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The diastereoselectivity of conventional polyene cyclization reactions is highly dependent on the configuration of the internal alkenes, where E-polyenes provide trans-decalins, while Z-polyenes of...

Sensory nerves promote osteogenesis through the release of neuropeptides. However, the potential application and mechanism in which sensory nerves promote healing of bone defects in the presence of biomaterials remain elusive. The present study identified that new bone formation was more abundantly produced after implantation of silicified collagen scaffolds into defects created in the distal femur of rats. The wound sites were accompanied by extensive nerve innervation and angiogenesis. Sensory nerve dysfunction by capsaicin injection resulted in significant inhibition of silicon-induced osteogenesis in the aforementioned rodent model. Application of extracellular silicon in vitro induced axon outgrowth and increased expression of semaphorin 3 A (Sema3A) and semaphorin 4D (Sema4D) in the dorsal root ganglion (DRG), as detected by the upregulation of signaling molecules. Culture medium derived from silicon-stimulated DRG cells promoted proliferation and differentiation of bone marrow mesenchymal stem cells and endothelial progenitor cells. These effects were inhibited by the use of Sema3A neutralizing antibodies but not by Sema4D neutralizing antibodies. Knockdown of Sema3A in DRG blocked silicon-induced osteogenesis and angiogenesis almost completely in a femoral defect rat model, whereas overexpression of Sema3A promoted the silicon-induced phenomena. Activation of “mechanistic target of rapamycin” (mTOR) pathway and increase of Sema3A production were identified in the DRG of rats that were implanted with silicified collagen scaffolds. These findings support the role of silicon in inducing Sema3A production by sensory nerves, which, in turn, stimulates osteogenesis and angiogenesis. Taken together, silicon has therapeutic potential in orthopedic rehabilitation.

Yue Yu,1,* Qinyan Yang,1,* Zhou Wang,1 Qian Ding,1 Meng Li,1 Yudong Fang,1 Qida He,1 Yi Zhun Zhu1,2 1State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, Macau SAR, People’s Republic of China; 2Shanghai Key Laboratory of Bioactive Small Molecules & School of Pharmacy, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zhun ZhuMacau University of Science and Technology, Block E, Avenida Wai Long, Taipa, Macau SAR, 999078, People’s Republic of ChinaTel +853 8897 2880Fax +853 2882 3575Email yzzhu@must.edu.moPurpose: Ketoprofen (KETO) is a traditional non-steroidal anti-inflammatory drug (NSAIDs) with good analgesic and antipyretic effects. However, as NASIDs, the toxicity of KETO towards gastrointestinal (GI) system might limit its clinical use. S-propargyl-cysteine (SPRC) is an excellent endogenous H2S donor showed wide application in the field of anti-inflammation, anti-oxidative stress, or even the protection of cardiovascular system through the elevation of endogenous H2S concentration. As recently studies reported, co-administration of H2S donor might potentially mitigate the GI toxicity and relevant side effects induced by series of NSAIDs.Methods: In this study, we established a SPRC and KETO co-encapsulated poly (lactic-co-glycolic acid) microsphere (SK@MS), and its particle size, morphology, storage stability and in vitro release profile were firstly investigated. The elevation of endogenous H2S level of SK@MS was then calculated, and the pharmacodynamic study (anti-inflammation and analgesic effects) of SK@MS, SPRC, and KETO towards adjuvant induced arthritis (AIA) in rats were also studied. Finally, to test the potential side effect, the heart, liver, spleen, lung, kidney, stomach, small intestine, and large intestine were resected from rats and examined by H&E staining.Results: A monodispersed SK@MS could be observed under the SEM, and particle size was calculated around 25.12 μm. The loading efficiency (LE) for SPRC and KETO were 6.67% and 2.64%, respectively, while the encapsulation efficiency (EE) for SPRC and KETO were 37.20% and 68.28%, respectively. SK@MS showed a sustained release of SPRC and KETO in vitro, which was up-to 15 days. SK@MS could achieve a long-term elevation of the H2S concentration in vivo, while SPRC showed an instant H2S elevation and metabolize within 6 h. Interestingly, the KETO did not show any influence on the H2S concentration in vivo. After establishment of AIA model, neither SPRC nor KETO showed scarcely anti-inflammation and anti-nociception effect, while conversely, SK@MS showed an obvious mitigation towards paw edema and pain in AIA rats, which indicated an improved anti-inflammation and anti-nociception effect when co-delivery of SRC and KETO. Besides, low stimulation towards major organs in rats observed in any experimental group.Conclusion: A monodispersed was successfully prepared in this study, and SK@MS showed a sustained SPRC and KETO release in vitro and H2S release in vivo. In the pharmacodynamics study, SK@MS not only exhibited an excellent anti-inflammation and analgesic effects in AIA rats but also showed low stimulation towards rats.Keywords: H2S donor, ketoprofen, adjuvant induced arthritis, anti-inflammation, analgesic effect

We report the first zinc isotope data (expressed as δ66Zn relative to the JMC-Lyon standard) for chromian spinels (Cr-spinels) and coexisting olivines in oceanic peridotites. All spinel-olivine pairs fall on the 1:1 fractionation line in the diagram of δ66Znspinel versus δ66Znolivine, suggesting equilibrium isotope fractionation. Cr-spinels are always isotopically lighter than coexisting olivines (Δ66Znspinel-olivine = δ66Znspinel − δ66Znolivine = −0.50‰ to −0.33‰; n = 13), which is opposite to the positive Zn isotope fractionation between Al-spinel and olivine observed in cratonic peridotites. The “inverse” Zn isotope fractionation between Cr-spinel and olivine is unlikely to have been caused by low-temperature alteration of the oceanic peridotites, given the lack of correlation between Δ66Znspinel-olivine values and chemical indices of serpentinization and weathering (e.g., LOIs, MgO/SiO2). Ionic model calculation indicates that even considering that Zn occurs at both tetrahedral and octahedral sites in the crystal lattice of spinel, the magnitude of equilibrium fractionation is still inconsistent with the observed Zn isotope fractionation between Cr-spinel and olivine. We suggest a “chemical effect” in which the Zn O bond length (tetrahedral site) in spinel increases when Cr substitutes Al in octahedral site, which is corroborated by the striking negative correlation of δ66Zn with Cr# [molar Cr3+/(Cr3+ + Al)] in natural spinels. Therefore, Zn isotopic compositions of natural spinels can be highly variable depending on their chemical compositions. During magma differentiation, zinc is moderately incompatible in silicate minerals (olivine and pyroxene) but highly compatible in Cr-spinels/chromites that have Zn contents tens of times higher than those of basaltic melts. Given its light Zn isotopic composition, chromite crystallization–if any–can evidently elevate δ66Zn and lower Zn contents of the residual melts. Lunar mare basalts are typically characterized by higher δ66Zn and lower Zn contents relative to terrestrial basalts, but modelling suggests that chromite crystallization during magmatic differentiation is unlikely to account for Zn isotopic and elemental data of lunar mare basalts. Global ocean island basalts (OIBs) and some intraplate alkali basalts have systematically higher δ66Zn and higher Zn contents than those of the normal mantle-derived melts (e.g., mid-ocean ridge basalts; MORBs), which contradicts with a chromite crystallization model. Instead, such signatures can reflect recycling of surface carbonates into the Earth’s deep mantle, reinforcing the application of zinc isotopes as a tracer of deep carbonate recycling.

Objective: PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade. The factors that drive inducible PD-L1 expression have been extensively studied, but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown. Methods: DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout. Protein function was inhibited by chemical inhibitors. Protein levels were examined by Western blot, mRNA levels were examined by real-time RT-PCR, and surface protein expression was determined by cellular immunofluorescence and flow cytometry. Immune evasion was examined by in vitro T cell-mediated killing. Results: We determined the core regions (chr9: 5, 496, 378–5, 499, 663) of a previously identified PD-L1L2-super-enhancer (SE). Through systematic analysis, we found that the E26 transformation-specific (ETS) variant transcription factor (ETV4) bound to this core DNA region but not to DNA surrounding PD-L1L2SE. Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2. ETV4 transcription was dependent on ERK activation, and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling from αvβ3 integrin, which profoundly affected ETV4 transcription and PD-L1/L2 expression. Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing. Conclusions: We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion. These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

Paralytic shellfish toxins (PSTs) produced by certain marine dinoflagellates accumulate in filter-feeding marine bivalves. We used LC-MS/MS to detect and quantify 13 PSTs in 188 shellfish samples of 14 species collected from Shenzhen city’s Buji seafood wholesale market from March 2019 to February 2020. Twenty-six of 188 shellfish samples (13.8%) were PSTs detectable. Within 14 species, 10 out of 34 noble clam Chlamys nobilis samples contain detectable PSTs with the highest detection rate 29.4%. Seven out of 17 samples from Nan’ao island contained detectable PSTs with the highest detection rate 41.2% among 11 origins. Samples containing PSTs were concentrated in spring and winter, with the highest levels in March>December>January. Among PSTs detected, C1 was dominant. Acute dietary exposure assessment for Shenzhen residents were based on mean adult body weight, 99th percentile daily shellfish consumption of Shenzhen food consumption survey 2008 and maximum PSTs concentration for each shellfish species. The outcome for Chlamys nobilis was 2.4~3.7-fold higher than recommended ARfDs. Mean PSTs concentration, P99, and mean shellfish consumption were used to assess chronic dietary exposure. The results were lower than recommended ARfDs. In conclusion, residents in Shenzhen are at risk for acute PSTs poisoning, while relatively safe from chronic PSTs exposure.

Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha-methylacyl-coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequencies ranging from 45% to 97%. The chimeric protein is translocated to the lysosomal membrane and activates the extracellular signal-regulated kinase signaling cascade. The fusion protein promotes cell growth, accelerates migration, resists serum starvation-induced cell death, and is essential for cancer growth in mouse xenograft cancer models. Introduction of SLC45A2-AMACR into the mouse liver using a sleeping beauty transposon system and somatic knockout of phosphatase and TENsin homolog (Pten) generated spontaneous liver cancers within a short period. Conclusion: The gene fusion between SLC45A2 and AMACR may be a driving event for human liver cancer development.

High-nitrogen energetic compounds are widely used in military and civil fields. To cope with some special conditions, materials with high melting point and good heat resistance are required. Herein, synthetic approach of two TACOT-derived compounds with high heat resistance and strong insensitivity for friction has been optimized. Significantly, 100 g-scale of aza-TACOT(I) was prepared with a total yield of 80% and a purity of 99.9%. Meanwhile, aza-TACOT(II) was obtained with a purity of 98.9% under the optimized conditions. This practical method features scalable and simple operations. In addition, an acceptable mechanism was firstly proposed for the critical step.

A green, efficient, and high active catalytic system for the hydrogenation of ketones and aldehydes to produce corresponding alcohols under atmospheric-pressure H2 gas and ambient temperature conditions was developed by a water-soluble metal–ligand bifunctional catalyst [Cp*Ir(2,2′-bpyO)(OH)][Na] in water without addition of a base. The catalyst exhibited high activity for the hydrogenation of ketones and aldehydes. Furthermore, it was worth noting that many readily reducible or labile functional groups in the same molecule, such as cyan, nitro, and ester groups, remained unchanged. Interestingly, the unsaturated aldehydes can be also selectively hydrogenated to give corresponding unsaturated alcohols with remaining C=C bond in good yields. In addition, this reaction could be extended to gram levels and has a large potential of wide application in future industrial.

Purpose S-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H2S) donor, could elevate H2S levels via the cystathionine γ-lyase (CSE)/H2S pathway both in vitro and in vivo. However, the immediate release of H2S in vivo and daily administration of SPRC potentially limited its clinical use. Methods To solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H2S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied. Results The spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H2S in a sustained manner through CSE/H2S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed. Conclusions A sustained H2S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H2S releasing donor might be of good use for the treatment of AIA.

Background Menaquinone (MK-7) is a highly valuable vitamin K2 produced by Bacillus subtilis. Common static metabolic engineering approaches for promoting the production of MK-7 have been studied previously. However, these approaches caused an accumulation of toxic substances and reduced product yield. Hence, dynamic regulation by the quorum sensing (QS) system is a promising method for achieving a balance between product synthesis and cell growth. Results In this study, the QS transcriptional regulator SinR, which plays a significant role in biofilm formation and MK production simultaneously, was selected, and its site-directed mutants were constructed. Among these mutants, sinR knock out strain (KO-SinR) increased the biofilm biomass by 2.8-fold compared to the wild-type. SinRquad maximized the yield of MK-7 (102.56 ± 2.84 mg/L). To decipher the mechanism of how this mutant regulates MK-7 synthesis and to find additional potential regulators that enhance MK-7 synthesis, RNA-seq was used to analyze expression changes in the QS system, biofilm formation, and MK-7 synthesis pathway. The results showed that the expressions of tapA, tasA and epsE were up-regulated 9.79-, 0.95-, and 4.42-fold, respectively. Therefore, SinRquad formed more wrinkly and smoother biofilms than BS168. The upregulated expressions of glpF, glpk, and glpD in this biofilm morphology facilitated the flow of glycerol through the biofilm. In addition, NADH dehydrogenases especially sdhA, sdhB, sdhC and glpD, increased 1.01-, 3.93-, 1.87-, and 1.11-fold, respectively. The increased expression levels of NADH dehydrogenases indicated that more electrons were produced for the electron transport system. Electrical hyperpolarization stimulated the synthesis of the electron transport chain components, such as cytochrome c and MK, to ensure the efficiency of electron transfer. Wrinkly and smooth biofilms formed a network of interconnected channels with a low resistance to liquid flow, which was beneficial for the uptake of glycerol, and facilitated the metabolic flux of four modules of the MK-7 synthesis pathway. Conclusions In this study, we report for the first time that SinRquad has significant effects on MK-7 synthesis by forming wrinkly and smooth biofilms, upregulating the expression level of most NADH dehydrogenases, and providing higher membrane potential to stimulate the accumulation of the components in the electron transport system.

Anthropogenic nitrogen (N) input is known to alter plant and microbial α-diversity, but how N enrichment influences β-diversity of plant and microbial communities remains poorly understood. Using a long-term multilevel N addition experiment in a temperate steppe, we show that plant, soil bacterial and fungal communities exhibited different responses in their β-diversity to N input. Plant β-diversity decreased linearly as N addition increased, as a result of increased directional environmental filtering, where soil environmental properties largely explained variation in plant β-diversity. Soil bacterial β-diversity first increased then decreased with increasing N input, which was best explained by corresponding changes in soil environmental heterogeneity. Soil fungal β-diversity, however, remained largely unchanged across the N gradient, with plant β-diversity, soil environmental properties, and heterogeneity together explaining an insignificant fraction of variation in fungal β-diversity, reflecting the importance of stochastic community assembly. Our study demonstrates the divergent effect of N enrichment on the assembly of plant, soil bacterial and fungal communities, emphasizing the need to examine closely associated fundamental components (i.e., plants and microorganisms) of ecosystems to gain a more complete understanding of ecological consequences of anthropogenic N enrichment.

Magnetic CoFe2O4 nanoparticles were successfully manufactured through the process of nitrate combustion using anhydrous ethanol as fuel, they together with their intermediate were characterized by thermo gravimetric (TG) analysis, selected area electron diffraction (SAED), transmission electron microscope (TEM), vibrating sample magnetometer (VSM), and X-ray diffraction (XRD). These results indicated a phenomenon that the magnetic CoFe2O4 nanoparticles could be formed at 400 °C, the average grain size, the specific magnetization, and the specific surface area of magnetic CoFe2O4 nanoparticles fabricated at 400 °C for 2 h with 30 mL anhydrous ethanol were corresponding 20 nm, 78.0 Am2/kg and 83.2 m2/kg. Magnetic CoFe2O4 nanoparticles were in application to adsorb methyl blue (MB) of wastewater, and their adsorption performances and electrochemical properties were investigated, the adsorption process data well agreed with the pseudo-second-order kinetics model in concentration ranging from 100 mg/L to 400 mg/L of MB. Compared with Freundlich model, Langmuir model (correlation coefficient R2 = 0.9976) could evaluate the adsorption equilibrium state of MB onto CoFe2O4 nanoparticles at indoor temperature, so the monomolecular layer adsorption mechanism was demonstrated to be the mechanism of the MB molecules' adsorption onto CoFe2O4 nanoparticles.

Terpenoids are an important class of secondary metabolites that play an important role in food, agriculture, and other fields. Microorganisms are rapidly emerging as a promising source for the production of terpenoids. As an oleaginous yeast, Yarrowia lipolytica contains a high lipid content which indicates that it must produce high amounts of acetyl-CoA, a necessary precursor for the biosynthesis of terpenoids. Y. lipolytica has a complete eukaryotic mevalonic acid (MVA) pathway but it has not yet seen commercial use due to its low productivity. Several metabolic engineering strategies have been developed to improve the terpenoids production of Y. lipolytica, including developing the orthogonal pathway for terpenoid synthesis, increasing the catalytic efficiency of terpenoids synthases, enhancing the supply of acetyl-CoA and NADPH, expressing rate-limiting genes, and modifying the branched pathway. Moreover, most of the acetyl-CoA is used to produce lipid, so it is an effective strategy to strike a balance of precursor distribution by rewiring the lipid biosynthesis pathway. Lastly, the latest developed non-homologous end-joining strategy for improving terpenoid production is introduced. This review summarizes the status and metabolic engineering strategies of terpenoids biosynthesis in Y. lipolytica and proposes new insights to move the field forward.

The candidate anticancer drug curaxins can insert into DNA base pairs and efficiently inhibit the growth of various cancers. However, how curaxins alter the genomic DNA structure and affect the DNA binding property of key proteins remains to be clarified. Here, we first showed that curaxin CBL0137 strongly stabilizes the interaction between the double strands of DNA and reduces DNA bending and twist rigidity simultaneously, by single-molecule magnetic tweezers. More importantly, we found that CBL0137 greatly impairs the binding of CTCF but facilitates trapping FACT on DNA. We revealed that CBL0137 clamps the DNA double helix that may induce a huge barrier for DNA unzipping during replication and transcription and causes the distinct binding response of CTCF and FACT on DNA. Our work provides a novel mechanical insight into CBL0137's anticancer mechanisms at the nucleic acid level.

Following hepatic ischemia-reperfusion injury, Kupffer cells could be activated by inflammatory factors released from damaged hepatocytes. Carbon monoxide (CO)-releasing molecule (CORM)-3, a water-soluble transition metal carbonyl, exhibits excellent anti-inflammatory and anti-pyroptosis properties. We investigated whether CORM-3 attenuated hemorrhagic shock and resuscitation (HSR)-induced pyroptosis of Kupffer cells through the soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal pathway. NS2028 (10 mg/kg), a blocker of sGC, was administrated at the onset of hemorrhage, but CORM-3 (4 mg/kg) was infused after resuscitation via femoral vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, tumor necrosis Factor-α (TNF-α), and interleukin-1β (IL-1β) were measured at 3, 6, 12, and 24 h after HSR, respectively. Six hours post-HSR, liver injury, pyroptosis of Kupffer cells, and expressions in total caspase-1, cleaved caspase-1, gasdermin D (GSDMD) N-terminal fragment, IL-1β, and IL-18 were measured by hematoxylin-eosin (H&E), immunofluorescence and western blot assays, respectively (Fig. 1). The rats exposed to HSR exhibited significant upregulated levels of serum ALT, AST, TNF-α, and IL-1β, elevated liver injury score, increased pyroptosis of Kupffer cells, and accumulated expressions of pyroptosis-associated protein including cleaved caspase-1, GSDMD N-terminal fragment, IL-1β, and IL-18 than sham-treated rats. However, CORM-3 administration markedly reduced liver injury and pyroptosis of Kupffer cells, whereas these protective effects could be partially blocked by NS2028. CORM-3 can mitigate pyroptosis of Kupffer cells in a blood loss and re-infusion model of rats via sGC-cGMP signal pathway.

Herein, we demonstrated for the first time the green fabrication of graphene by wet ball milling method which utilizes natural honey as exfoliation medium, further the 3D conductive networks (Graphene/Carbon nanotubes/PEDOT:PSS, G/CNT/PEDOT:PSS) were integrated into the biodegradable Starch/Chitosan/Poly vinyl alcohol (S/C/PVA) substrates. This electrode possesses an excellent optoelectronic performance (Rs = 43.2 Ω/sq., T = ca. 80% at 550 nm), and a very low Root Mean Square (RMS) roughness (approximately 1.38 nm). The sheet resistance of the films changed slightly after 1000 bending cycles and adhesion tests. The flexible green light OLED using G/CNT/PEDOT:PSS-S/C/PVA film as anode was successfully fabricated, the luminance of the device was 5701 cd/m2 at 15 V and the maximum current efficiency was 3.75 cd/A at 13 V. Moreover, this new type of OLED device degrades gradually within 10 min in 2 wt% lysozyme CH3COOH solution, which could be used to prepare the next generation of user-friendly, eco-friendly flexible wearable electronic devices.

P2-type layered oxides are considered as promising cathode materials for rechargeable sodium ion batteries, but preparing P2-type cathodes with high-operating voltage and long-life is still a big challenge. Herein, spherical P2-type cathode Na₀.₆₇Ni₀.₁₇Co₀.₁₇Mn₀.₆₆Ti₀.₀₅Mg₀.₀₅O₂ has been designed, and the critical roles of Ti and Mg on electrochemical performance of the cathodes are systematically investigated. The high-temperature XRD clearly exhibits the forming process of the pure phase material and suggests that the most suitable calcination temperature is 850 °C. The Ti/Mg cosubstitution does not break the long-range P2 structure and the spherical morphology of the material. In the electrochemical processes, the Na₀.₆₇Ni₀.₁₇Co₀.₁₇Mn₀.₅₆Ti₀.₀₅Mg₀.₀₅O₂ electrode exhibits better electrochemical performance than that of the undoped Na₀.₆₇Ni₀.₁₇Co₀.₁₇Mn₀.₆₆O₂. It delivers an initial reversible capacity of 151 mAh g–¹ (2–4.5 V) with an average voltage of 3.8 V and exhibits a high capacity retention of 87.7% after 300 cycles at 100 mA g–¹. The improved electrochemical performance benefits from the Ti/Mg cosubstitution; Ti improves the average voltage while Mg and Ti significantly mitigate the undesired P2 → O2 phase transition of the cathode, and these two elements jointly promote the development of the electrochemical performance. This strategy is also applicable to the optimization design of layered transition oxides and provides a new approach to prepare high-voltage, long-life cathodes for sodium ion batteries.

Although drug combination has proved to be an efficient strategy for clinic gastric cancer therapy, how to further improve their bioavailability and reduce the side effects are still challenges due to the low solubility and untargeted ability of drugs. Recently, newly emerging nanotechnology has provided an alternative for constructing new drug delivery systems with high targeting ability and solubility. In this study, a pH-responsive liposome (Liposome-PEO, LP) loaded with apatinib (AP) and cinobufagin (CS-1) was used for combinational therapy against gastric cancer after coating with a hybrid membrane (R/C). The results indicated that the constructed nanocomplex LP-R/C@AC not only efficiently killed tumor cells in vitro by inducing apoptosis, autophagy, and pyroptosis, but also significantly inhibited tumor invasion and metastasis via the VEGFR2/STAT3 pathway. Moreover, it showed stronger anti-tumor activity in gastric cancer-bearing mouse models, as compared to the sole drugs. A naturally-derived hybrid cell membrane coating bestowed nanocomplexes with enhanced biointerfacing including prolonged circulation time and targeting ability.

Hai-Tao Niu, Yang Liu, Yan-Zhou Wang, Yong Tian, Ming Yang, Hong-Sheng Jiang Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, People’s Republic of ChinaCorrespondence: Hai-Tao NiuDepartment of Neurosurgery, Cangzhou Central Hospital, No. 16, Xinhua West Road, Cangzhou, Hebei 061000, People’s Republic of ChinaEmail niujyrlps02495@163.comPurpose: At present, comprehensive therapy has been widely used in the treatment of glioma, but the curative effect is not good, and the survival rate of patients is low. Therefore, it is crucial to explore further the regulatory mechanism of the occurrence and development of glioma and find potential therapeutic targets. We aimed to investigate the columbamine (a tetrahydroisoquinoline alkaloid derived from the rhizome of Chinese herbal medicine Rhizoma Coptidis) on glioma progression.Methods: MTT, clone formation assay, wound healing assay, and transwell assay were performed to detect the cell viability, proliferation, migration, and invasion ability. Flow cytometry, TUNEL, and Western blot were used to identify the apoptosis level in glioma cells. PTEN inhibitor (SF1670) and AKT activator (SC79) were used to explore the mechanism of columbamine on glioma cell progression.Results: Columbamine inhibits proliferation, migration, invasion, and induces apoptosis in glioma cell lines (SHG44 and U251). Columbamine prevents phosphorylation of AKT and promotes the expression of PTEN. Blocking PTEN level or inducing phosphorylation of AKT attenuates columbamine function on SHG44 cells proliferation, metastasis, and apoptosis.Conclusion: In this research, we find that columbamine could inhibit proliferation and metastasis of glioma cell lines, and promote apoptosis of glioma cell lines via regulating PTEN/AKT signal pathway. It provides a new theoretical basis for the development of anti-glioma drugs.Keywords: columbamine, glioma, proliferation, PTEN, AKT

A series of new chiral salenCo(III)X complexes [salen = (R,R)-N,N′-bis(3-R-5-tert-butylsalicylidene)-1,2-cyclohexanediamine, X− = OAc−, R = CMe2CHMe2 (4a), CPhMe2 (4b), CPh2Me (4c); X− = 2,4-dinitrophenoxide anion (DNP), R = CMe2CHMe2 (5a), CPhMe2 (5b), CPh2Me (5c); X− = Br−, R = CMe2CHMe2 (6a), CPhMe2 (6b), CPh2Me (6c)] with bulky substituents at the 3,3′-positions of the salicylidene moiety were synthesized and investigated as catalysts in the copolymerization of CO2/propylene oxide (PO) and the sequential copolymerization of succinic anhydride/PO and CO2/PO. The effects of the reaction conditions were examined by using complex 4b as a representative catalyst for the copolymerization of CO2/PO. It was found that catalysts with different ligands and axial coordinating groups show remarkable differences in their catalytic properties. The catalysts with relatively small R groups show relatively high catalytic activity and produce copolymers with relatively high molecular weights, while the catalysts with relatively bulky R groups show relatively high stereoselectivity. Catalyst systems employing 4-(dimethylamino)pyridine (DMAP) as the cocatalyst show relatively low catalytic activity but high stereoselectivity in comparison with the ones observed in the systems with bis(triphenylphosphoranylidene) ammonium chloride (PPNCl) or PPNDNP as the cocatalyst. With the catalyst system of 5c/DMAP, a high kinetic resolution coefficient (Krel) of 10.6 for the insertion of (S)-PO over (R)-PO was obtained at 25 °C. High molecular weight PPCs (Mw > 100 kg mol−1) were prepared with 5a/PPNCl and 5a/PPNDNP catalyst systems. Stereoregular block copolymers poly(propylene succinate-block-carbonate) were obtained from sequential copolymerization via catalytic kinetic resolution.

Breast cancer is the most common cancer in women and occurs mostly with poor outcomes. Our objective was to endow synthetic lethality to the phytoconstituent chikusetsusaponin IVa methyl ester (CSME, S), a special phytoconstituent from traditional Chinese medicine (TCM), Panax japonicus, with the photodynamic agent chlorin e6 (Ce6, C) and enhance the therapeutic efficacy against breast cancer using cell membrane-coated liposome nanoparticles (liposome, L). The delivery system based on liposomes was camouflaged by a hybrid cell membrane (RBC membrane and cancer cell membrane, M) and RGD (R) surface modifications to improve the solubility, targeting and treatment outcomes of CSME. Our results showed the successful development of nanocomplexes with extended half-life, increased immune evasion and targeted ability at the tumor site and good antitumor activity without side effects to normal tissue. The anti-tumor mechanism of nanocomplexes is related to cell proliferation regulation and apoptosis induction. Overall, this drug-delivery system provides a good alternative for breast cancer therapy using a natural active phytoconstituent.

The precise prediction of end-point carbon content in liquid steel plays a critical role in increasing productivity as well as energy efficiency that can be achieved in the basic oxygen furnace (BOF) steelmaking process. Due to numerous and diversity of the studies on BOF end-point carbon prediction, it seems necessary to provide a comprehensive literature review on state-of-the-art developments in end-point carbon prediction for BOF steelmaking. This paper presents the characteristics of different end-point carbon prediction models. The end-point carbon prediction for BOF steelmaking has initially relied on the experience and skill of the operators. With the development of information technology and auto-detection methods, BOF end-point carbon prediction mainly has gone through three stages, such as static prediction, dynamic prediction, and intelligent prediction. Future contributions to the development and application of intelligent end-point carbon prediction in BOF steelmaking are still arduous tasks. However, it is envisaged that the intelligent end-point carbon prediction will witness more frequent applications and greatly improve the high-quality, high-efficiency, and stable production for BOF steelmaking in the future.

Magnetic magnesium ferrite nanoparticles were fabricated via the ethanol-assisted solution combustion and gel calcination route. The scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectrometer, Brunauer-Emmett-Teller (BET) surface area measurement, vibrating sample magnetometer (VSM) and X-ray diffraction (XRD) were applied to characterize magnetic magnesium ferrite nanoparticles which were prepared under the condition of 20 mL absolute alcohol and calcined at 600 °C for two hours. The results showed that the nanoparticles were spinel structure with the saturation magnetization of 183 emu·g−1, the average grain size of 52 nm, the specific surface area of 33.2 m2 · g−1. In addition, the electrochemical property and adsorption mechanism of neutral red (NR) onto the magnetic MgFe2O4 nanoparticles were investigated. The adsorption results were conformed to the pseudo-second-order adsorption kinetic and Temkin model, which implied that the multimolecular layer chemical adsorption had occurred. Moreover, the pH had little effect on the process of the adsorption, and the value of the magnetic magnesium ferrite nanoparticles for NR adsorption was up to 555 mg · g−1.

Aim: To investigate the effects of the different morphological characteristics of Prussian blue nanoparticles (PB NPs) on their biocompatibility and biosafety. Materials & methods: PB NPs with different sizes, shapes and charges were synthesized and their biosafety and biocompatibility performance were systematically compared in vitro and in vivo. Results: Increased size and positive charge of PB NPs adversely affected cell viability, while improving their peroxidase activity and photothermal conversion efficiency. In vivo analysis demonstrated good biocompatibility of PB NPs, without retention in the organs, but increased size retarded their metabolism. Meanwhile, increased size and positive charge adversely affected hepatic and renal function. Conclusion: This comprehensive exploration of biosafety and biocompatibility provides strong evidences for the use of PB NPs as nanodrug carrier and/or imaging agent.

Purpose Nitrous oxide (N2O) abuse has become an increasingly severe problem in China. The aim of the study was to summarize the features of N2O-induced neurology and enhance the awareness of this disease among physicians. Patients and methods We retrospectively reviewed the clinical, imaging, electrophysiological characteristics and the prognosis of patients with N2O neurotoxicity in our hospital from January 2016 to August 2019. Results Twenty-one patients (average age: 22.6±4.6 years) were collected. Eighty-six percent (18/21) patients presented with acute or subacute neurological disorders as their initial symptoms. The remaining fourteen percent (3/21) had psychiatric symptoms as the earliest symptoms. With progression, movement dysfunction appeared in ninety percent (19/21) of the patients with fifty-three percent (10/19) presented with weakness limited to both lower extremities. Sixty-two percent (13/21) of the patients presented with subjective sensory deficit. Seventy-one percent (15/21) had vibration sense impairment and positive Romberg's sign. Sixty-seven percent of the patients had hyporeflexia or areflexia. Fourteen percent (3/21) showed positive Babinski's sign. Seventy-eight percent (14/18) showed significantly increased homocysteine (HCY) level and only seventeen percent (3/18) showed decreased serum vitamin B12 level. T2 hyperintensity involving the posterior columns and lateral columns with inverted V sign in cervical spinal MRI had been observed in forty-seven percent (8/17) of the patients. Axonal peripheral neuropathy occurred in eighty-five percent (17/20) of the patients. The level of serum vitamin B12 and HCY, as well as imaging findings, were rapidly recovered after supplementation of Vitamin B12. Conclusion The N2O-induced neuropsychiatric disturbances mainly occurred in the young groups and should be recognized by clinicians. The prognosis of N2O intoxication is relatively good.

The marine sulfate inventory represents the largest standing pool of electron acceptors, which, via microbial sulfate reduction, is responsible for roughly half of the organic matter mineralization globally in marine sediments. In addition to the oxidation of buried organic matter, sulfate reduction can be coupled to the oxidation of methane migrating upward. Multiple sulfur isotope ratios were measured for porewater sulfate, sulfide, elemental sulfur and pyrite from core samples collected from continental shelf (19–96 m water depth) in the Baltic Sea and slope (1098 m water depth) in the Andaman Sea, in order to test if their isotope systematics can be used to trace the two different sulfate reduction processes. For shallow shelf sediments (34S and Δ33S values of porewater sulfate increased with increasing depth as a result of organoclastic sulfate reduction (OSR). However, the Δ33S values of both porewater sulfate and sulfide decreased as the δ34S values increased downcore at 43–73 cm depth where sulfate reduction was coupled to anaerobic oxidation of methane (AOM). Pyrite in shelf sediments yielded positive Δ33S values, reflecting Δ33S of porewater sulfide produced by OSR. In contrast, pyrite in slope sediments yielded negative Δ33S values as low as −0.15‰, as a result of mixing of sulfides derived from OSR and AOM. This is consistent with the slowly migrating sulfate–methane transition (SMT) in slope sediments inferred from sulfur and iron speciation, carbon isotope ratios of carbonates, and magnetic susceptibility data. A stable SMT, focusing AOM at roughly the same depth over the past few millennia, further provides favorable conditions for prolonged pyrite formation with the development of cubic crystals, while the sulfur isotope difference between bulk pyrite and macroscopic pyrite reflects the significance of OSR throughout the sediment column. We conclude that minor sulfur isotopes provide a unique proxy that can be applied to differentiate OSR and AOM and the origin of pyrite in diverse sediments and sedimentary rocks. This contribution highlights strong local diagenetic controls on pyrite formation and its multiple sulfur isotopic composition in various marine settings.

BACKGROUND Dutasteride administration reportedly improves lower urinary tract symptoms in patient with chronic, histologically-identified prostatic inflammation, potentially through estrogen receptor β (ERβ), activation of which has anti-inflammatory effects in the prostate tissue. Therefore, we investigated the effect of dutasteride on intraprostatic inflammatory responses and bladder activity using a rat model of chemically induced prostatic inflammation. METHODS Male Sprague-Dawley rats at 10 weeks old were used. Prostatic inflammation was induced by 5% formalin injection into ventral lobes of the prostate and saline was injected in the control group (control, n = 5). Rats with prostatic inflammation were divided into dutasteride therapy (dutasteride, n = 5) and placebo groups (placebo, n = 5). Dutasteride was administrated at a dose of 0.5 mg/kg daily from 2 days before induction of prostatic inflammation whereas placebo rats received vehicle only. Twenty-eight days later, cystometry was performed in a conscious condition to measure non-voiding contractions (NVCs), intercontraction intervals (ICI) and postvoid residual volume (RV). After cystometry, the prostate was excised for analysis of messenger RNA (mRNA) expression levels of ERα, ERβ, interleukin-1β (IL-1β), and IL-18 by quantitative polymerase chain reaction. RESULTS The mean number of NVCs was significantly greater in placebo group than that of control group without prostatic inflammation (p

As a breast cancer subtype with high mortality in women, the efficient treatment of Triple-negative breast cancer (TNBC) is still a challenge due to its unique metastatic mode and poor prognosis. In this study, we developed a biomimetic nanodelivery system (denoted as GTDC@M-R NPs) based on erythrocyte membrane (M)-camouflaged graphene oxide quantum dots (GOQDs, G) for TNBC therapy. The TAT (T) and RGD (R) peptides were used to endow targeting accumulation ability of Gamabufotalin (CS-6, C) and doxorubicin (DOX, D) in tumor tissue. In vitro assay indicated good biocompatibility, prolonged blood circulation time (3-fold longer than GT NPs), and effectively enhanced cell and nucleus targeting capability of this nanosystem. Fluorescence activated cell sorter (FACS) analysis indicated that the combination of DOX and CS-6 induced TNBC cell apoptosis more than 89 % under the ratio of 10:1. In vivo assay indicated that the accumulation of GTDC@M-R NPs in tumor sites increased about 2-fold compared to naked GTDC NPs, which was accompanied by high tumor apoptosis rates through blocking chemotherapy-activated cyclooxygenase-2 (COX-2) and enhancing DOX's anti-tumor activity of chemical drugs (85%). Moreover, comparing with the control, the average number of lung metastatic nodules in tumor-bearing mice reduced 84%, the molecular mechanism of which is related to the down expression of COX-2, matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF). Taken together, our results proved that the developed GTDC@M-R NPs can inhibit the growth and suppress metastasis of TNBC, which broaden our insights into the application of combinational strategy for efficient TNBC therapy. STATEMENT OF SIGNIFICANCE: In this study, we developed a biomimetic nanodelivery system (denoted as GTDC@M-R NPs) based on erythrocyte membrane (M)-camouflaged graphene oxide quantum dots (GOQDs, G) for TNBC therapy. The TAT (T) and RGD (R) peptides were used to endow targeting accumulation ability of Gamabufotalin (CS-6, C) and doxorubicin (DOX, D) in tumor tissue. These GTDC@M-R NPs indicated synergistic chemotherapy against TNBC cells through the precise cell and nuclear targeting, immune escape, and improved DOX sensitivity. A effective inhibition of tumor growth and metastasis was achieved by inhibiting Bcl-2/BAX, COX-2 and VEGF related signal pathways. Our finding suggests that the developed GTDC@M-R NPs present great treating effects in the preclinical models of TNBC, which broaden our insights into the application of combinational strategy for efficient TNBC therapy.

Background Elongation factor for RNA polymerase II 2 (ELL2) was reported as a putative tumor suppressor in the prostate. ELL2 is frequently down-regulated in prostatic adenocarcinoma specimens, and loss of ELL2 induced murine prostatic intraepithelial neoplasia and enhanced AR-positive prostate cancer cell proliferation. However, the ELL2 gene appears to be amplified in AR-negative neuroendocrine prostate tumors, suggesting a potential oncogenic role for ELL2 in AR-negative prostate cancer cells. In this study, we explored the potential function of ELL2 in PC-3 and DU145, two AR-negative prostate cancer cell lines. Materials and methods The role of ELL2 in PC-3 and DU145 cells was studied using siRNA-mediated ELL2 knockdown. Genes regulated by ELL2 knockdown in PC-3 cells were identified and analyzed using RNA-Seq and bioinformatics. The expression of representative genes was confirmed by Western blot and/or quantitative PCR. Cell growth was determined by BrdU, MTT and colony formation assays. Cell death was analyzed by 7-AAD/Annexin V staining and trypan blue exclusion staining. Cell cycle was determined by PI staining and flow cytometry. Results ELL2 knockdown inhibited the proliferation of PC-3 and DU145 cells. RNA-Seq analysis showed an enrichment in genes associated with cell death and survival following ELL2 knockdown. The interferon-γ pathway was identified as the top canonical pathway comprising of 55.6% of the genes regulated by ELL2. ELL2 knockdown induced an increase in STAT1 and IRF1 mRNA and an induction of total STAT1 and phosphorylated STAT1 protein. Inhibition of cell proliferation by ELL2 knockdown was partly abrogated by STAT1 knockdown. ELL2 knockdown inhibited colony formation and induced apoptosis in both PC-3 and DU145 cells. Furthermore, knockdown of ELL2 caused S-phase cell cycle arrest, inhibition of CDK2 phosphorylation and cyclin D1 expression, and increased expression of cyclin E. Conclusion ELL2 knockdown in PC-3 and DU145 cells induced S-phase cell cycle arrest and profound apoptosis, which was accompanied by the induction of genes associated with cell death and survival pathways. These observations suggest that ELL2 is a potential oncogenic protein required for survival and proliferation in AR-negative prostate cancer cells.

High-silica granites (typically > 70 wt.% SiO2) represent the products of extreme crustal differentiation, but whether their distinctive chemical compositions reflect source lithology or are produced via magmatic differentiation is commonly difficult to discriminate. To provide new insights into this issue, here we present high-precision Mg and Zn isotope data for high-silica, peraluminous leucogranites from the Himalayan orogen. The samples are subdivided into two-mica leucogranite, tourmaline leucogranite and garnet-bearing leucogranite based on their mineral assemblages. The two-mica leucogranites, representing the least evolved Himalayan leucogranites, have similar δ66ZnJMC 3-0749L (mean = 0.31 ± 0.06‰) but heavier δ26MgDSM-3 values (mean = −0.01 ± 0.12‰) relative to more mafic igneous rocks. This indicates that they were formed by anatexis of weathered silicates, consistent with the well-acknowledged metasedimentary source of the Himalayan leucogranites. In contrast, the more evolved tourmaline leucogranites and garnet-bearing leucogranites have lower δ26Mg and higher δ66Zn values compared with the two-mica leucogranites. The extremely low δ26Mg (−1.32‰ to −0.54‰) and high δ66Zn values (0.35–0.69‰) of garnet-bearing leucogranites vary systematically with indices of granitic differentiation (e.g., Zr/Hf, K/Rb, Eu/Eu*, 1/TiO2). Although exsolution of chlorine-rich fluid may result in elevated δ66Zn values, it is unlikely to explain the low δ26Mg signatures of the same samples. Analysis of major Mg-bearing minerals suggests that substantial segregation of tourmaline and/or Fe-Ti oxide could have driven the differentiated leucogranites towards very low δ26Mg values. In this regard, the slightly lower δ26Mg values (mean = −0.17 ± 0.06‰) of tourmaline leucogranites relative to the two-mica leucogranites may also reflect that the former were more differentiated than the latter. Thus, although source heterogeneity may be responsible for the Mg isotopic variations observed in some high-silica granites, our study implies that high-silica granites could be remarkably heterogeneous in terms of Mg isotopes primarily as a result of prolonged fractional crystallization at the late stage of melt evolution. The anomalously light Mg and heavy Zn isotopic signatures of garnet-bearing leucogranites highlight that Mg and Zn isotopes may be treated as important makers of highly fractionated granites in future studies.

A novel type of magnetic Fe2O3/Fe3O4 heterogeneous microparticles with ellipsoidal macropores was prepared via the ethanol-water reflux and rapid combustion process. The experimental results showed that the volume of absolute ethyl alcohol and the calcination temperature were the key factors to the grain sizes and the magnetic properties, the calcination temperature largely affected the saturation magnetization and the grain size of Fe2O3/Fe3O4 heterogeneous microparticles, and the amount of absolute ethyl alcohol also tremendously affected the saturation magnetization, however, the amount of absolute ethyl alcohol affected little on the grain size. Fe2O3/Fe3O4 heterogeneous microparticles calcined at 200 °C for 1 h with absolute ethyl alcohol of 20 mL had the largest saturation magnetization of 90.1 Am2/kg.

Led to significant capacity improvement to 1800 mA/h after 100 cycles for nano-graphene-N4, which is the first report for a carbonaceous materials anode. In addition, the doping level, id est, number of nitrogen atoms, had a significant influence on the molecular self-assembled structures through hierarchical self-assembly. As the nitrogen concentration increased, the d-space between the nanosheets increased from 3.4 to 4.3. The capacity of the nano-graphene increased greatly from 500 mAh/g for nano-graphene without N-doping to 1800 mAh/g for nano-graphene with nanographene-N4, indicating that the capacity is related to the structures, and was defined and the relationship between performance and structure was determined.

The α-Fe2O3 nanoparticles were prepared via the co-precipitation process, and they were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and selected area electron diffraction (SAED). The effect of the water bath temperature on the average grain size of the α-Fe2O3 nanoparticles was investigated. The minimum grain size of the α-Fe2O3 nanoparticles was 19.6 nm when the water bath temperature was 40 °C. Furthermore, the α-Fe2O3 nanoparticles were successfully modified with silica (SiO2) and chitosan (CTS) using the idea of nanoarchitectonics. the experimental results showed that, the average diameter of the as-prepared α-Fe2O3/SiO2 nanocomposites was around 65 nm; while, the average hydrodynamic diameter of the α-Fe2O3/CTS nanocomposites increased gradually with the increase of chitosan in solution. When the mass ratio of chitosan and the α-Fe2O3 nanoparticles reached 40:1, the diameter distribution range of the α-Fe2O3/CTS nanocomposites was very wide of 100– 900 nm, so the mass ratio of chitosan and the α-Fe2O3 nanoparticles was selected from 10:1 to 20:1 to be applied.

Magnetic Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles were synthesized by the absolute alcohol combustion method. The morphology, microstructure, and composition of as-prepared Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles were characterized by several techniques: the vibrating sample magnetometer (VSM), the scanning electron microscopy (SEM), the X-ray diffraction (XRD), and the energy dispersive spectroscopy (EDS). The experimental results showed that the calcination temperature and the solvent volume were the crucial factors for the synthesis of the magnetic Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles. The adsorption performance of Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles for congo red (CR) was investigated. The model of pseudo-second-order kinetic was optimal matching for obtaining the parameters of adsorption CR in the initial range of 100–400 mg/L−1, while, the isotherm data of CR onto Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles could conform to the Temkin model owing to the values of the square deviations, which revealed that the adsorption of CR onto Ni0.3Mg0.3Zn0.4Fe2O4 nanoparticles at room temperature was the monolayer and multilayer adsorption mechanism.

For energy storage system, it is still a huge challenge to achieve high energy density and high power density simultaneously. One potential solution is to fabricate electrochemical capacitors (ECs), which store electric energy through surface ion adsorption or redox reactions. Here we report a new electrode material, heavy nitrogen-doped(9.29 at.%) black titania (TiO2− x :N). This unique hybrid material, consisting of conductive amorphous shells supported on nanocrystalline cores, has rapid N-mediated redox reaction (TiO2− x Ny + z H+ + z e− « TiO2− x N y H z ), especially in acidic solutions, providing a specific capacitance of 750 F g−1 at 2 mV s−1 (707 F g−1 at 1 A g−1), great rate capability (503 F g−1 at 20 A g−1), and maintain stable after initial fading. Being a new developed supercapacitor material, nitrogen-doped black titania may revive the oxide-based supercapacitors.