To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of Treg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, Treg cell proliferation via cell-cell contact involving the IKK/IKBα-independent activation of the NF-κB/OX40L pathway. Intriguingly, treating wild-type mice with lipopolysaccharide selectively depletes Lkb1 protein in DCs, resulting in Treg cell expansion and suppressed inflammatory injury upon subsequent challenge. Loss of Lkb1 does not obviously upregulate proinflammatory molecules expression on DCs. We thus identify Lkb1 as a regulatory switch in DCs for controlling Treg cell homeostasis, immune response and tolerance.
The driving comfort of a straddle-type monorail, while considering the influence of the bridge structure, was studied on the basis of multibody dynamics and the finite element method. In this study, the coupled vehicle-bridge model was established through SIMPACK and ANSYS; the 3D model of the bridge was established in ANSYS, and the vehicle model with 35 degrees of freedom (DOFs) was established in SIMPACK. The influence of the vehicle speed, pier height, track irregularity, and vehicle load on riding comfort was studied. Overall, straddle-type monorails had a good running stability, and the lateral comfort of the vehicle was better than the vertical comfort, due to symmetrical horizontal wheels. As the vehicle speed increased, the acceleration of the bridge and vehicle increased accordingly. Track irregularity had a substantial influence on riding comfort. Three types of track irregularity were simulated, and this factor should be strictly controlled to be smoother than the Chinese national A-level road roughness. The bridge pier height had a notable influence on the lateral riding comfort. In addition, this study attempted to improve riding comfort from the perspective of increasing the bridge stiffness, which could be achieved by increasing the cross-beam thickness or the track beam height.
In
tumor therapy, polymer nanoparticles are ideal drug delivery
materials because they can mask the disadvantages of anti-tumor drugs
such as poor solubility in water, high toxicity, and side effects.
However, most polymer-based nanoparticles do not themselves have anti-tumor
properties. Herein, a novel pH-sensitive nanoparticle drug delivery
system based on Ganoderma lucidum polysaccharides
(GLPs), which have demonstrated anti-tumor activities, was designed
to enable the delivery of methotrexate (MTX) and 10-hydroxycamptothecin
(HCPT) to tumor cells, where they could exert synergistic anti-tumor
effects. The prepared nanoparticles were irregularly spherical in
shape with a uniform particle size of ∼190 nm, and they exhibited
a high drug-loading capacity (MTX 21.5% and HCPT 22.6%) and excellent
biocompatibility. Moreover, the loaded MTX and HCPT units were rapidly
released under acidic conditions within the tumor cells while remaining
stable under normal physiological conditions. Meanwhile, compared
to free MTX and HCPT, the GLP–APBA–MTX/HCPT nanoparticles
presented exhibited better tumor suppressive effects and fewer side
effects in vivo, which indicates that they may be
an effective anti-tumor treatment strategy.
Interleukin 37b (IL-37b) plays a key role in suppressing immune responses, partially by modulating the function of dendritic cells (DCs). However, the precise mechanisms are still largely unknown. Here, we investigated the effects of IL-37b on DC maturation and T cell responses induced by DCs, and explored the involved signaling pathways. It was found that IL-37b down-regulated the expressions of co-stimulatory molecules CD80 and CD86 on DCs in vitro. At the same time, the expressions of pro-inflammatory cytokines, such as TNF-α and IL-6, were suppressed, while the expression of the T cell inhibitory cytokine TGF-β was increased in IL-37b-treated DCs. In addition, the activation effect of DCs on T cells was impaired by IL-37b. We further revealed that extracellular single-regulated kinase (ERK), nuclear factor-κB (NF-κB), and mTOR-S6K signaling pathways were involved in the inhibition of DCs induced by IL-37b. This was confirmed by the similarly suppressive effect of chemical inhibitors against NF-κB, ERK, and S6K on the expressions of IL-6 and TNF-α in DCs. In conclusion, these results demonstrated that IL-37b suppressed DC maturation and immunostimulatory capacity in T cell priming by involving in ERK, NF-κB, and S6K-based inhibitory signaling pathways.
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