Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage ...differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
CD4
+
T helper (T
H
) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How T
H
differentiation is regulated ...by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on T
H
cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired T
H
1 differentiation without obviously affecting T
H
2 and T
H
17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted T
H
1 and T
H
17 differentiation
in vitro
and
in vivo
, leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of T
H
17 differentiation of DGKα and ζ double-deficient CD4
+
T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling.
The design of nano-drug delivery vehicles responsive to tumor microenvironment stimuli has become a crucial aspect in developing cancer therapy in recent years. Among them, the enzyme-responsive ...nano-drug delivery system is particularly effective, as it utilizes tumor-specific and highly expressed enzymes as precise targets, leading to increased drug release at the target sites, reduced nonspecific release, and improved efficacy while minimizing toxic side effects on normal tissues. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important reductase associated with cancer and is overexpressed in some cancer cells, particularly in lung and breast cancer. Thus, the design of nanocarriers with high selectivity and responsiveness to NQO1 is of great significance for tumor diagnosis and treatment. It has been reported that under physiological conditions, NQO1 can specifically reduce the trimethyl-locked benzoquinone structure through a two-electron reduction, resulting in rapid lactonization via an enzymatic reaction. Based on this, a novel reduction-sensitive polyurethane (PEG-PTU-PEG) block copolymer was designed and synthesized by copolymerizing diisocyanate, a reduction-sensitive monomer (TMBQ), and poly(ethylene glycol). The successful synthesis of monomers and polymers was verified by nuclear magnetic resonance (
H NMR) and gel permeation chromatography (GPC). Then, the PEG-PTU-PEG micelles were successfully prepared by self-assembly, and their reductive dissociation behavior in the presence of Na
S
O
was verified by dynamic light scattering (DLS),
H NMR, and GPC. Next, the model drug doxorubicin (DOX) was encapsulated into the hydrophobic core of this polyurethane micelles by microemulsion method. It was observed that the drug-loaded micelles could also achieve a redox response and rapidly release the encapsulated substances.
cell experiments demonstrated that PEG-PTU-PEG micelles had good biocompatibility and a low hemolysis rate (<5%). Furthermore, in the presence of an NQO1 enzyme inhibitor (dicoumarol), lower drug release from micelles was observed in A549 and 4T1 cells by both fluorescence microscopy and flow cytometry assays, but not in NIH-3T3 control cells. Predictably, DOX-loaded micelles also showed lower cytotoxicity in 4T1 cells in the presence of NQO1 enzyme inhibitors. These results indicate that drug-loaded polyurethane micelles could accomplish specific drug release in the reducing environment in the presence of NQO1 enzymes. Therefore, this study provides a new option for the construction of polyurethane nanocarriers for precise targeting and reductive release, which could benefit the intracellular drug-specific release and precision therapy of tumors.
In this note we show that every 2-local automorphism of a digraph algebra
A
is an automorphism if in addition
A
is symmetric. Moreover, we produce an example to clarify that the conclusion may not be ...true if
A
has not the extra condition of symmetry. By this means, we give a negative answer to the question about whether every 2-local automorphism of a digraph algebra is automatically an automorphism.
Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)‐mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for ...controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR‐induced DAG‐mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus‐cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer.
Diacylglycerol kinase ζ (DGKζ) converts TCR‐induced diacylglycerol (DAG) to phosphatidic acid (PA). WT DGKζ (DGKζWT) localizes in the cytosol but translocates to the nucleus before and after TCR stimulation. DGKζΔNLS, defective nuclear translocation, accumulates in the cytosol and cytoplasm membrane, accelerates DAG termination, and inhibits T cell maturation and activation.
Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33 (iVα19) TCR, which triggers ...signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signal cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development.
Inverse gas chromatography (IGC) was used to study the interactions of reactants and products with styrene divinylbenzene copolymer (SDB) and Pd supported on SDB catalysts for the propylene partial ...oxidation to acrylic acid. The adsorption heat, free energies, and specific interaction of propylene, oxygen, water, acrolein, and acrylic acid with the solid surface were measured and compared with n-alkane probe molecules. It was found that adsorption of oxygen on Pd/SDB catalysts is very weak, even weaker than methane. Water does not adsorb on the support or the catalyst, but strong adsorption of reaction products, acrolein, and acrylic acid was observed. Based on these results, a mechanism for propylene oxidation over Pd/SDB is proposed.
The performance of 0.2 wt% Pd/SDB catalyst used for partial oxidation of ethylene to acetic acid has been evaluated in a fixed-bed reactor. The catalyst has high activity and selectivity toward ...acetic acid, but it starts to deactivate after running 84 h at 120 °C and 1200 kPa. BET, XRD, FTIR and XPS have been employed to the characterization of the catalyst. It has been found that the deactivation of the catalyst is mainly due to the partial oxidative degradation of the SDB framework during reaction, particularly, in the presence of oxygen, which results in a decrease in surface area and an increase in hydrophilicity of the catalyst.
High energy ball milled KNaX zeolites were characterized using X-ray diffraction, BET, and FTIR techniques. The alkylation of toluene with methanol was chosen as a probe reaction for catalytic ...testing. Ball milling results in the collapse of the zeolite crystalline structure and its transformation into an XRD amorphous phase. Proper ball milling was shown to enhance the catalytic selectivity towards the formation of ethylbenzene + styrene during the alkylation. It was concluded that proper milling can moderately decrease both the Lewis base and Lewis acid sites concentration in alkali exchanged faujasite zeolites while deeply decreasing the strong Bronsted acid site density. The formation of xylenes is mainly dependent on Bronsted acid but not on Lewis acid site centers.
Step-response studies of propylene partial oxidation with oxygen over a hydrophobic Pd/SDB catalyst were conducted at 1000
kPa and 185°C in a fixed-bed reactor. CO
2 was found to be the only ...oxidation product when the feed contained only propylene and oxygen. CO
2 formation was significantly suppressed by addition of steam to the feed, and this addition leads to the formation of partial oxidation products: acrolein and acrylic acid. A competitive reaction mechanism involving water molecules is proposed to explain the significant influence of steam concentration on the rate of propylene oxidation and product selectivity.
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