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Heterocycles are the backbone of modern medical chemistry and drug development. The derivatization of "an olefin" inside aromatic rings represents an ideal approach to access functionalized saturated heterocycles from abundant aromatic building blocks. Here, we report an operationally simple, efficient, and practical method to selectively access hydrosilylated and reduced N-heterocycles from bicyclic aromatics via a key diradical intermediate. This approach is expected to facilitate complex heterocycle functionalizations that enable access to novel medicinally relevant scaffolds.

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C(sp2)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp3)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.

Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N-H/C-H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N-H heterocycles with substrates bearing (hetero)benzylic C-H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N-H heterocycle and benzylic C-H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.

Site selectivity represents a key challenge for nondirected C─H functionalization, even when the C─H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C─H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a Cu(II)-azide species via a radical-polar crossover pathway. Comparison of this method with other C─H azidation methods highlights the unique site-selectivity of this method, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Selenium (Se) is an essential trace element that maintains normal physiological functions in organisms. Since the discovery of glutathione peroxidase (GSH-PX), public interest in selenoproteins has gradually increased. Based on previous studies, dietary Se maintains erythrocyte homeostasis through selenoprotein-induced mediation of redox reactions. Furthermore, both the surface phosphatidylserine (PS) and intramembrane stomatin contents can be used as indicators of erythrocyte osmotic fragility. This study focused on the mechanism by which dietary Se deficiency increases erythrocyte osmotic fragility. We fed Se-deficient grain to mice for 8 weeks to establish a Se deficiency model in mice. We measured Se levels in the blood as well as the activities of antioxidant enzymes associated with selenoproteins in a Se-deficient environment. We used Western blotting, routine blood analysis, and other methods to detect red blood cell oxidative stress levels, membrane stomatin levels, and PS externalization. Fresh blood was collected to test erythrocyte osmotic fragility. The results showed that antioxidant enzyme activity was affected by dietary Se deficiency. Oxidative stress increased lipid peroxidation and the ROS content in the blood of the mice. Under such conditions, decreased PS exposure and stomatin content in the erythrocyte membrane eventually affected the structure of the erythrocyte membrane and increased erythrocyte osmotic fragility.

Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy., How phase separation participates in mitophagy remains unclear. Here the authors show that Nur77 and p62/SQSTM1 through “head-to-head” and “tail-to-tail” interactions form membraneless condensates capable of sequestering dysfunctional mitochondria and tethering them to autolysosome for degradation.

Mastitis caused by Staphylococcus aureus infection not only causes serious economic losses, but also affects human health. Se plays an important role in body immunity. However, the mechanisms by which Se regulates mastitis induced by S. aureus are still principally unknown. The purpose of this study is to investigate whether Se can inhibit mastitis induced by S. aureus through regulation of MerTK. Sixty BALB/c female mice were fed low, normal, or high Se concentrations for 7 weeks and then randomly divided into six groups (Se-Low Control group (LSN), Se-Normal Control group (NSN), Se-High Control group (HSN), Se-Low S. aureus group (LSS), Se-Normal S. aureus group (NSS), Se-High S. aureus group (HSS)). The regulation of Se on MerTK was detected via histopathological staining, western blot analysis, enzyme-linked immunosorbent assay, and qRT-PCR. With increased selenium concentrations, the levels of IL-1β, IL-6, and TNF-α decreased, while the phosphorylation levels of MerTK, PI3K, AKT, and mTOR increased. Therefore, this study showed that Se could alleviate S. aureus mastitis by activating MerTK and PI3K/AKT/mTOR pathway.

Cross-coupling reactions enable rapid, convergent synthesis of diverse molecules and provide the foundation for modern chemical synthesis. The most widely used methods employ sp2-hybridized coupling partners, such as aryl halides or related pre-functionalized substrates. Here, we demonstrate copper-catalysed oxidative cross coupling of benzylic C–H bonds with alcohols to afford benzyl ethers, enabled by a redox-buffering strategy that maintains the activity of the copper catalyst throughout the reaction. The reactions employ the C–H substrate as the limiting reagent and exhibit broad scope with respect to both coupling partners. This approach to direct site-selective functionalization of C(sp3)–H bonds provides the basis for efficient three-dimensional diversification of organic molecules and should find widespread utility in organic synthesis, particularly for medicinal chemistry applications., Graphical Abstract

Diabetic encephalopathy is a common complication of diabetes, leading to cognitive impairment. In this study, we investigated the therapeutic effects of Praeruptorin C (Pra-C), an active component of traditional Chinese herb medicine Peucedanum praeruptorum, on cognitive impairment in a mouse model of type 2 diabetes. Our results showed that Pra-C administration significantly reduced body weight and fasting blood glucose levels, relieved learning and memory behavioral deficits in diabetic model mice. The effects of Pra-C on learning and memory ability were further confirmed by late-phase LTP (L-LTP) facilitation, which was recorded by Med64 electrophysiology recording system. Pra-C also restored the activation of PI3K/AKT/GSK3β signaling pathway in hippocampus of mice suffering from diabetes. Taken together, this study demonstrates that Pra-C alleviates cognitive impairment in diabetic mice by restoring PI3K/AKT/GSK3β activation.

Cross coupling reactions enable rapid convergent synthesis of diverse molecules and provide the foundation for modern chemical synthesis. The most widely used methods employ sp2-hybridized coupling partners, such as aryl halides or related pre-functionalized substrates. Here, we demonstrate copper-catalyzed oxidative cross-coupling of benzylic C–H bonds with alcohols to afford benzyl ethers, enabled by mechanistic insights that led to a novel reductant-based strategy for in situ regeneration of the active copper catalyst. The reactions employ the C–H substrate as the limiting reagent and exhibit broad scope with respect to both substrate partners. This approach to direct site-selective functionalization of sp3 C–H bonds provides the basis for efficient three-dimensional diversification of organic molecules and should find widespread utility in organic synthesis, particularly for medicinal chemistry applications.

A clamping robot serving for several NC machines can recognize the best fit in manny blank parts. Forthermore, the shape information acquisition and pose measurment can be achieved by its computer vision system. The key question is that the clamping robot automatively choices the best fit part by statistical result of geometric dimension of all parts. The best fit part is the one that its length and its diameter are mostly proximate to the processing requirement. This choice method can save staff, reduce working allowance, and lessen finished cost. According to the shape information and position information, the robot can confirm the grab order, grab angle and finger joint distance. Firstly, the part image is smoothing by noise reduction technology, secondly, the feature points are extracted. The feature points present the information of the location of the mass center, the dip angle and diameter. Finally, the clamping robot can grab the most fit bar part by means of rotational motion, rectilinear motion, and finger open-close movement when the shape information and location information of the bar part have been confirmed.

Aluminum metal matrix composites (Al-MMCs) are new promising materials for aviation, aerospace and automotive industries. However, due to the poor weldability they have very limited applications. In this paper, the authors present the welding achievements of Al-MMCs developed by their scientific research team in recent years. Laser welding, liquid phase impact diffusion welding and vacuum brazing were utilized. Based on analysis of microstructure, good joints can be achieved by using these welding methods.

The Paper Works on the Intelligent Mobile Robot for Economic CNC Machine or Reformed CNC Machine According to the Chinese Enterprise’s Situation, which Can Automatically Finish next Three NC Procedures, Charging, Discharging and Tools Changer, so as to Economize on Manpower and Reduce Product Cost. the Actuator of Robot Is Double Four Bar Linkages, which Realized No Blind Zone in Workspace. in Order to Achieving Remote Control, CNC Machine Group Network Was Built by Newest Technology such as Zigbee Wireless Communication Technology, GPRS, and 3G Module. Except for these, Visual Navigation System Was Equipped to Accomplish the Accurate Orientation in the Procedure of Charging, Discharging and Tools Changer. the Robot Can Intelligently Estimate the Work Condition by Synthetically Use of Pattern Recognition Technology, Multi-sensor Information Technology, and Embedded Technology, which Impressively Improve Efficiency and Automation Level.

Finite element numerical dynamic simulation of the TLP bonding process of 20 steel tubes was conducted using ANSYS, finite element analysis software. The results show that there is a sharp decline in the performance of the joint and the neighboring parent material during the initial cooling stage in the transitional phase diffusion bonding process. When the isothermal solidification temperature is increased, the welding deformation becomes more apparent, and the residual stress on both sides of the joint is reduced. Thus, the weak area of TLP bonding can be found near the middle. A reasonable choice of interlayers can relieve stress concentration and increase the TLP bonding joint performance.

12Cr2MoV steel pipe and T91 steel pipe were joined by transient liquid phase diffusion bonding process (TLP) in argon atmosphere using FeNiCrSiB amorphous filler. TP304H steel pipe and 12Cr2MoV steel pipe were joined by the same method using Fe78Si9B13 and BNi2 amorphous filler. The qualified welding joint can be achieved by suitable adjustment of process parameters. The diffusion asymmetry in TLP of different metals has been analyzed. The research shows that there exists a diffusion asymmetry in TLP of different metals. The main reason is the difference of isothermal solidification rate in different materials, which results in a deviation of the bonding interface from the original centerline to T91 and TP304H side.

T91/12Cr2MoWVTiB was bonded by transient liquid phase bonding process with different pressures, one commercial FeNiCrSiB was used as the interlayer. The microstructure and components distribution of the bonded joints were examined by optical microscope and scanning electron microscopic techniques. Furthermore, the properties of the joints were also tested. The results indicate that with the increase of the pressure – from 2 MPa to 6 MPa – the microstructures and mechanical properties were improved, and more similar to those base alloys. A theoretical study also revealed that the isothermal solidification complication time can be shorter, because the maximum liquid width was reduced with the existence of pressure.

// Jie Qiao 1, * , Shu-Jian Cui 3, * , Lei-Lei Xu 1 , Si-Jie Chen 4 , Jun Yao 1 , Ying-Hua Jiang 1 , Gang Peng 4 , Cai-Yun Fang 2 , Peng-Yuan Yang 1, 2, * , Feng Liu 1, * 1 Department of Medical Systems Biology of School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China 2 Department of Chemistry, Fudan University, Shanghai 200433, China 3 College of Bioscience and Biotechnology, Key Laboratory of Crop Genetics and Physiology of Jiangsu Province, Yangzhou University, Yangzhou 225009, China. 4 Institutes of Brain Science, Fudan University, Shanghai 200032, China * These authors contributed equally to this work Correspondence to: Feng Liu, e-mail: liuf@fudan.edu.cn Peng-Yuan Yang, e-mail: pyyang@fudan.edu.cn Keywords: Gastric cancer, Proteomics, Filamin C, Metastasis, Tumor suppressor Received: July 03, 2014 Accepted: October 26, 2014 Published: November 28, 2014 ABSTRACT Gastric cancer (GC) is the fourth and fifth most common cancer in men and women, respectively. We identified 2,750 proteins at false discovery rates of 1.3% (protein) and 0.03% (spectrum) by comparing the proteomic profiles of three GC and a normal gastric cell lines. Nine proteins were significantly dysregulated in all three GC cell lines, including filamin C, a muscle-specific filamin and a large actin-cross-linking protein. Downregulation of filamin C in GC cell lines and tissues were verified using quantitative PCR and immunohistochemistry. Data-mining using public microarray datasets shown that filamin C was significantly reduced in many human primary and metastasis cancers. Transient expression or silencing of filamin C affected the proliferation and colony formation of cancer cells. Silencing of endogenous filamin C enhanced cancer cell migration and invasion, whereas ectopic expression of filamin C had opposing effects. Silencing of filamin C increased the expression of matrix metallopeptidase 2 and improved the metastasis of prostate cancer in a zebrafish model. High filamin C associated with better prognosis of prostate cancer, leukemia and breast cancer patients. These findings establish a functional role of filamin C in human cancers and these data will be valuable for further study of its mechanisms.

This article defines Generalized Entropy to simulate and then reveal complex interactions in transportation-economic complex system. By deploying the Maximum Entropy Principle and the SOM, the system complex interplays' structure is derived and the detail of agents' interplays could be studied. Finally some applications and simulation results are provided.