Package Of Cars And Mini Vans In Traffic By JC ...

In the United States, many government regulations simply have categories for "off-highway vehicles" which are loosely defined and often result in SUVs (along with pick-up trucks and minivans) being classified as light trucks.[10][26] For example, Corporate Average Fuel Economy (CAFE) regulations previously included "permit greater cargo-carrying capacity than passenger carrying volume" in the definition for trucks, resulting in SUVs being classified as light trucks.[27]

Package of Cars and Mini Vans in Traffic by JC ...

Another important challenge for the effective targeting of solid tumors with CAR T cell therapies is the immunosuppressive tumor milieu. Unlike many hematological malignancies that lack local immune suppression pathways, solid tumors can be strongly infiltrated by different cell types that support tumor growth, angiogenesis, and metastasis [121]. Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs) are the most prominent types of immune suppressor cells in the tumor environment [122, 123]. In addition to tumor cells, these cells facilitate tumor growth and proliferation by producing growth factors, local cytokines, and chemokines in solid tumors, including VEGF and IL-4, IL-10, and TGFβ. immune checkpoint molecules such as CTLA-4 and PD-1 also reduce antitumor immunity [120, 124]. In general, a tumor microenvironment with multiple cells and inhibitory agents can restrict the influence of CAR T cell treatment. A large number of studies have focused on enhancing CAR T cell function by modifying their metabolic profiles to improve cell activity in hostile environments. Usually, tumors are often described by a high degree of adenosine and reactive oxygen species (ROS), disrupting T cell responses (Fig. 5) [125, 126]. Likewise, tumors demonstrate promoted levels of extracellular potassium that prominently weaken TCR-driven Akt-mTOR phosphorylation and subsequent effector activity. T cell engineering aims to increase the expression of potassium channel to prepare greater potassium efflux successfully undoes this type of suppression and boost T cell function within the TME [127]. Researches have demonstrated that in the TME, the defeating of the immunosuppressive cells is routinely necessary to the high-level efficacy of CAR T cells. Using suppressor antibodies in association with genetic manipulation with the aim of depletion of regulatory T cells (Tregs), as well as myeloid-derived suppressor cells (MDSCs), leads to the promotion of T cell therapy efficacy in animal models (Fig. 5) [128, 129]. On the other hand, cancer-associated fibroblasts (CAFs) that include the most common types of TME cells and express fibroblast activation protein (FAP) in a high degree has a crucial role in shaping the immunosuppressive microenvironment and releasing of the ECM proteins to attenuate T cell penetration. Interestingly, applying the FAP-specific CAR T for reduction of CAF cell activity or engineering novel types of the CAR T cells aiming to secrete ECM-degrading enzymes can remarkably increase their potential to traffic and lyse tumors [130]. Otherwise, CAR T cell manipulation to secrete the pro-inflammatory cytokine IL-12 may modify the TME and finally enhance macrophage recruitment and functions [131]. Numerous groups have tried to improve CAR T cell activity by the combined use of the ACT with TME modulators. A hopeful therapeutic method that has exposed acceptable efficacy in tumors is the use of the checkpoint inhibitors, which target the PD-1/PD-L1 or CTLA-4 pathways (Fig. 5) [132, 133]; in this case, checkpoint blockade is ameliorated following improving the preparation of tumor-specific T cells and may rationally be composed with the adoptive transmission of CAR T cells, while the risk of toxicity may be improved in normal calls. On the other hand, particular CAR T cells have engineered to release anti-PD-L1 antibodies to PD-1 and LAG3 suppressing through CRISPR [134, 135]. While anti-CTLA-4 antibodies are able to increase endogenous T cell reactions to the cancers, the related mechanism by which they can promote CAR T cell responses is unknown. Furthermore, anti-CTLA-4 antibodies can trigger an immune reaction in a cell-extrinsic manner after diminishing of CTLA-4+ Treg cells, which in turn may likely assistance CAR T cells [136].

To further understand how the impact propagates from the targeted locations, be it for the divergence or the convergence attack, we plot the change in the number of vehicles in different streets as a function of the distance from the nearest target, while varying the disinformation follow-through rate. Since our traffic simulation is non-deterministic, we took an average over 100 simulations; the results are depicted in Fig. 2d,e for the divergence attack, and Fig. 2f for the convergence attack. The overall trend (depicted in black) is further disaggregated into the streets that experience lighter traffic (green) and those that experience heavier traffic (red). The insets zoom in on the latter category of streets within 200 m from a target, to facilitate comparison across the different settings. Starting with the divergence attacks (Fig. 2d,e), we observe that the closer a street is to a target, the greater is the impact on traffic, regardless of whether it is an increase (red plot) or a decrease (green plot) in the number of vehicles. The figures also show that higher follow-through rates result in greater impact on traffic. Comparing the insets of Fig. 2d,e reveals that when the targets are concentrated in one neighborhood the congestion is higher within 50 m from the targets, e.g., given a 75% follow-through rate, the number of vehicles throughout the day increases by about 6500 when the targets are concentrated, as opposed to approximately 5900 when they are not. However, as the distance from the nearest target increases, the impact on traffic fades away at a greater pace when targets are concentrated, e.g., at a distance of 100 m from the targets and given a 75% follow-through rate, the number of vehicles throughout the day increases by about 2300 when the targets are concentrated, as opposed to approximately 5300 when they are not. Commenting on the reach of the disruption caused by the divergence attack, we find that as the follow-through rate increases, the disruption extends farther away from the targets. We also find that the reach is greater when the targets are concentrated, with a considerable impact being felt as far as 2 km away from the closest target in the case of 75% follow-through rate. This could be due to the synergy between the different targets when they are within close proximity to one another. Having discussed the divergence attacks, we now analyze the propagation of the impact due to the convergence attack. Referring to Fig. 2f, there are two observations. First, as expected, increasing the follow-through rate results in a higher disruption. Second, although some streets experience an increase while others experience a decrease in traffic, the increase seems much more significant while the decrease seems negligible; this trend is not evident in Fig. 2c since the colors therein correspond to a logarithmic scale, making it difficult to visually infer the magnitude of the change in traffic.

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