Scheduling Performance Evaluation of Logistics Service Supply Chain Based on the Dynamic Index Weight

Scheduling is crucial to the operation of logistics service supply chain (LSSC), so scientific performance evaluation method is required to evaluate the scheduling performance. Different from general project performance evaluation, scheduling activities are usually continuous and multiperiod. Therefore, the weight of scheduling performance evaluation index is not unchanged, but dynamically varied. In this paper, the factors that influence the scheduling performance are analyzed in three levels which are strategic environment, operating process, and scheduling results. Based on these three levels, the scheduling performance evaluation index system of LSSC is established. In all, a new performance evaluation method proposed based on dynamic index weight will have three innovation points. Firstly, a multiphase dynamic interaction method is introduced to improve the quality of quantification. Secondly, due to the large quantity of second-level indexes and the requirements of dynamic weight adjustment, the maximum attribute deviation method is introduced to determine weight of second-level indexes, which can remove the uncertainty of subjective factors. Thirdly, an adjustment coefficient method based on set-valued statistics is introduced to determine the first-level indexes weight. In the end, an application example from a logistics company in China is given to illustrate the effectiveness of the proposed method

An Improved D-α-Tocopherol-Based Nanocarrier for Targeted Delivery of Doxorubicin with Reversal of Multidrug Resistance

Nanocarriers have recently emerged as an attractive platform for delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K-VE2/DOX in PC-3 and 4T1.2 cells. Cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have a potential to reverse the multidrug resistance, which was supported by its inhibition on P-gp ATPase. Pharmacokinetics (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accumulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~30 mg DOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated for PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX

A PEG-Fmoc conjugate as a nanocarrier for paclitaxel

We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25–30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and 13C-NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study

Discovery of Coumarin as Microtubule Affinity-Regulating Kinase 4 Inhibitor That Sensitize Hepatocellular Carcinoma to Paclitaxel

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. Nowadays, pharmacological therapy for HCC is in urgent needs. Paclitaxel is an effective drug against diverse solid tumors, but commonly resisted in HCC patients. We recently have disclosed that microtubule affinity-regulating kinase 4 (MARK4) increases the microtubule dynamics and confers paclitaxel resistance in HCC, suggesting MARK4 as an attractive target to overcome paclitaxel resistance. Herein, we synthesized and identified coumarin derivatives 50 as a novel MARK4 inhibitor. Biological evaluation indicated compound 50 directly interacted with MARK4 and inhibited its activity in vitro, suppressed cell viability and induced apoptosis of HCC cells in a MARK4-dependent manner. Importantly, compound 50 significantly increased the drug response of paclitaxel treatment to HCC cells, providing a promise strategy to HCC treatment and broadening the application of paclitaxel in cancer therapy

Mechanism of sphingolipid homeostasis revealed by structural analysis of \u3ci\u3eArabidopsis\u3c/i\u3e SPT-ORM1 complex

The serine palmitoyltransferase (SPT) complex catalyzes the first and rate-limiting step in sphingolipid biosynthesis in all eukaryotes. ORM/ORMDL proteins are negative regulators of SPT that respond to cellular sphingolipid levels. However, the molecular basis underlying ORM/ORMDL-dependent homeostatic regulation of SPT is not well understood.We determined the cryo–electron microscopy structure of Arabidopsis SPT-ORM1 complex, composed of LCB1, LCB2a, SPTssa, and ORM1, in an inhibited state. A ceramide molecule is sandwiched between ORM1 and LCB2a in the cytosolic membrane leaflet. Ceramide binding is critical for the ORM1-dependent SPT repression, and dihydroceramides and phytoceramides differentially affect this repression. A hybrid β sheet, formed by the amino termini of ORM1 and LCB2a and induced by ceramide binding, stabilizes the amino terminus of ORM1 in an inhibitory conformation. Our findings provide mechanistic insights into sphingolipid homeostatic regulation via the binding of ceramide to the SPT-ORM/ORMDL complex that may have implications for plant-specific processes such as the hypersensitive response for microbial pathogen resistance

Genome-wide analysis and identification of stress-responsive genes of the CCCH zinc finger family in Capsicum annuum L.

The CCCH zinc finger gene family encodes a class of proteins that can bind to both DNA and RNA, and an increasing number of studies have demonstrated that the CCCH gene family plays a key role in growth and development and responses to environmental stress. Here, we identified 57 CCCH genes in the pepper (Capsicum annuum L.) genome and explored the evolution and function of the CCCH gene family in C. annuum. Substantial variation was observed in the structure of these CCCH genes, and the number of exons ranged from one to fourteen. Analysis of gene duplication events revealed that segmental duplication was the main driver of gene expansion in the CCCH gene family in pepper. We found that the expression of CCCH genes was significantly up-regulated during the response to biotic and abiotic stress, especially cold and heat stress, indicating that CCCH genes play key roles in stress responses. Our results provide new information on CCCH genes in pepper and will aid future studies of the evolution, inheritance, and function of CCCH zinc finger genes in pepper

Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence

Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated β-galactosidase (SA-β-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP

Antibiotics (Macrolides and Lincosamides) Consumption Trends and Patterns in China’s Healthcare Institutes. Based on a 3 Year Procurement Records, 2015–2017

In this study, we investigated the trends and patterns of antibiotic consumption (macrolides and lincosamides) in China’s healthcare institutions from 2015 to 2017. The China Drug Supply Information Platform (CDSIP) was officially launched in 2015. We collected records from this national centralized bidding procurement system between 2015 and 2017. The use of J01F antibiotics (macrolides or lincosamides) was calculated in a defined daily dose per 1000 inhabitants per day (DID).Purchase data from 70,366 national medical facilities included in the CDSIP were collected. The procurement data of 66,007 medical facilities have not changed over 3 years. There is a slight decline in the consumption of J01F antibiotics, which decreased from 3.03 DID in 2015 to 2.91 DID in 2017. Azithromycin (20.6%) was the most commonly used antibiotic in 2017 among all classes, followed by clindamycin (17.9%) and erythromycin (13.7%). Parenteral antibiotics accounted for 32.0% of total antibiotic consumption and 59.6% of total antibiotics expenditure in 2017. The overall consumption of most antibiotics decreased slightly over the 3-yearstudy period. This may be owing to China’s health-related policies in the past few years. A gap still exists in antibiotic use between regions and dosage forms. Further studies are needed to optimize antibiotic prescribing and reduce antibiotic resistance

Robust Sparse Reduced-Rank Regression with Response Dependency

In multiple response regression, the reduced rank regression model is an effective method to reduce the number of model parameters and it takes advantage of interrelation among the response variables. To improve the prediction performance of the multiple response regression, a method for the sparse robust reduced rank regression with covariance estimation(Cov-SR4) is proposed, which can carry out variable selection, outlier detection, and covariance estimation simultaneously. The random error term of this model follows a multivariate normal distribution which is a symmetric distribution and the covariance matrix or precision matrix must be a symmetric matrix that reduces the number of parameters. Both the element-wise penalty function and row-wise penalty function can be used to handle different types of outliers. A numerical algorithm with a covariance estimation method is proposed to solve the robust sparse reduced rank regression. We compare our method with three recent reduced rank regression methods in a simulation study and real data analysis. Our method exhibits competitive performance both in prediction error and variable selection accuracy