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Can Chen,1,2,* Ting Wang,1,3,* Fengbo Wu,1,* Wei Huang,4 Gu He,1 Liang Ouyang,1 Mingli Xiang,1 Cheng Peng,4 Qinglin Jiang1,2 1State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 2College of Pharmacy and the First Affiliated Hospital, Chengdu Medical College, Chengdu, 3Department of Cardiology, Genenal Hospital of Chengdu Military Command, Chengdu, 4State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workAbstract: Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents.Keywords: pharmacophore, molecular docking, pyruvate kinase, virtual screening

Wen-tao Lin,1 Hong-lue Tan,1 Zhao-ling Duan,2 Bing Yue,1 Rui Ma,1 Guo He,2 Ting-ting Tang1 1Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 2State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China Abstract: Titania nanotubes loaded with antibiotics can deliver a high concentration of antibiotics locally at a specific site, thereby providing a promising strategy to prevent implant-associated infections. In this study we have fabricated titania nanotubes with various diameters (80, 120, 160, and 200 nm) and 200 nm length via electrochemical anodization. These nanotubes were loaded with 2 mg of gentamicin using a lyophilization method and vacuum drying. A standard strain, Staphylococcus epidermidis (American Type Culture Collection 35984), and two clinical isolates, S. aureus 376 and S. epidermidis 389, were selected to investigate the anti-infective ability of the gentamicin-loaded nanotubes (NT-G). Flat titanium (FlatTi) and nanotubes with no drug loading (NT) were also investigated and compared. We found that NT-G could significantly inhibit bacterial adhesion and biofilm formation compared to FlatTi or NT, and the NT-G with 160 nm and 200 nm diameters had stronger antibacterial activity because of the extended drug release time of NT-G with larger diameters. The NT also exhibited greater antibacterial ability than the FlatTi, while nanotubes with 80 nm or 120 nm diameters had better effects. Furthermore, human marrow derived mesenchymal stem cells were used to evaluate the effect of nanotubular topographies on the osteogenic differentiation of mesenchymal stem cells. Our results showed that NT-G and NT, especially those with 80 nm diameters, significantly promoted cell attachment, proliferation, spreading, and osteogenic differentiation when compared to FlatTi, and there was no significant difference between NT-G and NT with the same diameter. Therefore, nanotube modification and gentamicin loading can significantly improve the antibacterial ability and osteogenic activity of orthopedic implants. Keywords: titania nanotubes, gentamicin, bacteria adhesion, biofilm formation, osteogenic activity

Zhaoxiang Peng,1,2,* Jiahua Ni,3,* Kang Zheng,2 Yandong Shen,2 Xiaoqing Wang,1 Guo He,3 Sungho Jin,4 Tingting Tang1 1Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China; 2Department of Orthopaedic Surgery, Ningbo Medical Treatment Center Lihuili Hospital, Ningbo, People's Republic of China; 3State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China; 4Materials Science and Engineering, University of California, San Diego, La Jolla, CA, USA *These authors contributed equally to this work Abstract: Competition occurs between the osteoblasts in regional microenvironments and pathogens introduced during surgery, on the surface of bone implants, such as joint prostheses. The aim of this study was to modulate bacterial and osteoblast adhesion on implant surfaces by using a nanotube array. Titanium oxide (TiO2) nanotube arrays, 30 nm or 80 nm in diameter, were prepared by a two-step anodization on titanium substrates. Mechanically polished and acid-etched titanium samples were also prepared to serve as control groups. The standard strains of Staphylococcus epidermidis (S. epidermidis, American Type Culture Collection [ATCC]35984) and mouse C3H10T1/2 cell lines with osteogenic potential were used to evaluate the different responses to the nanotube arrays, in bacteria and eukaryotic cells. We found that the initial adhesion and colonization of S. epidermidis on the surface of the TiO2 nanotube arrays were significantly reduced and that the adhesion of C3H10T1/2 cells on the surface of the TiO2 nanotube arrays was significantly enhanced when compared with the control samples. Based on a surface analysis of all four groups, we observed increased surface roughness, decreased water contact angles, and an enhanced concentration of oxygen and fluorine atoms on the TiO2 nanotube surface. We conclude that the TiO2 nanotube surface can reduce bacterial colonization and enhance C3H10T1/2 cell adhesion; multiple physical and chemical properties of the TiO2 nanotube surface may contribute to these dual effects. Keywords: bacterial adhesion, titanium implant, surface modification

Mingli Xiang,1,* Kai Lei,1,* Wenjie Fan,1 Yuchun Lin,2 Gu He,1 Mingli Yang,3 Lijuan Chen,1 Yirong Mo41The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of China; 2Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA; 3Institute of Atomic and Molecular Physics, Sichuan University, Chengdu, People’s Republic of China; 4Department of Chemistry, Western Michigan University, Kalamazoo, MI, USA*These authors contributed equally to this workBackground: Epidermal growth factor receptor (EGFR) is an attractive therapeutic target for a number of human tumors including non-small cell lung cancer (NSCLC). Most patients with NSCLC and somatic mutations have shown a dramatic initial clinical response to reversible EGFR inhibitors. The clinical efficacy of reversible inhibitors is, however, ultimately limited due to the emergence of drug resistance, which is usually conferred by the EGFR T790M mutation. Importantly, irreversible, synthetic small molecule inhibitors are currently evaluated and some of them have been shown to overcome the acquired resistance that is oftentimes observed in these patients. Thus far, irreversible EGFR inhibitors as a drug class have not received regulatory approval due in part to their poor effectiveness at clinically achievable concentrations. Therefore, there is an urgent need to discover and develop novel, potent irreversible inhibitors against the EGFR T790M mutation.Material and methods: In the following study, we report a novel “hybrid strategy” to identify irreversible EGFR inhibitors with active scaffolds starting with the identification and extraction of a common chemical reactive feature and a pharmacophore feature. The chemical reactive feature was elucidated by investigating 138 currently known irreversible inhibitors at B3LYP/6-31G(d) level using the density function theory method. The pharmacophore feature was extracted from the same inhibitors using pharmacophore modeling. Based on these unique features, two constraints were set while calibrating the protocols of in silico screening. Compounds bearing these specific features were obtained from the National Cancer Institute diversity database to form our subsequent library. Finally, a structure based virtual screening against the library was conducted using standard protocols validated in our lab.Results: Twenty-eight candidate compounds that demonstrated antitumor activity and that had novel scaffolds different from commonly known quinazoline/quinoline analogs were obtained. The interaction modes between three representative candidates and our model system are similar to that between the model system and the reference compound T-001, which has previously been reported to be one of the most potent of the 138 irreversible inhibitors.Conclusion: The hybrid strategy starting with the extraction of common features is an effective approach to design potential irreversible inhibitors with novel scaffolds and therefore to obtain lead molecules in the selection process. These candidates possessing unique scaffolds have a strong likelihood to act as further starting points in the preclinical development of potent irreversible T790M EGFR inhibitors.Keywords: mutant EGFR, NCI database, virtual screening, drug resistant, quantum chemical calculation, pharmacophore modeling

The effects of cadmium (Cd) stress on the photosynthetic apparatus of the tobacco to Cd stress were analyzed. The results showed that the chlorophyll content in the tobacco leaves declined as the Cd concentration increased. In Cd-challenged tobacco leaves, the performance index on absorption basis (PIABS), which is based on light absorption, could better reflect Cd-induced toxicity to PS reaction centers than the maximum photochemical efficiency of PS (Fv/Fm). As the concentration of Cd increased, the relative variable fluorescence at the J step (VJ) was significantly increased in the tobacco leaves, and a VJ of 50 µmol·L-1 Cd was significantly different from that of the control (CK). As Cd concentration increased, the quantum yield for electron transport (fEo) was significantly reduced in the tobacco leaves, while maximum quantum yield for non-photochemical quenching (fDo) was markedly increased. Moreover, absorption flux per reaction center (ABS/RC) significantly increased when Cd concentration reached 100 mol·L-1. The above results suggest that the tobacco leaves adapt to Cd stress by lowering the electron transmission rate and the activity of PS? reaction centers and increasing thermal dissipation. [ABSTRACT FROM AUTHOR]

The increased susceptibility of MPXV-associated encephalitis in young children highlights the need for a high index of suspicion since early MPXV infections can be confused with other common viral infections (such as hand foot and mouth disease) in this age group. In total, there were seven cases of encephalitis, in which three patients died while two made a full recovery.[[2], [4], [6]] The youngest patient recorded was only 28 days at birth, while the oldest patient recorded was 43 years old. The human monkeypox virus (MPXV), a member of the Orthopoxvirus genus, causes monkeypox, a re-emerging zoonotic viral disease that has a similar but less severe clinical presentation to smallpox.[1] While MPXV is endemic in African countries, the most recent outbreak has seen it spread to several countries. [Extracted from the article]

This paper is presented to compare various wavy leading-edge protuberances on oscillating hydrofoil performance and power efficiency. The unsteady turbulent 3D flow simulations were carried out by using the StarCCM+ software. The 3D hydrofoil with a straight at the leading-edge is a NACA0015 section with a chord of 0.24 m and an aspect ratio of 7. Four new types of hydrofoils are proposed with wavy leading-edge protuberance. The RANS equations with the realizable k-e turbulence model are used to predict the turbulent flow around the hydrofoil under different conditions. In order to validate, a comparison of the numerical results of the forces coefficients and power efficiency of non-protuberance oscillating hydrofoil are shown in good agreement with experimental data. Then, four new profiles on the leading-edge of the hydrofoils are simulated and many results of the pressure distribution, vorticity contour, streamline velocity, and power coefficient for five hydrofoil types are presented and discussed. It is concluded that the hydrofoil of Type-M can achieve constantly higher efficiency of over 46% by employing appropriate heave and pitch amplitudes. [ABSTRACT FROM AUTHOR]