Synthesis and characterization of folate-poly(ethylene glycol) chitosan graft-polyethylenimine as a non-viral carrier for tumor-targeted gene delivery

The use of chitosan and chitosan derivatives for gene delivery is limited due to the low transfection efficiency and difficulty in transfecting into a variety of cell types, including some cancer cells overexpressing folate receptor (FRs). In order to solve this problem, folate (FA) and poly(ethylene glycol) (PEG) was conjugated to chitosan-graft-polyethylenimine (CHI-g-PEI) to enhance water-solubility and the transfection efficiency. In the present study, a cell specific targeting molecule FA was linked on PEG and then grafted the FA-PEG onto CHI-g-PEI. The FA-PEG-grafted CHI-g-PEI (FA-PEG-CHI-g-PEI) effectively condensed the plasmid DNA (pDNA) into nanoparticles with positive surface charge under the suitable nitrogen/phosphorus (N/P) ratio. In vitro, transfection efficiency of the FA-PEG-CHI-g-PEI /pDNA complex in 293T cells and LoVo cells (FRs over-expressing cell lines) increased with increasing N/P ratio under N/P = 15 and was more than 50%, but no significant difference in human lung carcinoma cells (A549) cells (FRs deficient cell lines). Importantly, in vivo luciferase expression showed that the efficiency of FA-PEG-CHI-g-PEI -mediated transfection (50 μg luciferase plasmid (pLuc), N/P ratio = 15) was comparable to that of adenovirus-mediated luciferase transduction (1 × 109 pfu) in melanomabearing mice. It was concluded that FA-PEG-CHI-g-PEI, which has improved transfection efficiency and FRs specificity in vitro and in vivo, may be useful in gene therapy.Key words: Folate poly(ethylene glycol)-chitosan-grafted-polyethylenimine (FA-PEG-CHI-g-PEI), gene transfection, non-virus vector, in vitro, in viv

Effectiveness of varenicline and counseling for smoking cessation in an observational cohort study in China

published_or_final_versio

Effectiveness of additional follow-up telephone counseling in a smoking cessation clinic in Beijing and predictors of quitting among Chinese male smokers

published_or_final_versio

Drought Occurring With Hot Extremes: Changes Under Future Climate Change on Loess Plateau, China

© 2019. The Authors. Drought is one of the most widespread and destructive hazards over the Loess Plateau (LP) of China. Due to climate change, extremely high temperature accompanied with drought (expressed as hot drought) may lead to intensive losses of both properties and human deaths in future. A hot drought probabilistic recognition system is developed to investigate how potential future climate changes will impact the simultaneous occurrence of drought and hot extremes (hot days exceeding certain values) on the LP. Two regional climate models, coupled with multiple bias-correction techniques and multivariate probabilistic inference, are innovative integrated into the hot drought probabilistic recognition system to reveal the concurrence risk of droughts and hot extremes under different Representative Concentration Pathway (RCP) scenarios. The hot-day index, TX90p, indicating the number of days with daily maximum temperature (Tmax) exceeding the 90th percentile threshold, and the Standardized Precipitation Index are applied to identify the joint risks on the LP using copula-based methods. The results show that precipitation will increase throughout most of the LP under both RCP4.5 and RCP8.5 scenarios of 2036–2095, while Tmax may increase significantly all over the LP (1.8–2.7 °C for RCP4.5 and 2.7–3.6 °C for RCP8.5). The joint return periods of Standardized Precipitation Index and TX90p show that fewer stations will experience severe drought with long-term hot extremes in two future scenarios. However, some stations may experience hot droughts that are more frequent and extreme, particularly certain stations in the southwest and south-central regions of the LP with recurrence period less than 10 years.This research was supported by the National Key Research and Development Plan (2016YFA0601502), the Natural Sciences Foundation (51520105013, 51679087), the 111 Program (B14008), the Natural Science and Engineering Research Council of Canada, and the Fundamental Research Funds for the Central Universities (2016XS89). The observed temperature and precipitation data are collected and available at the National Meteorological Information Center (http://data.cma.cn/). The RCM simulations are available at Climate Change Data Portal (http://chinaccdp.org/)

Profiling of the perturbed metabolomic state of mouse spleen during acute and chronic toxoplasmosis

Background Toxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections. Current therapeutic strategies for toxoplasmosis are not fully effective at curtailing disease progression in these cases. Given the parasite ability to influence host immunity and metabolism, understanding of the metabolic alterations in the host’s immune organs during T. gondii infection may enhance the understanding of the molecular mechanisms that define the pathophysiology of T. gondii infection. Methods We investigated the global metabolic changes in the spleen of BALB/c mice at early and late stage of infection with T. gondii using LC-MS/MS-based metabolomics. Multivariate data analysis methods, principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA), were used to identify metabolites that are influenced by T. gondii infection. Results Multivariate analyses clearly separated the metabolites of spleen of infected and control mice. A total of 132 differential metabolites were identified, 23 metabolites from acutely infected versus control mice and 109 metabolites from chronically infected versus control mice. Lipids, hormones, lactones, acids, peptides, antibiotics, alkaloids and natural toxins were the most influenced chemical groups. There were 12 shared differential metabolites between acutely infected versus control mice and chronically infected versus control mice, of which 4,4-Dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol was significantly upregulated and ubiquinone-8 was significantly downregulated. Major perturbed metabolic pathways included primary bile acid biosynthesis, steroid hormone biosynthesis, biotin metabolism, and steroid biosynthesis, with arachidonic acid metabolism being the most significantly impacted pathway. These metabolic changes suggest a multifactorial nature of the immunometabolic responses of mouse spleen to T. gondii infection. Conclusions This study demonstrated that T. gondii infection can cause significant metabolomic alterations in the spleen of infected mice. These findings provide new insights into the molecular mechanisms that underpin the pathogenesis of T. gondii infection

Molecular Cloning and Sequence Analysis of a Novel P450 Gene Encoding CYP345D3 from the Red Flour Beetle, Tribolium castaneum

A novel cDNA clone encoding a cytochrome P450 gene has been isolated from the insecticide-susceptible strain of the red flour beetle, Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). The nucleotide sequence of the clone, designated CYP345D3, was determined. The cDNA is 1554 bp in length and contains an open reading frame from base pairs 32 to 1513, encoding a protein of 493 amino acid residues and a predicted molecular weight of 57466 Daltons. The putative protein contains the classic heme-binding sequence motif FxxGxxxCxG (residues 430–439) conserved among all P450 enzymes as well as other characteristic motifs of the cytochrome P450s. Comparison of the deduced amino acid sequence with other CYP members shows that CYP345D3 shares 91% identity with the previously published sequence of CYP345D1 from the T. castaneum genome project and the nucleotide sequence identity between them is less than 80%. Phylogenetic analysis of amino acid sequences from members of various P450 families indicated close phylogenetic relationship of CYP345D3 with CYP6 of other insects than those from mammals and amore distant relationship to P450 from other families. CYP345D3 was submitted to GenBank, accession number EU008544

Filamin-A Regulates Neutrophil Uropod Retraction through RhoA during Chemotaxis

Filamin-A (FLNa) has been shown to be a key cross-linker of actin filaments in the leading edge of a motile melanoma cell line, however its role in neutrophils undergoing chemotaxis is unknown. Using a murine transgenic model in which FLNa is selectively deleted in granulocytes, we report that, while neutrophils lacking FLNa show normal polarization and pseudopod extension, they exhibit obvious defects in uropod retraction. This uropod retraction defect was found to be a direct result of reduced FLNa mediated activation of the small GTPase RhoA and myosin mediated actin contraction in the FLNa null cells. This results in a neutrophil recruitment defect in FLNa null mice. The compensatory increase in FLNb levels that was observed in the FLNa null neutrophils may be sufficient to compensate for the lack of FLNa at the leading edge allowing for normal polarization, however this compensation is unable to regulate RhoA activated tail retraction at the rear of the cell

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Alterations in Adenosine Metabolism and Signaling in Patients with Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Background: Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an upregulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated. Methodology/Principal Findings: The focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A2BR are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A2BR in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A 2BR, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A 2BR on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators. Conclusions/Significance: These findings suggest that components of adenosine metabolism and signaling are altered in

Premature ventricular contractions originating from the left ventricular septum: Results of Radiofrequency Catheter Ablation in twenty patients

<p>Abstract</p> <p>Background</p> <p>RFCA has been established as an effective and curative therapy for severely symptomatic PVC from the outflow tract in structurally normal hearts. However, it is unknown whether PVCs originating from the left ventricular septum, are effectively eliminated by RFCA. This study aimed to investigate electrophysiologic characteristics and effects of Radiofrequency catheter ablation (RFCA) for patients with symptomatic premature ventricular contraction (PVC) originating from the left ventricular septum without including fascicular PVCs.</p> <p>Methods</p> <p>Characteristics of body surface electrocardiogram (ECG) and electrophysiologic recordings endocardiogram in a successful RFCA target were analyzed in 20 patients with symptomatic PVCs originating from the left ventricular septum. RFCA was performed using pace mapping and activation mapping.</p> <p>Results</p> <p>The QRS morphology of PVCs originating from the left ventricular septum is similar to that seen in fascicular tachycardia. Most of the PVCs originated from the left septum appears in the form of ventricular parasystole. The incidence of ventricular parasystole was 70%. Sustained ventricular tachycardia was not inducible by electrical stimulation and isoproterenol infusion in all 20 patients, ablation at the site recording the earliest Purkinje potential was not effective in all 20 patients, and Purkinje potentials were not identified at successful sites during point mapping. Sixteen patients were successful with RFCA using pace mapping and activation mapping, 3 failed, and 1 recurrent.</p> <p>Conclusion</p> <p>Although the ECG characteristics of the PVCs arising from the left ventricular septum are similar to that seen in fascicular tachycardia, the electrophysiologic characteristics are different between the two types of PVCs. The distinguishing characteristic of the PVCs is that Purkinje potentials were not present at the site of successful ablation, suggesting a myocardial as opposed to fascicular substrate. RFCA is an effective curative therapy for symptomatic PVCs originating from the left ventricular septum (not from the left anterior and posterior fascicle).</p