YTHDF2 protein stabilization by the deubiquitinase OTUB1 promotes prostate cancer cell proliferation via PRSS8 mRNA degradation.

Prostate cancer is a leading cause of cancer-related mortality in males. Dysregulation of RNA adenine N-6 methylation (m6A) contributes to cancer malignancy. m6A on mRNA may affect mRNA splicing, turnover, transportation, and translation. m6A exerts these effects, at least partly, through dedicated m6A reader proteins, including YTH domain-containing family protein 2 (YTHDF2). YTHDF2 is necessary for development while its dysregulation is seen in various cancers, including prostate cancer. However, the mechanism underlying the dysregulation and function of YTHDF2 in cancer remains elusive. Here, we find that the deubiquitinase OUT domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) increases YTHDF2 protein stability by inhibiting its ubiquitination. With in vivo and in vitro ubiquitination assays, OTUB1 is shown to block ubiquitin transfer to YTHDF2 independent of its deubiquitinase activity. Furthermore, analysis of functional transcriptomic data and m6A-sequencing data identifies PRSS8 as a potential tumor suppressor gene. OTUB1 and YTHDF2 decrease mRNA and protein levels of PRSS8, which is a trypsin-like serine protease. Mechanistically, YTHDF2 binds PRSS8 mRNA and promotes its degradation in an m6A-dependent manner. Further functional study on cellular and mouse models reveals PRSS8 is a critical downstream effector of the OTUB1-YTHDF2 axis in prostate cancer. We find in prostate cancer cells, PRSS8 decreases nuclear ß-catenin level through E-cadherin, which is independent of its protease activity. Collectively, our study uncovers a key regulator of YTHDF2 protein stability and establishes a functional OTUB1-YTHDF2-PRSS8 axis in prostate cancer.

TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.

Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.

The P53-P21-RB1 pathway promotes BRD4 degradation in liver cancer through USP1.

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the pro-tumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer.

Rechargeable alkali metal-chlorine batteries: advances, challenges, and future perspectives.

The emergence of Li-SOCl2 batteries in the 1970s as a high-energy-density battery system sparked considerable interest among researchers. However, limitations in the primary cell characteristics have restricted their potential for widespread adoption in today's sustainable society. Encouragingly, recent developments in alkali/alkaline-earth metal-Cl2 (AM-Cl2) batteries have shown impressive reversibility with high specific capacity and cycle performance, revitalizing the potential of SOCl2 batteries and becoming a promising technology surpassing current lithium-ion batteries. In this review, the emerging AM-Cl2 batteries are comprehensively summarized for the first time. The development history and advantages of Li-SOCl2 batteries are traced, followed by the critical working mechanisms for achieving high rechargeability. The design concepts of electrodes and electrolytes for AM-Cl2 batteries as well as key characterization techniques are also demonstrated. Furthermore, the current challenges and corresponding strategies, as well as future directions regarding the battery are systematically discussed. This review aims to deepen the understanding of the state-of-the-art AM-Cl2 battery technology and accelerate the development of practical AM-Cl2 batteries for next-generation high-energy storage systems.

TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy.

Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss of function of TRIM28, a multifunction protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28-TFE3-KDM6A signal axis, which plays a critical role in kidney cancer cell autophagy and proliferation.

TiO2 Nanotube Arrays Inside Ultrafine Ti Tubes with an Aspect Ratio of 2500 for Sensing Needles: The Bubble Effect in a Confined Space.

Capillary metal tubes have attracted considerable interest for flexible electronics, portable devices, trace sampling, and detection. Tailoring the microstructure and wettability inside the capillary tubes is of paramount importance, yet it presents great difficulty because of the spatial confinement. Here, the coupling effect is revealed between the fluidic and electric field induced by bubble motion in a confined space during anodic oxidation. By controlling the bubble regeneration and flow rate, uniform and superhydrophilic TiO2 nanotube arrays are developed throughout the inner surface of an ultrafine Ti tube with a diameter of 0.4 mm and length of 1000 mm, equivalent to an aspect ratio of 2500 that is the largest value being ever reported. The inner surface of a capillary tube is further coated with a polytetrafluoroethylene layer and explored as a sensing needle for liquid detection in terms of concentration and species. This study provides an innovative approach to tailor the microstructure and wettability in a confined space for functional capillary tubes.

Superwetting Capillary Tubes: Surface Science under Confined Space.

Capillarity is a crucial and pervasive phenomenon in nature and has found important applications in wearable electronics, medical devices, and miniature energy systems. Capillary tubes are the transport vessels in which the surface wettability plays an essential role in efficient and accurate liquid delivery. However, it remains a challenging issue to tailor and measure the surface wettability inside the tubes in view of the confined space. Herein, recent progress on the surface science under confined space is discussed, with a particular focus on surface modification, wettability evaluation, and advanced applications of the superwetting capillary tubes. This Perspective aims to highlight the emerging opportunities in surface science with spatial confinement toward flexible and portable devices.

E3-Independent Constitutive Monoubiquitination Complements Histone Methyltransferase Activity of SETDB1.

Ubiquitination typically occurs through the sequential action of three enzymes catalyzing ubiquitin activation (E1), conjugation (E2), and ligation (E3) and regulates diverse eukaryotic cellular processes. Although monoubiquitination commonly confers nondegradative activities, mechanisms underlying its temporal and spatial regulation and functional plasticity still remain largely unknown. Here we demonstrate that SETDB1, a major histone H3K9 methyltransferase is monoubiquitinated at the evolutionarily conserved lysine-867 in its SET-Insertion domain. This ubiquitination is directly catalyzed by UBE2E family of E2 enzymes in an E3-independent manner while the conjugated-ubiquitin (Ub) is protected from active deubiquitination. The resulting constitutive lysine-867 monoubiquitination is essential for SETDB1's enzymatic activity and endogenous retrovirus silencing in murine embryonic stem cells. Furthermore, the canonical hydrophobic patch on the conjugated-Ub is critical for Ub protection and function. Together, our findings highlight an E3-independent mechanism for monoubiquitination and reveal mechanistic details of SETDB1's enzymatic activity and the functional significance of its SET-Insertion.

[Effect of Spatholobi Caulis extract from ethyl acetate on immune killing function of NK cells].

This study aims to investigate the regulatory effect of the Spatholobi Caulis extract from ethyl acetate(SEA) on natural killer(NK) cells under physiological conditions and elucidate the underlying mechanism. The C57BL/6 mice were randomized into NC and SEA groups, and NK-92 cells were respectively treated with 0, 25, 50, and 100 µg·mL~(-1) SEA. The body weight and immune organ index of the mice were compared between groups. The lactate dehydrogenase(LDH) assay was employed to examine the cytotoxicity of NK-92 cells treated with SEA and the killing activity of mouse NK cells against YAC-1 cells. The cell-counting kit-8(CCK-8) was used to examine the impact of SEA on the proliferation of NK-92 cells. Flow cytometry was employed to measure the number of NK cells in the peripheral blood as well as the expression levels of natural killer group 2 member A(NKG2A) and natural killer group 2 member D(NKG2D). The enzyme-linked immunosorbent assay(ELISA) was performed to determine the interferon(IFN)-γ secretion in the serum. Semi-quantitative PCR was conducted to determine the mRNA levels of NKG2A, NKG2D, and IFN-γ in spleen cells. Western blot was employed to investigate the involvement of phosphoinositide 3-kinase(PI3K)/extracellular regulated protein kinase 1(ERK1) signaling pathway. The results showed that SEA exhibited no adverse effects on the body, while significantly enhance the number of NK cells and augment the cytotoxicity of NK-92 cells against YAC-1 cells. Moreover, it suppressed the expression of NKG2A, enhanced the expression of NKG2D, promoted IFN-γ secretion, and upregulated the protein levels of PI3K and ERK. The findings suggest that SEA has the potential to enhance the immune recognition and effector function of NK cells by increasing the cell number, modulating the expression of functional receptors, and promoting IFN-γ secretion via the PI3K/ERK signaling pathway.

Organocatalytic Lithium Chloride Oxidation by Covalent Organic Frameworks for Rechargeable Lithium-Chlorine Batteries.

Rechargeable Li-Cl2 battery is a promising high energy density battery system. However, reasonable cycle life could only be achieved under low specific capacities due to the sluggish oxidation of LiCl to Cl2 . Herein, we propose an amine-functionalized covalent organic framework (COF) with catalytic activity, namely COF-NH2 , that significantly decreases the oxidation barrier of LiCl and accelerates the oxidation kinetics of LiCl in Li-Cl2 cell. The resulting Li-Cl2 cell using COF-NH2 (Li-Cl2 @COF-NH2 ) simultaneously exhibits low overpotential, ultrahigh discharge capacity up to 3500 mAh/g and a promoted utilization ratio of deposited LiCl at the first cycle (UR-LiCl) of 81.4 %, which is one of the highest reported values to date. Furthermore, the Li-Cl2 @COF-NH2 cell could be stably cycled for over 200 cycles when operating at a capacity of 2000 mAh/g at -20 °C with a Coulombic efficiency (CE) of ≈100 % and a discharge plateau of 3.5 V. Our superior Li-Cl2 batteries enabled by organocatalyst enlighten an arena towards high-energy storage applications.

Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) has a dismal prognosis. KDM1A (lysine demethylase 1A), overexpressed in multiple cancer types, is a lysine demethylase that targets both histone and nonhistone proteins. However, it is unclear how KDM1A expression affects HCC etiology. Here, we show that KDM1A can interact with and demethylate FKBP8 (FKBP prolyl isomerase 8), a cytoplasmic protein that regulates cell survival through the antiapoptotic protein BCL2 (B-cell lymphoma-2). We show that demethylation of FKBP8 enhances its ability to stabilize BCL2. Consistently, we observed positive correlation between KDM1A and BCL2 protein levels in liver cancer patients. Functionally, we reveal that FKBP8 demethylation by KDM1A is critical for liver cancer cell growth in vitro and in vivo. We went on to explore the mechanisms that might regulate KDM1A cytoplasmic localization. We found that the cytoplasmic localization and protein stability of KDM1A were promoted by acetylation at lysine-117 by the acetyl transferase KAT8 (lysine acetyltransferase 8). In agreement with this, we show that KDM1A-K117 (lysine 117) acetylation promotes demethylation of FKBP8 and level of BCL2. Finally, it has been shown that the efficacy of sorafenib, a first-line treatment for advanced HCC, is limited by clinical resistance. We show that KDM1A and BCL2 protein levels are increased during acquired sorafenib resistance, whereas inhibiting KDM1A can antagonize sorafenib resistance. Collectively, these results define a functional KDM1A-FKBP8-BCL2 axis in HCC.

Enrichment of Chlorine in Porous Organic Nanocages for High-Performance Rechargeable Lithium-Chlorine Batteries.

Rechargeable Li-Cl2 batteries are recognized as promising candidates for energy storage due to their ultrahigh energy densities and superior safety features. However, Li-Cl2 batteries suffer from a short cycle life and low Coulombic efficiency (CE) at a high specific cycling capacity due to a sluggish and insufficient Cl2 supply during the redox reaction. To achieve Li-Cl2 batteries with high discharge capacity and CE, herein, we propose and design an imine-functionalized porous organic nanocage (POC) to enrich Cl2 molecules. Based on density functional theory (DFT) calculations, the imine group sites in host cages strongly interact with Cl2 molecules, facilitating the rapid capture of Cl2. As a result, the output capacity of the Li-Cl2 battery using POC (Li-Cl2@POC) is significantly boosted, achieving an ultrahigh discharge capacity of 4000 mAh/g at ∼100% CE. Benefiting from the designed POC, the highest utilization ratio of deposited LiCl at the first cycle in the Li-Cl2@POC battery reaches as high as 85%, superior to all reported values. The Li-Cl2@POC battery exhibits excellent electrochemical performance even at low temperatures, delivering stable cycling over 200 cycles under a capacity of 2000 mAh/g at -20 °C with a voltage plateau of 3.5 V and an average CE of 99.7%. We also demonstrate that the Li-Cl2@POC cells can be assembled and well-operated in a dry room, showing advantages for mass production. Our designed POC promotes the practical deployment of rechargeable Li-Cl2 batteries.

[Research status and prospect of remyelination in multiple sclerosis based on "inflammation-tissue" homeostatic coupling].

Multiple sclerosis(MS) shows the pathological characteristics of "inflammatory injury of white matter" and "myelin repair disability" in the central nervous system(CNS). It is very essential for MS treatment and reduction of disease burden to strengthen repair, improve function, and reduce disability. Accordingly, different from the simple immunosuppression, we believe that key to strengthening remyelination and maintaining the "damage-repair" homeostasis of tissue is to change the current one-way immunosuppression strategy and achieve the "moderate pro-inflammation-effective inflammation removal" homeostasis. Traditional Chinese medicine shows huge potential in this strategy. Through literature research, this study summarized the research on remyelination, discussed the "mode-rate pro-inflammation-effective inflammation removal" homeostasis and the "damage-repair" homeostasis based on microglia, and summed up the key links in remyelination in MS. This review is expected to lay a theoretical basis for improving the function of MS patients and guide the application of traditional Chinese medicine.

Highly Stable Vanadium Redox-Flow Battery Assisted by Redox-Mediated Catalysis.

With good operation flexibility and scalability, vanadium redox-flow batteries (VRBs) stand out from various electrochemical energy storage (EES) technologies. However, traditional electrodes in VRBs, such as carbon and graphite felt with low electrochemical activities, impede the interfacial charge transfer processes and generate considerable overpotential loss, which significantly decrease the energy and voltage efficiencies of VRBs. Herein, by using a facile electrodeposition technique, Prussian blue/carbon felt (PB/CF) composite electrodes with high electrochemical activity for VRBs are successfully fabricated. The PB/CF electrode exhibits excellent electrochemical activity toward VO2+ /VO2 + redox couple in VRB with an average cell voltage efficiency (VE) of 90% and an energy efficiency (EE) of 88% at 100 mA cm-2 . In addition, due to the uniformly distributed PB particles that are strongly bound to the surface of carbon fibers in CF, VRBs with the PB/CF electrodes show much better long-term stabilities compared with the pristine CF-based battery due to the redox-mediated catalysis. A VRB stack consisting of three single cells (16 cm2 ) is also constructed to assess the reliability of the redox-mediated PB/CF electrodes for large-scale application. The facile technique for the high-performance electrode with redox-mediated reaction is expected to shed new light on commercial electrode design for VRBs.

Initial stage of MBE growth of MoSe2 monolayer.

An atomically thin MoSe2 layer has been synthesized on mica using molecular beam epitaxy (MBE). The polymorphous of the MoSe2 layer depends on the coverage and the growth temperature. At low coverages and low growth temperature, 1T-MoSe2 forms in addition to a comparable quantity of 2H-MoSe2. The metastable 1T-MoSe2 transfers gradually to the stable 2H-MoSe2 before the completion of the first monolayer. The current result sheds some light on the complexity of the nucleation and growth of transition metal dichalcogenide (TMDC) monolayers and implies a possible route for a phase selective synthesis using MBE.

Room-temperature up-conversion random lasing from CsPbBr3 quantum dots with TiO2 nanotubes.

We report successful room-temperature up-conversion random lasing by distributing CsPbBr3 quantum dots (QDs) uniformly into TiO2 nanotubes (NTs). In order to overcome the difficulty in purifying the QDs, TiO2 NTs were designed to collect QDs and enhance the optical multiple scattering effect. A threshold of 9.54 mJ/cm2 and narrow full width at half-maximum of 0.49 nm with a relatively high quality factor of 1089 were successfully observed. These results indicate that CsPbBr3QDs/TiO2 NTs can be high-performance up-conversion lasers for practical applications, especially when the phase matching required by conventional approaches cannot be fulfilled.

Reversibly tuning the surface state of Ag via the assistance of photocatalysis in Ag/BiOCl.

Silver (Ag) nanoparticles can be spontaneously oxidized and present in different oxidized surface phases. The impact of oxidation induced photo absorption property and related photocatalytic activity are still unclear in Ag-decorated semiconductor photocatalysts. Herein, Ag-decorated BiOCl with the metallic Ag0 to oxidized Ag+ were employed to investigate the effect of surface state of Ag on relative photocatalyst properties. A redshift of localized surface plasmon resonance was observed as the Ag0 oxidized to Ag+ and a reversible manipulation was realized in UV light-driven photocatalysis. It is found that the Ag0/BiOCl presents higher photocatalytic activity than Ag+/BiOCl, but this difference is gradually decreasing under UV light irradiation compared with visible light irradiation. A controlled experiment suggests that the reduction of Ag+ under UV light reduced the difference between Ag0/BiOCl and Ag+/BiOCl. The possible mechanism for electron transport and the conversion between Ag+ and Ag0 via the assistance of the photoelectric effect from BiOCl has been elucidated. This photocatalytic reaction assisted reversible tuning the surface state of Ag/BiOCl will open up the possibility of rationally designing Ag-decorated semiconductors for light harvesting.

[Efficacy and mechanism of Lianhua Qingwen Capsules(LHQW) on chemotaxis of macrophages in acute lung injury (ALI) animal model].

This paper was mainly to discuss the potential role and mechanism of Lianhua Qingwen Capsules(LHQW) in inhibiting pathological inflammation in the model of acute lung injury caused by bacterial infection. For in vitro study, the mRNA expression of MCP-1 in RAW264.7 cells and THP-1 cells, the content of MCP-1 in cell supernatant, as well as the effect of LHQW on chemotaxis of macrophages were detected. For in vivo study, mice were randomly divided into 7 groups, including normal group, model group(LPS 5 mg·kg~(-1)), LHQW 300, 600 and 1 200 mg·kg~(-1)(low, middle and high dose) groups, dexamethasone 5 mg·kg~(-1) group and penicillin-streptomycin group. Then, the anal temperature was detected two hours later. Dry weight and wet weight of lung tissues in mice were determined; TNF-α and MCP-1 levels in alveolar lavage fluid and MCP-1 in serum were detected. In addition, the infiltration of alveolar macrophages was also observed and the infiltration count of alveolar macrophages was measured by CCK-8 method. HE staining was also used to observe the inflammatory infiltration of lung tissues in mice. Both of the in vitro and in vivo data consistently have confirmed that: by down-regulating the expression of MCP-1, LHWQ could efficiently decrease the chemotaxis of monocytes toward the pulmonary infection foci, thus blocking the disease development in ALI animal model.

[Research advancement in natural anti-cancer product].

Human health has been severely threatened by malignant tumors continuously.Rational and effective drug use provides an effective means for the treatment of malignant tumors,and is expected to become an important way to solve the problem of tumor treatment in the future.In recent years,with the escalation of new cancer theories and the emergence of clinical drug resistance,innovative research and development of anti-cancer drugs has always been a hot spot and focus in cancer research.Among them,the discovery of novel anti-cancer drugs from natural compound is of top priority due to its strong anti-cancer efficacy and the abundant drug resources.Therefore,it is imperative to systematically summarize the cutting-edge advancements of the natural products and their potential pharmacological mechanisms according to the characteristics of tumor progression,and put forward the new directions and trends for further development of anti-cancer natural products in the future.Specifically,the research advancements on anti-cancer effect of natural products were reviewed,focusing on both the traditional and innovative application.We hope this review could bring the light on the research path of the natural anti-cancer products clearly and comprehensively,and also provide inspirations for innovative,safer and more effective anti-cancer drug development and exploration.

Evolution of Oxyhalide Crystals under Electron Beam Irradiation: An in Situ Method To Understand the Origin of Structural Instability.

The oxyhalides have attracted growing interest because of their excellent photocatalytic performance. However, their structural instability hampers further development toward practical applications, a major challenge of current concerns. It is appealing to figure out the origin of structural instability and guide the design of advanced oxyhalide crystals for efficient photocatalysis. In this study, the decomposition of BiOCl crystals, a typical oxyhalide, is triggered by electron beam irradiation and investigated in situ by transmission electron microscopy. The results indicate that the instability originates from the unique layered structure of BiOCl crystals; the interlayer van der Waals bonds are easily broken under electron beam irradiation via the assistance of hydroxyl groups. This facilitates the formation of O/Cl-deficient BiO1- xCl1- y species, Bi metal nanoparticles, and nanobubbles (gaseous substance) that are confined between the adjacent layers. Surface reconstruction would be an effective way to stabilize the oxyhalide crystals.