Efficient and stable acidic CO2 electrolysis to formic acid by a reservoir structure design.

Electrochemical synthesis of valuable chemicals and feedstocks through carbon dioxide (CO2) reduction in acidic electrolytes can surmount the considerable CO2 loss in alkaline and neutral conditions. However, achieving high productivity, while operating steadily in acidic electrolytes, remains a big challenge owing to the severe competing hydrogen evolution reaction. Here, we show that vertically grown bismuth nanosheets on a gas-diffusion layer can create numerous cavities as electrolyte reservoirs, which confine in situ-generated hydroxide and potassium ions and limit inward proton diffusion, producing locally alkaline environments. Based on this design, we achieve formic acid Faradaic efficiency of 96.3% and partial current density of 471 mA cm-2 at pH 2. When operated in a slim continuous-flow electrolyzer, the system exhibits a full-cell formic acid energy efficiency of 40% and a single pass carbon efficiency of 79% and performs steadily over 50 h. We further demonstrate the production of pure formic acid aqueous solution with a concentration of 4.2 weight %.

Nitrogen Doping-Roused Synergistic Active Sites in Perovskite Enabling Highly Selective CO2 Photoreduction into CH4.

The intricate protonation process in carbon dioxide reduction usually makes the product unpredictable. Thus, it is significant to control the reactive intermediates to manipulate the reaction steps. Here, we propose that the synergistic La-Ti active sites in the N-La2Ti2O7 nanosheets enable the highly selective carbon dioxide photoreduction into methane. In the photoreduction of CO2 over N-La2Ti2O7 nanosheets, in situ Fourier transform infrared spectra are utilized to monitor the *CH3O intermediate, pivotal for methane production, whereas such monitoring is not conducted for La2Ti2O7 nanosheets. Also, theoretical calculations testify to the increased charge densities on the Ti and La atoms and the regulated formation energy barrier of *CO and *CH3O intermediates by the constructed synergistic active sites. Accordingly, the methane formation rate of 7.97 µL h-1 exhibited by the N-La2Ti2O7 nanosheets, along with an electron selectivity of 96.6%, exceeds that of most previously reported catalysts under similar conditions.

Nitrogen-Mediated Promotion of Cobalt-Based Oxygen Evolution Catalyst for Practical Anion-Exchange Membrane Electrolysis.

Scarce and expensive iridium oxide is still the cornerstone catalyst of polymer-electrolyte membrane electrolyzers for green hydrogen production because of its exceptional stability under industrially relevant oxygen evolution reaction (OER) conditions. Earth-abundant transition metal oxides used for this task, however, show poor long-term stability. We demonstrate here the use of nitrogen-doped cobalt oxide as an effective iridium substitute. The catalyst exhibits a low overpotential of 240 mV at 10 mA cm-2 and negligible activity decay after 1000 h of operation in an alkaline electrolyte. Incorporation of nitrogen dopants not only triggers the OER mechanism switched from the traditional adsorbate evolution route to the lattice oxygen oxidation route but also achieves oxygen nonbonding (ONB) states as electron donors, thereby preventing structural destabilization. In a practical anion-exchange membrane water electrolyzer, this catalyst at anode delivers a current density of 1000 mA cm-2 at 1.78 V and an electrical efficiency of 47.8 kW-hours per kilogram hydrogen.

Optimizing the Intermediates Adsorption by Manipulating the Second Coordination Shell of Ir Single Atoms for Efficient Water Oxidation.

The precise regulation of single-atom catalysts (SACs) with the desired local chemical environment is vital to elucidate the relationship between the SACs structure and the catalytic performance. The debate on the effect of the local coordination environment is quite complicated even for the SACs with the same composition and chemical nature, calling for increased attention on the regulation of second coordination shell. For oxide-supported SACs, it remains a significant challenge to precisely manipulate the second coordination shell of single atoms supported on oxides due to the structural robustness of oxides. Here, Ir single atoms are anchored on NiO supports via different bonding strategies, resulting in the diverse Ir-O-Ni coordination numbers for Ir sites. Specifically, Ir1/NiO, Ir1-NiO, and Ir1@NiO SACs with increasing Ir-O-Ni coordination numbers of 3, 4, and 5 were synthesized, respectively. We found that the activity of the three samples towards oxygen evolution reaction (OER) exhibited a volcano-shaped relationship with the Ir-O-Ni coordination number, with Ir1-NiO showing the lowest overpotential of 225 mV at 10 mA cm-2. Mechanism investigations indicate that the moderate coordination number of Ir-O-Ni in Ir1-NiO creates the higher occupied Ir dz2 orbital, weakening the adsorption strength for *OOH intermediates and thereby enhancing the OER activity.

Breaking the Scaling Relationship in C-N Coupling via the Doping Effects for Efficient Urea Electrosynthesis.

Electrochemical C-N coupling reaction based on carbon dioxide and nitrate have been emerged as a new "green synthetic strategy" for the synthesis of urea, but the catalytic efficiency is seriously restricted by the inherent scaling relations of adsorption energies of the active sites, the improvement of catalytic activity is frequently accompanied by the decrease in selectivity. Herein, a doping engineering strategy was proposed to break the scaling relationship of intermediate binding and minimize the kinetic barrier of C-N coupling. A thus designed SrCo0.39Ru0.61O3-δ catalyst achieves a urea yield rate of 1522 µg h-1 mgcat. -1 and faradic efficiency of 34.1 % at -0.7 V versus reversible hydrogen electrode. A series of characterizations revealed that Co doping not only induces lattice distortion but also creates rich oxygen vacancies (OV) in the SrRuO3. The oxygen vacancies weaken the adsorption of *CO and *NH2 intermediates on the Co and Ru sites respectively, and the strain effects over the Co-Ru dual sites promoting the occurrence of C-N coupling of the two monomers instead of selective hydrogenating to form by-products. This work presents an insight into molecular coupling reactions towards urea synthesis via the doping engineering on SrRuO3.

Nanomicellar Electrolyte To Control Release Ions and Reconstruct Hydrogen Bonding Network for Ultrastable High-Energy-Density Zn-Mn Battery.

Zn-Mn batteries with two-electron conversion reactions simultaneously on the cathode and anode harvest a high voltage plateau and high energy density. However, the zinc anode faces dendrite growth and parasitic side reactions while the Mn2+/MnO2 reaction on the cathode involves oxygen evolution and possesses poor reversibility. Herein, a novel nanomicellar electrolyte using methylurea (Mu) has been developed that can encapsulate ions in the nanodomain structure to guide the homogeneous deposition of Zn2+/Mn2+ in the form of controlled release under an external electric field. Consecutive hydrogen bonding network is broken and a favorable local hydrogen bonding system is established, thus inhibiting the water-splitting-derived side reactions. Concomitantly, the solid-electrolyte interface protective layer is in situ generated on the Zn anode, further circumventing the corrosion issue resulting from the penetration of water molecules. The reversibility of the Mn2+/MnO2 conversion reaction is also significantly enhanced by regulating interfacial wettability and improving nucleation kinetics. Accordingly, the modified electrolyte endows the symmetric Zn∥Zn cell with extended cyclic stability of 800 h with suppressed dendrites growth at an areal capacity of 1 mAh cm-2. The assembled Zn-Mn electrolytic battery also demonstrates an exceptional capacity retention of nearly 100% after 800 cycles and a superior energy density of 800 Wh kg-1 at an areal capacity of 0.5 mAh cm-2.

Highly Enhanced Chloride Adsorption Mediates Efficient Neutral CO2 Electroreduction over a Dual-Phase Copper Catalyst.

Electrocatalytic carbon dioxide reduction (CO2R) in neutral electrolytes can mitigate the energy and carbon losses caused by carbonate formation but often experiences unsatisfied multicarbon selectivity and reaction rates because of the kinetic limitation to the critical carbon monoxide (CO)-CO coupling step. Here, we describe that a dual-phase copper-based catalyst with abundant Cu(I) sites at the amorphous-nanocrystalline interfaces, which is electrochemically robust in reducing environments, can enhance chloride-specific adsorption and consequently mediate local *CO coverage for improved CO-CO coupling kinetics. Using this catalyst design strategy, we demonstrate efficient multicarbon production from CO2R in a neutral potassium chloride electrolyte (pH ∼6.6) with a high Faradaic efficiency of 81% and a partial current density of 322 milliamperes per square centimeter. This catalyst is stable after 45 h of operation at current densities relevant to commercial CO2 electrolysis (300 mA per square centimeter).

Chemistry, bioactivity, biosynthesis, and total synthesis of stemmadenine alkaloids.

Covering: up to July 2022Stemmadenine alkaloids are a restrictive sub-group of monoterpene indole alkaloids, represented by two congeners: stemmadenine and vallesamine. Their skeleton is defined by the cleavage of the C-3-C-7 bond of the Strychnos group's pentacyclic scaffold in monoterpene indole alkaloids. The parent alkaloid stemmadenine acts as a key intermediate in the biosynthesis of several major monoterpene indole alkaloid families, including regular Strychnos alkaloids, Aspidosperma alkaloids, and Iboga alkaloids. In this review, a complete coverage of the stemmadenine alkaloids, from the early reports till the present day at 2022, are presented, and their diverse biological activities are briefly described. Moreover, the biosynthetic proposal for stemmadenine and the proposed biogenetic conversion of stemmadenine-type alkaloids into vallesamine-type congeners are discussed in detail. Moreover, the successful synthetic strategies to access the strained stemmadenine scaffolds are fully reviewed.

Anti-Inflammatory Activities of Monoterpene and Sesquiterpene Glycosides from the Aqueous Extract of Artemisia annua L.

Artemisia annua L. is a Chinese medicinal herb, but the origin of its pharmacological properties, including its anti-inflammatory activity, remain unknown. In this study, five new monoterpene glycosides (1-5) and two new sesquiterpene glycosides (6 and 7) were isolated from the aqueous extract of the aerial parts of A. annua. The structures of these glycosides were determined using high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, electronic circular dichroism calculations, and chemical hydrolysis methods. The anti-inflammatory activities of the isolated compounds were evaluated by down-regulating interleukin-6 (IL-6) in lipopolysaccharide-stimulated RAW 264.7 macrophages. Notably, all the new compounds significantly inhibited the expression of IL-6 in a dose-dependent manner.

Ethoxysanguinarine Induces Apoptosis, Inhibits Metastasis and Sensitizes cells to Docetaxel in Breast Cancer Cells through Inhibition of Hakai.

Ethoxysanguinarine (ESG) is a benzophenanthridine alkaloid extracted from plants of Papaveraceae family, such as Macleaya cordata (Willd) R. Br. The anti-cancer activity of ESG has been rarely reported. In this study, we investigated the anti-breast cancer effect of ESG and its underlying mechanism. MTT assay and flow cytometry analysis showed that ESG inhibited the viability and induced apoptosis in MCF7 and MDA-MB-231 human breast cancer cells. Western blot revealed that ESG triggered intrinsic and extrinsic apoptotic pathways, as evidenced by the activation of caspase-8, caspase-9 and caspase-3. ESG attenuated breast cancer cell migration and invasion through Hakai/E-cadherin/N-cadherin. Moreover, Hakai knockdown sensitized ESG-triggered viability and motility inhibition, suggesting that Hakai mediated the anti-breast cancer effect of ESG. In addition, ESG potentiated the anti-cancer activity of docetaxel (DTX) in breast cancer cells. Overall, our findings demonstrate that ESG exhibits outstanding pro-apoptosis and anti-metastasis effects on breast cancer via a mechanism related to Hakai-related signaling pathway.

Identification of an Alepterolic Acid Derivative as a Potent Anti-Breast-Cancer Agent via Inhibition of the Akt/p70S6K Signaling Pathway.

Alepterolic acid is a diterpene occurring in the fern Aleuritopteris argentea with potential biological activity that warrants further structural modification. In the present work, sixteen alepterolic acid derivatives were synthesized and evaluated for their anticancer activities. Among them, N-[m-(trifluoromethoxy)phenyl] alepterolamide displayed comparable activity (IC50 =4.20±0.21 µM) in MCF-7 cells. Moreover, mechanistic investigations indicated this compound was significantly capable of diminishing cell proliferation and viability of MCF-7 cells. After treatment with N-[m-(trifluoromethoxy)phenyl] alepterolamide, a significant increase in cleaved caspase-9, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP) and Bax/Bcl2 ratio were observed in MCF-7 cells, leading to caspase-dependent apoptotic pathways. Further studies showed this compound promoted cellular apoptosis and inhibited migration in MCF-7 cells via modulation of the Akt/p70S6K signaling pathway. All these results revealed the potential of N-[m-(trifluoromethoxy)phenyl] alepterolamide as an appealing therapeutic drug candidate for breast cancer.

Selective CO2 -to-C2 H4 Photoconversion Enabled by Oxygen-Mediated Triatomic Sites in Partially Oxidized Bimetallic Sulfide.

Selective CO2 photoreduction into C2 fuels under mild conditions suffers from low product yield and poor selectivity owing to the kinetic challenge of C-C coupling. Here, triatomic sites are introduced into bimetallic sulfide to promote C-C coupling for selectively forming C2 products. As an example, FeCoS2 atomic layers with different oxidation degrees are first synthesized, demonstrated by X-ray photoelectron spectroscopy and X-ray absorption near edge spectroscopy spectra. Both experiment and theoretical calculation verify more charges aggregate around the introduced oxygen atom, which enables the original Co-Fe dual sites to turn into Co-O-Fe triatomic sites, thus promoting C-C coupling of double *COOH intermediates. Accordingly, the mildly oxidized FeCoS2 atomic layers exhibit C2 H4 formation rate of 20.1 µmol g-1 h-1 , with the product selectivity and electron selectivity of 82.9 % and 96.7 %, outperforming most previously reported photocatalysts under similar conditions.

Engineered miniature H1 promoters with dedicated RNA polymerase II or III activity.

RNA polymerase III (Pol III) promoters, such as 7SK, U6, and H1, are widely used for the expression of small noncoding RNAs, including short hairpin RNAs for RNAi experiments and guide RNAs for CRISPR-mediated genome editing. We previously reported dual RNA polymerase activity (Pol II/III) for the human H1 promoter and demonstrated that this promiscuous RNA polymerase use can be exploited for the simultaneous expression of both a noncoding RNA and an mRNA. However, this combination is not a desired feature in other experimental and therapeutic settings. To overcome this limitation of the H1 promoter, we engineered a miniature H1/7SK hybrid promoter with minimal Pol II activity, thereby boosting Pol III activity to a level that is higher than that of either parental promoter. In parallel, we also engineered small Pol II-specific H1 promoter variants and explored their use as general Pol II promoters for protein expression. The newly engineered promoter variants form an attractive alternative to the commonly used H1 promoter in terms of not only activity and small promoter size but also concerning safety by exclusive expression of the desired therapeutic transcript (either pol II or pol III but not both).

Room-Temperature Photooxidation of CH4 to CH3OH with Nearly 100% Selectivity over Hetero-ZnO/Fe2O3 Porous Nanosheets.

The huge challenge for CH4 photooxidation into CH3OH lies in the activation of the inert C-H bond and the inhibition of CH3OH overoxidation. Herein, we design two-dimensional in-plane Z-scheme heterostructures composed of two different metal oxides, with efforts to polarize the symmetrical CH4 molecules and strengthen the O-H bond in CH3OH. As a prototype, we first fabricate ZnO/Fe2O3 porous nanosheets, where high-resolution transmission electron microscopy and in situ X-ray photoelectron spectroscopy affirm their in-plane Z-scheme heterostructure. In situ Fourier transform infrared spectra and in situ electron paramagnetic resonance spectra demonstrate their higher amount of ·CH3 radicals relative to the pristine ZnO porous nanosheets, in which density functional theory calculations validate that the high local charge accumulation on Fe sites lowers the CH4 adsorption energy from 0.14 to 0.06 eV. Moreover, the charge-accumulated Fe sites strengthen the polarity of the O-H bond in CH3OH through transferring electrons to the O atoms, confirmed by the increased barrier from 0.30 to 2.63 eV for *CH3O formation, which inhibits the homolytic O-H bond cleavage and thus suppresses CH3OH overoxidation. Accordingly, the CH3OH selectivity over ZnO/Fe2O3 porous nanosheets reaches up to nearly 100% with an activity of 178.3 µmol-1 gcat-1, outperforming previously reported photocatalysts without adding any oxidants under room temperature and ambient pressure.

A novel 8-hydroxyquinoline derivative induces breast cancer cell death through paraptosis and apoptosis.

Chemotherapy represents one of the main conventional therapies for breast cancer. However, tumor cells develop mechanisms to evade chemotherapeutic-induced apoptosis. Thus, it is of great significance to induce non-apoptotic cell death modes, such as paraptosis, in breast cancer. Herein, a novel 8-hydroxyquinoline derivative, 5,7-dibromo-8-(methoxymethoxy)-2-methylquinoline (HQ-11), was obtained and its potential anti-breast cancer mechanisms were investigated. Our results showed that extensive cytoplasmic vacuoles derived from the endoplasmic reticulum (ER) and mitochondria were appeared in MCF7 and MDA-MB-231 breast cancer cells by HQ-11 incubation, and pretreatment of cycloheximide was able to inhibit this vacuolation and HQ-11-induced cell death, showing the characteristics of paraptosis. ER stress was involved in HQ-11-caused paraptosis evidenced by the increase of glucose-regulated protein 78, C/EBP homologous protein and polyubiquitinated proteins. Molecular docking analysis revealed a favorable binding mode of HQ-11 in the active site of the chymotrypsin-like ß5 subunit of the proteasome, indicative of proteasome dysfunction under HQ-11 treatment, which might result in further aggravated ER stress. Furthermore, treatment of HQ-11 resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase, and inhibition of ERK with U0126 significantly attenuated HQ-11-induced ER stress and paraptosis. In addition, exposure to HQ-11 also caused apoptosis in breast cancer cells partially through activation of ERK pathway. All these results conclusively indicate that HQ-11 triggers two distinct cell death modes via inhibition of proteasome and activation of ERK pathway in breast cancer cells, providing a promising candidate in future anti-breast cancer therapy.

Synthesis and biological evaluation of cytotoxic activity of novel podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties.

Podophyllotoxin, as a natural lignan isolated from the dried rhizomes and roots of several plant species of Podophyllum family, exhibits potent activity of interfering polymerization of tubulin and causes cancer cell apoptosis. Structure-activity relationship research revealed that modification at 4-position was tolerable for its potency. In the present study, podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties at 4-position were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and mass spectral data. ADMET analysis proposed that these compounds had a good distribution and high clearance profile with little toxicity. The cytotoxicity of these derivatives was evaluated against four human cancer cell lines (MCF-7, A549, HeLa and PC-3) by MTT assay. Among all the compounds, compound 6e exhibited the best anti-proliferative properties with an IC50 = 0.08 ± 0.01 µM against MCF-7 cancer cell line. Further cellular mechanism studies by cell colony formation, mitochondrial membrane potential assay, nuclear morphology analysis and western blot confirmed that compound 6e could inhibit cancer cell proliferation and induce mitochondria-associated apoptosis in MCF-7 cells. Meanwhile, immunofluorescence assay revealed that compound 6e could apparently disrupt tubulin network in MCF-7 cells, and molecular docking further supported that compound 6e was able to bind into the colchicine site of tubulin. The above results might lay a foundation for further investigation for drug discovery based on podophyllotoxin.

Extinction of all infectious HIV in cell culture by the CRISPR-Cas12a system with only a single crRNA.

The CRISPR-Cas9 system has been used for genome editing of various organisms. We reported inhibition of the human immunodeficiency virus (HIV) in cell culture infections with a single guide RNA (gRNA) and subsequent viral escape, but complete inactivation of infectious HIV with certain combinations of two gRNAs. The new RNA-guided endonuclease system CRISPR-Cas12a (formerly Cpf1) may provide a more promising tool for genome engineering with increased activity and specificity. We compared Cas12a to the original Cas9 system for inactivation of the integrated HIV DNA genome. Superior antiviral activity is reported for Cas12a, which can achieve full HIV inactivation with only a single gRNA (called crRNA). We propose that the different architecture of Cas9 versus Cas12a endonuclease explains this effect. We also disclose that DNA cleavage by the Cas12a endonuclease and subsequent DNA repair causes mutations with a sequence profile that is distinct from that of Cas9. Both CRISPR systems can induce the typical small deletions around the site of DNA cleavage and subsequent repair, but Cas12a does not induce the pure DNA insertions that are routinely observed for Cas9. Although these typical signatures are apparent in many literature studies, this is the first report that documents these striking differences.

A Low-Power High-Data-Transmission Multi-Lead ECG Acquisition Sensor System.

This study presents a low-power multi-lead wearable electrocardiogram (ECG) signal sensor system design that can simultaneously acquire the electrocardiograms from three leads, I, II, and V1. The sensor system includes two parts, an ECG test clothing with five electrode patches and an acquisition device. Compared with the traditional 12-lead wired ECG detection instrument, which limits patient mobility and needs medical staff assistance to acquire the ECG signal, the proposed vest-type ECG acquisition system is very comfortable and easy to use by patients themselves anytime and anywhere, especially for the elderly. The proposed study incorporates three methods to reduce the power consumption of the system by optimizing the micro control unit (MCU) working mode, adjusting the radio frequency (RF) parameters, and compressing the transmitted data. In addition, Huffman lossless coding is used to compress the transmitted data in order to increase the sampling rate of the acquisition system. It makes the whole system operate continuously for a long period of time and acquire abundant ECG information, which is helpful for clinical diagnosis. Finally, a series of tests were performed on the designed wearable ECG device. The results have demonstrated that the multi-lead wearable ECG device can collect, process, and transmit ECG data through Bluetooth technology. The ECG waveforms collected by the device are clear, complete, and can be displayed in real-time on a mobile phone. The sampling rate of the proposed wearable sensor system is 250 Hz per lead, which is dependent on the lossless compression scheme. The device achieves a compression ratio of 2.31. By implementing a low power design on the device, the resulting overall operational current of the device is reduced by 37.6% to 9.87 mA under a supply voltage of 2.1 V. The proposed vest-type multi-lead ECG acquisition device can be easily employed by medical staff for clinical diagnosis and is a suitable wearable device in monitoring and nursing the off-ward patients.

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung.

Focal adhesion kinase-mediated activation of glycogen synthase kinase 3ß regulates IL-33 receptor internalization and IL-33 signaling.

IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3ß (GSK3ß) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3ß. GSK3ß was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3ß binding site mutant (ST2L(S446A)) and phosphorylation site mutant (ST2L(S442A)) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3ß activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3ß might serve as a unique strategy to lessen pulmonary inflammation.