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Supplemental Digital Content is Available in the Text.N-n-butyl haloperidol iodide (F2), a derivative of haloperidol developed by our group, exhibits potent antioxidative properties and confers protection against cardiac ischemia/reperfusion (I/R) injury. The protective mechanisms by which F2ameliorates I/R injury remain obscure. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor transactivating many antioxidative genes, also attenuates I/R-induced myocardial damage. The present study investigated whether the cardioprotective effect of F2depends on Nrf2 using a mouse heart I/R model. F2(0.1, 0.2 or 0.4 mg/kg) or vehicle was intravenously injected to mice 5 minutes before reperfusion. Systemic administration of 0.4 mg/kg F2led to a significant reduction in I/R injury, which was accompanied by enhanced activation of Nrf2 signaling. The cardioprotection conferred by F2was largely abrogated in Nrf2-deficient mice. Importantly, we found F2-induced activation of Nrf2 is silent information regulator of transcription 1 (SIRT1)-dependent, as pharmacologically inhibiting SIRT1 by the specific inhibitor EX527 blocked Nrf2 activation. Moreover, F2-upregulated expression of SIRT1 was also Nrf2-dependent, as Nrf2 deficiency inhibited SIRT1 upregulation. These results indicate that SIRT1-Nrf2 signaling loop activation is indispensable for the protective effect of F2against myocardial I/R injury and may provide new insights for the treatment of ischemic heart disease.

Purpose: Traditional anesthesia for video-assisted thoracoscopy (VATS) such as double-lumen tracheal intubation (DLT) and one-lung ventilation (OLV), may lead to post-operative pulmonary complications (PPCs). Non-intubation VATS (NIVATS) is an anesthetic technique that avoided DLT and OLV, maybe avoiding the PPCs. So we hypothesized that NIVATS would non-inferiority to intubation VATS (IVATS) in the risk of developing PPCs and some safety indicators. Methods: This study is a randomised, controlled, double-blind, non-inferiority trial, 120 patients were randomly assigned to the NIVATS group and IVATS group according to 1:1. The primary outcome was the incidence of PPCs with a pre-defined non-inferiority margin of 10%. The second outcome was the safety indicators, including the incidence of cough/body movement, hypoxemia, malignant arrhythmia, regurgitation and aspiration, and transferring to endobronchial intubation intraoperatively (The malignant arrhythmia was defined as an arrhythmia that caused hemodynamic disturbances in a short period of time, resulting in persistent hypotension or even cardiac arrest in the patient). Results: There was no significant difference in demographic indicators such as gender and age between the two groups. The incidence of PPCs in the NIVATS group was non-inferior to that in the IVATS group (1.67% vs. 3.33%, absolute difference: − 1.67%; 95%CI − 7.25 to 3.91). In additionan, no significant differences were found between the two groups for the incidence of cough/body movement (10.00% vs. 11.67%, p= 0.77), the incidence of hypoxemia (25% vs. 18.33%, p= 0.38), the incidence of malignant arrhythmia (1.67% vs. 6.67%, p= 0.36), the incidence of regurgitation and aspiration (0% vs. 0%, p> 0.999) and the incidence of transferring to endobronchial intubation intraoperatively (0% vs. 0%, p> 0.999). Conclusion: We conclude that when using the non-intubation anesthesia for VATS, the incidence of PPCs was not inferior to intubation anesthesia. Furthermore, NIVATS had little effect on perioperative safety.

The advancement of convolutional neural networks (CNNs) has greatly promoted the development of ship detection in SAR images. Oriented ship detection is practical and imperative, but the development of its fully-supervised methods is limited by the insufficiency of data annotated in an oriented bounding box (OBB). Therefore, we proposed a weakly supervised learning (WSL) paradigm to train the network by only data annotated in a horizontal bounding box (HBB) for oriented ship detection. The paradigm follows a coarse-to-fine prediction route, and the ships’ coarse orientations and high-quality pseudolabels both mined from images are used to train the network combined with the HBB annotations. The designed orientation initialization decoder (OID) utilizes the output from the prediction branch of ship coarse orientation (PBSCO) and the regression branch to decode coarse OBBs, based on the horizontal proposals, and then these OBBs are refined by the fine prediction head, which is jointly trained by high-quality pseudolabels and HBB annotation. Extensive experiments were conducted on the SAR ship detection dataset (SSDD) and the high-resolution SAR images dataset (HRSID) with both OBB and HBB annotations, and the results show that our proposed WSL paradigm can train network to attain the $AP_{50}$ and R in the same level of mainstream fully-supervised methods in remote sensing.

The convergence of 3D bioprinting with powerful manufacturing capability and cellular self-organization that can reproduce intricate tissue microarchitecture and function is a promising direction toward building functional tissues and has yet to be demonstrated. Here, we develop a granular aggregate-prevascularized (GAP) bioink for engineering highly vascularized bone tissues by capitalizing on the condensate-mimicking, self-organization, and angiogenic properties of prevascularized mesenchymal spheroids. The GAP bioink utilizes prevascularized aggregates as building blocks, which are embedded densely in extracellular matrices conducive to spontaneous self-organization. We printed various complex structures with high cell density (∼1.5 × 108cells/cm3), viability (∼80%), and shape fidelity using GAP bioink. After printing, the prevascularized mesenchymal spheroids developed an interconnected vascular network through angiogenic sprouting. We printed highly vascularized bone tissues using GAP bioink and found that prevascularized spheroids were more conducive to osteogenesis and angiogenesis. We envision that the design of the GAP bioink could be further integrated with human-induced pluripotent stem cell-derived organoids, which opens new avenues to create patient-specific vascularized tissues for therapeutic applications..

Titanium (Ti) and its alloys have been widely used as orthopedic implants, because of their favorable mechanical properties, corrosion resistance and biocompatibility. Despite their significant success in various clinical applications, the probability of failure, degradation and revision is undesirably high, especially for the patients with low bone density, insufficient quantity of bone or osteoporosis, which renders the studies on surface modification of Ti still active to further improve clinical results. It is discerned that surface physicochemical properties directly influence and even control the dynamic interaction that subsequently determines the success or rejection of orthopedic implants. Therefore, it is crucial to endow bulk materials with specific surface properties of high bioactivity that can be performed by surface modification to realize the osseointegration. This article first reviews surface characteristics of Ti materials and various conventional surface modification techniques involving mechanical, physical and chemical treatments based on the formation mechanism of the modified coatings. Such conventional methods are able to improve bioactivity of Ti implants, but the surfaces with static state cannot respond to the dynamic biological cascades from the living cells and tissues. Hence, beyond traditional static design, dynamic responsive avenues are then emerging. The dynamic stimuli sources for surface functionalization can originate from environmental triggers or physiological triggers. In short, this review surveys recent developments in the surface engineering of Ti materials, with a specific emphasis on advances in static to dynamic functionality, which provides perspectives for improving bioactivity and biocompatibility of Ti implants.

This study aims to circumvent the operation of conducting laboratory tests of soil shear strength through a hybrid machine learning approach. The proposed approach integrates extreme learning machine (ELM) and particle swarm optimisation (PSO) with adaptive acceleration coefficients. Three hybrid ELMs, namely PSO optimised ELM with time-varying acceleration coefficients (ELM-TP), ELM optimised by improved PSO (ELM-IP), and ELM optimised by modified PSO (ELM-MP), have been established. Subsequently, the concept of mean PSO has been incorporated, and three additional hybrid models, namely ELM-TP integrated with mean PSO (ELM-TMP), ELM-IP integrated with mean PSO (ELM-IMP), and ELM-MP integrated with mean PSO (ELM-MMP), are constructed. The proposed concept is also used to construct six artificial neural network (ANN)-based hybrid models (i.e. ANN-TP, ANN-IP, ANN-MP, ANN-TMP, ANN-IMP, and ANN-MMP). Experimental results exhibit that the constructed ELM-IMP and ANN-IMP models can achieve the most desired accuracies in predicting the shear strength of soils.

The bio-engineered ovary is an essential technology for treating female infertility. Especially the development of relevant in vitromodels could be a critical step in a drug study. Herein, we develop a semi-opened culturing system (SOCS) strategy that maintains a 3D structure of follicles during the culture. Based on the SOCS, we further developed micro-cavity ovary (MCO) with mouse follicles by the microsphere-templated technique, where sacrificial gelatin microspheres were mixed with photo-crosslinkable gelatin methacryloyl (GelMA) to engineer a micro-cavity niche for follicle growth. The semi-opened MCO could support the follicle growing to the antral stage, secreting hormones, and ovulating cumulus-oocyte complex out of the MCO without extra manipulation. The MCO-ovulated oocyte exhibits a highly similar transcriptome to the in vivocounterpart (correlation of 0.97) and can be fertilized. Moreover, we found that a high ROS level could affect the cumulus expansion, which may result in anovulation disorder. The damage could be rescued by melatonin, but the end of cumulus expansion was 3h earlier than anticipation, validating that MCO has the potential for investigating ovarian toxic agents in vitro. We provide a novel approach for building an in vitroovarian model to recapitulate ovarian functions and test chemical toxicity, suggesting it has the potential for clinical research in the future.

Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Bunge (Danshen), displays strong antiproliferative activity against cancer cells. However, their protein targets remain unknown. Here, we deconvoluted the protein targets of SAA using chemoproteomics and phosphoproteomics. By using alkynylated SAA as a probe, we discovered that SAA is a covalent ligand that can modify cellular proteins via its electrophilic α,β-unsaturated ester moiety. The subsequent chemoproteomics profiling revealed that 46 proteins were covalently modified by SAA, including Raptor, a subunit of mTORC1 for recruiting substrates for mTORC1. Although gene ontology enrichment analysis of these proteins suggested that SAA displays a promiscuous protein interaction, phosphoproteomics profiling revealed that the SAA modulated phosphoproteins were mainly enriched in the signaling pathways of PI3K-Akt-mTOR, which is closely related to cell growth and proliferation. This was confirmed by the biochemical assay with purified mTORC1, a Western blot assay with phospho-specific antibodies, and a cellular thermal shift assay. Our work discovered that SAA is a covalent ligand for protein modification and mTORC1 is one of its targets. Moreover, our work demonstrated that the integrative profiling of chemoproteomics and phosphoproteomics can be a powerful tool for target deconvolution for bioactive natural products.

Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis, and its levels are elevated in various human cancers. Recent studies suggest that DCLK1 may relate to inflammatory responses in the mouse model of colitis. However, cellular pathways engaged by DCLK1, and potential substrates of the kinase remain undefined. To understand how DCLK1 regulates inflammatory responses, we utilized the well-established lipopolysaccharide (LPS)-stimulated macrophages and mouse model. Through a range of macrophage-based and cell-free platforms, we discovered that DCLK1 binds directly with the inhibitor of κB kinase β (IKKβ) and induces IKKβ phosphorylation on Ser177/181 to initiate nuclear factor-κB (NF-κB) pathway. Deficiency in DCLK1, achieved by silencing or through pharmacological inhibition, prevented LPS-induced NF-κB activation and cytokine production in macrophages. We further show that mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment are protected against LPS-induced acute lung injury and septic death. Our studies report a novel functional role of macrophage DCLK1 as a direct IKKβ regulator in inflammatory signaling and suggest targeted therapy against DCLK1 for inflammatory diseases.

Polyether-ether-ketone (PEEK), as one kind of thermoplastic polymers, exhibits a great deal of remarkable properties and plays an important role in aerospace, electronics, automotive and medicine. An investigation of single-pulse laser drilling on Polyether-ether-ketone (PEEK) was reported to show the influence of irradiation energy on the hole sidewall. In-situ evolution of drilling process was observed by the high-speed camera. The surface morphology and microstructural characteristics of the hole sidewall were evaluated by different characterization techniques. The hole sidewall was divided into three parts: expanded zone at the entrance, linear zone in the middle, and U-shaped zone at the bottom. It was found that the quality of inner sidewall could be obviously improved under high single-pulse energy (>1 J), in terms of the surface morphology with small heat-affected zone (HAZ) thickness and surface roughness, as well as the least adhesion. Besides, chemical and structural characteristics of the hole sidewall changed a lot under high energy. The C content of three parts increased as the energy increased. The crystallinity of the hole sidewall decreased from 35 % to 25 % after laser-energy irradiation, but there was little change under different single-pulse energy. New diffraction peaks appeared in X-ray diffraction images and the intensity of the relative peaks in Raman spectra decreased when the energy was over 1 J. It was proven that some chemical bonds (phenyl ring (1597 cm−1) and C–O–C (1148 cm−1)) would break under high energy, contributing to mass removal of the keyhole. Moreover, the HAZ thickness of the hole sidewall was calculated based on a viscous flow model, which showed a good consistency with experimental results. These results reveal material-removal mechanism accompanying the appearance of direct decomposition of the material and breaking of chemical bonds under high energy. It can provide references for understanding mechanisms of HAZ formation and material-removal and improving surface quality for laser drilling of polymers.

With the increasing demand for transportation infrastructure, the construction of urban tunnel systems linking different areas is indispensable. The deformation and the failure process during a tunnel excavation are essential concerns for geotechnical engineers. However, few studies have systematically investigated the effect of the ground loss ratio on tunnel deformation and the inequality between the ground loss ratio and the volume of the settlement trough. An experimental study using the transparent soil testing technique is performed herein for better visualization and digitization purposes. The three dimensional vertical and horizontal deformation patterns of a single tunnel are investigated for both the surface and the stratum right below considering different ground loss ratios. The relationship among the empirical constant of the settlement trough width, buried depth, depth–diameter ratio, and ground loss ratio is presented.

Class integration test order generation is a key step in integration testing, researching this problem can help find unknown bugs and improve the efficiency of software testing. The challenge of this problem is ordering the classes to be integrated to minimize the cost of required stubs. However, the existing approaches of generating class integration test orders cannot satisfy this requirement well. Considering the excellent performance of reinforcement learning in sequence decision problems, this paper proposes a class integration test order generation approach based on Sarsa algorithm, which is a data-driven model-free reinforcement learning algorithm. This approach takes the stubbing complexity as the indicator to evaluate the stubbing cost and uses it to measure the quality of a class integration test order. The Sarsa algorithm is used to train the agent, and three indicators such as test return, dependency complexity, and the number of cycles are integrated into the design of the reward function to evaluate the merits of the current action. By recording an action path of the agent from its initial state to its termination state, a class integration test order can be obtained. The experimental results on 10 systems show that the class integration test order generation approach based on Sarsa algorithm can generate the class integration test orders with lower stubbing cost.

The synthesis of large-scale monolayer single-crystal MX2(M = Mo, W; X = S, Se), a typical transition metal dichalcogenide (TMD), is the premise for their future applications. Compared with insulating substrates such as SiO2and sapphire, Au is more favourable for the fast growth of TMDs by chemical vapor deposition (CVD). Recently, large-scale single-crystal WX2was successfully grown and transferred on Au. In sharp contrast, the growth and transfer for monolayer MoX2is still very challenging, because Au has a higher solubility of Mo and stronger interaction with MoX2than WX2. Compared with the most studied MoS2, MoSe2is superior in many aspects because of the narrower band gap and tunable excitonic charging effects. However, the synthesis of large-scale single-crystal MoSe2on Au has not been reported so far. Here, a pre-alloying CVD method was developed to solve the problems for the growth and non-destructive transfer of MoX2. It has realized the ultrafast growth (30 s) of submillimeter-scale (560 μm) single-crystal MoSe2for the first time. As-grown samples are strictly monolayers with good optical and electrical properties, which can be easily transferred without sacrificing Au foils by the electrochemical bubbling method. It was found that pre-alloying not only passivates the energetically active sites on Au but also weakens the interaction between Au and MoSe2, which is responsible for the ultrafast growth and easy transfer of MoSe2. This method is also universal for the fast growth and non-destructive transfer of other 2D TMDs.

Defects, such as uncontrollable vacancies, will intensively degrade the material properties and device performance of CVD-grown transition metal dichalcogenides (TMDs). Although vacancies can be repaired by some post-processing measures, these treatments are usually time-consuming, complicated and may introduce uncontrollable chemical contaminants into TMDs. How to efficiently suppress the uncontrollable defects during CVD growth and acquire intrinsic high-quality CVD-grown TMDs without any after-treatment remains a critical challenge, and has not yet been well resolved. Here, an alternate-growth-etching (AGE) CVD method was demonstrated to fabricate defect-suppressed submillimeter-scale monolayer WS2single crystals. Compared with normal CVD, the grain size of the as-grown WS2can be enlarged by 4–5 times (∼520 μm) and the growth rate of ∼14.4 μm min−1is also at a high level compared to reported results. Moreover, AGE-CVD can efficiently suppress atomic vacancies in WS2. In every growth-etching cycle, the etching of WS2occurs preferentially at the defective sites, which will be healed at the following growth stage. As a result, WS2monolayers obtained by AGE-CVD possess higher crystal quality, carrier mobility (8.3 cm2V−1s−1) and PL quantum yield (QY, 52.6%) than those by normal CVD. In particular, such a PL QY is the highest value ever reported for in situCVD-grown TMDs without any after-treatment, and is even comparable to the values of mechanically exfoliated samples. This AGE-CVD method is also appropriate for the synthesis of other high-quality TMD single crystals on a large-scale.

This paper discusses accelerating iterative methods for solving the fully implicit (FI) scheme of equilibrium radiation diffusion problem. Together with the FI Picard factorization (PF) iteration method, three new nonlinear iterative methods, namely, the FI Picard-Newton factorization (PNF), FI Picard-Newton (PN) and derivative free Picard-Newton factorization (DFPNF) iteration methods are studied, in which the resulting linear equations can preserve the parabolic feature of the original PDE. By using the induction reasoning technique to deal with the strong nonlinearity of the problem, rigorous theoretical analysis is performed on the fundamental properties of the four iteration methods. It shows that they all have first-order time and second-order space convergence, and moreover, can preserve the positivity of solutions. It is also proved that the iterative sequences of the PF iteration method and the three Newton-type iteration methods converge to the solution of the FI scheme with a linear and a quadratic speed respectively. Numerical tests are presented to confirm the theoretical results and highlight the high performance of these Newton acceleration methods.

ABSTRACTSevere Helicobacter pylori-linked gastric disorders are especially prevalent in the East Asia region. The ability of H. pylorito cause different clinical outcomes is thought to be associated with unique sets of its genetic features. However, only few genetic features have been definitively linked to specific gastrointestinal pathologies. Genome heterogeneity of clinical H. pyloristrains from patients with four different gastric disorders was studied to explore the population structure and molecular genomic features and their association with pathogenicity. Population analysis showed that 92.9% of the Shanghai H. pyloriisolates were clustered in the East Asia group. Among 2,866 genes detected in all genomes, 1,146 genes formed the core genome, whereas 209 unique genes were detected in individual disease groups. The unique genes of peptic ulcer and gastric cancer groups represented the inorganic ion transport and metabolism function gene clusters. Sixteen virulence genes were detected with statistically different detection rates among the four disease groups. Furthermore, 127 clustered regularly interspaced short palindromic repeats were found with significantly different rates in the four disease groups. A total of 337 putative genomic islands were identified, and three genomic islands were individually found in more than 10% of strains. The genomic islands included several metabolism-associated genes and many genes with unknown function. In total, 88 sequence types were detected among the 112 Shanghai H. pyloriisolates. Our study provides an essential milestone in the mapping of specific genomic features and their functions to identify factors needed to induce specific gastric disorders in H. pylori.

A stable, rapid and effective neural differentiation method is essential for the clinical applications of human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in treating neurological disorders and diseases. Herein, we established a novel and robust monolayer differentiation method to produce functional neural progenitor cells (NPCs) from human ESC/iPSCs on Type I Collagen. The derived cells not only displayed the requisite markers, but also behaved similarly to classic NPCs both in vitroand in vivo. Upon transplantation into traumatic brain injury model, the derived NPCs facilitated recovery from injury. We also found that SMAD signaling stayed down throughout the differentiation process on Type I Collagen, and the pluripotent signals were rapidly downregulated along with raising up of neural early markers on the third day. Meanwhile, ATAC-seq data showed the related mediation of distinct transcriptome and global chromatin dynamics during NPC induction. Totally, our results thus provide a convenient way to generate NPCs from human ESC/iPSCs for neural diseases’ treatment.

Supplemental Digital Content is available in the text.

Cancer-associated lymphatic endothelial cells (LECs) are an active barrier to the effector arm of the anti-tumor immune response; however, it remains unclear how LECs become immunosuppressive in the tumor microenvironment (TME). Exosomal microRNAs (miRNAs) have recently been implicated in intercellular crosstalk within the TME. Here, we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated microRNA (miR)-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Subsequently, exosomal miR-1468-5p epigenetically activates the JAK2/STAT3 pathway in LECs by directly targeting homeobox containing 1 (HMBOX1) in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to escape anti-cancer immunity. Furthermore, clinical data reveal that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer (CCa) patients. Taken together, our results suggest that cancer-secreted exosomal miR-1468-5p instructs LECs to form an integrated immunosuppressive TME component and may be a prognostic biomarker and therapeutic target for CCa.

Surface structures and physicochemical properties critically influence osseointegration of titanium (Ti) implants. Previous studies have shown that the surface with both micro- and nanoscale roughness may provide multiple features comparable to cell dimensions and thus efficiently regulate cell-material interaction. However, less attention has been made to further optimize the physicochemical properties (e.g., crystalline phase) and to further improve the bioactivity of micro/nanostructured surfaces. Herein, micro/nanostructured titania surfaces with different crystalline phases (amorphous, anatase and anatase/rutile) were prepared and hydroxyapatite (HA) nanorods were deposited onto the as-prepared surfaces by a spin-assisted layer-by-layer assembly method without greatly altering the initial multi-scale morphology and wettability. The effects of crystalline phase, chemical composition and wettability on osteoblast response were investigated. It is noted that all the micro/nanostructured surfaces with/without HA modification presented superamphiphilic. The activities of MC3T3-E1 cells suggested that the proliferation trend on the micro/nanostructured surfaces was greatly influenced by different crystalline phases, and the highest proliferation rate was obtained on the anatase/rutile surface, followed by the anatase; but the cell differentiation and extracellular matrix mineralization were almost the same among them. After ultrathin HA modification on the micro/nanostructured surfaces with different crystalline phases, it exhibited similar proliferation trend as the original surfaces; however, the cell differentiation and extracellular matrix mineralization were significantly improved. The results indicate that the introduction of ultrathin HA to the micro/nanostructured surfaces with optimized crystalline phase benefits cell proliferation, differentiation and maturation, which suggests a favorable biomimetic microenvironment and provides the potential for enhanced implant osseointegration in vivo.

The subfamily Agavoideae comprises crassulacean acid metabolism (CAM), C3, and C4 plants with a young age of speciation and slower mutation accumulation, making it a model crop for studying CAM evolution. However, the genetic mechanism underlying CAM evolution remains unclear because of lacking genomic information. This study assembled the genome of Agave hybridNO.11648, a constitutive CAM plant belonging to subfamily Agavoideae, at the chromosome level using data generated from high-throughput chromosome conformation capture, Nanopore, and Illumina techniques, resulting in 30 pseudo-chromosomes with a size of 4.87 Gb and scaffold N50of 186.42 Mb. The genome annotation revealed 58 841 protein-coding genes and 76.91% repetitive sequences, with the dominant repetitive sequences being the I-type repeats (Copia and Gypsy accounting for 18.34% and 13.5% of the genome, respectively). Our findings also provide support for a whole genome duplication event in the lineage leading to A. hybrid, which occurred after its divergence from subfamily Asparagoideae. Moreover, we identified a gene duplication event in the phosphoenolpyruvate carboxylase kinase (PEPCK) gene family and revealed that three PEPCKgenes (PEPCK3, PEPCK5,and PEPCK12) were involved in the CAM pathway. More importantly, we identified transcription factors enriched in the circadian rhythm, MAPK signaling, and plant hormone signal pathway that regulate the PEPCK3expression by analysing the transcriptome and using yeast one-hybrid assays. Our results shed light on CAM evolution and offer an essential resource for the molecular breeding program of Agavespp.

Aim:We evaluated the direct high-throughput multiple genetic detection system (dHMGS) for Helicobacter pyloriin gastric biopsies. Materials & methods:One hundred and thirty-three specimens were concurrently analyzed by dHMGS, rapid urease test, culture and sequencing. Results:dHMGS was highly sensitive and specific for H. pyloriidentification compared with culture and rapid urease test. The correlation coefficient of the quantitative standard curve was R2 0.983. A significant difference in the relative H. pyloriDNA abundance was found in different gastroduodenal diseases. Concordance rates between dHMGS and sequencing for resistance mutations were 97.1, 100.0, 85.3 and 97.1, respectively. Finally, dHMGS could efficiently distinguish mixed infection in biopsy specimens. Conclusion:The dHMGS could efficiently diagnose and quantify H. pyloriburden in biopsies, simultaneously screening for virulence, antibiotic resistance and presence of the multistrain infections.

With the development of global urbanization, the utilization of underground space is more critical and attractive for civil purposes. Various shapes of shield tunnels have been gradually proposed to cope with different geological conditions and service purposes of underground structures. Generally, reducing the burial depth of shield tunnel is conducive to construction and cost saving. However, extremely small overburden depth cannot provide sufficient uplift resistance to maintain the stability and serviceability of the tunnel. To this end, this paper firstly reviewed the status of deriving the minimum sand overburden depth of circular shield tunnel using mechanical equilibrium (ME) method. It revealed that the estimated depth is rather conservative. Then, the uplift resistance mechanism of both circular and rectangular tunnels was deduced theoretically and verified with the model tests. The theoretical uplift resistance is consistent with the experimental values, indicating the feasibility of the proposed equations. Furthermore, the determination of the minimum soil overburden depth of rectangular shield tunnel under various working conditions was presented through integrated ME method, which can provide more reasonable estimations of suggested tunnel burial depth for practical construction. Additionally, optimizations were made for calculating the uplift resistance, and the soil thickness providing uplift resistance is suggested to be adjusted according to the testing results. The results can provide reference for the design and construction of various shapes of shield tunnels in urban underground space exploitation.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-? promoter, and enhances IFN-? transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-? signalling to suppress and exhaust CD8+T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

Protein Preferentially Expressed Antigen in Melanoma (Prame), a tumor-associated antigen, has been found to frequently overexpress in various cancers, which indicates advanced cancer stages and poor clinical prognosis. Moreover, previous reports noted that Prame functions as a substrate recognizing receptor protein of Cullin RING E3 ligases (CRLs) to mediate potential substrates degradation through Ubiquitin Proteasome System (UPS). However, none of the Prame specific substrate has been identified so far. In this study, proteomic analysis of RBX1-interacting proteins revealed p14/ARF, a well-known tumor suppressor, as a novel ubiquitin target of RBX1. Subsequently, immunoprecipitation and in vivo ubiquitination assay determined Cullin2-RBX1-Transcription Elongation Factor B Subunit 2 (EloB) assembled CRL2 E3 ligase complex to regulate the ubiquitination and subsequent degradation of p14/ARF. Finally, through siRNA screening, Prame was identified as the specific receptor protein responsible for recognizing p14/ARF to be degraded. Additionally, via bioinformatics analysis of TCGA database and clinical samples, Prame was determined to overexpress in tumor tissues vs. paired adjacent tissues and associated with poor prognosis of cancer patients. As such, downregulation of Prame expression significantly restrained cancer cell growth by inducing G2/M phase cell cycle arrest, which could be rescued by simultaneously knocking down of p14/ARF. Altogether, targeting overexpressed Prame in cancer cells inactivated RBX1-Cullin2-EloB-Prame E3 ligase (CRL2Prame) and halted p14/ARF degradation to restrain tumor growth by inducing G2/M phase cell cycle arrest.

Integration testing is a very important step in software testing. Existing methods evaluate the stubbing cost for class integration test orders by considering only the interclass direct relationships such as inheritance, aggregation, and association, but they omit the interclass indirect relationship caused by control coupling, which can also affect the test orders and the stubbing cost. In this paper, we introduce an integration test order strategy to consider control coupling. We advance the concept of transitive relationship to describe this kind of interclass dependency and propose a new measurement method to estimate the complexity of control coupling, which is the complexity of stubs created for a transitive relationship. We evaluate our integration test order strategy on 10 programs on various scales. The results show that considering the transitive relationship when generating class integration test orders can significantly reduce the stubbing cost for most programs and that our integration test order strategy obtains satisfactory results more quickly than other methods.

By applying a three-step anodic oxidation method followed by etching and pore widening treatment, etched micro-/submicroscale pits of ∼2 μm and ∼230 nm as well as anodized nanopores of ∼70 nm are combined to form hierarchically porous anodic aluminum oxide (HP-AAO) templates. Hierarchical micro-/submicro-/nanostructured polypropylene/graphene (HMSNS-PP/GP) superhydrophobic surfaces are laminated by a single HP-AAO template, exhibiting the similar arrangement, size, and shape with hierarchical papillae on lotus leaf surfaces. As expected, such a lotus-inspired HMSNS-PP/GP surface has an extremely small roll-off angle of ∼0.5° and a large contact angle of 155.0°, exhibiting high-efficiency self-cleaning characteristics. The HMSNS-PP/GP surface is endowed with static and dynamic wetting stabilities, which are reflected in immersion and impacting tests. After immersion, the HMSNS-PP/GP replica remains fully spotless accompanied with the ability to work under a hydrostatic pressure of ∼3626 Pa for at least 60 min. After impact, the maximum height of bounced droplets is up to 12.4 mm (i.e., 5.3 times the diameter of the droplet) at a Weber number of ∼32.12.

Aim:To identify intestinal microbiota compositions in elderly functional constipation (FC) patients. Materials & methods:Fecal samples from 61 FC patients and 48 healthy age-matched volunteers were analyzed through 16S rRNA gene sequencing. Results:The intestinal microbiota compositions of FC patients were significantly different from healthy controls. Additionally, the species diversity of healthy controls was greater than that of FC patients. Indeed, the abundance of Firmicutesand Proteobacteriawas significantly decreased, whereas that of Bacteroides, Prevotella, Lactococcus, Ruminococcusand Butyricimonaswas remarkably increased in FC patients. Conclusion:Elderly FC patients appear to have a unique intestinal microbiota profile. Our findings should provide insight regarding the pathogenic mechanism of FC and evidence for exploring new therapeutic strategies in elderly FC patients.

Metastasis, the development of secondary malignant growths at a distance from a primary tumor, is the cause of death for 90% of cancer patients, but little is known about how metastatic cancer cells adapt to and colonize new tissue environments. Here, using clinical samples, patient-derived xenograft (PDX) samples, PDX cells, and primary/metastatic cell lines, we discovered that liver metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program yet gain a liver-specific gene transcription program. We showed that this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical enhancers and super-enhancers. Further, we identified that the liver-specific transcription factors FOXA2 and HNF1A can bind to the gained enhancers and activate the liver-specific gene transcription, thereby driving CRC liver metastasis. Importantly, similar transcription reprogramming can be observed in multiple cancer types. Our data suggest that reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.

Xu Zechen has been acclaimed as the “best writer born in the 1970s” in China. In this interview by literary critic Zhang Xiumei, Xu talks about his works, in particular his novel Jerusalem, the fiction writing of other ’70s generation Chinese writers, and his view of literature in general. Some key concepts in his fiction, such as the “world” and the hometown, are discussed in connection with notions about history, religion, spiritual search, and growth. Xu conceives of his fiction writing as a means to answer questions, and one central question he seeks to answer concerns the origin and destination of life as a never-ending journey.

Background: Parasite diversity and population structure influence malaria control measures. Malaria transmission at international borders affects indigenous residents and migrants, defying management efforts and resulting in malaria re-introduction. Here we aimed to determine the extent and distribution of genetic variations in Plasmodium vivaxpopulations and the complexity of infections along the China–Myanmar border. Methods: We collected clinical P. vivaxsamples from local and migrant malaria patients from Laiza and Myitsone, Kachin State, Myanmar, respectively. We characterized the polymorphisms in two P. vivaxmerozoite surface protein markers, Pvmsp-3αand Pvmsp-3β, by PCR-restriction fragment length polymorphism (PCR–RFLP) analysis. We sought to determine whether these genetic markers could differentiate these two neighboring parasite populations. Results: PCR revealed three major size variants for Pvmsp-3αand four for Pvmsp-3βamong the 370 and 378 samples, respectively. PCR–RFLP resolved 26 fragment-size alleles by digesting Pvmsp-3αwith AluI and HhaI and 28 alleles by digesting Pvmsp-3βwith PstI. PCR–RFLP analysis of Pvmsp-3αfound that infections in migrant laborers from Myitsone bore more alleles than did infections in residents of Laiza, while such difference was not evident from genotyping Pvmsp-3β. Infections originating from these two places contained distinct but overlapping subpopulations of P. vivax.Infections from Myitsone had a higher multiplicity of infection as judged by the size of the Pvmsp-3αamplicons and alleles after AluI/HhaI digestion. Conclusions: Migrant laborers from Myitsone and indigenous residents from Laiza harbored overlapping but genetically distinct P. vivaxparasite populations. The results suggested a more diverse P. vivaxpopulation in Myitsone than in the border town of Laiza. PCR–RFLP of Pvmsp-3αoffers a convenient method to determine the complexity of P. vivaxinfections and differentiate parasite populations.

Tumor-associated macrophages (TAMs) are the most abundant cancer stromal cells and play an essential role in tumor immunosuppression, providing a suitable microenvironment for cancer development and progression. However, mechanisms of regulating TAMs infiltration in tumor sites are not fully understood. Here, we show that inactivation of neddylation pathway significantly inhibits infiltration of TAMs, leading to the suppression of lung cancer metastasis. RNA-sequencing analysis revealed that neddylation inactivation suppresses the transactivation of chemotactic cytokine ligand 2 (CCL2). Mechanistically, neddylation inactivation inhibits the activity of Cullin-RING ligases (CRLs) and induces the accumulation of its substrate IκBα to block NF-κB transcriptional activity and CCL2 transactivation. As a result, neddylation inactivation exhibits lower chemotaxis of monocytes, thereby decreasing TAMs infiltration, which can be alleviated by CCL2 addition. Moreover, the expression level of NEDD8 is positively correlated with high CCL2 expression in lung adenocarcinoma, conferring a worse overall patient survival. Together, neddylation pathway promotes CCL2 transactivation and TAMs infiltration in lung cancer to provide a tumor-promoting microenvironment, which validates neddylation pathway as a promising target for anti-TAMs therapeutic strategies.

A schlieren detection algorithm is proposed for the ground-to-air background oriented schlieren (BOS) system to achieve high-speed airplane shock waves visualization. The proposed method consists of three steps. Firstly, image registration is incorporated for reducing errors caused by the camera motion. Then, the background subtraction dual-model single Gaussian model (BS-DSGtVI) is proposed to build a precise background model. The BS-DSGM could prevent the background model from being contaminated by the shock waves. Finally, the two-dimensional orthogonal discrete wavelet transformation is used to extract schlieren information and averaging schlieren data. Experimental results show our proposed algorithm is able to detect the aircraft in-flight and to extract the schlieren information. The precision of schlieren detection algorithm is 0.96. Three image quality evaluation indices are chosen for quantitative analysis of the shock waves visualization. The white Gaussian noise is added in the frames to validate the robustness of the proposed algorithm. Moreover, we adopt two times and four times down sampling to simulate different imaging distances for revealing how the imaging distance affects the schlieren information in the BOS system. [ABSTRACT FROM AUTHOR]

The cellular mechanism underlying bacteria responses to silver nanoparticles (AgNPs) has not been fully elucidated. Especially, it is difficult to distinguish the contact killing from release killing as Ag+releases from AgNPs. In this paper, AgNPs gradient was designed for evaluating the size effect of AgNPs on contact killing. A size gradient of AgNPs (5–45 nm) was achieved on TiO2nanotubes (TNTs) by rational design of bipolar electrochemical reaction, including applied voltage, electrolyte concentration, and sample size. High-throughput investigation of cellular responses showed that the smallest AgNPs were the most efficient in suppressing bacteria whereas the largest AgNPs were more favorable for MC3T3-E1 cell adhesion and proliferation. As Ag+concentration was the same for the entire gradient, the difference in cellular responses was dominated by the contact effect (rather than difference in released Ag+) which was tuned by AgNPs size. This method offers new prospect for efficient evaluation of the contact effect of nanoparticles, such as Ag, Au, and Cu.

Many efforts have been devoted to the integration of magnetic nanoparticles and metal organic frameworks, which makes it easy and simple to separate the nano-sized metal organic frameworks from liquid phase. Amino-functionalized magnetic metal organic frameworks[Fe3O4@MIL-100(Fe)-NH2] were prepared by a stepwise assembly method followed by post-modification with electron-rich reagent. This magnetic catalyst was characterized by means of X-ray diffraction(XRD), transmission electron microscopy(TEM), scanning electron microscopy(SEM) and nitrogen adsorption, and tested in Knoevenagel condensation as a base catalyst. The magnetic catalyst exhibits a core-shell structure and can afford a high activity for the Knoevenagel condensation due to its bifunctional property and reduced diffusion limitation. Furthermore, it could be recovered magnetically and recycled three times. Although activity loss was observed in the recycle experiments, it could be reactivated by dispersing in a fresh modifier solution.

The dimension of TiO2nanotubes (TNTs) ranges from several nanometers to hundreds of nanometers. This variety raises the difficulty of screening suitable nanotube dimension for biomedical applications. Herein, we report the use of a simple one-step bipolar anodization method for fabrication of TNT gradients with diameter range from 30 to 100 nm. The gradient TNTs were successfully applied for high-throughput screening of TNT size effect on cell responses, including cell adhesion, proliferation, and differentiation. Results reveal that no significant difference in adherent cell number could be found within the range of 30–87 nm in both the presence and absence of serum proteins. On the contrary, large nanotubes (with outer diameter >87 nm) profoundly reduce cell adhesion in both the presence and absence of serum proteins, indicating TNT size could affect cell adhesion directly without the adsorbed proteins. The size effect on cell behavior becomes prominent with time that cell proliferation and differentiation decrease with increasing nanotube size. This size effect can be comprehended by protein adsorption and the formation of focal adhesion. Another two sample applications of gradient TNTs demonstrate gradient TNTs are promising for high-throughput screening.

This article contends that current service recommendation algorithms are still unable to meet the dynamic and diverse demands of users, so a service recommendation algorithm considering dynamic and diverse demands is proposed. The latent Dirichlet allocation model of machine learning field is adopted to extract the user implicit demand factors, and then the bipartite graph modeling and random-walk algorithm are used to extend implicit demand factors to predict short-term changes and diversity of user demand. At last, the service recommendation list is generated based on these demand factors. Experimental results on a real-world data set regarding service composition show that the proposed algorithm can represent dynamic and diverse user demands, and the performance of the proposed algorithm is better than that of the other algorithms in terms of accuracy, novelty, and diversity.

Carbon fiber reinforced polymer composites used in the aircraft structures often face the problems of open-hole and low temperature. A better understanding of the effects of low temperature and large open-hole on the tensile behaviors of carbon fiber reinforced polymer laminates is highly desirable. In this study the open-hole tensile tests on the carbon fiber/epoxy laminate-T700/SYE20005 with the stacking sequence of [0/90]4Swere conducted at both room temperature and low temperature of −60 °C, where the specimens with three different ratios of hole diameter Dover the specimen width Wwere considered. The results showed that the notched strength of the laminates decreases by 54.1% with the increase of the ratio D/Wfrom 0.3 to 0.7 at room temperature. One interesting result is that low temperature greatly improves the strength of laminates with the ratios of D/W = 0.3 and 0.5, producing the increase of 13% in the notched strength, while it has an unobvious effect on the laminate with the ratio of D/W = 0.7. The observations of fracture surface of specimens show that the failure of the laminate with small open hole is mostly dominated by the fiber breakage and axial splits, and the interlaminar delamination and intralaminar matrix cracks are also found for the laminated specimen with large open hole.

The aim of testing based fault localization (TBFL) involves improving the efficiency of program debugging by providing developers with a guide of ranked list of suspicious statements. However, collection of testing information of the whole original test-suite is excessively expensive or even infeasible for developers to conduct TBFL. Traditional test-suite reduction (TSR) techniques are utilized to reduce the size of test-suite. However, they entail a time-consuming process of whole testing information collection. In this study, the distance based test-suite reduction (DTSR) technique is proposed. As opposed to the whole testing information, the distances among the test cases are used to guide the process of test-suite reduction in DTSR. Hence, it is only necessary to collect the testing information for a portion of the test cases for TSR and TBFL. The investigation on the Siemens and SIR benchmarks reveals that DTSR can effectively reduce the size of the given test-suite as well as the time cost of TBFL. Additionally, the fault locating effectiveness of DTSR results is close to that when the whole test-suite is used.

The low success rate of lending is the main drawback of development of online P2P lending platforms in China. Based on the theory of social capital, this study analysed the influence factors of success rate of P2P lending platform in China, using social network method and multiple linear regression model. Soft information, such as bidding record, has been creatively employed to study the corresponding topics. Data used in this study comes from the largest online P2P lending platform in China. The results show that: compared with other influence factors, the bidding record has a more significant effect on the success rate, and the users depend more on the social capital; the bidding records reduce the asymmetry of information, and help increasing the success rate of lending and decreasing the cost of online P2P lending.

The upgrading of heavy oil from Karamay using supercritical methanol (SC-MeOH) as a solvent was studied in a batch reaction. Through orthogonal experiments, the effects of the temperature, mass ratio of methanol to oil, reaction time, and agitation speed were investigated. The optimal reaction conditions, depending on the boiling range of light products such as maltenes and the yields of byproducts such as asphaltenes, were as follows: reaction temperature of 350 °C, reaction time of 60 min, stirring agitation of 900 rpm, and mass ratio of methanol to oil of 1:1. A simultaneous increase agitation speed would significantly reduce the condensation behavior. Analysis of the simulated distillation of maltenes indicated that the components with boiling points lower than 380 °C increased from 19 wt % in the raw material to 38 wt % in the maltenes products. The viscosity of light products decreased to 24.1 mPa·s. The FTIR of asphaltene results showed that the temperature has contradictory influence on upgrading of heavy oils. With increasing temperature, the degree of aromatic ring condensation increases and the lengths of aliphatic side chains decrease. High temperature can promote the breakage of alkyl side chains and condensation of aromatic rings. The TG-FTIR spectrum proves that SC-MeOH can participant in the reaction as a reactant. However, heteroatom O was introduced into the maltene molecules. All these results proved that SC-MeOH is an excellent solvent for oil pyrolysis. However, the quantity of light products should be improved, the secondary generation of asphaltenes removal needs to be restrained, and heteroatoms need more detailed research.

This paper presents two kinds of K-level co-prime linear array geometries and the corresponding direction of arrival estimation algorithm based on the multi-resolution difference co-array (MRDCA) perspective. The MRDCA can simultaneously improve the degree of freedom and the angle-resolution by utilizing a class of virtual sparse uniform linear arrays generated by vectorizing the covariance matrix of the received observations of the K-level large scale sparse array. Compared to the prior two level co-prime/nested arrays, the aperture and the angle-resolution can be significantly increased with K th power law for the K-level array, while the dimension of its scanning space is reduced to 1 / K resulted from the spatial aliasing of the MRDCA. As a result, a low-complexity DOA estimation algorithm is proposed by combining a multi-resolution estimation at each level of sparse MRDCA and a followed probability decision strategy which aims at effectively identifying the genuine DOAs and excluding the replicas. In the end, the simulation results are provided to numerically validate the performance of the proposed array geometries. [ABSTRACT FROM AUTHOR]

A method for the screening of histone deacetylase 1 (HDAC1) inhibitors in natural products by using capillary electrophoresis (CE) coupled with laser induced fluorescence (LIF) detection was developed. The method was developed by employing a 5-carboxyfluorescein labelled peptide with an acetylated lysine residue as the substrate of HDAC1 and a small chemical library composed of 38 purified natural products. The biochemical assay was performed by means of CE separation, i.e.the deacetylated product in the enzymatic reaction solution was separated from the substrate peptide; therefore, the enzyme activity can be accurately calculated through the measurement of the peak area of the deacetylated product. For inhibitor screening, the tested samples were spiked in the substrate solution and the resulting solution mixtures were then incubated with the enzyme solution for proceeding the deacetylation reaction for a short period of time at 30 °C. After quenching the reaction by putting the reaction vial in boiling water, the resulting solution was injected for CE separation with 100 mM Tris–H3PO4buffer (pH 8.0) containing 30 mM NaCl and 0.05% (m/v) hexadimethrine bromide (HDB). The inhibitor could be readily identified as long as the peak area of the deacetylated product is reduced in comparison with that of the negative control in the absence of any inhibitor. Dynamically coating the capillary wall with positively charged HDB is very necessary to diminish the serious adsorption of the substrate and product peptides onto the capillary wall. A rapid, cost-effective method for HDAC1 inhibitor screening is proposed.

Groundwater level change stands a momentous role in affecting the geotechnical construction stability and safety of underground structures. Global warming and active underground construction cause conspicuous changes in the groundwater level, which further leaves an impact on the underground structures’ serviceability. To reveal the interaction between underground structure and soil under groundwater level change in the sand layer, model tests of circular transportation tunnel and rectangular utility tunnel were carried out. With the self-designed experimental equipment and innovative experimental methods, the changes in tunnel stress, bending moment, buoyancy, and vertical displacement of the rise and drawdown of the groundwater level in the sand layer were studied. The results revealed the developments of concentrated structural forces during the rising and falling process of the groundwater water level, indicating critical locations that should be strengthened. Meanwhile, both tunnels showed the same movement trend: settling first, floating afterwards and settling at last. And it is concluded that no reduction is required when calculating buoyancy in sands using measured pore pressure. Conclusions can provide a notable reference for future related research and engineering designs.

Magnetic separation is an attractive alternative to filtration or centrifugation for separating solid catalysts from a liquid phase. Here, core-shell Fe3O4@UiO-66-NH2nanohybrids with well-defined structures were constructed by dispersing magnets in a dimethylformamide (DMF) solution containing two metal–organic framework (MOF) precursors, namely ZrCl4and 2-aminobenzenetricarboxylic acid. This method is simpler and more efficient than previously reported step-by-step method in which magnets were consecutively dispersed in DMF solutions each containing one MOF precursor, and the obtained Fe3O4@UiO-66-NH2with three assembly cycles has a higher degree of crystallinity and porosity. The core-shell Fe3O4@UiO-66-NH2is highly active and selective in Knoevenagel condensations because of the bifunctionality of UiO-66-NH2and better mass transfer in the nano-sized shells. It also has good recycling stability, and can be recovered magnetically and reused at least four times without significant loss of catalytic activity and framework integrity. The effects of substitution on the reactivity of benzaldehyde and of substrate size were also investigated.

Coxibs are a class of powerful drugs used by millions of people worldwide to treat a wide variety of ailments such as muscular skeletal pain and inflammation. The primary mechanism of action of coxibs is the potent inhibition of the COX-2 enzyme. Unfortunately, their use is limited to patients due to a variety of factors including poor solubility, negative effects on renal clearance and increased risk of cardiovascular pathology. However, because of their effectiveness in blocking PGE2 mediated inflammation, a key pathway that drives many diseases, there is a clear unmet medical need to develop new COX-2 inhibitors that are free of the aforementioned problems. The purpose of this prospectus is to define the specific properties that are desired in 3rd generation coxibs as a starting point for the development of new and better drugs.