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Neuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.

Chen-jian Zhou,1 Hui-jun Wang,2 Chun-yan Zhou,2 Chao-fan Li,2 Ming-Jia Zhu,2 Xiang-jun Qiu2 1Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, 325027, People’s Republic of China; 2School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A method for the determination of selinexor by UPLC-MS/MS was established to study the effect of posaconazole on the pharmacokinetics of selinexor in rats.Methods: The experiment rats were divided into group A (0.5% CMC-Na) and group B (posaconazole, 20 mg/kg), 6 rats in each group. 30 minutes after administration of 0.5% CMC-Na or posaconazole, all the rats were given selinexor (8 mg/kg), and plasma samples were collected. The plasma samples underwent acetonitrile protein precipitation, and were separated by UPLC on an Acquity UPLC BEH C18 column with gradient elution. Acetonitrile and 0.1% formic acid were used as the mobile phases. The analyte detection was used a Xevo TQ-S triple quadrupole tandem mass spectrometer and multiple reaction monitoring (MRM) for analyte monitoring. We use acetonitrile for protein precipitation.Results: Selinexor had good linearity (1.0– 1000 ng/mL, r2= 0.996 2), and the accuracy and precision, recovery rate and matrix effects(ME) were also met the FDA approval guidelines. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 60.33%, 48.28% and 48.27%, and Tmax increased by 53.92%, CLz/F reduced by 32.08%.Conclusion: This bioanalysis method had been applied to the study of drug interactions in rats. It was found that posaconazole significantly increased the concentration of selinexor in rats. Therefore, when selinexor and posaconazole are combined, we should pay attention to the possible drug–drug interactions to reduce adverse reactions.Keywords: UPLC-MS/MS, selinexor, posaconazole, pharmacokinetics, DDIs, rats

The drug resistance caused due to the overuse of antibiotics has grown into an emerging threat. It is urgent to develop novel strategies to combat bacterial resistance. In this work, a quinine-based quaternized polymer with amphiphilicity (QMTA) was prepared by free-radical copolymerization of quinine and (2-methacryloyloxyethyl) trimethyl ammonium chloride (MTA). Biological activity assays revealed that the polymer sterilized the drug-resistant Gram-negative E. coli and non-resistant Gram-positive bacteria B. subtilis, exhibiting a MIC value of 2 μg mL−1 and a bactericidal rate of more than 95%. Most importantly, both E. coli and B. subtilis treated with the polymer didn't develop resistance even after their 16th passages. Also, the polymer has low toxicity at a dose of up to 128 μg mL−1. The mechanism studies through SEM and 3D-SIM images, fluorescence staining and membrane potential determination reveal that the positively charged QMTA initially concentrates on the surface of bacteria by electrostatic adsorption, changes the membrane potential, binds to the bacteria by its quinine chain, and destroys the membrane structure of the bacteria. This study provides a potential approach through the existing drug to develop new bactericidal reagent/polymer materials without resistance.

It is imperative to develop innovative and efficient antibacterial agents, on account of the mounting prevalence of complicated infections induced by multidrug-resistant bacteria. In this work, Chol-b-Lys nanoparticles (CL-NPs) with a diameter of 304.9 nm were prepared by ring-opening polymerization of the monomers cholesterol-ethylenediamine conjugate (Chol-NH2) and L-Lys-N-carboxyanhydrides (L-Lys-NCAs) and further self-assembly. The nanoparticles exhibited biological activity against the drug-resistant and non-resistant bacteria, including Gram-negative E. coli and Gram-positive B. subtilis, E. faecalis and S. aureus, with a MIC value in the range of 32–2 μg mL−1 and a more than 95% bactericidal rate. Importantly, both bacteria treated with CL-NPs didn’t develop resistance even after their 16th passages. Also, the CL-NPs have low toxicity (32 μg mL−1). The mechanism characterization shows that the positively charged nanoparticles are initially gathered on the surface of bacteria by electrostatic adsorption, changes the membrane permeability, inserts into the lipid bilayer bacteria membrane with cholesterol groups, destroys the membrane structure and results in bacterial apoptosis. This work provides a potential approach by mimicking the structure of cell membrane to develop new bactericidal reagent/nanoparticle materials which is hard to cause resistance.

Conductive coordination polymers (CPs) have potential in a wide range of applications because of their inherent structural and functional diversity. Three electrically conductive CPs (Cux C6 S6 , x=3, 4 or 5.5) derived from the same organic linker (benzenehexathiol) and metal node (copper(I)) were synthesized and studied. Cux C6 S6 materials are organic-inorganic hybrid copper sulfides comprising a π-π stacking structure and cooper sulfur networks. Charge-transport pathways within the network facilitate conductivity and offer control of the Fermi level through modulation of the oxidation level of the non-innocent redox-active ligand. Two Cux C6 S6 (x=4 or 5.5) CPs display high electrical conductivity and they feature a tunable structural topology and electronic structure. Cu4 C6 S6 and Cu5.5 C6 S6 act as degenerate semiconductors. Moreover, Cu5.5 C6 S6 is a p-type thermoelectric material with a ZT value of 0.12 at 390 K, which is a record-breaking performance for p-type CPs.

Monolithic all-perovskite tandem solar cells offer an avenue to increase power conversion efficiency beyond the limits of single-junction cells. It is an important priority to unite efficiency, uniformity and stability, yet this has proven challenging because of high trap density and ready oxidation in narrow-bandgap mixed lead–tin perovskite subcells. Here we report simultaneous enhancements in the efficiency, uniformity and stability of narrow-bandgap subcells using strongly reductive surface-anchoring zwitterionic molecules. The zwitterionic antioxidant inhibits Sn2+ oxidation and passivates defects at the grain surfaces in mixed lead–tin perovskite films, enabling an efficiency of 21.7% (certified 20.7%) for single-junction solar cells. We further obtain a certified efficiency of 24.2% in 1-cm2-area all-perovskite tandem cells and in-lab power conversion efficiencies of 25.6% and 21.4% for 0.049 cm2 and 12 cm2 devices, respectively. The encapsulated tandem devices retain 88% of their initial performance following 500 hours of operation at a device temperature of 54–60 °C under one-sun illumination in ambient conditions. Ensuring both stability and efficiency in mixed lead–tin perovskite solar cells is crucial to the development of all-perovskite tandems. Xiao et al. use an antioxidant zwitterionic molecule to suppress tin oxidation thus enabling large-area tandem cells with 24.2% efficiency and operational stability over 500 hours.

This study was to investigate the inotropic effect of atractylodin and its underlying mechanism. The cardiac pressure-volume loop (P-V loop), Langendroff-perfused isolated rat heart, patch-clamp, Ca2+ transient and western blot techniques were used. The results demonstrated that atractylodin (3 mg/kg, ip) remarkably increased the left ventricular stroke work, cardiac output, stroke volume, heart rate, ejection fraction, end-systolic pressure, peak rates of rise and fall of left ventricular pressures (+dP/dtmax , -dP/dtmax ), the slopes of end-systolic pressure-volume relationship (also named as end-systolic elastance, Ees) and reducing end-systolic volume and end-diastolic volume in the in vivo rat study. Also, atractylodin (3 mg/kg, ip) significantly decreased diastolic blood pressure and the arterial elastance (Ea) without significant systolic blood pressure change. In addition, atractylodin (0.1, 1, 10 µmol/L) also increased the isolated rat heart left ventricular developed pressure which is the difference between the systolic and diastolic pressure in non-pacing and pacing modes. Furthermore, JMV-2959 (1 μmol/L), a ghrelin receptor unbiased antagonist, blocked the increased left ventricular developed pressure of atractylodin in isolated rat hearts. Finally, atractylodin (5 µmol/L) increased the amplitude of Ca2+ transient by enhancing SERCA2a activity, the sarcoplasmic reticulum Ca2+ content and the phosphorylation of phospholamban at 16-serine. These results demonstrated that atractylodin had a positive inotropic effect by enhancing SERCA2a activity which might be mediated by acting ghrelin receptor in myocardium. In conclusion, atractylodin which had the positive inotropic effect and decreased diastolic blood pressure might serve as an agent for the treatment of heart failure in clinical settings.

It is growingly concerned about methamphetamine (MA)‐induced lung toxicity. IMP1 is identified as a key molecule for cell life processes, but the role of IMP1 in MA‐induced senescence remains unclear. The purpose of this study was to investigate whether chronic exposure to MA can cause autophagy and senescence of the lungs, whether there are interactions between Mammalian target of rapamycin (mTOR) and IMP1 and whether IMP1 is involved in pulmonary senescence promoted by mTOR‐autophagy. The rats were randomly divided into control group and MA group, following by H&E staining, immunohistochemistry staining and Western blot. The alveolar epithelial cells were proceeded by ß‐galactosidase staining, cell cycle detection, transfection and co‐immunoprecipitation. Long‐term exposure to MA led to the thickening of alveolar septum and more compact lungs. MA promoted the conversion of LC3‐I to LC3‐II and inhibited the activation of mTOR to induce autophagy. Bioinformatics and co‐immunoprecipitation results presented the interactions between IMP1 and mTOR. MA induced cell senescence by decreasing IMP1, up‐regulating p21 and p53, arresting cell cycle and increasing SA‐β‐gal. Overexpression of IMP1 reduced p21 and SA‐β‐gal to inhibit the senescence of alveolar epithelial cells. These results demonstrated that mTOR‐autophagy promotes pulmonary senescence through IMP1 in chronic toxicity of methamphetamine.

Background The prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients. Patients and methods The study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019. Results Fifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15-41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65-90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6-5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related. Conclusion Apatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

Slow kinetics of polysulfide conversion reactions lead to severe issues for lithium-sulfur (Li-S) batteries, for example, low rate capability, polysulfide migration, and low Coulombic efficiencies. These challenges hinder the practical applications of Li-S batteries. In this study, we proposed a rational strategy of tuning the d-band of catalysts to accelerate the conversion of polysulfides. Nitrogen vacancies were engineered in hexagonal Ni3N (space group P6322) to tune its d-band center, leading to the strong interaction between polysulfides and Ni3N. Because of the greater electron population in the lowest occupied molecular orbital of Li2S4, the terminal S-S bonds were weakened for breaking. Temperature-dependent experiments confirm that Ni3N0.85 demonstrates a much low activation energy, thereby accelerating the conversion of polysulfides. A Li-S cell using Ni3N0.85 can deliver a high initial discharge capacity of 1445.9 mAh g-1 (at 0.02 C) and low decay per cycle (0.039%). The Ni3N0.85 cell can also demonstrate an initial capacity of 1200.4 mAh g-1 for up to 100 cycles at a high loading of 5.2 mg cm-2. The high efficiency of rationally designed Ni3N0.85 demonstrates the effectiveness of the d-band tuning strategy to develop low-activation-energy catalysts and to promote the atomic understanding of polysulfide conversion in Li-S batteries.

Developing novel and visible-light drive photocatalysts is a hot topic, and bismuth oxychloride is one of the popular photocatalysts. In this paper, a series of bismuth oxychloride were synthesized by ultrasonic-hydrothermal method with different ultrasonic time. By simply changing the ultrasonic time, we can control the morphology, structure, stoichiometry and photoelectric performance of bismuth oxychloride. The possible mechanism for the formation of BixOyCl photocatalysts involved the ultrasonic destruction of chemical bonds and increase of oxygen vacancy concentration, and the influence of ultrasonic on the pH during preparation. The sample of ultrasonic 30 min (U-30) showed the best photocatalytic activity due to the suitable morphology, structure, photoelectric performance, the formation of the heterostructure, and the presence of oxygen vacancies. For the removal of Rhodamine B (/Ciprofloxacin), the reaction rate constant for U-30 was 10.4 (/3.6), 4.9 (/1.6), 6.9 (/4.8), and 9.3 (/2.3) times that of the U-0, U-10, U-20, and U-40, respectively. Photoluminescence spectra showed that the photogenerated electron-hole recombination rate decreased gradually with the ultrasonic time. Further, the possible mechanism of photocatalytic process was investigated. This research provides a green, economical and simple method to modify bismuth oxychloride.

Strategies for selectively imaging and delivering drugs to tumours typically leverage differentially upregulated surface molecules on cancer cells. Here, we show that intravenously injected carbon quantum dots, functionalized with multiple paired α-carboxyl and amino groups that bind to the large neutral amino acid transporter 1 (which is expressed in most tumours), selectively accumulate in human tumour xenografts in mice and in an orthotopic mouse model of human glioma. The functionalized quantum dots, which structurally mimic large amino acids and can be loaded with aromatic drugs through π–π stacking interactions, enabled—in the absence of detectable toxicity—near-infrared fluorescence and photoacoustic imaging of the tumours and a reduction in tumour burden after the targeted delivery of chemotherapeutics to the tumours. The versatility of functionalization and high tumour selectivity of the quantum dots make them broadly suitable for tumour-specific imaging and drug delivery., Intravenously injected functionalized carbon quantum dots that bind to the large neutral amino acid transporter 1 and that structurally mimic large amino acids selectively accumulate in human tumours in mice, facilitating targeted theranostics.

New findings What is the central question of this study? The therapeutic effect of ivabradine on patients with chronic heart failure and chronic stable angina pectoris is mediated through a reduction in heart rate: what are the haemodynamic characteristics and the mechanism of the inotropic effect? What is the main finding and its importance? Ivabradine has a positive inotropic effect and lowers the heart rate both in vivo and in vitro. These effects are likely mediated by ivabradine's significant increase of the fast component rate constant mediated by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and decrease of the slow component rate constant that is mediated by the Na+ /Ca2+ exchanger and sarcolemmal Ca2+ -ATPase during the Ca2+ transient decay phase. Abstract Ivabradine's therapeutic effect is mediated by a reduction of the heart rate; however, its haemodynamic characteristics and the mechanism of its inotropic effect are poorly understood. We aimed to investigate the positive inotropic effect of ivabradine and its underlying mechanism. The results demonstrated that ivabradine increased the positive inotropy of the rat heart in vivo by increasing the stroke work, cardiac output, stroke volume, end-diastolic volume, end-systolic pressure, ejection fraction, ±dP/dtmax , left ventricular end-systolic elastance and systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both non-paced and paced rat isolated heart. Ivabradine increased the Ca2+ transient amplitude and the reuptake rates of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), lowered the diastolic Ca2+ level and suppressed the combined extrusion rate of the Na+ /Ca2+ exchanger and the sarcolemmal Ca2+ -ATPase. In addition, ivabradine widened the action potential duration, hyperpolarized the resting membrane potential, increased sarcoplasmic reticulum Ca2+ content and reduced Ca2+ leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure.

A catalytic amount of FeCl3 combined with benzoyl trifluoroacetone (Hbtfa) (FeCl3/Hbtfa = 1/2) was used to catalyze sulfonylation/acylation of diols and polyols using diisopropylethylamine (DIPEA) or potassium carbonate (K2CO3) as a base. The catalytic system exhibited high catalytic activity, leading to excellent isolated yields of sulfonylation/acylation products with high regioselectivities. Mechanism studies indicated that FeCl3 initially formed [Fe(btfa)3] (btfa = benzoyl trifluoroacetonate) with twice the amount of Hbtfa under basic conditions in the solvent acetonitrile at room temperature. Then, Fe(btfa)3 and two hydroxyl groups of the substrates formed a five- or six-membered ring intermediate in the presence of the base. The subsequent reaction between the cyclic intermediate and a sulfonylation reagent led to the selective sulfonylation of the substrate. All key intermediates were captured in the high-resolution mass spectrometry assay, therefore demonstrating this mechanism for the first time.

In this study, we reported the regio/site-selective alkylation of substrates containing a cis-, 1,2- or 1,3-diol with FeCl3 as a key catalyst. A catalytic system consisting of FeCl3 (0.01–0.1 equiv.) and dipivaloylmethane (FeCl3/dipivaloylmethane = 1/2) was used to catalyze the alkylation in the presence of a base. The produced selectivities and isolated yields were similar to those obtained by methods using the same amount of FeL3 (L = acylacetone ligand) as the catalyst in most cases. The previously reported FeL3 catalysts for alkylation are not commercially available and have to be synthesized prior to use. In contrast, FeCl3 and dipivaloylmethane (Hdipm) are very common and inexpensive nontoxic reagents in the lab, thereby making the method much greener and easier to handle. Mechanism studies confirmed for the first time that FeCl3 initially reacts with two equivalents of Hdipm to form [Fe(dipm)3] in the presence of a base in acetonitrile, followed by the formation of a five or six-membered ring intermediate between [Fe(dipm)3] and two hydroxyl groups of the substrate. A subsequent reaction between the cyclic intermediate and the alkylating agent results in selective alkylation of the substrate.

Background: To study the protective effects of ganoderic acid A (GAA) on bleomycin (BLM)-induced pulmonary fibrosis. Methods: ICR mice were intratracheally instilled with BLM to induce pulmonary fibrosis on day 0. Then the mice were orally given GAA (25, 50 mg/kg) or dexamethasone (2 mg/kg). After treatment for 21 days, the mice were sacrificed. Wet dry weight (W/D) ratio of lung was used to detect pulmonary edema. Myeloperoxidase (MPO), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining was used to evaluate the pathological changes. The levels of transforming growth factor β (TGF-β), phosphorylated-smad3 (p-smad3), p-IκB, and p-nuclear factor-kappa B (NF-κB) in lung tissue were detected by western blot. Results: GAA treatment significantly improved MPO activity, W/D ratio, and lung histopathology. The protective effect of GAA may be related to downregulation of TNF-α, IL-1β, IL-6, MDA and upregulation of SOD. In addition, GAA significantly decreased the levels of TGF-β, p-smad3, p-IκB, and p-NF-κB, compared with those in BLM group. Conclusion: GAA has protective effect on BLM-induced lung injury, and TGF-β/Smad-3/NF-κB signaling pathway may play an important role in the pathogenesis of BLM-induced lung injury.

Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.

A series of Schiff base diphenylamines (SDs) have been successfully prepared in a one-pot synthesis process. These novel antioxidants exhibit higher antioxidative activities than the traditional an...

Development for new solid substrates for protein adsorption is important, given the massive potential in a number of fields including food production, medicine, biotechnology, and pharmaceutical pr...

BackgroundIbrutinib as a widely used Bruton’s tyrosine kinase inhibitor has shown outstanding value in clinical therapy for chronic lymphocytic leukemia (CLL). However, the bottleneck of ibrutinib resistance has caused widespread concerns, necessitating the exploration of novel targets. MethodsSingle-cell RNA sequencing (scRNA-seq) was used to characterize the heterogeneity of ibrutinib-sensitive (IBS) and -resistant (IBR) CLL patients and single-cell stemness estimation and metabolic pathway enrichment analysis were performed. Lectin galactoside-binding soluble 1 (LGALS1) and lymphocyte-activating gene 3 (LAG3) were screened as key factors by analyzing the RNA-sequencing data at bulk and single cell levels. Subsequently, pseudo-time trajectory analysis and gene set enrichment analysis were conducted. In addition, an IBR CLL cell line (MEC1-IR) was generated and RT-qPCR, western blotting, and immunofluorescence were performed to detect the expression of LGALS1 and LAG3. OTX008, a selective inhibitor of galectin-1 (Gal-1, encoded by LGALS1) was assessed in CLL cells and CCK8 and apoptotic assays were conducted for functional analysis.ResultsIBR CLL showed significantly different characteristics from IBS in terms of transcriptome expression and energy metabolism. LGALS1 and LAG3 were gradually upregulated in B cells along the evolution trajectory from IBS to IBR. Their expression was verified to be closely related to the prognosis of CLL, as well as sensitivity to ibrutinib. OTX008 could effectively suppress the proliferation and induce apoptosis of CLL cells, especially for those with ibrutinib resistance.ConclusionsAn LGALS1 and LAG3 gene panel is a promising indicator of ibrutinib resistance and a prognostic marker for CLL. OTX008 displays pronounced performance against CLL cells, especially with IBR, and might represent a novel therapeutic strategy for CLL.

Bacterial resistance caused by metallo-β-lactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O-aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase-1 (IMP-1) and New Delhi metallo-β-lactamase-1 (NDM-1), exhibiting an IC50 value in the range of 0.10-18.42 and 0.23-22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP-MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active-site of IMP-1, while the rapid dilution, thermal shift and MALDI-TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF-7 cells. This work provided a potent scaffold for the development of MβLs inhibitors.

Due to the coronavirus disease 2019 (COVID-19) pandemic, human activities and industrial productions were strictly restricted during January–March 2020 in China. Despite the fact that anthropogenic aerosol emissions largely decreased, haze events still occurred. Characterization of aerosol transport pathways and attribution of aerosol sources from specific regions are beneficial to air quality and pandemic control strategies. This study establishes source–receptor relationships in various regions covering all of China during the COVID-19 outbreak based on the Community Atmosphere Model version 5 with Explicit Aerosol Source Tagging (CAM5-EAST). Our analysis shows that PM2.5 burden over the North China Plain between 30 January and 19 February is mostly contributed by local emissions (40 %–66 %). For other regions in China, PM2.5 burden is largely contributed from nonlocal sources. During the most polluted days of the COVID-19 outbreak, local emissions within the North China Plain and eastern China contributed 66 % and 87 % to the increase in surface PM2.5 concentrations, respectively. This is associated with the anomalous mid-tropospheric high pressure at the location of the climatological East Asia trough and the consequently weakened winds in the lower troposphere, leading to the local aerosol accumulation. The emissions outside China, especially those from South Asia and Southeast Asia, contribute over 50 % to the increase in PM2.5 concentration in southwestern China through transboundary transport during the most polluted day. As the reduction in emissions in the near future is desirable, aerosols from long-range transport and unfavorable meteorological conditions are increasingly important to regional air quality and need to be taken into account in clean-air plans.

The clinical application of cisplatin was mainly limited by severe nephrotoxicity. Danshensu was the main pharmacological active diterpenoids which extracted from the roots of Salvia milthiorriza Bunge. This study is aimed to investigate the protective effects and potential mechanisms of Danshensu against cisplatin-induced nephrotoxicity. After fasting for 12 h, all mice groups except the control group were administered a single intraperitoneal injection of 25 mg/kg cisplatin. 1 h later, cisplatin (25 mg/kg) + Danshensu (15 mg/kg, 30 mg/kg, 60 mg/kg) groups were treated with corresponding doses of Danshensu once a day for 7 consecutive days. Blood urea nitrogen (BUN), creatinine, reactive oxygen species (ROS), superoxide dismutase (SOD), Glutathione peroxidase (GPx), Catalase (CAT) and malondialdehyde (MDA) were assayed in this study. The expression of inflammatory cytokines TNF-α, IL-6 and IL-1β were examined by ELISA. The results showed that Danshensu could improve kidney damage, attenuate serum BUN, creatinine, cytokines and oxidative stress markers. Further studies showed that Danshensu can induce Nrf2/HO-1 activation and inhibition of NF-κB pathway. In conclusion, Danshensu exerts the protective effects on cisplatin-induced nephrotoxicity, which may be related to the activation of Nrf2/HO-1 and inhibition of NF-ĸB pathway.

The conversion of solar energy into usable chemical fuels, such as hydrogen gas, via photo(electro)chemical water splitting is a promising approach for creating a carbon neutral energy ecosystem. The deployment of this technology industrially and at scale requires photoelectrodes that are highly active, cost-effective, and stable. To create these new photoelectrodes, transition metal-based electrocatalysts have been proposed as potential cocatalysts for improving the performance of water splitting catalysts. Layered double hydroxides (LDHs) are a class of clays with brucite like layers and intercalated anions. Transition metal-based LDHs are increasingly popular in the field of photo(electro)chemical water splitting due to their unique physicochemical properties. This article aims to review recent advances in transition metal-based LDHs for photo(electro)chemical water splitting. This article provides a brief overview of the research in a format approachable for the general scientific audience. Specifically, this review examines the following areas: (i) routes for synthesis of transition metal-based LDHs, (ii) recent developments in transition metal-based LDHs for photo(electro)chemical water splitting, and (iii) an overview of the structure-property relationships therein.

Doping has been widely used to control the charge carrier concentration in organic semiconductors. However, in conjugated polymers, n-doping is often limited by the tradeoff between doping efficiency and charge carrier mobilities, since dopants often randomly distribute within polymers, leading to significant structural and energetic disorder. Here, we screen a large number of polymer building block combinations and explore the possibility of designing n-type conjugated polymers with good tolerance to dopant-induced disorder. We show that a carefully designed conjugated polymer with a single dominant planar backbone conformation, high torsional barrier at each dihedral angle, and zigzag backbone curvature is highly dopable and can tolerate dopant-induced disorder. With these features, the designed diketopyrrolopyrrole (DPP)-based polymer can be efficiently n-doped and exhibit high n-type electrical conductivities over 120 S cm−1, much higher than the reference polymers with similar chemical structures. This work provides a polymer design concept for highly dopable and highly conductive polymeric semiconductors., In conjugated polymers, n-doping is often limited by the tradeoff between doping efficiency and charge carrier mobilities, since dopants often randomly distribute within polymers, leading to significant structural and energetic disorder. Here, the authors screen a large number of polymer building block combinations and explore the possibility of designing n-type conjugated polymers with good tolerance to dopant-induced disorder.

Background: Chronic lymphocytic leukemia (CLL) is a highly heterogeneous malignant lymphoproliferative B-cell disorder that can be treated using ibrutinib, a Bruton’s tyrosine kinase inhibitor. However, the ibrutinib resistance of CLL patients has caused widespread concerns, necessitating the development of novel treatment strategies. Methods: Here, we identified lectin galactoside-binding soluble 1 (LGALS1) and lymphocyte-activating gene 3 (LAG3) as potential markers for ibrutinib-resistant CLL using single-cell RNA sequencing (scRNA-seq), and the results were validated in an ibrutinib-resistant CLL cell line (MEC1-IR) and primary cells from CLL patients. Marker-gene expression was detected while functional analyses were conducted with or without OTX008, a selective Galectin-1 inhibitor. ScRNA-seq revealed that the biological features, gene expression profiles, and clonal signatures of peripheral blood mononuclear cells (PBMCs) from patients with ibrutinib-resistant CLL were distinct from those displayed by PBMCs from ibrutinib-sensitive patients. Findings: A close correlation between LGALS1 and LAG3 expression was observed and these factors were found to be highly expressed in ibrutinib-resistant CLL, with diagnostic and prognostic stratification, indicating that they may serve as drivers of ibrutinib-resistant CLL. Concordantly, LGALS1 and LAG3 expression was higher in ibrutinib-resistant CLL cells and primary cells, and OTX008 suppressed proliferation and induced apoptosis in both cells. Interpretation: LGALS1 and LAG3 gene panel is promising indicator of ibrutinib-sensitivity and prognosis marker of CLL. LGALS1 inhibitor OTX008 is effective in CLL patients, both those naive to and those resistant to ibrutinib. This work highlights the pathogenic mechanism and represents a novel therapeutic target for CLL. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (Grant #81720108002, 81970146, 81770166, 81972358 and 91959113), Key Research & Development Program of Jiangsu Province (Grant #BE2017733), Basic Research Program of Jiangsu Province (Grant #BK20180036), Jiangsu Province’s Medical Elite Programme (Grant #ZDRCA2016022), Project of National Key Clinical Specialty, Jiangsu Provincial Special Program of Medical Science (Grant #BE2017751), Six Top Talent Project of Jiangsu Province (Grant #WSN-001). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Human sample study was approved by the Medical Ethics Committee of First Affiliated Hospital of Nanjing Medical University. Written informed consent was obtained from all participants.

Deployment of functional circuits on a 3D freeform surface is of significant interest to wearable devices on curvilinear skin/tissue surfaces or smart Internet-of-Things with sensors on 3D objects. Here we present a new fabrication strategy that can directly print functional circuits either transient or long-lasting onto freeform surfaces by intense pulsed light-induced mass transfer of zinc nanoparticles (Zn NPs). The intense pulsed light can locally raise the temperature of Zn NPs to cause evaporation. Lamination of a kirigami-patterned soft semi-transparent polymer film with Zn NPs conforming to a 3D surface results in condensation of Zn NPs to form conductive yet degradable Zn patterns onto a 3D freeform surface for constructing transient electronics. Immersing the Zn patterns into a copper sulfate or silver nitrate solution can further convert the transient device to a long-lasting device with copper or silver. Functional circuits with integrated sensors and a wireless communication component on 3D glass beakers and seashells with complex surface geometries demonstrate the viability of this manufacturing strategy.

BACKGROUND Osteoporosis (OP) is a bone disease characterized by reduced amount and quality of bone. This study was designed to explore the role and mechanism of lncRNA IGF2-AS in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS Human lncRNA and miRNA microarray analyses were performed to measure the differential expression levels of lncRNAs and miRNAs in undifferentiated and osteogenically differentiated BMSCs. lncRNA IGF2-AS, miR-3,126-5p, and KLK4 levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Osteogenic differentiation of BMSCs was assessed by alkaline phosphatase (ALP) staining and Alizarin Red staining (ARS). Protein levels of osterix (Osx), osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) were examined by RT-PCR and western blot assays. The binding relationship between miR-3,126-5p and lncRNA IGF2-AS or KLK4 was predicted by TargetScan (http://www.targetscan.org/vert_72/) and then verified with a dual-luciferase reporter assay. RESULTS lncRNA IGF2-AS and KLK4 were highly expressed and miR-3,126-5p was weakly expressed in osteogenically differentiated BMSCs. Moreover, lncRNA IGF2-AS overexpression enhanced the osteogenic differentiation of BMSCs. In contrast, lncRNA IGF2-AS knockdown showed the opposite trend. Moreover, miR-3,126-5p overexpression abolished the lncRNA IGF2-AS-mediated osteogenic differentiation of BMSCs. lncRNA IGF2-AS functions as a sponge of miR-3,126-5p to regulate KLK4 expression. CONCLUSION lncRNA IGF2-AS enhances the osteogenic differentiation of BMSCs by modulating the miR-3,126-5p/KLK4 axis, suggesting a promising therapeutic target for bone-related diseases.

Photochemical pollution over the North China Plain (NCP) are attracting considerable concern. Peroxyacetyl nitrate (PAN) is usually viewed as the second most important photochemical pollutant featuring high mixing ratios during warm seasons. Our observations at a background site in the NCP identified high PAN concentrations even during cold-season haze events. The abrupt increasing rates of PAN by 244 % and 178 % over the morning hours (8:00–12:00) on 10/20 and 10/25, 2020 were 10.6 and 7.7 times those on clean days. The pollution days were characterized by higher temperature and humidity, accompanied by anomalous southerlies. Enhanced local photochemistry has been identified as the dominant factor that controls PAN increase in the morning at the rural site, as the time when prevailing wind turned to southerlies was too late to facilitate direct transport of PAN from the polluted urban region. By removing the effect of direct transport of PAN, we provide a quantitative assessment of net PAN chemical production rate of 0.45 ppb h−1 on the polluted morning, also demonstrating the strong local photochemistry. Using observations and calculated photolysis rates, we find that oxidation of acetaldehyde by hydroxyl radical (OH) is the primary pathway of peroxyacetyl radical formation at the rural site. Acetaldehyde concentrations and production rates of HOx (HOx = OH + HO2) radical on pollution days were 2.8 and 2 times that on clean days, respectively, leading to the abrupt increase of PAN in the morning. Formaldehyde (HCHO) photolysis dominates the daytime HOx production thus contributing to fast photochemistry of PAN. Our observational results fully explain the cause of rapid increase of PAN during cold days at a rural site of the NCP, as well as provide the evidence of important role of HCHO photolysis in secondary pollutants at lower nitrogen oxide emissions. This highlights the imperative to implement strict volatile organic compounds controls out of summer seasons over the NCP.

Fine particulate matter (PM2.5) decreased by 30–40% across China during 2013–2017 in response to the governmental Clean Air Action. However, surface ozone pollution worsened over the same period. Model simulations have suggested that the increase in ozone could be driven by the decrease in PM2.5, because PM2.5 scavenges hydroperoxy (HO2) and NOx radicals that would otherwise produce ozone. Here we show observational evidence for this effect with 2013–2018 summer data of hourly ozone and PM2.5 concentrations from 106 sites in the North China Plain. The observations show suppression of ozone pollution at high PM2.5 concentrations, consistent with a model simulation in which PM2.5 scavenging of HO2 and NOx depresses ozone concentrations by 25 ppb relative to PM2.5-free conditions. PM2.5 chemistry makes ozone pollution less sensitive to NOx emission controls, emphasizing the need for controlling emissions of volatile organic compounds (VOCs), which so far have not decreased in China. The new 2018–2020 Clean Air Action plan calls for a 10% decrease in VOC emissions that should begin to reverse the long-term ozone increase even as PM2.5 continues to decrease. Aggressive reduction of NOx and aromatic VOC emissions should be particularly effective for decreasing both PM2.5 and ozone. Observations confirm that cleaning up fine particulate matter in the North China Plain has exacerbated ozone pollution, suggesting that both NOx and VOC emissions need to be reduced to improve air quality.

Combining wide-bandgap and narrow-bandgap perovskites to construct monolithic all-perovskite tandem solar cells offers avenues for continued increases in photovoltaic (PV) power conversion efficiencies (PCEs). However, actual efficiencies today are diminished by the subpar performance of narrow-bandgap subcells. Here we report a strategy to reduce Sn vacancies in mixed Pb–Sn narrow-bandgap perovskites that use metallic tin to reduce the Sn4+ (an oxidation product of Sn2+) to Sn2+ via a comproportionation reaction. We increase, thereby, the charge-carrier diffusion length in narrow-bandgap perovskites to 3 μm for the best materials. We obtain a PCE of 21.1% for 1.22-eV narrow-bandgap solar cells. We fabricate monolithic all-perovskite tandem cells with certified PCEs of 24.8% for small-area devices (0.049 cm2) and of 22.1% for large-area devices (1.05 cm2). The tandem cells retain 90% of their performance following 463 h of operation at the maximum power point under full 1-sun illumination. Improvements in the efficiency and stability of low-bandgap perovskite solar cells are key to enabling all-perovskite solar cells. Here, Lin et al. use metallic tin to prevent oxidation in such low-gap perovskite and demonstrate 24.8%-efficient tandems that are stable for over 400 h under operating conditions.

A cobalt sulfide (CoS)/graphene sheets (GS) nanocomposite was successfully synthesized through a simple one-pot hydrothermal route assisted by ethylenediamine. The crystalline phase, structure and morphology of this nanocomposite were systematically characterized via X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), nitrogen (N₂) absorption-desorption isotherm, Raman spectroscopy and thermogravimetric analysis (TGA). The results revealed that the CoS nanoparticles with size distribution of 30-100 nm were highly dispersed on or well anchored in the creasy GS substrate. Integrating nanosized CoS compound and GS outstanding merits, the as-obtained CoS/GS nanocomposite as an anode material for lithiumion battery exhibited high reversible capacity, excellent long-cycle stability and remarkable high-rate capability, which were all superior to those of pristine CoS. Moreover, this nanocomposite maintained a high capacity of ˜600 mAh·g-1 after 200 cycles at a current density of 100 mA·g-1. The approach presented in this work is readily applicable to nanoparticle decoration of graphene sheets and preparation of other graphene-based nanocomposites as anode materials for lithium-ion batteries.

The charge-transport properties of charge-transfer complexes (CTCs) play a key role in the potential applications toward novel optoelectronic devices. We have systematically studied the charge-transport properties of perylene-F4TCNQ CTCs with different stoichiometric ratios by first-principles calculations. Our calculated results showed that 1P1F4 (perylene-F4TCNQ 1:1) exhibits a higher charge-carrier mobility than 3P2F4 (perylene-F4TCNQ 3:2) due to the strong interlayer interactions in 3P2F4. Compared with the perylene-TCNQ CTC, the higher charge-carrier mobility in perylene-F4TCNQ CTC indicates that introducing fluorine atoms can enhance the charge-carrier mobility due to stronger intermolecular interactions. More importantly, the experimental measurements carried out with 1P1F4- and 3P2F4-based field-effect transistors are consistent with the theoretical predictions. Our study reveals that tuning the charge-transport properties in CTCs by controlling the stoichiometry between the donor and acceptor is a promising strategy in accelerating the development of high-performance organic electronic materials.

Nowadays, water shortage has become an ever-increasing severe problem for human beings. Lately, there has been exciting progress in two different ways for desalination, namely, interfacial solar evaporation and film filtration. Graphene oxide based film is playing a critical role in both developments due to its high absorption, porous structure, high chemical stability, hydrophilicity, and excellent anti-fouling properties. In this works, we first introduce the mechanisms and key requirements for interfacial solar evaporation and filtration based desalination, and then explain how various forms of graphene oxide can be tailored for both types of desalination. Then, we summarize and discuss recent researches concerning both relevant technology advances and persisting problems, and finally provide a prospective view.