Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

SENP3 senses oxidative stress to facilitate STING-dependent dendritic cell antitumor function.

STING-dependent cytosolic DNA sensing in dendritic cells (DCs) initiates antitumor immune responses, but how STING signaling is metabolically regulated in the tumor microenvironment remains unknown. Here, we show that oxidative stress is required for STING-induced DC antitumor function through a process that directs SUMO-specific protease 3 (SENP3) activity. DC-specific deletion of Senp3 drives tumor progression by blunting STING-dependent type-I interferon (IFN) signaling in DCs and dampening antitumor immune responses. DC-derived reactive oxygen species (ROS) trigger SENP3 accumulation and the SENP3-IFI204 interaction, thereby catalyzing IFI204 deSUMOylation and boosting STING signaling activation in mice. Consistently, SENP3 senses ROS to facilitate STING-dependent DC activity in tissue samples from colorectal cancer patients. Our results reveal that oxidative stress as a metabolic regulator promotes STING-mediated DC antitumor immune responses and highlights SENP3 as an overflow valve for STING signaling induction in the metabolically abnormal tumor microenvironment.

Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid.

The proinflammatory cytokines interleukin 12 (IL-12) and IL-23 connect innate responses and adaptive immune responses and are also involved in autoimmune and inflammatory diseases. Here we describe an epigenetic mechanism for regulation of the genes encoding IL-12 (Il12a and Il12b; collectively called 'Il12' here) and IL-23 (Il23a and Il12b; collectively called 'Il23' here) involving the deubiquitinase Trabid. Deletion of Zranb1 (which encodes Trabid) in dendritic cells inhibited induction of the expression of Il12 and Il23 by Toll-like receptors (TLRs), which impaired the differentiation of inflammatory T cells and protected mice from autoimmune inflammation. Trabid facilitated TLR-induced histone modifications at the promoters of Il12 and Il23, which involved deubiqutination and stabilization of the histone demethylase Jmjd2d. Our findings highlight an epigenetic mechanism for the regulation of Il12 and Il23 and establish Trabid as an innate immunological regulator of inflammatory T cell responses.

USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses.

Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.

RNA m6A demethylase ALKBH5 regulates the development of γδ T cells.

γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.

Promoting Li2S Nucleation/Dissolution Kinetics via Multiple Active Sites over TiVCrMoC3Tx Interface.

Lithium-sulfur batteries (LSBs) are still limited by some issues such as polysulfides shuttle and lithium dendrites. Recently, the concept "high-entropy" has been considered as the research hotspot and international frontier. Herein, a high entropy MXene (TiVCrMoC3Tx, HE-MXene) doped graphene is designed as the modified coating on commercial separators for LSBs. The HE-MXene affords multiple metal active sites, fast Li+ diffusion rate, and efficient adsorption toward polysulfide intermediates. Furthermore, strong lithophilic property is favorable for uniform Li+ deposition. The combination of in situ characterizations confirms TiVCrMoC3Tx effectively promotes the Li2S nucleation/dissolution kinetics, reduces the Li+ diffusion barrier, and exhibits favorable lithium uniform deposition behavior. This TiVCrMoC3Tx/G@PP provides a high-capacity retention rate after 1000 cycles at 1 C and 2 C, with a capacity decay rate of merely 0.021% and 0.022% per cycle. Surprisingly, the cell operates at a low potential of 48 mV while maintaining at 5 mA cm-2/5 mAh cm-2 for 4000 h. Furthermore, it still maintains a high-capacity retention rate under a high sulfur loading of 4.8/6.4 mg cm-2 and a low E/S ratio of 8.6/7.5 µg mL-1. This work reveals a technical roadmap for simultaneously addressing the cathode and anode challenge, thus achieving potential commercially viable LSBs.

Malassezia restricta as an unexpected cause of infectious osteomyelitis diagnosed by metagenomic sequencing: a case report and literature review.

BACKGROUND: Malassezia restricta, a lipophilic and lipodependent yeast belonging to the basidiomycetes group, is an opportunistic fungal pathogen associated with various skin diseases, including seborrheic dermatitis and dandruff. Typically, Malassezia infection in neonates manifests as fungemia or hematogenous dissemination to the bone or lungs. However, vertebral osteomyelitis caused by these fungi is rarely reported owing to non-specific clinical presentations and laboratory/imaging findings. The Pathogen Metagenomics Sequencing (PMseq) technique enables direct high-throughput sequencing of infected specimens, facilitating the rapid and accurate detection of all microorganisms in clinical samples through comprehensive reports. CASE PRESENTATION: A 52-year-old male was admitted to our hospital on July 20, 2022 with a 3-month history of ambulatory difficulties and localized low back pain. Magnetic Resonance Imaging (MRI) examination of the spinal column revealed irregular bone destruction affecting the L2, L3, and L5 vertebral bodies. Additionally, low T1 and high T2 intensity lesions were observed at the intervertebral discs between L3 and L5. The presumptive diagnosis of tuberculous spondylitis was made based on the imaging findings, despite negative results in all mycobacterium tests. However, the patient exhibited no improvement after receiving regular anti-tuberculosis treatment for 3 months. Subsequent MRI revealed an expansive abnormal signal within the vertebral body, leading to progressive bone destruction. The absence of spinal tuberculosis or other infective microorganisms was confirmed through culture from blood and pathological tissue from the L4 vertebral body. Subsequently, PMseq was performed on the specimens, revealing M. restricta as the predominant pathogen with the highest relative abundance value. The pathological examination revealed the presence of fungal mycelium in the L4 vertebral body, with positive findings on periodic Schiff-methenamine and periodic acid-Schiff staining. The anti-tuberculosis treatment was discontinued, and an antifungal combination of fluconazole and voriconazole was administered. All symptoms were resolved after 7 consecutive months of treatment, and the patient was able to ambulate autonomously. Vertebral lesions were reduced on MRI during the 13-month follow-up. CONCLUSIONS: M. restricta is not a commonly recognized pathogen associated with infectious vertebral osteomyelitis. However, PMseq can aid in diagnosis, timely treatment, and decision making for some non-specific infectious diseases.

Staged Immediate Nipple Reconstruction With Tube Flap in Immediate Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction.

BACKGROUND: In the setting of immediate breast reconstruction by deep inferior epigastric artery perforator (DIEP) flap, the excessive DIEP flap skin is de-epithelialized and then buried under the mastectomy skin. In this study, by virtue of tube flap technique, we hypothesize that the skin supposed to be abandoned could be transferred to the apex of reconstructed breast mound for nipple reconstruction. METHODS: A total of 60 female patients were recruited between January 2019 and December 2020. All these patients underwent mastectomy including nipple-areola complex and immediate DIEP flap breast reconstruction. A ladder-shaped pedicled flap was raised from the DIEP flap and rolled into a tube. The free end of tube flap was inset into the future nipple position of the reconstructed breast mound 1 week later. After revascularization for 1 month, we divided the previous pedicle and used the tube on the apex of the breast mound to recreate a new nipple. RESULTS: All reconstructed breasts and nipples survived well postoperatively. The average nipple projection was 12.5 ± 2.0 mm immediately after the surgery, which gradually decreased to 9.4 ± 1.5 mm at 1-year follow-up, with the projection loss from the initial measurement as 24.9% ± 1.8%. In total, 51 patients considered the overall impression of breast and nipple reconstruction to be very good or good. CONCLUSIONS: We provided an ideal technique that could improve the maintenance of reconstructed nipple projection and have aesthetically acceptable outcomes, without DIEP flap tissue loss, breast mound distortion, or additional scars.

Semantic-Aware Fusion Network Based on Super-Resolution.

The aim of infrared and visible image fusion is to generate a fused image that not only contains salient targets and rich texture details, but also facilitates high-level vision tasks. However, due to the hardware limitations of digital cameras and other devices, there are more low-resolution images in the existing datasets, and low-resolution images are often accompanied by the problem of losing details and structural information. At the same time, existing fusion algorithms focus too much on the visual quality of the fused images, while ignoring the requirements of high-level vision tasks. To address the above challenges, in this paper, we skillfully unite the super-resolution network, fusion network and segmentation network, and propose a super-resolution-based semantic-aware fusion network. First, we design a super-resolution network based on a multi-branch hybrid attention module (MHAM), which aims to enhance the quality and details of the source image, enabling the fusion network to integrate the features of the source image more accurately. Then, a comprehensive information extraction module (STDC) is designed in the fusion network to enhance the network's ability to extract finer-grained complementary information from the source image. Finally, the fusion network and segmentation network are jointly trained to utilize semantic loss to guide the semantic information back to the fusion network, which effectively improves the performance of the fused images on high-level vision tasks. Extensive experiments show that our method is more effective than other state-of-the-art image fusion methods. In particular, our fused images not only have excellent visual perception effects, but also help to improve the performance of high-level vision tasks.

Amphibious Multifunctional Hydrogel Flexible Haptic Sensor with Self-Compensation Mechanism.

In recent years, hydrogel-based wearable flexible electronic devices have attracted much attention. However, hydrogel-based sensors are affected by structural fatigue, material aging, and water absorption and swelling, making stability and accuracy a major challenge. In this study, we present a DN-SPEZ dual-network hydrogel prepared using polyvinyl alcohol (PVA), sodium alginate (SA), ethylene glycol (EG), and ZnSO4 and propose a self-calibration compensation strategy. The strategy utilizes a metal salt solution to adjust the carrier concentration of the hydrogel to mitigate the resistance drift phenomenon to improve the stability and accuracy of hydrogel sensors in amphibious scenarios, such as land and water. The ExpGrow model was used to characterize the trend of the ∆R/R0 dynamic response curves of the hydrogels in the stress tests, and the average deviation of the fitted curves ϵ¯ was calculated to quantify the stability differences of different groups. The results showed that the stability of the uncompensated group was much lower than that of the compensated group utilizing LiCl, NaCl, KCl, MgCl2, and AlCl3 solutions (ϵ¯ in the uncompensated group in air was 276.158, 1.888, 2.971, 30.586, and 13.561 times higher than that of the compensated group in LiCl, NaCl, KCl, MgCl2, and AlCl3, respectively; ϵ¯ in the uncompensated group in seawater was 10.287 times, 1.008 times, 1.161 times, 4.986 times, 1.281 times, respectively, higher than that of the compensated group in LiCl, NaCl, KCl, MgCl2 and AlCl3). In addition, for the ranking of the compensation effect of different compensation solutions, the concentration of the compensation solution and the ionic radius and charge of the cation were found to be important factors in determining the compensation effect. Detection of events in amphibious environments such as swallowing, robotic arm grasping, Morse code, and finger-wrist bending was also performed in this study. This work provides a viable method for stability and accuracy enhancement of dual-network hydrogel sensors with strain and pressure sensing capabilities and offers solutions for sensor applications in both airborne and underwater amphibious environments.

Realization of Multiple Charge-Density Waves in NbTe2 at the Monolayer Limit.

Layered transition-metal dichalcogenides down to the monolayer (ML) limit provide a fertile platform for exploring charge-density waves (CDWs). Here, we experimentally unveil the richness of the CDW phases in ML-NbTe2 for the first time. Not only the theoretically predicted 4 × 4 and 4 × 1 phases but also two unexpected 28×28 and 19×19 phases are realized. For such a complex CDW system, we establish an exhaustive growth phase diagram via systematic efforts in the material synthesis and scanning tunneling microscope characterization. Moreover, the energetically stable phase is the larger-scale order (19×19), which is surprisingly in contradiction to the prior prediction (4 × 4). These findings are confirmed using two different kinetic pathways: i.e., direct growth at proper growth temperatures (T) and low-T growth followed by high-T annealing. Our results provide a comprehensive diagram of the "zoo" of CDW orders in ML-NbTe2.

Noncanonical NF-κB pathway controls the production of type I interferons in antiviral innate immunity.

Production of type I interferons (IFN-I) is a crucial innate immune mechanism against viral infections. IFN-I induction is subject to negative regulation by both viral and cellular factors, but the underlying mechanism remains unclear. We report that the noncanonical NF-κB pathway was stimulated along with innate immune cell differentiation and viral infections and had a vital role in negatively regulating IFN-I induction. Genetic deficiencies in major components of the noncanonical NF-κB pathway caused IFN-I hyperinduction and rendered cells and mice substantially more resistant to viral infection. Noncanonical NF-κB suppressed signal-induced histone modifications at the Ifnb promoter, an action that involved attenuated recruitment of the transcription factor RelA and a histone demethylase, JMJD2A. These findings reveal an unexpected function of the noncanonical NF-κB pathway and highlight an important mechanism regulating antiviral innate immunity.

The role of AGK in thrombocytopoiesis and possible therapeutic strategies.

Abnormal megakaryocyte development and platelet production lead to thrombocytopenia or thrombocythemia and increase the risk of hemorrhage or thrombosis. Acylglycerol kinase (AGK) is a mitochondrial membrane kinase that catalyzes the formation of phosphatidic acid and lysophosphatidic acid. Mutation of AGK has been described as the major cause of Sengers syndrome, and the patients with Sengers syndrome have been reported to exhibit thrombocytopenia. In this study, we found that megakaryocyte/platelet-specific AGK-deficient mice developed thrombocytopenia and splenomegaly, mainly caused by inefficient bone marrow thrombocytopoiesis and excessive extramedullary hematopoiesis, but not by apoptosis of circulating platelets. It has been reported that the G126E mutation arrests the kinase activity of AGK. The AGK G126E mutation did not affect peripheral platelet counts or megakaryocyte differentiation, suggesting that the involvement of AGK in megakaryocyte development and platelet biogenesis was not dependent on its kinase activity. The Mpl/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (Stat3) pathway is the major signaling pathway regulating megakaryocyte development. Our study confirmed that AGK can bind to JAK2 in megakaryocytes/platelets. More interestingly, we found that the JAK2 V617F mutation dramatically enhanced the binding of AGK to JAK2 and greatly facilitated JAK2/Stat3 signaling in megakaryocytes/platelets in response to thrombopoietin. We also found that the JAK2 JAK homology 2 domain peptide YGVCF617CGDENI enhanced the binding of AGK to JAK2 and that cell-permeable peptides containing YGVCF617CGDENI sequences accelerated proplatelet formation. Therefore, our study reveals critical roles of AGK in megakaryocyte differentiation and platelet biogenesis and suggests that targeting the interaction between AGK and JAK2 may be a novel strategy for the treatment of thrombocytopenia or thrombocythemia.

RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis.

Most cancer deaths are due to the colonization of tumor cells in distant organs. More evidence indicates that overexpression of RACGAP1 plays a critical role in cancer metastasis. However, the underlying mechanism still remains poorly understood. Here we found that RACGAP1 promoted breast cancer metastasis through regulating mitochondrial quality control. Overexpression of RACGAP1 in breast cancer cells led to the fragmentation of mitochondria, increased mitophagy intensity, mitochondrial turnover, and aerobic glycolysis ATP production. We showed that RACGAP1 promoted mitochondrial fission through recruiting ECT2 during anaphase and subsequently had activated ERK-DRP1 pathway. We further demonstrated the phosphorylation of RACGAP1 is essential for its ability of binding with ECT2 and its downstream effects. RACGAP1 overexpression also increased the expression of PGC-1a, a key mitochondrial biogenesis regulator, presumably by the increased mitophagy intensity induced by RACGAP1. PGC-1a increased the enrichment of DNMT1 in mitochondria, mitochondrial DNMT1 augmented mitochondrial DNA methylation and upregulated mitochondrial genome transcription. Our data indicated that RACGAP1 simultaneously facilitated mitophagy and mitochondrial biogenesis through regulating DRP1 phosphorylation and PGC-1a expression, eventually improved mitochondrial quality control in breast cancer cells. Our study provided a new angle in understanding the RACGAP1-overexpression related malignancy in breast cancer patients.

Characteristics, formation, and sources of PM2.5 in 2020 in Suzhou, Yangtze River Delta, China.

Here we present seasonal chemical characteristics, formations, sources of PM2.5 in the year 2020 in Suzhou, Yangtze River Delta, China. Expectedly, organic matter (OM) found to be the most dominant component of PM2.5, with a year-average value of 10.3 ± 5.5 µg m-3, followed by NO3- (6.7 ± 6.5 µg m-3), SO42- (3.3 ± 2.5 µg m-3), NH4+ (3.2 ± 2.8 µg m-3), EC (1.1 ± 1.3 µg m-3), Cl- (0.57 ± 0.56 µg m-3), Ca2+ (0.55 ± 0.91 µg m-3), K+ (0.2 ± 1.0 µg m-3), Na+ (0.18 ± 0.45 µg m-3), and Mg2+ (0.09 ± 0.15 µg m-3). Seasonal variations of PM2.5 showed the highest average value in spring, followed by winter, fall, and summer. Meanwhile, the formation mechanisms of the major PM2.5 species (NO3-, SO42-, and OM) varied in seasons. Interestingly, NO2 may have the highest conversion rate to NO3- in spring, which might be linked with the nighttime chemistry due to the high relative humidity. Moreover, OM in summer was mainly produced by the daytime oxidation of volatile organic compounds, while local primary organic aerosols might play a significant role in other seasons. Source apportionment showed that the more-aged PM2.5 contributed significantly to the PM2.5 mass (42%), followed by the dust-related PM2.5 (38%) and the less-aged PM2.5 (21%). Potential contribution source function (PSCF) results indicated that aged PM2.5 were less affected by transportation than dust-related PM2.5.

The predictive ability of occipital to C3 angle for dysphagia after occipitocervical fusion in patients with combined C2-3 Klippel-Feil syndrome.

BACKGROUND: Improper occipitocervical alignment after occipitocervical fusion (OCF) may lead to devastating complications, such as dysphagia and/or dyspnea. The occipital to C2 angle (O-C2a), occipital and external acoustic meatus to axis angle (O-EAa) have been used to evaluate occipitospinal alignment. However, it may be difficult to identify the inferior endplate of the C2 vertebra in patients with C2-3 Klippel-Feil syndrome (KFS). The purpose of this study aimed to compare four different parameters for predicting dysphagia after OCF in patients with C2-3 KFS. METHODS: There were 40 patients with C2-3 KFS undergoing OCF between 2010 and 2019. Radiographs of these patients were collected to measure the occipital to C3 angle (O-C3a), O-C2a, occipito-odontoid angle (O-Da), occipital to axial angle (Oc-Axa), and narrowest oropharyngeal airway space (nPAS). The presence of dysphagia was defined as the patient complaining of difficulty or excess endeavor to swallow. Patients were divided into two groups according to whether they had postoperative dysphagia. We evaluated the relationship between each of the angle parameters and nPAS and analyzed their influence to the postoperative dysphagia. RESULTS: The incidence of dysphagia after OCF was 25% in patients with C2-3 KFS. The Oc-Axa, and nPAS were smaller in the dysphagia group compared to non-dysphagia group at the final follow-up (p < 0.05). Receiver-operating characteristic (ROC) curves showed that dO-C3a had the highest accuracy as a predictor of the dysphagia with an area under the curve (AUC) of 0.868. The differences in O-C3a, O-C2a, O-Da, and Oc-Axa were all linearly correlated with nPAS scores preoperatively and at the final follow-up within C2-3 KFS patients, while there was a higher R2 value between the dO-C3a and dnPAS. Multiple linear regression analysis showed that the difference of O-C3a was the only significant predictor for dnPAS (ß = 0.670, p < 0.001). CONCLUSIONS: The change of O-C3a (dO-C3a) is the most reliable indicator for evaluating occipitocervical alignment and predicting postoperative dysphagia in C2-3 KFS patients. Moreover, dO-C3a should be more than - 2° during OCF to reduce the occurrence of postoperative dysphagia.

Tomonaga-Luttinger Liquid in the Topological Edge Channel of Multilayer FeSe.

A two-dimensional topological insulator exhibits helical edge states topologically protected against single-particle backscattering. Such protection breaks down, however, when electron-electron interactions are significant or when edge reconstruction occurs, leading to a suppressed density of states (DOS) at the Fermi level that follows universal scaling with temperature and energy, characteristic of Tomonaga-Luttinger liquid (TLL). Here, we grow multilayer FeSe on SrTiO3 by molecular beam epitaxy and observe robust edge states at both the {100}Se and the {110}Se steps using scanning tunneling microscopy/spectroscopy. We determine the DOS follows a power law, resulting in the Luttinger parameter K of 0.26 ± 0.02 and 0.43 ± 0.07 for the {100}Se and {110}Se edges, respectively. The smaller K for the {100}Se edge also indicates strong correlations, attributed to ferromagnetic ordering likely present due to checkerboard antiferromagnetic fluctuations in FeSe. These results demonstrate TLL in FeSe helical edge channels, providing an exciting model system for novel topological excitations arising from superconductivity and interacting helical edge states.

Consequences and Mechanisms of Left Atrium Remodeling in Aging Rabbits.

To investigate the consequences and mechanisms of myocardium remodeling of aging left atrium, we analyzed the main cardiac electrophysiological parameters such as rest membrane potential, action potential amplitude, maximum rate of action potential increase (max dV/dt), action potential plateau, and 30, 50, and 90% action potential duration (APD30, APD50, and APD90, respectively), as well as the inducibility and duration of atrial arrhythmias in adult and aging rabbits. L-type calcium current was also recorded. The collagen content in the myocardium and ultrastructure of left atrial cells were also studied. Significant changes were detected in the electrophysiological parameters and structure in aged left atrium, which can contribute to atrial susceptibility to arrhythmia in aged rabbits.

Atomically thin half-van der Waals metals enabled by confinement heteroepitaxy.

Atomically thin two-dimensional (2D) metals may be key ingredients in next-generation quantum and optoelectronic devices. However, 2D metals must be stabilized against environmental degradation and integrated into heterostructure devices at the wafer scale. The high-energy interface between silicon carbide and epitaxial graphene provides an intriguing framework for stabilizing a diverse range of 2D metals. Here we demonstrate large-area, environmentally stable, single-crystal 2D gallium, indium and tin that are stabilized at the interface of epitaxial graphene and silicon carbide. The 2D metals are covalently bonded to SiC below but present a non-bonded interface to the graphene overlayer; that is, they are 'half van der Waals' metals with strong internal gradients in bonding character. These non-centrosymmetric 2D metals offer compelling opportunities for superconducting devices, topological phenomena and advanced optoelectronic properties. For example, the reported 2D Ga is a superconductor that combines six strongly coupled Ga-derived electron pockets with a large nearly free-electron Fermi surface that closely approaches the Dirac points of the graphene overlayer.

IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma.

BACKGROUND: Hepatitis B virus (HBV) has a crucial role in the progression of hepatocellular carcinoma (HCC). Tumour cells must develop anoikis resistance in order to survive before metastasis. This study aimed to investigate the mechanism of IQGAP1 in HBV-mediated anoikis evasion and metastasis in HCC cells. METHODS: IQGAP1 expression was detected by immunohistochemistry, real-time PCR and immunoblot analysis. Lentiviral-mediated stable upregulation or knockdown of IGAQP1, immunoprecipitation, etc. were used in function and mechanism study. RESULTS: IQGAP1 was markedly upregulated in HBV-positive compared with HBV-negative HCC cells and tissues. IQGAP1 was positively correlated to poor prognosis of HBV-associated HCC patients. IQGAP1 overexpression significantly enhanced the anchorage-independent growth and metastasis, whereas IQGAP1-deficient HCC cells are more sensitive to anoikis. Mechanistically, we found that HBV-induced ROS enhanced the association of IQGAP1 and Rac1 that activated Rac1, leading to phosphorylation of Src/FAK pathway. Antioxidants efficiently inhibited IQGAP1-mediated anoikis resistance and metastasis. CONCLUSIONS: Our study indicated an important mechanism by which upregulated IQGAP1 by HBV promoted anoikis resistance, migration and invasion of HCC cells through Rac1-dependent ROS accumulation and activation of Src/FAK signalling, suggesting IQGAP1 as a prognostic indicator and a novel therapeutic target in HCC patients with HBV infection.