Estimation of the ice melting point in molecular dynamics simulations based on the finite-size effects.

Predicting the ice melting point using molecular dynamics (MD) simulations is nontrivial due to uncertainty associated with the stochastic nature of the simulation and effect of finite domain sizes on the simulated ice-water phase transition. We developed a method based on the percolation theory to make use of the finite size effects to allow determination of a unique critical phase transition temperature as the melting point. The method involves construction of melting/freezing probability curves from multiple simulations with varying temperatures for different domain sizes. While the domain sizes affect the apparent melting/freezing probability and hence generate different curves with a wider probability distribution for a smaller size, the intersection of these curves is unique and locates the melting point. Based on MD simulations using the Tip4p/Ice water model, we tested and demonstrated the effectiveness of this method in locating the critical ice-water phase transition at a melting temperature of 268.78 K. Our analysis also showed that the apparent melting probability at this critical point is ∼0.69, not 0.5 assumed in the ad hoc method used previously. Our method, making no assumption about the system size, may provide a generic framework for analyzing phase transitions influenced by the finite size effects in MD simulations.

Impacts of evaporation and inundation on near-surface salinity at a coastal wetland park.

Salinization is one of the main causes of conversion between different ecosystems and landuse functions in coastal wetlands. In this paper, we studied the spatiotemporal dynamics of soil moisture and salinity in a reclaimed national wetland park in Guangdong Province, China. We found that diel evaporation affected soil water up to 40 cm deep. Extreme rainfall only increased topsoil moisture with limited leaching effects on soil salinity. Salt accumulation occurred between 40 and 70 cm depth in rainy season, lasting until the end of monitoring period. Whereas the topsoil was salinized between land-surface to 30 cm deep in dry season, which was recovered after rainfall. This result suggested that the force balance between capillarity and gravity created a relative stable saline layer which was not flushed out during inundation. Therefore, considering these site-specific features could lead to the improved understanding of the migration of salinity in the soil profiles.

Identification of driver genes with aberrantly alternative splicing events in pediatric patients with retinoblastoma.

Retinoblastoma (RB) is one of the most common cancer in children. However, the specific mechanism about RB tumorigenesis has not been fully understood. In this study, to comprehensively characterize the splicing alterations in the tumorigenesis of RB, we analyzed the differential alternative splicing events in RB. Specifically, the isoforms of RB1 were downregulated in the RB samples, and a large proportion of differentially expressed genes had multiple differentially expressed transcripts (64%). We identified 1453 genes with differential alternative splicing, among which, SE accounted for the majority, followed by MXE, RI, A3SS, and A5SS. Furthermore, the biological function related to the normal function of eyes, and E2F family TFs were significantly enriched by the genes with differential alternative splicing. Among the genes associated with visual sense, ABCA4 was found to have two mutually exclusive exons, resulting in two isoforms with different functionalities. Notably, DAZAP1 was identified as one of the critical splicing factors in RB, which was potentially involved in E2F and RB pathways. Functionally, differential binding sites in DAZAP1 protein were significantly observed between RB and normal samples. Based on the comprehensive analysis of the differential alternative splicing events and splicing factors, we identified some driver genes with differential alternative splicing and critical splicing factors involved in RB, which would greatly improve our understanding of the alternative splicing process in the tumorigenesis of RB.

Tadalafil-loaded PLGA microspheres for pulmonary administration: preparation and evaluation

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 µm. The encapsulation efficiency and drug loading yield of TDF-PLGA-MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF-PLGA-MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 µm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF-PLGA-MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung ​​were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy.

Tamibarotene-Loaded PLGA Microspheres for Intratumoral Injection Administration: Preparation and Evaluation.

Tamibarotene (Am80) has good curative effect on advanced hepatocellular carcinoma (HCC). To improve the therapeutic efficacy furtherly, we prepared tamibarotene-loaded PLGA microspheres (Am80-PLGA-MS) for intratumoral injection. Firstly, Am80-PLGA-MS were prepared by emulsion-solvent evaporation method. Subsequently, microspheres were characterized by particle size analysis, drug loading (DL), and entrapment efficiency (EE). Finally, the drug release characteristics in vitro, pharmacokinetic, and pharmacodynamics were studied separately. According to results obtained, microspheres were spherical with a uniform particle size 7.04 ± 0.03 µm and its EE and DL were 82.23 ± 0.74 and 11.74 ± 0.11%, respectively. In vitro, Am80-PLGA-MS can release drug for 14 days and its release behavior was fitted with the Higuchi equation. In pharmacokinetic studies, the t1/2ß, MRT, and AUC of microspheres were 15.43-fold, 8.62-fold, and 9.98-fold those of Am80 solution, respectively, which revealed that the utilization of drug was improved obviously. The pharmacodynamics studies showed that the tumor doubling time, growth inhibition rate, and specific growth rate of tumor of Am80-PLGA-MS were 1.34 times, 2.63 times, and 0.72 times those of drug solution, respectively, indicating that the inhibitory effect on tumor by the microspheres was significantly improved. In summary, Am80-PLGA-MS are promising carrier to enhance the inhibitory effect on tumor, which will provide significantly clinical value for treatment of HCC.

Construction and evaluation in vitro and in vivo of tedizolid phosphate loaded cationic liposomes.

First, the SA-TDZA-Lips were prepared by reverse-phase evaporation method. Then, the drug release behaviour was evaluated by dynamic membrane dialysis in vitro and the preliminary safety was evaluated by haemolysis method. Finally, with tedizolid phosphate injection (TDZA-Inj) and tedizolid phosphate loaded liposomes (TDZA-Lips) as the control groups, the pharmacokinetic characteristic and tissues distribution of SA-TDZA-Lips were evaluated after intravenous injection. As a result, the stearylamine modified tedizolid phosphate liposomal delivery system was constructed successfully and the particle size was 194.9 ± 2.93 nm. The encapsulation efficiency (EE) was 53.52 ± 2.18%. The in vitro release of SA-TDZA-Lips was in accordance with Weibull equation. And there was no haemolysis happened, which indicated good preliminary safety for injection. The results of pharmacokinetics showed that the t1/2ß increased by 0.74 times and 0.51 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The MRT of SA-TDZA-Lips was 1.30 and 1.09 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The AUC was 2.40 times and 0.23 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The tissue distribution results showed that the relative uptake rate (Re) of TDZA in the lung was 1.527, which indicated the targeting. In conclusion, the SA-TDZA-Lips prepared in this study had several advantages like positive charge, strong cell affinity, prolonged circulation time in vivo, sustained release effect, and increased drug concentration in lungs. All advantages above provided significant clinical value of application for the treatment of bacterial pneumonia with tedizolid phosphate.

Preparation and Evaluation of Artemether Liposomes for Enhanced Anti-Tumor Therapy.

The aim of the study was to design liposomes (Lips) of artemether (ARM), a plant-derived drug for treatment of metastatic tumors, for the intravenous delivery. The ARM-Lips were prepared using ethanol injection method. Based on the optimization of formulation with single-factor experiments, ARM-Lips were spherical with a uniform particle size (187.3 ± 1.83) nm and its EE and DL were (94.49 ± 1.18)% and (10.94 ± 0.10)%, respectively. The in vitro drug release characteristics of ARM-Lips possessed a sustained release characteristic, and their behavior was in accordance with the first-order kinetics equation. In vivo, after intravenous injection to mice, the t1/2ß, MRT, and AUC of ARM-Lips were 8.38-, 3.38-, and 3.11-fold those of ARM solution (ARM-Sol), respectively. In the pharmacodynamics studies, the tumor doubling time, growth inhibition rate, and specific growth rate of tumor of ARM-Lips were 1.97 times, 1.54 times, and 0.51 times those of ARM-Sol, respectively, which indicated that the anti-tumor effect of ARM-Lips was significantly stronger than that of ARM-Sol. These encouraging results revealed that ARM-Lips would serve as an efficient carrier for ARM for increasing therapeutic efficacy on tumor.

Intra-articular delivery of tetramethylpyrazine microspheres with enhanced articular cavity retention for treating osteoarthritis.

Tetramethylpyrazine (TMP) is a traditional Chinese herbal medicine with strong anti-inflammatory and cartilage protection activities, and thus a promising candidate for treating osteoarthritis. However, TMP is rapidly cleared from the joint cavity after intra-articular injection and requires multiple injections to maintain efficacy. The aim of this study was to encapsulate TMP into poly (lactic-co-glycolic acid) (PLGA) microspheres to enhance the TMP retention in the joint, reducing injection frequencies and decreasing dosage. TMP microspheres were prepared by emulsion/solvent evaporation method. The intra-articular retention of the drug was assessed by detecting the drug concentration distributed in the joint tissue at different time points. The therapeutic effect of TMP microspheres was evaluated by the swelling of knee joints and histologic analysis in papain-induced OA rat model. The prepared freeze-dried microspheres with a particle size of about 10 µm can effectively prolong the retention time of the drug in the articular cavity to 30 d, which is 4.7 times that of the TMP solution. Intra-articular injection of TMP microspheres efficiently relieved inflammatory symptoms, improved joint lesions and decreased the depletion of proteoglycan. In conclusion, intra-articular injection of TMP loaded microspheres was a promising therapeutic method in the treatment of OA.

Probabilistic model predicts dynamics of vegetation biomass in a desert ecosystem in NW China.

The temporal dynamics of vegetation biomass are of key importance for evaluating the sustainability of arid and semiarid ecosystems. In these ecosystems, biomass and soil moisture are coupled stochastic variables externally driven, mainly, by the rainfall dynamics. Based on long-term field observations in northwestern (NW) China, we test a recently developed analytical scheme for the description of the leaf biomass dynamics undergoing seasonal cycles with different rainfall characteristics. The probabilistic characterization of such dynamics agrees remarkably well with the field measurements, providing a tool to forecast the changes to be expected in biomass for arid and semiarid ecosystems under climate change conditions. These changes will depend-for each season-on the forecasted rate of rainy days, mean depth of rain in a rainy day, and duration of the season. For the site in NW China, the current scenario of an increase of 10% in rate of rainy days, 10% in mean rain depth in a rainy day, and no change in the season duration leads to forecasted increases in mean leaf biomass near 25% in both seasons.

Chitosan coated vancomycin hydrochloride liposomes: Characterizations and evaluation.

The present work evaluated the feasibility of chitosan coated liposomes (c-Lips) for the intravenous delivery of vancomycin hydrochloride (VANH), a water-soluble antibiotic for the treatment of gram-positive bacterial infections like osteomyelitis, arthritis, endocarditis, pneumonia, etc. The objective of this research was to develop a suitable drug delivery system in vivo which could improve therapeutic efficacy and decrease side effects especially nephrotoxicity. Firstly, the vancomycin hydrochloride liposomes (VANH-Lips) were prepared by modified reverse phase evaporation method, then the chitosan wrapped vancomycin hydrochloride liposomes (c-VANH-Lips) nanosuspension was formulated by the method of electrostatic deposition. Based on the optimized results of single-factor screening experiment, the c-VANH-Lips were found to be relatively uniform in size (220.40 ± 3.56 nm) with a narrow polydispersity index (PI) (0.21 ± 0.03) and a positive zeta potential (25.7 ± 1.12 mV). The average drug entrapment efficiency (EE) and drug loading (DL) were 32.65 ± 0.59% and 2.18 ± 0.04%, respectively. The in vitro release profile of c-VANH-Lips possessed a sustained release Characterization and the release behavior was in accordance with the Weibull equation. Hemolysis experiments showed that its intravenous injection had preliminary safety. In vivo, after intravenous injection to mice, c-VANH-Lips showed a longer retention time and higher AUC values compared with the VANH injection (VANH-Inj) and VANH-Lips. In addition, biodistribution results clearly demonstrated that c-VANH-Lips preferentially decreased the drug distribution in kidney of mice after intravenous injection. These results revealed that injectable c-VANH-Lips may serve as a promising carrier for VANH to increase therapeutic efficacy on gram-positive bacterial infections and reduce nephrotoxicity, which provides significantly clinical value for long-term use of VANH.

Development and characterization of drug-loaded biodegradable PLA microcarriers prepared by the electrospraying technique.

Biodegradable particles are extremely useful in the development of novel drug delivery systems. Recent studies have suggested that morphology can influence the mechanisms of drug delivery in many ways. In the present study, biodegradable microparticles with different morphologies were prepared from poly(L­lactide) (PLA) using the electrospraying technique. The microparticles were then systematically examined by scanning using an electron microscope. The results revealed that the preparation of drug-loaded microspheres through electrospraying is a simple and efficient method, and the processing parameters, such as polymer molecular weight, concentration, surfactant and solvent play an important role in obtaining high quality microcarriers. The association between microcarrier morphology and the processing parameters used was also investigated. Rifampin-loaded PLA microspheres were also prepared according to the above-mentioned model. Our data demonstrate that the drug release from PLA microspheres can be sustained in vitro for over 60 h. Our study focused on obtaining electrosprayed medicated microparticles from complex polyester particles. Further studies are required to explore the potential commercial use of these microparticles.