Qiang Lv

pH-Responsive Poly(ethylene glycol)/Poly(L-lactide) Supramolecular Micelles Based on Host-Guest Interaction.

pH-responsive supramolecular amphiphilic micelles based on benzimidazole-terminated poly(ethylene glycol) (PEG-BM) and β-cyclodextrin-modified poly(L-lactide) (CD-PLLA) were developed by exploiting the host-guest interaction between benzimidazole (BM) and β-cyclodextrin (β-CD). The dissociation of the supramolecular micelles was triggered in acidic environments. An antineoplastic drug, doxorubicin (DOX), was loaded into the supramolecular micelles as a model drug. The release of DOX from the supramolecular micelles was clearly accelerated as the pH was reduced from 7.4 to 5.5. The DOX-loaded PEG-BM/CD-PLLA supramolecular micelles displayed an enhanced intracellular drug-release rate in HepG2 cells compared to the pH-insensitive DOX-loaded PEG-b-PLLA counterpart. After intravenous injection into nude mice bearing HepG2 xenografts by the tail vein, the DOX-loaded supramolecular micelles exhibited significantly higher tumor inhibition efficacy and reduced systemic toxicity compared to free DOX. Furthermore, the DOX-loaded supramolecular micelles showed a blood clearance rate markedly lower than that of free DOX and comparable to that of the DOX-loaded PEG-b-PLLA micelles after intravenous injection into rats. Therefore, the pH-responsive PEG-BM/CD-PLLA supramolecular micelles hold potential as a smart nanocarrier for anticancer drug delivery.

Effect of Interfacial Bonding on Interphase Properties in SiO2/Epoxy Nanocomposite: A Molecular Dynamics Simulation Study

Atomistic molecular dynamics simulations have been performed to explore the effect of interfacial bonding on the interphase properties of a nanocomposite system that consists of a silica nanoparticle and the highly cross-linked epoxy matrix. For the structural properties, results show that interfacial covalent bonding can broaden the interphase region by increasing the radial effect range of fluctuated mass density and oriented chains, as well as strengthen the interphase region by improving the thermal stability of interfacial van der Waals excluded volume and reducing the proportion of cis conformers of epoxy segments. The improved thermal stability of the interphase region in the covalently bonded model results in an increase of ∼21 K in the glass transition temperature (Tg) compared to that of the pure epoxy. It is also found that interfacial covalent bonding mainly restricts the volume thermal expansion of the model at temperatures near or larger than Tg. Furthermore, investigations from mean-square displacement and fraction of immobile atoms point out that interfacial covalent and noncovalent bonding induces lower and higher mobility of interphase atoms than that of the pure epoxy, respectively. The obtained critical interfacial bonding ratio when the interphase and matrix atoms have the same mobility is 5.8%. These results demonstrate that the glass transitions of the interphase and matrix will be asynchronous when the interfacial bonding ratio is not 5.8%. Specifically, the interphase region will trigger the glass transition of the matrix when the ratio is larger than 5.8%, whereas it restrains the glass transition of the matrix when the ratio is smaller than 5.8%.

Combined analysis of mRNA and miRNA identifies dehydration and salinity responsive key molecular players in citrus roots

Citrus is one of the most economically important fruit crops around world. Drought and salinity stresses adversely affected its productivity and fruit quality. However, the genetic regulatory networks and signaling pathways involved in drought and salinity remain to be elucidated. With RNA-seq and sRNA-seq, an integrative analysis of miRNA and mRNA expression profiling and their regulatory networks were conducted using citrus roots subjected to dehydration and salt treatment. Differentially expressed (DE) mRNA and miRNA profiles were obtained according to fold change analysis and the relationships between miRNAs and target mRNAs were found to be coherent and incoherent in the regulatory networks. GO enrichment analysis revealed that some crucial biological processes related to signal transduction (e.g. ‘MAPK cascade’), hormone-mediated signaling pathways (e.g. abscisic acid- activated signaling pathway’), reactive oxygen species (ROS) metabolic process (e.g. ‘hydrogen peroxide catabolic process’) and transcription factors (e.g., ‘MYB, ZFP and bZIP’) were involved in dehydration and/or salt treatment. The molecular players in response to dehydration and salt treatment were partially overlapping. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis further confirmed the results from RNA-seq and sRNA-seq analysis. This study provides new insights into the molecular mechanisms how citrus roots respond to dehydration and salt treatment.

pH‐Triggered Charge‐Reversal Polyurethane Micelles for Controlled Release of Doxorubicin

A series of pH-triggered charge-reversal polyurethane copolymers (PS-PUs) containing methoxyl-poly(ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups is presented in this work. The obtained PS-PUs copolymers can form into stable micelles at pH 7.4, which response to a narrow pH change (5.5-7.5) and show a tunable pH-triggered charge-reversal property. Doxorubicin (DOX) is encapsulated into the PS-PU micelles as a model drug. The drug release of DOX-loaded PS-PU micelles shows an obviously stepped-up with reducing the pH. Meanwhile, it is found that the charge-reversal property can improve the cellular uptake behavior and intracellular drug release in both HeLa cells and MCF-7 cells. Additionally, the time-dependent cytotoxicity of the DOX-loaded PS-PU micelles is confirmed by MTT assay. Attributed to the tunable charge-reversal property through changing the molar ratio of piperazine/carboxyl, the PS-PU micelles will be a potential candidate as an intelligent drug delivery system in future studies.

pH and reduction dual responsive cross-linked polyurethane micelles as an intracellular drug delivery system

Nano-vehicles that exhibit enhanced stability in blood circulation while spontaneously releasing therapeutic cargos at pathological sites in response to specific biological triggers are of interest for on-demand drug delivery. In this work, disulfide cross-linked polyurethane micelles (CL-PUMs) that respond to pH change and an intracellular reducing agent were developed. The micelles were prepared by cross-linking of poly(ethylene glycol)–polyurethane multiblock copolymers containing tertiary amino and cyclic disulfide moieties via a thiol–disulfide exchange reaction. The CL-PUMs tended to swell or decompose under a weakly acidic environment or in the presence of an intracellular reducing agent, glutathione (GSH), likely owing to the protonation of the tertiary amino groups and cleavage of the disulfide cross-linking bonds. The doxorubicin (DOX)-loaded CL-PUMs suppressed the initial burst release at pH 7.4 without GSH, while they displayed a triggered drug release manner in response to an acidic environment and GSH. It was found that the intracellular DOX release of the DOX-loaded CL-PUMs in HepG2 cells was accelerated by an acidic environment or enhanced intracellular GSH concentration. Moreover, the time-dependent cytotoxicity against HepG2 and HeLa cells of the DOX-loaded CL-PUMs was confirmed by an MTT assay. Overall, due to the enhanced stability, selective swelling and decomposition properties in response to intracellular micro-environments, the pH- and reduction-sensitive polyurethane cross-linked nano-carriers can serve as a potential system for intracellular drug delivery.

The Association between Ambient Temperature and Childhood Hand, Foot, and Mouth Disease in Chengdu, China: A Distributed Lag Non-linear Analysis

Hand, foot and mouth disease (HFMD) has recently been recognized as a critical challenge to disease control and public health response in China. This study aimed to quantify the association between temperature and HFMD in Chengdu. Daily HFMD cases and meteorological variables in Chengdu between January 2010 and December 2013 were obtained to construct the time series. A distributed lag non-linear model was performed to investigate the temporal lagged association of daily temperature with age- and gender-specific HFMD. A total of 76,403 HFMD cases aged 0–14 years were reported in Chengdu during the study period, and a bimodal seasonal pattern was observed. The temperature-HFMD relationships were non-linear in all age and gender groups, with the first peak at 14.0–14.1 °C and the second peak at 23.1–23.2 °C. The high temperatures had acute and short-term effects and declined quickly over time, while the effects in low temperature ranges were persistent over longer lag periods. Males and children aged <1 year were more vulnerable to temperature variations. Temperature played an important role in HFMD incidence with non-linear and delayed effects. The success of HFMD intervention strategies could benefit from giving more consideration to local climatic conditions.

Spatio-Temporal Pattern and Socio-Economic Factors of Bacillary Dysentery at County Level in Sichuan Province, China.

Bacillary dysentery (BD) remains a big public health problem in China. Effective spatio-temporal monitoring of BD incidence is important for successful implementation of control and prevention measures. This study aimed to examine the spatio-temporal pattern of BD and analyze socio-economic factors that may affect BD incidence in Sichuan province, China. Firstly, we used space-time scan statistic to detect the high risk spatio-temporal clusters in each year. Then, bivariate spatial correlation and Bayesian spatio-temporal model were utilized to examine the associations between the socio-economic factors and BD incidence. Spatio-temporal clusters of BD were mainly located in the northern-southern belt of the midwest area of Sichuan province. The proportion of primary industry, the proportion of rural population and the rates of BD incidence show statistically significant positive correlation. The proportion of secondary industry, proportion of tertiary Industry, number of beds in hospitals per thousand persons, medical and technical personnel per thousand persons, per capital GDP and the rate of BD incidence show statistically significant negative correlation. The best fitting spatio-temporal model showed that medical and technical personnel per thousand persons and per capital GDP were significantly negative related to the risk of BD.

A 78 kDa host cell invasion protein of Neospora caninum as a potential vaccine candidate.

Neosporosis is an intracellular protozoan disease caused by Neospora caninum. Until now, there is no effective vaccine to prevent neosporosis. The host cell binding protein has the potential as neosporosis vaccine. In the present study, a T7 phage display library was constructed and screened using Vero cells to obtain host cell binding protein of N. caninum. Two host cell binding proteins, a hypothetical protein of 78 kDa (named as NcP78) homologous to the acylglycerol lipase of Toxoplasma gondii ME49 (XP_002370319.1) and NcGRA7 (known as a dense granules protein that is involved in the invasion of N. caninum to the host cells), were identified. Immune responses induced by recombinant NcP78 and NcGRA7 proteins and their protective efficacies against homologous challenge in BALB/c mice were evaluated respectively. Results showed that recombinant NcP78 and NcGRA7 could elicit both Th1 and Th2 immune responses (with the elevated levels of IgG1 and IgG2a antibody), but predominately a Th2 immune response with a high level of IgG1. The ani-NcP78 and anti-NcGRA7 serum also had inhibitory effects on N. caninum invasion to Vero cells in vitro, which indicated that both NcP78 and NcGRA7 proteins were involved in host cell invasion. Recombinant NcP78 and NcGRA7 could not prolong the survival times and improve the survival rates of dams, but could prolong the survival times and improve the survival rates of offspring significantly. Moreover, the recombinant NcP78 and NcGRA7 could reduce the brain parasite load of dams and offspring. Though these protein vaccines could not effectively alleviate the symptom of abortion, they could increase the number of born offspring significantly, indicating that Nc78 and NcGRA7 recombinant proteins could provide a partial protection against N. caninum infection in mice.

The association between diurnal temperature range and childhood hand, foot, and mouth disease: a distributed lag non-linear analysis.

In recent years, hand, foot, and mouth disease (HFMD) has been increasingly recognized as a critical challenge to disease control and prevention in China. Previous studies have found that meteorological factors such as mean temperature and relative humidity were associated with HFMD. However, little is known about whether the diurnal temperature range (DTR) has any impact on HFMD. This study aimed to quantify the impact of DTR on childhood HFMD in 18 cities in Sichuan Province. A distributed lag non-linear model was adopted to explore the temporal lagged association of daily temperature with age-, gender- and pathogen-specific HFMD. A total of 290 123 HFMD cases aged 0-14 years were reported in the 18 cities in Sichuan Province. The DTR-HFMD relationships were non-linear in all subgroups. Children aged 6-14 years and male children were more vulnerable to the temperature changes. Large DTR had the higher risk estimates of HFMD incidence in cases of EV71 infection, while small DTR had the higher risk estimates of HFMD incidence in cases of CV-A16 infection. Our study suggested that DTR played an important role in the transmission of HFMD with non-linear and delayed effects.

DOX/IL-2/IFN-γ co-loaded thermo-sensitive polypeptide hydrogel for efficient melanoma treatment

Melanoma has been a serious threat to the human health; however, effective therapeutic methods of this cancer are still limited. Combined local therapy is a crucial approach for achieving a superior anti-tumor efficacy. In this paper, a chemo-immunotherapy system of DOX, IL-2 and IFN-γ based on poly(γ-ethyl-L-glutamate)-poly(ethylene glycol)-poly(γ-ethyl-L-glutamate) (PELG-PEG-PELG) hydrogel was developed for local treatment of melanoma xenograft. The drug release process of this system exhibited a short term of burst release (the first 3 days), followed by a long-term sustained release (the following 26 days). The hydrogel degraded completely within 3 weeks without obvious inflammatory responses in the subcutaneous layer of rats, showing a good biodegradability and biocompatibility. The DOX/IL-2/IFN-γ co-loaded hydrogel also showed enhanced anti-tumor effect against B16F10 cells in vitro, through increasing the ratio of cell apoptosis and G2/S phage cycle arrest. Moreover, the combined strategy presented improved therapy efficacy against B16F10 melanoma xenograft without obvious systemic side effects in a nude mice model, which was likely related to both the enhanced tumor cell apoptosis and the increased proliferation of the CD3+/CD4+ T-lymphocytes and CD3+/CD8+ T-lymphocytes. Overall, the strategy of localized co-delivery of DOX/IL-2/IFN-γ using the polypeptide hydrogel provided a promising approach for efficient melanoma therapy.