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Mimicking the nitric oxide (NO)-release and glycocalyx functions of native vascular endothelium on cardiovascular stent surfaces has been demonstrated to reduce in-stent restenosis (ISR) effectively. However, the practical performance of such an endothelium-mimicking surfaces is strictly limited by the durability of both NO release and bioactivity of the glycocalyx component. Herein, we present a mussel-inspired amine-bearing adhesive coating able to firmly tether the NO-generating species (e.g., Cu-DOTA coordination complex) and glycocalyx-like component (e.g., heparin) to create a durable endothelium-mimicking surface. The stent surface was firstly coated with polydopamine (pDA), followed by a surface chemical cross-link with polyamine (pAM) to form a durable pAMDA coating. Using a stepwise grafting strategy, Cu-DOTA and heparin were covalently grafted on the pAMDA-coated stent based on carbodiimide chemistry. Owing to both the high chemical stability of the pAMDA coating and covalent immobilization manner of the molecules, this proposed strategy could provide 62.4% bioactivity retention ratio of heparin, meanwhile persistently generate NO at physiological level from 5.9 ± 0.3 to 4.8 ± 0.4 × 10−10 mol cm−2 min−1 in 1 month. As a result, the functionalized vascular stent showed long-term endothelium-mimicking physiological effects on inhibition of thrombosis, inflammation, and intimal hyperplasia, enhanced re-endothelialization, and hence efficiently reduced ISR., Graphical abstract Image 1, Highlights • A durable endothelium-mimicking coating was developed for surface bioengineering of cardiovascular stents. • The durable endothelium-mimicking surface was realized by stepwise grafting of Cu-DOTA and heparin on a robust coating. • The durable endothelium-mimicking coating endows the vascular stents with ability to dramatically reduce restenosis.

BACKGROUND: Three novel acute treatments for migraine-lasmiditan, ubrogepant, and rimegepant-were approved by the FDA in 2019 and 2020 for adults with migraine with and without aura. American Headache Society guidance recommends that these novel acute treatments be considered for patients who are contraindicated to or fail to respond or tolerate oral triptans, the current standard of acute care. OBJECTIVE: To estimate, from a US commercial plan perspective, the budget impact of adding lasmiditan as an option to a formulary that already includes ubrogepant and rimegepant. METHODS: Epidemiologic data were drawn from US Census data, the American Migraine Prevalence and Preventive study, and the first wave of the OVERCOME US survey, a web-based survey that included 21,000 patients with migraine. A model with a 3-year time horizon was built assuming that demand for the novel acute treatments would not vary based on whether lasmiditan is included in the formulary. The model examined a variety of populations, in particular beneficiaries with previous use of 1 or more oral triptans or contraindicated to triptans and beneficiaries with previous use of 2 or more oral triptans or contraindicated to triptans. Primary outcomes were the incremental differences in total cost and average cost per member per month (PMPM) between scenarios with and without lasmiditan. One-way sensitivity analyses with model parameters that were varied by plus or minus 15% were conducted to assess the effect of key parameters on the incremental total cost over 3 years. RESULTS: The addition of lasmiditan to a formulary that already includes ubrogepant and rimegepant resulted in a total savings of -$927,657 (-1.5% compared with the scenario without lasmiditan) over a 3-year time horizon in the population with previous history of using 1 or more oral triptans or contraindicated to a triptan. In the population with previous history of using 2 or more oral triptans or contraindicated, the addition of lasmiditan resulted in a total budget impact of -$466,518 (-1.3%) over a 3-year time horizon. Most of the cost savings was attributable to reductions in drug acquisition cost. Savings in total costs resulted in average incremental cost per PMPM of -0.03 and -$0.01, respectively. CONCLUSIONS: The addition of lasmiditan to the formulary as a novel acute treatment option for migraine alongside ubrogepant and rimegepant resulted in lower budget impact on a 3-year time horizon from a US commercial payer's perspective. This result is important to US commercial payers as they seek to incorporate the emerging novel acute treatments for migraine into their benefit designs. DISCLOSURES: This work was funded by Eli Lilly and Company. Milev and Sun are employed by Evidera, which received funding from Eli Lilly and Company for work on this project. Pohl, Mason, Njuguna, and Loo are employees and stockholders of Eli Lilly and Company.

Polycomb group (PcG) proteins are crucial chromatin regulators during development. H2AK119ub1 (H2Aub) and H3K27me3 are catalyzed by Polycomb-repressive complex 1 and 2 (PRC1/2) respectively, and they largely overlap in the genome due to mutual recruitment of the two complexes. However, it is unclear whether PRC1/H2Aub and PRC2/H3K27me3 can also function independently. By developing an ultra-sensitive carrier-DNA-assisted chromatin immunoprecipitation sequencing method termed CATCH-Seq, we generated allelic H2Aub profiles in mouse gametes and early embryos. Our results revealed an unexpected genomewide decoupling of H2Aub and H3K27me3 in mouse preimplantation embryos, where H2Aub but not H3K27me3 was enriched at PcG targets while only H3K27me3 was deposited in the broad distal domains associated with DNA methylation-independent non-canonical imprinting. These observations suggest that H2Aub represses future bivalent genes during early embryogenesis without H3K27me3, but it is not required for the maintenance of non-canonical imprinting, which is mediated by maternal H3K27me3. Thus, our study reveals the distinct depositions and independent functions of H2Aub and H3K27me3 during early mammalian development.

In the present study, exopolysaccharides (EPS) production by Cupriavidus pauculus 1490 was optimized by response surface methodology. The results showed that sodium gluconate (4.15 g/L), NH4Cl (0.52 g/L), and Na2HPO4·12H2O (0.04 g/L) were the optimal medium components and concentrations. The actual EPS yield of 293.2 m g/L in the optimized medium was in close agreement with the predicted value of 283.35 m g/L. Analysis of fourier transform infrared spectroscopy indicated the EPS contained abundant functional groups, such as –OH, C=O and C–O–C, and all of them were attributed to the characteristics of polysaccharides. Mannose, glucuronic acid, glucose and xylose were detected as the main monosaccharide composition of EPS. Rheological analysis suggested that the rheogram of EPS has similar trend with Xanthan and presented the property of non-Newtonian fluid. Moreover, the addition of NaCl and KCl would partly weaken the shear stress of EPS. Three in vitro assays were conducted to evaluate the antioxidant potential of the EPS. Results demonstrated that the EPS possessed scavenging capacity on hydroxyl radical, DPPH radical and superoxide anion radical in a dose-dependent way. As indicated by above results, the EPS isolated from C. pauculus 1490 might serve as a potential antioxidant agent to be applied in nutraceutical and pharmaceutical industries.

Scavenger receptor is pattern-recognition receptor (PRR) that plays a crucial function in host defense against pathogens. Scavenger receptor C (SR-C) is present only in invertebrates and its function has not been studied in detail. In this study, an SR-C homologous gene from the silkworm, Bombyx mori, was identified and characterized. SR-C was largely expressed in hemocytes and Malpighian tubules, with continuous expression in hemocytes. The peak expression was observed in hemocytes during molting and wandering stages both at mRNA and protein levels. Furthermore, immunofluorescence demonstrated it to be mainly distributed in the cell membranes of hemocytes, including oenocytoids and granulocytes. The recombinant SR-C protein (rSR-C) could bind to different types of bacteria and pathogen-associated molecular patterns (PAMPs), with strong binding to gram-positive bacteria and Lys-type peptidoglycans. The overexpression of SR-C induced the expression of genes related to the Toll pathway and antibacterial peptides. While the knockdown of SR-C reduced the expression of AMPs and inhibited the Toll pathway, it impaired the bacterial clearance ability of silkworm larvae, thus decreasing silkworm larvae's survival rate. Altogether, SR-C is a PRR that protect silkworms against bacterial pathogens by enhancing the expression of AMPs expression via the Toll pathway in hemocytes.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an “ion therapy” approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis., Graphical abstract Image 1, Highlights ● A novel treatment of pulmonary fibrosis based on ion therapy using bioactive ionic solution derived from silicate bioceramics (CS) was demonstrated. ● CS solution can stimulate the alveolar epithelial cells to repair damaged lung tissue. ● CS solution can regulate immune cells to inhibit inflammatory factor secretion and reduce the number of inflammatory cells in lung tissue.

The aim of this study is to examine the effect of bamboo sphere on the organic matter decomposition and humification of food waste composting. Food waste composting were carried out on four treatments, namely control (CK), 3% (T1), 6% (T2) and 9% (T3) (w/w) bamboo sphere treatments. Results showed that adding bamboo sphere facilitated the organic matter decomposition and increased the seed germination index. The number of cells in T2 treatment was always the highest during the composting process. Furthermore, the final humic substances and humic acid contents increased by 41.08% and 68.3%, respectively, in 6% bamboo sphere treatment. Fourier transform infrared and excitation-emission matrix fluorescence spectroscopy analysis revealed that adding bamboo sphere accelerated the humification of composting with more aromatic structures and humic acid-like substances. GC-MS studies revealed that the compost products of 6% bamboo sphere treatment had more ring structures, and thus enhanced the humification.

Geranylgeraniol (GGOH) is found in edible oils such as olive, linseed, and sunflower oils, which have favorable metabolic effects. However, it is unknown whether these physiological benefits are mediated through the gut microbiome. Thus, the purpose of this study was to test the hypothesis that GGOH supplementation would improve glucose homeostasis and benefit the bone microstructure in obese mice through suppression of inflammation and modification of gut microbiota composition. Thirty-six male C57BL/6J mice were divided into 3 groups: a low-fat diet, a high-fat diet (HFD), and an HFD supplemented with 800 mg GGOH/kg diet (GG) for 14 weeks. Glucose and insulin tolerance tests were measured at baseline and end of study. The concentrations of adipokine cytokines (resistin, leptin, monocyte chemoattractant protein-1, interleukin-6) were measured via ELISA. Bone microarchitecture and quality were measured by micro-CT. Microbiome analysis was performed using 16S rRNA amplicon sequencing on cecal content. Relative to the HFD group, the GG group: (1) improved glucose tolerance and insulin sensitivity; (2) reduced production of pro-inflammatory adipokines, (3) increased serum procollagen I intact N-terminal propeptide (bone formation marker) concentrations, while decreasing serum collagen type 1 cross-linked C-telopeptide (bone resorption marker) levels, and (4) increased stiffness at both femur and LV-4 and cortical thickness at femoral midshaft. Compared to the HFD group, the GG group had an increased abundance of Butyricicoccus pullicaecorum and decreased Dorea longicatena in the cecal microbiome. Collectively, GGOH improves glucose homeostasis and bone microstructure in obese mice, probably via suppression of pro-inflammation and modification of microbiome composition.

Acute lung injury (ALI) is mainly caused by severe infection, shock, trauma, and burn, which causes the extensive release of inflammatory factors and other mediators. As a major bioactive constituent of traditional Chinese herb licorice, glycyrrhizic acid (GA) plays an important effect on inflammatory regulation. Nevertheless, the exact mechanism of this effect remains unclear. The present study aims to explore the potential protective effect of GA on LPS-induced ALI. Our results showed that GA significantly attenuated LPS-induced ALI and decreased the production of inflammatory factors, including IL-1β, MCP-1, COX2, HMGB1, and adhesion molecules, such as E-selectin, VCAM-1, and modulated expression of angiotensin-converting enzyme 2 (ACE2). Moreover, treatment of ACE2 inhibitor (MLN-4760) reversed the effects of GA on the secretion of pro-inflammatory factors in ALI. Additionally, GA exerts its protective effect by regulating the ACE2 and caveolin-1/NF-κB signaling pathway. In conclusion, this study showed that GA alleviated LPS-induced ALI by upregulating ACE2 and inhibiting the caveolin-1/NF-κB signaling pathway.

H2S and H2O2 are two redox regulating molecules that play important roles in many physiological and pathological processes. While each of them has distinct biosynthetic pathways and signaling mechanisms, the crosstalk between these two species is also known to cause critical biological responses such as protein S-persulfidation. So far, many chemical tools for the studies of H2S and H2O2 have been developed, such as the donors and sensors for H2S and H2O2. However, these tools are normally targeting single species (e.g., only H2S or only H2O2). As such, the crosstalk and synergetic effects between H2S and H2O2 have hardly been studied with those tools. In this work, we report a unique H2S/H2O2 dual donor system by employing 1-thio-β-d-glucose and glucose oxidase (GOx) as the substrates. This enzymatic system can simultaneously produce H2S and H2O2 in a slow and controllable fashion, without generating any bio-unfriendly byproducts. This system was demonstrated to cause efficient S-persulfidation on proteins. In addition, we expanded the system to thiolactose and thioglucose-disulfide; therefore, additional factors (β-galactosidase and cellular reductants) could be introduced to further control the release of H2S/H2O2. This dual release system should be useful for future research on H2S and H2O2.

Background Enterovirus 71 (EV-A71) is a highly infectious pathogen associated with hand, foot and mouth disease, herpangina, and various neurological complications, so it is important for the early detection and treatment of EV-A71. An aptamer is a nucleotide sequence that screened in vitro by the technology named systematic evolution of ligands by exponential enrichment technology (SELEX). Similar to antibodies, aptamers can bind to the targets with high specificity and affinity. Besides, emerging aptamers have many advantages comparing with antibodies, such as ease of synthesis and modification, having a wide variety of target materials, low manufacturing cost and easy flexibility in amending. Therefore, aptamers are promising in virus detection and anti-virus therapy. Methods Aptamers were selected by SELEX. Specificity, affinity and second structure were used to characterize the selected aptamers. Chemiluminescence was adopted to build an aptamer-based detection method for EV-A71. Cytopathogenic effects trial, the level of intracellular EV-A71 RNA and protein expression were used to evaluate the antiviral effect of the selected aptamers. Results Three DNA aptamers with high specificity and affinity for EV-A71structual protein VP1 were screened out. A rapid chemiluminutesescence aptamer biosensor for EV-A71 detection was designed out. The selected aptamers could inhibit the RNA replication and protein expression of EV-A71 in RD cells and ameliorate the cytopathogenic effects. Conclusions The aptamers against EV-A71 have the potentiality to be applied as attractive candidates used for EV-A71 detection and treatment in the future.

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28’s role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

BACKGROUND The common bed bug, Cimex lectularius L., and the tropical bed bug, Cimex hemipterus (F.), are now widely regarded as important public health pests following their rapid global resurgence, largely due to insecticide resistance and an increased rate of global travel. The insecticide resistance mechanisms are well documented in C. lectularius, however, only one mechanism is validated in C. hemipterus thus far. This demands further understanding on the resistance mechanisms involved in C. hemipterus. RESULTS Here, we identified differences in resistance to fenitrothion (organophosphate) and imidacloprid (neonicotinoid) related cuticle thickness in C. hemipterus. There is evidence of a possible association between cuticle thickness and resistance, but the association can be tenuous, likely because resistance is multifactorial in C. hemipterus. We also discovered a novel T1011 residue in domain IIS6 of the voltage-gated sodium channel that likely enhanced susceptibility to deltamethrin (pyrethroid) despite the presence of a L1014F mutation known to confer pyrethroid resistance in C. hemipterus. Our findings also confirmed that the M918I mutation enhanced resistance to pyrethroid when present with the L1014F mutation, which was consistent with a super-kdr phenotype, as reported previously. Multiple resistance mechanisms can be found within a single C. hemipterus population, and the presence of both M918I + L1014F mutations likely masked the influence of cuticle thickness in conferring resistance against deltamethrin. The elevated metabolic enzyme activities in some strains were not necessarily associated with increased insecticide resistance. CONCLUSION This study has enhanced our understanding on the penetration resistance mechanism and target site insensitivity of sodium channels in C. hemipterus.

A novel type of polyacid corrosion inhibitor (PCI) was synthesized from the residue of 2-vinylpyridine, which could reduce the cost of hazardous waste disposal in production enterprises, and solve the environmental pollution caused by residue. Herein, the components of the residue were analyzed and a special solvent is selected to dissolve it. Then, synergistic experiments of the residual solution with different inhibitor were carried out to select the corrosion inhibitor components, and the optimal ratio of each component was determined by orthogonal experiments. The performance of PCI was estimated by weight loss method, and its electrochemical type was detected by electrochemical experiments. It indicated that the main components of 2-vinylpyridine residue are pyridine derivatives and hydrocarbons. The developed PCI is composed by four components, which could be suitable for HCl, citric acid, sulfamic acid, other acid systems, and has good corrosion inhibition effect on carbon steel, brass, and other materials. The corrosion rate of N80 carbon steel can reach to 0.5491 g m−2 h−1 at 60 ℃ in 5% HCl, which fully meets the requirements of China national standards. The electrochemical polarization curve showed that PCI is a kind of highly effective mixed inhibitor, which can inhibit both cathode and anode simultaneously.

Cervical cancer is a common female malignant tumor that seriously threatens human health. This study explored the anticervical cancer effects and potential mechanisms of Rotundifuran (RTF), a natural product isolated from Vitex trifolia L. In this study, we found that RTF can suppress the proliferation of cervical cancer cell lines, including HeLa and SiHa cells (with the IC50 less than 10 μM), via induction of apoptosis in vitro, and the antitumor effect of RTF is further confirmed on the HeLa cell-inoculated xenograft model. In addition, our results proved that the antitumor effects of RTF might be related with the reactive oxygen species- (ROS-) induced mitochondrial-dependent apoptosis through MAPK and PI3K/Akt signal pathways. Using proteomics analysis and the drug affinity responsive target stability- (DARTS-) combined mass spectrometry (DARTS-MS), Cyr61 was indicated as a potential target for RTF in cervical cancer cells. Our present study would be beneficial for the development of RTF as a candidate for treatment of cervical cancer in the future.

End-group fidelity is the most important property for end-functional polymers. Compared to other controlled living polymerization methods, reversible addition-fragmentation chain transfer (RAFT) polymerization often yields polymers with a lower end-group fidelity, which greatly affects their applications. Herein, we report a staged-thermal-initiation RAFT polymerization for the synthesis of polymers with high thiol end-group fidelity and their high efficiencies for grafting to various gold nanoparticles (GNPs). We experimentally prove that the decrease of end-group fidelity with their molecular weight is caused by the gradual decomposition of the initiator rather than the degradation of chain-transfer agents. We show that the staged-thermal-initiation RAFT polymerization is more effective for synthesis of polymers with high thiol end-group fidelity. The grafting-to assays for various GNPs illustrate the positive correlation between the end-group fidelity of polymers and grafting-to efficiency. This work highlights the prospects for synthesis of high end-group fidelity polymers and their application in the preparation of nanoparticles-polymer hybrid materials.

A series of SnS2/Au nanocomposites were synthesized by photocatalytic deposition of Au nanoparticles on the surface of SnS2 nanoplates at room temperature. The photocatalytic properties of the as-synthesized SnS2/Au nanocomposites were tested via both the reduction of Cr(VI) and degradation of MO in water under the irradiation of visible light (λ > 420 nm). SnS2/Au-1.0% was found to be the most photocatalytically active nanocomposite. The photocatalytic Cr(VI) reduction rate over SnS2/Au-1.0% was 2.1 times as that over SnS2 under visible light irradiation. Moreover, SnS2/Au-1.0% was also efficient and stable in the visible light-driven photocatalytic degradation of methyl orange (MO). Based on the test results of photoabsorption, transient photocurrent response and electrochemical impedance, the best photocatalytic performance of SnS2/Au-1.0% was likely attributed to its most efficient separation and transfer of photo-generated electrons and holes. Besides, the mechanisms of photocatalytic Cr(VI) reduction and MO degradation by SnS2/Au-1.0% were also explored.

Oxidation of α-siloxy thioethers leads to the formation of the corresponding sulfoxides as unstable intermediates, which undergo an intramolecular oxygen-to-oxygen silyl migration to break the C-S linkage. This process produces silyl protected sulfenic acids and subsequently thiosulfinates. It was used to develop oxidation-triggered allicin donors.

Surface coating can greatly enhance the lifetime of cold extrusion die. It is a significant issue to evaluate the performance of coatings and even predict the lifetime of cold extrusion die. In this work, the titanium-based nitride coatings including TiN, TiAlN, and TiAlCrN were, respectively, deposited on the surface of high-speed steel substrate W6Mo5Cr4V2 (M2) by the physical vapor deposition technology. The hardness test, scratch test, Rockwell adhesion test, and pin-on-disc (POD) wear test were carried out aiming to investigate the performances of the three coatings including hardness, adhesion strength, and wear resistance. The results show that the TiAlCrN coating exhibits the highest hardness of 3,033 HV in comparison with TiN coating (1,222 HV) and TiAlN coating (1,916 HV), while it possesses poor adhesion strength and inferior wear resistance. Furthermore, the TiAlN coating presents the highest resistance to wear and spalling from the substrate. In addition, the Archard wear model of the coatings was solved and applied in the finite element model of cold extrusion to calculate the wear depth and lifetime of the cold extrusion dies. The results suggest that TiAlN coating is the optimal option for cold extrusion die as compared with TiAlCrN and TiN coatings. TiAlN coating can prolong the lifetime of the substrate die up to 260%.

Objectives The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. Background MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. Methods A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. Results A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m2), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. Conclusions Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 )

Exploring the mechanism through which berberine (Ber) reverses the multidrug resistance (MDR) of breast cancer is of great importance. Herein, we used the methyl thiazolyl tetrazolium assay to determine the drug resistance and cytotoxicity of Ber and doxorubicin (DOX) alone or in combination on the breast cancer cell line MCF-7/DOXFluc. The results showed that Ber could synergistically enhance the inhibitory effect of DOX on tumor cell proliferation in vitro, and the optimal combination ratio was Ber/DOX = 2:1. Using a luciferase reporter assay system combined with the bioluminescence imaging technology, the efflux kinetics of d-luciferin potassium salt in MCF-7/DOXFluc cells treated with Ber in vivo was investigated. The results showed that Ber could significantly reduce the efflux of d-luciferin potassium salt in MCF-7/DOXFluc cells. In addition, western blot and immunohistochemistry experiments showed that the expression of P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) in MCF-7/DOXFluc cells was downregulated upon Ber treatment. Finally, high-performance liquid chromatography was used to investigate the effect of Ber on DOX tissue distribution in vivo, and the results showed that the uptake of DOX in tumor tissues increased significantly when combined with Ber (P < 0.05). Thus, the results illustrated that Ber can reverse MDR by inhibiting the efflux function of ATP-binding cassette transporters and downregulating their expression levels.

Gibbosterol A (1), a water-soluble 14-membered carbocyclic steroid with a twisted trans-9,11-epoxy ring, was discovered from the South China Sea dinoflagellate, Amphidinium gibbosum, together with its acid-induced cyclization product 2. It exhibits marked agonistic effects against human pregnane-X-receptor in a dose-dependent manner within the concentration range of 100 nM to 10 μM. Its 5/14-carbobicyclic nucleus is proposed to be originated from late-stage oxidative cleavage of the C5-C10 and C8-C9 bonds of β-sitosterol.

In this study, a distinct inoculum was investigated as an isolated variable within sequencing batch reactors via a comparison of the 4-fluoroaniline (4-FA) or 2,4-difluoroaniline (2,4-DFA) removal amounts. The inocula were derived from a treatment plant for treating pharmaceutical wastewater plus a small amount of municipal sewage (PMS), a treatment plant for treating fluoridated hydrocarbon wastewater (FHS), and a treatment plant for treating the comprehensive wastewater in an industrial park (CIS). There were slight differences among the degradation patterns of the 4-FA for the three inocula, whether during the enrichment period or the high concentration shock period. In contrast, it was observed that the degradation efficiency of 2,4-DFA initially varied with the inocula. The FHS-derived inoculum was determined to be optimal, exhibiting the earliest degradation reaction only after an acclimation of 7 days had the highest degradation rate constant of 0.519 h−1, and had the fastest recovery time of three weeks after high concentration shock. Additionally, compared with the PMS-derived inoculum, the CIS-derived inoculum exhibited an earlier degradation reaction within three weeks, and a higher microbial diversity, but a lower shock resistance and degradation rate constant of 0.257 h−1. High-throughput sequencing demonstrated that each final consortium was different in composition, and the microbial consortia developed well on the inoculum and substrate. In comparison of the similarity among the three 2,4-DFA enrichment cultures, the higher similarity (63.9–70.0%) among three final consortia enriching with 4-FA was observed. The results indicated that the inoculum played an important role in the degradation of FAs and the microbial bacterial communities of final consortia, and the effect extent might well depend on the fluorinated level of FAs.

Li-ion hybrid capacitors (LIHC) are becoming a prospective candidate for energy storage and can achieve high energy density and power density at the same time. As it uses a battery-type anode, impr...

Super-carbon-chain compounds (SCCCs) are marine organic molecules featuring long polyol carbon chains with numerous stereocenters. Polyol–polyene compounds (PPCs) and ladder-frame polyethers (LFPs) are two major families. It is highly challenging to establish the absolute configurations of SCCCs. In this century, few new SCCC families have been reported. Benthol A, an aberrant SCCC, was obtained from a South China Sea benthic dinoflagellate that should belong to a new taxon. Its planar structure and absolute configuration, containing thirty-five carbon stereocenters, were unambiguously established by a combination of extensive NMR spectroscopic investigations, periodate degradation of the 1,2-diol groups, ozonolysis of the carbon–carbon double bonds, J-based configurational analysis, NOE interactions, modified Mosher's MTPA ester method, and DFT-NMR 13C chemical-shift calculations aided by DP4+ statistical analysis. Benthol A displayed potent antimalarial activity against Plasmodium falciparum 3D7 parasites. This new molecule combines extraordinary structural features, particularly eight scattered ether rings on a C72 backbone chain, which places it within a new SCCC family between PPCs and LFPs, herein termed polyol–polyether compounds. This suggestion was strongly supported by principal component analysis. The discovery of benthol A does not only provide new insights into the untapped biosynthetic potential of marine dinoflagellates, but also opens up a new window for skeletal diversity of SCCCs., The discovery of benthol A, a marine natural product featuring thirty-five carbon stereocenters and eight scattered ether rings within a C72 backbone chain, inaugurates a new family of super-carbon-chain compounds.

Cyanobacteria are promising adsorbents that are widely used for heavy metal removal in aqueous solutions. However, the underlying adsorption mechanism of Synechocystis sp. PCC6803 is currently unclear. In this study, the adsorption behavior and mechanism of cadmium (Cd2+) were investigated. Batch biosorption experiments showed that the optimal adsorption conditions were pH 7.0, 30 °C, 15 min, and an initial ion concentration of 4.0 mg L−1. The adsorption process fitted well with the pseudo-second order kinetic model, mainly based on chemisorption. Complexation of Cd2+ with carboxyl, hydroxyl, carbonyl, and amido groups was demonstrated by Fourier-transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS) analyses. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy-dispersive X-ray spectrometry (EDX) analyses confirmed the presence of Cd2+ on the cyanobacterial cell surface and intracellularly. Cd2+ could lead to reactive oxygen species (ROS) accumulation and photosynthesis inhibition in cyanobacterial cells, and glutathione (GSH) played an important role in alleviating Cd2+ toxicity. Analyses of three-dimensional fluorescence spectroscopy (3D-EEM) and high performance anion exchange chromatography-pulsed amperometric detection (HPAEC-PAD) revealed the changes of the composition and content of EPS after Cd2+ adsorption, respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) revealed the potential molecular regulatory mechanisms involved in Cd2+ biosorption. These results revealed the adsorption mechanism of Cd2+ by Synechocystis sp. PCC6803 and provided theoretical guidance for insight into the biosorption mechanisms of heavy metals by other strains.

The requirement of hydrogen adsorption Gibbs free energy (ΔGH*) approximating to 0 eV limits the hydrogen evolution reaction (HER) activity of most electrocatalysts in alkaline media. The construction of interface and defects engineering is an effective strategy to obtain the optimal ΔGH*. Ni3N exhibits poor HER activity due to its undesirable ΔGH*. By cooperating with Nb2O5, the d-band center of Ni3N was reduced, improving its catalytic performance. The optimized Nb2O5–Ni3N displays an overpotential of 80 mV at 10 mA cm−2 and superior activity than the benchmark Pt/C catalyst when the current density is greater than 125 mA cm−2. Experimental and density functional theory results demonstrate that the improved catalytic activity is because the electronic interaction between Ni and Nb changes the coordination numbers of these two atoms, resulting in oxygen vacancies at the interface. Under the synergistic effect of Nb2O5 and Ni3N, the catalyst exhibits optimal ΔGH* and water adsorption energy.

A sailboat-shaped 20-membered macrolide, named gibbosolide A, featuring a rare cis-fused 2-methylhexahydro-2H-furo[3,2-b]pyran motif, was obtained from the South China Sea dinoflagellate, Amphidinium gibbosum. Its planar structure and absolute configuration, containing twelve carbon stereocenters, were unambiguously established by extensive NMR investigations, J-based configuration analysis, NOE interactions, ozonolysis of the carbon–carbon double bonds, and the modified Mosher's α-methoxy-α-(trifluoromethyl)phenylacetyl (MTPA) ester method. It displays activation effects on human farnesoid–X–receptor within the concentration range of 200.0 nM to 2.0 μM. Its late-stage cyclization mechanisms are proposed. Most notably, ozonolysis of the carbon–carbon double bonds combined with the modified Mosher's ester method is a useful approach for the unambiguous determination of absolute configurations of hydroxy-bearing carbon stereocenters within the complex macrolide core.

Resonance-stabilized cyclopentadienyl radicals are important intermediate species in the combustion of transportation fuels. It not only serves as precursors for polycyclic aromatic hydrocarbon (PAH) formation, but also involves in the formation of fundamental PAH precursors such as propargyl and acetylene. In this work, the unimolecular reactions of the cyclopentadienyl radicals are theoretically studied based on high-level quantum chemistry and RRKM/master equation calculations. Stationary points on the potential energy surface (PES) are calculated at the CCSD(T)/CBS//M06–2X/6–311++(d,p) level of theory. The branching ratios of unimolecular reactions of the cyclopentadienyl radicals are analyzed for a broad temperature range from 500 to 2500 K and pressures from 0.01 to 100 atm. It is found that the isomerization reaction of the cyclopentadienyl radical via 1,2-hydrogen transfer dominates at low temperatures and high pressures, while the well-skipping decomposition reaction which forms propargyl and acetylene is important at high temperatures and low pressures. Both the decomposition reaction of the cyclopentadienyl radicals and its reverse reaction show pronounced pressure dependence, and their reaction rate constants are compared against available low-pressure experimental measurements and theoretical studies. The temperature- and pressure-dependent rate coefficients for important reactions involved on the C5H5 PES are calculated and updated in a chemical kinetic model. Impacts of the unimolecular reactions of the cyclopentadienyl radicals on the PAH formation are explored by the numerical modeling of a low-pressure cyclopentene counterflow diffusion flame.

Scavenging reactive oxygen species (ROS) by antioxidants has been demonstrated as the most effective strategy for preventing percutaneous coronary intervention (PCI)-related complications. However, topical and long-term delivery of ROS antioxidants to a specific vascular tissue is proven to be a great challenge. Herein, an ROS scavenger of 4-hydroxy-2,2,6,6-tetramethylpiperidine- N -oxyl (TEMPOL) is incorporated into electrospun nanofibers with a tunable loading amount to achieve its topical applicability and long-term anti-radical capability. Biological functions of such TEMPOL-loaded electrospun membranes are evaluated by cell proliferation, ROS-scavenging capability, monocyte adhesion, cell migration, inflammatory molecule secretion and mRNA expression in vitro . After optimizing the loading amount of TEMPOL, such an electrospun membrane presents a superior ROS-scavenging and anti-inflammation performance for both endothelial cells and macrophages. The expression of endothelial prothrombogenic molecules and the migration of vascular smooth muscle cells (VSMCs) are also effectively inhibited. Thus, it is bravely predicted that the topical use of such a TEMPOL-loaded electrospun system will be a promising pathway for the anti-restenosis therapy, especially when used as a novel coating on stent for long-term and topical delivery of antioxidant drugs.

Crop plants, such as watermelon, suffer from severe Aluminum (Al3+)-toxicity in acidic soils with their primary root elongation being first arrested. However, the significance of apoplastic or symplastic Al3+-toxicity in watermelon root is scarcely reported. In this work, we identified a medium fruit type (ZJ) and a small fruit type (NBT) as Al+3-tolerant and sensitive based on their differential primary root elongation rate respectively, and used them to show the effects of symplastic besides apoplastic Al distribution in the watermelon's root. Although the Al content was higher in the root of NBT than ZJ, Al+3 allocated in their apoplast, vacuole and plastid fractions were not significantly different between the two cultivars. Thus, only a few proportion of Al+3 differentially distributed in the nucleus and mitochondria corresponded to interesting differential morphological and physiological disorders recorded in the root under Al+3-stress. The symplastic amount of Al+3 substantially induced the energy efficient catalase pathway in ZJ, and the energy consuming ascorbate peroxidase pathway in NBT. These findings coincided with obvious starch granule visibility in the root ultra-structure of ZJ than NBT, suggesting a differential energy was used in supporting the root elongation and nutrient uptake for Al+3-tolerance in the two cultivars. This work provides clues that could be further investigated in the identification of genetic components and molecular mechanisms associated with Al+3-tolerance in watermelon.

The sluggish electrochemical kinetics of sulfur species has impeded the wide adoption of lithium-sulfur battery, which is one of the most promising candidates for next-generation energy storage system. Here, we present the electronic and geometric structures of all possible sulfur species and construct an electronic energy diagram to unveil their reaction pathways in batteries, as well as the molecular origin of their sluggish kinetics. By decoupling the contradictory requirements of accelerating charging and discharging processes, we select two pseudocapacitive oxides as electron-ion source and drain to enable the efficient transport of electron/Li+ to and from sulfur intermediates respectively. After incorporating dual oxides, the electrochemical kinetics of sulfur cathode is significantly accelerated. This strategy, which couples a fast-electrochemical reaction with a spontaneous chemical reaction to bypass a slow-electrochemical reaction pathway, offers a solution to accelerate an electrochemical reaction, providing new perspectives for the development of high-energy battery systems., The sluggish electrochemical kinetics of sulfur species remains a major hurdle for the broad adoption of lithium-sulfur batteries. Here, the authors construct an energy diagram of sulfur species to unveil their reaction pathways and propose a general strategy to accelerate electrochemical reactions.

Gel polymer electrolytes (GPL) that comprise polymer, lithium salts, and organic plasticizers hold great promise for safer lithium-ion batteries, because of liquid-like ionic conductivity, as well ...

Exploring high active, durable, and earth-abundant electrocatalysts for sustainable hydrogen production is a necessary prerequisite of the future hydrogen economy. Herein, anion-regulation of 3D fl...

Originally developed for metrology, optical frequency combs are becoming increasingly pervasive in a wider range of research topics including optical communications, spectroscopy, and radio or microwave signal processing. However, application demands in these fields can be more challenging as they require compact sources with a high tolerance to temperature variations that are capable of delivering flat comb spectra, high power per tone, narrow linewidth and high optical signal-to-noise ratio (OSNR). To date, there has not been a frequency comb technology that is able to simultaneously achieve all these requirements. This work reports the generation of a flat, high power frequency comb in the telecom band using a 17-mm fully-integrated silicon core fibre (SCF) as a parametric mixer. Our all-fibre, cavity-free source combines the materials benefits of planar waveguide structures with the advantageous properties of fibre platforms to achieve a 30 nm bandwidth comb source containing 143 tones with 30 dB OSNR over the entire spectral region. The unique combination of technical features offered by this SCF-based source opens a path towards a new class of high-performance frequency comb generators for communications and signal processing applications.

Context: Curcumin has shown efficacy in promoting radiosensitivity combined with radiotherapy. However, the role and mechanism of curcumin on radiosensitivity in laryngeal squamous cell cancer (LSC...

In this study, the roles of extracellular polymeric substances (EPSs) excreted by Pandoraea sp. XY-2 in the removal of tetracycline (TC) were investigated. In the early stage, TC in the solution was mainly removed by the adsorption of EPSs, which accounted for 20% of TC. Thereafter, large amount of TC was transported into the intracellular and biodegraded. EPSs was extracted and the contents of polyprotein and polysaccharides reached their maximum values (30.84 mg/g and 11.15 mg/g) in the first four days. Fourier transform infrared spectroscopy analysis revealed that hydroxyl, methylidyne, methylene and amide I groups in EPSs participated in the adsorption of TC. Furthermore, three-dimensional excitation-emission matrix fluorescence spectroscopy analysis revealed that TC caused the quenching of EPSs fluorescent groups. The quenching mechanism was attributed to static quenching and protein-like substances in EPSs from Pandoraea sp. XY-2 dominated the TC adsorption process. Bioinformatic analysis of Pandoraea sp. XY-2 genome identified multiple genes involved in exopolysaccharide synthesis and EPSs formation. The insights gained in this study might provide a better understanding about the adsorption process of EPSs in tetracycline-contaminated environment.

Antimony (Sb)-oxidizing bacteria play an important role in Sb biogeochemical cycle in soil, but the benefits of microbial oxidation for plants have not been well documented. The aim of this study was to explore the contribution of Sb(III)-oxidizing bacteria to alleviate the Sb toxicity in plants. The plant growth-promoting (PGP) characteristics of Sb(III)-oxidizing bacterium Bacillus sp. S3 and the effects of bacterial inoculation on Arabidopsis plants were evaluated under controlled and Sb stressed conditions. Indole acetic acid (IAA) production and 1-aminocyclopropane-1-carboxylate-deaminase (ACC-deaminase) activity were the only two PGP strategies that Bacillus sp. S3 possessed, despite the production level of IAA and the activity of ACC deaminase sharply decreased under Sb stress. Bacillus sp. S3 inoculation significantly increased the plant biomass and chlorophyll content, alleviated the peroxidation of membrane lipids, decreased the activities of the antioxidant enzymes, and reduced the transcription of Sb transporters and reactive oxygen species (ROS)-related enzymes in Arabidopsis. Noteworthily, inoculation of Bacillus sp. S3 not only significantly decreased the Sb accumulation but also reduced the percentage of Sb(III) of total Sb in Arabidopsis. This study indicates that the Sb(III)-oxidizing strain of Bacillus sp. S3 is a promising inoculant used for bacteria-assisted phytoremediation on Sb-contaminated sites.

Two Ac4ManNAz (AAM) derivatives with octadecanoic ester (C18 ester) and octadecyl ether (C18 ether) attached to the anomeric hydroxyl groups were synthesized and used in preparation of liposomes. Both liposomes show strong cell-labeling efficiencies on MDA-MB-231 cancer cells. The cell surface-anchored azide group can react with DBCO-Cy5 via Cu-free click chemistry. The two liposomes exhibit different azide placement mechanisms; C18-ether-AAM-treated cells have azido placement through direct insertion, while C18-ester-AAM-treated cells express azido more through metabolic glycoengineering.

Radio-resistance is recognized as a main factor in the failure of radiotherapy in oesophageal squamous cell carcinoma (ESCC). Aberrant cell surface glycosylation has been reported to correlate with radio-resistance in different kinds of tumours. However, glycomic alterations and the corresponding enzymes associated with ESCC radio-resistance have not yet been defined. Two radioresistant cell lines, EC109R and TE-1R, were established from parental ESCC cell lines EC109 and TE-1 by fractionated irradiation. A lectin microarray was used to screen for altered glycan patterns. RNA-sequencing (RNA-seq) was employed to identify differentially expressed glycosyltransferases. Cell Counting Kit-8, colony formation and flow cytometry assays were used to measure cell viability and radiosensitivity. Expression of glycosyltransferase in ESCC tissues was assessed by immunohistochemistry. In vivo radiosensitivity was analysed using a nude mouse xenograft model. Downstream effectors of the enzyme were verified using a lectin-based pull-down assay combined with mass spectrometry. We found that EC109R and TE-1R cells were more resistant to irradiation than the parental EC109 and TE-1 cells. Using lectin microarrays combined with RNA sequencing, we found that α1, 6-fucosyltransferase (FUT8) was overexpressed in the radioresistant ESCC cell lines. Both gain- and loss-of-function studies confirmed that FUT8 regulates the sensitivity of ESCC cells to irradiation. Importantly, we found that high FUT8 expression was positively linked to radio-resistance and a poor prognosis in ESCC patients who received radiation therapy. Moreover, FUT8 inhibition suppressed the growth and formation of xenograft tumours in nude mice after irradiation. Using a lectin-based pull-down assay and mass spectrometry, we found that CD147 could be glycosylated by FUT8. As expected, inhibition of CD147 partly reversed FUT8-induced radio-resistance in ESCC cells. Our results indicate that FUT8 functions as a driver of radio-resistance in ESCC by targeting CD147. Therefore, FUT8 may serve as a marker for predicting the response to radiation therapy in patients with ESCC.

A new phenolic compound, 6-(2-acetyl-3,5-dihydroxybenzyl)-4-hydroxy-3-methyl-2H-pyran-2-one (1), along with other six known phenolic derivatives (2-7), were isolated from the mangrove rhizosphere fungus Penicillium janthinellum HK1-6 cultured in potato dextrose broth medium containing 30 g L-1 of natural sea salt. The structure of the new compound (1) was elucidated by comprehensive analysis of spectroscopic data including 1D and 2D NMR spectra. The proposed biosynthetic pathway of compound 1 was also studied in this research. Interestingly, a brominated phenolic derivative, aryl bromide (compound 8), was obtained from this fungal strain cultured in medium containing 30 g L-1 of NaBr instead of natural sea salt. Compound 8 is proposed as a new natural product and formed through bromination of compound 7 when the fungus was cultured with NaBr. The neuroprotective effect of compound 1 on oxygen-glucose deprivation (OGD)-induced injury was investigated in rat spinal cord astrocytes. MTT assay demonstrated that compound 1 can attenuate OGD-induced cell viability loss in rat spinal cord astrocytes.