Abstract
Innate lymphoid cells (ILCs) play an important role in maintaining tissue homeostasis and various inflammatory responses. ILCs are typically classified into three subsets, as is the case for ...T-cells. Recent studies have reported that IL-10-producing type 2 ILCs (ILC2
10
s) have an immunoregulatory function dependent on IL-10. However, the surface markers of ILC2
10
s and the role of ILC2
10
s in contact hypersensitivity (CHS) are largely unknown. Our study revealed that splenic ILC2
10
s are extensively included in PD-L1
high
Sca-1
+
ILCs and that IL-27 amplifies the development of PD-L1
high
Sca-1
+
ILCs and ILC2
10
s. Adoptive transfer of PD-L1
high
Sca-1
+
ILCs suppressed oxazolone-induced CHS in an IL-10-dependent manner Taken together, our results demonstrate that ILC2
10
s are critical for the control of CHS and suggest that ILC2
10
s can be used as target cells for the treatment of CHS.
Receptor activator of NF-kB ligand (RANKL) generates intracellular reactive oxygen species (ROS), which increase RANKL-mediated signaling in osteoclast (OC) precursor bone marrow macrophages (BMMs). ...Here we show that a ROS scavenging protein DJ-1 negatively regulates RANKL-driven OC differentiation, also called osteoclastogenesis. DJ-1 ablation in mice leads to a decreased bone volume and an increase in OC numbers. In vitro, the activation of RANK-dependent signals is enhanced in DJ-1-deficient BMMs as compared to wild-type BMMs. DJ-1 suppresses the activation of both RANK-TRAF6 and RANK-FcRγ/Syk signaling pathways because of activation of Src homology region 2 domain-containing phosphatase-1, which is inhibited by ROS. Ablation of DJ-1 in mouse models of arthritis and RANKL-induced bone disease leads to an increase in the number of OCs, and exacerbation of bone damage. Overall, our results suggest that DJ-1 plays a role in bone homeostasis in normal physiology and in bone-associated pathology by negatively regulating osteoclastogenesis.
Semiconducting ink based on 2D single‐crystal flakes with dangling‐bond‐free surfaces enables the implementation of high‐performance devices on form‐free substrates by cost‐effective and scalable ...printing processes. However, the lack of solution‐processed p‐type 2D semiconducting inks with high mobility is an obstacle to the development of complementary integrated circuits. Here, a versatile strategy of doping with Br2 is reported to enhance the hole mobility by orders of magnitude for p‐type transistors with 2D layered materials. Br2‐doped WSe2 transistors show a field‐effect hole mobility of more than 27 cm2 V−1 s−1, and a high on/off current ratio of ≈107, and exhibits excellent operational stability during the on‐off switching, cycling, and bias stressing testing. Moreover, complementary inverters composed of patterned p‐type WSe2 and n‐type MoS2 layered films are demonstrated with an ultra‐high gain of 1280 under a driving voltage (VDD) of 7 V. This work unveils the high potential of solution‐processed 2D semiconductors with low‐temperature processability for flexible devices and monolithic circuitry.
Solution‐processed high‐performance p‐type WSe2 thin‐film transistor is successfully fabricated by Br2‐doping with a field‐effect hole mobility of more than 27 cm2 V−1 s−1, and a high on/off current ratio of ≈107. The resulting complementary inverters with patterned p‐type WSe2 and n‐type MoS2 layered films reaches an ultra‐high gain of 1280 under a driving voltage (VDD) of 7 V.
The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we ...develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity.
Van der Waals (vdW) heterostructures have drawn much interest over the last decade owing to their absence of dangling bonds and their intriguing low‐dimensional properties. The emergence of 2D ...materials has enabled the achievement of significant progress in both the discovery of physical phenomena and the realization of superior devices. In this work, the group IV metal chalcogenide 2D‐layered Ge4Se9 is introduced as a new selection of insulating vdW material. 2D‐layered Ge4Se9 is synthesized with a rectangular shape using the metalcorganic chemical vapor deposition system using a liquid germanium precursor at 240 °C. By stacking the Ge4Se9 and MoS2, vdW heterostructure devices are fabricated with a giant memory window of 129 V by sweeping back gate range of ±80 V. The gate‐independent decay time reveals that the large hysteresis is induced by the interfacial charge transfer, which originates from the low band offset. Moreover, repeatable conductance changes are observed over the 2250 pulses with low non‐linearity values of 0.26 and 0.95 for potentiation and depression curves, respectively. The energy consumption of the MoS2/Ge4Se9 device is about 15 fJ for operating energy and the learning accuracy of image classification reaches 88.3%, which further proves the great potential of artificial synapses.
Ge4Se9, a new insulating 2D‐layered material, is synthesized using metal–organic chemical vapor deposition at 240 °C with low‐reactive precursors. The 2D‐layered Ge4Se9 forms a low band offset with MoS2, exhibiting a large memory window with linear gate‐tunability. As an artificial synapse, the MoS2/Ge4Se9 heterostructure exhibits synaptic updates with low non‐linearity of 0.26 and low energy consumption of 15 fJ.
The interaction between immune cells and phosphatidylserine (PS) molecules exposed on the surface of apoptotic-tumor bodies, such as those induced by chemotherapies, contributes to the formation of ...an immunosuppressive tumor microenvironment (TME). Annexin A5 (AnxA5) binds with high affinity to PS externalized by apoptotic cells, thereby hindering their interaction with immune cells. Here, we show that AnxA5 administration rescue the immunosuppressive state of the TME induced by chemotherapy. Due to the preferential homing of AnxA5 to the TME enriched with PS+ tumor cells, we demonstrate in vivo that fusing tumor-antigen peptide to AnxA5 significantly enhances its immunogenicity and antitumor efficacy when administered after chemotherapy. Also, the therapeutic antitumor effect of an AnxA5-peptide fusion can be further enhanced by administration of other immune checkpoint inhibitors. Our findings support the administration of AnxA5 following chemotherapy as a promising immune checkpoint inhibitor for cancer treatment.
The fruit of Citrus unshiu MARKOVICH used for various purposes in traditional medicine has various pharmacological properties including antioxidant, anti-inflammatory, and antibacterial effects. ...Recently, the possibility of anti-cancer activity of the extracts or components of this fruit has been reported; however, the exact mechanism has not yet been fully understood. In this study, we evaluated the anti-proliferative effect of water extract of C. unshiu peel (WECU) on human breast cancer MCF-7 cells and investigated the underlying mechanism. Our results showed that reduction of MCF-7 cell survival by WECU was associated with the induction of apoptosis. WECU-induced apoptotic cell death was related to the activation of caspase-8 and -9, representative initiate caspases of extrinsic and intrinsic apoptosis pathways, respectively, and increase in the Bax : Bcl-2 ratio accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). WECU also increased the mitochondrial dysfunction and cytosolic release of cytochrome c. In addition, AMP-activated protein kinase (AMPK) and its downstream target molecule, acetyl-CoA carboxylase, were activated in a concentration-dependent manner in WECU-treated cells. In contrast, compound C, an AMPK inhibitor, significantly inhibited WECU-induced apoptosis, while inhibiting increased expression of Bax and decreased expression of Bcl-2 by WECU and inhibition of WECU-induced PARP degradation. Furthermore, WECU provoked the production of reactive oxygen species (ROS); however, the activation of AMKP and apoptosis by WECU were prevented, when the ROS production was blocked by antioxidant N-acetyl cysteine. Therefore, our data indicate that WECU suppresses MCF-7 cell proliferation by activating the intrinsic and extrinsic apoptosis pathways through ROS-dependent AMPK pathway activation.
The low therapeutic efficacy of current cancer immunotherapy is related to nonimmunogenic and immunosuppressive tumor microenvironments (TMEs). To overcome these limitations, both the immune priming ...of antitumoral lymphocytes and the reprogramming of immunosuppressive factors in TMEs are essential. Here, we suggest a nanoemulsion (NE)-based immunotherapeutic platform that can not only modulate tumor-induced suppression but also induce an effective cell-mediated immune response for T cell proliferation. Multifunctional NEs can be fabricated by integrating the efficacy of NEs as delivery systems and the multifaceted immunomodulation characteristics (i.e., immunostimulation and reprogramming of immunosuppression) of small molecule-based Toll-like receptor 7/8 agonists. Local in situ vaccination of melanoma and cervical tumor models with tumor antigens (protein and peptide) adjuvanted with NE loaded with TLR7/8 agonists NE (TLR7/8a) induced the recruitment and activation of innate immune cells, infiltration of lymphocytes, and polarization of tumor-associated M2 macrophages, which resulted in inhibition of tumor growth and prolonged survival in both primary and rechallenged tumor models. Antibody-depletion experiments also suggested that macrophages, type I IFN (IFN-α and IFN-β), CD8+ T cells, and NK1.1+ cells contributed to the antitumor effect of NE (TLR7/8a). The combination of antitumoral lymphocytes and reprogramming of immunosuppressive TMEs induced by NE (TLR7/8a) treatment evoked a synergistic antitumor immune response with immune checkpoint blockade therapy (anti-PD-1 and anti-PD-L1).
Alzheimer's disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting ...amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.
Engineering the boundary structures in 2D materials provides an unprecedented opportunity to program the physical properties of the materials with extensive tunability and realize innovative devices ...with advanced functionalities. However, structural engineering technology is still in its infancy, and creating artificial boundary structures with high reproducibility remains difficult. In this review, various emergent properties of 2D materials with different grain boundaries, and the current techniques to control the structures, are introduced. The remaining challenges for scalable and reproducible structure control and the outlook on the future directions of the related techniques are also discussed.
Grain boundary engineering in 2D electronic materials for emergent properties is reviewed. Reported structural engineering methods and emergent properties are introduced for various stacking and stitching boundaries such as twist boundary, tilt boundary, stacking fault, and dislocation arrays. Also, remaining challenges and outlook for the future research directions are discussed.
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