS NOVICE TEEN DRIVERS: RESPONSE TO SIMULATED SUDDEN DRIVING EVENTS.

PubMed

Loeb, Helen S; Kandadai, Venk; McDonald, Catherine C; Winston, Flaura K

Motor vehicle crashes remain the leading cause of death in teens in the United States. Newly licensed drivers are the group most at risk for crashes. Their driving skills are very new, still very often untested, so that their ability to properly react in an emergency situation remains a research question. Since it is impossible to expose human subjects to critical life threatening driving scenarios, researchers have been increasingly using driving simulators to assess driving skills. This paper summarizes the results of a driving scenario in a study comparing the driving performance of novice teen drivers (n=21) 16-17 year olds with 90 days of provisional licensure with that of experienced adult drivers (n=17) 25-50 year olds with at least 5 years of PA licensure, at least 100 miles driven per week and no self-reported collisions in the previous 3 years. As part of a 30 to 35 simulated drive that encompassed the most common scenarios that result in serious crashes, participants were exposed to a sudden car event. As the participant drove on a suburban road, a car surged from a driveway hidden by a fence on the right side of the road. To avoid the crash, participants must hard brake, exhibiting dynamic control over both attentional and motor resources. The results showed strong differences between the experienced adult and novice teen drivers in the brake pressure applied. When placed in the same situation, the novice teens decelerated on average 50% less than the experienced adults (p<0.01).

Real-time modeling of primitive environments through wavelet sensors and Hebbian learning

NASA Astrophysics Data System (ADS)

Vaccaro, James M.; Yaworsky, Paul S.

1999-06-01

Modeling the world through sensory input necessarily provides a unique perspective for the observer. Given a limited perspective, objects and events cannot always be encoded precisely but must involve crude, quick approximations to deal with sensory information in a real- time manner. As an example, when avoiding an oncoming car, a pedestrian needs to identify the fact that a car is approaching before ascertaining the model or color of the vehicle. In our methodology, we use wavelet-based sensors with self-organized learning to encode basic sensory information in real-time. The wavelet-based sensors provide necessary transformations while a rank-based Hebbian learning scheme encodes a self-organized environment through translation, scale and orientation invariant sensors. Such a self-organized environment is made possible by combining wavelet sets which are orthonormal, log-scale with linear orientation and have automatically generated membership functions. In earlier work we used Gabor wavelet filters, rank-based Hebbian learning and an exponential modulation function to encode textural information from images. Many different types of modulation are possible, but based on biological findings the exponential modulation function provided a good approximation of first spike coding of `integrate and fire' neurons. These types of Hebbian encoding schemes (e.g., exponential modulation, etc.) are useful for quick response and learning, provide several advantages over contemporary neural network learning approaches, and have been found to quantize data nonlinearly. By combining wavelets with Hebbian learning we can provide a real-time front-end for modeling an intelligent process, such as the autonomous control of agents in a simulated environment.

EMERGENCY BRAKING IN ADULTS VERSUS NOVICE TEEN DRIVERS: RESPONSE TO SIMULATED SUDDEN DRIVING EVENTS

PubMed Central

Kandadai, Venk; McDonald, Catherine C.; Winston, Flaura K.

2015-01-01

Motor vehicle crashes remain the leading cause of death in teens in the United States. Newly licensed drivers are the group most at risk for crashes. Their driving skills are very new, still very often untested, so that their ability to properly react in an emergency situation remains a research question. Since it is impossible to expose human subjects to critical life threatening driving scenarios, researchers have been increasingly using driving simulators to assess driving skills. This paper summarizes the results of a driving scenario in a study comparing the driving performance of novice teen drivers (n=21) 16–17 year olds with 90 days of provisional licensure with that of experienced adult drivers (n=17) 25–50 year olds with at least 5 years of PA licensure, at least 100 miles driven per week and no self-reported collisions in the previous 3 years. As part of a 30 to 35 simulated drive that encompassed the most common scenarios that result in serious crashes, participants were exposed to a sudden car event. As the participant drove on a suburban road, a car surged from a driveway hidden by a fence on the right side of the road. To avoid the crash, participants must hard brake, exhibiting dynamic control over both attentional and motor resources. The results showed strong differences between the experienced adult and novice teen drivers in the brake pressure applied. When placed in the same situation, the novice teens decelerated on average 50% less than the experienced adults (p<0.01). PMID:26709330

CoCAR: An Online Synchronous Training Model for Empowering ICT Capacity of Teachers of Chinese as a Foreign Language

ERIC Educational Resources Information Center

Lan, Yu-Ju; Chang, Kuo-En; Chen, Nian-Shing

2012-01-01

In response to the need to cultivate pre-service Chinese as a foreign language (CFL) teachers' information and communication technology (ICT) competency in online synchronous environments, this research adopted a three-stage cyclical model named "cooperation-based cognition, action, and reflection" (CoCAR). The model was implemented in an 18-week…

Car Club Teacher's Guide. An Educational Program on Safety Belt Use for Junior High School Students.

ERIC Educational Resources Information Center

National Highway Traffic Safety Administration (DOT), Washington, DC.

This information packet describes the teacher's role in Car Club, a program designed to convince junior high school students to use motor vehicle safety belts. Students are approached as both passengers and future drivers to help them examine their roles and responsibilities relating to safety belts and occupant protection systems, including air…

Responses to Deceleration during Car Following: Roles of Optic Flow, Warnings, Expectations, and Interruptions

ERIC Educational Resources Information Center

DeLucia, Patricia R.; Tharanathan, Anand

2009-01-01

More than 25% of accidents are rear-end collisions. It is essential to identify the factors that contribute to such collisions. One such factor is a driver's ability to respond to the deceleration of the car ahead. In Experiment 1, we measured effects of optic flow information and discrete visual and auditory warnings (brake lights, tones) on…

The cortisol awakening response and memory performance in older men and women.

PubMed

Almela, Mercedes; van der Meij, Leander; Hidalgo, Vanesa; Villada, Carolina; Salvador, Alicia

2012-12-01

The activity and regulation of the hypothalamus-pituitary-adrenal axis has been related to cognitive decline during aging. This study investigated whether the cortisol awakening response (CAR) is related to memory performance among older adults. The sample was composed of 88 participants (44 men and 44 women) from 55 to 77 years old. The memory assessment consisted of two tests measuring declarative memory (a paragraph recall test and a word list learning test) and two tests measuring working memory (a spatial span test and a spatial working memory test). Among those participants who showed the CAR on two consecutive days, we found that a greater CAR was related to poorer declarative memory performance in both men and women, and to better working memory performance only in men. The results of our study suggest that the relationship between CAR and memory performance is negative in men and women when memory performance is largely dependent on hippocampal functioning (i.e. declarative memory), and positive, but only in men, when memory performance is largely dependent on prefrontal cortex functioning (i.e. working memory). Copyright © 2012 Elsevier Ltd. All rights reserved.

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis.

PubMed

Grigor, Emma J M; Fergusson, Dean A; Haggar, Fatima; Kekre, Natasha; Atkins, Harold; Shorr, Risa; Holt, Robert A; Hutton, Brian; Ramsay, Tim; Seftel, Matthew; Jonker, Derek; Daugaard, Mads; Thavorn, Kednapa; Presseau, Justin; Lalu, Manoj M

2017-12-29

Patients with relapsed or refractory malignancies have a poor prognosis. Immunotherapy with chimeric antigen receptor T (CAR-T) cells redirects a patient's immune cells against the tumour antigen. CAR-T cell therapy has demonstrated promise in treating patients with several haematological malignancies, including acute B-cell lymphoblastic leukaemia and B-cell lymphomas. CAR-T cell therapy for patients with other solid tumours is also being tested. Safety is an important consideration in CAR-T cell therapy given the potential for serious adverse events, including death. Previous reviews on CAR-T cell therapy have been limited in scope and methodology. Herein, we present a protocol for a systematic review to identify CAR-T cell interventional studies and examine the safety and efficacy of this therapy in patients with haematology malignancies and solid tumours. We will search MEDLINE, including In-Process and Epub Ahead of Print, EMBASE and the Cochrane Central Register of Controlled Trials from 1946 to 22 February 2017. Studies will be screened by title, abstract and full text independently and in duplicate. Studies that report administering CAR-T cells of any chimeric antigen receptor construct targeting antigens in patients with haematological malignancies and solid tumours will be eligible for inclusion. Outcomes to be extracted will include complete response rate (primary outcome), overall response rate, overall survival, relapse and adverse events. A meta-analysis will be performed to synthesise the prevalence of outcomes reported as proportions with 95% CIs. The potential for bias within included studies will be assessed using a modified Institute of Health Economics tool. Heterogeneity of effect sizes will be determined using the Cochrane I 2 statistic. The review findings will be submitted for peer-reviewed journal publication and presented at relevant conferences and scientific meetings to promote knowledge transfer. CRD42017075331. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Congruence between Spouses’ Perceptions and Observers’ Ratings of Responsiveness: The Role of Attachment Avoidance

PubMed Central

Beck, Lindsey A.; Pietromonaco, Paula R.; DeVito, Cassandra C.; Powers, Sally I.; Boyle, Alysia M.

2016-01-01

Although close relationships require partners to depend on one another for mutual responsiveness, avoidantly-attached individuals are especially averse to risking such dependency. The authors propose that both avoidant and non-avoidant individuals perceive signs of their own and their partners’ responsiveness in ways that reflect motivated perceptions of dependency. The present research examined how the interplay between spouses’ attachment avoidance and observed responsive behaviors during marital conflict shaped perceptions of their own and their partners’ responsiveness. Newlywed couples attempted to resolve a relationship conflict, then reported perceptions of their own and their partners’ responsiveness during the conflict. Observers also coded both partners’ responsive behaviors during the conflict. Avoidant husbands perceived themselves as less responsive than did observers; avoidant wives’ perceptions that their husbands were less responsive matched observers’ ratings. The discussion highlights the role of gender role norms in understanding links between attachment and responsiveness. PMID:24132245

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.

Rail and Motor Outloading Capability Study, Fort Chaffee, Arkansas,

DTIC Science & Technology

1978-11-01

instructors at Fort Eustis, Virginia, indicated that, to avoid wasted man - hours, there should be no more than eight men per crew, regardless of experience...level, total men per Man has to walk to front of vehicle as guide vehicle and to straighten bridge PL’s. Delays if all vehicles not at site at loading...vehicle (Storm, rain not included in total time) MILVAN married together 6-8 Some older cars have trailer hitches which Some 20-ft semis and man crew

Impact of improving vehicle front design on the burden of pedestrian injuries in Germany, the United States, and India.

PubMed

Moran, Dane; Bose, Dipan; Bhalla, Kavi

2017-11-17

European car design regulations and New Car Assessment Program (NCAP) ratings have led to reductions in pedestrian injuries. The aim of this study was to evaluate the impact of improving vehicle front design on mortality and morbidity due to pedestrian injuries in a European country (Germany) and 2 countries (the United States and India) that do not have pedestrian-focused NCAP testing or design regulations. We used data from the International Road Traffic and Accident Database and the Global Burden of Disease project to estimate baseline pedestrian deaths and nonfatal injuries in each country in 2013. The effect of improved passenger car star ratings on probability of pedestrian injury was based on recent evaluations of pedestrian crash data from Germany. The effect of improved heavy motor vehicle (HMV) front end design on pedestrian injuries was based on estimates reported by simulation studies. We used burden of disease methods to estimate population health loss by combining the burden of morbidity and mortality in disability-adjusted life years (DALYs) lost. Extrapolating from evaluations in Germany suggests that improving front end design of cars can potentially reduce the burden of pedestrian injuries due to cars by up to 24% in the United States and 41% in India. In Germany, where cars comply with the United Nations regulation on pedestrian safety, additional improvements would have led to a 1% reduction. Similarly, improved HMV design would reduce DALYs lost by pedestrian victims hit by HMVs by 20% in each country. Overall, improved vehicle design would reduce DALYs lost to road traffic injuries (RTIs) by 0.8% in Germany, 4.1% in the United States, and 6.7% in India. Recent evaluations show a strong correlation between Euro NCAP pedestrian scores and real-life pedestrian injuries, suggesting that improved car front end design in Europe has led to substantial reductions in pedestrian injuries. Although the United States has fewer pedestrian crashes, it would nevertheless benefit substantially by adopting similar regulations and instituting pedestrian NCAP testing. The maximum benefit would be realized in low- and middle-income countries like India that have a high proportion of pedestrian crashes. Though crash avoidance technologies are being developed to protect pedestrians, supplemental protection through design regulations may significantly improve injury countermeasures for vulnerable road users.

Milestones on the way to a reconfigurable automotive instrument cluster

NASA Astrophysics Data System (ADS)

Knoll, Peter M.; Kosmowski, Bogdan B.

2002-06-01

Nowadays, the car driver are faced with a rapidly increasing flood of information. In addition to established information systems (car radio, vehicle monitoring, mobile phones), high class vehicles feature navigation systems almost as standard. In the current decade, driver assistance and collision avoidance systems will appear in vehicles. Hence, there is an increasing demand for supplying the driver with more information that help him to drive safer and more economical. The price decline in the computer market and the availability of powerful graphic hard- and software concepts make it possible to enhance the classical functions of the instrument board to an interactive multifunctional information panel - an interface between information systems of the car and the driver. Therefore, the question of additional visual and cognitive stress, and a possible distraction of the driver by the large amount of information, and its complexity becomes predominant. Reconfigurable instruments, based on a microprocessor controlled active matrix color display, provide a powerful alternative to the usual mechanical/electromechanical instrument clusters in vehicles. They will help to strengthen passive safety, they adapt to user and situation requirements, and they are easy to install, to configure, and to maintain. Reconfigurable instruments in future cars will have a high impact on traffic since they can provide the driver with much more information, presenting it in a way that is flexibly matched to the importance of particular data and to the ergonomic properties of the driver. The functions are manifold and span from classical driver information like speed to navigation prompts and ultimately to video and multimedia access.

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.

48 CFR 4.604 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-10-01

... MATTERS Contract Reporting 4.604 Responsibilities. (a) The Senior Procurement Executive in coordination... guidance, by January 5, an annual certification of whether, and to what degree, agency CAR data for the...

At the Bench: Chimeric antigen receptor (CAR) T cell therapy for the treatment of B cell malignancies.

PubMed

Daniyan, Anthony F O; Brentjens, Renier J

2016-12-01

The chimeric antigen receptor (CAR) represents the epitome of cellular engineering and is one of the best examples of rational biologic design of a synthetic molecule. The CAR is a single polypeptide with modular domains, consisting of an antibody-derived targeting moiety, fused in line with T cell-derived signaling domains, allowing for T cell activation upon ligand binding. T cells expressing a CAR are able to eradicate selectively antigen-expressing tumor cells in a MHC-independent fashion. CD19, a tumor-associated antigen (TAA) present on normal B cells, as well as most B cell-derived malignancies, was an early target of this technology. Through years of experimental refinement and preclinical optimization, autologously derived CD19-targeting CAR T cells have been successfully, clinically deployed, resulting in dramatic and durable antitumor responses but not without therapy-associated toxicity. As CD19-targeted CAR T cells continue to show clinical success, work at the bench continues to be undertaken to increase further the efficacy of this therapy, while simultaneously minimizing the risk for treatment-related morbidities. In this review, we cover the history and evolution of CAR technology and its adaptation to targeting CD19. Furthermore, we discuss the future of CAR T cell therapy and the need to ask, as well as answer, critical questions as this treatment modality is being translated to the clinic. © Society for Leukocyte Biology.

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.

A comparison of personal exposure to air pollutants in different travel modes on national highways in India.

PubMed

Kolluru, Soma Sekhara Rao; Patra, Aditya Kumar; Sahu, Satya Prakash

2018-04-01

People often travel a long distance on highways to the nearest city for professional/business activities. However, relatively few publications on passenger exposure to pollutants on highways in India or elsewhere are available. The aim of this study was to examine the contribution of different travel modes to passengers' pollutant exposure for a long distance travel on a national highway in India. We measured PM 2.5 and CO exposure levels of the passengers over 200km on a national highway using two portable air monitors, EVM-7 and EPAM-5000. Personal concentration exposures and per min-, per hour-, per trip- and round trip mass exposures for three travel modes were calculated for 9 trips. Association between pollutants and weather variables were evaluated using levels Spearman correlation. ANOVA was carried out to evaluate the influence of travel mode, the timing of trips, temperature and RH on personal exposures. On an average, PM 2.5 personal concentration exposure levels were highest in the car (85.41±61.85μgm -3 ), followed by the bus (75.08±55.39μgm -3 ) and lowest in the car (ac) (54.43±34.09μgm -3 ). In contrast, CO personal exposure was highest in the car (ac) (1.81±1.3ppm). Travel mode explained the highest variability for CO (18.1%), CO 2 (9.9%), PM 2.5 (1.2%) exposures. In-city mass exposures were higher than trip averages; PM 2.5 :1.21-1.22, 1.13-1.19 and 1.03-1.28 times; CO: 1.20-1.57, 1.37-2.10 and 1.76-2.22 times for bus, car and car (ac) respectively. Traveling by car (ac) results in the lowest PM 2.5 exposures, although it exposes the passenger to high CO level. Avoiding national highways passing through cities can reduce up to 25% PM 2.5 and 50% CO mass exposures. This information can be useful for increasing environmental awareness among the passengers and for framing better pollution control strategies on highways. Copyright © 2017 Elsevier B.V. All rights reserved.

ErbB-targeted CAR T-cell immunotherapy of cancer.

PubMed

Whilding, Lynsey M; Maher, John

2015-01-01

Chimeric antigen receptor (CAR) based immunotherapy has been under development for the last 25 years and is now a promising new treatment modality in the field of cancer immunotherapy. The approach involves genetically engineering T cells to target malignant cells through expression of a bespoke fusion receptor that couples an HLA-independent antigen recognition domain to one or more intracellular T-cell activating modules. Multiple clinical trials are now underway in several centers to investigate CAR T-cell immunotherapy of diverse hematologic and solid tumor types. The most successful results have been achieved in the treatment of patients with B-cell malignancies, in whom several complete and durable responses have been achieved. This review focuses on the preclinical and clinical development of CAR T-cell immunotherapy of solid cancers, targeted against members of the ErbB family.

Traffic jam driving with NMV avoidance

NASA Astrophysics Data System (ADS)

Milanés, Vicente; Alonso, Luciano; Villagrá, Jorge; Godoy, Jorge; de Pedro, Teresa; Oria, Juan P.

2012-08-01

In recent years, the development of advanced driver assistance systems (ADAS) - mainly based on lidar and cameras - has considerably improved the safety of driving in urban environments. These systems provide warning signals for the driver in the case that any unexpected traffic circumstance is detected. The next step is to develop systems capable not only of warning the driver but also of taking over control of the car to avoid a potential collision. In the present communication, a system capable of autonomously avoiding collisions in traffic jam situations is presented. First, a perception system was developed for urban situations—in which not only vehicles have to be considered, but also pedestrians and other non-motor-vehicles (NMV). It comprises a differential global positioning system (DGPS) and wireless communication for vehicle detection, and an ultrasound sensor for NMV detection. Then, the vehicle's actuators - brake and throttle pedals - were modified to permit autonomous control. Finally, a fuzzy logic controller was implemented capable of analyzing the information provided by the perception system and of sending control commands to the vehicle's actuators so as to avoid accidents. The feasibility of the integrated system was tested by mounting it in a commercial vehicle, with the results being encouraging.

Saving Resources - Lesson plan of ESD in Geography

NASA Astrophysics Data System (ADS)

Iwamura, Takuya

2010-05-01

Geographical education has to perceive the world from diversified viewpoints by involving ESD (Education for Sustainable Development). This can be realized by teaching geography as an integrated science, including ESD that considers ecological, economic and social aspects.. In Japan especially, geographical education tends to emphasize the environmental aspects. The investigation of circumstances from diversified viewpoints helps to analyse the society scientifically and generates? the qualities of a global citizenship toward a sustainable society. And ESD aims at creating the values of sustainability, which is necessary for a global citizenship. In this context, I have developed the lesson plan of ESD in Geography at a secondary level.. Can advanced technologies foster sustainable development? The presentation shows the advanced technology-generated products and analyses the merits and failures with their effects on the global society. The examples of these products are hybrid cars and mobile phones. Cars are necessary for the mobility of our widespread modern society. On the other hand, it is also true that environmental pollution is becoming more serious by the increasing number of cars. We usually assume that economic development and environmental protection are contradictory. But hybrid cars which are coming to world attention now, have good gas mileage compared with normal cars, so they can conserve energy and cut down on the amount of exhaust at the same time. Mobile phones are necessary in business situations, as a tool that helps to communicate while moving. In addition, mobile phones are means that support the life of people living in sparsely populated areas like in Northern Europe. Here, we can curb costs for transmission facilities that were needed otherwise. There is one thing that underlies these advanced technology-generated products such as hybrid cars and mobile phones. The resource that makes the hybrid car technology and the miniaturization of mobile phones possible: rare metals. Quite an amount of them are needed to produce a hybrid car. There are, however, few metals in Japanese mines. As a result, Japanese companies have to import these metals from overseas like China or the USA. It means that Japanese car companies would not be able to produce their cars if these countries which produce rare metals refused to export to Japan. To avoid such a condition, Japan tries to establish good relationships with countries exporting resources. In order to build mobile phones, we need tantalum which is used to produce capacitors to miniaturize them. The main producing country of tantalum is the Democratic Republic of Congo. Congo is one of the countries suffering from a civil war now. Some armed groups mine tantalum illegally; it has become their main source of income. The civil war is quite convenient for this illegal mining. We as consumers must seriously consider the use of such electronic devices. The lesson plan for ESD in Geography on the issue of the rare metals, is meant to develop the value of sustainability and helps to build a sustainable society at multi scale levels.

Do smoke-free car laws work? Evidence from a quasi-experiment.

PubMed

Nguyen, Hai V

2013-01-01

In response to increased risks of second-hand smoke exposure for children travelling in cars and its resulting deleterious health impacts, several jurisdictions passed legislation that bans smoking in private vehicles when children are present. In this study, I exploit a unique quasi-experiment from Canada and employ the difference-in-differences and triple-differences techniques to empirically evaluate this legislation. I find that the legislation reduces exposure to second-hand smoke inside cars for children. Further, there appears no marked increase in smoking at home after the implementation of the legislation. Copyright © 2012 Elsevier B.V. All rights reserved.

Engineered chimeric antigen receptor-expressing T cells for the treatment of pancreatic ductal adenocarcinoma

PubMed Central

Beatty, Gregory L

2014-01-01

Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells is under investigation as an approach to restore productive T cell immunosurveillance in patients with pancreatic ductal adenocarcinoma. Early findings demonstrate safety of this cell-based therapy and the capacity of CAR-expressing T cells to mediate anti-tumor activity as well as induce endogeneous antitumoral immune responses. PMID:25050204

The Evaluation of the Safety Benefits of Combined Passive and On-Board Active Safety Applications

PubMed Central

Page, Yves; Cuny, Sophie; Zangmeister, Tobias; Kreiss, Jens-Peter; Hermitte, Thierry

2009-01-01

One of the objectives of the European TRACE project (TRaffic Accident Causation in Europe, 2006–2008) was to estimate the proportion of injury accidents that could be avoided and/or the proportion of injury accidents where the severity could be mitigated for on-the-market safety applications, if 100 % of the car fleet would be equipped with them. We have selected for evaluation the Electronic Stability Control (ESC) and the Emergency Brake Assist (EBA) applications. As for passive safety systems, recent cars are designed to offer overall safety protection. Car structure, load limiters, front airbags, side airbags, knee airbags, pretensioners, padding and non aggressive structures in the door panel, the dashboard, the windshield, the seats, and the head rest also contribute to applying more protection. The whole safety package is very difficult to evaluate separately, one element independently segmented from the others. We decided to consider evaluating the effectivenessof the whole passive safety package, This package,, for the sake of simplicity, was the number of stars awarded at the Euro NCAP testing. The challenges were to compare the effectiveness of some safety configuration SC I, with the effectiveness of a different safety configuration SC II. A safety configuration is understood as a package of safety functions. Ten comparisons have been carried out such as the evaluation of the safety benefit of a fifth star given that the car has four stars and an EBA. The main outcome of this analysis is that any addition of a passive or active safety function selected in this analysis is producing increased safety benefits. For example, if all cars were five stars fitted with EBA and ESC, instead of four stars without ESC and EBA, injury accidents would be reduced by 47.2% for severe injuries and 69.5% for fatal injuries. PMID:20184838

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.

Molecular characterisation of two α-esterase genes involving chlorpyrifos detoxification in the diamondback moth, Plutella xylostella.

PubMed

Xie, Miao; Ren, Na-Na; You, Yan-Chun; Chen, Wei-Jun; Song, Qi-Sheng; You, Min-Sheng

2017-06-01

Carboxylesterases (CarEs) are involved in metabolic detoxification of dietary and environmental xenobiotics in insects. However, owing to the complexity of the protein family, the involvement of CarEs in insecticide metabolism in Plutella xylostella has not been fully elucidated. This study aimed to characterise two CarE genes and assess their potential roles in response to chlorpyrifos in P. xylostella. Synergistic tests showed that triphenyl phosphate decreased the resistance of the third-instar larvae to chlorpyrifos. The treatment of the third-instar larvae with chlorpyrifos at the LC 30 dose led to a significant increase in CarE activity. Two CarE cDNAs (Pxae18 and Pxae28) were subsequently sequenced and characterised. Both genes were expressed predominantly in the larval midgut. Most importantly, two CarE genes showed significantly higher expression in the chlorpyrifos-resistant strain than in the susceptible strain. RNAi knockdown of Pxae18 and Pxae28 significantly increased the mortality to chlorpyrifos from 40% in the control to 73.8 and 63.3% respectively. RNAi knockdown of Pxae18 and Pxae28 significantly inhibited detoxification ability and increased the mortality in P. xylostella. The results indicate that these two CarE genes play important roles in the detoxification of chlorpyrifos in P. xylostella. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide.

PubMed

Sakamoto, Yohei; Yoshida, Midori; Tamura, Kei; Takahashi, Miwa; Kodama, Yukio; Inoue, Kaoru

2015-12-01

Nuclear receptors play important roles in chemically induced liver hypertrophy in rodents. To clarify the involvement of constitutive androstane receptor (CAR) and other nuclear receptors in mouse liver hypertrophy induced by different doses of piperonyl butoxide (PBO), wild-type and CAR-knockout mice were administered PBO (200, 1,000, or 5,000 ppm) in the basal diet for 1 week. Increased liver weight and diffuse hepatocellular hypertrophy were observed at 5,000 ppm for both genotypes, accompanied by increased Cyp3a11 mRNA and CYP3A protein expression, suggesting that CAR-independent pathway, possibly pregnane X receptor (PXR), plays a major role in the induction of hypertrophy. Moreover, wild-type mice at 5,000 ppm showed enhanced hepatocellular hypertrophy and strong positive staining for CYP2B in the centrilobular area, suggesting the localized contribution of CAR. At 1,000 ppm, only wild-type mice showed liver weight increase and centrilobular hepatocellular hypertrophy concurrent with elevated Cyp2b10 mRNA expression and strong CYP2B staining, indicating that CAR was essential at 1,000 ppm. We concluded that high-dose PBO induced hypertrophy via CAR and another pathway, while lower dose of PBO induced a pathway mediated predominantly by CAR. The dose-responsiveness on liver hypertrophy is important for understanding the involvement of nuclear receptors.

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.

Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.

PubMed

Johnson, Laura A; Scholler, John; Ohkuri, Takayuki; Kosaka, Akemi; Patel, Prachi R; McGettigan, Shannon E; Nace, Arben K; Dentchev, Tzvete; Thekkat, Pramod; Loew, Andreas; Boesteanu, Alina C; Cogdill, Alexandria P; Chen, Taylor; Fraietta, Joseph A; Kloss, Christopher C; Posey, Avery D; Engels, Boris; Singh, Reshma; Ezell, Tucker; Idamakanti, Neeraja; Ramones, Melissa H; Li, Na; Zhou, Li; Plesa, Gabriela; Seykora, John T; Okada, Hideho; June, Carl H; Brogdon, Jennifer L; Maus, Marcela V

2015-02-18

Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376). Copyright © 2015, American Association for the Advancement of Science.

Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas

PubMed Central

Long, Adrienne H.; Highfill, Steven L.; Cui, Yongzhi; Smith, Jillian P.; Walker, Alec J.; Ramakrishna, Sneha; El-Etriby, Rana; Galli, Susana; Tsokos, Maria G.; Orentas, Rimas J.; Mackall, Crystal L.

2016-01-01

Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CARs) have shown impressive activity against B cell malignancies, and preliminary results suggest that T cells expressing a first generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18/18 (100%) of osteosarcomas, 2/15 (13%) of rhabdomyosarcomas, and 7/35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro. However in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSCs) that inhibited human CAR T-cell responses in vitro. Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. PMID:27549124

Looking away from faces: influence of high-level visual processes on saccade programming.

PubMed

Morand, Stéphanie M; Grosbras, Marie-Hélène; Caldara, Roberto; Harvey, Monika

2010-03-30

Human faces capture attention more than other visual stimuli. Here we investigated whether such face-specific biases rely on automatic (involuntary) or voluntary orienting responses. To this end, we used an anti-saccade paradigm, which requires the ability to inhibit a reflexive automatic response and to generate a voluntary saccade in the opposite direction of the stimulus. To control for potential low-level confounds in the eye-movement data, we manipulated the high-level visual properties of the stimuli while normalizing their global low-level visual properties. Eye movements were recorded in 21 participants who performed either pro- or anti-saccades to a face, car, or noise pattern, randomly presented to the left or right of a fixation point. For each trial, a symbolic cue instructed the observer to generate either a pro-saccade or an anti-saccade. We report a significant increase in anti-saccade error rates for faces compared to cars and noise patterns, as well as faster pro-saccades to faces and cars in comparison to noise patterns. These results indicate that human faces induce stronger involuntary orienting responses than other visual objects, i.e., responses that are beyond the control of the observer. Importantly, this involuntary processing cannot be accounted for by global low-level visual factors.

Gravitropism in Phycomyces: violation of the so-called resultant law - evidence for two response components.

PubMed

Göttig, M; Galland, P

2014-01-01

We investigated gravitropic bending of sporangiophores of the zygomycete fungus Phycomyces blakesleeanus in response to centrifugal accelerations to test the so-called resultant law of gravitropism ('Resultantengesetz'; Jahrbuch der wissenschaftlichen Botanik, 71, 325, 1929; Der Geotropismus der Pflanzen, Gustav Fischer, Jena, Germany, 1932), which predicts that gravitropic organs orient in a centrifuge rotor parallel to the stimulus vector resulting from the centrifugal acceleration and gravity. Sporangiophores of wild-type strain C171 carAcarR and of several gravitropism mutants were subjected for 7 h to centrifugal accelerations in a dynamic range between 0.01 and 3 × g. The stimulus-response curves that were obtained for C171 carA carR, C2 carA geo and C148 carA geo madC were complex and displayed two response components: a low-acceleration component between 0.01 and 0.5 × g and a high-acceleration component above 0.5 × g. The low acceleration component is characterised by bending angles exceeding those predicted by the resultant law and kinetics faster than that of the second component; in contrast, the high-acceleration component is characterised by bending slightly below the predicted level and kinetics slower than that of the first component. Sporangiophores of the wild-type C171 centrifuged horizontally displayed the opposite behaviour, i.e. low accelerations diminished and high accelerations slightly enhanced bending. Further proof for the existence of the two response components was provided by the phenotype of gravitropism mutants that either lacked the first response component or which caused its overexpression. The tropism mutant C148 with defective madC gene, which codes for a RasGap protein (Fungal Genetics Reports, 60 (Suppl.), Abstract # 211, 2013), displayed hypergravitropism and concomitant deviations from the resultant law that were twice as high as in the wild-type C171. Gravitropism mutants with defects in the genes madF, madG and madJ lacked the low-response component below 0.5 × g. Our data are at variance with the so-called resultant law and imply that gravitropic orientation cannot depend exclusively on the classical sine stimulus (i.e. acting perpendicularly on the side walls); it rather must also be controlled by the cosine stimulus acting parallel to the longitudinal axis of the gravisensing organ. Our studies indicate that the threshold for the cosine response is the same as that of the sine response, and thus close to 0.01 × g. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

CAR T-cells merge into the fast lane of cancer care.

PubMed

Frey, Noelle V; Porter, David L

2016-01-01

Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD19+ malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include B-cell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions. © 2015 Wiley Periodicals, Inc.

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.

Interaction and Communication of Agents in Networks and Language Complexity Estimates

NASA Technical Reports Server (NTRS)

Smid, Jan; Obitko, Marek; Fisher, David; Truszkowski, Walt

2004-01-01

Knowledge acquisition and sharing are arguably the most critical activities of communicating agents. We report about our on-going project featuring knowledge acquisition and sharing among communicating agents embedded in a network. The applications we target range from hardware robots to virtual entities such as internet agents. Agent experiments can be simulated using a convenient simulation language. We analyzed the complexity of communicating agent simulations using Java and Easel. Scenarios we have studied are listed below. The communication among agents can range from declarative queries to sub-natural language queries. 1) A set of agents monitoring an object are asked to build activity profiles based on exchanging elementary observations; 2) A set of car drivers form a line, where every car is following its predecessor. An unsafe distance cm create a strong wave in the line. Individual agents are asked to incorporate and apply directions how to avoid the wave. 3) A set of micro-vehicles form a grid and are asked to propagate information and concepts to a central server.

A stereo vision-based obstacle detection system in vehicles

NASA Astrophysics Data System (ADS)

Huh, Kunsoo; Park, Jaehak; Hwang, Junyeon; Hong, Daegun

2008-02-01

Obstacle detection is a crucial issue for driver assistance systems as well as for autonomous vehicle guidance function and it has to be performed with high reliability to avoid any potential collision with the front vehicle. The vision-based obstacle detection systems are regarded promising for this purpose because they require little infrastructure on a highway. However, the feasibility of these systems in passenger car requires accurate and robust sensing performance. In this paper, an obstacle detection system using stereo vision sensors is developed. This system utilizes feature matching, epipoplar constraint and feature aggregation in order to robustly detect the initial corresponding pairs. After the initial detection, the system executes the tracking algorithm for the obstacles. The proposed system can detect a front obstacle, a leading vehicle and a vehicle cutting into the lane. Then, the position parameters of the obstacles and leading vehicles can be obtained. The proposed obstacle detection system is implemented on a passenger car and its performance is verified experimentally.

Photoprotection and triplet energy transfer in higher plants: the role of electronic and nuclear fluctuations.

PubMed

Cupellini, Lorenzo; Jurinovich, Sandro; Prandi, Ingrid G; Caprasecca, Stefano; Mennucci, Benedetta

2016-04-28

Photosynthetic organisms employ several photoprotection strategies to avoid damage due to the excess energy in high light conditions. Among these, quenching of triplet chlorophylls by neighboring carotenoids (Cars) is fundamental in preventing the formation of singlet oxygen. Cars are able to accept the triplets from chlorophylls by triplet energy transfer (TET). We have here studied TET rates in CP29, a minor light-harvesting complex (LHC) of the Photosystem II in plants. A fully atomistic strategy combining classical molecular dynamics of the LHC in its natural environment with a hybrid time-dependent density functional theory/polarizable MM description of the TET is used. We find that the structural fluctuations of the pigment-protein complex can largely enhance the transfer rates with respect to those predicted using the crystal structure, reducing the triplet quenching times in the subnanosecond scale. These findings add a new perspective for the interpretation of the photoprotection function and its relation with structural motions of the LHC.

Validation of the American version of the CareGiver Oncology Quality of Life (CarGOQoL) questionnaire.

PubMed

Kaveney, Sarah C; Baumstarck, Karine; Minaya-Flores, Patricia; Shannon, Tarrah; Symes, Philip; Loundou, Anderson; Auquier, Pascal

2016-05-28

The CareGiver Oncology Quality of Life (CarGOQoL) questionnaire, a 29-item, multidimensional, self-administered questionnaire, was validated using a large French sample. We reported the linguistic validation process and the metric validity of the English version of CarGOQoL in the United- States. The translation process consisted of 3 consecutive steps: forward-backward translation, acceptability testing, and cognitive interviews. The psychometric testing was applied to caregivers of consecutive patients with representative cancers who were recruited from the Regional Cancer Center in northwestern Pennsylvania. All individuals completed the CarGOQoL at baseline, day- 30, and day- 90. Internal consistency, reliability, external validity, reproducibility, and sensitivity to change were tested. The translated version was validated on a total of 87 American cancer caregivers. The dimensions of the CarGOQoL generally demonstrated a high internal consistency (Cronbach's alpha > 0.70 for all but four domain scores). External validity testing revealed that the CarGOQoL index score correlated significantly with all SF-36 dimension scores except the physical composite score (Pearson's correlation: 0.28-0.70). Reproducibility was satisfactory at day- 30 (intraclass correlation coefficient: 0.46-0.94) and day- 90 (0.43-0.92). Four specific dimensions of CarGOQoL showed responsiveness: the Psychological well-being, the Relationships with health care system, the Social support and the Finances. The American version of the CarGOQoL constitutes a useful instrument to measure QoL in caregivers of cancer patients in the United- States.

Musculoskeletal symptoms in pharmaceutical sales representatives.

PubMed

Sang, Katherine; Gyi, Diane; Haslam, Cheryl

2010-03-01

Musculoskeletal disorders (MSDs) are a leading cause of work-related ill health. Existing literature indicates that pharmaceutical sales representatives (PSRs) report a high prevalence of MSDs, possibly exacerbated by the nature of work (prolonged driving and manual handling). In addition, they experience difficulty in accessing occupational health services. To assess the prevalence of musculoskeletal symptoms and associated risk factors among PSRs in order to assist their occupational health management through raising risk awareness. A self-completed questionnaire distributed to 205 PSRs within a UK pharmaceutical company was used to assess the prevalence of musculoskeletal symptoms, psychosocial factors, work tasks undertaken and company car use. To assist understanding of work tasks and organizational factors, semi-structured interviews were undertaken with a sample of 12 key personnel. The questionnaire response rate was 68%. PSRs reported high mileage and 100% reported working from the car in a typical day. Forty-seven per cent reported both manual handling for > or = 4 h/day and 'often' or 'sometimes' working from the car. Fifty-seven per cent reported low back symptoms in the last 12 months. Interview data revealed issues relating to car choice, storage in the boot and working from the car, which should be considered when developing priorities for preventive management of MSDs. Musculoskeletal symptoms appear to be a problem for PSRs, with risk factors reported as prolonged driving, sitting in the car, working from the car and manual handling. Interventions to facilitate their occupational health management should focus on raising awareness of the risks of prolonged driving and working from the car.

The influence of parental education and other socio-economic factors on child car seat use.

PubMed

Rok Simon, Mateja; Korošec, Aleš; Bilban, Marjan

2017-03-01

The behaviour of parents in ensuring car passenger safety for their children is associated with socio-economic (SE) status of the family; however, the influence of parental education has rarely been researched and the findings are contradictory. The aim of the study was to clarify whether parental education influences the use of a child car seat during short rides. A cross-sectional survey was carried out in outpatient clinics for children's healthcare across Slovenia. 904 parents of 3-year-old children participated in the study; the response rate was 95.9%. A self-administered questionnaire was used. A binary multiple logistic regression was applied to assess the association between parental unsafe behaviour as dependent variable, and education and other SE factors as independent variables. 14.6% of parents did not use a child car seat during short rides. Families where mother had low or college education had higher odds of the non-use of a child car seat than families where mother had a university education. Single-parent families and those who lived in areas with low or medium SE status also had higher odds of the non-use of a child car seat. Low educational attainment influences parents' behaviour regarding the non-use of a child car seat. Low parental education is not the only risk factor since some highly educated parents also have high odds of unsafe behaviour. All parents should therefore be included in individually tailored safety counselling programmes. SE inequalities could be further reduced with provision of free child car seats for eligible families.

IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas

PubMed Central

Huang, Xin; Park, Haein; Greene, Joseph; Zhou, Sophia X.; Albert, Catherine M.; Moy, Fred; Sachdev, Deepali; Yee, Douglas; Rader, Christoph; Hamby, Carl V.; Loeb, David M.; Cairo, Mitchell S.; Zhou, Xianzheng

2015-01-01

Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients. PMID:26173023

IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.

PubMed

Huang, Xin; Park, Haein; Greene, Joseph; Pao, James; Mulvey, Erin; Zhou, Sophia X; Albert, Catherine M; Moy, Fred; Sachdev, Deepali; Yee, Douglas; Rader, Christoph; Hamby, Carl V; Loeb, David M; Cairo, Mitchell S; Zhou, Xianzheng

2015-01-01

Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.

A life cycle approach to the management of household food waste - A Swedish full-scale case study

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

Bernstad, A., E-mail: anna.bernstad@chemeng.lth.se; Cour Jansen, J. la

2011-08-15

Research Highlights: > The comparison of three different methods for management of household food waste show that anaerobic digestion provides greater environmental benefits in relation to global warming potential, acidification and ozone depilation compared to incineration and composting of food waste. Use of produced biogas as car fuel provides larger environmental benefits compared to a use of biogas for heat and power production. > The use of produced digestate from the anaerobic digestion as substitution for chemical fertilizer on farmland provides avoidance of environmental burdens in the same ratio as the substitution of fossil fuels with produced biogas. > Sensitivitymore » analyses show that results are highly sensitive to assumptions regarding the environmental burdens connected to heat and energy supposedly substituted by the waste treatment. - Abstract: Environmental impacts from incineration, decentralised composting and centralised anaerobic digestion of solid organic household waste are compared using the EASEWASTE LCA-tool. The comparison is based on a full scale case study in southern Sweden and used input-data related to aspects such as source-separation behaviour, transport distances, etc. are site-specific. Results show that biological treatment methods - both anaerobic and aerobic, result in net avoidance of GHG-emissions, but give a larger contribution both to nutrient enrichment and acidification when compared to incineration. Results are to a high degree dependent on energy substitution and emissions during biological processes. It was seen that if it is assumed that produced biogas substitute electricity based on Danish coal power, this is preferable before use of biogas as car fuel. Use of biogas for Danish electricity substitution was also determined to be more beneficial compared to incineration of organic household waste. This is a result mainly of the use of plastic bags in the incineration alternative (compared to paper bags in the anaerobic) and the use of biofertiliser (digestate) from anaerobic treatment as substitution of chemical fertilisers used in an incineration alternative. Net impact related to GWP from the management chain varies from a contribution of 2.6 kg CO{sub 2}-eq/household and year if incineration is utilised, to an avoidance of 5.6 kg CO{sub 2}-eq/household and year if choosing anaerobic digestion and using produced biogas as car fuel. Impacts are often dependent on processes allocated far from the control of local decision-makers, indicating the importance of a holistic approach and extended collaboration between agents in the waste management chain.« less

Overactivating CAR T cells interferes with their ability to fight cancer in mice | Center for Cancer Research

Cancer.gov

CAR T-cell therapy, in which a patient’s T cells are reprogrammed in the lab to boost their ability to recognize and destroy cancer cells when they are returned to the body, has led to dramatic responses for many patients with certain blood cancers. Not all patients respond to the treatment, however, and many who do eventually relapse. Read more…

Short-Wavelength Light Enhances Cortisol Awakening Response in Sleep-Restricted Adolescents

PubMed Central

Figueiro, Mariana G.; Rea, Mark S.

2012-01-01

Levels of cortisol, a hormone produced by the adrenal gland, follow a daily, 24-hour rhythm with concentrations reaching a minimum in the evening and a peak near rising time. In addition, cortisol levels exhibit a sharp peak in concentration within the first hour after waking; this is known as the cortisol awakening response (CAR). The present study is a secondary analysis of a larger study investigating the impact of short-wavelength (λ max ≈ 470 nm) light on CAR in adolescents who were sleep restricted. The study ran over the course of three overnight sessions, at least one week apart. The experimental sessions differed in terms of the light exposure scenarios experienced during the evening prior to sleeping in the laboratory and during the morning after waking from a 4.5-hour sleep opportunity. Eighteen adolescents aged 12–17 years were exposed to dim light or to 40 lux (0.401 W/m2) of 470-nm peaking light for 80 minutes after awakening. Saliva samples were collected every 20 minutes to assess CAR. Exposure to short-wavelength light in the morning significantly enhanced CAR compared to dim light. Morning exposure to short-wavelength light may be a simple, yet practical way to better prepare adolescents for an active day. PMID:22899916

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities.

PubMed

Shum, Thomas; Kruse, Robert L; Rooney, Cliona M

2018-05-04

Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.

Optimization of a reversible hood for protecting a pedestrian's head during car collisions.

PubMed

Huang, Sunan; Yang, Jikuang

2010-07-01

This study evaluated and optimized the performance of a reversible hood (RH) for the prevention of the head injuries of an adult pedestrian from car collisions. The FE model of a production car front was introduced and validated. The baseline RH was developed from the original hood in the validated car front model. In order to evaluate the protective performance of the baseline RH, the FE models of an adult headform and a 50th percentile human head were used in parallel to impact the baseline RH. Based on the evaluation, the response surface method was applied to optimize the RH in terms of the material stiffness, lifting speed, and lifted height. Finally, the headform model and the human head model were again used to evaluate the protective performance of the optimized RH. It was found that the lifted baseline RH can obviously reduce the impact responses of the headform model and the human head model by comparing with the retracted and lifting baseline RH. When the optimized RH was lifted, the HIC values of the headform model and the human head model were further reduced to much lower than 1000. The risk of pedestrian head injuries can be prevented as required by EEVC WG17. Copyright 2009 Elsevier Ltd. All rights reserved.

Chimeric antigen receptors with human scFvs preferentially induce T cell anti-tumor activity against tumors with high B7H6 expression.

PubMed

Gacerez, Albert T; Hua, Casey K; Ackerman, Margaret E; Sentman, Charles L

2018-05-01

B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.

The influence of the current intensity on the damping characteristics for a magneto-rheological damper of passenger car

NASA Astrophysics Data System (ADS)

Dobre, A.; Andreescu, C. N.; Stan, C.

2016-08-01

Due to their simplicity and controllability, adaptive dampers became very popular in automotive engineering industry, especially in the passenger cars industry, in spite of technological obstacles inherent and the high cost of the magnetic fluid. “MagneRide” is the first technology which uses smart fluids in the shock absorbers of the vehicles adaptive suspensions. Since the discovery of the magneto-rheological effect there is a consistent progress regarding the control algorithms and hardware part itself. These magneto-rheological devices have a major potential which can be explored in various fields of applications. At present many companies make researches for the improvement of the response time and for obtaining a better response at low frequency and amplitude of the body car oscillations. The main objective of this paper is to determine the damping characteristic of a magnetorheological shock absorber of a passenger car. The authors aim to observe how to modify the damping characteristic by changing the intensity of the electric current. The experimental researches have being carried out on a complex and modern test bench especially built for testing shock absorbers, in order to compare the damping characteristic of the classical damper with the magneto-rheological damper.

Does the cortisol awakening response link childhood adversity to adult BMI?

PubMed

Miller, Kelly F; Arbel, Reout; Shapiro, Lauren S; Han, Sohyun C; Margolin, Gayla

2018-06-01

Childhood adversity is a risk factor for the development of obesity in adulthood. Dysregulated hypothalamic-pituitary-adrenal (HPA) activity, which has been associated separately with both adverse childhood experiences and obesity, has been posited as a mechanism by which stressful experiences influence body mass index (BMI); however, this mechanism has not yet been tested longitudinally. The present study uses multireporter, longitudinal data across three time points to test whether the adolescent cortisol awakening response (CAR), an index of diurnal HPA activity, mediates the association between adversity in childhood and BMI in adulthood. Eighty-two youth, mothers, and fathers reported on adverse childhood experiences from middle childhood to late adolescence. During adolescence, youth provided saliva samples three times each morning across three days, which were assayed for cortisol to calculate CAR. During early adulthood, youth reported height and weight to calculate BMI. Greater adversity predicted flatter CAR and higher young adult BMI. Flatter CAR partially mediated the association between childhood adversity and young adult BMI. Stress-related alterations to HPA activity account in part for the childhood adversity-adult obesity link. Findings are consistent with theoretical models implicating HPA alterations as linking childhood adversity to metabolic and behavioral determinants of BMI in adulthood. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Binding of serum response factor to cystic fibrosis transmembrane conductance regulator CArG-like elements, as a new potential CFTR transcriptional regulation pathway

PubMed Central

René, Céline; Taulan, Magali; Iral, Florence; Doudement, Julien; L'Honoré, Aurore; Gerbon, Catherine; Demaille, Jacques; Claustres, Mireille; Romey, Marie-Catherine

2005-01-01

CFTR expression is tightly controlled by a complex network of ubiquitous and tissue-specific cis-elements and trans-factors. To better understand mechanisms that regulate transcription of CFTR, we examined transcription factors that specifically bind a CFTR CArG-like motif we have previously shown to modulate CFTR expression. Gel mobility shift assays and chromatin immunoprecipitation analyses demonstrated the CFTR CArG-like motif binds serum response factor both in vitro and in vivo. Transient co-transfections with various SRF expression vector, including dominant-negative forms and small interfering RNA, demonstrated that SRF significantly increases CFTR transcriptional activity in bronchial epithelial cells. Mutagenesis studies suggested that in addition to SRF other co-factors, such as Yin Yang 1 (YY1) previously shown to bind the CFTR promoter, are potentially involved in the CFTR regulation. Here, we show that functional interplay between SRF and YY1 might provide interesting perspectives to further characterize the underlying molecular mechanism of the basal CFTR transcriptional activity. Furthermore, the identification of multiple CArG binding sites in highly conserved CFTR untranslated regions, which form specific SRF complexes, provides direct evidence for a considerable role of SRF in the CFTR transcriptional regulation into specialized epithelial lung cells. PMID:16170155

Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice.

PubMed

Chinnasamy, Dhanalakshmi; Yu, Zhiya; Theoret, Marc R; Zhao, Yangbing; Shrimali, Rajeev K; Morgan, Richard A; Feldman, Steven A; Restifo, Nicholas P; Rosenberg, Steven A

2010-11-01

Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2-expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers.

Foliar Desiccators Glyphosate, Carfentrazone, and Paraquat Affect the Technological and Chemical Properties of Cowpea Grains.

PubMed

Lindemann, Igor da Silva; Lang, Gustavo Heinrich; Hoffmann, Jessica Fernanda; Rombaldi, Cesar Valmor; de Oliveira, Maurício; Elias, Moacir Cardoso; Vanier, Nathan Levien

2017-08-16

The effects of the use of glyphosate (GLY), glyphosate plus carfentrazone (GLY/CAR), and paraquat (PAR) as plant desiccators on the technological and chemical properties of cowpea grains were investigated. All studied desiccants provided lower cooking time to freshly harvested cowpea. However, the coat color of PAR- and GLY/CAR-treated cowpea was reddish in comparison to the control treatment. Principal component analysis (PCA) from liquid chromatography-mass spectrometry (LC-MS) data sets showed a clear distinction among cowpea from the different treatments. Catechin-3-glucoside and epicatechin significantly contributed for discriminating GLY-treated cowpea, while citric acid was responsible for discriminating GLY/CAR-treated cowpea. Quercetin derivative and gluconic acid were responsible for discriminating control treatment. Residual glyphosate and paraquat content was higher than the maximum limits allowed by Codex Alimentarius and the European Union Commission. Improvements in the technological and chemical properties of cowpea may not be overlapped by the risks that those desiccants exhibit when exceeding the maximum limits of tolerance in food.

Comparative study of Waste Isolation Pilot Plant (WIPP) transportation alternatives

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

Not Available

WIPP transportation studies in the Final Supplement Environmental Impact Statement for WIPP are the baseline for this report. In an attempt to present the most current analysis, this study incorporates the most relevant data available. The following three transportation options are evaluated for the Disposal Phase, which is assumed to be 20 years: Truck shipments, consisting of a tractor and trailer, with three TRUPACT-IIs or one RH-72B; Regular commercial train shipments consisting of up to three railcars carrying up to 18 TRUPACT-IIs or up to six RH-72Bs; Dedicated train shipments consisting of a locomotive, an idle car, railcars carrying 18more » TRUPACT-IIs or six RH-72Bs, another idle car, and a caboose or passenger car with an emergency response specialist. No other cargo is carried. This report includes: A consideration of occupational and public risks and exposures, and other environmental impacts; A consideration of emergency response capabilities; and An extimation of comparative costs.« less

CAR T-Cell Therapies in Glioblastoma: A First Look.

PubMed

Migliorini, Denis; Dietrich, Pierre-Yves; Stupp, Roger; Linette, Gerald P; Posey, Avery D; June, Carl H

2018-02-01

Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier. Results from three first-in-man chimeric antigen receptor (CAR) T-cell trials targeting IL13Rα2, Her2/CMV, and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T-cell trafficking to CNS, engraftment and persistence, tumor microenvironment remodeling, and monitoring of glioma response to CAR T cells. Objective radiologic responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. Clin Cancer Res; 24(3); 535-40. ©2017 AACR . ©2017 American Association for Cancer Research.

Plasticity and evolution of (+)-3-carene synthase and (-)-sabinene synthase functions of a sitka spruce monoterpene synthase gene family associated with weevil resistance.

PubMed

Roach, Christopher R; Hall, Dawn E; Zerbe, Philipp; Bohlmann, Jörg

2014-08-22

The monoterpene (+)-3-carene is associated with resistance of Sitka spruce against white pine weevil, a major North American forest insect pest of pine and spruce. High and low levels of (+)-3-carene in, respectively, resistant and susceptible Sitka spruce genotypes are due to variation of (+)-3-carene synthase gene copy number, transcript and protein expression levels, enzyme product profiles, and enzyme catalytic efficiency. A family of multiproduct (+)-3-carene synthase-like genes of Sitka spruce include the three (+)-3-carene synthases, PsTPS-3car1, PsTPS-3car2, PsTPS-3car3, and the (-)-sabinene synthase PsTPS-sab. Of these, PsTPS-3car2 is responsible for the relatively higher levels of (+)-3-carene in weevil-resistant trees. Here, we identified features of the PsTPS-3car1, PsTPS-3car2, PsTPS-3car3, and PsTPS-sab proteins that determine different product profiles. A series of domain swap and site-directed mutations, supported by structural comparisons, identified the amino acid in position 596 as critical for product profiles dominated by (+)-3-carene in PsTPS-3car1, PsTPS-3car2, and PsTPS-3car3, or (-)-sabinene in PsTPS-sab. A leucine in this position promotes formation of (+)-3-carene, whereas phenylalanine promotes (-)-sabinene. Homology modeling predicts that position 596 directs product profiles through differential stabilization of the reaction intermediate. Kinetic analysis revealed position 596 also plays a role in catalytic efficiency. Mutations of position 596 with different side chain properties resulted in a series of enzymes with different product profiles, further highlighting the inherent plasticity and potential for evolution of alternative product profiles of these monoterpene synthases of conifer defense against insects. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Rapid Assessment of Environmental Health Impacts for Policy Support: The Example of Road Transport in New Zealand

PubMed Central

Briggs, David; Mason, Kylie; Borman, Barry

2015-01-01

An integrated environmental health impact assessment of road transport in New Zealand was carried out, using a rapid assessment. The disease and injury burden was assessed from traffic-related accidents, air pollution, noise and physical (in)activity, and impacts attributed back to modal source. In total, road transport was found to be responsible for 650 deaths in 2012 (2.1% of annual mortality): 308 from traffic accidents, 283 as a result of air pollution, and 59 from noise. Together with morbidity, these represent a total burden of disease of 26,610 disability-adjusted life years (DALYs). An estimated 40 deaths and 1874 DALYs were avoided through active transport. Cars are responsible for about 52% of attributable deaths, but heavy goods vehicles (6% of vehicle kilometres travelled, vkt) accounted for 21% of deaths. Motorcycles (1 per cent of vkt) are implicated in nearly 8% of deaths. Overall, impacts of traffic-related air pollution and noise are low compared to other developed countries, but road accident rates are high. Results highlight the need for policies targeted at road accidents, and especially at heavy goods vehicles and motorcycles, along with more general action to reduce the reliance on private road transport. The study also provides a framework for national indicator development. PMID:26703699

Rapid Assessment of Environmental Health Impacts for Policy Support: The Example of Road Transport in New Zealand.

PubMed

Briggs, David; Mason, Kylie; Borman, Barry

2015-12-22

An integrated environmental health impact assessment of road transport in New Zealand was carried out, using a rapid assessment. The disease and injury burden was assessed from traffic-related accidents, air pollution, noise and physical (in)activity, and impacts attributed back to modal source. In total, road transport was found to be responsible for 650 deaths in 2012 (2.1% of annual mortality): 308 from traffic accidents, 283 as a result of air pollution, and 59 from noise. Together with morbidity, these represent a total burden of disease of 26,610 disability-adjusted life years (DALYs). An estimated 40 deaths and 1874 DALYs were avoided through active transport. Cars are responsible for about 52% of attributable deaths, but heavy goods vehicles (6% of vehicle kilometres travelled, vkt) accounted for 21% of deaths. Motorcycles (1 per cent of vkt) are implicated in nearly 8% of deaths. Overall, impacts of traffic-related air pollution and noise are low compared to other developed countries, but road accident rates are high. Results highlight the need for policies targeted at road accidents, and especially at heavy goods vehicles and motorcycles, along with more general action to reduce the reliance on private road transport. The study also provides a framework for national indicator development.

Haptic-Multimodal Flight Control System Update

NASA Technical Reports Server (NTRS)

Goodrich, Kenneth H.; Schutte, Paul C.; Williams, Ralph A.

2011-01-01

The rapidly advancing capabilities of autonomous aircraft suggest a future where many of the responsibilities of today s pilot transition to the vehicle, transforming the pilot s job into something akin to driving a car or simply being a passenger. Notionally, this transition will reduce the specialized skills, training, and attention required of the human user while improving safety and performance. However, our experience with highly automated aircraft highlights many challenges to this transition including: lack of automation resilience; adverse human-automation interaction under stress; and the difficulty of developing certification standards and methods of compliance for complex systems performing critical functions traditionally performed by the pilot (e.g., sense and avoid vs. see and avoid). Recognizing these opportunities and realities, researchers at NASA Langley are developing a haptic-multimodal flight control (HFC) system concept that can serve as a bridge between today s state of the art aircraft that are highly automated but have little autonomy and can only be operated safely by highly trained experts (i.e., pilots) to a future in which non-experts (e.g., drivers) can safely and reliably use autonomous aircraft to perform a variety of missions. This paper reviews the motivation and theoretical basis of the HFC system, describes its current state of development, and presents results from two pilot-in-the-loop simulation studies. These preliminary studies suggest the HFC reshapes human-automation interaction in a way well-suited to revolutionary ease-of-use.

Formation of met-cars and face-centered cubic structures. Thermodynamically or kinetically controlled

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

Wei, S.; Guo, B.C.; Deng, H.T.

1994-05-18

On the basis of a series of experimental studies from our laboratory, it is well established that metallocarbohedrenes, or Met-Cars for short, are a stable class of cluster materials. To account for their exceptional stability, we initially proposed a pentagonal dodecahedron structure. This cage-like structure is consistent with all the experimental findings. In general, there are two possible structures that can be developed in these metal-carbon systems, i.e., Met-Cars and cubes. Since only one structural pattern is generally observed for one particular cluster system, it has been suggested that their thermodynamical stabilities might be responsible for the selective formation ofmore » specific structures, e.g., Met-Cars or fcc structures. Herein, we present new experimental results on the system of Nb[sub m]C[sub n] under various conditions. It is shown that the experimental conditions are extremely critical for the formation of either Met-Cars or cubic structures, as predicted by Reddy and Khanma. Moreover, the new data show that the cubic structures do not develop on top of Met-Cars, but rather, they grow independently. The experiments were performed by using both time-of-flight and quadrupole mass spectrometer techniques coupled with a laser vaporization source. 23 refs., 1 fig.« less

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models

PubMed Central

Han, Yali; Liu, Chuanyong; Li, Guanhua; Li, Juan; Lv, Xingyan; Shi, Huan; Liu, Jie; Liu, Shuai; Yan, Peng; Wang, Shuyun; Sun, Yuping; Sun, Meili

2018-01-01

New immunotherapeutic approaches are urgently needed for gastric cancer due to its poor survival and unsatisfactory treatment. Here we applied the humanized chA21 scfv based chimeric antigen receptor (CAR) modified T cells approach to the HER2 overexpressing gastric cancer treatment. The chA21-4-1BBz CAR T cells specifically exerted Th1 skewed cytokine response and efficient cytolysis of HER2 overexpressing human gastric cancer cells in vitro. Both the cytokine production and cytotoxicity levels were correlated with the level of HER2 surface expression by tumor cells. In established subcutaneous xenograft and peritoneal metastasis models, chA21-4-1BBz CAR T cells dramatically facilitated regression of HER2 overexpressing tumor and prolonged survival of tumor-bearing mice, whereas spared the progression of HER2 low-expressing tumor. Additionally, the capability of these CAR T cells to persist in circulation, as well as specifically home to, and accumulate in tumor sites were identified. Taken together, these results provide the basis for the future clinical investigation of the humanized chA21 scFv based, 4-1BB costimulated CAR T cells for the treatment of gastric cancer, and other HER2-expressing solid tumors. PMID:29416924

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.

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma.

PubMed

Skuljec, Jelena; Chmielewski, Markus; Happle, Christine; Habener, Anika; Busse, Mandy; Abken, Hinrich; Hansen, Gesine

2017-01-01

Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

Differential item functioning analysis of the Vanderbilt Expertise Test for cars.

PubMed

Lee, Woo-Yeol; Cho, Sun-Joo; McGugin, Rankin W; Van Gulick, Ana Beth; Gauthier, Isabel

2015-01-01

The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge.

Associations among sugar sweetened beverage intake, visceral fat, and cortisol awakening response in minority youth

PubMed Central

Shearrer, GE; Daniels, MJ; Toledo-Corral, CM; Weigensberg, MJ; Spruijt-Metz, D; Davis, JN

2016-01-01

Context Abdominal adiposity has long been associated with excess caloric intake possibly resulting from increased psychosocial stress and associated cortisol dysfunction. However, the relationship of sugar-sweetened beverage (SSB) intake specifically with cortisol variability and visceral adipose tissue (VAT) is unknown. Objective To examine the relationships between SSB intake, VAT, and cortisol response in minority youth. Design A cross-sectional analysis. Setting The University of Southern California. Participants 60 overweight/obese Non-Hispanic Black and Hispanic adolescents ages 14–18 years. Main Outcome Measures VAT via Magnet Resonance Imaging (MRI), cortisol awakening response (CAR) via multiple salivary samples, and SSB intake via multiple 24-hour diet recalls. SSB intake was divided into the following: low SSB consumers (< 1 servings per day), medium SSB consumers (≥1 - <2 servings per day), high SSB consumers (≥2 servings per day). Analysis of covariance were run with VAT and CAR as dependent variables and SSB intake categories (independent variable) with the following a priori covariates: sex, Tanner stage, ethnicity, caloric intake, and body mass index. Results The high SSB intake group exhibited a 7% higher VAT compared to the low SSB intake group (β=0.25, CI:(0.03, 0.33), p=0.02). CAR was associated with VAT (β=0.31, CI:(0.01,0.23), p=0.02). The high SSB intake group exhibited 22% higher CAR compared to the low SSB intake group (β=0.30, CI:(0.02,0.48), p=0.04). Conclusion This is the first study exploring the relationship between SSB, VAT, and CAR. SSB consumption appears to be independently associated greater abdominal adiposity and higher morning cortisol variability in overweight and obese minority youth. This study highlights potential targets for interventions specifically to reduce SSB intake in a minority youth population. PMID:27660033

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

Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors

PubMed Central

Heiblig, Maël; Elhamri, Mohamed; Michallet, Mauricette; Thomas, Xavier

2015-01-01

Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90’s, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding “living drug” specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia. PMID:26328018

Work/non-workday differences in mother, child, and mother-child morning cortisol in a sample of working mothers and their children.

PubMed

Hibel, Leah C; Trumbell, Jill M; Mercado, Evelyn

2014-01-01

Mothers have been shown to have higher morning cortisol on days they go to work compared to non-workdays; however, it is unknown how maternal workday associates with child morning cortisol or the attunement of mother-child morning cortisol. This study examined the presence and stability of morning cortisol levels and slopes (i.e., cortisol awakening response or CAR) in a sample of 2-4year old children in out-of-home child care with working mothers. In addition, we examined the differential contributions of maternal workday on mother-child attunement in morning cortisol. Mother and child morning cortisol was sampled twice a day (awakening and 30min later) across four consecutive days (2 non-workdays; 2 workdays) among 47 working mothers and their young children. Mothers also reported on compliance with sampling procedures and provided demographic information. While children exhibited stability in cortisol levels, children's CARs were variable, with children's non-work CARs not predictive of work CARs. Similarly, a significant morning rise in cortisol was only found on workdays, not non-workdays. Overall, mothers had higher cortisol levels and steeper CARs than their children. Further, maternal workday moderated the attunement of mother-child morning cortisol, such that mothers and children had concordant cortisol levels on non-workdays, but discordant cortisol levels on workdays. Morning cortisol may be more variable in pre-school aged children than adults but may be similarly responsive to the social environment. Further, workday mornings may be a time of reduced mother-child cortisol attunement. Copyright © 2013 Elsevier Ltd. All rights reserved.

Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress.

PubMed

Yoda, Emiko; Paszek, Miles; Konopnicki, Camille; Fujiwara, Ryoichi; Chen, Shujuan; Tukey, Robert H

2017-04-19

Isothiocyanates, such as phenethyl isothiocyanate (PEITC), are formed following the consumption of cruciferous vegetables and generate reactive oxygen species (ROS) that lead to the induction of cytoprotective genes such as the UDP-glucuronosyltransferases (UGTs). The induction of ROS activates the Nrf2-Keap 1 pathway leading to the induction of genes through antioxidant response elements (AREs). UGT1A1, the sole enzyme responsible for the metabolism of bilirubin, can be induced following activation of Nrf2. When neonatal humanized UGT1 (hUGT1) mice, which exhibit severe levels of total serum bilirubin (TSB) because of a developmental delay in expression of the UGT1A1 gene, were treated with PEITC, TSB levels were reduced. Liver and intestinal UGT1A1 were induced, along with murine CYP2B10, a consensus CAR target gene. In both neonatal and adult hUGT1/Car -/- mice, PEITC was unable to induce CYP2B10. A similar result was observed following analysis of UGT1A1 expression in liver. However, TSB levels were still reduced in hUGT1/Car -/- neonatal mice because of ROS induction of intestinal UGT1A1. When oxidative stress was blocked by exposing mice to N-acetylcysteine, induction of liver UGT1A1 and CYP2B10 by PEITC was prevented. Thus, new findings in this report link an important role in CAR activation that is dependent upon oxidative stress.

Driver braking behavior analysis to improve autonomous emergency braking systems in typical Chinese vehicle-bicycle conflicts.

PubMed

Duan, Jingliang; Li, Renjie; Hou, Lian; Wang, Wenjun; Li, Guofa; Li, Shengbo Eben; Cheng, Bo; Gao, Hongbo

2017-11-01

Bicycling is one of the fundamental modes of transportation especially in developing countries. Because of the lack of effective protection for bicyclists, vehicle-bicycle (V-B) accident has become a primary contributor to traffic fatalities. Although AEB (Autonomous Emergency Braking) systems have been developed to avoid or mitigate collisions, they need to be further adapted in various conflict situations. This paper analyzes the driver's braking behavior in typical V-B conflicts of China to improve the performance of Bicyclist-AEB systems. Naturalistic driving data were collected, from which the top three scenarios of V-B accidents in China were extracted, including SCR (a bicycle crossing the road from right while a car is driving straight), SCL (a bicycle crossing the road from left while a car is driving straight) and SSR (a bicycle swerving in front of the car from right while a car is driving straight). For safety and data reliability, a driving simulator was employed to reconstruct these three scenarios and some 25 licensed drivers were recruited for braking behavior analysis. Results revealed that driver's braking behavior was significantly influenced by V-B conflict types. Pre-decelerating behaviors were found in SCL and SSR conflicts, whereas in SCR the subjects were less vigilant. The brake reaction time and brake severity in lateral V-B conflicts (SCR and SCL) was shorter and higher than that in longitudinal conflicts (SSR). The findings improve their applications in the Bicyclist-AEB and test protocol enactment to enhance the performance of Bicyclist-AEB systems in mixed traffic situations especially for developing countries. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Rage against the machine? Google's self-driving cars versus human drivers.

PubMed

Teoh, Eric R; Kidd, David G

2017-12-01

Automated driving represents both challenges and opportunities in highway safety. Google has been developing self-driving cars and testing them under employee supervision on public roads since 2009. These vehicles have been involved in several crashes, and it is of interest how this testing program compares to human drivers in terms of safety. Google car crashes were coded by type and severity based on narratives released by Google. Crash rates per million vehicle miles traveled (VMT) were computed for crashes deemed severe enough to be reportable to police. These were compared with police-reported crash rates for human drivers. Crash types also were compared. Google cars had a much lower rate of police-reportable crashes per million VMT than human drivers in Mountain View, Calif., during 2009-2015 (2.19 vs 6.06), but the difference was not statistically significant. The most common type of collision involving Google cars was when they got rear-ended by another (human-driven) vehicle. Google cars shared responsibility for only one crash. These results suggest Google self-driving cars, while a test program, are safer than conventional human-driven passenger vehicles; however, currently there is insufficient information to fully examine the extent to which disengagements affected these results. Results suggest that highly-automated vehicles can perform more safely than human drivers in certain conditions, but will continue to be involved in crashes with conventionally-driven vehicles. Copyright © 2017. Published by Elsevier Ltd.

Biocidal treatment and preservation of liquid fuels

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

Siegert, W.

1995-05-01

Strict microbiological limit values are the result of damage caused by microorganisms in fuels. With MAR 71, a biocide based on methylenebisoxazolidine, a product is available which has been tested and approved by leading car manufacturers, the mineral oil industry, and NATO. Depending on the degree of microbiological contamination, different decontamination concepts are presented, and recommendations for the treatment of fuels which are contaminated when purchased are given. In order to avoid recontamination, planning principles or the new design of tanks are necessary. The possibility of convenient, economical and regular drainage is a key factor.

Stimulus conflict triggers behavioral avoidance.

PubMed

Dignath, David; Eder, Andreas B

2015-12-01

According to a recent extension of the conflict-monitoring theory, conflict between two competing response tendencies is registered as an aversive event and triggers a motivation to avoid the source of conflict. In the present study, we tested this assumption. Over five experiments, we examined whether conflict is associated with an avoidance motivation and whether stimulus conflict or response conflict triggers an avoidance tendency. Participants first performed a color Stroop task. In a subsequent motivation test, participants responded to Stroop stimuli with approach- and avoidance-related lever movements. These results showed that Stroop-conflict stimuli increased the frequency of avoidance responses in a free-choice motivation test, and also increased the speed of avoidance relative to approach responses in a forced-choice test. High and low proportions of response conflict in the Stroop task had no effect on avoidance in the motivation test. Avoidance of conflict was, however, obtained even with new conflict stimuli that had not been presented before in a Stroop task, and when the Stroop task was replaced with an unrelated filler task. Taken together, these results suggest that stimulus conflict is sufficient to trigger avoidance.

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.

PubMed

Shum, Thomas; Omer, Bilal; Tashiro, Haruko; Kruse, Robert L; Wagner, Dimitrios L; Parikh, Kathan; Yi, Zhongzhen; Sauer, Tim; Liu, Daofeng; Parihar, Robin; Castillo, Paul; Liu, Hao; Brenner, Malcolm K; Metelitsa, Leonid S; Gottschalk, Stephen; Rooney, Cliona M

2017-11-01

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201 . ©2017 American Association for Cancer Research.

Robust expertise effects in right FFA

PubMed Central

McGugin, Rankin Williams; Newton, Allen T; Gore, John C; Gauthier, Isabel

2015-01-01

The fusiform face area (FFA) is one of several areas in occipito-temporal cortex whose activity is correlated with perceptual expertise for objects. Here, we investigate the robustness of expertise effects in FFA and other areas to a strong task manipulation that increases both perceptual and attentional demands. With high-resolution fMRI at 7Telsa, we measured responses to images of cars, faces and a category globally visually similar to cars (sofas) in 26 subjects who varied in expertise with cars, in (a) a low load 1-back task with a single object category and (b) a high load task in which objects from two categories rapidly alternated and attention was required to both categories. The low load condition revealed several areas more active as a function of expertise, including both posterior and anterior portions of FFA bilaterally (FFA1/FFA2 respectively). Under high load, fewer areas were positively correlated with expertise and several areas were even negatively correlated, but the expertise effect in face-selective voxels in the anterior portion of FFA (FFA2) remained robust. Finally, we found that behavioral car expertise also predicted increased responses to sofa images but no behavioral advantages in sofa discrimination, suggesting that global shape similarity to a category of expertise is enough to elicit a response in FFA and other areas sensitive to experience, even when the category itself is not of special interest. The robustness of expertise effects in right FFA2 and the expertise effects driven by visual similarity both argue against attention being the sole determinant of expertise effects in extrastriate areas. PMID:25192631

DHA down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes by attenuating CAR translocation

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

Li, C.-C.; Lii, C.-K.; Liu, K.-L.

The constitutive androstane receptor (CAR) plays an important role in regulating the expression of detoxifying enzymes, including cytochrome P450 2B (CYP 2B). Phenobarbital (PB) induction of human CYP 2B6 and mouse CYP 2b10 has been shown to be mediated by CAR. Our previous study showed that PB-induced CYP 2B1 expression in rat primary hepatocytes is down-regulated by both n-6 and n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA); however, the mechanism for this down-regulation by DHA was previously unknown. The objective of the present study was to determine whether change in CAR translocation is involved in the down-regulation bymore » n-6 and n-3 PUFAs of PB-induced CYP 2B1 expression in rat primary hepatocytes. We used 100 {mu}M arachidonic acid, linoleic acid, eicosapentaenoic acid, and DHA to test this hypothesis. PB triggered the translocation of CAR from the cytosol into the nucleus in a dose-dependent and time-dependent manner in our hepatocyte system, and the CAR distribution in rat primary hepatocytes was significantly affected by DHA. DHA treatment decreased PB-inducible accumulation of CAR in the nuclear fraction and increased it in the cytosolic fraction in a dose-dependent manner. The down-regulation of CYP 2B1 expression by DHA occurred in a dose-dependent manner, and a similar pattern was found for the nuclear accumulation of CAR. The results of immunoprecipitation showed a CAR/RXR heterodimer bound to nuclear receptor binding site 1 (NR-1) of the PB-responsive enhancer module (PBREM) of the CYP 2B1gene. The EMSA results showed that PB-induced CAR binding to NR-1 was attenuated by DHA. Taken together, these results suggest that attenuation of CAR translocation and decreased subsequent binding to NR-1 are involved in DHA's down-regulation of PB-induced CYP 2B1 expression.« less

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.

An evaluation of the real-world safety effect of a lane change driver support system and characteristics of lane change crashes based on insurance claims data.

PubMed

Isaksson-Hellman, Irene; Lindman, Magdalena

2018-02-28

Lane changes, which frequently occur when vehicles travel on major roads, may contribute to critical situations that significantly affect the traffic flow and traffic safety. Thus, knowledge of lane change situations is important for infrastructure improvements as well as for driver support systems and automated driving development projects. The objectives of this study were to evaluate the crash avoidance performance of a lane change driver support system, the Blind Spot Information System (BLIS) in Volvo car models, and to describe the characteristics of lane change crashes by analyzing detailed information from insurance claim reports. An overall evaluation of the safety effect of BLIS was performed by analyzing crash rate differences in lane change situations for cars with and without the optionally mounted BLIS system based on a population of 380,000 insured vehicle years. Further, crashes in which the repair cost of the host vehicle exceeded approximately US$1,250 were selected and compared. Finally, the study examined different precrash factors and crash configurations, using in-depth insurance claims data from representative lane change crash cases including all severity levels in a population of more than 200,000 insured vehicle years. The technology did not significantly reduce the overall number of crashes when all types of lane change crashes and severity levels were considered, though a significant crash-reducing effect of 31% for BLIS cars was found when more severe crashes with a repair cost exceeding US$1,250 were analysed. Cars with the BLIS technology also have a 30% lower claim cost on average for reported lane change crashes, indicating reduced crash severity. When stratifying the data into specific situations, by collecting precrash information in a case-by-case study, the influence of BLIS was indicated to differ for the evaluated situations, although no significant results were found. For example, during general lane change maneuvers (i.e., not while exiting or entering highways or during weaving/merging situations) the crash rate was reduced by 14%, whereas in weaving/merging situations the crash rate increased. The insurance data analyzed provided useful information about real-world lane change crash characteristics by covering collisions in all crash severities and thus revealed information beyond what is available in, for example, data sets of police-reported crashes. This will guide further development of driver support systems. For crashes with repair cost exceeding US$1,250, a significant crash reduction was found, although the technology did not significantly reduce the total number of lane change crashes. An average lower insurance claim cost for cars equipped with the BLIS technology also indicated that the technology contributes to reduced crash severity even if crashes were not totally avoided. Stratifying the data into different lane change crash situations gave indications of the condition-specific performance of the system, even if the results were not statistically significant at the 95% level.

Psychological coping styles and cortisol over the day in healthy older adults.

PubMed

O'Donnell, Katie; Badrick, Ellena; Kumari, Meena; Steptoe, Andrew

2008-06-01

Patterns of psychological coping are associated with a variety of health outcomes but the underlying pathways are not yet established. The purpose of this study was to assess the relationship between salivary cortisol output over the course of a day and coping style. Data were available from 350 men and 192 women with an average age of 60.9 years. Participants were drawn from the Whitehall II cohort, and had no history of cardiovascular disease. Individuals who were taking medication that might affect cortisol levels were also excluded. Saliva samples were provided on waking, then 0.5, 2.5, 8 and 12h after waking, and just before the participant went to sleep. Coping style was measured with a standard instrument, the COPE, and data were factor analysed to generate three factors: seeking social support, problem engagement and problem avoidance. The relationships between these factors and the cortisol awakening response (CAR), the slope of cortisol change over the day and total cortisol output over the day (excluding the waking period) were assessed using multiple linear regression. Cortisol output over the day was inversely associated with coping with stress by seeking social support (p=0.034) and by problem engagement (p=0.003), independently of age, gender, body mass index, smoking, depression, self-rated health, time of waking and income. Individuals who coped by problem engagement and seeking support had lower cortisol levels. Additionally, gender, BMI, smoking, self-rated health and time of waking were independently related to cortisol output over the day. There were no significant associations between coping and the CAR or cortisol slope over the day. The results indicate that adaptive coping styles are related to low levels of cortisol over the day, suggesting that neuroendocrine pathways may partly mediate relationships between psychological coping and health.

Chimeric Antigen Receptors that Recognize Mesothelin for Cancer Immunotherapy | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed chimeric antigen receptors (CARs) with a high affinity for mesothelin to be used as an immunotherapy to treat pancreatic cancer, ovarian cancer, and mesothelioma. Cells that express CARs, most notably T cells, are highly reactive against their specific tumor antigen in an MHC-unrestricted manner to generate an immune response that promotes robust tumor cell elimination when infused into cancer patients.

Evaluation of the effects of plant-derived essential oils on central nervous system function using discrete shuttle-type conditioned avoidance response in mice.

PubMed

Umezu, Toyoshi

2012-06-01

Although plant-derived essential oils (EOs) have been used to treat various mental disorders, their central nervous system (CNS) acting effects have not been clarified. The present study compared the effects of 20 kinds of EOs with the effects of already-known CNS acting drugs to examine whether the EOs exhibited CNS stimulant-like effects, CNS depressant-like effects, or neither. All agents were tested using a discrete shuttle-type conditioned avoidance task in mice. Essential oils of peppermint and chamomile exhibited CNS stimulant-like effects; that is, they increased the response rate (number of shuttlings/min) of the avoidance response. Linden also increased the response rate, however, the effect was not dose-dependent. In contrast, EOs of orange, grapefruit, and cypress exhibited CNS depressant-like effects; that is, they decreased the response rate of the avoidance response. Essential oils of eucalyptus and rose decreased the avoidance rate (number of avoidance responses/number of avoidance trials) without affecting the response rate, indicating that they may exhibit some CNS acting effects. Essential oils of 12 other plants, including juniper, patchouli, geranium, jasmine, clary sage, neroli, lavender, lemon, ylang-ylang, niaouli, vetivert and frankincense had no effect on the avoidance response in mice. Copyright © 2011 John Wiley & Sons, Ltd.

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

Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor

PubMed Central

Kochenderfer, James N.; Dudley, Mark E.; Kassim, Sadik H.; Somerville, Robert P.T.; Carpenter, Robert O.; Stetler-Stevenson, Maryalice; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Sherry, Richard M.; Raffeld, Mark; Feldman, Steven; Lu, Lily; Li, Yong F.; Ngo, Lien T.; Goy, Andre; Feldman, Tatyana; Spaner, David E.; Wang, Michael L.; Chen, Clara C.; Kranick, Sarah M.; Nath, Avindra; Nathan, Debbie-Ann N.; Morton, Kathleen E.; Toomey, Mary Ann; Rosenberg, Steven A.

2015-01-01

Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19+ B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. Conclusion This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach. PMID:25154820

Energy-absorbing car seat designs for reducing whiplash.

PubMed

Himmetoglu, S; Acar, M; Bouazza-Marouf, K; Taylor, A J

2008-12-01

This study presents an investigation of anti-whiplash features that can be implemented in a car seat to reduce whiplash injuries in the case of a rear impact. The main emphasis is on achieving a seat design with good energy absorption properties. A biofidelic 50th percentile male multi-body human model for rear impact is developed to evaluate the performance of car seat design concepts. The model is validated using the responses of 7 volunteers from the Japanese Automobile Research Institute (JARI) sled tests, which were performed at an impact speed of 8 kph with a rigid seat and without head restraint and seatbelt. A generic multi-body car seat model is also developed to implement various seatback and recliner properties, anti-whiplash devices, and head restraints. Using the same driving posture and the rigid seat in the JARI sled tests as the basic configuration, several anti-whiplash seats are designed to allow different types of motion for the seatback and seat-pan. The anti-whiplash car seat design concepts limit neck internal motion successfully until the head-to-head restraint contact occurs and they exhibit low NIC(max) values (7 m(2)/s(2) on average). They are also effective in reducing neck compression forces and T1 forward accelerations. In principle, these car seat design concepts employ controlled recliner rotation and seat-pan displacement to limit the formation of S-shape. This is accomplished by using anti-whiplash devices that absorb the crash energy in such a way that an optimum protection is provided at different severities. The results indicate that the energy absorbing car seat design concepts all demonstrate good whiplash-reducing performances at the IIWPG standard pulse. Especially in higher severity rear impacts, two of the car seat design concepts reduce the ramping of the occupant considerably.

Children's Secondhand Smoke Exposure in Private Homes and Cars: An Ethical Analysis

PubMed Central

Jarvie, Jill A.

2008-01-01

Secondhand smoke (SHS) exposure is a known cause of disease among nonsmokers, contributing to lung cancer, heart disease, and sudden infant death syndrome, as well as other diseases. In response to the growing body of scientific literature linking SHS with serious diseases, many countries, states, and cities have established policies mandating smoke-free public spaces. Yet thousands of children remain unprotected from exposure to SHS in private homes and cars. New initiatives targeting SHS in these spaces have raised ethical questions about imposing constraints on private behavior. We reviewed legislation and court cases related to such initiatives and used a principlist approach to analyze the ethical implications of policies banning smoking in private cars and homes in which children are present. PMID:18923115

CARs in Chronic Lymphocytic Leukemia – Ready to Drive

PubMed Central

Wierda, William; Jena, Bipulendu; Cooper, Laurence J. N.; Shpall, Elizabeth

2013-01-01

Adoptive transfer of antigen-specific T cells has been adapted by investigators for treatment of chronic lymphocytic leukemia (CLL). To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens (TAAs), robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve potency. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, these early-phase trials are demonstrating impressive anti-tumor effects, particularly for CLL patients, paving the way for multi-center trials to establish the efficacy of CAR+ T cell therapy. PMID:23225251

Functional customization: Value creation by individual storage elements in the car interior.

PubMed

Wagner, A-S; Kilincsoy, Ü; Reitmeir, M; Vink, P

2016-07-27

Mobility demands change due to differing life stages of car owners. Car sharing and retail markets seldom offer a possibility for customization by the user in contrast to the freedom of choice of an initial owner of a car. The value creation of functional customization is investigated. Prior to a test with a concept design, different use case scenarios of car drivers are identified regarding the preferred storage location of their personal belongings in different situations. A study with 70 subjects was conducted in order to evaluate the value added by functional customization. Storage habits of users were investigated in general and in relation to a concept design offering the possibility for flexible storage. Smartphones, supplies, beverages and wallets were the most relevant belongings in all driving situations (commuting, leisure, vacation and special occasions) complemented by sports equipment. Smartphones and other valuables are stored within reach and sight of the user. The emotional responses, recorded before and after the test, subdivided in attraction, hope and joy indicated positive feedback. The ease of use and the design proved to be crucial product characteristics of individually adaptable storage solutions. Positive emotions are contributing factors for a user's purchasing decision.

Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.

PubMed

Park, Jae H; Brentjens, Renier J

2010-04-01

Chemotherapy-resistant B-cell hematologic malignancies may be cured with allogeneic hematopoietic stem cell transplantation (HSCT), demonstrating the potential susceptibility of these tumors to donor T-cell mediated immune responses. However, high rates of transplant-related morbidity and mortality limit this approach. For this reason, there is an urgent need for less-toxic forms of immune-based cellular therapy to treat these malignancies. Adoptive transfer of autologous T cells genetically modified to express chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens represents an attractive means of overcoming the limitations of conventional HSCT. To this end, investigators have generated CARs targeted to various antigens expressed by B-cell malignancies, optimized the design of these CARs to enhance receptor mediated T cell signaling, and demonstrated significant anti-tumor efficacy of the resulting CAR modified T cells both in vitro and in vivo mouse tumor models. These encouraging preclinical data have justified the translation of this approach to the clinical setting with currently 12 open clinical trials and one completed clinical trial treating various B-cell malignancies utilizing CAR modified T cells targeted to either the CD19 or CD20 B-cell specific antigens.

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.

Investigate moped-car conflicts in China using a naturalistic driving study approach.

PubMed

Glaser, Yi G; Guo, Feng; Fang, Youjia; Deng, Bing; Hankey, Jonathan

2017-12-01

Mopeds are a popular transportation mode in Europe and Asia. Moped-related traffic accidents account for a large proportion of crash fatalities. To develop moped-related crash countermeasures, it is important to understand the characteristics of moped-related conflicts. Naturalistic driving study data were collected in Shanghai, China from 36 car drivers. The data included 2,878h and 78,296km driven from 13,149 trips. Moped-car conflicts were identified and examined from the passenger car driver's perspective using kinematic trigger algorithms and manual video reduction. A total of 119 moped-car conflicts were identified, including 74 high g-force conflicts and 45 low g-force events. These conflicts were classified into 22 on-road configurations where both similarities and differences were found as compared to Western Countries. The majority of the conflicts occurred on secondary main roads and branch roads. Hard braking was the primary response that the car drivers made to these conflicts rather than hard steering. The identified on-road vehicle-moped conflict configurations in Shanghai, China may be attributed to the complicated traffic environment and risky behavior of moped riders. The lower prevalence of hard steering in Shanghai as compared to the United States may be due to the lower speeds at event onsets or less available steering space, e.g., less available shoulder area on Chinese urban roads. The characteristics of moped-car conflicts may impact the design of active safety countermeasures on passenger cars. The pilot data from Shanghai urban areas suggest that countermeasures developed for China may require some modifications to those developed for the United States and European countries, although this recommendation may not be conclusive given the small sample size of the study. Future studies with large samples may help better understand the characteristics of moped-car conflicts. Copyright © 2017 National Safety Council and Elsevier Ltd. All rights reserved.

Use of a Remote Car Starter in Relation to Smog and Climate Change Perceptions: A Population Survey in Québec (Canada)

PubMed Central

Bélanger, Diane; Gosselin, Pierre; Valois, Pierre; Germain, Stéphane; Abdous, Belkacem

2009-01-01

Remote car starters encourage motorists to warm up their vehicles by idling the motor – thus increasing atmospheric pollutants, including several greenhouse gas (GHG) with impacts on public health. This study about climate change (CC) adaptation and mitigation actions examined perceptions on air pollution and climate change and individual characteristics associated with the use of a remote car starter. A telephone survey (n = 2,570; response rate: 70%) of adults living in Québec (Canada) measured the respondents’ beliefs and current behaviours regarding CC. Approximately 32.9% (daily car users) and 27.4% (occasional users) reported using a remote car starter during winter. The odds of the use of a remote car starter was higher in the less densely populated central (OR: 1.5) and peripheral regions (OR: 2.7) compared to the urban centers (ex. Montreal). The odds was also higher in population with a mother tongue other than English or French (OR: 2.6) and francophones than anglophones (OR: 2.1), women than men (OR: 1.5), daily drivers than occasional ones (OR: 1.2), and respondents who at least sometimes consulted temperature/humidity reports than those who consulted them less often (OR: 1.5). In multivariate analysis, the perception of living in a region susceptible to winter smog, being aware of smog warnings, or the belief in the human contribution to CC did not significantly influence the use of a remote car starter. The use of remote car starters encourages idling which produces increased atmospheric pollution and GHG production and it should be more efficiently and vigorously managed by various activities. A five-minute daily reduction in idling is equivalent to reducing the total car emissions by 1.8%. This would constitute a “no-regrets” approach to CC as it can simultaneously reduce GHG, air pollution and their health impacts. PMID:19440410

Use of a remote car starter in relation to smog and climate change perceptions: a population survey in Québec (Canada).

PubMed

Bélanger, Diane; Gosselin, Pierre; Valois, Pierre; Germain, Stéphane; Abdous, Belkacem

2009-02-01

Remote car starters encourage motorists to warm up their vehicles by idling the motor--thus increasing atmospheric pollutants, including several greenhouse gas (GHG) with impacts on public health. This study about climate change (CC) adaptation and mitigation actions examined perceptions on air pollution and climate change and individual characteristics associated with the use of a remote car starter. A telephone survey (n = 2,570; response rate: 70%) of adults living in Québec (Canada) measured the respondents' beliefs and current behaviours regarding CC. Approximately 32.9% (daily car users) and 27.4% (occasional users) reported using a remote car starter during winter. The odds of the use of a remote car starter was higher in the less densely populated central (OR: 1.5) and peripheral regions (OR: 2.7) compared to the urban centers (ex. Montreal). The odds was also higher in population with a mother tongue other than English or French (OR: 2.6) and francophones than anglophones (OR: 2.1), women than men (OR: 1.5), daily drivers than occasional ones (OR: 1.2), and respondents who at least sometimes consulted temperature/humidity reports than those who consulted them less often (OR: 1.5). In multivariate analysis, the perception of living in a region susceptible to winter smog, being aware of smog warnings, or the belief in the human contribution to CC did not significantly influence the use of a remote car starter. The use of remote car starters encourages idling which produces increased atmospheric pollution and GHG production and it should be more efficiently and vigorously managed by various activities. A five-minute daily reduction in idling is equivalent to reducing the total car emissions by 1.8%. This would constitute a "no-regrets" approach to CC as it can simultaneously reduce GHG, air pollution and their health impacts.

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

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.

Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling

PubMed Central

Diaz, Maira; Sanchez-Barrena, Maria Jose; Gonzalez-Rubio, Juana Maria; Rodriguez, Lesia; Fernandez, Daniel; Antoni, Regina; Yunta, Cristina; Belda-Palazon, Borja; Gonzalez-Guzman, Miguel; Peirats-Llobet, Marta; Menendez, Margarita; Boskovic, Jasminka; Marquez, Jose A.; Rodriguez, Pedro L.; Albert, Armando

2016-01-01

Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca2+ are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca2+ signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca2+-dependent recruitment of the pyrabactin resistance 1/PYR1-like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca2+ sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca2+-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress. PMID:26719420

Memory performance is related to the cortisol awakening response in older people, but not to the diurnal cortisol slope.

PubMed

Hidalgo, Vanesa; Almela, Mercedes; Pulopulos, Matias M; Salvador, Alicia

2016-09-01

There are large individual differences in age-related cognitive decline. Hypothalamic-pituitary-adrenal axis (HPA-axis) functioning has been suggested as one of the mechanisms underlying these differences. This study aimed to investigate the relationships between the diurnal cortisol cycle, measured as the cortisol awakening response (CAR), and the diurnal cortisol slope (DCS) and the memory performance of healthy older people. To do so, we assessed the verbal, visual, and working memory performance of 64 participants (32 men) from 57 to 76 years old who also provided 14 saliva samples on two consecutive weekdays to determine their diurnal cortisol cycle. The CAR was linearly and negatively associated with verbal (significantly) and visual (marginally) memory domains, but not with working memory. Sex did not moderate these relationships. Furthermore, no associations were found between the DCS and any of the three memory domains assessed. Our results indicate that the two components of the diurnal cortisol cycle have different relationships with memory performance, with the CAR being more relevant than DCS in understanding the link from HPA-axis activity and regulation to different types of memory. These results suggest that the CAR is related to memory domains dependent on hippocampal functioning (i.e., declarative memory), but not to those that are more dependent on prefrontal cortex functioning (i.e., working memory). Copyright © 2016 Elsevier Ltd. All rights reserved.

CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results.

PubMed

Till, Brian G; Jensen, Michael C; Wang, Jinjuan; Qian, Xiaojun; Gopal, Ajay K; Maloney, David G; Lindgren, Catherine G; Lin, Yukang; Pagel, John M; Budde, Lihua E; Raubitschek, Andrew; Forman, Stephen J; Greenberg, Philip D; Riddell, Stanley R; Press, Oliver W

2012-04-26

Cellular immune responses have the potential to elicit dramatic and sustained clinical remissions in lymphoma patients. Recent clinical trial data demonstrate that modification of T cells with chimeric antigen receptors (CARs) is a promising strategy. T cells containing CARs with costimulatory domains exhibit improved activity against tumors. We conducted a pilot clinical trial testing a "third-generation" CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. Four patients were enrolled, and 3 received T-cell infusions after cyclophosphamide lymphodepletion. Treatment was well tolerated, although one patient developed transient infusional symptoms. Two patients without evaluable disease remained progression-free for 12 and 24 months. The third patient had an objective partial remission and relapsed at 12 months after infusions. Modified T cells were detected by quantitative PCR at tumor sites and up to 1 year in peripheral blood, albeit at low levels. No evidence of host immune responses against infused cells was detected. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity. We will pursue alternative gene transfer technologies and culture conditions in future studies to improve CAR expression and cell production efficiency.

Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling.

PubMed

Diaz, Maira; Sanchez-Barrena, Maria Jose; Gonzalez-Rubio, Juana Maria; Rodriguez, Lesia; Fernandez, Daniel; Antoni, Regina; Yunta, Cristina; Belda-Palazon, Borja; Gonzalez-Guzman, Miguel; Peirats-Llobet, Marta; Menendez, Margarita; Boskovic, Jasminka; Marquez, Jose A; Rodriguez, Pedro L; Albert, Armando

2016-01-19

Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca(2+) are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca(2+) signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca(2+)-dependent recruitment of the pyrabactin resistance 1/PYR1-like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca(2+) sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca(2+)-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress.

Influence of carvacrol and thymol on the physiological attributes, enterotoxin production and surface characteristics of Staphylococcus aureus strains isolated from foods

PubMed Central

Souza, E.L.; Oliveira, C.E.V.; Stamford, T.L.M.; Conceição, M.L.; Neto, N.J. Gomes

2013-01-01

This study evaluated the influence of the phenolic compounds carvacrol (CAR) and thymol (THY) on some physiological characteristics and on the modulation of the secretion of some staphylococcal virulence factors, that is, coagulase and enterotoxin. This study also investigated possible mechanisms for the establishment of the anti-staphylococcal activity of these compounds. Sublethal concentrations (0.3 and 0.15 μL/mL) of CAR and THY inhibited the activity of the enzymes coagulase and lipase and led to a decrease in salt tolerance. At the tested sublethal concentrations, both CAR and THY led to a total suppression of enterotoxin production. The loss of a 260-nm-absorbing material and an efflux of potassium ions occurred immediately after the addition of CAR and THY at 0.6 and 1.2 μL/mL and increased up to 120 min of exposure. Electron microscopy of cells exposed to CAR and THY (0.6 μL/mL) revealed that individual cells appeared to be deformed, with projections of cellular material. The observations of leakage of cellular material and an altered cell surface suggest that gross damage to a cell’s cytoplasmic membrane, which results in a disruption in protein secretion, could be responsible for the anti-staphylococcal properties of CAR and THY. PMID:24159280

The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells.

PubMed

Ramachandran, Mohanraj; Dimberg, Anna; Essand, Magnus

2017-08-01

Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient-based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Intelligent Control Electromagnetic Actuated Continuously Variable Transmission System for Passenger Car

NASA Astrophysics Data System (ADS)

Rahman, Ataur; Sharif, Sazzad; Mohiuddin, AKM; Faris Ismail, Ahmed; Izan, Sany Ihsan

2017-03-01

Continuously variable transmission (CVT) system transmits the engine /battery power to the car driving wheel smoothly and efficiently. Cars with CVT produces some noise and slow acceleration to meet the car power demand on initial start-ups and slow speed. The car noise is produced as a result of CVT adjustment the engine speed with the hydraulic pressure. The current CVT problems incurred due to the slow response of hydraulic pressure and CVT fluid viscosity due to the development of heat.The aim of this study is to develop electromagnetic actuated CVT (EMA-CVT) with intelligent switching controlling system (ICS). The experimental results of ¼ scale EMA shows that it make the acceleration time of the car in 3.5-5 sec which is 40% less than the hydraulic CVT in the market. The EMA develops the electromagnetic force in the ranged of 350 -1200 N for the supply current in the range of 10-15 amp. This study introduced fuzzy intelligent system (FIS) to predict the EMA system dynamic behaviour in order to identify the current control for the EMA actuation during operation of the CVT. It is expecting that the up scale EMA-CVT would reduce the 75% of vehicle power transmission loss by accelerating vehicle in 5 sec and save the IC engine power consumption about 20% which will makes the vehicle energy efficient (EEV) and reduction of green house gas reduction.

Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don’t Forget the Fuel

PubMed Central

Irving, Melita; Vuillefroy de Silly, Romain; Scholten, Kirsten; Dilek, Nahzli; Coukos, George

2017-01-01

T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation. CAR therapy targeting CD19 has yielded extraordinary clinical responses against some hematological tumors. Solid tumors, however, remain an important challenge to CAR T-cells due to issues of homing, tumor vasculature and stromal barriers, and a range of obstacles in the tumor bed. Protumoral immune infiltrate including T regulatory cells and myeloid-derived suppressor cells have been well characterized for their ability to upregulate inhibitory receptors and molecules that hinder effector T-cells. A critical role for metabolic barriers in the tumor microenvironment (TME) is emerging. High glucose consumption and competition for key amino acids by tumor cells can leave T-cells with insufficient energy and biosynthetic precursors to support activities such as cytokine secretion and lead to a phenotypic state of anergy or exhaustion. CAR T-cell expansion protocols that promote a less differentiated phenotype, combined with optimal receptor design and coengineering strategies, along with immunomodulatory therapies that also promote endogenous immunity, offer great promise in surmounting immunometabolic barriers in the TME and curing solid tumors. PMID:28421069

Active avoidance requires inhibitory signaling in the rodent prelimbic prefrontal cortex

PubMed Central

Bravo-Rivera, Christian; Rodriguez-Romaguera, Jose; Pagan-Rivera, Pablo A; Burgos-Robles, Anthony; Roman-Ortiz, Ciorana; Quirk, Gregory J

2018-01-01

Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses. PMID:29851381

Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells.

PubMed

Jensen, Michael C; Riddell, Stanley R

2014-01-01

A major advance in adoptive T-cell therapy (ACT) is the ability to efficiently endow patient's T cells with reactivity for tumor antigens through the stable or regulated introduction of genes that encode high affinity tumor-targeting T-cell receptors (TCRs) or synthetic chimeric antigen receptors (CARs). Case reports and small series of patients treated with TCR- or CAR-modified T cells have shown durable responses in a subset of patients, particularly with B-cell malignancies treated with T cells modified to express a CAR that targets the CD19 molecule. However, many patients do not respond to therapy and serious on and off-target toxicities have been observed with TCR- and CAR-modified T cells. Thus, challenges remain to make ACT with gene-modified T cells a reproducibly effective and safe therapy and to expand the breadth of patients that can be treated to include those with common epithelial malignancies. This review discusses research topics in our laboratories that focus on the design and implementation of ACT with CAR-modified T cells. These include cell intrinsic properties of distinct T-cell subsets that may facilitate preparing therapeutic T-cell products of defined composition for reproducible efficacy and safety, the design of tumor targeting receptors that optimize signaling of T-cell effector functions and facilitate tracking of migration of CAR-modified T cells in vivo, and novel CAR designs that have alternative ligand binding domains or confer regulated function and/or survival of transduced T cells. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Differential item functioning analysis of the Vanderbilt Expertise Test for cars

PubMed Central

Lee, Woo-Yeol; Cho, Sun-Joo; McGugin, Rankin W.; Van Gulick, Ana Beth; Gauthier, Isabel

2015-01-01

The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge. PMID:26418499

Improving Drive Files for Vehicle Road Simulations

NASA Astrophysics Data System (ADS)

Cherng, John G.; Goktan, Ali; French, Mark; Gu, Yi; Jacob, Anil

2001-09-01

Shaker tables are commonly used in laboratories for automotive vehicle component testing to study durability and acoustics performance. An example is development testing of car seats. However, it is difficult to repeat the measured road data perfectly with the response of a shaker table as there are basic differences in dynamic characteristics between a flexible vehicle and substantially rigid shaker table. In addition, there are performance limits in the shaker table drive systems that can limit correlation. In practice, an optimal drive signal for the actuators is created iteratively. During each iteration, the error between the road data and the response data is minimised by an optimising algorithm which is generally a part of the feed back loop of the shake table controller. This study presents a systematic investigation to the errors in time and frequency domains as well as joint time-frequency domain and an evaluation of different digital signal processing techniques that have been used in previous work. In addition, we present an innovative approach that integrates the dynamic characteristics of car seats and the human body into the error-minimising iteration process. We found that the iteration process can be shortened and the error reduced by using a weighting function created by normalising the frequency response function of the car seat. Two road data test sets were used in the study.

Computational methods to predict railcar response to track cross-level variations

DOT National Transportation Integrated Search

1976-09-01

The rocking response of railroad freight cars to track cross-level variations is studied using: (1) a reduced complexity digital simulation model, and (2) a quasi-linear describing function analysis. The reduced complexity digital simulation model em...

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome.

PubMed

Cui, Julia Yue; Klaassen, Curtis D

2016-09-01

The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in the liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200mg/kg, i.p. once daily for 4days in corn oil) or the prototypical CAR ligand TCPOBOP (3mg/kg, i.p., once daily for 4days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated DPGs, phase-I and -II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the entire hepatic transcriptome correlated with a marked change in the expression of many DNA and histone epigenetic modifiers. In conclusion, the present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands. Results from this study will further support the role of these receptors in regulating the homeostasis of xenobiotic and intermediary metabolism in the liver, and aid in distinguishing between PXR and CAR signaling at various physiological and pathophysiological conditions. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2016 Elsevier B.V. All rights reserved.

Nuclear carbonic anhydrase 6B associates with PRMT5 to epigenetically promote IL-12 expression in innate response.

PubMed

Xu, Jia; Xu, Xiaoqing; Wang, Bingjing; Ma, Yuanwu; Zhang, Lianfeng; Xu, Henan; Hu, Ye; Wu, Jiacheng; Cao, Xuetao

2017-08-08

Interleukin-12 (IL-12) is critical for induction of protective immunity against intracellular bacterial infection. However, the mechanisms for efficient induction of IL-12 in innate response remain poorly understood. Here we report that the B type of carbonic anhydrase 6 ( Car6-b , which encoded CA-VI B) is essential for host defense against Listeria monocytogenes (LM) infection by epigenetically promoting IL-12 expression independent of its carbonic anhydrase activity. Deficiency of Car6-b attenuated IL-12 production upon LM infection both in vitro and in vivo. Car6 -/- mice were more susceptible to LM infection with less production of IL-12. Mechanistically, the nuclear localized CA-VI B selectively promotes IL-12 expression by interaction with protein arginine N -methyltransferase 5 (PRMT5), which reduces symmetric dimethylation of histone H3 arginine 8 modification (H3R8me2s) at Il12 promoters to facilitate chromatin accessibility, selectively enhancing c-Rel binding to the Il12b promoter. Our findings add insights to the epigenetic regulation of IL-12 induction in innate immunity.

Preliminary evidence for obesity and elevations in fasting insulin mediating associations between cortisol awakening response and hippocampal volumes and frontal atrophy.

PubMed

Ursache, Alexandra; Wedin, William; Tirsi, Aziz; Convit, Antonio

2012-08-01

Recent studies have demonstrated alterations in the cortisol awakening response (CAR) and brain abnormalities in adults with obesity and type 2 diabetes mellitus (T2DM). While adolescents with T2DM exhibit similar brain abnormalities, less is known about whether brain impairments and hypothalamic-pituitary-adrenal (HPA) axis abnormalities are already present in adolescents with pre-diabetic conditions such as insulin resistance (IR). This study included 33 adolescents with IR and 20 without IR. Adolescents with IR had a blunted CAR, smaller hippocampal volumes, and greater frontal lobe atrophy compared to controls. Mediation analyses indicated pathways whereby a smaller CAR was associated with higher BMI which was in turn associated with fasting insulin levels, which in turn was related to smaller hippocampal volume and greater frontal lobe atrophy. While we had hypothesized that HPA dysregulation may result from brain abnormalities, our findings suggest that HPA dysregulation may also impact brain structures through associations with metabolic abnormalities. Copyright © 2012 Elsevier Ltd. All rights reserved.

Fast epi-detected broadband multiplex CARS and SHG imaging of mouse skull cells

PubMed Central

Capitaine, Erwan; Moussa, Nawel Ould; Louot, Christophe; Bardet, Sylvia M.; Kano, Hideaki; Duponchel, Ludovic; Lévêque, Philippe; Couderc, Vincent; Leproux, Philippe

2017-01-01

We present a bimodal imaging system able to obtain epi-detected mutiplex coherent anti-Stokes Raman scattering (M-CARS) and second harmonic generation (SHG) signals coming from biological samples. We studied a fragment of mouse parietal bone and could detect broadband anti-Stokes and SHG responses originating from bone cells and collagen respectively. In addition we compared two post-processing methods to retrieve the imaginary part of the third-order nonlinear susceptibility related to the spontaneous Raman scattering. PMID:29359100

Experiential avoidance as an emotion regulatory function: an empirical analysis of experiential avoidance in relation to behavioral avoidance, cognitive reappraisal, and response suppression.

PubMed

Wolgast, Martin; Lundh, Lars-Gunnar; Viborg, Gardar

2013-01-01

The purpose of the present study was to empirically test the suggestion that experiential avoidance in an emotion regulation context is best understood as an emotion regulatory function of topographically distinct strategies. To do this we examined whether a measure of experiential avoidance could statistically account for the effects of emotion regulation strategies intervening at different points of the emotion-generative process as conceptualized by Gross' (1998) process model of emotion regulation. The strategies under examination were behavioral avoidance, cognitive reappraisal, and response suppression. The specific hypotheses to be tested were (1) that behavioral avoidance, cognitive reappraisal, and response suppression would statistically mediate the differences in measures of psychological well-being between a clinical and nonclinical sample, but that (2) these indirect effects would be reduced to nonsignificant levels when controlling for differences in experiential avoidance. The results provide clear support for the first hypothesis with regard to all the studied strategies. In contrast to the second hypothesis, the results showed the predicted outcome pattern only for the response-focused strategy "response suppression" and not for cognitive reappraisal or behavioral avoidance. The results are interpreted and discussed in relation to theories on experiential avoidance and emotion regulation.

Neurobehavioral impairments produced by developmental lead exposure persisted for generations in zebrafish (Danio rerio).

PubMed

Xu, Xiaojuan; Weber, Daniel; Burge, Rebekah; VanAmberg, Kelsey

2016-01-01

The zebrafish has become a useful animal model for studying the effects of environmental contaminants on neurobehavioral development due to its ease of breeding, high number of eggs per female, short generation times, and a well-established avoidance conditioning paradigm. Using avoidance conditioning as the behavioral paradigm, the present study investigated the effects of embryonic exposure to lead (Pb) on learning in adult zebrafish and the third (F3) generation of those fish. In Experiment 1, adult zebrafish that were developmentally exposed to 0.0, 0.1, 1.0 or 10.0μM Pb (2-24h post fertilization) as embryos were trained and tested for avoidance responses. The results showed that adult zebrafish hatched from embryos exposed to 0.0 or 0.1μM Pb learned avoidance responses during training and displayed significantly increased avoidance responses during testing, while those hatched from embryos exposed to 1.0 or 10.0μM Pb displayed no significant increases in avoidance responses from training to testing. In Experiment 2, the F3 generation of zebrafish that were developmentally exposed to an identical exposure regimen as in Experiment 1 were trained and tested for avoidance responses. The results showed that the F3 generation of zebrafish developmentally exposed as embryos to 0.0 or 0.1μM Pb learned avoidance responses during training and displayed significantly increased avoidance responses during testing, while the F3 generation of zebrafish developmentally exposed as embryos to 1.0 or 10.0μM Pb displayed no significant changes in avoidance responses from training to testing. Thus, developmental Pb exposure produced learning impairments that persisted for at least three generations, demonstrating trans-generational effects of embryonic exposure to Pb. Copyright © 2015. Published by Elsevier B.V.

Shared internal models for feedforward and feedback control.

PubMed

Wagner, Mark J; Smith, Maurice A

2008-10-15

A child often learns to ride a bicycle in the driveway, free of unforeseen obstacles. Yet when she first rides in the street, we hope that if a car suddenly pulls out in front of her, she will combine her innate goal of avoiding an accident with her learned knowledge of the bicycle, and steer away or brake. In general, when we train to perform a new motor task, our learning is most robust if it updates the rules of online error correction to reflect the rules and goals of the new task. Here we provide direct evidence that, after a new feedforward motor adaptation, motor feedback responses to unanticipated errors become precisely task appropriate, even when such errors were never experienced during training. To study this ability, we asked how, if at all, do online responses to occasional, unanticipated force pulses during reaching arm movements change after adapting to altered arm dynamics? Specifically, do they change in a task-appropriate manner? In our task, subjects learned novel velocity-dependent dynamics. However, occasional force-pulse perturbations produced unanticipated changes in velocity. Therefore, after adaptation, task-appropriate responses to unanticipated pulses should compensate corresponding changes in velocity-dependent dynamics. We found that after adaptation, pulse responses precisely compensated these changes, although they were never trained to do so. These results provide evidence for a smart feedback controller which automatically produces responses specific to the learned dynamics of the current task. To accomplish this, the neural processes underlying feedback control must (1) be capable of accurate real-time state prediction for velocity via a forward model and (2) have access to recently learned changes in internal models of limb dynamics.

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.

Research on an Active Seat Belt System

NASA Astrophysics Data System (ADS)

Kawashima, Takeshi

In a car crash, permanent injury can be avoided if deformation of an occupant's rib cage is maintained within the allowable value. In order to realize this condition, the occupant's seat belt tension must be instantaneously adjusted by a feedback control system. In this study, a seat belt tension control system based on the active shock control system is proposed. The semi-active control law used is derived from the sliding mode control method. One advantage of this proposed system is that it does not require a large power actuator because the seat belt tension is controlled by a brake mechanism. The effectiveness is confirmed by numerical simulation using general parameters of a human thorax and a passenger car in a collision scenario with a wall at a velocity of 100 km/h. The feasibility is then confirmed with a control experiment using a scale model of about 1/10 scale. The relative displacement of the thorax model approaches the allowable value smoothly along the control reference and settles near this value. Thus, the proposed seat belt tension control system design is established.

Impacts analysis of car following models considering variable vehicular gap policies

NASA Astrophysics Data System (ADS)

Xin, Qi; Yang, Nan; Fu, Rui; Yu, Shaowei; Shi, Zhongke

2018-07-01

Due to the important roles playing in the vehicles' adaptive cruise control system, variable vehicular gap polices were employed to full velocity difference model (FVDM) to investigate the traffic flow properties. In this paper, two new car following models were put forward by taking constant time headway(CTH) policy and variable time headway(VTH) policy into optimal velocity function, separately. By steady state analysis of the new models, an equivalent optimal velocity function was defined. To determine the linear stable conditions of the new models, we introduce equivalent expressions of safe vehicular gap, and then apply small amplitude perturbation analysis and long terms of wave expansion techniques to obtain the new models' linear stable conditions. Additionally, the first order approximate solutions of the new models were drawn at the stable region, by transforming the models into typical Burger's partial differential equations with reductive perturbation method. The FVDM based numerical simulations indicate that the variable vehicular gap polices with proper parameters directly contribute to the improvement of the traffic flows' stability and the avoidance of the unstable traffic phenomena.

Intelligent on-board system for driving assistance

NASA Astrophysics Data System (ADS)

Rombaut, Michele; Le Fort-Piat, N.

1995-09-01

We present in this paper, an electronic copilot embedded in a real car. The system objective is to help the driver by sending alarms or warnings in order to avoid dangerous situtations. An onboard perception system based on CCD cameras and proprioceptive sensors is used ot provide information concerning the environment and the internal state of the vehicle. From this set of information, the copilot is able to analyze the situation and to generate adequate warnings to the driver according to the circumstances. The definition and the development of such a system deal with multisensor data fusion and supervision strategies. The framework of this work was the European Prometheus Pro-Art program. The electronic copilot has been integrated in a prototype vehicle called Prolab2. This French demonstrator integrates the works of nine research laboratories and two car companies: PSA and RENAULT. After a brief presentation of the global demonstrator, we present the two principal parts developed in our laboratory corresponding to the high level modules of the system: the dynamic data manager and the situation supervision.

Modeling and analysis of friction clutch at a driveline for suppressing car starting judder

NASA Astrophysics Data System (ADS)

Li, Liping; Lu, Zhaijun; Liu, Xue-Lai; Sun, Tao; Jing, Xingjian; Shangguan, Wen-Bin

2018-06-01

Car judder is a kind of back-forth vibration during vehicle starting which caused by the torsional oscillation of the driveline. This paper presents a systematic study on the dynamic response characteristics of the clutch driven disc for suppression of the judder during vehicle starting. Self-excited vibration behavior of the clutch driven disc is analyzed based on the developed 4DOF non-linear multi-body dynamic model of the clutch driving process considering stick-slip characteristics and using Karnopp friction models. Physical parameters of a clutch determining the generations of the judder behaviors are discussed and the revised designs of the driven disc of a clutch for suppression of the judder are consequently investigated and validated with experiments for two real cars.

3. West portal of Tunnel 23, view to north, 135mm ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. West portal of Tunnel 23, view to north, 135mm lens. Concrete foundation in right foreground was from 'telltale,' a simple post-and-beam frame that spanned the tracks with lengths of rope suspended from the beam. In the days when brakemen were required to be on, and walk along, the tops of freight cars to set brakes, the 'telltale' ropes would strike the unwary to warn of the tunnel ahead, allowing them to lie flat and avoid being struck by the tunnel portal. - Central Pacific Transcontinental Railroad, Tunnel No. 23, Milepost 132.69, Applegate, Placer County, CA

The MIT - Cornell Collision and Why it Happened

DTIC Science & Technology

2008-10-01

George Boulevard Ben and Team UCF’s Knight Rider Section 2.2 2h00m North Nevada and Red Zone CarOLO’s Caroline turns across MIT’s Talos Section 2.3...3h00m White Zone Caroline and Talos collide. Section 2.4 4h00m Carolina Avenue and Texas Avenue Talos swerves to avoid Victor Tango’s Odin Section 2.5...stopped in time to prevent a collision. 2.3 Caroline and Talos at North Nevada and Red Zone N or th N ev ad a Av e C ar ol in a Av e Red Zone

The role of carbonic anhydrase VI in bitter taste perception: evidence from the Car6−/− mouse model

PubMed Central

2014-01-01

Background Carbonic anhydrase VI (CA VI) is a secretory isozyme of the α-CA gene family. It is highly expressed in the salivary and mammary glands and secreted into saliva and milk. Although CA VI was first described as a gustatory protein, its exact functional roles have remained enigmatic. Interestingly, polymorphism of the CA6 gene was recently linked to bitter taste perception in humans. In this study, we compared the preference of Car6−/− and wild-type mice for different taste modalities in an IntelliCage monitoring environment. Morphologies of taste buds, tongue papillae, and von Ebner’s glands were evaluated by light microscopy. Cell proliferation and rate of apoptosis in tongue specimens were examined by Ki67 immunostaining and fluorescent DNA fragmentation staining, respectively. Results The behavioral follow up of the mice in an IntelliCage system revealed that Car6−/− mice preferred 3 μM quinine (bitter) solution, whereas wild type mice preferred water. When the quinine concentration increased, both groups preferentially selected water. Histological analysis, Ki67 immunostaining and detection of apoptosis did not reveal any significant changes between tongue specimens of the knockout and wild type mice. Conclusions Our knockout mouse model confirms that CA VI is involved in bitter taste perception. CA VI may be one of the factors which contribute to avoidance of bitter, potentially harmful, substances. PMID:25134447

Teleconsultations reduce greenhouse gas emissions.

PubMed

Oliveira, Tiago Cravo; Barlow, James; Gonçalves, Luís; Bayer, Steffen

2013-10-01

Health services contribute significantly to greenhouse gas emissions. New models of delivering care closer to patients have the potential to reduce travelling and associated emissions. We aimed to compare the emissions of patients attending a teleconsultation - an outpatient appointment using video-conferencing equipment - with those of patients attending a face-to-face appointment. We estimated the total distances travelled and the direct and indirect greenhouse gas emissions for 20,824 teleconsultations performed between 2004 and 2011 in Alentejo, a Portuguese region. These were compared to the distances and emissions that would have resulted if teleconsultations were not available and patients had to attend face-to-face outpatient appointments. Estimates were calculated using survey data on mode of transport, and national aggregate data for car engine size and fuel. A sensitivity analysis using the lower and upper quartiles for survey distances was performed. Teleconsultations led to reductions in distances and emissions of 95%. 2,313,819 km of travelling and 455 tonnes of greenhouse gas emissions were avoided (22 kg of carbon dioxide equivalent per patient). The incorporation of modes of transport and car engine size and fuel in the analysis led to emission estimates which were 12% smaller than those assuming all patients used an average car. The availability of remote care services can significantly reduce road travel and associated emissions. At a time when many countries are committed to reducing their carbon footprint, it is desirable to explore how these reductions could be incorporated into technology assessments and economic evaluations.

Acculturation, childhood trauma and the cortisol awakening response in Mexican-American adults.

PubMed

Mangold, Deborah; Wand, Gary; Javors, Martin; Mintz, James

2010-09-01

Exposure to chronic and traumatic stress has been associated with the dysregulation of crucial stress response systems. Acculturation has been associated with unique forms of chronic psychosocial stress. The purpose of this study was to examine the effects of exposure to early traumatic stress and acculturation on dysregulation of the cortisol awakening response (CAR) in Mexican-American adults. Salivary cortisol samples were collected at awakening and 30, 45, and 60 min thereafter, on two consecutive weekdays from 59 healthy Mexican-American adult males (26) and females (33), ages 18-38 years. Participants were assessed for level of acculturation and exposure to early trauma. Data were analyzed using a mixed effects regression model with repeated measures at four time points. Mixed effects regression results indicated a significant Early Trauma x Time interaction (p=.0029) and a significant Acculturation x Time interaction (p=.0015), after controlling for age and sex. Subsequent analyses of the interaction of Trauma x Acculturation x Time showed that more than minimal exposure to either risk factor was associated with attenuation of the awakening cortisol response (p=.0002). Higher levels of acculturation with greater Anglo-orientation were associated with attenuation of the CAR in Mexican-American adults. Both moderate and higher levels of exposure to early trauma were associated with an attenuated CAR. However, greater exposure to both risk factors was only incrementally worse than exposure to either one. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Analyzing life-history traits and lipid storage using CARS microscopy for assessing effects of copper on the fitness of Caenorhabditis elegans.

PubMed

Fueser, Hendrik; Majdi, Nabil; Haegerbaeumer, Arne; Pilger, Christian; Hachmeister, Henning; Greife, Paul; Huser, Thomas; Traunspurger, Walter

2018-07-30

Lipid storage provides energy for cell survival, growth, and reproduction and is closely related to the organismal response to stress imposed by toxic chemicals. However, the effects of toxicants on energy storage as it impacts certain life-history traits have rarely been investigated. Here, we used the nematode Caenorhabditis elegans as a test species for a chronic exposure to copper (Cu) at EC20 (0.50 mg Cu/l). Effects on the fatty acid distribution in C. elegans body were determined using coherent anti-Stokes Raman spectroscopy (CARS) to link population fitness responses with individual ecophysiological responses. Cu inhibited nematode reproductive capacity and offspring growth in addition to shortening the lifespan of exposed individuals. In adult nematodes, Cu exposure led to significant reduction of lipid storage compared to the Cu-free control: Under Cu, lipids filled only 0.5% of the nematode body volume vs. 7.5% in control nematodes, lipid droplets were on average 74% smaller and the number of tiny lipids (0-10 µm 2 ) was increased. These results suggest that (1) Cu has an important effect on the life-history traits of nematodes; (2) the quantification of lipid storage can provide important information on the response of organisms to toxic stress; and (3) CARS microscopy is a promising tool for non-invasive quantitative and qualitative analyses of lipids as a measure of nematode fitness. Copyright © 2018 Elsevier Inc. All rights reserved.

Risk factors for the severity of injury incurred in crashes involving on-duty police cars.

PubMed

Chu, Hsing-Chung

2016-07-03

This article explores the risk factors associated with police cars on routine patrol and/or on an emergency run and their effects on the severity of injuries in crashes. The binary probit model is used to examine the effects of important factors on the risk of injuries sustained in crashes involving on-duty police cars. Several factors significantly increase the probability of crashes that cause severe injuries. Among those causes are police officers who drive at excessive speeds, traffic violations during emergency responses or pursuits, and driving during the evening (6 to 12 p.m.) or in rainy weather. Findings also indicate some potential issues associated with an increase in the probability of crashes that cause injuries. Younger police drivers were found to be more likely to be involved in crashes causing injuries than middle-aged drivers were. Distracted driving by on-duty police officers as well as civilian drivers who did not pull over to let a police car pass in emergency situations also caused serious crashes. Police cars are exempted from certain traffic laws under emergency circumstances. However, to reduce the probability of being involved in a crash resulting in severe injuries, officers are still obligated to drive safely and follow safety procedures when responding to emergencies or pursuing a car. Enhancement of training techniques for emergency situations or driving in pursuit of an offender and following the safety procedures are essential for safety in driving during an emergency run by police.

Predicting injury risk with "New Car Assessment Program" crashworthiness ratings.

PubMed

Jones, I S; Whitfield, R A

1988-12-01

The relationship between crashworthiness ratings produced by the National Highway Traffic Safety Administration's (NHTSA's) New Car Assessment Program (NCAP) and the risk of incapacitating injury or death for drivers who are involved in single-car, fixed-object, frontal collisions was examined. The results are based on 6,405 such crashes from the Motor Vehicle Traffic Accident file of the Texas Department of Highways and Public Transportation. The risk of injury was modeled using logistic regression taking into account the NCAP test results for each individual model of car and the intervening effects of car mass, age of the driver, restraint use, and crash severity. Three measures of anthropometric dummy response, Head Injury Criterion (HIC), Chest Deceleration (CD), and femur load were used to indicate vehicle crash test performance. The results show that there is a significant relationship between the results of the NCAP tests and the risk of serious injury or death in actual single-car frontal accidents. In terms of overall injury, chest deceleration was a better predictor than the Head Injury Criterion. For restrained drivers, crash severity, driver age, and chest deceleration were significant parameters for predicting risk of serious injury or death; the risk of injury decreased as chest deceleration decreased. The results were similar for unrestrained drivers although vehicle mass and femur load were also significant factors in the model. The risk of overall injury decreased as chest deceleration decreased but appeared to decrease as femur load increased.

Parent versus child reporting of tobacco smoke exposure at home and in the car.

PubMed

Glover, Marewa; Hadwen, Georgy; Chelimo, Carol; Scragg, Robert; Bullen, Chris; Gentles, Dudley; Nosa, Vili; McCool, Judith

2013-05-31

To compare self-reported exposure to tobacco smoke in the home or in cars between parents and their pre-adolescent children. We analysed data on self-reported exposure to secondhand smoke from 3,645 matched pairs of children at baseline (aged between 10 and 13 years) and their parents whether smokers or not, who were participants in Keeping Kids Smokefree (KKS), a community-based study in South Auckland, New Zealand from 2007-2009. The study aimed to reduce children's smoking initiation through parental behaviour change. The responses of the parent-child pairs were analysed using proportions, Kappa scores, and McNemar's Chi-squared test. Additionally, 679 children were biochemically tested for smoking exposure using exhaled carbon monoxide. There was approximately a 30% discordance between the self-reports of children and their parents, with parents reporting less smoking in homes or cars than their children. Kappa scores for parent-child agreement by ethnicity ranged from 0.15 to 0.41 for smoking at home and 0.17 to 0.54 for smoking in cars. Biochemical testing suggested that around 30% of children had been exposed to secondhand smoke, corroborating their self-reported proportion of 37% (baseline in the home) whereas few parents (11%) reported smoking in home or cars. Parents were significantly less likely than children to report smoking inside the home or car. Biochemical testing indicated that children's reporting is more accurate. This has implications for future studies relying on self-reporting by children and/or their caregivers.

Investigating Nitrogen Pollution: Activities and Models.

ERIC Educational Resources Information Center

Green Teacher, 2000

2000-01-01

Introduces activities on nitrogen, nitrogen pollution from school commuters, nitrogen response in native and introduced species, and nutrient loading models. These activities help students determine the nitrogen contribution from their parents' cars, test native plant responses to nitrogen, and experiment with the results of removing water from…

Observations on the phenotypic relationships between anti-CarLA salivary IgA antibody response, nematode infection levels and growth rates in farmed red (Cervus elaphus) and wapiti hybrid deer (Cervus elaphus canadensis).

PubMed

Mackintosh, C G; Johnstone, P; Shaw, R J

2014-06-16

Nematode parasites are one of the most significant production limiting factors in farmed deer in New Zealand. One long term strategy to reduce reliance on anthelmintics is to select deer that develop resistance to parasites. It has been shown in sheep that secretory antibody (IgA) in the saliva against a Carbohydrate Larval Antigen (CarLA) on infective larvae (L3) of a wide range of gastro-intestinal nematodes protects against reinfection. This paper describes a longitudinal slaughter study undertaken to measure anti-CarLA IgA antibody (CarLA-IgA) levels in the saliva of 5-12 month old farmed red and wapiti-cross-red deer (wapx) grazed together and to attempt to relate these levels to parasite burdens and productivity. The study showed that salivary CarLA-IgA levels peaked in June (late autumn) and October (mid spring), but the levels in wapx deer were significantly lower than in red deer. Over the May-December period 55% of red deer had CarLA-IgA values ≥2 units compared with 26% of wapx deer and over this period red deer had consistently lower adult abomasal parasite burdens than wapx deer. The average number of adult abomasal nematodes was significantly lower at each slaughter from May to December for all deer with CarLA-IgA ≥2 units vs <2 units. There were no demonstrable correlations with liveweight gain in these small groups of deer. Copyright © 2014 Elsevier B.V. All rights reserved.

Cooperation between Paxillin-like Protein Pxl1 and Glucan Synthase Bgs1 Is Essential for Actomyosin Ring Stability and Septum Formation in Fission Yeast

PubMed Central

G. Cortés, Juan C.; Pujol, Nuria; Sato, Mamiko; Pinar, Mario; Ramos, Mariona; Moreno, Belén; Osumi, Masako; Ribas, Juan Carlos; Pérez, Pilar

2015-01-01

In fungal cells cytokinesis requires coordinated closure of a contractile actomyosin ring (CAR) and synthesis of a special cell wall structure known as the division septum. Many CAR proteins have been identified and characterized, but how these molecules interact with the septum synthesis enzymes to form the septum remains unclear. Our genetic study using fission yeast shows that cooperation between the paxillin homolog Pxl1, required for ring integrity, and Bgs1, the enzyme responsible for linear β(1,3)glucan synthesis and primary septum formation, is required for stable anchorage of the CAR to the plasma membrane before septation onset, and for cleavage furrow formation. Thus, lack of Pxl1 in combination with Bgs1 depletion, causes failure of ring contraction and lateral cell wall overgrowth towards the cell lumen without septum formation. We also describe here that Pxl1 concentration at the CAR increases during cytokinesis and that this increase depends on the SH3 domain of the F-BAR protein Cdc15. In consequence, Bgs1 depletion in cells carrying a cdc15ΔSH3 allele causes ring disassembly and septation blockage, as it does in cells lacking Pxl1. On the other hand, the absence of Pxl1 is lethal when Cdc15 function is affected, generating a large sliding of the CAR with deposition of septum wall material along the cell cortex, and suggesting additional functions for both Pxl1 and Cdc15 proteins. In conclusion, our findings indicate that CAR anchorage to the plasma membrane through Cdc15 and Pxl1, and concomitant Bgs1 activity, are necessary for CAR maintenance and septum formation in fission yeast. PMID:26132084

Cooperation between Paxillin-like Protein Pxl1 and Glucan Synthase Bgs1 Is Essential for Actomyosin Ring Stability and Septum Formation in Fission Yeast.

PubMed

Cortés, Juan C G; Pujol, Nuria; Sato, Mamiko; Pinar, Mario; Ramos, Mariona; Moreno, Belén; Osumi, Masako; Ribas, Juan Carlos; Pérez, Pilar

2015-07-01

In fungal cells cytokinesis requires coordinated closure of a contractile actomyosin ring (CAR) and synthesis of a special cell wall structure known as the division septum. Many CAR proteins have been identified and characterized, but how these molecules interact with the septum synthesis enzymes to form the septum remains unclear. Our genetic study using fission yeast shows that cooperation between the paxillin homolog Pxl1, required for ring integrity, and Bgs1, the enzyme responsible for linear β(1,3)glucan synthesis and primary septum formation, is required for stable anchorage of the CAR to the plasma membrane before septation onset, and for cleavage furrow formation. Thus, lack of Pxl1 in combination with Bgs1 depletion, causes failure of ring contraction and lateral cell wall overgrowth towards the cell lumen without septum formation. We also describe here that Pxl1 concentration at the CAR increases during cytokinesis and that this increase depends on the SH3 domain of the F-BAR protein Cdc15. In consequence, Bgs1 depletion in cells carrying a cdc15ΔSH3 allele causes ring disassembly and septation blockage, as it does in cells lacking Pxl1. On the other hand, the absence of Pxl1 is lethal when Cdc15 function is affected, generating a large sliding of the CAR with deposition of septum wall material along the cell cortex, and suggesting additional functions for both Pxl1 and Cdc15 proteins. In conclusion, our findings indicate that CAR anchorage to the plasma membrane through Cdc15 and Pxl1, and concomitant Bgs1 activity, are necessary for CAR maintenance and septum formation in fission yeast.

Applying face identification to detecting hijacking of airplane

NASA Astrophysics Data System (ADS)

Luo, Xuanwen; Cheng, Qiang

2004-09-01

That terrorists hijacked the airplanes and crashed the World Trade Center is disaster to civilization. To avoid the happening of hijack is critical to homeland security. To report the hijacking in time, limit the terrorist to operate the plane if happened and land the plane to the nearest airport could be an efficient way to avoid the misery. Image processing technique in human face recognition or identification could be used for this task. Before the plane take off, the face images of pilots are input into a face identification system installed in the airplane. The camera in front of pilot seat keeps taking the pilot face image during the flight and comparing it with pre-input pilot face images. If a different face is detected, a warning signal is sent to ground automatically. At the same time, the automatic cruise system is started or the plane is controlled by the ground. The terrorists will have no control over the plane. The plane will be landed to a nearest or appropriate airport under the control of the ground or cruise system. This technique could also be used in automobile industry as an image key to avoid car stealth.

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

Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L-DOPS

PubMed Central

Goldstein, David S.; Holmes, Courtney; Sewell, LaToya; Pechnik, Sandra; Kopin, Irwin J.

2016-01-01

Background L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson’s disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic aminoacid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect. Methods Twelve patients with autonomic failure took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15 000th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS. Conclusions After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation. PMID:20220040

Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS.

PubMed

Goldstein, David S; Holmes, Courtney; Sewell, LaToya; Pechnik, Sandra; Kopin, Irwin J

2011-01-01

L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic amino-acid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect. Twelve patients with autonomic failure took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15,000 th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS. After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation.

Biological impact of α genes, β haplotypes, and G6PD activity in sickle cell anemia at baseline and with hydroxyurea

PubMed Central

Arnaud, Cécile; Kamdem, Annie; Hau, Isabelle; Lelong, Françoise; Epaud, Ralph; Pondarré, Corinne; Pissard, Serge

2018-01-01

Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study. Homozygous β-haplotype patients represented 74% of cases (37.4% CAR/CAR, 24.3% BEN/BEN, and 12.1% SEN/SEN). HU was given to 168 cohort SCA children. Hematological parameters were recorded when HbF was maximal, and changes (ΔHU-T0) were calculated. At baseline, CAR-haplotype and α-gene numbers were independently and negatively correlated with Hb and positively correlated with lactate dehydrogenase. HbF was negatively correlated with CAR-haplotype numbers and positively with BEN- and SEN-haplotype numbers. The BCL11A/rs1427407 “T” allele, which is favorable for HbF expression, was positively correlated with BEN- and negatively correlated with CAR-haplotype numbers. With HU treatment, Δ and HbF values were positively correlated with the BEN-haplotype number. BEN/BEN patients had higher HbF and Hb levels than CAR/CAR and SEN/SEN patients. In conclusion, we show that BEN/BEN patients have the best response on HU and suggest that this could be related to the higher prevalence of the favorable BCL11A/rs1427407/T/allele for HbF expression in these patients. PMID:29555644

Cyclists and drivers in road interactions: A comparison of perceived crash risk.

PubMed

Chaurand, Nadine; Delhomme, Patricia

2013-01-01

Today's increase in the number of cyclists has triggered a change in the interactions to be handled by road users. However, few studies have investigated crash risk perceived by cyclists interacting with other users, and few have compared cyclists' and drivers' perceptions of crash risk in bike-car interactions, the most dangerous situation for cyclists. Our aims here are to study perceived crash risk (no matter the seriousness of the crash) in six common road situations during which cyclist crashes are frequent and also to study cyclists' and drivers' perceived risk in bike-car interactions, in comparison to other interaction types (cyclist vs. cyclist and driver vs. driver). We predicted that perceived risk of being involved in a crash during a particular interaction would be greater when in interaction with a car than with a bike, and that drivers would perceive more risk than cyclists would. We also predicted that perceived risk would decrease with drivers' and cyclists' experience of their transportation mode and their perceived control over the interaction situation. We ran an online survey on two samples, experienced cyclists (N=336) and non-cyclist car drivers (N=92). Participants evaluated their personal risk - as cyclists or as drivers - of being involved in a road crash if they were in an interaction with a bike or a car for each of six risky road situations. Experience was measured in terms of years of vehicle driving and driven km; perceived control was measured in terms of perceived skill and responsibility for the risky behavior. The results validated our hypotheses: perceived risk was higher for car drivers than for cyclists and for interacting with a car than with a bike. The implications of these results for interventions to improve road safety for both cyclists and car drivers are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells

PubMed Central

Takwi, Apana A; Wang, Yue-Ming; Wu, Jing; Michaelis, Martin; Cinatl, Jindrich; Chen, Taosheng

2013-01-01

Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is down-regulated in resistant cells. miR-137 over-expression resulted in down-regulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 down-regulates CAR expression and CAR down-regulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance. PMID:23934188

The effects of verbal information and approach-avoidance training on children's fear-related responses

PubMed Central

Lester, Kathryn J.; Lisk, Stephen C.; Mikita, Nina; Mitchell, Sophie; Huijding, Jorg; Rinck, Mike; Field, Andy P.

2015-01-01

Background and objectives This study examined the effects of verbal information and approach-avoidance training on fear-related cognitive and behavioural responses about novel animals. Methods One hundred and sixty children (7–11 years) were randomly allocated to receive: a) positive verbal information about one novel animal and threat information about a second novel animal (verbal information condition); b) approach-avoidance training in which they repeatedly pushed away (avoid) or pulled closer (approach) pictures of the animals (approach-avoidance training), c) a combined condition in which verbal information was given prior to approach-avoidance training (verbal information + approach-avoidance training) and d) a combined condition in which approach-avoidance training was given prior to verbal information (approach-avoidance training + verbal information). Results Threat and positive information significantly increased and decreased fear beliefs and avoidance behaviour respectively. Approach-avoidance training was successful in training the desired behavioural responses but had limited effects on fear-related responses. Verbal information and both combined conditions resulted in significantly larger effects than approach-avoidance training. We found no evidence for an additive effect of these pathways. Limitations This study used a non-clinical sample and focused on novel animals rather than animals about which children already had experience or established fears. The study also compared positive information/approach with threat information/avoid training, limiting specific conclusions regarding the independent effects of these conditions. Conclusions The present study finds little evidence in support of a possible causal role for behavioural response training in the aetiology of childhood fear. However, the provision of verbal information appears to be an important pathway involved in the aetiology of childhood fear. PMID:25698069

The effects of verbal information and approach-avoidance training on children's fear-related responses.

PubMed

Lester, Kathryn J; Lisk, Stephen C; Mikita, Nina; Mitchell, Sophie; Huijding, Jorg; Rinck, Mike; Field, Andy P

2015-09-01

This study examined the effects of verbal information and approach-avoidance training on fear-related cognitive and behavioural responses about novel animals. One hundred and sixty children (7-11 years) were randomly allocated to receive: a) positive verbal information about one novel animal and threat information about a second novel animal (verbal information condition); b) approach-avoidance training in which they repeatedly pushed away (avoid) or pulled closer (approach) pictures of the animals (approach-avoidance training), c) a combined condition in which verbal information was given prior to approach-avoidance training (verbal information + approach-avoidance training) and d) a combined condition in which approach-avoidance training was given prior to verbal information (approach-avoidance training + verbal information). Threat and positive information significantly increased and decreased fear beliefs and avoidance behaviour respectively. Approach-avoidance training was successful in training the desired behavioural responses but had limited effects on fear-related responses. Verbal information and both combined conditions resulted in significantly larger effects than approach-avoidance training. We found no evidence for an additive effect of these pathways. This study used a non-clinical sample and focused on novel animals rather than animals about which children already had experience or established fears. The study also compared positive information/approach with threat information/avoid training, limiting specific conclusions regarding the independent effects of these conditions. The present study finds little evidence in support of a possible causal role for behavioural response training in the aetiology of childhood fear. However, the provision of verbal information appears to be an important pathway involved in the aetiology of childhood fear. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Molecular and Functional Characterization of cDNAs Putatively Encoding Carboxylesterases from the Migratory Locust, Locusta migratoria

PubMed Central

Zhang, Jianqin; Li, Daqi; Ge, Pingting; Guo, Yaping; Zhu, Kun Yan; Ma, Enbo; Zhang, Jianzhen

2014-01-01

Carboxylesterases (CarEs) belong to a superfamily of metabolic enzymes encoded by a number of genes and are widely distributed in microbes, plants and animals including insects. These enzymes play important roles in detoxification of insecticides and other xenobiotics, degradation of pheromones, regulation of neurodevelopment, and control of animal development. In this study, we characterized a total of 39 full-length cDNAs putatively encoding different CarEs from the migratory locust, Locusta migratoria, one of the most severe insect pests in many regions of the world, and evaluated the role of four CarE genes in insecticide detoxification. Our phylogenetic analysis grouped the 39 CarEs into five different clades including 20 CarEs in clade A, 3 in D, 13 in E, 1 in F and 2 in I. Four CarE genes (LmCesA3, LmCesA20, LmCesD1, LmCesE1), representing three different clades (A, D and E), were selected for further analyses. The transcripts of the four genes were detectable in all the developmental stages and tissues examined. LmCesA3 and LmCesE1 were mainly expressed in the fat bodies and Malpighian tubules, whereas LmCesA20 and LmCesD1 were predominately expressed in the muscles and hemolymph, respectively. The injection of double-stranded RNA (dsRNA) synthesized from each of the four CarE genes followed by the bioassay with each of four insecticides (chlorpyrifos, malathion, carbaryl and deltamethrin) increased the nymphal mortalities by 37.2 and 28.4% in response to malathion after LmCesA20 and LmCesE1 were silenced, respectively. Thus, we proposed that both LmCesA20 and LmCesE1 played an important role in detoxification of malathion in the locust. These results are expected to help researchers reveal the characteristics of diverse CarEs and assess the risk of insecticide resistance conferred by CarEs in the locust and other insect species. PMID:24722667

An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder.

PubMed

Rodriguez-Romaguera, Jose; Greenberg, Benjamin D; Rasmussen, Steven A; Quirk, Gregory J

2016-10-01

Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients' response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder. Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance. Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP. DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients' response to ERP therapy. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Teaching French via Driver Education.

ERIC Educational Resources Information Center

Berwald, Jean-Pierre

1980-01-01

Driver instruction through the medium of a foreign language is useful in teaching vocabulary, grammar, and culture. The maps, driving manuals, and cars stimulate discussion and communication. Course techniques can include Asher's concept of Total Physical Response wherein students act in response to commands in the foreign language. (PMJ)

Numerical reconstruction and injury biomechanism in a car-pedestrian crash accident.

PubMed

Zou, Dong-Hua; Li, Zheng-Dong; Shao, Yu; Feng, Hao; Chen, Jian-Guo; Liu, Ning-Guo; Huang, Ping; Chen, Yi-Jiu

2012-12-01

To reconstruct a car-pedestrian crash accident using numerical simulation technology and explore the injury biomechanism as forensic evidence for injury identification. An integration of multi-body dynamic, finite element (FE), and classical method was applied to a car-pedestrian crash accident. The location of the collision and the details of the traffic accident were determined by vehicle trace verification and autopsy. The accident reconstruction was performed by coupling the three-dimensional car behavior from PC-CRASH with a MADYMO dummy model. The collision FE models of head and leg, developed from CT scans of human remains, were loaded with calculated dummy collision parameters. The data of the impact biomechanical responses were extracted in terms of von Mises stress, relative displacement, strain and stress fringes. The accident reconstruction results were identical with the examined ones and the biomechanism of head and leg injuries, illustrated through the FE methods, were consistent with the classical injury theories. The numerical simulation technology is proved to be effective in identifying traffic accidents and exploring of injury biomechanism.

Regulation of G-protein coupled receptor traffic by an evolutionary conserved hydrophobic signal.

PubMed

Angelotti, Tim; Daunt, David; Shcherbakova, Olga G; Kobilka, Brian; Hurt, Carl M

2010-04-01

Plasma membrane (PM) expression of G-protein coupled receptors (GPCRs) is required for activation by extracellular ligands; however, mechanisms that regulate PM expression of GPCRs are poorly understood. For some GPCRs, such as alpha2c-adrenergic receptors (alpha(2c)-ARs), heterologous expression in non-native cells results in limited PM expression and extensive endoplasmic reticulum (ER) retention. Recently, ER export/retentions signals have been proposed to regulate cellular trafficking of several GPCRs. By utilizing a chimeric alpha(2a)/alpha(2c)-AR strategy, we identified an evolutionary conserved hydrophobic sequence (ALAAALAAAAA) in the extracellular amino terminal region that is responsible in part for alpha(2c)-AR subtype-specific trafficking. To our knowledge, this is the first luminal ER retention signal reported for a GPCR. Removal or disruption of the ER retention signal dramatically increased PM expression and decreased ER retention. Conversely, transplantation of this hydrophobic sequence into alpha(2a)-ARs reduced their PM expression and increased ER retention. This evolutionary conserved hydrophobic trafficking signal within alpha(2c)-ARs serves as a regulator of GPCR trafficking.

Car glass microphones using piezoelectric transducers for external alarm detection and localization

NASA Astrophysics Data System (ADS)

Bolzmacher, Christian; Le Guelvouit, Valentin

2015-05-01

This work describes the potential use of car windows as a long range acoustic sensing device for external alarm signals. The goal is to detect and localize siren signals (e.g. ambulances and police cars) and to alert presbycusic drivers of its presence by visual and acoustic feedback in order to improve individual mobility and increase the sense of security. The glass panes of a Renault Zoé operating as an acoustic antenna have been equipped with large 50 mm outer diameter piezoceramic rings, hidden in the lower part of the door structure and the lower part of the windshield and the rear window. The response of the glass to quasi-static signals and sweep excitation has been recorded. In general, the glass pane is acting as a high pass filter due to its inherent stiffness and provides only little damping. This effect is compensated by using a charge amplifier electronic circuit. The detection capability up to 120 m as well as a dynamic test where the car is moving towards the sound source is reported.

Neuroticism, acculturation and the cortisol awakening response in Mexican American adults.

PubMed

Mangold, Deborah; Mintz, Jim; Javors, Martin; Marino, Elise

2012-01-01

Neuroticism is associated with greater susceptibility to the adverse effects of stress and greater exposure to the stressors associated with acculturation in U.S. born Mexican Americans. Neuroticism and acculturation have been associated with injury to crucial stress response systems and are known risk factors for certain mood and anxiety disorders. The purpose of the current study was to examine the effects of neuroticism, and acculturation on the cortisol awakening response (CAR) in healthy Mexican-American adults. Salivary cortisol samples were collected at awakening and 30, 45, and 60 min thereafter, on two consecutive weekdays from 59 healthy Mexican American adult males (26) and females (33), ages 18 to 38 years. Participants were assessed for level of neuroticism and acculturation. Data were analyzed using a mixed effects regression model with repeated measures at four time points. Results showed a significant Neuroticism×Acculturation×Time interaction. The CAR was virtually eliminated in highly acculturated Mexican Americans with greater Anglo orientation and high neuroticism compared with less acculturated Mexican Americans with greater Mexican orientation and lower neuroticism. Findings suggest that some Mexican Americans with high levels of neuroticism may be particularly susceptible to certain challenges and stressors associated with acculturation leading over time to the development of allostatic load, desensitization of the Hypothalamic CRF system and attenuation of the CAR. Copyright © 2011 Elsevier Inc. All rights reserved.

Constraints on the Progenitor of SN 2010jl and Pre-existing Hot Dust in its Surrounding Medium

NASA Technical Reports Server (NTRS)

Dwek, Eli; Arendt, Richard G.; Fox, Ori D.; Kelly, Patrick L.; Smith, Nathan; Van Dyk, Schuyler D.; Filippenko, Alexei, V.; Andrews, Jennifer; Shivvers, Isaac

2017-01-01

A search for the progenitor of SN 2010jl, an unusually luminous core-collapse supernova of Type IIn, using pre-explosion Hubble/WFPC2 and Spitzer/IRAC images of the region, yielded upper limits on the UV and near infrared (IR) fluxes from any candidate star. These upper limits constrain the luminosity and effective temperature of the progenitor, the mass of any pre-existing dust in its surrounding circumstellar medium (CSM), and dust proximity to the star. A lower limit on the CSM dust mass is required to hide a luminous progenitor from detection by Hubble. Upper limits on the CSM dust mass and constraints on its proximity to the star are set by requiring that the absorbed and reradiated IR emission not exceed the IRAC upper limits. Using the combined extinction-IR emission constraints, we present viable M(sub d)-R(sub 1) combinations, where M(sub d) and R(sub 1) are the CSM dust mass and its inner radius. These depend on the CSM outer radius, dust composition and grain size, and the properties of the progenitor. The results constrain the pre-supernova evolution of the progenitor, and the nature and origin of the observed post-explosion IR emission from SN 2010jl. In particular, an eta Car-type progenitor will require at least 4 mag of visual extinction to avoid detection by Hubble. This can be achieved with dust masses greater than approximately equal to 10(exp -3) solar mass (less than the estimated 0.2-0.5 solar mass around eta Car), which must be located at distances of greater than approximately equal to 10(exp 16) cm from the star to avoid detection by Spitzer.

A life cycle approach to the management of household food waste - A Swedish full-scale case study.

PubMed

Bernstad, A; la Cour Jansen, J

2011-08-01

Environmental impacts from incineration, decentralised composting and centralised anaerobic digestion of solid organic household waste are compared using the EASEWASTE LCA-tool. The comparison is based on a full scale case study in southern Sweden and used input-data related to aspects such as source-separation behaviour, transport distances, etc. are site-specific. Results show that biological treatment methods - both anaerobic and aerobic, result in net avoidance of GHG-emissions, but give a larger contribution both to nutrient enrichment and acidification when compared to incineration. Results are to a high degree dependent on energy substitution and emissions during biological processes. It was seen that if it is assumed that produced biogas substitute electricity based on Danish coal power, this is preferable before use of biogas as car fuel. Use of biogas for Danish electricity substitution was also determined to be more beneficial compared to incineration of organic household waste. This is a result mainly of the use of plastic bags in the incineration alternative (compared to paper bags in the anaerobic) and the use of biofertiliser (digestate) from anaerobic treatment as substitution of chemical fertilisers used in an incineration alternative. Net impact related to GWP from the management chain varies from a contribution of 2.6kg CO(2)-eq/household and year if incineration is utilised, to an avoidance of 5.6kg CO(2)-eq/household and year if choosing anaerobic digestion and using produced biogas as car fuel. Impacts are often dependent on processes allocated far from the control of local decision-makers, indicating the importance of a holistic approach and extended collaboration between agents in the waste management chain. Copyright © 2011 Elsevier Ltd. All rights reserved.

Testing the CaR-FA-X model: investigating the mechanisms underlying reduced autobiographical memory specificity in individuals with and without a history of depression.

PubMed

Sumner, Jennifer A; Mineka, Susan; Adam, Emma K; Craske, Michelle G; Vrshek-Schallhorn, Suzanne; Wolitzky-Taylor, Kate; Zinbarg, Richard E

2014-08-01

Reduced autobiographical memory specificity (AMS) is an important cognitive phenomenon in major depressive disorder (MDD), but knowledge about mechanisms is lacking. The CaR-FA-X model of Williams and colleagues (2007) proposed that 3 processes contributed to reduce AMS: capture and rumination (CaR), functional avoidance (FA), and impaired executive control (X). However, the entire CaR-FA-X model has not been tested. We addressed this gap in the literature by investigating contributions of the CaR-FA-X mechanisms to reduced AMS, alone or in interaction, in a subset of young adults (N = 439) from the Northwestern-UCLA Youth Emotion Project. Participants were classified as those with (n = 164) and without (n = 275) a history of MDD at AMS assessment. They completed measures of: AMS; rumination (the brooding factor; CaR); childhood, adolescent, and early adulthood adversity (FA); avoidant coping (FA); and verbal fluency (X). Using structural equation modeling, we found greatest support for associations between reduced AMS and the capture and rumination, and impaired executive control mechanisms. In those with and without a history of MDD, brooding and verbal fluency interacted to contribute to reduced AMS. For participants without a history of MDD, lower verbal fluency (indicating impaired executive control) was associated with reduced AMS among those high on brooding. For participants with a history of MDD, lower verbal fluency was associated with reduced AMS among those low on brooding. The first finding was consistent with the CaR-FA-X model but the latter was not. Implications for conceptualizations of reduced AMS and its mechanisms are discussed. (c) 2014 APA, all rights reserved.

Broadband CARS spectral phase retrieval using a time-domain Kramers–Kronig transform

PubMed Central

Liu, Yuexin; Lee, Young Jong; Cicerone, Marcus T.

2014-01-01

We describe a closed-form approach for performing a Kramers–Kronig (KK) transform that can be used to rapidly and reliably retrieve the phase, and thus the resonant imaginary component, from a broadband coherent anti-Stokes Raman scattering (CARS) spectrum with a nonflat background. In this approach we transform the frequency-domain data to the time domain, perform an operation that ensures a causality criterion is met, then transform back to the frequency domain. The fact that this method handles causality in the time domain allows us to conveniently account for spectrally varying nonresonant background from CARS as a response function with a finite rise time. A phase error accompanies KK transform of data with finite frequency range. In examples shown here, that phase error leads to small (<1%) errors in the retrieved resonant spectra. PMID:19412273

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.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

PubMed

Wood, Amanda G; Nadebaum, Caroline; Anderson, Vicki; Reutens, David; Barton, Sarah; O'Brien, Terence J; Vajda, Frank

2015-07-01

The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Determination of Steering Wheel Angles during CAR Alignment by Image Analysis Methods

NASA Astrophysics Data System (ADS)

Mueller, M.; Voegtle, T.

2016-06-01

Optical systems for automatic visual inspections are of increasing importance in the field of automation in the industrial domain. A new application is the determination of steering wheel angles during wheel track setting of the final inspection of car manufacturing. The camera has to be positioned outside the car to avoid interruptions of the processes and therefore, oblique images of the steering wheel must be acquired. Three different approaches of computer vision are considered in this paper, i.e. a 2D shape-based matching (by means of a plane to plane rectification of the oblique images and detection of a shape model with a particular rotation), a 3D shape-based matching approach (by means of a series of different perspectives of the spatial shape of the steering wheel derived from a CAD design model) and a point-to-point matching (by means of the extraction of significant elements (e.g. multifunctional buttons) of a steering wheel and a pairwise connection of these points to straight lines). The HALCON system (HALCON, 2016) was used for all software developments and necessary adaptions. As reference a mechanical balance with an accuracy of 0.1° was used. The quality assessment was based on two different approaches, a laboratory test and a test during production process. In the laboratory a standard deviation of ±0.035° (2D shape-based matching), ±0.12° (3D approach) and ±0.029° (point-to-point matching) could be obtained. The field test of 291 measurements (27 cars with varying poses and angles of the steering wheel) results in a detection rate of 100% and ±0.48° (2D matching) and ±0.24° (point-to-point matching). Both methods also fulfil the request of real time processing (three measurements per second).

Autonomous intelligent cars: proof that the EPSRC Principles are future-proof

NASA Astrophysics Data System (ADS)

de Cock Buning, Madeleine; de Bruin, Roeland

2017-07-01

Principle 2 of the EPSRC's principles of robotics (AISB workshop on Principles of Robotics, 2016) proves to be future proof when applied to the current state of the art of law and technology surrounding autonomous intelligent cars (AICs). Humans, not AICS, are responsible agents. AICs should be designed; operated as far as is practicable to comply with existing laws and fundamental rights and freedoms, including privacy by design. It will show that some legal questions arising from autonomous intelligent driving technology can be answered by the technology itself.

High Anger Expression is Associated with Reduced Cortisol Awakening Response and Health Complaints in Healthy Young Adults.

PubMed

Romero-Martínez, Ángel; Moya-Albiol, Luis

2016-04-29

The extant evidence suggests a robust positive association between expression (anger expression-out) and suppression (anger expression-in) of anger and compromised health. Nevertheless, the underlying psychobiological mechanisms which explain these relationships are not well understood. This study examined whether anger expression would predict general health, cortisol awakening response (CAR) and evening cortisol levels in a community sample of 156 healthy young adults of both genders. Participants were distributed into two groups according to their anger expression scores: high and low anger expression (HAE and LAE, respectively). Findings indicated that those with HAE had worse self-reported health (p = .02) and higher CAR than the LAE group (p = .04). Moreover, high levels of anger expression-out (p < .01) and -in (p < .01, for all) predicted a worse self-reported health in both groups. On the other hand, high anger expression-out was associated with flattened CAR but only in the HAE group (p < .01). This study reinforces the need to develop effective strategies to provide mechanisms to regulate anger expression by promoting personal growth and positive skills that enhance individuals' well-being and quality of life and, in turn, their own health.

Real-time CARS imaging reveals a calpain-dependent pathway for paranodal myelin retraction during high-frequency stimulation.

PubMed

Huff, Terry B; Shi, Yunzhou; Sun, Wenjing; Wu, Wei; Shi, Riyi; Cheng, Ji-Xin

2011-03-03

High-frequency electrical stimulation is becoming a promising therapy for neurological disorders, however the response of the central nervous system to stimulation remains poorly understood. The current work investigates the response of myelin to electrical stimulation by laser-scanning coherent anti-Stokes Raman scattering (CARS) imaging of myelin in live spinal tissues in real time. Paranodal myelin retraction at the nodes of Ranvier was observed during 200 Hz electrical stimulation. Retraction was seen to begin minutes after the onset of stimulation and continue for up to 10 min after stimulation was ceased, but was found to reverse after a 2 h recovery period. The myelin retraction resulted in exposure of Kv 1.2 potassium channels visualized by immunofluorescence. Accordingly, treating the stimulated tissue with a potassium channel blocker, 4-aminopyridine, led to the appearance of a shoulder peak in the compound action potential curve. Label-free CARS imaging of myelin coupled with multiphoton fluorescence imaging of immuno-labeled proteins at the nodes of Ranvier revealed that high-frequency stimulation induced paranodal myelin retraction via pathologic calcium influx into axons, calpain activation, and cytoskeleton degradation through spectrin break-down.

Self-reported health and cortisol awakening response in parents of people with asperger syndrome: the role of trait anger and anxiety, coping and burden.

PubMed

Ruiz-Robledillo, N; Moya-Albiol, L

2013-11-01

Caring for offspring with autism spectrum disorders entails high levels of stress for a long period of time and is associated with several types of health complaints. Few studies have focused on specific effects of particular disorders in the spectrum. This study was carried out with the aim of evaluating the global health of parents of people with Asperger syndrome (N = 53) compared to those of typically developing children (N = 54) through self-reported measures (medication consumption and somatic symptoms) and biological markers (cortisol awakening response [CAR]). Additionally, we analysed various psychological variables as potential predictors of caregiver health. We found that caregivers take more medication and have worse self-reported health than controls, but there were no significant differences in CAR between the groups. However, after controlling for negative affect, differences between groups in CAR reached significance. With regards to predictor variables, anxiety trait, cognitive-coping style, burden and anger temperament were significantly associated with caregiver's self-reported health. These findings underline the need to develop interventions that foster improvements in the health of caregivers, reduce their burden and enhance their quality of life.

Adjuvant activity of diesel-exhaust particulates for the production of IgE antibody in mice.

PubMed

Muranaka, M; Suzuki, S; Koizumi, K; Takafuji, S; Miyamoto, T; Ikemori, R; Tokiwa, H

1986-04-01

The prevalence rate of allergic rhinitis caused by pollen has strikingly increased in Japan in the last three decades. The number of diesel cars in use has also rapidly increased in the country. This fact urged us to study the effects of particulates emitted from diesel cars on the production of IgE antibody. The primary IgE antibody responses in mice immunized with intraperitoneal injection of ovalbumin (OA) mixed with diesel-exhaust particulates (DEP) were higher than those in the animals immunized with OA alone. This effect of DEP on the production of IgE antibody in mice was also demonstrated when mice were immunized with repeated injections of dinitrophenylated-OA. In addition, persistent IgE-antibody response to major allergen of Japanese cedar pollen (JCPA), a most common pollen causing allergic rhinitis in Japan, was observed in mice immunized with JCPA mixed with DEP but not in the animals immunized with JCPA alone. The results do indicate that the adjuvant activity of DEP can not be excluded as a possible cause of the associated change in the number of diesel cars and allergic rhinitis caused by pollen in Japan.

Punishment and the potential for negative reinforcement with histamine injection.

PubMed

Mayer, Paulo César Morales; de Carvalho Neto, Marcus Bentes; Katz, Jonathan L

2018-03-01

The present study examined punishment of responding with histamine injection, and its potential to generate avoidance of punishment. Sprague-Dawley rats were trained under concurrent schedules in which responses on one lever (the punishment lever) produced food under a variable-interval schedule, and under some conditions intermittent injections of histamine, which suppressed behavior. Responses on a second (avoidance) lever prevented histamine injections scheduled on the punishment lever. After stabilization of punished responding, a variable-interval 15-s schedule of cancellation of histamine (avoidance) was added for responding on the second/avoidance lever, without subsequent acquisition of responding on that lever. Progressive decreases in the length of the punishment variable-interval schedule increased suppression on the punishment lever without increases in response rates on the avoidance lever. Exchanging contingencies on the levers ensured that response rates on the avoidance lever were sufficiently high to decrease the histamine injection frequency; nonetheless response rates on the avoidance lever decreased over subsequent sessions. Under no condition was responding maintained on the avoidance lever despite continued punishing effectiveness of histamine throughout. The present results suggest that avoidance conditioning is not a necessary condition for effective punishment, and confirm the importance of empirical rather than presumed categorization of behavioral effects of stimulus events. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

The Calcium-Sensing Receptor Couples to Gαs and Regulates PTHrP and ACTH Secretion in Pituitary Cells

PubMed Central

Mamillapalli, Ramanaiah; Wysolmerski, John

2013-01-01

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor (GPCR) that binds and signals in response to extracellular calcium and other polycations. It is highly expressed on parathyroid and kidney cells, where it participates in the regulation of systemic calcium homeostasis. It is also expressed on many other cell types and is involved in a wide array of biological functions such as cell growth and differentiation, ion transport and hormone secretion. It has been described to couple to several different G-proteins including Gαi/0, Gαq/11 and Gα12/13. Recently, it has also been shown to stimulate cAMP production by coupling to Gαs in immortalized or malignant breast cells. The CaR is expressed on cells in the anterior pituitary and had previously been described to stimulate cAMP production in these cells. In this report, we examined signaling from the CaR in murine pituitary corticotroph-derived, AtT-20 cells. We found that CaR activation led to the stimulation of cAMP production, and PTHrP and ACTH secretion from these cells. Furthermore, manipulation of cAMP levels was able to modulate PTHrP and ACTH secretion independent of changes in extracellular calcium. Finally, we demonstrated that the CaR couples to Gαs in AtT-20 cells. Therefore, in pituitary corticotroph-like cells, as in breast cancer cells, the CaR utilizes Gαs and activates cAMP production to stimulate hormone secretion. PMID:20032198

Stress Markers During a Rally Car Competition.

PubMed

Del Rosso, Sebastián; Abreu, Laurinda; Webb, Heather E; Zouhal, Hassane; Boullosa, Daniel A

2016-03-01

The aim of the study was to assess the stress responses in drivers during an official rally car race and the influence of fitness and body composition on stress hormones. Fitness and body composition were assessed in 9 rally car drivers with an incremental exercise test for determination of maximum aerobic speed (MAS) and 6-site skinfold method, respectively. Before (pre) and after (post) the first stage of an official rally car race, data were collected for heart rate (HR), blood samples were collected for analysis of hormones (i.e., epinephrine [EPI], norepinephrine [NE], cortisol, and aldosterone) and metabolites (i.e., lactate [LA], glucose, and ammonia). There were significant (p ≤ 0.05) increases in all assessed variables except glucose at postrace. Heart rate increased 93% (p ≤ 0.05) at the end of the race stage, reaching 88.77 ± 4.96% of HRpeak. Also, EPI and NE significantly (p = 0.001) increased by 45 and 65%, respectively, and LA increased by 395% (p < 0.001). Significant correlations between percent body fat (%BF) and postrace EPI (r = 0.95; p < 0.001), and percentage change of EPI (r = 0.83; p = 0.012) were observed. The MAS was not associated to any metabolic or hormonal variable. These results suggest that psycho-physiological stress induced by the race elicited important changes in hormonal and metabolic variables and that %BF could be an important mediator of psycho-physiological stress in rally car drivers. Specific programs, including both strength and aerobic training, and nutritional plans should be implemented for appropriate conditioning of rally car drivers.

Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

PubMed Central

Tomuleasa, Ciprian; Fuji, Shigeo; Berce, Cristian; Onaciu, Anca; Chira, Sergiu; Petrushev, Bobe; Micu, Wilhelm-Thomas; Moisoiu, Vlad; Osan, Ciprian; Constantinescu, Catalin; Pasca, Sergiu; Jurj, Ancuta; Pop, Laura; Berindan-Neagoe, Ioana; Dima, Delia; Kitano, Shigehisa

2018-01-01

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects. PMID:29515572

Evidence of a unique and common genetic etiology between the CAR and the remaining part of the diurnal cycle: A study of 14 year-old twins.

PubMed

Ouellet-Morin, Isabelle; Brendgen, Mara; Girard, Alain; Lupien, Sonia J; Dionne, Ginette; Vitaro, Frank; Boivin, Michel

2016-04-01

By and large, studies have reported moderate contributions of genetic factors to cortisol secreted in the early morning and even smaller estimates later in the day. In contrast, the cortisol awakening response (CAR) has shown much stronger heritability estimates, which prompted the hypothesis that the etiology of cortisol secretion may vary according to the time of day. A direct test of this possibility has, however, not yet been performed. To describe the specific and common etiology of the CAR, awakening level and cortisol change from morning to evening in an age-homogenous sample of twin adolescents. A total of 592 participants of the Québec Newborn Twin Study, a population-based 1995-1998 cohort of families with twins in Canada, have collected saliva at awakening, 30 min later, at the end of afternoon and in the evening over four collection days. Multivariate Cholesky models showed both specific and common sources of variance between the CAR, awakening and cortisol diurnal change. The CAR had the strongest heritability estimates, which, for the most part, did not overlap with the other indicators. Conversely, similar magnitudes of genetic and environmental contributions were detected at awakening and for diurnal change, which partially overlapped. Our study unraveled differences between the latent etiologies of the CAR and the rest of the diurnal cycle, which may contribute to identify regulatory genes and environments and detangle how these indicators each relate to physical and mental health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia.

PubMed

Tomuleasa, Ciprian; Fuji, Shigeo; Berce, Cristian; Onaciu, Anca; Chira, Sergiu; Petrushev, Bobe; Micu, Wilhelm-Thomas; Moisoiu, Vlad; Osan, Ciprian; Constantinescu, Catalin; Pasca, Sergiu; Jurj, Ancuta; Pop, Laura; Berindan-Neagoe, Ioana; Dima, Delia; Kitano, Shigehisa

2018-01-01

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

Engineering Chimeric Antigen Receptor T cells to Treat Glioblastoma.

PubMed

Choi, Bryan D; O'Rourke, Donald M; Maus, Marcela V

2017-08-01

Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed. A mutated version of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase that is expressed on the surface of GBM and other common neoplasms, but completely absent from all normal tissues. We have recently generated CAR T cells directed against EGFRvIII and reported results from a Phase I clinical trial investigating this platform in patients with EGFRvIII-expressing GBM. Our study showed that despite conventional notions of central nervous system "immune-privilege," EGFRvIII CAR T cells trafficked to intracerebral tumors, leading to successful targeting and eradication of this antigen in the brain. Here, we review our experience with EGFRvIII CAR T cells and highlight important considerations for the clinical translation of this therapy in patients with GBM.

Glancing and Stopping Behavior of Motorcyclists and Car Drivers at Intersections

PubMed Central

Muttart, Jeffrey W.; Peck, Louis R.; Guderian, Steve; Bartlett, Wade; Ton, Lisa P.; Kauderer, Chris; Fisher, Donald L.; Manning, Joseph E.

2012-01-01

For the past decade, motorcycle fatalities have risen while other motor vehicle fatalities have declined. Many motorcycle fatalities occurred within intersections after a driver failed to see a motorcyclist. However, little is known about the behavior of motorcyclists when they negotiate an intersection. A study was undertaken to compare the behavior at intersections of an experienced group of motorcyclists when they were operating a motorcycle with their behavior when they were driving a car. Each participant navigated a course through low-volume, open roads. Participants wore eye-tracking equipment to record eye-glance information, and the motorcycle and car were instrumented with an onboard accelerometer and Global Positioning System apparatus. Results showed that participants were more likely to make last glances toward the direction of the most threatening traffic before they made a turn when they were driving a car than when they were riding a motorcycle. In addition, motorcyclists were less likely to come to a complete stop at a stop sign than car drivers. These results suggested that motorcyclists were exposing themselves to unnecessary risk. Specifically, motorcyclists frequently failed to make proper glances and practice optimal riding techniques. The behavior of the motorcyclists was compared with the current Motorcycle Safety Foundation curriculum. The results suggested that threat-response and delayed-apex techniques should be added to the training curriculum. PMID:23112436

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

PubMed

Hege, Kristen M; Bergsland, Emily K; Fisher, George A; Nemunaitis, John J; Warren, Robert S; McArthur, James G; Lin, Andy A; Schlom, Jeffrey; June, Carl H; Sherwin, Stephen A

2017-01-01

T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s. Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 10 10 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72. Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111 Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed. These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.

Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma.

PubMed

Locke, Frederick L; Neelapu, Sattva S; Bartlett, Nancy L; Siddiqi, Tanya; Chavez, Julio C; Hosing, Chitra M; Ghobadi, Armin; Budde, Lihua E; Bot, Adrian; Rossi, John M; Jiang, Yizhou; Xue, Allen X; Elias, Meg; Aycock, Jeff; Wiezorek, Jeff; Go, William Y

2017-01-04

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m 2 ) and fludarabine (30 mg/m 2 ) for 3 days followed by KTE-C19 at a target dose of 2 × 10 6 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Functional CAR models for large spatially correlated functional datasets.

PubMed

Zhang, Lin; Baladandayuthapani, Veerabhadran; Zhu, Hongxiao; Baggerly, Keith A; Majewski, Tadeusz; Czerniak, Bogdan A; Morris, Jeffrey S

2016-01-01

We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain. Using basis transformation strategies, the nonseparable spatial-functional model is computationally scalable to enormous functional datasets, generalizable to different basis functions, and can be used on functions defined on higher dimensional domains such as images. Through simulation studies, we demonstrate that accounting for the spatial correlation in our modeling leads to improved functional regression performance. Applied to a high-throughput spatially correlated copy number dataset, the model identifies genetic markers not identified by comparable methods that ignore spatial correlations.

Adoptive Cell Therapy for Metastatic Melanoma.

PubMed

Merhavi-Shoham, Efrat; Itzhaki, Orit; Markel, Gal; Schachter, Jacob; Besser, Michal J

Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.

Optimisation of lateral car dynamics taking into account parameter uncertainties

NASA Astrophysics Data System (ADS)

Busch, Jochen; Bestle, Dieter

2014-02-01

Simulation studies on an active all-wheel-steering car show that disturbance of vehicle parameters have high influence on lateral car dynamics. This motivates the need of robust design against such parameter uncertainties. A specific parametrisation is established combining deterministic, velocity-dependent steering control parameters with partly uncertain, velocity-independent vehicle parameters for simultaneous use in a numerical optimisation process. Model-based objectives are formulated and summarised in a multi-objective optimisation problem where especially the lateral steady-state behaviour is improved by an adaption strategy based on measurable uncertainties. The normally distributed uncertainties are generated by optimal Latin hypercube sampling and a response surface based strategy helps to cut down time consuming model evaluations which offers the possibility to use a genetic optimisation algorithm. Optimisation results are discussed in different criterion spaces and the achieved improvements confirm the validity of the proposed procedure.

Rotating Wheel Wake

NASA Astrophysics Data System (ADS)

Lombard, Jean-Eloi; Xu, Hui; Moxey, Dave; Sherwin, Spencer

2016-11-01

For open wheel race-cars, such as Formula One, or IndyCar, the wheels are responsible for 40 % of the total drag. For road cars, drag associated to the wheels and under-carriage can represent 20 - 60 % of total drag at highway cruise speeds. Experimental observations have reported two, three or more pairs of counter rotating vortices, the relative strength of which still remains an open question. The near wake of an unsteady rotating wheel. The numerical investigation by means of direct numerical simulation at ReD =400-1000 is presented here to further the understanding of bifurcations the flow undergoes as the Reynolds number is increased. Direct numerical simulation is performed using Nektar++, the results of which are compared to those of Pirozzoli et al. (2012). Both proper orthogonal decomposition and dynamic mode decomposition, as well as spectral analysis are leveraged to gain unprecedented insight into the bifurcations and subsequent topological differences of the wake as the Reynolds number is increased.

The prepared emotional reflex: intentional preparation of automatic approach and avoidance tendencies as a means to regulate emotional responding.

PubMed

Eder, Andreas B; Rothermund, Klaus; Proctor, Robert W

2010-08-01

Advance preparation of action courses toward emotional stimuli is an effective means to regulate impulsive emotional behavior. Our experiment shows that performing intentional acts of approach and avoidance in an evaluation task influences the unintended activation of approach and avoidance tendencies in another task in which stimulus valence is irrelevant. For the evaluation-relevant blocks, participants received either congruent (positive-approach, negative-avoidance) or incongruent (positive-avoidance, negative-approach) mapping instructions. In the evaluation-irrelevant blocks, approach- and avoidance-related lever movements were selected in response to a stimulus feature other than valence (affective Simon task). Response mapping in the evaluation task influenced performance in the evaluation-irrelevant task: An enhanced affective Simon effect was observed with congruent mapping instructions; in contrast, the effect was reversed when the evaluation task required incongruent responses. Thus, action instructions toward affective stimuli received in one task determined affective response tendencies in another task where these instructions were not in effect. These findings suggest that intentionally prepared short-term links between affective valence and motor responses elicit associated responses without a deliberate act of will, operating like a "prepared reflex." Copyright 2010 APA

Shade avoidance components and pathways in adult plants revealed by phenotypic profiling.

PubMed

Nozue, Kazunari; Tat, An V; Kumar Devisetty, Upendra; Robinson, Matthew; Mumbach, Maxwell R; Ichihashi, Yasunori; Lekkala, Saradadevi; Maloof, Julin N

2015-04-01

Shade from neighboring plants limits light for photosynthesis; as a consequence, plants have a variety of strategies to avoid canopy shade and compete with their neighbors for light. Collectively the response to foliar shade is called the shade avoidance syndrome (SAS). The SAS includes elongation of a variety of organs, acceleration of flowering time, and additional physiological responses, which are seen throughout the plant life cycle. However, current mechanistic knowledge is mainly limited to shade-induced elongation of seedlings. Here we use phenotypic profiling of seedling, leaf, and flowering time traits to untangle complex SAS networks. We used over-representation analysis (ORA) of shade-responsive genes, combined with previous annotation, to logically select 59 known and candidate novel mutants for phenotyping. Our analysis reveals shared and separate pathways for each shade avoidance response. In particular, auxin pathway components were required for shade avoidance responses in hypocotyl, petiole, and flowering time, whereas jasmonic acid pathway components were only required for petiole and flowering time responses. Our phenotypic profiling allowed discovery of seventeen novel shade avoidance mutants. Our results demonstrate that logical selection of mutants increased success of phenotypic profiling to dissect complex traits and discover novel components.

Emotion avoidance and fear bradycardia in patients with borderline personality disorder and healthy controls.

PubMed

Stoffels, Malou; Nijs, Maurits; Spinhoven, Philip; Mesbah, Rahele; Hagenaars, Muriel A

2017-12-01

Exaggerated emotional reactivity is supposed to be essential in the etiology of borderline personality disorder (BPD). More specifically, models of defensive behavior would predict reduced freezing behavior -indicated by fear bradycardia-in response to threat. This study examined automatic fear bradycardia responses in BPD versus healthy controls and the role of emotion dysregulation, more specifically tendencies to avoid emotions. Patients with BPD (n = 23) and healthy controls (n = 18) completed questionnaires and then watched neutral, pleasant and unpleasant pictures while heart rate was assessed. Emotion avoidance interacted with group: it was associated with distinct autonomic responses in healthy controls but not in BPD patients. Controls with lower emotion avoidance tendencies showed bradycardia in response to unpleasant pictures, while controls with higher emotion avoidance tendencies did not. BPD patients showed no bradycardia, irrespective of their emotion avoidance tendencies. This study is limited by a small sample size. Comorbidity or medication intake were not controlled for. The results may suggest impaired automatic defense responses in BPD. Further understanding of the regulation of distress and defense responses might improve BPD treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.