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.

OBJECTIVE: Diarrhea occurs in up to 50% of cases of COVID-19. Nonetheless, the pathophysiologic mechanism(s) have not been determined.
METHODS: This was examined using normal human enteroid monolayers exposed apically to live SARS-CoV-2 or non-replicating virus-like particles (VLPs) bearing the 4 SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes.
RESULTS: Live virus and VLPs incrieased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3, and DRA. Interleukin (IL)-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA and protein. Neither VLPs nor IL-6 plus IL-8 alone altered Cl- secretion, but together they caused Cl- secretion, which was Ca2+-dependent, CFTR-independent, blocked partially by a specific TMEM16A inhibitor, and entirely by a general TMEM16 family inhibitor. VLPs and irradiated virus, but not IL-6 plus IL-8, produced Ca2+ waves that began within minutes of VLP exposure, lasted for at least 60 minutes, and were prevented by pretreatment with apyrase, a P2Y1 receptor antagonist, and general TMEM16 family inhibitor but not by the specific TMEM16A inhibitor.
CONCLUSIONS: The pathophysiology of COVID-19 diarrhea appears to be a unique example of a calcium-dependent inflammatory diarrhea that is caused by direct viral effects plus the virus-induced intestinal epithelial cytokine secretion.

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.

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.

The calcium-activated chloride channel TMEM16A is a potential drug target to treat hypertension, secretory diarrhea, and several cancers. However, all reported TMEM16A structures are either closed or desensitized, and direct inhibition of the open state by drug molecules lacks a reliable structural basis. Therefore, revealing the druggable pocket of TMEM16A exposed in the open state is important for understanding protein-ligand interactions and facilitating rational drug design. Here, we reconstructed the calcium-activated open conformation of TMEM16A using an enhanced sampling algorithm and segmental modeling. Furthermore, we identified an open-state druggable pocket and screened a potent TMEM16A inhibitor, etoposide, which is a derivative of a traditional herbal monomer. Molecular simulations and site-directed mutagenesis showed that etoposide binds to the open state of TMEM16A, thereby blocking the ion conductance pore of the channel. Finally, we demonstrated that etoposide can target TMEM16A to inhibit the proliferation of prostate cancer PC-3 cells. Together, these findings provide a deep understanding of the TMEM16A open state at an atomic level and identify pockets for the design of novel inhibitors with broad applications in chloride channel biology, biophysics, and medicinal chemistry.

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 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.

Muscarinic acetylcholine receptor subtype 3 (M3 receptor) is a G Protein-Coupled Receptor (GPCR) that mediates many important physiological functions. Currently, most M3 receptor drugs also have high affinity for other subtypes of muscarinic acetylcholine receptors (mAChRs) and produce the risk of side effects. Therefore, in order to find M3 receptor drugs with high specificity, high activity and low side effects, we established a cell model and method for efficient and sensitive screening of M3 receptor based on calcium-activated chloride channels (CaCCs), and this method is also suitable for the screening of other GPCR drugs. This screening model consists of Fischer rat thyroid follicular epithelial (FRT) cells that endogenously express M3 receptors, CaCCs, and the indicator YFP-H148Q/I152L. We verified that the model can sensitively detect changes in intracellular Ca2+ concentration using fluorescence quenching kinetics experiments, confirmed the screening function of the model by applying available M3 receptor drugs, and also evaluated the good performance of the model in high-throughput screening.

Dry eye disease (DED) is a multifactorial disease with an incidence of approximately 50% worldwide. DED seriously affects quality of life and work. The prevalence of environmental DED (eDED) ranges from 35 to 48%. Conjunctival fluid secretion dysfunction may be one of the major causes of DED. Notably, the Cl- flux corresponds to the conjunctival fluid secretion and could be affected by ATP. Both the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca2+-activated Cl- channel (CaCC) are Cl- channels involved in epithelial fluid secretion. Conjunctival fluid secretion could be increased by activating P2Y2R (an ATP receptor) in DED. However, the role of the CaCC and CFTR channels regulated by P2Y2R in eDED remains unclear. In this study, we established a rabbit eDED model using a controlled drying system. A Ussing chamber was used to perform a conjunctival short-circuit current induced by ATP to evaluate the reactivity of the ion channels to the ATP. Our results revealed that eDED accompanied by conjunctival fluid secretion impairment was caused by a P2Y2R dysfunction, which is related to CaCC-CFTR signaling in the conjunctiva epithelium. Notably, the coupling effect of the ATP-induced CaCC-CFTR activation and intracellular Ca2+ may represent a promising therapeutic target for treating eDED.

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.