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

Microbial Taxa and Soil Organic Carbon Accumulation Driven by Tree Roots

Rhizosphere microbes in forests are key elements for carbon accumulation in terrestrial ecosystems. To date, little is known on the rhizomicrobial community changes occurring during soil carbon accumulation. Using high-throughput DNA sequencing, we identified the phyla composing the rhizomicrobial communities of Pinus tabuliformis Carr. and Quercus variabilis Blume forests in North China and their abundance. These results were correlated with the soil organic carbon (SOC) accumulation driven by tree roots. Rhizomicrobial community composition and abundance and SOC accumulation varied with tree species, but root presence benefited SOC accumulation significantly. Different phyla played different roles in root-driven carbon accumulation during the succession of a recovery forest ecosystem, but Proteobacteria and Basidiomycota were keystones for root-driven carbon accumulation

Phosphorus Limitation of Trees Influences Forest Soil Fungal Diversity in China

Fungal-biogeography studies have shown global patterns of biotic interactions on microbial biogeography. However, the mechanisms underlying these patterns remain relatively unexplored. To determine the dominant factors affecting forest soil fungal diversity in China, soil and leaves from 33 mountain forest reserves were sampled, and their properties were measured. We tested three hypotheses and established the most realistic one for China. The results showed that the soil fungal diversity (Shannon index) varied unimodally with latitude. The relative abundance of ectomycorrhizae was significantly positively correlated with the leaf nitrogen/phosphorus. The effects of soil available phosphorus and pH on fungal diversity depended on the ectomycorrhizal fungi, and the fungal diversity shifted by 93% due to available phosphorus, potassium, and pH. Therefore, we concluded that latitudinal changes in temperature and the variations in interactions between different fungal guilds (ectomycorrhizal, saprotrophic, and plant pathogenic fungi) did not have a major influence. Forest soil fungal diversity was affected by soil pH, available phosphorus, and potassium, which are driven by the phosphorus limitation of trees

Microbial Taxa and Soil Organic Carbon Accumulation Driven by Tree Roots

Rhizosphere microbes in forests are key elements for carbon accumulation in terrestrial ecosystems. To date, little is known on the rhizomicrobial community changes occurring during soil carbon accumulation. Using high-throughput DNA sequencing, we identified the phyla composing the rhizomicrobial communities of Pinus tabuliformis Carr. and Quercus variabilis Blume forests in North China and their abundance. These results were correlated with the soil organic carbon (SOC) accumulation driven by tree roots. Rhizomicrobial community composition and abundance and SOC accumulation varied with tree species, but root presence benefited SOC accumulation significantly. Different phyla played different roles in root-driven carbon accumulation during the succession of a recovery forest ecosystem, but Proteobacteria and Basidiomycota were keystones for root-driven carbon accumulation

Discussion on operation flexibility of Zhonggui natural gas pipeline

Zhongwei station of West to east natural gas pipeline is connected to the north of Zhonggui line, and Guiyang station of China-Myanmar natural gas pipeline is connected to the south, which has important strategic significance in Southwest China. At present, the tie line mainly carries out gas transmission from Zhongwei to Guiyang. Only some pipeline sections and offload stations have reverse transmission function, while all compressor stations have no reverse transmission and pressurization function. In order to evaluate the flexibility of the operation of the Zhonggui line and give some suggestions for the preliminary reconstruction, this paper uses the SPS software to establish the pipeline model and simulate the specific working conditions, focusing on the two working conditions of the intermediate station injection forward transmission and the whole line reverse transmission. Through the simulation, we can get the following conclusions: 1. When the intermediate station injects forward gas transmission, which compressor station, gas transmission range and joint operation condition with China-Myanmar line need to be started for Zhonggui line; 2. When the whole tie line is reversed, it is necessary to change the location of the compressor station with the function of reverse transmission and pressurization. Through this study, we can give some reference and evaluation opinions on the lack of flexibility of the current tie line, and also give some reference opinions on the specific implementation of the improvement of the tie line operation flexibility in the future

Study on influencing factors and monitoring cycle of wall thickness at key locations of natural gas station

In recent years, the safe and stable operation of natural gas pipeline has become the focus of the whole society. Long distance natural gas pipelines are mostly large-diameter and high pressure pipelines, so their safe operation is particularly critical. In the high-pressure natural gas pipeline transportation industry, the wall thickness of key points (elbows and tees) will be thinned due to long-term erosion of gas, resulting in serious consequences. Therefore, its wall thickness monitoring is a key work of long-distance natural gas pipeline operation units. At present, most of them adopt off-line monitoring, but the standardized monitoring cycle cannot be effectively determined, and there are no relevant standards in the industry. The author uses fluent simulation software to establish the model, and then modifies the model combined with the field data. Then, the model is used to analyze the influencing factors of key points (elbow and TEE) one by one, and select more important influencing factors to formulate the monitoring cycle of different points. The monitoring cycle can provide reference for the daily work of on-site operators, and then ensure the safe and stable operation of long-distance natural gas pipeline

Effects of frequency and amount of stover mulching on the microbial community composition and structure in the endosphere and rhizosphere

Stover mulching, as a sustainable agricultural conservation practice, has been shown to effectively increase soil organic matter and enhance crop yields. The impact of stover mulching on soil microorganisms has been extensively studied. However, less attention has been given to endophytic and rhizospheric microorganisms that have closer relationships with crops. How do the quality and frequency of stover mulching affect the composition and structure of these endosphere and rhizosphere microbial communities? And what is their influence on critical indicators of soil health such as bacterial plant pathogen and Rhizobiales? These questions remain unresolved. Therefore, we investigated the responses of the microbial functional guilds in the endosphere and rhizosphere to maize stover mulching qualities (0%, 33%, 67%, and total stover mulching every year) and frequencies (once every 3 years and twice every 3 years) under 10-year no-till management. Results showed significant correlations between Bacillales and Rhizobiales orders and soil SOC, NO3−N, and NH4+N; Hypocreales and Eurotiales orders were significantly correlated with soil NO3−N, with the Aspergillus genus also showing a significant correlation with soil SOC. The frequency and quality of stover mulching had a significant effect on root and rhizospheric microbial communities, with the lowest relative abundance of bacterial plant pathogens and highest relative abundance of nitrogen-fixing bacteria such as Rhizobiales and Hypocreales observed under F1/3 and F2/3 conditions. The most complex structures in endosphere and rhizospheric microbial communities were found under Q33 and Q67 conditions, respectively. This research indicates that from a soil health perspective, low-frequency high-coverage stover mulching is beneficial for the composition of endosphere and rhizosphere microbial communities, while moderate coverage levels are conducive to more complex structures within these communities. This study holds significant ecological implications for agricultural production and crop protection

Modeling of Gas Migration in Large Elevation Difference Oil Transmission Pipelines during the Commissioning Process

Oil pipeline construction and operation in mountainous areas have increased in southwestern China, with oil consumption increasing. Such liquid pipelines laid in mountainous areas continuously undulate along the terrain, resulting in many large elevation difference pipe segments. Serious gas block problems often occur during the commissioning process of these pipelines due to the gas/air accumulation at the high point of the pipe, which causes pipeline overpressure and vibration, and even safety accidents such as bursting pipes. To solve this problem, the gas–liquid replacement model and its numerical solution are established with consideration of the initial gas accumulation formation and the gas segment compression processes in a U-shaped pipe during the initial start-up operation. Additionally, considering the interactions of the gas-phase transfer in the continuous U-shaped pipe, and the influence of the length, inclination angle, and backpressure on the air vent process, the gas migration model for a continuous U-shaped pipe is established to predict the gas movement process. Finally, the field oil pipe production data were applied to verify the model. The results demonstrate that the maximum deviation between the calculated pressure during the start-up process and real data is 0.3 MPa, and the critical point of crushing the gas in the pipe section is about 0.2 Mpa. Additionally, the results show that the mass transfer of the gas section in the multi-pipe hydraulic air vent process causes the gas accumulation section to increase in downstream of the pipe. This study’s achievements can provide theoretical guidance and technical support for the safe and stable operation of continuous undulating liquid pipelines with large drops

Linking Leaf Functional Traits with Soil and Climate Factors in Forest Ecosystems in China

Plant leaf functional traits can reflect the adaptive strategies of plants to environmental changes. Exploring the patterns and causes of geographic variation in leaf functional traits is pivotal for improving ecological theory at the macroscopic scale. In order to explore the geographical variation and the dominant factors of leaf functional traits in the forest ecosystems of China, we measured 15 environmental factors on 16 leaf functional traits in 33 forest reserves in China. The results showed leaf area (LA), carbon-to-nitrogen ratio (C/N), carbon-to-phosphorus ratio (C/P), nitrogen-to-phosphorus ratio (N/P), phosphorus mass per area (Pa) and nitrogen isotope abundance (δ15N)) were correlated with latitude significantly. LA, Pa and δ15N were also correlated with longitude significantly. The leaf functional traits in southern China were predominantly affected by climatic factors, whereas those in northern China were mainly influenced by soil factors. Mean annual temperature (MAT), mean annual precipitation (MAP) and mean annual humidity (MAH) were shown to be the important climate factors, whereas available calcium (ACa), available potassium (AK), and available magnesium (AMg) were shown to be the important climate factors that affect the leaf functional traits of the forests in China. Our study fills the gap in the study of drivers and large-scale geographical variability of leaf functional traits, and our results elucidate the operational mechanisms of forest–soil–climate systems. We provide reliable support for modeling global forest dynamics