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Herein, Mo2FeB2-based cermets, with nominal composition of Mo2FeB2-2.06Fe-2.9Ni-2.5Cr-xWC-0.04C (x = 0, 2.5, 5, 10 wt %), are fabricated by multi-step sintering to investigate influence of tungsten carbide (WC) content on microstructure and mechanical properties. Results reveal that the microstructure of WC-free cermets resembles that of traditional cermets. However, microstructure of WC-containing cermets (x = 2.5 wt %) is composed of fine black core/grey rim Mo2FeB2 grains and coarse white-colored coreless Fe3(W,Mo)3C grains. Furthermore, at x ≥ 5 wt %, most of white coreless Fe3(W,Mo)3C grains are transformed into a white core/black rim structure. From these observations, it can be concluded that growth of nearly round-shaped Mo2FeB2 grains is through diffusion-control, leading to normal grain growth (NGG), whereas the growth of polyhedral Fe3(W,Mo)3C grains is dictated by the interfacial reactions, resulting in 2D nucleation and partially abnormal grain growth (AGG). In addition, grain size distribution of WC-containing cermets exhibits distinct bimodal characteristics, where average grain size is smaller than that of WC-free cermets. More importantly, presence of WC significantly improves the mechanical properties, resulting in superior fracture toughness of 25.1 ± 0.5 MPa m1/2 and hardness of 90.3 ± 0.1 HRA, at x = 5 wt %, without compromising much of transverse rupture strength.

Complete solid-solution Ti(C,N)-based cermet, with no typical core-rim structure, was synthesized through mechanical activation and subsequent in situ carbothermal reduction method. XRD, SEM, TEM, and C/N analysis were used to investigate the microstructure, phase transformation, and the interfacial characteristics of the present cermets. During solid-state sintering, the (Ti,Mo)C/(Ti,Mo)(C,N) phases formed through the transformation of Mo-based solid solution which generated by mechanical activation. Then, the formed (Ti,Mo)C/(Ti,Mo)(C,N) continuously dissolved into the nickel-based binder above 1100 °C. It was found that in the subsequent stage of liquid sintering, the mechanical activation and also the presence of extremely fine TiC/Ti(C,N) particles accelerated the Mo diffusion into the hard phase, resulting in a large quantity of (Ti,Mo)(C,N) solid solutions formed in the nickel-based binder. Finally, complete (Ti,Mo)(C,N) solid-solution phase was obtained via dissolution and re-precipitation. The higher toughness and transverse rupture strength (TRS) of the synthesized new cermet, as compared with traditional cermets, were mainly caused by the increased crack deflection and transgranular fracture of the novel cermets. Moreover, the interface among the Ni-based binder phase and complete solid solution hard phase exhibited a semi-coherency state with high-density dislocations, which also significantly improved the TRS and toughness of the synthesized cermets.

Herein, Ti(C,N)-based cermets prepared via mechanical activation and subsequent in situ carbothermal reduction was studied. The correlation between microstructural and mechanical performance of these cermets was investigated by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Results indicated that with the increase in tungsten carbide (WC) content, hard particles of ceramic gradually evolved from complete solid solution to partial solid solution with a little quantity of core–rim structure. Mean particle size of the cermet first increased, and then, slightly decreased. In addition, grain shape gradually changed from relatively faceted to nearly round. Initially, with the increase in WC content, the increase in transverse rupture strength (TRS) and slight increase in hardness were related to the strengthening of both solid solution and fine grains. However, with further addition of WC, the decrease in hardness was primarily because of lower hardness of (Ti,W,Mo) (C,N) phase with higher W content. Extremely high toughness of cermets with WC content of 0 and 3 wt% was mainly due to the decrease in interface area compared to traditional cermets, which resulted in significant reduction in interfacial strain between the rim and core. Moreover, toughness improvement of cermets containing 6 to 12 wt% of WC was due to comprehensive effect of superb coherent relationship of black core/grey rim particles, semi-coherent relationship with high-density dislocations of solid-solution particles, and solid-solution strengthening of white core-grey rim particles.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment., Graphical Abstract

Introduction Enterococcus faecalis is a significant cause of nosocomial infections and is difficult to treat because of intrinsic and acquired resistance to many antibiotics. In addition, the emergence of linezolid-resistant E. faecalis (LZR-Efa) is reducing the choices available for anti-infective therapy. The aim of this study was to examine the in vitro antibacterial effects of fosfomycin (FM), vancomycin (VAN) and daptomycin (DAP), alone and in combination, against LZR-Efa. Methods Five LZR-Efa strains and E. faecalis ATCC 29212 were studied. The antibacterial effects of FM, and of FM, VAN and DAP, were assessed using the time–kill assay. Biofilm formation and elimination were evaluated by crystal violet staining. Results When used at concentrations greater than 0.5 × MIC, FM did not produce dose-dependent effects against LZR-Efa isolates. The use of DAP (47.1 mg/L) alone, and FM (83 mg/L) combined with DAP (20.6 mg/L), produced a persistent inhibitory effect against both planktonic LZR-Efa isolates and those forming biofilms. In addition, FM and VAN combined with glucose-6-phosphate produced visible eradication effects against biofilms grown for 24 h, while DAP alone or combined with FM resulted in the best eradication activity against biofilms grown for 72 h prior to exposure. Conclusion The use of FM combined with DAP provided the best potential therapeutic option for treating LZR-Efa infections out of those tested. In addition, the optimum treatment for biofilm elimination depended on the stage of biofilm formation. Electronic supplementary material The online version of this article (10.1007/s40121-020-00342-1) contains supplementary material, which is available to authorized users.

Background and aim Globally, China has the highest chronic hepatitis C (CHC) burden, but its real-world direct-acting antiviral (DAA) data are limited. Our aim is to investigate the real-world outcome of China Food and Drug Administration-approved DAA therapies across mainland China including those with genotype (GT) 3. Methods The REAL-C is a multinational real-world interferon-free DAA-treated CHC registry of several mainland China and other Asian centers. We evaluated the sustained virological response rate 12 weeks after end of treatment (SVR12), adverse events, and treatment effect on liver function and fibrosis (fibrosis-4 index). Results We analyzed 859 DAA-treated CHC patients (6/1/2017-5/30/2019) from 12 mainland China centers (three municipalities and nine provinces): median age 52, 49.9% male, 33.1% cirrhosis, 95% treatment naive, and 2.5% HBsAg+ . The most common GT was GT1b (523, 62.2%), followed by GT2a (156, 18.5%), GT3b (74, 8.8%), GT3a (41, 4.9%), and GT6 (37, 4.4%). SVR12 rates were 98.0% overall (95% confidence interval 96.9-98.8%), 98.1% for GT1b, 96.8% GT2a, 100% GT3a, 97.3% GT3b, and 100% GT6. Baseline cirrhosis and male sex but not prior treatment history, renal dysfunction, age, and GTs were associated with SVR12. For both cirrhotic and non-cirrhotic patients, there were significant improvement in liver function tests, alpha fetoprotein, and fibrosis-4 index with SVR12. Serious adverse events were rare (1.1%) with only nine patients discontinuing therapy prematurely and anemia being the most common adverse event (13.1%, mostly with ribavirin). Conclusions In real-world Chinese patients with diverse GTs, Chinese Food and Drug Administration-approved interferon-free DAAs were well tolerated, provided high cure rates (98.0% overall) including GT3a/3b, and led to improvement of liver function.

The influence of Cr and W addition on microstructure and mechanical properties of Mo2FeB2-based cermets, prepared by multi-step sintering, is systematically evaluated by XRD, SEM, EDS, and TEM. After liquid-phase sintering, the final microstructure of Cr-doped Mo2FeB2-based cermets is similar to that of traditional Mo2FeB2-based cermets. The cermet, with 2.5% Cr content, exhibits superior comprehensive mechanical properties, i.e., Rockwell hardness, transverse rupture strength (TRS) and fracture toughness of 87.6 HRA, 2179 MPa and 21.7 MPa m1/2, respectively. In contrast, for W-doped Mo2FeB2-based cermets, a large amount of W-enriched (Mo,Fe,W)3B2 solid solutions precipitated around undissolved Mo2FeB2 particles, resulting in the formation of black core/gray rim structure. Particularly, a transition layer, with several atomic layer thickness, is observed between (Mo,Fe,W)3B2 rim phase and Fe-based binder phase, which corresponds to B-deficient (Mo,Fe,W)3B2−x orthorhombic boride phase. Moreover, the lattice mismatch between (Mo,Fe,W)3B2 and (Mo,Fe,W)3B2−x is found to be 1.9%. When doped with 5 wt% W, Mo2FeB2-based cermet exhibit superior comprehensive mechanical properties with Rockwell hardness of 84.6 HRA, TRS of 2088 MPa and fracture toughness of 24.4 MPa m1/2. The increase of fracture toughness (KIC) can be ascribed to the presence of W-rich transition layer.

To tackle global water pollution and shortage, solar-driven interfacial water evaporation has been demonstrated as a promising strategy for clean water generation. However, most of the previously reported interfacial evaporation systems only work in rich sunlight, which vastly limits their application under dark conditions. Herein, we propose an all-day solar-driven vapor generator based on metal foam via the photothermal effect in combination with Joule heating. A copper oxide (CuO) needle array and carbon black (CB) nanoparticles were assembled around a copper (Cu) skeleton to obtain CuO/Cu–CB foam with decent interfacial evaporation and salt resistance performance. The water evaporation rate reached 1.65 kg m−2 h−1 under one sun irradiation. Moreover, the vapor generation rate of the device reached 4.50 kg m−2 h−1 when a voltage as low as 2 V was applied. Besides, the CuO/Cu–CB foam can effectively remove the pollutants in the water and the methylene blue (MB) removal efficiency reached ∼98% without any oxide agents after 12 hours of illumination. Therefore, this all-day solar-driven vapor generation device supplies an effective pathway to mitigate freshwater scarcity.

Tropomyosin receptor kinase A (Trk A) is a receptor tyrosine kinase activated by nerve growth factor (NGF). TrkA plays an important role in pain sensation, which leads to significant interest in the development of small molecule inhibitors of TrkA. However, TrkA and the other two highly homologous isoforms, TrkB and TrkC, are highly conserved in the ATP binding site, which suggests that achieving TrkA subtype selectivity over TrkB and TrkC in this site may be extremely challenging. Allosteric inhibitors without making any interactions with the conserved ATP binding site may present a more promising approach. Recently, selective TrkA inhibitors

A novel multi-step sintering approach was adopted to eliminate the boride reticular structure from Mo2FeB2-based cermets. First, Mo2FeB2 hard phase was synthesized by reaction boronizing sintering and pulverized into powders. Subsequently, the pre-sintered powders were mixed with other compositions, and then the mixture was pressed and sintered. During solid-state sintering, most of the coarse Mo2FeB2 hard phase particles remained undissolved. The boride complex solid solutions containing small amounts of Cr and W precipitated around the remaining Mo2FeB2 hard phase particles during liquid phase sintering, resulting in a black core/gray rim structure. The SAED analysis revealed that the black cores and the gray rims of Mo2FeB2 grains possessed the same crystal structure with similar lattice parameters. Notably, the gray rims enriched in W and Cr improved the wettability of the system, leading to the elimination of large pores. Furthermore, the as-prepared Mo2FeB2-based cermet demonstrated superior mechanical properties, i.e., transverse rupture strength of 2219 MPa and fracture toughness of 23.1 MPa m1/2, which were 15% and 25.5% higher than the traditional Mo2FeB2-based cermet, respectively.

Functionally graded WC–Co cemented carbides (FG WC–Co) with plate-like WC grains were fabricated by carburizing of cemented carbides with no η phase. The phase composition and microstructure of FG WC–Co were investigated by XRD, SEM and EDX. The results showed that a cobalt-deficient layer was formed due to difference in affinity among carbon and other alloying elements. WC grain size increased while the ratio of side length to thickness decreased slightly in the surface zone due to difference of growth rate between different planes of WC grains. Moreover, FG WC–Co possessed an 80 μm deep cobalt-deficient layer, and showed excellent mechanical properties with a surface hardness of 1748 HV and fracture toughness of 9.6 MPa · m1/2 in the surface zone.

Glioma is the most common and aggressive tumor of the central nervous system. The uncontrolled proliferation, cellular heterogeneity, and diffusive capacity of glioma cells contribute to a very poor prognosis of patients with high grade glioma. Compared to normal cells, cancer cells exhibit a higher rate of glucose uptake, which is accompanied with the metabolic switch from oxidative phosphorylation to aerobic glycolysis. The metabolic reprogramming of cancer cell supports excessive cell proliferation, which are frequently mediated by the activation of oncogenes or the perturbations of tumor suppressor genes. Recently, a growing body of evidence has started to reveal that long noncoding RNAs (lncRNAs) are implicated in a wide spectrum of biological processes in glioma, including malignant phenotypes and aerobic glycolysis. However, the mechanisms of diverse lncRNAs in the initiation and progression of gliomas remain to be fully unveiled. In this review, we summarized the diverse roles of lncRNAs in shaping the biological features and aerobic glycolysis of glioma. The thorough understanding of lncRNAs in glioma biology provides opportunities for developing diagnostic biomarkers and novel therapeutic strategies targeting gliomas.

As a promising therapeutic target for gout, hURAT1 has attracted increasing attention. In this work, we identified a novel scaffold of hURAT1 inhibitors from a personal natural product database of verified herb-treated gout. First, we constructed more than 800 natural compounds from Chinese medicine that were verified to treat gout. Following the application of both shape-based and docking-based virtual screening (VS) methods, taking into account the shape similarity and flexibility of the target, we identified isopentenyl dihydroflavones that might inhibit hURAT1. Specifically, 9 compounds with commercial availability were tested with biochemical assays for the inhibition of 14C-uric acid uptake in high-expression hURAT1 cells (HEK293-hURAT1), and their structure-activity relationship was evaluated. As a result, 8-isopentenyl dihydroflavone was identified as a novel scaffold of hURAT1 inhibitors since isobavachin (DHF3) inhibited hURAT1 with an IC50 value of 0.39 ± 0.17 μM, which was comparable to verinurad with an IC50 value of 0.32 ± 0.23 μM. Remarkably, isobavachin also displayed an eminent effect in the decline of serum uric acid in vivo experiments. Taken together, isobavachin is a promising candidate for the treatment of hyperuricemia and gout.

In this study, different metal-salt catalyzed pretreatment was presented to disorganize the obstinate structure by eliminating the majority of hemicellulose, fractional of lignin, and improve the enzymatic saccharification of sugarcane bagasse. With the accession of Tween 80 during enzymolysis, all metal-salt pretreated substrates presented higher glucose yields, especially for CuCl2. Furthermore, Tween 80 was added to the pretreatment, enhancing the elimination of hemicellulose and lignin, decreasing the degradation of sugars to inhibitors, and presenting superior performance on improving glucose yield. In addition, the maximum glucose yield of 88.0% was achieved by using Tween 80 concomitantly with AlCl3 pretreatment and enzymolysis. It was also found that adding Tween 80 during pretreatment or/and enzymolysis after 24 h could liberate the similar glucose without Tween 80 after 72 h. However, the enhancement of Tween 80 at 6 h was higher than that at 72 h.

Combination therapy is an important method for treating advanced hepatocellular carcinoma (HCC). Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor, which has profound effects on HCC. The purpose of the present study was to investigate the effects of genistein in combination with gefitinib on the proliferation and apoptosis of HCC cells and the associated mechanism. Cell counting kit-8 assay was performed to calculate the IC50 values and cytotoxicity, whilst flow cytometry was used to assess cell apoptosis. Protein expression was detected using western blot analysis. The IC50 of genistein and gefitinib on Hep3B cells were calculated to be 128.078 and 13.657 µM, respectively. Genistein in combination with gefitinib significantly inhibited cell viability, promoted apoptosis and reduced EGFR, vascular endothelial growth factor receptor and platelet-derived growth factor receptor phosphorylation. Genistein in combination with gefitinib promoted the expression of cleaved caspase-3 and cleaved poly ADP-ribose polymerase. In addition, combined treatment of genistein and gefitinib strongly inhibited the activation of the Akt/Erk/mTOR signaling pathway. In conclusion, findings from the present study suggest that genistein in combination with gefitinib inhibit HCC cell proliferation and promote apoptosis by inhibiting the Akt/Erk/mTOR pathway.

The chemical mechanical polishing (CMP) of ruthenium (Ru) based barrier layer has been a pivotal process in the manufacture of a novel copper (Cu) interconnect structure. This paper mainly investigated the role of NH4+ in colloidal silica slurries for Ru CMP. The polishing results show that the Ru removal rate increases with the increasing concentration of NH4+. The influence mechanism of NH4+ on removal rate of Ru was investigated by electrochemistry, scanning electron microscope (SEM) and zeta potential. It is revealed that the NH4+ can promote the surface corrosion rate of Ru by forming a water-soluble Ru-NH4 complex with Ru oxide, meanwhile can also result in the neutralization of the zeta potentials of both silica particles and the Ru surface, and thus can lead to the decrease of the electrostatic repulsive force and the increase of the mechanical abrasion intensity between silica particles and Ru surface. Further, the surface quality of the polished Ru wafer and slurry stability were evaluated, and the results show that the addition of an appropriate amount of NH4+ can achieve a low surface roughness of Ru and a high slurry stability.

Objectives The aim of this study was to investigate the mechanism of linezolid resistance and evaluate the risk factors for linezolid-resistant Enterococcus faecalis (LZR-Efa) infections. Methods A total of 730 E. faecalis isolates were collected, and whole-genome sequencing and bioinformatics analysis were performed. Meanwhile, risk factors related to linezolid resistance were analyzed by binary logistic regression. Results Twenty-six LZR-Efa were isolated from various clinical samples, and 24 isolates were multidrug resistant. Four isolates were daptomycin nonsusceptible, while all LZR-Efa were susceptible to vancomycin. Thirteen different sequence types (STs) were identified, and the most prevalent type was ST16 (23.1%). The genes dfrE, lsaA, and emeA were identified in all isolates. A total of 23 E. faecalis were positive for optrA gene, and six amino acids mutations were identified among 18 LZR-Efa in OptrA. The 23S rRNA mutation was found in 16 LZR-Efa isolates. However, the presence of cfr was not identified. Furthermore, there were 41 virulence genes detected, and 10 genes (ace, bopD, cpsA, cpsB, ebpB, ebpC, efaA, fss1, fss2, and srtC) were found in all isolates. A total of nine isolates were positive for multiple virulent factors (ace, asa1, cylA, efaA, esp, and gelE). There was no difference in the number of virulence factors among different specimens (P=0.825). It is of note that all patients had not been prescribed linezolid or traveled abroad previously. Moreover, previous use of carbapenems was a risk factor for LZR-Efa infections. Conclusion The main trends of LZR-Efa, with lower level of resistance, were sporadic mainly in the department of surgery. optrA and 23S rRNA were the main resistance mechanisms. In addition, carbapenems use was an independent predictor of LZR-Efa infections.

Background The aim of this study was to investigate the mechanism of Listeria monocytogenes (Lm) pathogenicity and resistance. In addition, the effect of existing treatment options against Lm were systematically evaluated. Methods Six Lm isolates were collected and antimicrobial susceptibility testing of 15 antibiotics were done. Subsequently, whole genome sequencing and bioinformatics analysis were performed. Biofilm formation was evaluated by crystal violet staining. Furthermore, the effect of meropenem, linezolid, penicillin, vancomycin, and trimethoprim/sulfamethoxazole were determined using the time-kill assay. Results Four sequence types (STs) were identified (ST1, ST3, ST87, ST451). Multivirulence-locus sequence typing results classified ST87 isolates into cluster. All isolates were resistant to fosfomycin and daptomycin with fosX and mprF. In addition, a total of 80 virulence genes were detected and 72 genes were found in all 6 isolates. Seven genes associated with hemolysin were found in 26530 and 115423. However, due to lack of one genomic island including virulence genes related to flagellar synthesis, isolate 115423 produced less biofilm than 5 other isolates. Although all isolates were susceptible to vancomycin, the in vitro time-kill assay showed that vancomycin monotherapy resulted in less than 2 log10 cerebrospinal fluid (CFU)/mL compared with the initial count. Trimethoprim/sulfamethoxazole at serum or CFU concentrations had bactericidal effect against tested Lm strains at 24 hours. Conclusions ST87 clone was a typical prevalent ST in clinical Lm isolates in China. Trimethoprim/sulfamethoxazole might be greater potential therapeutic option against Lm infections., The present study revealed ST87 clone was the predominant sequence type among clinical Listeria monocytogenes (Lm) isolates in China. Although all isolates were susceptible to vancomycin, the effect was still unsatisfactory. Trimethoprim/sulfamethoxazole was a potent option against Lm infections.

The epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma

The effect of NaOH catalytic ethanol pretreatment under various temperatures (130–180 °C) and time (15–90 min) on the chemical composition and enzymatic saccharification of sugarcane bagasse was investigated in this study. The results showed that NaOH catalytic ethanol pretreatment assisted delignification and the reservation of cellulose and hemicellulose. When sugarcane bagasse was pretreated at 180 °C for 30 min, a substantial glucose yield of 91.6% was obtained after hydrolysis for 72 h, representing 94.6% of glucose in pretreated residue. This yield was promoted with respect to the compositional change and surface alteration of pretreated substrate. With the supplement of Tween 80, the enzyme usage would be saved by 50% and the enzymolysis time could be shortened to 24 h while obtaining comparable glucose yield. This study provided an economical feasible and gradual process for the generation of glucose, which was followed by fermentation and conversion to platform chemicals.

With regard to surface-enhanced Raman spectroscopy (SERS), the preparation of substrates with high homogeneity and low cost remains a challenge. In this paper, cheap commercial DVD-R plates were adopted as supports, whose 3D periodic structure was transferred onto the surface of flexible polydimethylsiloxane (PDMS) easily. Then, silver nanoparticles were grown both on DVD and PDMS substrates by the in situ reduction method, and the SERS performances of these two substrates were investigated. The results confirmed that the PDMS-based substrate exhibited better enhancement performance and higher uniformity ( R S D = 4.16 % ). In addition, due to the flexibility and transparency of PDMS, it is not restricted by the surface shape of the object when applied in in situ detection. This low-cost, simple method will be widely used in the in situ detection of surfaces of objects of any shape.

In this paper, we designed and synthesized two analog compounds M1 and T1 that have a Michael acceptor warhead. Although only slightly diversity existed in the structures of M1 and T1, their inhibitory activities against wild type epidermal growth factor receptor (EGFRWT) and T790M/L858R mutant epidermal growth factor receptor (EGFRT790M/L858R) were significant different. Thus, multiple computational approaches were applied to investigate the interactions between the compounds with EGFRWT and EGFRT790M/L858R in order to explore the effect of different compounds. The molecular docking and MD simulations were performed to study the intermolecular interactions between compounds and EGFR. The binding free energy revealed that M1-EGFRWT and M1-EGFRT790M/L858R complexes have stronger binding affinity compared with the corresponding T1-EGFRWT and T1-EGFRT790M/L858R complexes, respectively. And the binding free energy decompositions for each residue analysis indicated that the van der Waals interactions are the major contributor to enhance the compounds to bind with EGFR. In addition, covalent binding complexes of M1-EGFRWT and M1-EGFRT790M/L858R were constructed and studied. Moreover, quantum mechanics method was applied to investigate the reaction mechanism of covalent binding of the compound and EGFR. The results will provide the details of structural and energetic information to develop potent covalent EGFR inhibitors in the future.

Cyanobacteria are a major force for primary production via oxygenic photosynthesis in the ocean. A marine cyanobacterium, PCC7002, is actively involved in sulfide metabolism. It uses SQR to detoxify exogenous sulfide, enabling it to survive better than its Δsqr mutant in sulfide-rich environments. PCC7002 also uses SQR to oxidize endogenously generated sulfide to S0, which is required for the proper expression of key genes involved in photosynthesis. Thus, SQR has at least two physiological functions in PCC7002. The observation provides a new perspective for the interplays of C and S cycles., Eutrophication and deoxygenation possibly occur in coastal waters due to excessive nutrients from agricultural and aquacultural activities, leading to sulfide accumulation. Cyanobacteria, as photosynthetic prokaryotes, play significant roles in carbon fixation in the ocean. Although some cyanobacteria can use sulfide as the electron donor for photosynthesis under anaerobic conditions, little is known on how they interact with sulfide under aerobic conditions. In this study, we report that Synechococcus sp. strain PCC7002 (PCC7002), harboring an sqr gene encoding sulfide:quinone oxidoreductase (SQR), oxidized self-produced sulfide to S0, present as persulfide and polysulfide in the cell. The Δsqr mutant contained less cellular S0 and had increased expression of key genes involved in photosynthesis, but it was less competitive than the wild type in cocultures. Further, PCC7002 with SQR and persulfide dioxygenase (PDO) oxidized exogenous sulfide to tolerate high sulfide levels. Thus, SQR offers some benefits to cyanobacteria even under aerobic conditions, explaining the common presence of SQR in cyanobacteria.

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

Aiming to explore novel BRAFV600E and VEGFR-2 dual inhibitors, a series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and biologically evaluated in this study. Most of the synthesized 1H-pyrazolo[3,4-d]pyrimidine compounds displayed moderate to high potent activity in both enzymatic and cellular proliferation assays. Among these compounds, 9e, 9g, 9m and 9u showed remarkably high inhibitory activities against both BRAFV600E and VEGFR-2 kinase comparable to positive control Sorafenib. Particularly, compound 9u also showed potent anti-proliferative activity against BRAFV600E-expressing A375 (IC50 = 1.74 μM) and H-29 (IC50 = 6.92 μM) as well as VEGFR-2-expressing HUVEC (IC50 = 5.89 μM), which was also comparable to Sorafenib. Furthermore, kinase selectivity profile showed that 9u had almost poor or no significant inhibitory activity against wild-type BRAF and 15 other tested protein kinases. Flow cytometric analysis showed that compound 9u mainly arrested the A375 and HUVEC cell lines in the G0/G1 stage with a concentration-dependent effect. In addition, the molecular docking and molecular dynamics simulations suggested that 9u adopted a similar binding pattern with Sorafenib at the ATP-binding sites of BRAFV600E and VEGFR-2. Taken together, these results indicated that compound 9u may serve as novel lead compound in research on more effective BRAFV600E and VEGFR-2 dual inhibitors.

The peptide segment of prostatic acid phosphatase (PAP248-286) aggregates to form SEVI (semen-derived enhancer of virus infection) amyloid fibrils. These are characteristic seminal amyloids that have the ability to promote the effect of HIV infection. In this paper, we explore the binding of sulfonated compounds with PAP248-286 through an in silico study. Three derivatives of suramin, NF110, NF279, and NF340, are selected. All of these sulfonated molecules bind to PAP248-286 and alter the conformation of the peptide, even though they have various structures, sizes, and configurations. The compounds bind with PAP248-286 through multiple interactions, such as hydrogen-bonding interactions, hydrophobic interactions, π-π stacking interactions, and electrostatic interactions. However, NF110, which has an X-shaped configuration, has the highest binding affinity of the three derivatives investigated. We also perform surface plasmon resonance and a Congo red assay to validate the results. The interactions between PAP248-286 and the sulfonated compounds are proposed to depend on the orientations of the sulfonate groups and the specific configurations of the compounds instead of the number of sulfonate groups. NF110 molecules occupy the exposed binding sites of PAP248-286, blocking interactions between the peptides. Therefore, these compounds are important in inhibiting the aggregation of PAP248-286. Herein, we provide useful information to develop new efficient microbicides to antagonize seminal amyloid fibrils and to block HIV transmission.

Ternary boride based cermets were prepared by two-step sintering technique. The first pre-coarsening step was short at a relatively high-temperature in order to yield critical density and render pores unstable. The second step at lower temperatures for long holding duration facilitated further densification with limited grain growth occurring by the slower grain-boundary diffusion. It was shown that for fine-grained Mo2FeB2-based cermets, the optimum processing condition included pre-coarsening temperature (T1) = 1160 °C, pre-coarsening duration (t1) = 30 min, subsequent sintering temperature (T2) = 1080 °C and (t2) = 20 h. The cermets exhibited excellent mechanical properties with the transverse rupture strength of 2139.5 MPa and the hardness of 90.2HRA. Compared to conventional vacuum sintering, the grain size of the cermets prepared by two-step sintering technique was reduced from 1.89 μm to 1.21 μm.

With the aim of discovering potential and selective inhibitors targeting ROS1 kinase, we rationally designed, synthesized and evaluated two series of novel 2-amino-pyridine derivatives with 1-phenylethoxy at C-3 and C-4 position. The enzymic assays results indicated that six of the new compounds 13b-13d and 14a-14c showed remarkably higher inhibitory activities against ROS1 kinase. The most promising compounds, 13d and 14c displayed the most desired ROS1 inhibitory activity with IC50 values of 440 nM and 370 nM respectively. Furthermore, 13d and 14c displayed ROS1 inhibitory selectivity of about 7-fold and 12-fold, relative to that of ALK sharing about 49% amino acid sequence homology in the kinase domains. They also showed good anti-proliferative effects against ROS1-addicted HCC78 cell lines with the IC50 values of 8.1 μM and 65.3 μM, respectively. Moreover, molecular docking and molecular dynamics simulation studies disclosed that compound 14c and 13d shared similar binding poses with Crizotinib except the selective binding site of ROS1. It also gave a probable molecular explanation for their activity and selectivity, which the methoxyl group in benzene ring was the crucial to the selectivity to ROS1 versus ALK.

ROS1 and ALK are promising targets of anticancer drugs for non-small-cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, the selective ROS1 inhibitor is relatively rare. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear. In order to disclose the binding preference toward ROS1 over ALK and to aid the design of selective ROS1 inhibitors, the specific interactions and difference of conformational changes in the dual and selective ROS1/ALK inhibitors systems were investigated by molecular dynamics (MD) simulation and principle component analysis (PCA) in our work. Afterward, binding free energies (MM/GBSA) and binding free energies decomposition analysis indicated that the dominating effect of Van der Waals interaction drives the specific binding process of the type-I inhibitor, and residues of the P-loop and the DFG motif would play an important role in selectivity. On the basis of the modeling results, the new designed compound 14c was verified as a selective ROS1 inhibitor versus ALK, and SMU-B was a dual ROS1/ALK inhibitor by the kinase inhibitory study. These results are expected to facilitate the discovery and rational design of novel and specific ROS1 inhibitors.

BRAFV600E small-molecule inhibitors have recently received increasing attention as very effective agents for the therapy of cancer, especially melanoma. In this current work, a computational investigation was performed to investigate the interaction details of BRAFV600E kinase with inhibitors Vemurafenib (PLX4032) and its analog PLX4720. Binding free energy calculations based on molecular dynamics simulations reveal that ligands PLX4032 and PLX4720 bind to and stabilize the DFG-in conformation of BRAFV600E. Component analysis of binding free energy revealed that vdWaals interactions play a dominating effect on BRAFV600E inhibition. Furthermore, the per-residue binding free energy decomposition revealed that the most favorable contribution came from Ile463, Val471, Ala481, Lys483, Leu514, Ile527, Thr529, Gln530, Trp531, Cys532, Phe583, Gly593, and Asp594. These results agree well with experimental data, which provide valuable resources for understanding the inhibition mechanism of BRAFV600E by PLX4032 and PLX4720 and clues for the design of novel potent BRAFV600E inhibitors.

Background Due to the intact structure of lignocellulosic biomass, pretreatment was a prerequisite to improve the enzymatic hydrolysis by disrupting the recalcitrant lignocellulose and increasing the accessibility of cellulose to enzyme. In this study, an alkaline hydrogen peroxide (AHP) pretreatment of sugarcane bagasse with various loadings of H2O2 (1.25–6.25 wt%) at temperatures of 60–160 °C was proposed to degrade hemicellulose/lignin and improve the enzymatic digestibility. Results It was found that increasing H2O2 loadings during pretreatment lead to the enhancement of substrate digestibility, whereas the alkali (only NaOH)-pretreated solid generated higher glucose yield than that pretreated under AHP pretreatment with lower loading of H2O2. This enhancement of enzymatic digestibility was due to the degradation of hemicellulose and lignin. Furthermore, Tween 80 was added to promote enzymatic digestibility, however, the increased yields were different with various substrates and hydrolysis time. The highest glucose yield of 77.6% was obtained after pretreatment at 160 °C for 60 min with 6.25% H2O2 and the addition of Tween 80, representing 89.1% of glucose in pretreated substrate. Conclusions This study demonstrated that the AHP pretreatment could greatly enhance the enzymatic saccharification. The addition of Tween 80 played remarkable performances in promoting the glucose yield during enzymatic hydrolysis by stabilizing and protecting the enzyme activity. This study provided an economical feasible and gradual process for the generation of glucose, which will be subsequently converted to bioethanol and bio-chemicals. Electronic supplementary material The online version of this article (10.1186/s13068-019-1454-3) contains supplementary material, which is available to authorized users.

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 μM and 10.71 μM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.

The effect of ammonium ion (NH 4 +) on the chemical mechanical polishing of ruthenium (Ru) was studied. The results reveal that the combination of H 2 O 2 and NH 4 + can significantly improve the Ru removal rate by an order of magnitude. The influence mechanism of NH 4 + on removal rate of Ru was investigated by X-Ray photoelectron spectroscopy(XPS). It can be concluded that NH 4 + can accelerates the oxidation of Ru, thereby increasing the removal rate of Ru.

In this paper, a kind of BTA derivative 2,2′-[[(Methyl-1H-benzotriazol-1-yl)methyl]imino]bisthn ol (TT-LYK) was used to reduce the galvanic corrosion between copper (Cu) and ruthenim (Ru) during chemical mechanical process (CMP). The effect of TT-LYK on the galvanic corrosion current (I GC ) of Ru and Cu in potassium periodate (KIO 4 ) based slurry was investigated. The electrochemical experiment result show that the corrosion currents for Cu/Ru galvanic couple can be decreased in the presence of TT-LYK based on potassium periodate slolutions..

Magnetic mesoporous silica microspheres with core-shell structure and large pores are highly desired in macromolecules delivery and biocatalysis, biospeparation, and adsorption. In this work, a controllable solvent evaporation induced solution-phase interface co-assembly approach was developed to synthesize core-shell structural magnetic mesoporous silica microspheres with ultralarge mesopore size (denoted as LP-MMS). The synthesis was achieved by employing large-molecular-weight amphiphilic block copolymers poly(ethylene oxide)-block-poly(methyl methacrylate) (PEO-b-PMMA) and small surfactant cetyltrimethylammonium bromide as colates, which can co-assemble with silica source in tetrahydrofuran/water solutions. The obtained LP-MMS microspheres possess uniform rasberry-like morphology with a diameter of 600 nm, large primary spherical mesopores (ca. 36 nm), large specific surface area (348 m2/g), high specific pore volume (0.59 cm3/g), and fast magnetic responsivity with high magnetization (15.9 emu/g). The mesopore morphology can be transformed from spherical to cylindrical through introducing a shearing force during the interfacial co-assembly in the synthesis system. The designed LP-MMS microspheres turn out to be good carriers for enzyme (trypsin) immobilization with a high loading capacity of 80 ?g/mg and demonstrate excellent biocatalysis efficiency up to 99.1% for protein digestion within 30 min and good recycling stability with negligible decay in digestion efficiency after reuse for five times. This work was supported by the NSF of China (21673048, 21701153, and 21875044), Key Basic Research Program of Science and Technology Commission of Shanghai Municipality (17JC1400100), Qatar University under GCC Co-Fund Program Grant GCC-2017-001, and Youth Top-notch Talent Support Program of China. Scopus

Lung cancer is the leading cause of cancer death, and epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding. Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In this study, molecular dynamics simulations and free energy calculations were carried out on EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.

Background The recalcitrant structure of lignocellulosic biomass made it challenging for their bioconversion into biofuels and biochemicals. Pretreatment was required to deconstruct the intact structure by the removal of hemicellulose/lignin, improving the cellulose accessibility of enzyme. Combinatorial pretreatments with liquid hot water/H2SO4 and ethanol/NaOH of sugarcane bagasse were developed to improve enzymatic hydrolysis under mild conditions. Results After one-step 60% ethanol containing 0.5% NaOH pretreatment with solid to liquid ratio of 1/10, the glucose yield after hydrolysis for 72 h with enzyme dosage of 20 FPU/g substrate was enhanced by 41% and 205% compared to that of NaOH or 60% ethanol pretreated solids, respectively. This improvement was correlated with the removal of hemicellulose and lignin. However, using combinatorial pretreatments with 1% H2SO4 followed by 60% ethanol containing 0.5% NaOH, the highest glucose yield with Tween 80 reached 76%, representing 84.5% of theoretical glucose in pretreated substrate. While retaining similar glucose yield, the addition of Tween 80 capacitated either a reduction of enzyme loading by 50% or shortening hydrolysis time to 24 h. However, the enhancement with the addition of Tween 80 decreased as hydrolysis time was extended. Conclusions This study demonstrated that a combinatorial pretreatment with 1% H2SO4 followed by 60% ethanol containing 0.5% NaOH had significant effects on improving the enzymatic hydrolysis of sugarcane bagasse. The addition of Tween 80 enabled reducing the enzyme loading or shortening the hydrolysis time. This study provided an economically feasible and mild process for the generation of glucose, which will be subsequently converted to bioethanol and biochemicals. Electronic supplementary material The online version of this article (10.1186/s13068-018-1313-7) contains supplementary material, which is available to authorized users.

Nicotine is an important indicator in the quality evaluation of tobacco and its related products. Moreover, it is essential to monitor nicotine presence in the environment, food, and human organs. Therefore, the development of a suitable and efficient determination method is crucial to precisely detect nicotine in various samples and complicated matrices. This article reviews the methods of sample preparation (molecular imprinting technology and solid phase/liquid phase microextraction) and methods for nicotine analysis, such as spectrophotometry, liquid chromatography, gas chromatography, capillary electrophoresis, and electrochemical methods, reported in recent years. The advancement in the applications and scopes of these methods are discussed. Furthermore, the sensitivity, accuracy, and detection efficiency of these methods are elaborated on the basis of the reported nicotine determination methods.

Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 μM and 5.87 μM, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process.

In this work, a novel ion exchange stationary phase based on different generations of poly (amidoamine) dendrimers (PAMAM) was developed for the determination of inorganic anions and carbohydrates. Synthesis of the PAMAM was carried out with the polymerization reaction of ethylenediamine and methyl acrylate. The synthesized PAMAM was then grafted to the polystyrene-divinylbenzene-glycidyl methacrylate (PS-GMA) to form PAMAM-based beads. These beads were finally modified with 1,4-butanediol diglycidyl ether (BDDE) to generate the anion exchanger, which were characterized by scanning electron microscopy (SEM), brunauer-emmett-teller (BET), fourier transform infrared spectroscopy (FTIR), and elemental analysis. Elemental analysis, breakthrough curves and capacity factors showed that more epoxy groups and higher PAMAM generations in stationary phase could result in higher anion exchange capacity. The efficiency, durability and stability of the proposed anion exchanger were investigated by using six inorganic anions (fluoride, chloride, nitrite, bromide, nitrate and sulfate) and four carbohydrates (trehalose, glucose, maltotriose and galacturonic acid) as analytes, respectively. The reliability of the proposed ion chromatographic stationary phase was demonstrated by determining the content of galacturonic acid in polysaccharides from Poria cocos and Atractylodes macrocephala. The relative standard deviations of retention time, peak height, and peak area for galacturonic acid were 0.39%, 1.22%, and 2.02%, respectively. The spiked recoveries were in the range of 88.29%-100.51% for plant polysaccharides. Due to the good structural homogeneity, intense internal porosity, biological compatibility and high density of active groups in PAMAM, this grafted stationary phase showed good ion-exchange characteristics, especially in biological charged molecules.

A standard-free and sensitive method was developed for analysis of sucrose acetates in a crude 6-O-acetyl sucrose (S-6-a) product by on-line hydrolysis-high-performance liquid chromatography with pulsed amperometric detection (PAD). Sucrose, three regio-isomers of acetyl sucrose and five regio-isomers of diacetyl sucrose were separated on a C18 column using 3% (v/v) acetonitrile in water as eluent within 25 min. After purification with LC followed by semi-preparative HPLC, their chemical structures were identified by 1D, 2D NMR and LC–MS. Moreover, quantification of those regio-isomers was achieved by on-line alkaline hydrolysis to liberate sucrose using a post-column delivery system, and then detected by PAD for indirect estimation of the sucrose acetate content. Under optimal conditions, the linear ranges were from 0.03 to 150 μmol L−1 for sucrose corresponding to sucrose acetates with coefficient of determination as 0.9997 and detection limit as 0.01 μmol L−1 (S/N = 3). Good repeatability was obtained (RSD < 3%, n = 6). Furthermore, this method has been successfully applied to the analysis of sucrose and sucrose acetates in a crude S-6-a product during synthesis, purification and structure elucidation studies. The recoveries were from 94.89% to 102.31% for sucrose and sucrose acetates.

The reinforcement of rubber by graphene has generated great interest in recent years. The dispersion of graphene in a rubber matrix, however, remains a challenge. In this study, ferroferric oxide (Fe3O4) was used as a carrier to prepare graphene/Fe3O4 hybrid particles, in order to improve the dispersion of graphene in nitrile rubber (NBR). The graphene hybrid particles prepared by co-precipitation synthesis was added into NBR solution to prepare composites. Results show that there was about 90% improvement in tensile strength when 4 phr of graphene hybrid particles (equally only 0.5 phr of graphene in NBR) were added to the matrix. In contrast, the tensile strength of NBR decreased when 4 phr of Fe3O4 were added. SEM and XRD both explained the mechanism for the reinforcement of graphene hybrid particles. The DMA results show higher Tg and a higher value of tanδ for the modified NBR, further proving the reinforcement mechanism, i.e. the hybridization of graphene and Fe3O4 improves the dispersion of graphene in NBR and the interfacial action of graphene with NBR. Moreover, addition of graphene hybrid particles gives NBR extra properties such as surface wettability and magnetism, providing a useful guide for the preparation of functional graphene/rubber composites.

In this study, NaOH-catalyzed organosolv pretreatment with different loading of NaOH (0–10%) was proposed to disrupt the recalcitrant structure by degrading lignin, reserve the majority of cellulose and hemicellulose, and improve the enzymatic efficiency of sugarcane bagasse. It was found that the higher loading of NaOH during organosolv pretreatment yielded more glucose, and the synergistic performance of NaOH and ethanol on enzymolysis was superior to that pretreated with only NaOH and only ethanol during two-step pretreatment. Furthermore, Tween 80 was added to determine its influence on enzymolysis after NaOH-catalyzed organosolv pretreatment, leading to the highest glucose yield of 95.1% at 24 h, which saved 2/3 hydrolysis time while generating the similar glucose yield comparing with that without Tween 80. However, the increased yields of glucose by adding Tween 80 were decreased as hydrolysis time was prolonged from 6 h to 24 h.

In this study, Ti(C,N)-WC/Mo2C-(Ta,Nb)C-Co/Ni cermets with varying [Mo]/([W] + [Mo]) mole ratios and constant [W] + [Mo] content were prepared by using TiO2 and carbon as substitutes for a part of Ti(C,N). In situ carbothermal reaction took place with subsequent liquid phase sintering. The thermal behavior and outgassing behavior were conducted using differential thermal analysis/thermal gravity analysis (DTA-TG) and mass-spectrometric evolving gas analysis (MS-EGA). The microstructure was investigated by scanning electron microscopy (SEM). After being sintered in N2 atmosphere, cermets without TiO2 additions generally showed rimless microstructures with black grains independently distributed from other phases, whereas the cermets with TiO2 addition showed complete core-rim microstructures. The average grain size generally decreased with increasing Mo content, and increased with increasing TiO2 substitution. Moreover, the average grain size increased with decreased N2 pressure from 50 mbar to 10 mbar at any [Mo]/([Mo] + [W]) ratio. The most interesting result was for the Mo-free cermets with 5 mol% TiO2 and 10 mol% TiO2 addition sintered in 50 mbar N2: both the hardness and fracture toughness increased compared with the cermets without TiO2 addition. The HV-KIC behavior of the majority of the cermets was superior to the industrial grades.

A novel small molecule tyrosine kinase inhibitor 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (SMU-B) had good activity against ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) targets in non-small-cell lung cancer. The excellent bioactivity of SMU-B highlights the importance of determining its metabolic traits, which could provide meaningful information for further pharmacokinetic studies of SMU-B. In this work, we studied the metabolism of SMU-B in human liver microsomes. Three metabolites of SMU-B were identified by a quadrupole-time of flight tandem mass spectrometer (Q-TOF-MS), and the metabolic pathways of SMU-B were demethylation, dehydrogenation and oxidation. CYP3A4/5 was the principal isoform involved in SMU-B metabolism, as shown by chemical inhibition and recombination human enzyme studies. Additionally, a predication with a molecular docking model confirmed that SMU-B could interact with the active sites of CYP3A4 and CYP3A5. This study illuminates the metabolic profile of the anti-tumor drug SMU-B, which will accelerate its clinical use.

Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.