G protein‐coupled estrogen receptor‐1 (GPER), a member of the G protein‐coupled receptor (GPCR) superfamily, mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. ...However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non‐BCSCs of three patient‐derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER‐mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD‐Ser118 to sustain BCSC characteristics. Transfection with a dominant‐negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.
What's new?
G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.
Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the TH2 cytokines ...IL-5 and IL-13, which promote acute asthma exacerbation. Short-chain fatty acids (SCFAs) have been shown to attenuate T cell–mediated allergic airway inflammation. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.
We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
We assessed the role of SCFAs in regulating survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in the ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.
We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma.
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Abstract
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is ...controversial. Here, we show that Treg cell development is normal in mice with Foxp3-specific knockout (KO) of HIF-1α or HIF-2α. However, HIF-2α-KO (but not HIF-1α-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2α-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2α and HIF-1α, and that HIF-2α represses HIF-1α expression. HIF-1α is upregulated in HIF-2α-KO Treg cells and further deletion of HIF-1α restores the inhibitory function of HIF-2α-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells.
Shape memory materials are a class of smart materials able to convert heat into mechanical strain (or strain into heat) by virtue of a martensitic phase transformation. Some brittle materials such as ...intermetallics and ceramics exhibit a martensitic transformation but fail by cracking at low strains and after only a few applied strain cycles. Here we show that such failure can be suppressed in normally brittle martensitic ceramics by providing a fine-scale structure with few crystal grains. Such oligocrystalline structures reduce internal mismatch stresses during the martensitic transformation and lead to robust shape memory ceramics that are capable of many superelastic cycles up to large strains; here we describe samples cycled as many as 50 times and samples that can withstand strains over 7%. Shape memory ceramics with these properties represent a new class of actuators or smart materials with a set of properties that include high energy output, high energy damping, and high-temperature usage.
Background
Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL‐33 is elevated and promotes immune cell activation, leading to the development ...of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL‐33‐activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection‐triggered pathophysiology.
Methods
The role of IL‐33/ILC2 axis in RSV‐induced AHR inflammation and eosinophilia were evaluated in the IL‐33‐deficient and YetCre‐13 Rosa‐DTA mice. Myeloid‐specific, IL‐33‐deficient or ST2‐deficient mice were employed to examine the role of IL‐33 and ST2 signaling in myeloid cells.
Results
We found that IL‐33‐activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2‐derived IL‐13 was sufficient for RSV‐driven AHR, since reconstitution of wild‐type ILC2 rescued RSV‐driven AHR in IL‐13‐deficient mice. Meanwhile, myeloid cell‐derived IL‐33 was required for airway inflammation, ST2+ myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL‐33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL‐33 signaling.
Conclusions
This study highlights the importance of IL‐33‐activated ILC2s in mediating RSV‐triggered AHR and eosinophilia. In addition, IL‐33 signaling in myeloid cells is crucial for airway inflammation.
Respiratory syncytial virus induces ILC2 to produce IL‐5 and IL‐13 through IL‐33, which is crucial for the development of airway hyperreactivity and airway inflammation. Myeloid cell‐derived IL‐33 and suppression of tumorigenicity 2‐positive myeloid cells contribute to cytokine production and cellular inflammation in airway. Both ILC2 and myeloid cell IL‐33 signaling contribute to local and peripheral eosinophilia.
Electric field driven phase transformations require two phases with a mismatch in their electric polarization, as seen in antiferroelectric-to-ferroelectric transformations, where the ferroelectric ...phase has a permanent polarization that is favored under field. Many other nonferroelectric dielectric materials can become electrically polarized according to their electrical susceptibility, yet such induced polarizations are not generally considered capable of enabling a phase transformation. Here we explore a susceptibility-mismatch phase transformation in a paraelectric ceramic, yttria-doped zirconia. Using in situ x-ray diffraction at 550 °C we show that the monoclinic-to-tetragonal transformation can be driven directly by an electric field, providing experimental evidence of a paraelectric-to-paraelectric phase transformation. Considering the ∼1% mechanical strain of this transformation, the resulting electromechanical coupling may have potential for solid-state electrical actuators.
Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high‐resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble ...into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5‐triple‐knockout (Trpc1/4/5−/−) mice, lacking any TRPC1‐, TRPC4‐, or TRPC5‐containing channels, action potential‐triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged. Likewise, evoked postsynaptic responses in hippocampal slice recordings and transient potentiation after tetanic stimulation were decreased. In vivo, Trpc1/4/5−/− mice displayed impaired cross‐frequency coupling in hippocampal networks and deficits in spatial working memory, while spatial reference memory was unaltered. Trpc1/4/5−/− animals also exhibited deficiencies in adapting to a new challenge in a relearning task. Our results indicate the contribution of heteromultimeric channels from TRPC1, TRPC4, and TRPC5 subunits to the regulation of mechanisms underlying spatial working memory and flexible relearning by facilitating proper synaptic transmission in hippocampal neurons.
Synopsis
Heteromers from TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and specific mnemonic behavior.
TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus.
TRPC1/4/5 deficiency reduced action potential evoked responses in vitro and in situ, but LTP and depotentiation remained unchanged.
In Trpc1/4/5 triple knockout mice cross‐frequency phase‐amplitude coupling is impaired while basal neuronal network oscillations are unchanged.
Trpc1/4/5 triple knock out mice display deficits in spatial working memory and when adapting to a new challenge in a re‐learning task, whereas the acquisition of spatial reference memory remains unaltered.
Spatial working memory and flexible relearning requires the formation and function of hetero‐multimeric complexes of specific TRP channels in the mouse brain.
Group 2 innate lymphoid cells (ILC2s) are important mediators of allergic asthma. Bacterial components, such as unmethylated CpG DNA, a Toll-like receptor (TLR) 9 agonist, are known to possess ...beneficial immunomodulatory effects in patients with T cell–mediated chronic asthma. However, their roles in regulating ILC2s remain unclear.
We sought to determine the role of TLR9 activation in regulating ILC2 function and to evaluate the therapeutic utility of an immunomodulatory microparticle containing natural TLR9 ligand (MIS416).
We evaluated the immunomodulatory effects of CpG A in IL-33–induced airway hyperreactivity (AHR) and airway inflammation. The roles of interferons were examined in vivo and in vitro by using signal transducer and activator of transcription 1 (Stat1)−/− mice and neutralizing antibodies against IFN-γ and IFN-α/β receptor subunit 1, and their cellular sources were identified. The therapeutic utility of MIS416 was investigated in the Alternaria alternata model of allergic asthma and in humanized NSG mice.
We show that TLR9 activation by CpG A suppresses IL-33–mediated AHR and airway inflammation through inhibition of ILC2s. Activation of TLR9 leads to production of IFN-α, which drives IFN-γ production by natural killer cells. Importantly, IFN-γ is essential for TLR9-driven suppression, and IFN-α cannot compensate for impaired IFN-γ signaling. We further show that IFN-γ directly inhibits ILC2 function through a STAT1-dependent mechanism. Finally, we demonstrate the therapeutic potential of MIS416 in A alternata–induced airway inflammation and validated these findings in human subjects.
TLR9 activation alleviates ILC2-driven AHR and airway inflammation through direct suppression of cell function. Microparticle-based delivery of TLR9 ligands might serve as a therapeutic strategy for asthma treatment.
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Small volume samples of zirconia can survive stress-induced martensitic transformation without cracking, which enables in-depth explorations of martensite mechanics using micro-scale specimens. Here ...we present a systematic investigation of the orientation dependence of tetragonal crystals undergoing a uniaxial stress-driven martensitic transformation to the monoclinic phase, in single crystal zirconia pillars doped with yttria and titania. The Young’s modulus, martensitic transformation stress and transformation strain are highly dependent on the crystallographic orientation, and generally align with expectations based on known tensor properties and transformation crystallography. However, in some orientations, fracture or plastic slip are apparently preferred to martensitic transformation, and thus crystallography favors certain orientations if superelasticity or shape memory properties are specifically desired in zirconia ceramics.
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This paper aims to explore the application of deep learning in smart contract vulnerabilities detection. Smart contracts are an essential part of blockchain technology and are crucial for developing ...decentralized applications. However, smart contract vulnerabilities can cause financial losses and system crashes. Static analysis tools are frequently used to detect vulnerabilities in smart contracts, but they often result in false positives and false negatives because of their high reliance on predefined rules and lack of semantic analysis capabilities. Furthermore, these predefined rules quickly become obsolete and fail to adapt or generalize to new data. In contrast, deep learning methods do not require predefined detection rules and can learn the features of vulnerabilities during the training process. In this paper, we introduce a solution called Lightning Cat which is based on deep learning techniques. We train three deep learning models for detecting vulnerabilities in smart contract: Optimized-CodeBERT, Optimized-LSTM, and Optimized-CNN. Experimental results show that, in the Lightning Cat we propose, Optimized-CodeBERT model surpasses other methods, achieving an f1-score of 93.53%. To precisely extract vulnerability features, we acquire segments of vulnerable code functions to retain critical vulnerability features. Using the CodeBERT pre-training model for data preprocessing, we could capture the syntax and semantics of the code more accurately. To demonstrate the feasibility of our proposed solution, we evaluate its performance using the SolidiFI-benchmark dataset, which consists of 9369 vulnerable contracts injected with vulnerabilities from seven different types.
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