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The development of alternative fuels is important in the fight against climate change. Both hydrogen and ammonia are renewable energy sources and are carbon-free combustible fuels. In a recent experimental study, the performance and emission characteristics of a spark-ignition engine burning a premixed hydrogen/ammonia/air mixture were evaluated. The manifold absolute pressure was adjusted to 61 kPa and the engine speed was stabilized at 1300 rpm. The difference between a mixture with a 2.2% volume fraction of ammonia and a pure hydrogen fuel was analyzed in comparison. Specifically, the addition of ammonia increased the ignition delay and flame development periods and reduced the rate of in-cylinder pressure rise. In conjunction with the ignition timing strategy, the addition of ammonia did not affect the engine performance. Nitrogen oxides emissions are increased due to the addition of ammonia. The experimental results suggest that ammonia can be used as a combustion inhibitor, which provides a new reference for the development of hydrogen-fuelled engines.

Based on the novel allosteric site of deoxyhypusine synthase (DHPS), two series of 30 novel 5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-amine derivatives as DHPS inhibitors were designed and synthesized. Among them, compound 8m, with the best DHPS inhibitory potency (IC50 = 0.014 μM), exhibited excellent inhibition against melanoma cells, which was superior to that of GC7. Besides, molecular docking and molecular dynamics (MD) simulations further proved that compound 8m was tightly bound to the allosteric site of DHPS. Flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA) showed that compound 8m could inhibit the intracellular reactive oxygen species (ROS) level. Furthermore, by western blot analysis, compound 8m effectively activated caspase 3 and decreased the expressions of GP-100, tyrosinase, eIF5A2, MMP2, and MMP9. Moreover, both Transwell analysis and wound healing analysis showed that compound 8m could inhibit the invasion and migration of melanoma cells. In the in vivo study, the tumor xenograft model showed that compound 8m effectively inhibited melanoma development with low toxicity.

To investigate the property of the promising and eco-friendly hydrogen-fueled rotary engine, the effect of excess air ratio on the combustion and emission characteristic of it was explored by experiment. The test was conducted under 1500 rpm and 5 CAD ADTC ignition timing. The test results demonstrated that with the decrease of excess air ratio from 2 to 0.85, the thermal efficiency of the hydrogen-fueled rotary engine increases first and then decreases. Besides, increasing MAP is beneficial to improve thermal efficiency. Among the tested condition, the highest brake thermal efficiency is realized when the rotary engine operates at 1.4 excess air ratio and 88 kPa MAP, about 18.34%. And the excellent HC and NO emissions can be obtained at the highest efficiency point. Besides, with the decrease of excess air ratio and the increase of load, the stability and flame development period gradually decrease. With a decreased excess air ratio, the flame propagation period decrease first and then increases, whereas work capacity and thermal efficiency increase first and then decrease. For NO emission, it will increase sharply near the equivalent ratio and gradually decrease after rich combustion. Also, according to the analytical model, it is found that the power performance of the rotary engine depends on the trade-off relationship of in-cylinder pressure and its angle of action.

Kitchen waste and wind erosion are two worldwide environmental concerns. This study investigated the feasibility of using kitchen waste for Sporosarcina pasteurii cultivation and its application in wind erosion control of desert soil via microbially induced carbonate precipitation (MICP). Enzymatic hydrolysis was adopted to improve the release and recovery of protein in kitchen waste for subsequent microorganism production. After conditions optimized, the maximum biomass concentration (OD600) and urease activity of Sporosarcina pasteurii in the kitchen waste-based medium reached 4.19, and 14.32 mM urea min−1, respectively, which were comparable to those obtained in conventional standard media. The harvested Sporosarcina pasteurii was then used to catalyze the precipitation of calcium carbonate in the desert soil, and its performance in wind erosion control was evaluated through wind tunnel tests. The microbially mediated calcium carbonate could significantly decrease wind erosion loss of the desert soil even after 12 wet–dry or freeze–thaw cycles. Scanning electron microscopy (SEM) with energy-dispersive X-ray (EDX) confirmed the bridge effect of calcium carbonate crystals in the soil matrix. The kitchen waste, as a cost-effective alternative nutrient for bacterial cultivation and carbonate precipitation, showed great potential for large-scale applications in wind erosion control of desert soils.

Formaldehyde (HCHO) is a reactive one-carbon compound that is interesting for biosynthesis. The assimilation of HCHO depends on the catalysis of aldolase. Here, we present a novel synthetic pathway...

Schaftoside and isoschaftoside are bioactive natural products widely distributed in higher plants including cereal crops and medicinal herbs. Their biosynthesis may be related with plant defense. However, little is known on the glycosylation biosynthetic pathway of these flavonoid di-C-glycosides with different sugar residues. Herein, we report that the biosynthesis of (iso)schaftosides is sequentially catalyzed by two C-glycosyltransferases (CGTs), i.e., CGTa for C-glucosylation of the 2-hydroxyflavanone aglycone and CGTb for C-arabinosylation of the mono-C-glucoside. The two enzymes of the same plant exhibit high homology but remarkably different sugar acceptor and donor selectivities. A total of 14 CGTa and CGTb enzymes were cloned and characterized from seven dicot and monocot plants, including Scutellaria baicalensis, Glycyrrhiza uralensis, Oryza sativa ssp. japonica, and Zea mays, and the in vivo functions for three enzymes were verified by RNA interference and overexpression. Through transcriptome analysis, we found homologous genes in 119 other plants, indicating this pathway is general for the biosynthesis of (iso)schaftosides. Furthermore, we resolved the crystal structures of five CGTs and realized the functional switch of SbCGTb to SbCGTa by structural analysis and mutagenesis of key amino acids. The CGT enzymes discovered in this paper allow efficient synthesis of (iso)schaftosides, and the general glycosylation pathway presents a platform to study the chemical defense mechanisms of higher plants.

Graphical abstract, Introduction The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment. Objectives Our research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC). Methods We obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound’s effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model. Results A series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX. Conclusion The anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC.

Wind erosion is a major cause of land desertification and sandstorm formation in arid and semi-arid areas. The objective of this study was to evaluate the potential of soybeans crude extract induced calcium carbonate precipitation (SICP) on reducing wind erosion risk of sandy soil. Field tests were carried out in Ulan Buh Desert, Ningxia Hui Autonomous Region, China. Results showed that the SICP method could significantly enhance the surface strength and wind erosion resistance of the topsoil. The optimal cementation solution (urea-CaCl2) concentration and spraying volume, according to experiments conducted on sandy land, were 0.2 mol/L and 4 L/m2, respectively. Under this condition, the CaCO3 content was approximately 0.45%, the surface strength of sandy soil could reach 306.2 kPa, and the depth of wind erosion was approximately zero, after 30 d completion of SICP treatment. Soil surface strength declined with the increase of time, and long-term sand fixation effects of SICP treatment varied depending on topography. Whereas wind erosion in the top area of the windward slope was remarkable, sandy soils on the bottom area of the windward slope still maintained a relatively high level of surface strength and a low degree of wind erosion 12 month after SICP treatment. Scanning electron microscopy (SEM) tests with energy dispersive X-ray (EDX) confirmed the precipitation of CaCO3 and its bridge effect. These findings suggested that the SICP method is a promising candidate to protect sandy soil from wind erosion in desert areas.

Serine protease Omi/HtrA2, a member of the HtrA family, is closely related to the maintenance of mitochondrial integrity and participates in apoptosis but its role in cerebral ischemia/reperfusion (I/R) injury and cellular oxidative stress response remains unclear. In this study, we found that I/R injury resulted in a time-dependent increase in Omi/HtrA2 expression in rat brain tissue. Inhibition of Omi/HtrA2 significantly inhibited XIAP cleavage in H2O2-induced PC12 cells. In addition, inhibition of Omi/HtrA2 significantly inhibited the up-regulation of mitochondrial stress proteins CHOP and ClpP, significantly reduced mitochondrial aggregation, and attenuated the decline of mitochondrial ΔΨm in PC12 cells. Studies show that there is a physical interaction between Omi/HtrA2 and OPA1. We found that Omi/HtrA2 and OPA1 are closely related to the oxidative stress mitochondrial response in PC12 cells. The current study has demonstrated that Omi/HtrA2 is upregulated in brain I/R injury in vivo and is implicated in mitochondrial response to oxidative stress in vitro by regulating mitochondrial stress proteins CHOP and CLpP and by interacting with mitochondrial cristae remodeling protein OPA1. These findings suggest that Omi/HtrA2 could be a candidate molecular target in diseases that involve oxidative stress such as in I/R injury. Abbreviation: ATP: Adenosine tripHospHate; Bax: BCL2-Associated X; Bcl-2: B-cell lympHoma-2; BSA: Albumin from bovine serum; DMEM: Dulbecco’s Minimum Essential Medium; DMSO: Dimethyl sulfoxide; HSP60: Heat shock protein60, 70; L-OPA1: Long forms of OPA1; Omi/HtrA2: high-temperature-regulated A2; MCAO: Middle cerebral artery occlusion; OPA1: Optic AtropHy; PBS: PHospHate buffered saline; PMSF: pHenylmethyl sulfonylfluoride; ROS: reactive oxygen species; SDS: Sodium dodecyl sulfate; S-OPA1: Short forms of OPA1; TTC: TripHenyltetrazalium chloride; XIAP: X-linked inhibitor apoptosis protein, GRAPHICAL ABSTRACT

Hitting SARS-CoV-2 in a new spot A key target for therapeutic antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the spike protein, a trimeric protein complex with each monomer comprising an S1 and an S2 domain that mediate binding to host cells and membrane fusion, respectively. In addition to the receptor binding domain (RBD), S1 has an N-terminal domain (NTD). In searching for neutralizing antibodies, there has been a focus on the RBD. Chi et al. isolated antibodies from 10 convalescent patients and identified an antibody that potently neutralizes the virus but does not bind the RBD. Cryo–electron microscopy revealed the epitope as the NTD. This NTD-targeting antibody may be useful to combine with RBD-targeting antibodies in therapeutic cocktails. Science , this issue p. 650

MXene is a rising star of two-dimensional (2D) materials for energy relative applications, however, the traditional synthesis of MXene etched by hazard HF acid or LiF+HCl mixed solution is highly dangerous with the risk of splashing or pouring liquid solutions. In this work, we developed a water-free ionothermal synthesis of 2D Ti3C2 MXene via etching pristine Ti3AlC2 MAX in low-cost choline chloride and oxalic acid based deep eutectic solvents (DES) with the presence of NH4F, thus it was highly safe and convenient to operate solid precursor and product materials at room temperature. Benefited from the low vapor pressure and solvating properties of DES, the prepared Ti3C2 (denoted as DES-Ti3C2) possessed a high purity up to 98% compared with 95% for HF etched Ti3C2 (denoted as HF-Ti3C2). Notably, an expanded interlayer spacing of 1.35 nm could be achieved due to the intercalation of choline cations in DES-Ti3C2, larger than that of HF-Ti3C2 (0.98 nm). As a result, the DES-Ti3C2 anodes exhibited enhanced lithium storage performance, such as high reversible capacity of 208 mAh g−1 at 0.5 A g−1, and long cycle life over 400 times, outperforming most reported pure MXene anodes. The ionothermal synthesis of MXene developed here may pave a new way to safely prepare other MXene for various energy relating applications.

Background. The casein kinase 2-interacting protein-1 (CKIP-1) is important in the development of osteoblasts and cardiomyocytes. However, the effects of CKIP-1 on osteoblast precursor mesenchymal stem cells (MSCs) remain unclear. This study aimed to determine whether CKIP-1 affects osteogenic differentiation in MSCs and explore the relationship of CKIP-1 and inflammation. Methods. Bone marrow MSCs of CKIP-1 wild type (WT) and knockout (KO) mice were cultivated in vitro. Cell phenotype was analyzed by flow cytometry, colony formation was detected to study the proliferative ability. Osteogenic and adipogenic induction were performed. The osteogenic ability was explored by alizarin red staining, alkaline phosphatase (ALP) staining and ALP activity detection. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to determine the mRNA expression levels of osteoblast marker genes. The adipogenic ability was detected by oil red O staining. Content of the bone was analyzed to observe the differences of bone imaging parameters including trabecular bone volume/tissue volume (BV/TV), bone surface area fraction/trabecular BV, trabecular number (Tb.N), and trabecular spacing (Tb.sp). Interleukin (IL)-1β was injected on WT mice of 2 months old and 18 months old, respectively. Difference in CKIP-1 expression was detected by RT-PCR and western blot. The relationship between CKIP-1 and inflammation was explored by RT-PCR and western blot. Results. ALP assays, alizarin red staining, and qRT-PCR showed that MSCs derived from CKIP-1 KO mice exhibited a stronger capability for osteogenesis. Micro-computed tomography detection showed that among 18-month-old mice, CKIP-1 KO mice presented significantly higher bone mass compared with WT mice (P = 0.02). No significant difference was observed in 2-month-old mice. In vivo data showed that expression of CKIP-1 was higher in the bone marrow of aging mice than in young mice (4.3-fold increase at the mRNA level, P = 0.04). Finally, the expression levels of CKIP-1 in bone marrow (3.2-fold increase at the mRNA level, P = 0.03) and cultured MSCs were up-regulated on chronic inflammatory stimulation by IL-1β. Conclusions. CKIP-1 is responsible for negative regulation of MSC osteogenesis with age-dependent effects. Increasing levels of inflammation with aging may be the primary factor responsible for higher expression levels of CKIP-1 but may not necessarily affect MSC aging.

Composite particles of carbon nanotubes (CNTs) and titanium dioxide (TiO2) were prepared by a sol-flux method. Characterization of TiO2/CNTs nanocomposite was performed by X-ray powder diffraction (XRD), transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS). The results show that TiO2 nanocrystals (mixed anatase and rutile) are successfully deposited on the surface of CNTs, forming a granular coating with a thickness of about 2 nm. It is possible that the growth of TiO2 on the surface of CNTs is implemented by anchoring TiO2 through hydroxyl and carboxylic functional groups. In the presence of TiO2/CNTs nanocomposite, the peak temperature of the high-temperature decomposition of ammonium perchlorate (AP) decreased by 52.5 °C, better than other samples including the one of simply mixed TiO2 and CNTs. The catalytic influence is evident even with 1% catalyst concentration. The thermal kinetic constant for the catalytic decomposition of AP is computed using model free (isoconversional) Flynn–Wall–Ozawa approach. It shows that although the two exothermic decomposition peaks merged into one, the low-temperature decomposition stage still exists, and accounts for about thirty percent of the whole reaction.

In this paper, the effects of direct water injection (WI) on characteristics of combustion and emission for a hydrogen (H2)-fueled spark ignition (SI) engine were experimentally investigated. The experiments conducted under different amounts of water injection (AWI) and varied water injection timing (WIT). The experimental results showed that in-cylinder pressure decreased, indicated thermal efficiency (ITE) increased, and the flame development (CA0-10) and propagation (CA10-90) periods prolonged when AWI raised. When AIW grew to 4.5 mg/cycle, Nitrogen oxides (NOx) expelled from the original engine decreased by 53.7% when excess air ratio (λ) was 1.15. Early WIT had positive effects on the reduction of NOx emissions. When WIT retarded, in-cylinder pressure increased, ITE decreased and CA0-10 and CA10-90 shortened, NOx emissions rapidly increased.

Cu-based catalysts have drawn much attention in ammonia-selective catalytic reduction (NH3-SCR) of NOx because of their outstanding low-temperature denitration (de-NOx) potential. Although satisfactory SCR performance was obtained with support from the catalytic activity of CuOx species in recent studies, the effect of the valence distribution of CuOx species on NH3-SCR reaction is still ambiguous, and elaborate exploration is necessary. Here, a series of CuAl-layered double oxide/carbon nanotubes-x (CuAl-LDO/CNTs-x) nanocatalysts with a tunable valence distribution of highly dispersed CuOx species was constructed from the topotactic transformation of CuAl-layered double hydroxide (CuAl-LDH) precursor and a controllable carbothermal reduction reaction. Multiple characterization techniques, including XRD, NH3-TPD, H2-TPR, NOx-TPD, XPS, in situ DRIFTS, and HR-TEM, were employed to elucidate the inherent relationship between the chemical properties and catalytic activity of the as-prepared catalysts. The obtained CuAl-LDO/CNTs-2 catalyst exhibited optimum catalytic performance, with NOx conversion exceeding 90% in the temperature range 180–305 °C. Such high catalytic efficiency can be attributed to the appropriate valence distribution of CuOx species, which can significantly improve the redox capacity and surface acidity of the catalysts, thereby promoting the adsorption and activation of the reactants. Combined with further theoretical calculation, a synergistic catalytic mechanism of Cu2O/CuO in the NH3-SCR reaction is tentatively proposed. Notably, the CuO active center can function as the dominant adsorption site of NO and NH3 to promote the formation of NO+ active species and the dehydrogenation activation of NH3. The Cu2O active center can act as the adsorption site for O, promoting the formation of active oxygen species O−. Consequently, the synergistic effect between Cu2O and CuO can lead to the rapid formation of reactive intermediates, proceeding via the Langmuir–Hinshelwood (reaction between adsorbed NH3 and adsorbed NOx) or Eley–Rideal (reaction between adsorbed NH3 and gaseous NO) mechanism reaction routes to complete the catalytic cycle. This work provides a fundamental understanding on Cu2O/CuO synergistic catalysis of NH3-SCR, which is propitious for the rational design and optimization of Cu-based oxide de-NOx catalysts.

Enzyme immobilization engineering is considered a valid strategy to improve the insensitivity of free enzymes to extreme conditions and thus extend their utilization in actual reactions. Although metal–organic frameworks (MOFs) are extensively applied as supports in enzyme immobilization, their separation from the liquid system after catalytic processes is problematic. In comparison, MOF-based membranes show more convenience in the subsequent solid–liquid separation. In this work, we constructed hybrid membranes by incorporating UiO-66 particles into porous polyvinylidene fluoride (PVDF) and then used them to immobilize lipase for the first time. Because of the strong affinity of UiO-66 towards lipase and the large cavity of PVDF, the hybrid membranes exhibited excellent immobilization ability towards lipase, and the resulting immobilized lipase showed an elevated operating temperature in the range of 40–70 °C with preserved activity and evidently improved thermal stability even after being stored at high temperatures for a definite time. The application of PVDF membrane makes the subsequent separation of the immobilized enzyme from the solutions easier. The immobilization kinetics, isotherm, and thermodynamics were analyzed in detail, and the immobilization mechanism was proposed. Furthermore, the immobilized lipase showed reusability and retained 48.2% of its initial activity after 7 cyclic reactions.

A facile synthetic route, by using rhombic dodecahedral zeolitic imidazolate framework-8 (ZIF-8) as the structure template, is devoted to fabricating the ZnS/ZnIn2S4 hybrid heterojunction; the compact heterostructure was produced by combining the sulfurization of ZIF-8 and the in situ precipitation of ZnIn2S4 in one pot. The resulting ZnS nanoparticles of about 100 nm were uniformly dispersed in the folds of flower-like ZnIn2S4, whose structure is beneficial for charge transfer at the heterointerface. The additional quantities of ZIF-8 are varied to find an optimum ratio of the two components to obtain the best photocatalytic activity. In the photocatalytic hydrogen generation irradiated by simulated solar light, all the ZnS/ZnIn2S4 hybrid photocatalysts displayed improved hydrogen production rates compared to single ZnS or ZnIn2S4, and the best hydrogen production rate of 453.4 μmol h−1 g−1 is obtained by ZnS/ZIS-20, whose value is approximately 4 times higher than that of single ZnIn2S4. The electrochemical properties of the ZnS/ZnIn2S4 hybrid photocatalysts were measured to explore the charge transfer mode at the interface, and the band structure and enhanced photocatalytic hydrogen generation mechanism have been proposed. The excellent recycling properties of hydrogen production indicated the prospective applications of this kind of ZIF-derived metal sulfide in photocatalytic reactions.

As a type of biological macromolecule, the conformation of proteins dynamically changes in a solution, which often results in a change in their function. However, traditional biological assays have significant drawbacks in detecting the conformation properties of proteins. Alternatively, nanopores have potential advantages in this area, which can detect protein in high throughput and without labelling. Herein, we investigated the translocation of calmodulins through silicon nitride nanopores using molecular dynamics (MD) simulation. Initially, the calmodulins were fixed in the nanopore. Distinguished blocked ionic currents were obtained between the two forms of calmodulin. Next, in the translocation simulations, a prominent difference in time resolution was easily found between the two states of calmodulin by using the appropriate voltage and comparable size of pore to protein, rp/rg→ 1, 4.5 nm (where rp is the protein radius and rg is the gyration radius). These simulations on the nanoscale are helpful for developing Ca2+-sensitive ion channels and nanodevices.

Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1β, IL-1β and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.

Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found that YH-9 could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover, YH-9 could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably, YH-9 could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis.

Exocytosis is a Ca2+-regulated process that requires the participation of Ca2+ sensors. In the 1980s, two classes of Ca2+-binding proteins were proposed as putative Ca2+ sensors: EF-hand protein calmodulin, and the C2 domain protein synaptotagmin. In the next few decades, numerous studies determined that in the final stage of membrane fusion triggered by a micromolar boost in the level of Ca2+, the low affinity Ca2+-binding protein synaptotagmin, especially synaptotagmin 1 and 2, acts as the primary Ca2+ sensor, whereas calmodulin is unlikely to be functional due to its high Ca2+ affinity. However, in the meantime emerging evidence has revealed that calmodulin is involved in the earlier exocytotic steps prior to fusion, such as vesicle trafficking, docking and priming by acting as a high affinity Ca2+ sensor activated at submicromolar level of Ca2+. Calmodulin directly interacts with multiple regulatory proteins involved in the regulation of exocytosis, including VAMP, myosin V, Munc13, synapsin, GAP43 and Rab3, and switches on key kinases, such as type II Ca2+/calmodulin-dependent protein kinase, to phosphorylate a series of exocytosis regulators, including syntaxin, synapsin, RIM and Ca2+ channels. Moreover, calmodulin interacts with synaptotagmin through either direct binding or indirect phosphorylation. In summary, calmodulin and synaptotagmin are Ca2+ sensors that play complementary roles throughout the process of exocytosis. In this review, we discuss the complementary roles that calmodulin and synaptotagmin play as Ca2+ sensors during exocytosis.

1,2-Dichloroethane (1,2-DCE) is a pervasive environmental pollutant found in ambient and residential air, as well as ground and drinking water. Overexposure to it results in cortex edema, in both animals and humans. 1,2-DCE induces apoptosis in the cerebellum, liver and testes. This promotes the hypothesis that 1,2-DCE may induce apoptosis in the cortex as brain edema progresses. To validate our hypothesis, 40 NIH male mice were exposed to 0, 100, 350, 700 mg/m3 1,2-DCE by whole-body dynamic inhalation for 28 consecutive days. MicroRNA (miRNA) and mRNA microarray combined with TdT-mediated dUTP nick-end labeling, flow cytometry, and mitochondrial membrane potential (mtΔΨ) measurement were applied to identify the cortex apoptosis pathways' specific responses to 1,2-DCE, in vitro and in vivo. The results showed that 1,2-DCE caused brain edema and increased apoptosis in the mouse cortexes. We confirmed that 1,2-DCE induced increased apoptosis via mitochondrial pathway, both in vitro and in vivo, as evidenced by increased Caspase-3, cleaved Caspase-3, Cytochrome c and Bax expression, and decreased Bcl-2 expression. Additionally, mtΔΨ decreased after 1,2-DCE treatment in vitro. 1,2-DCE exposure increased miR-182-5p and decreased phospholipase D1 (PLD1) in the cerebral cortex of mice. MiR-182-5p overexpression and PLD1 inhibition reduced mtΔΨ and increased astrocyte apoptosis, yet miR-182-5p inhibition alleviated the 1,2-DCE-induced PLD1 down-regulation and the increased apoptosis. Finally, PLD1 was confirmed to be a target of miR-182-5p by luciferase assay. Taken together, our findings indicate that 1,2-DCE exposure induces apoptosis in the cortex via a mitochondria-dependent pathway. This pathway is regulated by a miR-182-5p⊣PLD1 axie.

MOF/polymer hybrid membranes integrate the surface activity of MOFs and the advantages of PVDF membranes, and can be used as adsorption membranes in the efficient removal of target organics. In this work, a new hybrid membrane of ZIF-67/PVDF with varying ZIF-67 dosages has been fabricated through a facile mechanical blending followed by a lyotropic phase transition. Methods including field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), FT-IR analyses and surface hydrophobicity/hydrophilicity measurements are applied to characterize the structure, physicochemical properties and membrane performances. Two synthetic triarylmethane dyes, cationic malachite green (MG) and anionic fuchsin acid (FA), are chosen as the main adsorption targets to evaluate the adsorption capacities of the resulting ZIF-67/PVDF hybrid membranes. Interestingly, all of the ZIF-67/PVDF hybrid membranes exhibit distinctly favorable efficiencies and selectivities toward MG and FA compared to pristine PVDF, which proves the positive roles of ZIF-67 in the adsorption ability of the hybrid membranes. The adsorption conditions are optimized and the adsorption kinetics and thermodynamics are analysed to study the adsorption mechanism. The reusability and the structural stability of the hybrid membranes undergoing cyclic adsorption processes are also discussed. To the best of our knowledge, this is the first time that good adsorption capacities for MG and FA for these MOF/PVDF membranes have been reported. This work highlights the prospective applications of MOF/PVDF hybrid membranes in the rapid and effective removal of target organics in the treatment of waste water.

Extending applications of the mesoporous MOFs in the efficient removal of organic dyes have being concentrated on. In this paper, a nanoscale, mesoporous and amino-functionalized NH2-MIL-101(Cr) sized in 50 nm with uniform mesopores of 3.93 nm has been synthesized, the isoelectric point of which is at pH 8.5. The adsorption activities of NH2-MIL-101(Cr) toward the organic dyes including congo red (CR), methyl orange, direct blue 80, acid blue 1, rhodamine B and methyl blue have been studied. Comparatively, NH2-MIL-101(Cr) nanoadsorbents present the highest adsorption activity toward CR, which value is higher than most previously reported adsorption results of CR on other solid adsorbents. The CR adsorption is featured Langmuir monolayer adsorption, endothermic, increase entropy and spontaneous process with a negative ΔG°. The best adsorption selectivity for CR is attributed to the hydrogen bonding formed between CR and NH2-MIL-101(Cr), the matched molecular size and the electrostatic attraction.

CO2 dilution is an effective strategy for combustion control. To understand the detailed dilution effects of CO2 (including physical effects and chemical effects) on CH4 and H2 combustion, an open-source CFD package laminarSMOKE was utilized to simulate the transient one-dimensional outwardly spherical flame combustion process in a closed chamber under 0–15% CO2 dilution mole fraction (α), at 293 K, 1 bar, stoichiometric ratio. The overall CO2 dilution effects decrease the unstretched/stretched flame propagation speed, maximum combustion pressure and prolong the combustion duration. In most conditions, physical effects play a dominant role and chemical effects amplify the dilution effects. Typically, the maximum combustion pressure of CH4-CO2-air flame at α = 15% reduces 1.15 bar compared with the undiluted case, the reduction percentage caused by physical and chemical effects is 12% and 1.5%, respectively. In addition, opposite overall effects of CO2 dilution on Markstein length (Lb) of CH4 flames and H2 flame are performed. The physical effects of CO2 dilution increase the Lb of CH4 flames but decrease that of H2 flames. Chemical effects are similar to physical effects for CH4 flames, but non-monotonic behavior is performed for H2 flame due to the combined effects of density ratio and mixture reactivity changes.

Objective To investigate the effect of gross saponins of Tribulus terrestris (GSTT) on erectile function in rats resulting from type 2 diabetes mellitus (T2DMED). Methods The T2DMED model was constructed by high-fat and high-sugar feeding and streptozotocin injection. After 4 weeks of GSTT intervention. Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured in each group. The level of nitric oxide (NO) in the cavernous tissue was detected using the nitrate reductase method. The production of reactive oxygen species (ROS) was detected using DHE fluorescent probe detection. Cyclic adenosine monophosphate (cGMP) level was detected by enzyme-linked immunosorbent assay, and endothelial nitric oxide synthase (eNOS) was detected using immunohistochemistry. Masson staining was used to detect the cavernosal smooth muscle/collagen ratio. Apoptosis in endothelial cells was measured using TUNEL. Western blotting method to detect the protein expression level of eNOS, TIMP-1, cleaved caspase 3, and cleaved caspase 9. Results After treatment, the ICP and ICP/MAP values of the GSTT were significantly higher than those of the T2DMED group (P 0.05), and the mixed group had higher levels than these two groups (P

In this study, three kinds of CuAl-LDO/CNT (LDO, layered double oxide) catalysts were prepared by the assembly of CNTs and CuAl-LDH (LDH, layered double hydroxides) as well as subsequently structural topological transformation. The effects of the assembly method on the surface structure property and the DeNOx performance of the prepared samples were systematically investigated. It was found that three CuAl-LDO/CNT catalysts showed preferable NH3-SCR catalytic performance compared with CuAl-LDO where the catalyst CuAl-LDO/CNTs(I) exhibited optimum NOx conversion (>80%) and N2 selectivity (>90%) within 180-300 °C. Such fine catalytic performance can be attributed to the proper surface acidity and redox ability of the catalyst, which might be correlated with the high dispersion of Cu-based active centers caused by the induced nucleation and effective separation action of LDH by carbon nanotubes. In addition, the outstanding H2O and SO2 resistance of the CuAl-LDO/CNTs(I) catalyst was also obtained because of the synergistic effect between CuAl-LDO and CNTs, which could greatly promote the activation and decomposition of ammonium sulfate at lower temperatures.

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.

Thymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC50 = 0.67 μM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.

This study presents a direct-writing structure color patterns on electrospun colloidal fibers by inkjet printing. The colloidal fiber was obtained by electrospinning the aqueous mixture of colloidal particles of poly(styrene-methyl methacrylate-acrylic acid) and poly(vinyl alcohol). The pattern was obtained by directly inkjet printing water onto the electrospun colloidal fiber. The pattern formation was attributed to the morphological transition of the colloidal fiber from the fiber aggregation to latex aggregation and the corresponding color change due to the dissolution of poly(vinyl alcohol) by water. Interestingly, a clear and clean image was successfully obtained on the ethanol-treated colloidal fibers film in comparison to a confused and blur image onto the freshly-made film. It is because the treatment process can compact the fiber structure and lower the spreading/wetting behavior of ink on the fiber structure, contributing to the formation of high-quality pattern. Various letters or quick response code were flexibly designed and printed on to colloidal fibers. Furthermore, the pattern can be easily transferred onto flexible substrate, i.e., a flexible printed bracelet. This work will be of great significance for the development of novel wearable functional materials/devices based on electrospun colloidal fibers.

As a novel alkaloid, trolline is a potential methionine aminopeptidase Ⅱ inhibitor. However, up to now, no informations about the quantification of trolline were available in biosamples. In this study, a simple, specific and sensitive analytical method based on UHPLC-MS/MS method has been established and validated for determination of trolline in rat plasma and tissues after intravenous administration. Sample preparation was carried out by a simple liquid-liquid extraction and carbamazepine was used as internal standard (I.S.). Chromatographic separation was achieved by using a Waters BEH C18 column and involving the optimized mobile phase of 0.1% formic acid aqueous solution and acetonitrile with gradient elution flow of 0.20 ml/min. Trolline and I.S. were detected by multiple reaction monitoring (MRM) modes with positive electrospray ionization and transitions at m/z 220.0→136.8 for trolline and m/z 237.0→193.9 for carbamazepine (I.S.). Good linearity was ranged from 10.0 ng/ml to 4000 ng/ml for trolline both in plasma and various tissues. The lower limit of quantification (LLOQ) was 10 ng/ml in all samples. The intra- and inter-day precision (RSD%) were below 11.3% and the accuracy (RE%) was ranged from -10.2% to 12.3%. The validated method was successfully applied to the pharmacokinetics and tissue distribution study of trolline after intravenous administration.

MOFs/polymer hybrid membranes combine the special surface activity of MOFs and the excellent carries nature of porous polymer and thus exhibit unexpected adsorption/separation performances in the solid-phase extraction. In this paper, a new kind of MOFs/polymer composite membrane, MIL-68(Al)/PVDF have been fabricated for the first time through blending the MIL-68(Al) nanoparticles and polyvinylidene fluoride (PVDF) casting solution and following the lyotropic phase transition. Some means such as SEM, XRD and FT-IR are used to character the structure of these hybrid membranes. The membrane performances including the hydrophilic/hydrophobic properties, membrane porosity and membrane water flux are also measured. The effects of doping amount of MIL-68(Al) on the structure and performances of MIL-68(Al)/PVDF hybrid membranes are discussed. Two persistent organic pollutants: p-nitrophenol (PNP) and methylene blue (MB) are chosen as main adsorption objects to evaluate the adsorption activity of MIL-68(Al)/PVDF hybrid membranes. The influences of various conditions on the adsorption activities are investigated in detail and the optimum adsorption conditions are determined. All the MIL-68(Al)/PVDF hybrid membranes exhibit enhanced adsorption capacity compared to pristine PVDF, and the adsorption activities of hybrid membranes are promoted continually with the increasing doping contents of MIL-68(Al). The adsorption thermodynamics analysis indicates that the adsorption process is mainly characterized by Langmuir monolayer adsorption and chemical adsorption. The coordination bonding formed between NO2 of PNP and Al(III) of MIL-68(Al), and the acid-base interaction between the sulfur of MB and Al(III) of MIL-68(Al) may be responsible to the highest removal efficiency of PNP and MB. The good dynamics adsorption and regeneration performances indicate the prospect applications of these MOFs/PVDF hybrid membranes in the separation of organic contaminants from industrial waste water.

China's carbon emissions is heavily influenced by economic growth, which can be largely related to the local officials' promotion incentives. The current study was conducted to test the hypothesis that the influence of local officials' individual characteristics on carbon emissions was driven by the promotion incentives. Yangtze River Delta where carbon emissions accounted for around 13.95% of China's total emissions was selected as the research area. The multiple linear regression model was applied to determine the relationship between local officials' characteristics and total carbon emissions and carbon emissions from different sectors. The results indicated that local officials' promotion source, tenure and age significantly influenced the total carbon emission. Despite insignificance influence of officials' academic level on carbon emissions, the professional background in economics and management had a significant influence on carbon reduction. Our results indicated the importance of local officials' promotion incentives for carbon emission in China. Therefore, low carbon development should be included as an important part of official promotion system.

Recently, metal-organic frameworks (MOFs) have been applied in the efficient removal of persistent organic dyes owing to their high porosity, large surface area and tunable pore size. In this paper, polyethyleneimine (PEI) incorporated Cu-BTC composites have been applied in the efficient removal of congo red for the first time. Some means such as Field emission scanning electron microscope (FESEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy(XPS), Fourier-transform infrared spectroscopy (FT-IR), Thermal gravity analysis (TG) and Zeta potential measurement have been employed to character these Cu-BTC composites. The modification of PEI with a certain loading amount can alter the morphology and also change the surface charge of Cu-BTC evidently, as a result the PEI-modified Cu-BTC composites present the positive zeta potential within a wide pH range, that is beneficial for the effective adsorption toward anionic dyes. Four persistent anionic dyes including congo red (CR), acid blue 1(AB1), methyl orange(MO) and direct blue 80 (DB80) are used to evaluate the adsorption activity of PEI-modified Cu-BTC, and among them CR displays the best adsorption selectivity, which capacity is about 20 times of the values of other three dyes. And the adsorption capacity of CR is also higher than the most reported removal rate by other MOF-based adsorbents. The adsorption kinetics analyses demonstrate that a combined physical and chemical interaction have worked in the CR adsorption at room temperature, and the adsorption thermodynamics indicates a endothermic, increase of entropy and spontaneous process with a negative ΔGƟ. The adsorption mechanism is also discussed, and the hydrogen bond formed between PEI-modified Cu-BTC and CR might be responsible for the ultra-high adsorption capacity of CR. The better reusability indicates that these PEI-modified Cu-BTC can be applied in the efficient removal of CR from practical waste water.

Herein, a series of NiTi-LDHs were synthesized, calcined and tested in the removal of NOx by selective catalytic reduction with NH3 (NH3-SCR). Appropriate calcination temperatures as well as Ni/Ti molar ratios of LDH precursors were systematically identified to achieve optimal catalysis; the results pronouncedly affirmed that the catalytic performances of the as-acquired catalysts were vulnerable to the calcination temperature and Ni/Ti molar ratios, where the Ni4Ti1-400 catalyst presented optimal DeNOx activity (over 90% NOx conversion with nearly 95% N2 selectivity in the region of 240–360 °C), SO2 resistance and stability. Multiple characterization techniques revealed that the excellent catalytic performance of Ni4Ti1-400 could be attributed to the favorable interaction between the Ni and Ti species, consequently resulting in higher specific surface area, enhanced acidity, increased content of the surface Ni3+ species, and improved cycle reactions of NH3-SCR.

The residual capacity of energy storage battery is an important index of flight safety as well as an essential parameter in the process of flight strategy design of a solar powered communication/remote-sensing UAV. SOC (State-Of-Charge) is generally used to represent the residual capacity of energy storage battery. Its physical meaning is the ratio of the residual capacity of battery and its capacity in completely charging state. The energy storage battery module will take the charge-discharge power as input and SOC as output. As for the practical application of the battery, the accuracy of models and parameters become technical difficulties. Through the test and analysis of lithium batteries, various factors affecting the performance of batteries are found out and the test data of lithium batteries are obtained. This paper analyzes the test data and the models together and evaluates the parameters of lithium batteries through exponential curve fitting and least-square parameter identification. Moreover, the application effects of the two methods are summarized and compared.

A novel CuAlOx/CNTs catalyst was prepared by facile one-step carbothermal reduction decomposition method and tested for low temperature selective catalytic reduction of NOx with NH3 (NH3-SCR). Resulting samples were characterized by XRD, FT-IR, XPS, H2-TPR, NOx-TPD and TEM techniques. As the results presented, more favourable formation of Cu+ active sites, better dispersion of active CuO species and higher surface adsorbed oxygen were constructed in CuAlOx/CNTs catalyst, which are crucial for excellent DeNOx activity. Meanwhile, the outstanding SO2/H2O tolerance was also obtained, indicating its potential practical value.

Background Micro- and nanoplastic pollution has become a global environmental problem. Nanoplastics in the environment are still hard to detect because of analysis technology limitations. It is believed that when microplastics are found in the environment, more undetected nanoplastics are around. The current “microplastic exposure” is in fact the mixture of micro- and nanoplastic exposures. Therefore, the biological interaction between organisms among different sizes of micro- and nanoplastics should not be neglected. Results We measured the biodistribution of three polystyrene (PS) particles (50 nm PS, PS50; 500 nm PS, PS500; 5000 nm PS, PS5000) under single and co-exposure conditions in mice. We explored the underlying mechanisms by investigating the effects on three major components of the intestinal barrier (the mucus layer, tight junctions and the epithelial cells) in four intestine segments (duodenum, jejunum, ileum and colon) of mice. We found that the amounts of both PS500 and PS5000 increased when they were co-exposed with PS50 for 24 h in the mice. These increased amounts were due primarily to the increased permeability in the mouse intestines. We also confirmed there was a combined toxicity of PS50 and PS500 in the mouse intestines. This manifested as the mixture of PS50 and PS500 causing more severe dysfunction of the intestinal barrier than that caused by PS50 or PS500 alone. We found that the combined toxicity of PS micro- and nanoplastics on intestinal barrier dysfunction was caused primarily by reactive oxygen species (ROS)-mediated epithelial cell apoptosis in the mice. These findings were further confirmed by an oxidants or antioxidants pretreatment study. In addition, the combined toxicity of PS micro- and nanoplastics was also found in the mice after a 28-day repeated dose exposure. Conclusions There is a combined toxicity of PS50 and PS500 in the mouse intestines, which was caused primarily by ROS-mediated epithelial cell apoptosis in the mice. Considering that most recent studies on PS micro- and nanoplastics have been conducted using a single particle size, the health risks of exposure to PS micro- and nanoplastics on organisms may be underestimated.

This study is to investigate the underlying mechanisms of mitochondrial quality control (MQC) regulated by HtrA2/Omi during ischemia/reperfusion (I/R). We utilized the mnd2 mouse model, which has a missense mutation in HtrA2/Omi, to investigate the HtrA2/Omi regulation in mitochondria after I/R injury in the cerebral cortex. Compared to homozygous (HtrA2mnd2) mice, heterozygous (HtrA2Hetero) mice showed aging signs at a later age, increased HtrA2/Omi expression in the brain cortex, and lesser neurodegenerative signs. The brain cortex of HtrA2Hetero mice had increased superoxide dismutase (SOD) activity; lower levels of malondialdehyde (MDA); higher expressions of mitochondrial unfolded protein response (mtUPR)-related proteins, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (Ndufs7), and uncoupling protein 2 (UCP2) proteins; more mitochondrial fission; higher levels of ATP and mtDNA copies; elevated sirtuin 3 (SIRT3) activity; and increased NAD+/NADH ratio. After 1.5 h of I/R, the brain cortex of HtrA2Hetero mice had a larger infarction size, reduced HtrA2/Omi expression, decreased S-X-linked inhibitor of apoptosis protein (XIAP), and increased C-Caspase3 than that of wild-type animals (WT). Mitochondria from the HtrA2Hetero brain cortex showed decreased ATP production and MQC deficiency after 1.5 h I/R. Genipin pre-treatment reduced the aforementioned I/R injury in the HtrA2Hetero brain cortex. In conclusion, mitochondrial function is compensated in the HtrA2Hetero brain cortex via the upregulation of the UCP2-SIRT3-PGC1 axis. Decreased HtrA2/Omi function damages mitochondrial quality in the HtrA2Hetero mouse brain cortex, leading to more brain I/R injury. Genipin pre-treatment ameliorates brain damages via the mitochondrial UCP2-SIRT3-PGC1 axis.

In this study, a combination of network pharmacology, bioinformatics analysis, molecular docking and transcriptomics was used to investigate the active ingredient and potential target ofGelsemium elegansin the treatment of colorectal cancer. Koumine was screened as the active component by targeting PDK1 through network pharmacology and reverse docking. RNA-Seq, enrichment analysis and validation experiment were then further employed to reveal koumine might function in inhibiting Akt/mTOR/HK2 pathway to regulate cell glycolysis and detachment of HK2 from mitochondria and VDAC-1 to activate cell apoptosis bothin vitroandin vivo. In the present study, we provide a systematical approach for the identification of effective ingredient and potential target of herbal medicine. Our results have important implication for the intensive study of koumine as novel anticancer agents for colorectal cancer and could be supportive in its further structural modification.

An amendment to this paper has been published and can be accessed via the original article.

Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC50 = 0.62 μM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC50 = 8.91 μM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors.

Src plays a crucial role in many signaling pathways and contributes to a variety of cancers. Therefore, Src has long been considered an attractive drug target in oncology. However, the development of Src inhibitors with selectivity and novelty has been challenging. In the present study, pharmacophore-based virtual screening and molecular docking were carried out to identify potential Src inhibitors. A total of 891 molecules were obtained after pharmacophore-based virtual screening, and 10 molecules with high docking scores and strong interactions were selected as potential active molecules for further study. Absorption, distribution, metabolism, elimination and toxicity (ADMET) property evaluation was used to ascertain the drug-like properties of the obtained molecules. The proposed inhibitor&ndash, protein complexes were further subjected to molecular dynamics (MD) simulations involving root-mean-square deviation and root-mean-square fluctuation to explore the binding mode stability inside active pockets. Finally, two molecules (ZINC3214460 and ZINC1380384) were obtained as potential lead compounds against Src kinase. All these analyses provide a reference for the further development of novel Src inhibitors.

To detect parts per billion (ppb)-level volatile organic compounds (VOCs) in automobiles, a pre-concentrator is generally needed for electronic noses (e-noses), which can enrich ppb-level concentration to parts per million (ppm) level. However, the current e-nose chamber structure could dilute the pre-concentrated gases and then the detection performance is reduced. To solve this problem, a novel chamber design was proposed in this paper. The core design idea was to reduce the space for the gas flow in the chamber, taking into account the shape and size of the gas sensors. Specially, for the pin-type gas sensors, a series of cylindrical structure design was adopted, and for the micro-electro-mechanical system (MEMS) patch-type sensors, the headspace was compressed. The results of computational fluid dynamics (CFD) based simulation showed that the concentration of pre-concentrated gases in the novel chamber was higher than that of the traditional chamber. The designed chambers were manufactured using polylactic acid (PLA) material by 3D printing. Experimental gases were prepared from polyurethane (PU) leather and polyvinyl chloride (PVC) leather to verify the performance of the chambers, and the results demonstrated that the proposed new e-nose chamber was superior to the traditional one in terms of the pre-concentration effect, repeatability and classification performance.

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.