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GlyH-101 and CaCCinh-A01 are effective blockers of cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated chloride channels (CaCCs), respectively. Available evidence suggests that GlyH-101 and CaCCinh-A01 can suppress cell proliferation, block invasion and metastasis, and cause several cancer cell types to undergo apoptosis, demonstrating their anti-tumor properties. The aim of this study was to investigate the effect of GlyH-101 and CaCCinh-A01 on HT-29 cell activity and to suggest the possible molecular mechanisms by which inhibitors of CFTR and CaCCs inhibit HT-29 cell activity.BACKGROUND/AIMGlyH-101 and CaCCinh-A01 are effective blockers of cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated chloride channels (CaCCs), respectively. Available evidence suggests that GlyH-101 and CaCCinh-A01 can suppress cell proliferation, block invasion and metastasis, and cause several cancer cell types to undergo apoptosis, demonstrating their anti-tumor properties. The aim of this study was to investigate the effect of GlyH-101 and CaCCinh-A01 on HT-29 cell activity and to suggest the possible molecular mechanisms by which inhibitors of CFTR and CaCCs inhibit HT-29 cell activity.Human colon HT-29 cancer cells were treated with GlyH-101 or CaCCinh-A01 or GlyH-101 plus CaCCinh-A01 complex. Cell viability was determined by MTT assay, the apoptosis and cell cycle were determined by flow cytometry, and reactive oxygen species (ROS) leves were determined by 2',7'-Dichlorodihydrofluorescein diacetate staining. The expression of proteins related to apoptosis and cell cycle regulation was measured by western blotting.MATERIALS AND METHODSHuman colon HT-29 cancer cells were treated with GlyH-101 or CaCCinh-A01 or GlyH-101 plus CaCCinh-A01 complex. Cell viability was determined by MTT assay, the apoptosis and cell cycle were determined by flow cytometry, and reactive oxygen species (ROS) leves were determined by 2',7'-Dichlorodihydrofluorescein diacetate staining. The expression of proteins related to apoptosis and cell cycle regulation was measured by western blotting.The proliferative ability of HT-29 cells was dose- and time-dependently reduced by GlyH-101 and CaCCinh-A01. Treatment with GlyH-101 and CaCCinh-A01 resulted in cell necrosis and apoptosis, up-regulated ROS levels, activated the mitochondrial apoptosis pathway, prompted arrest of the cell cycle in S phase, and increased the levels of proteins related to the cell cycle. Additionally, the combination of these two inhibitors had a stronger regulatory effect on HT-29 cell proliferation than either GlyH-101 or CaCCinh-A01 treated alone.RESULTSThe proliferative ability of HT-29 cells was dose- and time-dependently reduced by GlyH-101 and CaCCinh-A01. Treatment with GlyH-101 and CaCCinh-A01 resulted in cell necrosis and apoptosis, up-regulated ROS levels, activated the mitochondrial apoptosis pathway, prompted arrest of the cell cycle in S phase, and increased the levels of proteins related to the cell cycle. Additionally, the combination of these two inhibitors had a stronger regulatory effect on HT-29 cell proliferation than either GlyH-101 or CaCCinh-A01 treated alone.GlyH-101 and CaCCinh-A01 inhibited cell proliferation through cell cycle arrest and mitochondrial-related pathways in vitro. The combination of these inhibitors could further enhance their anti-proliferative effects. Our findings propose new lead compounds with anti-colon cancer activity, and also provide new evidence for the effectiveness of chloride channels-targeted therapy in anticancer therapy.CONCLUSIONGlyH-101 and CaCCinh-A01 inhibited cell proliferation through cell cycle arrest and mitochondrial-related pathways in vitro. The combination of these inhibitors could further enhance their anti-proliferative effects. Our findings propose new lead compounds with anti-colon cancer activity, and also provide new evidence for the effectiveness of chloride channels-targeted therapy in anticancer therapy.

Currently, the increase of transport demands along with the limited capacity of the road network have increased traffic congestion in urban and highway scenarios. Technologies such as Cooperative Adaptive Cruise Control (CACC) emerge as efficient solutions. However, a higher level of cooperation among multiple vehicle platoons is needed to improve, effectively, the traffic flow. In this paper, a global solution to merge two platoons is presented. This approach combines: (i) a longitudinal controller based on a feed-back/feed-forward architecture focusing on providing CACC capacities and (ii) hybrid trajectory planning to merge platooning on straight paths. Experiments were performed using Tecnalia’s previous basis. These are the AUDRIC modular architecture for automated driving and the highly reliable simulation environment DYNACAR. A simulation test case was conducted using five vehicles, two of them executing the merging and three opening the gap to the upcoming vehicles. The results showed the good performance of both domains, longitudinal and lateral, merging multiple vehicles while ensuring safety and comfort and without propagating speed changes.

In this paper, we propose systematic controller design guidelines to ensure both individual vehicle stability and string stability in cooperative adaptive cruise control (CACC)-based platoon systems, assuming a homogeneous platoon where all vehicles share identical dynamic models. We rigorously demonstrate that the limitation of conventional adaptive cruise control (ACC) in maintaining the target inter-vehicle distance can be effectively overcome by incorporating the desired acceleration of the preceding vehicle as a static feedforward input. Furthermore, by formulating transfer functions in the frequency domain, we analytically derive the conditions required to ensure both individual vehicle stability and string stability of the CACC system. Building on this insight, we propose a practical and theoretically well-founded design guideline for determining the proportional, derivative, and feedforward gains of control input under a constant time gap spacing policy. The proposed guidelines are validated through simulations conducted in a realistic platooning scenario involving multiple vehicles.

A suitable control architecture for connected vehicle platoons may be seen as a promising solution for today’s traffic problems, by improving road safety and traffic flow, reducing emissions and fuel consumption, and increasing driver comfort. This paper provides a comprehensive overview concerning the defining levels of a general control architecture for connected vehicle platoons, intending to illustrate the options available in terms of sensor technologies, in-vehicle networks, vehicular communication, and control solutions. Moreover, starting from the proposed control architecture, a solution that implements a Cooperative Adaptive Cruise Control (CACC) functionality for a vehicle platoon is designed. Also, two control algorithms based on the distributed model-based predictive control (DMPC) strategy and the feedback gain matrix method for the control level of the CACC functionality are proposed. The designed architecture was tested in a simulation scenario, and the obtained results show the control performances achieved using the proposed solutions suitable for the longitudinal dynamics of vehicle platoons.

Vehicle to Everything (V2X) technology is fast evolving, and it will soon transform our driving experience. Vehicles employ On-Board Units (OBUs) to interact with various V2X devices, and these data are used for calculation and detection. Safety, efficiency, and information services are among its core uses, which are currently in the testing stage. Developers gather logs during the real field test to see if the application is fair. Field testing, on the other hand, has low efficiency, coverage, controllability, and stability, as well as the inability to recreate extreme hazardous scenarios. The shortcomings of actual road testing can be compensated for by indoor testing. An HIL-based laboratory simulation test framework for V2X-related testing is built in this study, together with the relevant test cases and a test evaluation system. The framework can test common applications such as Forward Collision Warning (FCW), Intersection Collision Warning (ICW) and others, as well as more advanced features such as Cooperative Adaptive Cruise Control (CACC) testing and Global Navigation Satellite System (GNSS) injection testing. The results of the tests reveal that the framework (CarTest) has reliable output, strong repeatability, the capacity to simulate severe danger scenarios, and is highly scalable, according to this study. Meanwhile, for the benefit of researchers, this publication highlights several relevant HIL challenges and solutions.

Cytoplasmic calcium (Ca2+) activates the bestrophin anion channel, allowing chloride ions to flow down their electrochemical gradient. Mutations in bestrophin 1 (BEST1) cause macular degenerative disorders. Previously, we determined an X-ray structure of chicken BEST1 that revealed the architecture of the channel. Here, we present electrophysiological studies of purified wild-type and mutant BEST1 channels and an X-ray structure of a Ca2+-independent mutant. From these experiments, we identify regions of BEST1 responsible for Ca2+ activation and ion selectivity. A “Ca2+ clasp” within the channel’s intracellular region acts as a sensor of cytoplasmic Ca2+. Alanine substitutions within a hydrophobic “neck” of the pore, which widen it, cause the channel to be constitutively active, irrespective of Ca2+. We conclude that the primary function of the neck is as a “gate” that controls chloride permeation in a Ca2+-dependent manner. In contrast to what others have proposed, we find that the neck is not a major contributor to the channel’s ion selectivity. We find that mutation of a cytosolic “aperture” of the pore does not perturb the Ca2+ dependence of the channel or its preference for anions over cations, but its mutation dramatically alters relative permeabilities among anions. The data suggest that the aperture functions as a size-selective filter that permits the passage of small entities such as partially dehydrated chloride ions while excluding larger molecules such as amino acids. Thus, unlike ion channels that have a single “selectivity filter,” in bestrophin, distinct regions of the pore govern anion-vs.-cation selectivity and the relative permeabilities among anions.

TMEM16A Ca2+-activated chloride channels are involved in multiple cellular functions and are proposed targets for diseases such as hypertension, stroke, and cystic fibrosis. This therapeutic endeavor, however, suffers from paucity of selective and potent modulators. Here, exploiting a synthetic small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we shed light on sites of the channel amenable for pharmacological intervention. Mutant channels with the intracellular gate constitutively open were generated. These channels were entirely insensitive to extracellular A9C when intracellular Ca2+ was omitted. However, when physiological Ca2+ levels were reestablished, the mutants regained sensitivity to A9C. Thus, intracellular Ca2+ is mandatory for the channel response to an extracellular modulator. The underlying mechanism is a conformational change in the outer pore that enables A9C to enter the pore to reach its binding site. The explanation of this structural rearrangement highlights a critical site for pharmacological intervention and reveals an aspect of Ca2+ gating in the TMEM16A channel.

In this paper, we investigate the problem of reducing the use of radio resources for vehicle-to-vehicle communications in an autonomous platooning scenario. Achieving reliable communications, which is a key element allowing for the tight coordination of platoon vehicles’ motion, might be challenging in a case of heavy road traffic. Thus, in this paper, we propose to reduce the number of intra-platoon transmissions required to facilitate the safe autonomous control of vehicle mobility, by analyzing the impact of cars’ behaviors (in terms of acceleration changes) on the evolution of the inter-vehicle distance errors within the platoon. We derive formulas representing the relation between the platoon leader’s acceleration changes and the evolution of the distance error, velocity difference, and the accelerations for the first pair of vehicles. Furthermore, we propose a heuristic algorithm for selection of the intra-platoon messaging period for each platoon vehicle that minimizes the use of radio resources subject to the safety constraint, represented as the fraction of the total time when emergency braking is activated. The presented simulation results indicate that the proposed approach is capable of ensuring safe platoon operation and simultaneously providing a significant reduction in the use of resources, compared with conventional fixed-period transmission.

Globally, the increases in vehicle numbers, traffic congestion, and road accidents are serious issues. Autonomous vehicles (AVs) traveling in platoons provide innovative solutions for efficient traffic flow management, especially for congestion mitigation, thus reducing accidents. In recent years, platoon-based driving, also known as vehicle platoon, has emerged as an extensive research area. Vehicle platooning reduces travel time and increases road capacity by reducing the safety distance between vehicles. For connected and automated vehicles, cooperative adaptive cruise control (CACC) systems and platoon management systems play a significant role. Platoon vehicles can maintain a closer safety distance due to CACC systems, which are based on vehicle status data obtained through vehicular communications. This paper proposes an adaptive traffic flow and collision avoidance approach for vehicular platoons based on CACC. The proposed approach considers the creation and evolution of platoons to govern the traffic flow during congestion and avoid collisions in uncertain situations. Different obstructing scenarios are identified during travel, and solutions to these challenging situations are proposed. The merge and join maneuvers are performed to help the platoon’s steady movement. The simulation results show a significant improvement in traffic flow due to the mitigation of congestion using platooning, minimizing travel time, and avoiding collisions.

In the pursuit of string stability within CACC (cooperative adaptive cruise control) platoons, prevalent research has favored constant time gap (CTG) spacing policies; namely, vehicle interspacing increases linearly with the speed. Although constant distance gap (CDG) spacing policies have greater potential to enhance traffic capacity, they suffer from notable limitations regarding string stability and diminished safety margins at high velocities. In our previous work, we proposed applying CDG in specific scenarios, such as starting platoons at signalized intersections, where traffic throughput is critical and safety requirements can be met due to relatively low speeds. We demonstrated the substantial potential of CDG to increase the capacity of signalized intersections under oversaturated conditions. However, our study also revealed potential performance drops of CDG in dense traffic networks. To address these issues, we propose close-range coordination between vehicles to (1) limit platoon length, (2) create gaps for merging, and (3) avoid entering intersections when there is a high likelihood of stopping within the intersection area. In this paper, we extend our previous work by implementing these three measures. We successfully evaluate their positive impact on CDG’s performance in entire traffic systems through large-scale traffic simulations involving several thousand vehicles, thereby affirming our earlier hypothesis