Regioselective Pyridine to Benzene Edit Inspired by Water-Displacement.

Late-stage derivatization of drug-like functional groups can accelerate drug discovery efforts by swiftly exchanging hydrogen-bond donors with acceptors, or by modulating key physicochemical properties like logP, solubility, or polar surface area. A proven derivatization strategy to improve ligand potency is to extend the ligand to displace water molecules that are mediating the interactions with a receptor. Inspired by this application, we developed a method to regioselectively transmute the nitrogen atom from pyridine into carbon bearing an ester, a flexible functional group handle. We applied this method to a variety of substituted pyridines, as well as late-stage transformation of FDA-approved drugs.

Precision native polysaccharides from living polymerization of anhydrosugars.

The composition, sequence, length and type of glycosidic linkage of polysaccharides profoundly affect their biological and physical properties. However, investigation of the structure-function relationship of polysaccharides is hampered by difficulties in accessing well-defined polysaccharides in sufficient quantities. Here we report a chemical approach to precision polysaccharides with native glycosidic linkages via living cationic ring-opening polymerization of 1,6-anhydrosugars. We synthesized well-defined polysaccharides with tunable molecular weight, low dispersity and excellent regio- and stereo-selectivity using a boron trifluoride etherate catalyst and glycosyl fluoride initiators. Computational studies revealed that the reaction propagated through the monomer α-addition to the oxocarbenium and was controlled by the reversible deactivation of the propagating oxocarbenium to form the glycosyl fluoride dormant species. Our method afforded a facile and scalable pathway to multiple biologically relevant precision polysaccharides, including D-glucan, D-mannan and an unusual L-glucan. We demonstrated that catalytic depolymerization of precision polysaccharides efficiently regenerated monomers, suggesting their potential utility as a class of chemically recyclable materials with tailored thermal and mechanical properties.

17-Year Follow-up of Comparing Mastoscopic and Conventional Axillary Dissection in Breast Cancer: A Multicenter, Randomized Controlled Trial.

INTRODUCTION: Longer follow-up was necessary to determine the exact value of mastoscopic axillary lymph node dissection (MALND). METHODS: From January 1, 2003, to December 31, 2005, 1027 patients with breast cancer were randomly assigned to two groups: MALND and CALND (conventional axillary lymph node dissection); 996 eligible patients were enrolled. RESULTS: The final cohort of 996 patients was followed for an average of 198 months. Events other than death differed significantly between the two cohorts (p = 0.0311; 46.3% in MALND and 53.2% in CALND, respectively). The sum of events other than death and deaths from other causes was much higher in the CALND (59.6%) than MALND (53.4%) group (p = 0.0494). The 17-year disease-free survival DFS rates were 36.7% for the MALND and 33.6% for the CALND group, respectively. There was a significant difference between the groups (p = 0.0306). Overall survival (OS) rates were 53.2% after MALND and 46.0% after CALND (p = 0.0119). MALND patients had much less axillary pain (p = 0.0000), numbness or paresthesia (p = 0.0000), arm mobility (p = 0.0000) and arm swelling on the operated side (p = 0.0000). Aesthetic appearance of the axilla was much better in the MALND than CALND group (p = 0.0000) at an average follow-up of 17 years. CONCLUSIONS: The use of MALND in breast cancer surgery not only decreases the relapse and arm complications but also improves long-term survival of patients. Therefore, MALND should be one of the preferred approaches for breast cancer surgery when ALND is needed. TRIAL REGISTRATION INFORMATION: The comparison of long-term outcomes of mastoscopic and conventional axillary lymph node dissection in breast cancer: a multicenter randomized control trial. ChiCTR-TRC-11001477, CHiCTR. First registration 08/14/2011.

λ/12 Super Resolution Achieved in Maskless Optical Projection Nanolithography for Efficient Cross-Scale Patterning.

The emerging demand for device miniaturization and integration prompts the patterning technique of micronano-cross-scale structures as an urgent desire. Lithography, as a sufficient patterning technique, has been playing an important role in achieving functional micronanoscale structures for decades. As a promising alternative, we have proposed and demonstrated the maskless optical projection nanolithography (MLOP-NL) technique for efficient cross-scale patterning. A minimum feature size of 32 nm, which is λ/12 super resolution breaking the optical diffraction limit, has been achieved by a single exposure. Furthermore, multiscale two-dimensional micronano-hybrid structures with the size over hundreds of micrometers and the precision at tens of nanometers have been fabricated by simply controlling the exposure conditions. The proposed MLOP-NL technique provides a powerful tool for achieving cross-scale patterning with both large-scale and precise configuration with high efficiency, which can be potentially used in the fabrication of multiscale integrated microsystems.

Chemoproteomics-Enabled De Novo Discovery of Photoswitchable Carboxylesterase Inhibitors for Optically Controlled Drug Metabolism.

Herein, we report arylazopyrazole ureas and sulfones as a novel class of photoswitchable serine hydrolase inhibitors and present a chemoproteomic platform for rapid discovery of optically controlled serine hydrolase targets in complex proteomes. Specifically, we identify highly potent and selective photoswitchable inhibitors of the drug-metabolizing enzymes carboxylesterases 1 and 2 and demonstrate their pharmacological application by optically controlling the metabolism of the immunosuppressant drug mycophenolate mofetil. Collectively, this proof-of-concept study provides a first example of photopharmacological tools to optically control drug metabolism by modulating the activity of a metabolizing enzyme. Our arylazopyrazole ureas and sulfones offer synthetically accessible scaffolds that can be expanded to identify specific photoswitchable inhibitors for other serine hydrolases, including lipases, peptidases, and proteases. Our chemoproteomic platform can be applied to other photoswitches and scaffolds to achieve optical control over diverse protein classes.

EIF3J-AS1 promotes glioma cell growth via up-regulating ANXA11 through sponging miR-1343-3p.

BACKGROUND: Glioma is one prevalent malignant tumor originates from the central nervous system. Dysregulation of long non-coding RNAs (lncRNAs) has been found to be a molecular signature behind the pathology of a variety of cancers, including glioma. EIF3J antisense RNA 1 (EIF3J-AS1) is a novel lncRNA, whose performance in carcinogenesis has been unfolded. Nevertheless, the role of EIF3J-AS1 has never been investigated in glioma. METHODS: qRT-PCR analysis was adopted to evaluate the relative levels of RNAs. In vitro functional assays, including colony formation, EdU, TUNEL and caspase-3/8/9 activity assays were conducted to study the impacts of EIF3J-AS1 on glioma. Dual-luciferase activity assays, RNA pull down assay and RIP assay were performed to elucidate molecular interplay among genes. RESULTS: EIF3J-AS1 was overexpressed in glioma cell lines. Knockdown of EIF3J-AS1 hampered glioma malignant phenotypes. MiR-1343-3p could bind to EIF3J-AS1. Moreover, miR-1343-3p targeted Annexin A11 (ANXA11) in its 3'UTR region. Mechanistically, EIF3J-AS1 relieved ANXA11 from miR-1343-3p silencing in the EIF3J-AS1/miR-1343-3p/ANXA11 RNA induced silencing complex (RISC), thus eliciting promoting effects on glioma progression. MiR-1343-3p inhibitor and ANXA11 overexpression offset the inhibitory impacts of EIF3J-AS1 silencing on glioma development. CONCLUSION: EIF3J-AS1/miR-1343-3p/ANXA11 axis significantly affected biological behaviors in glioma, suggesting new therapeutic target for glioma treatment.

Difluorinative ring expansions of benzo-fused carbocycles and heterocycles are achieved with p-(difluoroiodo)toluene.

A chemoselective fluorinative ring expansion has been realized using the hypervalent iodine (HVI) reagent p-TolIF2, which delivers ß,ß-difluoroalkyl arenes in yields up to 89% and allylic gem-difluorides in yields up to 78%. This rapid reaction exploits the ambiphilic nature of alkenes and allenes, and incorporates both fluorine atoms of the (difluoroiodo)arene in the products. The mechanism involves a 1,2-phenyl shift, which provides access in one step to important fluorinated building blocks for bioactive molecule synthesis.

Denitrogenative Hydrotrifluoromethylation of Benzaldehyde Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes.

Reacting hydrazones of arylaldehydes with Togni's CF3 -benziodoxolone reagent, in the presence of potassium hydroxide and cesium fluoride, induces a denitrogenative hydrotrifluoromethylation event to produce (2,2,2-trifluoroethyl)arenes. This novel reaction was tolerant to many electronically-diverse functional groups and substitution patterns, as well as naphthyl- and heteroaryl-derived substrates. Advantages of this process include the easy access to hydrazone precursors on a large scale, speed and operational simplicity, and being transition metal-free.

Cucurbit[7]uril-Carbazole Two-Photon Photoinitiators for the Fabrication of Biocompatible Three-Dimensional Hydrogel Scaffolds by Laser Direct Writing in Aqueous Solutions.

We have introduced a novel water-soluble two-photon photoinitiator based on the host-guest interaction between 3,6-bis[2-(1-methyl-pyridinium)vinyl]-9-pentyl-carbazole diiodide (BMVPC) and cucurbit[7]uril (CB7) because most of the commercial photoinitiators have poor two-photon initiating efficiency in aqueous solutions. The binding ratio of BMVPC and CB7 was determined as 1:1 by isothermal titration calorimetry and quantum chemical calculation. The formation of the host-guest complex increases the two-photon absorption cross-section about five times, and improves the water solubility required as the photoinitiator for hydrogel fabrication. The BMVPC-CB7 inclusion complex was used as the one-component photoinitiator, and the polyethylene glycol diacrylate with promising biocompatibility was used as the hydrogel monomer to form the aqueous-phase photoresist system applied to two-photon polymerization microfabrication. A relatively low laser threshold of 4.5 mW, a high fabricating resolution of 180 nm, and the true three-dimensional (3D) fabricating capability in the aqueous solution have been obtained by using the as-prepared photoresist system. Finally, 3D engineering hydrogel scaffold microstructures with low toxicity and good biocompatibility have been fabricated and cocultured with living HeLa cells, which demonstrates the potential for further application in tissue engineering.

Biocompatible Three-Dimensional Hydrogel Cell Scaffold Fabricated by Sodium Hyaluronate and Chitosan Assisted Two-Photon Polymerization.

The biocompatibility of the three-dimensional (3D) hydrogel cell scaffolds that sodium hyaluronate (SH) and carboxymethyl chitosan (Chitosan) has been investigated. The minimum processing threshold of 2.94 mW and the feature line width of 80 nm have been obtained by the two-photon polymerization (TPP) technology using the as-prepared biocompatible photoresist. Through tuning the contents of the cross-linker in the hydrogel, the mechanical property of 3D hydrogel scaffold can be optimized to ensure the stability and affinity of scaffold. Furthermore, we have fabricated the SH and Chitosan assisted 3D hydrogel cell scaffolds and investigated the biocompatibility. This study provides a facile method to develop 3D biocompatible hydrogel cell scaffold, which would open up new avenues for the potential application in tissue engineering.

Oxidative, Iodoarene-Catalyzed Intramolecular Alkene Arylation for the Synthesis of Polycyclic Aromatic Hydrocarbons.

A catalytic, metal-free and chemoselective oxidative intramolecular coupling of arene and alkene C-H bonds is reported. The active hypervalent iodine (HVI) reagent, generated catalytically in situ from iodotoluene and meta-chloroperoxybenzoic acid (m-CPBA), reacts with o-vinylbiphenyls to generate polyaromatic hydrocarbons in up to 95 % yield. Experimental evidence suggests the reactions proceed though vinyliodonium and, possibly, vinylenephenonium intermediates.

Chlorination of phenylallene derivatives with 1-chloro-1,2-benziodoxol-3-one: synthesis of vicinal-dichlorides and chlorodienes.

Allyl and vinyl chlorides represent important structural motifs in organic chemistry. Herein is described the chemoselective and regioselective reaction of aryl- and α-substituted phenylallenes with the hypervalent iodine (HVI) reagent 1-chloro-1,2-benziodoxol-3-one. The reaction typically results in vicinal dichlorides, except with proton-containing α-alkyl substituents, which instead give chlorinated dienes as the major product. Experimental evidence suggests that a radical mechanism is involved.

Electrical and thermal properties of silver nanowire fabricated on a flexible substrate by two-beam laser direct writing for designing a thermometer.

Accurate knowledge of electrical conductivity and thermal conductivity temperature dependence plays a crucial role in the design of a thermometer. Here, by using a two-beam laser direct writing system, an individual silver nanowire (AgNW) with well-defined dimensions is fabricated on a polyethylene terephthalate (PET) substrate. The temperature dependence of the resistivity of the fabricated AgNW is measured ranging from 10 to 300 K, and fitted with the Bloch-Grüneisen formula. The residual resistivity ((1.62 ± 0.20) × 10-7 Ω m) of the AgNW is larger than that of the bulk material (1 × 10-11 Ω m). The electron-phonon coupling constant of the AgNW is (1.08 ± 0.13) × 10-7 Ω m, which is larger than that of the bulk silver (5.24 × 10-8 Ω m). Moreover, the Debye temperature of the AgNW is 199.30 K and is lower than that of the bulk silver (235 K). The Lorenz number of the fabricated AgNW is found to decrease as the temperature increases. Besides, the Lorenz number (2.66 × 10-7 W Ω K-2) is larger than the Sommerfeld value (2.44 × 10-8 W Ω K-2) at room temperature. The measurement results allow one to design a thermometer in the temperature range 40-300 K. The flexibility of the AgNW is also excellent, and the resistance increase of the AgNW is only 2.58% when the AgNW bending about 1000 times with a bending radius of 1 mm.

Fluorinative Rearrangements of Substituted Phenylallenes Mediated by (Difluoroiodo)toluene: Synthesis of α-(Difluoromethyl)styrenes.

Phenylallenes undergo fluorinative rearrangement upon the action of (difluoroiodo)toluene in the presence of 20 mol % BF3 ⋅OEt2 to yield α-difluoromethyl styrenes. This unprecedented reaction was entirely chemoselective for the internal allene π bond, and showed remarkable regioselectivity during the fluorination event. Substituted phenylallenes, phenylallenes possessing both phenyl- and α-allenyl substituents, and diphenylallenes were investigated, and good functional-group compatibility was observed throughout. The ease with which allenes can be prepared on a large scale, and the operational simplicity of this reaction allowed us to rapidly access fluorine-containing building blocks that have not been accessed by conventional deoxyfluorination strategies.

The Conductive Silver Nanowires Fabricated by Two-beam Laser Direct Writing on the Flexible Sheet.

Flexible electrically conductive nanowires are now a key component in the fields of flexible devices. The achievement of metal nanowire with good flexibility, conductivity, compact and smooth morphology is recognized as one critical milestone for the flexible devices. In this study, a two-beam laser direct writing system is designed to fabricate AgNW on PET sheet. The minimum width of the AgNW fabricated by this method is 187 ± 34 nm with the height of 84 ± 4 nm. We have investigated the electrical resistance under different voltages and the applicable voltage per meter range is determined to be less than 7.5 × 103 V/m for the fabricated AgNW. The flexibility of the AgNW is very excellent, since the resistance only increases 6.63% even after the stretched bending of 2000 times at such a small bending radius of 1.0 mm. The proposed two-beam laser direct writing is an efficient method to fabricate AgNW on the flexible sheet, which could be applied in flexible micro/nano devices.

Tissue distribution of marbofloxacin in pigs after a single intramuscular injection.

Tissue distribution of marbofloxacin was studied in pigs after a single intramuscular injection at 2.5 mg/kg body weight. Samples of plasma, muscle, liver, kidney, heart, lung, and muscle at the injection site were randomly collected from five pigs at 2, 6, 10, 24, 48, 72, and 96 h after administration. Marbofloxacin concentrations were determined by using high-performance liquid chromatography with ultraviolet detection and were subjected to non-compartmental analysis to obtain kinetic parameters. The elimination half-life (t1/2λz) of marbofloxacin at the injection site was 22.12 h, while those in kidney, plasma, liver, lung, heart, and muscle were 16.75, 21.48, 21.84, 24.00, 24.45, and 28.91 h, respectively. Areas under the concentration-time curve from 0 h to ∞ (AUC0-∞s) were calculated to be 31.17 hㆍµgㆍmL-1 for plasma and 32.97, 33.92, 34.78, 37.58, 42.02, and 98.80 hㆍµgㆍg-1 for heart, muscle, lung, liver, kidney, and injection site, respectively. The peak concentration (Cmax) of marbofloxacin was 1.62 µg/mL in plasma and 1.71, 1.74, 1.86, 1.93, 2.45, and 7.64 µg/g in heart, lung, muscle, kidney, liver, and injection site, respectively. The results show that marbofloxacin was fast absorbed, extensively distributed, and slowly eliminated from pigs after a single intramuscular administration.

Transition of lasing modes in polymeric opal photonic crystal resonating cavity.

We demonstrate the transition of lasing modes in the resonating cavity constructed by polystyrene opal photonic crystals and 7 wt. % tert-butyl Rhodamine B doped polymer film. Both single mode and multiple mode lasing emission are observed from the resonating cavity. The lasing threshold is determined to be 0.81 µJ/pulse for single mode lasing emission and 2.25 µJ/pulse for multiple mode lasing emission. The single mode lasing emission is attributed to photonic lasing resulting from the photonic bandgap effect of the opal photonic crystals, while the multiple mode lasing emission is assigned to random lasing due to the defects in the photonic crystals. The result would benefit the development of low threshold polymeric solid state photonic crystal lasers.

Carboxylated Nanodiamond: Aggregation Properties in Aqueous Dispersion System and Application in Living Cell Fluorescence Imaging.

Nanodiamond, which has a lattice defect, the energy band gap and good biocompatibility, is an ideal inorganic fluorescent imaging material for cells. However, the nanodiamond aggregation is not exactly suitable for cells' endocytosis if the size is too small or too big. Therefore, it has a profound meaning to modify the surface of nanodiamond and control the dispersion of nanodiamond aggregate. In this study, the surface of the detonated nanodiamond is modified into carboxylated nanodiamond by using the method of mixed acid oxidation. Then, the nanodiamond aggregates' dispersion in water is regulated by adjusting the pH, which is first discussed as a factor influencing the size of nanodiamond aggregation. This process further induces the corresponding change of the electrostatic force between nanoparticles, improves its applicability in the field of living cell fluorescence imaging.

Low threshold photonic crystal laser based on a Rhodamine dye doped high gain polymer.

We demonstrate low threshold lasing oscillation in a photonic crystal (PhC) laser by using tert-butyl Rhodamine B (t-Bu-RhB) doped gain media. Lactonic t-Bu-RhB is synthesized to improve doping concentration in polymethylmethacrylate (PMMA) films, and then isomerized to the zwitterion form to achieve highly fluorescent gain medium. The t-Bu-RhB doped PMMA film is sandwiched by a pair of polystyrene colloidal crystals to construct a PhC resonating cavity. Single-mode laser oscillation at 592 nm is observed when the PhC resonating cavity is pumped by a Nd:YAG laser. The lasing threshold is 0.12 MW cm(-2) utilizing 6.9 wt% t-Bu-RhB doped PMMA films, which is only 1/60 of that with 3 wt% t-Bu-RhB doped PMMA films. The concentration-dependent lasing action is attributed to different gain factors of the t-Bu-RhB doped PMMA films. Furthermore, a spatially and spectrally coherent laser beam from the PhC resonating cavity is verified by exploring the far-field image and angular dependence of the lasing emission. The approach provides a facile and efficient strategy to reduce the lasing threshold for fabricating low threshold PhC lasers.

In vivo observation of the pH alternation in mitochondria for various external stimuli.

The pH of mitochondria (pHm) has a close relationship with many biological processes. Here we developed a new indicator Mito-pH-1 for the ratiometric fluorescence detection of the mitochondria pH value, which has excellent tolerance to environmental change. And Mito-pH-1 has been used for the first time to monitor the change of pHm under temperature and H2O2 stimuli in living cells.