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ObjectiveThe systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing.DesignWhole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells.ResultsBased on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells.ConclusionOur results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

This paper is concerned with a semi-linear elliptic problem with Robin boundary condition: \begin{document}$ \begin{equation} \left\{\begin{array}{lll} \varepsilon \Delta w-\lambda w^{1+\chi} = 0, &\text{in} \ \Omega\\ \nabla w \cdot \vec{n}+\gamma w = 0, & \text{on} \ \partial \Omega \end{array}\right. \end{equation} ~~~~~~~~~~~~~~~~~~~~(*)$\end{document} where \begin{document}$ \Omega \subset {\mathbb R}^N (N\geq 1) $\end{document} is a bounded domain with smooth boundary, \begin{document}$ \vec{n} $\end{document} denotes the unit outward normal vector of \begin{document}$ \partial \Omega $\end{document} and \begin{document}$ \gamma \in {\mathbb R}/\{0\} $\end{document} . \begin{document}$ \varepsilon $\end{document} and \begin{document}$ \lambda $\end{document} are positive constants. The problem (*) is derived from the well-known singular Keller-Segel system. When \begin{document}$ \gamma>0 $\end{document} , we show there is only trivial solution \begin{document}$ w = 0 $\end{document} . When \begin{document}$ \gamma and \begin{document}$ \Omega = B_R(0) $\end{document} is a ball, we show that problem (*) has a non-constant solution which converges to zero uniformly as \begin{document}$ \varepsilon $\end{document} tends to zero. The main idea of this paper is to transform the Robin problem (*) to a nonlocal Dirichelt problem by a Cole-Hopf type transformation and then use the shooting method to obtain the existence of the transformed nonlocal Dirichlet problem. With the results for (*), we get the existence of non-constant stationary solutions to the original singular Keller-Segel system.

Metal-organic framework (MOF) membranes have enormous potential in separation applications. There are several MOF membranes grown on polymer substrates aimed for scale-up, but their brittleness hampers any industrial application. Herein, intergrown continuous polypropylene (PP)-supported ZIF-8 membranes have been successfully synthesized via fast current-driven synthesis (FCDS) within 1 h. The PP-supported ZIF-8 membranes exhibit a promising separation factor of 122 ± 13 for binary C3H6-C3H8 mixtures combined with excellent flexibility behavior. The C3H6/C3H8 separation performance of the PP-supported ZIF-8 membrane was found to be constant after bending the supported ZIF-8 film with a curvature of 92 m-1. This outstanding mechanical property is crucial for practical applications. Moreover, we further synthesized ZIF-8 membranes on various polymer substrates and even polymer hollow fibers to demonstrate the production scalability.

Though the boundary layer formation in the chemotactic process has been observed in experiment (cf. [63] ), the mathematical study on the boundary layer solutions of chemotaxis models is just in its infant stage. Apart from the sophisticated theoretical tools involved in the analysis, how to impose/derive physical boundary conditions is a state-of-the-art in studying the boundary layer problem of chemotaxis models. This paper will proceed with a previous work [24] in one dimension to establish the convergence of boundary layer solutions of the Keller–Segel model with singular sensitivity in a two-dimensional space (half-plane) with respect to the chemical diffusion rate denoted by e ≥ 0 . Compared to the one-dimensional boundary layer problem, there are many new issues arising from multi-dimensions such as possible Prandtl type degeneracy, curl-free preservation and well-posedness of large-data solutions. In this paper, we shall derive appropriate physical boundary conditions and gradually overcome these barriers and hence establish the convergence of boundary layer solutions of the singular Keller–Segel system in the half-plane as the chemical diffusion rate vanishes. Specially speaking, we justify that the boundary layer converges to the outer layer (solution with e = 0 ) plus the inner layer as e → 0 , where both outer and inner layer profiles are precisely derived and well understood. By doing this, the structure of boundary layer solutions is clearly characterized. We hope that our results and methods can shed lights on the understanding of underlying mechanisms of the boundary layer patterns observed in the experiment for chemotaxis such as the work by Tuval et al. [63] , and open a new window in the future theoretical study of chemotaxis models.

A novel ratio electrochemical biosensor based on multi-functional nanocomposite was developed. Fe

Surface and interfacial behavior of protein molecules are crucial for the protein function involved in many biochemical processes and biomedical products such as enzyme design, bio-separation, drug design and delivery. This article is devoted to an overview of design and regulation of the surface and interfacial behavior of protein molecules. The improvement of enzyme surface such as the directed evolution and the rational design of enzymes is introduced at first, followed by the rational design of protein interface for the protein assembly. Thereafter, the design of micro-environment and ligands are described as two examples for the design guided by protein surface. Then the design of protein surface and interface with the help of artificial intelligence will be discussed.

Objective: The objective of this study was to summarize the clinicopathological characteristics of the CLDN18-ARHGAP fusion gene in gastric cancer patients.Background: The CLDN18-ARHGAP26 fusion gene is one of the most frequent somatic genomic rearrangements in gastric cancer, especially in the genomically stable (GS) subtype. However, the clinical and prognostic meaning of the CLDN18-ARHGAP fusion in gastric cancer patients is unclear.Methods: Studies that investigated CLDN18-ARHGAP fusion gastric cancer patients were identified systematically from the PubMed, Cochrane, and Embase databases through the 28th of February 2020. A systematic review and meta-analysis were performed to estimate the clinical significance of CLDN18-ARHGAP fusion in patients.Results: A total of five eligible studies covering 1908 patients were selected for inclusion in the meta-analysis based on specified inclusion and exclusion criteria. Several fusion patterns were observed linking CLDN18 and ARHGAP26 or ARHGAP6, with the most common type being CLDN18/exon5-ARHGAP26/exon12. The survival outcome meta-analysis of the CLDN18-ARHGAP fusion gene showed that it was associated with overall survival outcomes in gastric cancer (HR, 2.03, 95% CI 1.26–3.26, P < 0.01, random-effects). In addition, diffuse gastric cancer had a greater proportion of CLDN18-ARHGAP fusions than intestinal gastric cancer (13.3%, 151/1,138 vs. 1.8%, 8/442; p < 0.001). Moreover, gastric cancer patients with the CLDN18-ARHGAP fusion gene are more likely to be female or have a younger age, lymph node metastasis and advanced TNM stages.Conclusion: The CLDN18-ARHGAP fusion is one of the molecular characteristics of diffuse gastric cancer and is also an independent prognostic risk factor for gastric cancer. In addition, it is also related to multiple clinical characteristics, including age, sex, lymph node metastasis and tumor stage. However, the mechanism of the CLDN18-ARHGAP fusion gene and potential targeted therapeutic strategies need further exploration.

NOV1 is a stilbene cleavage oxygenase (SCO) responsible for the oxidative cleavage of the central double bond of stilbenes, forming two phenolic aldehydes. In the active site of NOV1, the iron cofactor is coordinated by four histidines and no negatively charged ligand, which is unusual for iron-containing enzymes. Here, on the basis of the recently obtained crystal structure of NOV1, we performed quantum mechanics/molecular mechanics (QM/MM) calculations to elucidate the reaction mechanism of NOV1. According to our calculations, two binding modes of O2 to Fe(II) (end-on and side-on modes) have been recognized, and the end-on mode is suitable for catalysis. The side-on mode, which has been obtained from the crystal, is an inactive form, which should first change to the end-on mode to initiate the catalytic reaction. For the reactant in end-on mode, the triplet and quintet states correspond to very similar energies. Of the three considered pathways, two pathways (path_a and path_b1, which differ only in the order of the first C–O bond formation) involving the dioxetane intermediate are calculated to be favorable, which can confirm the dioxygenase mechanism of NOV1. However, the pathway (path_b2) involving the epoxide intermediate corresponds to high energy barriers for the formation of the second C–O bond (27.49 and 31.56 kcal mol−1 on the triplet and quintet state surfaces) and can be ruled out. However, in path_b2, the formation of the epoxide intermediate is easy, which may react with the solvent water (non-enzymatic reaction) to form the by-product. In addition, the different protonation states of 4′-OH of the substrate and K134, as well as the coordination of additional water molecules with the iron, do not influence the reaction barrier.

Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.

ZIF-8 membrane has the potential for CO2 /CH4 separation based on size exclusion. But if traditionally prepared by solvothermal methods, it shows only negligible selectivity due to the linker mobility. Here, ≈500 nm-thin hybrid ZIF-7x -8 membranes with suppressed linker mobility and narrowed window aperture are prepared by a fast current-driven synthesis (FCDS) within 20 min. The in situ electric field during FCDS allows the formation of stiffened ZIF-8_Cm as parent skeleton and the mixed-linker strategy is applied to narrow the aperture size simultaneously. The ZIF-722 -8 membrane shows significantly sharpened molecular sieving for CO2 /CH4 with a separation factor above 25, which soared tenfold compared with other unmodified ZIF-8 membranes. Additionally, the membrane shows exceptional separation performance for H2 /CH4 and CO2 /N2 , with separation factors of 71 and 20, respectively. After 180 h temperature swing operation, it still maintains the excellent separation performance.

Continental flow plays a significant role in the global ecosystem. With increased global warming and a booming economy exacerbating water scarcity, global analyses of continental discharge are of great relevance to water management. In this paper, the Mann-Kendall (MK) test, with variations accounting for lag-1 autocorrelation, full autocorrelation, and long-term persistence, was used to detect the long-term flow trends in 916 of the world’s largest ocean-reaching rivers over the period 1948–2004. Field significance was evaluated using Walker’s test. Globally, the results revealed more decreases in streamflow than increases. With the traditional MK test, 503 rivers had decreased streamflow, with 120 showing significant decreases, whereas 408 rivers had increased streamflow, with 51 showing significant increases. Regionally, positive streamflow trends mainly occurred in high-latitude areas and negative streamflow trends mainly occurred in low-latitude areas, a pattern that can be attributed to uneven precipitation and the effects of global warming. When the full autocorrelation structure and long-term persistence behavior were taken into account in the trend analysis, there was a large reduction in the number of rivers with significant changes in streamflow. Negligible departures from the traditional MK results were observed when only the lag-1 autocorrelation was taken into consideration. For the Americas and Europe, annual integrated river flow showed a slight upward trend; for other continents, there was a slight downward trend. For all oceans except the Arctic Ocean, integrated river flow had a downward trend. We investigated the causal relationships between streamflow and ocean signals using the Granger causality test. El Nino–Southern Oscillation (ENSO) signals were significantly causal for river flow in over 36% of global rivers tested. The influence of the Arctic Oscillation (AO) and the North Atlantic Oscillation (NAO) was significant in more than a quarter of rivers studied. The Pacific Decadal Oscillation (PDO) was responsible for the variation in streamflow for over a quarter of rivers studied. Streamflow was affected by the interactions between ocean signals as well as by anthropogenic activities.

This paper is concerned with the stability of boundary layer solutions for a viscous hyperbolic system transformed via a Cole--Hopf transformation from a singular chemotactic system modeling the in...

// Qianqian Hou 1, * , Fei Liao 1, * , Shouyue Zhang 1, * , Duyu Zhang 1, * , Yan Zhang 2 , Xueyan Zhou 1 , Xuyang Xia 1 , Yuanxin Ye 8 , Hanshuo Yang 3 , Zhaozhi Li 1 , Leiming Wang 4 , Xi Wang 5 , Zhigui Ma 6 , Yiping Zhu 6 , Liang Ouyang 3 , Yuelan Wang 1 , Hui Zhang 7 , Li Yang 3 , Heng Xu 1, 8 , Yang Shu 1 1 Department of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China 2 Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China 3 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China 4 Department of Molecular Biology, Baylor College of Medicine, Houston, Texas, USA 5 Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angles, Los Angles, California, USA 6 Department of Pediatric Hematology/Oncology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China 7 Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA 8 Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China * These authors contributed equally to this work Correspondence to: Heng Xu, email: xuheng81916@scu.edu.cn Yang Shu, email: shuyang1986@gmail.com Keywords: GATA3, acute lymphoblastic leukemia, tissue-specific regulation network, microarray datasets Received: February 21, 2017 Accepted: March 11, 2017 Published: March 21, 2017 ABSTRACT GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene expression association analyses to reveal expression associated genes and pathways in nine independent B-ALL patient cohorts. In B-ALL patients, 173 candidates were identified to be significantly associated with GATA3 expression, including some reported GATA3 -related genes (e.g., ITM2A ) and well-known tumor-related genes (e.g., STAT4 ). Some of the candidates exhibit tissue-specific and subtype-specific association with GATA3 . Through overexpression and down-regulation of GATA3 in leukemia cell lines, several reported and novel GATA3 regulated genes were validated. Moreover, association of GATA3 expression and its targets can be impacted by SNPs (e.g., rs4894953), which locate in the potential GATA3 binding motif. Our findings suggest that GATA3 may be involved in multiple tumor-related pathways (e.g., STAT/JAK pathway) in B-ALL to impact leukemogenesis through epigenetic regulation.

International audience; Nucleoside analogues represent an important class of drug candidates. With the aim of searching for novel bioactive nucleosides, we developed an efficient synthetic way to construct a series of aryl 1,2,3-triazole acyclic C-azanucleosides via Huisgen 1,3-dipolar cycloaddition. The aryl 1,2,3-triazole motifs within these azanucleosides showed coplanar features, suggesting they could act as surrogates for large planar aromatic systems or nucleobases. Moreover, several aryltriazole acyclic C-azanucleosides bearing long alkyl chains exhibited potent antiproliferative activity against various cancer cell lines via induction of apoptosis. Most interestingly, the lead compound significantly down-regulated the key proteins involved in the heat shock response pathway, representing the first anticancer acyclic azanucleoside with such a mode of action. These novel aryl 1,2,3-triazole cyclic C-azanucleosides therefore serve as promising paradigms for further exploring anticancer drug candidates.

Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.

Drug resistance and disease relapse are still challenging problems in the chemotherapy of colorectal cancer (CRC). Programmed cell death factor 4 (PDCD4) has previously been reported to act as a tumor suppressor and was implicated in the chemosensitivity of numerous types of human malignancy. In this study, the effect of PDCD4 in the sensitivity of CRC to the chemotherapy drug Taxol was investigated. The results confirmed that lower PDCD4 expression was present in CRC tumor tissues, when compared with in normal adjacent tissues (p) and closely associated with the prognosis of patients with CRC. Upregulation of PDCD4 significantly enhanced the sensitivity of CRC cells to Taxol, by partially contributing to pro-apoptosis and anti-invasion pathways, both through upregulation of the apoptosis-associated protein Bax, and downregulation of the anti-apoptosis protein Bcl-2 and invasion-associated proteins MMP-9. These findings might present a novel strategy for sensitizing tumor cells to apoptosis and, thus, overcoming chemotherapy resistance in CRC.

Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13-10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.

This paper is concerned with the boundary layer problem for a hyperbolic system transformed via a Cole–Hopf type transformation from a repulsive chemotaxis model with logarithmic sensitivity proposed in [23] , [34] modeling the biological movement of reinforced random walkers which deposit a non-diffusible (or slowly moving) signal that modifies the local environment for succeeding passages. By prescribing the Dirichlet boundary conditions to the transformed hyperbolic system in an interval ( 0 , 1 ) , we show that the system has the boundary layer solutions as the chemical diffusion coefficient e → 0 , and further use the formal asymptotic analysis to show that the boundary layer thickness is e 1 / 2 . Our work justifies the boundary layer phenomenon that was numerically found in the recent work [25] . However we find that the original chemotaxis system does not possess boundary layer solutions when the results are reverted to the pre-transformed system.

Posttranslational modification is a critical process in the cellular regulation, an example of which is the carboxylation of lysine. Pyruvate carboxylase is an enzyme, in which a carboxylated lysine has been found in the metal coordination shell of the active center. In our previous study, the reaction mechanism of the carboxyl transferase domain of the pyruvate carboxylase from Staphylococcus aureus has been investigated by using QM/MM calculations. The suggested mechanism supports the previous proposal, and most of the results are consistent with the experimental data. However, the calculated overall barrier is too high for an enzymatic reaction, which may be the result of the used model failing to take into account the modification of the metal-coordinated lysine. Here, we present a successive study to investigate the importance of lysine carboxylation in the reaction and also to examine if the Zn-coordinated water molecule is required for the catalysis. The reaction mechanism from the new models is consistent with the previous suggestion. More importantly, the energy barriers of all elementary steps are calculated to be much lower than those in our previous work. Notably, the calculated barrier of the overall reaction is ~ 14 kcal/mol, which is in good agreement with the experimental value. Therefore, this study supplies a theoretical evidence for the importance of the modification of Zn-coordinated lysine in the pyruvate carboxylase-catalyzed reaction. In addition, the water molecule in the zinc coordination shell is suggested to contribute to the catalysis.

Bioproduction of organic acids under low pH condition without adding inducer and neutralizer is an economical craft to decrease downstream cost. Candida glycerinogenes had higher tolerances to low pH and lactic acid than Saccharomyces cerevisiae. QRT-PCR analysis showed that four of fifteen candidates functioned as potentially acid-inducible promoters in C. glycerinogenes. In particular, PCggmt1 showed the strongest induction ability at pH 2.5. Fluorescence analysis indicated that the induction ability of PCggmt1 gradually increased as the pH decreased. In addition, PCggmt1 had the binding sites of Msn2p/4p, Azf1p, and Nrg1p. PCggmt1 was further used to control the expression of lactate dehydrogenase gene from Rhizopus oryzae in C. glycerinogenes. Compared with pH 5.5, the specific activity of lactate dehydrogenase and lactic acid titer at pH 2.5 were increased by 229% and 218%, reaching 13.8 mU/mg and 12.3 g/L, respectively. These results presented here showed a potential to produce organic acid economically at low pH by the stress tolerant C. glycerinogenes and the novel low-pH inducible promoter PCggmt1.

ZIF-8 membrane has the potential for CO

Salicylate hydroxylase (SALH) is a Flavin-dependent monooxygenase responsible for the transformation of salicylate to catechol. In this article, on the basis of the crystal structure obtained from Pseudomonas putida S-1, we performed combined quantum mechanical/molecular mechanical (QM/MM) calculations to investigate the reaction mechanism of SALH. Since the formation of C4a-hydroperoxyflavin has been theoretically proven to be a barrierless process, our calculations started from the C4a-hydroperoxyflavin intermediate. The whole enzymatic reaction contains two parts: the hydroxylation and decarboxylation. Our calculation results indicate that the deprotonated substrate is the active form, whereas the neutral form of salicylate corresponds to very a high energy barrier (39.8 kcal/mol) for the hydroxylation process, which is in line with the experimental result that the optimum pH is 7.6. The calculated results with the deprotonated substrate indicate that the hydroxylation and decarboxylation occur in a stepwise manner and the decarboxylation process is calculated to be the rate-limiting step with an energy barrier of 14.5 kal/mol. Calculations using different functionals (B3LYP, BP, BVWN, PBE, M06 and TPSSH) suggest that the catalytic reaction is highly exothermic, which is consistent with its similar enzyme (PHBH).

Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC., Signet-ring cell carcinoma (SRCC) is a unique type of gastric cancer with no prognostic features. Here, the authors report a CLDN18-ARHGAP26/6 gene fusion in patients with a high signet-ring cell content, poor survival outcomes, and who experience no benefit from platinum/fluoropyrimidines-based chemotherapy.

ZIF-8 membranes with inborn-suppressed linker mobility sharpen molecular sieving with C3H6/C3H8 separation factor above 300., Metal-organic framework (MOF) membranes show great promise for propene/propane separation, yet a sharp molecular sieving has not been achieved due to their inherent linker mobility. Here, zeolitic imidazolate framework ZIF-8–type membranes with suppressed linker mobility are prepared by a fast current–driven synthesis (FCDS) strategy within 20 min, showing sharpened molecular sieving for propene/propane separation with a separation factor above 300. During membrane synthesis, the direct current promotes the metal ions and ligands to assemble into inborn-distorted and stiffer frameworks with ZIF-8_Cm (a newly discovered polymorph of ZIF-8) accounting for 60 to 70% of the membrane composition. Molecular dynamics simulations further verify that ZIF-8_Cm is superior to ZIF-8_I 4¯3m (the common cubic phase) for propene/propane separation. FCDS holds great potential to produce high-quality, ultrathin MOF membranes on a large scale.

Serum paraoxonase 1 (PON1) is a calcium-dependent enzyme that can catalyze the hydrolysis of multiple substrates, including lactones, thiolactones, carbonates, esters and phosphotriesters, as well as the formation of a variety of lactones. To better understand the lactonase mechanism of PON1, the hydrolysis of dihydrocoumarin, which is considered as a native substrate of PON1, has been investigated by using a combined quantum mechanics and molecular mechanics (QM/MM) approach. Two possible reaction pathways with either Glu53 or His115 acts as the general base have been considered. On the basis of our calculations, these two pathways correspond to the overall energy barriers of 12.5 and 9.0 kcal mol−1, respectively. During the catalytic reaction, if one of the two residues (Glu53 and His115) acts as the catalytic base, the other one forms strong hydrogen bonding interaction with the attacking hydroxide to facilitate the hydrolysis. However, mutation studies reveal that Glu53 is necessary for hydrolysis, whereas His115 is not essential but can promote the activity of PON1. Natural population analysis indicates that the catalytic Ca2+ does not act as Lewis acid but plays structural role in fixing the orientations of the substrate and related residues. In addition, Asp269 is found to coordinate with Ca2+ cation and facilitate the protonation of the alkoxide leaving group by forming hydrogen bond with lactone. These results can explain the fact that mutation of Glu53 results in the loss of activity of PON1, and the hydrolysis of dihydrocoumarin is unaffected by mutation of H115.

Buprofezin is a commonly used chemical with satisfactory biological activity against sucking insect pests, but its disposal can cause serious environmental problems. To study the feasibility of remedying contamination by buprofezin, microcosm experiments were carried out to study the effects of various concentrations of buprofezin and Sphingobium sp. LY-6 on soil bacterial communities in soils collected from vegetable fields. In this experiment, the results showed that buprofezin was effectively degraded by Sphingobium sp. LY-6 in incubation soils. Comparing to non-incubated soils, the cumulative degradation ratio of buprofezin was significantly increased, up to the extent of 85 and 51%, in the initial concentration of 10 and 100 mg kg(-1). The abundance and community structure of the bacterial communities were analysed by real-time PCR (qPCR) and terminal-restriction fragment length polymorphism (T-RFLP). The findings suggest that buprofezin had a negative effect on soil bacterial community, and decreases in bacterial abundance were observed in the later part of the incubation period. The bacterial community structure and diversity shifted significantly at each sampling time. In conclusion, the buprofezin-degrading strain LY-6 played a major role in the bioremediation of the buprofezin-contaminated soil and influenced the dynamics and structure of the bacterial community, demonstrating the great potential of exogenous microorganisms for soil remediation.

Silver nanoparticles were prepared by chemical reduction. Fusarium graminearum was used as the test strain. To study the inhibition of F. graminearum by silver nanoparticles, we studied the activities of protective enzymes superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and the contents of osmotic adjustment substances soluble protein, soluble sugar and malonaldehyde (MDA) in F. graminearum. Silver nanoparticles inhibited F. graminearum and the inhibitory effect was increased with the concentration of silver nanoparticles. The inhibition rate of 10 μg/mL silver nanoparticles was more than 90% and EC50 was 0.59 μg/mL. When the treating time prolonged (2, 4, 6, 8 and 10 h), the activity of SOD, CAT and POD increased firstly and then declined. SOD, POD and CAT reached the maximum at 4 hours, and decreased to minimum at 10 hours. Silver nanoparticles also increased the MDA content and reduced the soluble sugar and protein contents in pathogens. These results indicated that cell integrity was destroyed in the presence of silver. This may be one of the inhibiting mechanisms of silver nanoparticles on the growth of F. graminearum.采用化学还原法制备纳米银，以小麦赤霉病菌为受试菌株，研究纳米银对小麦赤霉病菌抗菌活性、对细胞内3 种保护酶：超氧化物歧化酶 (SOD)、过氧化物酶 (POD)、过氧化氢酶 (CAT) 活性和对细胞渗透调节物质：丙二醛 (MDA)、可溶性蛋白、可溶性糖含量的影响。结果表明：纳米银能显著抑制小麦赤霉病菌的生长，抑制作用随着浓度的增加而不断增大，10 μg/mL 的纳米银对病原菌的抑制率达90%以上，有效中浓度 (EC50)为0.59 μg/mL。随着纳米银处理时间 (2、4、6、8 和10 h) 的增长，3 种酶的活性均出现先增加后降低的变化。SOD、POD 和CAT 均在4 h 出现最高值，10 h 降至最低。纳米银使得菌体内丙二醛含量增加，可溶性蛋白和可溶性糖含量降低。纳米银破坏了病原真菌体内细胞的完整性，这可能是纳米银抑制病原菌生长的机理之一。.