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[Image: see text] The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR(Del19/T790M/C797S) mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC(50) of 8 nM. It also showed good antiproliferation activity (IC(50) = 0.02 μM) against Ba/F3-EGFR(Del19/T790M/C797S) cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.

Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.

Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound

PROteolysis TArgeting Chimeras (PROTACs) have been extensively explored for targeted protein degradation and cancer therapy. However, clinic translation of the conventional small molecular PROTACs is challenged by their unfavorable pharmacokinetic profiles and the systemic toxicity due to on-target but off-tumor protein degradation. Herein we presented a tumor microenvironment-activatable polymeric PROTAC (namely POLYTAC) nanoplatform for tumor-specific PROTAC delivery and combinatory cancer therapy. The POLYTAC nanoparticles were engineered by integrating metalloproteinase-liable poly(ethylene glycol) shell, intracellular acidity-responsive hydrophobic core and reduction-activatable PROTACs into one nanoplatform. The resultant POLYTAC nanoparticles can specifically accumulate at the tumor site and release the PROTACs inside the tumor cells for protein degradation. The POLYTAC nanoparticles can be further engineered for bioorthogonal click reaction-enforced tumor-specific delivery of the PROTACs. In combination with photodynamic therapy, we demonstrated that the bioorthogonal POLYTAC nanoparticles remarkably suppressed tumor growth by synergistically inducing cellular apoptosis of the tumor cells in mouse model of MDA-MB-231 breast cancer. The POLYTAC approach might pave the way for tumor-targeted protein degradation and translation of PROTAC-based cancer therapy.

Aberrantly activated Janus kinase 3 (JAK3) has been constantly detected in various immune disorders and hematopoietic cancers, suggesting its potential of being an attractive therapeutic target for these indications. Clinical benefits of drugs selectively targeting JAK3 versus pan-JAK inhibitors remain unclear. In this study, we report the design and synthesis of a new series of JAK3 covalent inhibitors with a pyrido[2,3-d]pyrimidin-7-one scaffold. After the extensive SAR study, compound 10f emerged to be the most potent JAK3 inhibitor with an IC

In order to solve the problem of Distributed Denial of Service (DDoS) attack detection in software defined network (SDN), we proposed a cooperative DDoS attack detection scheme based on entropy and ensemble learning. This method sets up a coarse grained initial detection module based on entropy in the edge switch to monitor the network status in real time and report to the controller if any abnormality is found. Simultaneously, a fine grained precise attack detection module is designed in the controller, and a ensemble learning-based algorithm is utilized to further identify abnormal traffic accurately. In this framework, the idle computing capability of edge switches is fully utilized with the design idea of edge computing to offload part of the detection task from the control plane to the data plane innovatively. Simulation results of two common DDoS attack methods, ICMP and SYN, show that the system can effectively detect DDoS attacks and greatly reduce the southbound communication overhead and the burden of the controller as well as the detection delay of the attacks.

In this paper, the stochastic model of wind power generation is considered. Under all possible load conditions, the ability of power system to meet the demand of system load power supply, i.e. the adequacy of power system, is studied. Through Monte Carlo simulation method, the adequacy of power system in a given area is calculated and analyzed, and the reliability indexes such as load loss probability are studied. In order to further Considering the adequacy of various energy systems provides a reference value.

With the penetration of renewable energy (RE) into power system, the coupling degree of transmission and distribution network is increasing, and the independent transmission network planning method is no longer applicable consequentially. It is necessary to consider the transmission network planning coordinated with the distribution networks (TEPCDN). However, there is a lack of standard test system for coordination planning research. This paper constructs a transmission expansion planning test system coordinated with distribution networks named HRPTD-20 system. “HRP” stands for high renewable penetration and the installed proportion of RE is more than 50%. The test system includes 3 voltage levels, 3 traditional and 3 typical future distribution network structures, with distinct spatial and temporal characteristics of source-grid-load. Then, a multi-scenario distributed TEPCDN model is proposed, aiming at minimizing the sum of investment cost of transmission network and operation cost of transmission and distribution networks, taking active power and voltage as interactive variables, and is solved by the optimization algorithm based on analytical target cascading (ATC). Finally, benchmark planning scheme for the HRPTD-20 system is provided. Compared with independent transmission network planning, the TEPCDN helps to improve the economic benefits and RE consumption ratio.

Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.

The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790M inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790M kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.

Energy efficiency evaluation of distribution systems is to estimate the efficiency of energy utilization on the premise of safe operation. With the continuous development of new technologies, such as diversified load, renewable energy and demand-side management, new requirements for energy efficiency evaluation are put forward. However, previous works mainly focus on traditional distribution networks and primarily based on subjective methods such as the analytic hierarchy process. In this paper, a comprehensive evaluation model of distribution network energy efficiency is proposed based on the coefficient of variation (CV) - Grey clustering method. Firstly, the evaluation index system of energy efficiency was established from the aspects of equipment, planning, operation and management. Secondly, a grey clustering method based on evaluation model of energy efficiency is introduced. It includes two steps: 1) the weights are determined based on the CV method, 2) the comprehensive evaluation model is established based on the grey triangular whitenization weight function. Finally, the efficiency level of an actual distribution network in eastern China is evaluated as an example. Case analysis shows that the proposed method could scientifically evaluate the energy efficiency, identify the weaknesses and provide references for planning and construction strategy of distribution networks.

Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.

Different from the well-known objectives (minimizing travel time or maximizing throughput), we proposed the energy efficiency model for robotic mobile fulfillment system (RFMS) based on the force and work analysis of robot. The factors related on reducing energy consumption including batch size, storage strategies and locations of workstations are investigated by simulation. From the simulation result based on different viewpoints, we obtain the following findings. Smaller batch size is preferred in terms of turnover time, but the larger batch size is preferred in energy efficiency. The full-turnover storage strategy significantly outperforms the random and class-based storage strategies. And storing items with high turnover rates nearby the workstation is beneficial for both operation efficiency and energy efficiency.

As the blossom of e-commerce in the recent years, warehouse operation faces the challenges of small orders, large assortment, tight delivery schedules and varying workloads. Some advanced operation strategies are proposed to tackle these challenges during the order fulfillment in e-commence warehouse in practice. The flow-picking is a typical example, which has been successfully applied in several Chinese online retailers’ warehouses by its outstanding performance. In this paper, a new routing strategy with local return area is proposed based on the prototype of flow-picking system. Simulation experiments are conducted to obtain several valuable findings: 1) local return strategy can improve the system performance by reducing the average throughout time of orders in most scenarios; 2) local return strategy with different storage assignment policies has different impact on system performance. Among the three mentioned storage policies, full-turnover storage policy performs best; 3) the size of return area has important influence on the system performance. Too big or too small may lead to unsatisfactory results.

We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.

With the development of smart distribution network, distributed energy and diversified load are more and more involved in distribution network planning and operation. Their characteristics of `both power and load' should be emphasized. These make power restoration in extreme weather conditions possible, and meanwhile, make the evaluation of high-reliability distribution network more difficult. A comprehensive evaluation method of distribution network considering resilience is proposed in this paper. Firstly, a new evaluation index system is established under the background of distribution network resilience research. Secondly, based on K-means clustering method, the evaluation criteria considering huge regional differences in China are proposed. Thirdly, the scientific weights of evaluation indices are determined based on the variation coefficient method. Finally, an actual distribution network in eastern China was evaluated as an example. Case analysis shows that the evaluation index system proposed in this paper is effective and could reasonably indicate the comprehensive performance of the distribution network.

The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFRT790M mutant. One of the most promising compounds, 9f, tightly binds to the EGFRT790M mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFRT790M mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR

The EGFRT790M mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFRT790M-related resistance. We have designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC50 values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFRL858R/T790M, while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer effic...

A novel copper-catalyzed tandem reaction of 1-(2-iodoaryl)-2-yn-1-ones with isocyanides is described. The reaction is through a formal [3 + 2] cycloaddition/coupling tandem process and leads to efficient formation of 4-oxo-indeno[1,2-b]pyrroles.

Acetamiprid, which belongs to the new neonicotinoid class insecticides, has been widely used to control sucking-type insects on fruits, leafy vegetables and tea trees. Although it is noted as relatively low acute and chronic mammalian toxicity, its accumulation in fruits and vegetables still cause potential risk to human health, owing to the frequent and extensive usage. Therefore, practical methods with rapid, non-destructive and highly sensitive characteristics for simple detection of acetamiprid residues are crucial for human health. In this research, a novel Surface Enhanced Raman Spectroscopy (SERS) method is developed using silver colloid and with a self-developed Raman system for the fast, sensitive and nondestructive detection of acetamiprid in fruits (apple, pear, orange and mango). The main advantages of using silver colloid for SERS measurement are the easy formation and manipulation for analytical study. The SERS spectra are obtained using 785 nm exciting radiation. The peaks of Raman spectra at 634 cm -1 , 1111 cm -1 and 2172 cm -1 are used for the identification and the determination of acetamiprid. The lowest detectable level of acetamiprid in apple is 0.04 mg/kg, which is sensitive enough for identifying apple contaminated with acetamiprid above the maximum residue level. The quantitative curves indicate good linear relationship between the Raman intensity and the concentration of acetamiprid, with coefficients of determination more than 0.94. The silver colloid used for the detection of acetamiprid in different kinds of fruits shows excellent signal enhancement effect. The present study demonstrates a novel approach to detect acetamiprid in fruits with good performance, which shows great potential for the evaluation and identification of pesticide residues in agricultural products.

Conventional microbiological detection and enumeration methods are time-consuming, labor-intensive, and giving retrospective information. The objectives of the present work are to study the capability of surface enhanced Raman scattering (SERS) to detect Escherichia coli (E. coli) using the presented silver colloidal substrate. The obtained results showed that the adaptive iteratively reweighed Penalized Leas t Squares (airPLS) algorithm could effectively remove the fluorescent background from original Raman spectra, and Raman characteristic peaks of 558, 682, 726, 1128, 1210 and 1328 cm -1 could be observed stably in the baseline corrected SE RS spectra of all studied b acterial concentrations. The detection limit of SERS could be determined to be as low as 0.73 log CFU/ml for E. coli with the prepared silver colloidal substrate. The quantitative prediction results using the intensity values of characteristic peaks were not good, with the correlation coefficients of calibration set and cross validation set of 0.99 and 0.64, respectively. Keywords: surface enhanced Raman scattering, microbial safety, Escherichia coli , rapid detection, adaptive iteratively reweighed Penalized Least Squares (airPLS)

Benzoyl peroxide is a common flour additive that improves the whiteness of flour and the storage properties of flour products. However, benzoyl peroxide adversely affects the nutritional content of flour, and excess consumption causes nausea, dizziness, other poisoning, and serious liver damage. This study was focus on detection of the benzoyl peroxide added in wheat flour. A Raman scattering spectroscopy system was used to acquire spectral signal from sample data and identify benzoyl peroxide based on Raman spectral peak position. The optical devices consisted of Raman spectrometer and CCD camera, 785 nm laser module, optical fiber, prober, and a translation stage to develop a real-time, nondestructive detection system. Pure flour, pure benzoyl peroxide and different concentrations of benzoyl peroxide mixed with flour were prepared as three sets samples to measure the Raman spectrum. These samples were placed in the same type of petri dish to maintain a fixed distance between the Raman CCD and petri dish during spectral collection. The mixed samples were worked by pretreatment of homogenization and collected multiple sets of data of each mixture. The exposure time of this experiment was set at 0.5s. The Savitzky Golay (S-G) algorithm and polynomial curve-fitting method was applied to remove the fluorescence background from the Raman spectrum. The Raman spectral peaks at 619 cm-1, 848 cm-1, 890 cm-1, 1001 cm-1, 1234 cm-1, 1603cm-1, 1777cm-1 were identified as the Raman fingerprint of benzoyl peroxide. Based on the relationship between the Raman intensity of the most prominent peak at around 1001 cm-1 and log values of benzoyl peroxide concentrations, the chemical concentration prediction model was developed. This research demonstrated that Raman detection system could effectively and rapidly identify benzoyl peroxide adulteration in wheat flour. The experimental result is promising and the system with further modification can be applicable for more products in near future.

Residual pesticides in fruits and vegetables have become one of the major food safety concerns around the world. At present, routine analytical methods used for the determination of pesticide residue on the surface of fruits and vegetables are destructive, complex, time-consuming, high cost and not environmentally friendly. In this study, a novel Surface Enhanced Raman Spectroscopy (SERS) method with silver colloid was developed for fast and sensitive nondestructive detection of residual pesticides in fruits and vegetables by using a self-developed Raman system. SERS technology is a combination of Raman spectroscopy and nanotechnology. SERS can greatly enhance the Raman signal intensity, achieve single-molecule detection, and has a simple sample pre-treatment characteristic of high sensitivity and no damage; in recent years it has begun to be used in food safety testing research. In this study a rapid and sensitive method was developed to identify and analyze mixed pesticides of chlorpyrifos, deltamethrin and acetamiprid in apple samples by SERS. Silver colloid was used for SERS measurement by hydroxylamine hydrochloride reduced. The advantages of this method are seen in its fast preparation at room temperature, good reproducibility and immediate applicability. Raman spectrum is highly interfered by noise signals and fluorescence background, which make it too complex to get good result. In this study the noise signals and fluorescence background were removed by Savitzky-Golay filter and min-max signal adaptive zooming method. Under optimal conditions, pesticide residues in apple samples can be detected by SERS at 0.005 μg/cm2 and 0.002 μg/cm2 for individual acetamiprid and thiram, respectively. When mixing the two pesticides at low concentrations, their characteristic peaks can still be identified from the SERS spectrum of the mixture. Based on the synthesized material and its application in SERS operation, the method represents an ultrasensitive SERS performance in apple samples detection without sample pre-treatment, which indicates that it could be served as a useful means in monitoring pesticide residues.

Different chemicals are sprayed in fruits and vegetables before and after harvest for better yield and longer shelf-life of crops. Cases of pesticide poisoning to human health are regularly reported due to excessive application of such chemicals for greater economic benefit. Different analytical technologies exist to detect trace amount of pesticides in fruits and vegetables, but are expensive, sample destructive, and require longer processing time. This study explores the application of Raman spectroscopy for rapid and non-destructive detection of pesticide residue in agricultural products. Raman spectroscopy with laser module of 785 nm was used to collect Raman spectral information from the surface of Gala apples contaminated with different concentrations of commercially available organophosphorous (48% chlorpyrifos) pesticide. Apples within 15 days of harvest from same orchard were used in this study. The Raman spectral signal was processed by Savitzky-Golay (SG) filter for noise removal, Multiplicative Scatter Correction (MSC) for drift removal and finally polynomial fitting was used to eliminate the fluorescence background. The Raman spectral peak at 677 cm-1 was recognized as Raman fingerprint of chlorpyrifos. Presence of Raman peak at 677 cm-1 after fluorescence background removal was used to develop classification model (presence and absence of pesticide). The peak intensity was correlated with actual pesticide concentration obtained using Gas Chromatography and MLR prediction model was developed with correlation coefficient of calibration and validation of 0.86 and 0.81 respectively. Result shows that Raman spectroscopy is a promising tool for rapid, real-time and non-destructive detection of pesticide residue in agro-products.