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Aluthough High-entropy oxides have the diversity of elements composition and structures, these compounds always maintain a single-phase crystal structure and show excellent physical and chemical properties. Inspired by this, we have synthesized high-entropy pyrochlore oxide (LaY) (Zr0·5Ti0·5Ce0.5Hf0.5)O7 with the sol-gel method, which is denoted as HEPO. To begin with, the HEPO samples calcinated at various temperatures were investigated by using a series of technique, such as TG, FT-IR, XRD and electrochemical workstation and the results indicated that 800 °C was the best processing temperature for HEPO. Besides, a super-concentrated sugar-based solution was used as the electrolyte for the HEPO-800 electrodes and increased the electrochemical window to 3V. Moreover, the HEPO-800 electrode also showed the excellent capacitance of 703.3F·g−1 at a current density of 1A·g−1. Consequently, the symmetrical HEPO-800//HEPO-800 supercapacitor device presents a high capacitance of 128.5F·g−1 at a current density of 3A·g−1. In addition, this device exhibits a high energy density of 160.6 Wh·kg−1 at a corresponding power density of 4500W·kg−1 with outstanding cycling life.

Purpose Radiation-induced gastrointestinal syndrome (RIGS) is currently the main cause of death for people exposed to a high dose of irradiation during nuclear incidents, and there is currently no approved effective therapy. Here, we found that CBP/P300 inhibitors, with high efficacy and low toxicity, might be promising radiation mitigators that can cure RIGS. Methods and Materials Ex vivo 3D organoid cultures derived from mouse jejunum and human ileum and colon were used to examine the radio-mitigative effects of CBP/P300 inhibitors. The radio-mitigative effect was evaluated by quantifying the survival rate and size of organoids after radiation. SGC-CBP30 (50 mg/kg body weight), an inhibitor of CBP/P300, was intraperitoneally injected into C57B/6J mice 24 hours after subtotal-body irradiation or whole-body irradiation. The regenerated crypts and animal survival were determined by microcolony assay and the Kaplan-Meier method, respectively. Lgr5-lacZ mice were used to evaluate the survival of intestinal stem cells after treatments. Results We found that CBP/P300 inhibitors were effective mitigators that could be used to treat RIGS. CBP/P300 inhibition promoted the regeneration of intestinal organoids in vitro and of crypts in vivo. Remarkably, the administration of CBP/P300 inhibitors to mice 24 hours after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, resulting in improved mouse survival. Moreover, our data show that CBP/P300 inhibitors rescued irradiated mice from RIGS by delaying intestinal epithelial cell cycle progression after radiation. Conclusions These data demonstrate that CBP/P300 inhibitors are effective medical countermeasures to mitigate gastrointestinal toxicity from radiation.

Since the previous research confirms the lanthanum titanate (LTO) flexible self-supporting film can be considered as excellent energy storage material, we intend to maximize the performance of LTO to provide higher energy density for practical application. In order to achieve this goal, the Sr element was a choice to substitute with La for increasing the amount of oxygen vacancies in this study, and mechanical flexibility of the film was also maximally preserved. For determining the most appropriate amount of Sr doping, a serious of Sr-doped LTO films marked as LTO-x (0.1 ≤ x ≤ 0.5) were synthesized by electrospinning combined with calcination method. After analyzed by the XRD, SEM, TEM, XPS and electrochemical work station, the LTO-0.3 sample shows the best properties with a maximum capacitance of 1.8 F·cm−2 at 2 mA·cm−2. As a result of that, we fabricated the flexible all-solid-state supercapacitor device with two LTO-0.3 electrodes and PVA-Na2SO4 gel. This LTO-0.3//LTO-0.3 device exhibits excellent cycling stability, outstanding flexibility and high energy density of 209.4 μWh·cm−2 with the corresponding power density of 2.1 mW·cm−2.

Summary Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury, although the repair mechanisms are unclear. Here, we found that Bach2 deficiency promotes intestinal epithelial cell proliferation during homeostasis. Moreover, genetic inactivation of Bach2 in mouse intestinal epithelium facilitated crypt regeneration after irradiation, resulting in a reduction in mortality. RNA-sequencing analysis of isolated crypts revealed that Bach2 deficiency altered the expression of numerous genes, including those regulating double-strand break repair. Mechanistic characterizations indicated that Bach2 deletion facilitated DNA repair in intestinal crypt cells, as evidenced by faster resolution of γ-H2AX and 53BP1 foci in Bach2−/− crypt cells, compared with Bach2+/+ control. Together, our studies highlight that Bach2 deficiency promotes intestinal regeneration by accelerating DNA repair in intestinal stem cells after radiation damage., Graphical Abstract, Highlights • Bach2 deficiency facilitates intestinal recovery after irradiation damage • Bach2 deficiency promotes the regeneration of crypt intestinal stem cells (ISCs) • Bach2 deletion accelerates DNA repair in ISCs, Radiation causes intestinal injury, as occurs in abdominal and pelvic tumor radiotherapy. Intestinal stem cells (ISCs) are critical for epithelial regeneration. In this article, Hua and colleagues show that Bach2 deficiency promotes intestinal epithelial regeneration by accelerating DNA repair in ISCs, resulting in a reduction in mortality during radiation-induced intestine injury.

Flexible all-solid-state supercapacitors have drawn more attention owing to the rapid growth of wearable electronic equipments. Herein, we have succeeded in synthesizing a series of Y-doped lanthanum titanate flexible self-supporting films (LSF-x, 0.1 ≤ x ≤ 0.5) and investigating the change of microstructures, morphological characteristics, and lattice structures of these films affected by different Y-doping contents. To further determine the optimum Y-doping content, we have explored the electrochemical properties of working electrodes prepared by LSF-x (0.1 ≤ x ≤ 0.5) samples as the main active material. As the LSF-0.2 electrode has the best areal capacitance of 1.3 F·cm-2 at 2 mA·cm-2, we use the LSF-0.2 electrodes and PVA-Na2SO4 gel to fabricate a flexible all-solid-state supercapacitor device. This device has a high areal capacitance of 255.9 mF·cm-2 at a current density of 2 mA·cm-2 with a high cell voltage of 2.1 V, while the corresponding energy density is 156.8 μWh·cm-2 with a power density of 2.1 mW·cm-2. Moreover, it also shows a long cycling life and outstanding flexibility. Therefore, the LSF-0.2 sample can be used as an excellent energy-storage material for a wearable electronic device.

Estrogen is very important to the differentiation of B lymphocytes; B lymphopoiesis induced by OVX was supposedly involved in osteoporosis. But the effects of B lymphocytes on the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) are not clear. In this study, we detected bone quality and bone loss in a trabecular bone by electronic universal material testing machine and microcomputed tomography (micro-CT) in OVX and splenectomized-ovariectomy (SPX-OVX) rats. Additionally, changes in lymphocytes (B lymphocyte, CD4+ and CD8+ T lymphocytes, and macrophages) in the bone marrow were analyzed by flow cytometry. The osteogenesis of BMSCs cocultured with normal and LPS-pretreated B lymphocytes was detected by BCIP/NBT and Alizarin red S staining. Measurement of the Notch2, Notch4, Hey1, Hey2, Hes1, and runt-related transcription factor 2 (Runx2) expression in BMSCs cocultured with B lymphocytes was done using real-time PCR. The effects of dexamethasone and DAPT (inhibitor of Notch signaling) on osteogenesis of BMSCs were detected by BCIP/NBT, Alizarin red S staining, and real-time PCR. Osteoporosis happened in OVX rats, more serious in SPX-OVX rats, B lymphocytes increased in OVX rats, and sharply higher in SPX-OVX rats. Osteoporosis did not happen in SPX rats which is still companied with a high increase of B lymphocytes. LPS-pretreated B lymphocytes suppressed the osteogenesis of BMSCs, but the normal B lymphocytes could not. The LPS-pretreated B lymphocytes upregulated the expression of Notch4, Hes1, and Hey2 and downregulated the expression of Runx2 in BMSCs. Dexamethasone and DAPT could downregulate the high expression of Notch4, Hes1, Hey2 and upregulate the low expression of Runx2 in BMSCs which cocultured with LPS treated B lymphocytes, the inhibited ALP and Alizarin red staining in BMSCs which cocultured with LPS treated B lymphocytes also partly restored.

e15598 Background: 5-FU-based regimens are the mainstay treatment for colorectal cancer. However, the limited response rate to 5-FU-based regimens hampered the increase in the treatment efficacy of locally advanced rectal cancer. During the drug screening in the rectal cancer organoid biobank (n = 106), we found out that more than half of the organoids that were resistant to 5-FU monotherapy and sensitive to irinotecan maintained sensitive status to the treatment of 5-FU combined with irinotecan (combination-sensitive), while a quite proportion of them turn to become remarkably resistant to 5-FU plus irinotecan (combination-resistant). Some studies suggested the mechanism of 5-FU-based resistance was associated with the activation of some oncogenic pathways. However, the mechanism of the addition of 5-FU promoting the resistance to irinotecan is still unclear. Methods: To investigate the relationship between the combination-resistant organoids and corresponding patient responses, we collected patient clinical responses and survival outcomes. RNA sequencing and ATAC sequencing were performed to identify differential genes and their enrichment pathways. Moreover, small molecule inhibitors were used to try to reverse the resistance induced by 5-FU. Results: Twenty-one organoids showed sensitivity to irinotecan and resistance to 5-FU. Among them, 8 organoids (38.1%) were combination-resistant and 13 organoids (61.9%) showed sensitivity to combination treatment. Combination-resistant organoids corresponding patients had worse pathologic tumor regression grades (pTRGs) distribution (8/8, 100% had TRGs of 2-3 versus 100% had TRGs of 0-1 in combination-sensitive patients; p < 0.05) and disease-free survival (DFS) rates (HR:11.57, 95% IC:1.025-130.5; p = 0.0047) than patients whose organoids were combination-sensitive. Combination-resistant organoids had higher expression of Ki-67 and CD44 and reduced cleaved-caspase 3 in the combination treatment group and 5-FU group compared with the irinotecan group and control. Furthermore, we identified hedgehog pathway activation after adding 5-FU to irinotecan in combination-resistant organoids through RNA sequencing and ATAC sequencing. GANT-61, an inhibitor of the hedgehog pathway, increased sensitivity to the combination of 5-FU and irinotecan in combination-resistant organoids. Conclusions: We found that organoids which are sensitive to irinotecan turn to become resistant to 5-FU combined with irinotecan. Moreover, corresponding patients had worse responses and a lower DFS rate. The hedgehog pathway is activated in these organoids after the addition of 5-FU to irinotecan, and GANT-61 could reverse the resistance caused by 5-FU. However, more organoid-associated trials with large-scale patients are warranted to reverse the 5-FU-based resistance in the future.

Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic, phenotypic and behavioral trait of in vivo organs, which can be established from both pluripotent stem cells and adult stem cells. Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues, and organoids can also be genetically manipulated by CRISPR-Cas9 technology. Applications of organoids in basic research involve the modeling of human development and diseases, including genetic, infectious and malignant diseases. Importantly, accumulating evidence suggests that biobanks of patient-derived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine. In addition, organoids hold promise for regenerative medicine. In the present review, we discuss the applications of organoids in the basic and translational research.

High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.

Metformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water systems where this emerging micropollutant is inevitably transformed during chlorination process. Whether MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exist in drinking water remains unknown. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health is still uncharacterized. Here we reveal that MET and byproduct C are present in worldwide drinking water with the highest doses detected for MET and C as 1203.5 ng/L and 9.7 ng/L respectively. Under simulated chlorination conditions, we also demonstrate that both byproducts can be increasingly produced with increment of MET concentration, suggesting a hidden threat on the safety and sustainability of global water supply. Through systematic evaluations, we demonstrate that MET chlorination byproducts Y and C exhibit toxicities instead of genotoxicity to live worms and human HepG2 cells at millimolar doses. Moreover, both byproducts are harmful to mice and particularly Y at 250 ng/L destroys the mouse small intestine integrity. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective alternative solutions that may be in urgent demand globally for removing these byproducts from drinking water.

Metformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water sources where chlorination inevitably transforms MET into chlorination byproducts. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health remains largely unknown. Here we reveal that MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exhibit marked toxicity, even higher than that of the well-known poisonous arsenic, to live worms and human cells. Moreover, both byproducts are harmful to mice and Y at 250 ng/L destroys the mouse small intestine integrity. Strikingly, we detected MET and byproduct C in worldwide drinking water. Both byproducts are increasingly produced with more MET present during chlorination process. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective solutions that are in urgent demand globally for removing these byproducts from water.

With the rapid development of wearable electronics devices, there is increasing demand for the development of new flexible energy storage devices with high security, and this has become a hot research topic. Although flexible supercapacitors are considered to be high-performance energy-storage equipment because of their fast charging/discharging ability, long cycle life, good reliability, wide operating temperature range, and so on, there are still many drawbacks that need to be overcome. Herein, the La2 Zr2 O7 (LZO) thin film is synthesized as a new energy-storage material by using a facile electrospinning method and calcination at low temperature. In addition, the mechanism of producing the flexibility of this film is determined by TG, IR, and XRD analyses. As previous studies have suggested that the charge storage of the LZO film can be attributed to the mechanism of oxygen intercalation, the Y element is doped into the LZO film to increase the concentration of oxygen vacancies. The changes in structural and electrochemical properties of La2 Yx Zr2-x O3 (0≤x≤0.5) nanofibers (LNF-x) with increasing Y content are studied carefully to obtain the best doping sample. The LNF-0.1 sample shows the highest areal capacitance of 605.3 mF cm-2 at 2 mA cm-2 , so a symmetrical flexible device is fabricated with LNF-0.1 electrodes. This device has a high energy density (76.7 μW h cm-2 at 2 mW cm-2 ), good cycling stability, and excellent mechanical flexibility. This study thus provides a new research trend for portable and wearable electronics.

Besides the DC faults, AC faults and faults in converter, the dynamic process of control system has its influence on commutation failure. As an important element in LCC-HVDC control system, PLL provides the reference phase of receiving end power system for valve control system. When there is a difference between the real phase of receiving end power system and the output from PLL, control system cannot adjust extinction angle accurately. In this paper, the function of PLL in HVDC control system and the characteristic of PLL’s tracking process are analysed. Then the influence of the phase error caused by PLL’s tracking process on the extinction angle is discussed. At last, a detailed LCC-HVDC model is used to prove the impact of PLL’s dynamic process on commutation failure and test the influence of PLL with different parameters on commutation failure.

Taste loss is one of the debilitating complications in radiation-induced oral mucositis (RIOM), as occurs in head and neck cancer patients undergoing radiotherapy. We report here a radio-mitigation effect of Sirtuin 1 (SIRT1) inhibitors in taste bud organoids and a mouse model of radiation-induced taste bud injury. The organoids, developed from circumvallate (CV) papilla, were irradiated with single dose of X-rays and inhibitors of SIRT1 or SIRT2 were added 24 h later. The survival was evaluated by measuring the number and size of regenerated organoids after irradiation (IR). Oral mucositis (OM) was induced by IR of the oral region of Lgr5-lacZ transgenic mice. The surviving Lgr5+ taste bud stem cells were identified after lacZ-staining and the mucosal ulceration on tongue dorsal surface was determined by histological methods. Results showed that SIRT1 inhibitors (nicotinamide, EX527, salermide and sirtinol), but not SIRT2 inhibitors, significantly improve taste bud organoid survival after IR. Remarkably, administration of nicotinamide (NAM), a recognized inhibitor of SIRT1 to mice 24 h after IR promotes the survival of Lgr5+ taste bud stem cells, resulting in alleviated tongue mucositis. In conclusion, SIRT1 inhibitors promote Lgr5+ taste bud stem cell survival and mitigate RIOM in mice. These observations have important implications for efforts to develop therapeutic strategies against taste dysfunction and mucosal ulceration in RIOM.

In this study, we succeed to synthesize the lanthanum titanate (LTO) flexible self-supporting film, and the flexible electrode based on the self-supporting film as active material were also provided to verify the electrochemical energy storage performance. The self-supporting film with both excellent flexibility and outstanding crystalline structure has been prepared by electrospinning combined with calcination method. To further optimize calcination processing, the microstructure, morphological characteristics and lattice structure of the self-supporting films can be explored by using SEM、TG、XRD and FT-IR. What’s more, the electrochemical properties of the flexible electrode prepared by LTO self-supporting film have been determined in various solutions. Comparing with the other aqueous, the highest areal capacitance of 806.2 mF cm−2 at 2 mA cm−2 was got form 1 M Na2SO4 aqueous electrolyte. Moreover, the symmetrical LTO//LTO flexible device fabricated by two LTO electrodes has a maximum areal capacitance of 149.2 mF cm−2 at a current density of 2 mA cm−2 with a high cell voltage of 2.1 V. As the result of that, this device exhibits a high energy density of 91.4 μWh·cm−2 at a low power density of 2.1 mW cm−2 with outstanding cycling life and excellent bending stability. Therefore, the LTO self-supporting film can be considered as a prospective material for wearable energy storage device.

Thymoma is the most common neoplasm of the anterosuperior mediastinum. Activation of the Wnt signaling pathway has a role in a variety of human cancers. The present objective was to examine c-Jun N-terminal kinase (JNK) mRNA and protein expression in thymoma cells undergoing apoptosis subsequent to downregulation of Wnt4. Wnt4 and JNK mRNA and protein expression was analyzed by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in 15 thymoma tissues and 6 thymus cyst tissues. Thymoma cells were cultured and transfected with shRNA plasmids targeting the Wnt4 gene. Wnt4 and JNK protein expression was detected by western blot analysis. Apoptosis was analyzed using Wright-Giemsa staining, Hoechst-33342/propidium iodine double staining and flow cytometry. The results showed that Wnt4 and JNK mRNA and protein expression were significantly increased in thymoma compared with normal thymus tissue. Subsequent to transfection, thymoma Wnt4 and JNK mRNA and protein expression were significantly decreased in shRNA-treated groups, with the strongest inhibition being 52.37%. Characteristic apoptotic morphological changes were observed and apoptosis increased. Overall, the present concluded that Wnt4 has an important role in thymoma development, which appears to be activated through a JNK mediated planar cell polarity-like pathway.