A theta-scheme approximation of basic reproduction number for an age-structured epidemic system in a finite horizon.

This paper focuses on numerical approximation of the basic reproduction number R0, which is the threshold defined by the spectral radius of the next-generation operator in epidemiology. Generally speaking, R0 cannot be explicitly calculated for most age-structured epidemic systems. In this paper, for a deterministic age-structured epidemic system and its stochastic version, we discretize a linear operator produced by the infective population with a theta scheme in a finite horizon, which transforms the abstract problem into the problem of solving the positive dominant eigenvalue of the next-generation matrix. This leads to a corresponding threshold R0,n . Using the spectral approximation theory, we obtain that R0,n → R0 as n → +∞. Some numerical simulations are provided to certify the theoretical results.

A model of HBV infection with intervention strategies: dynamics analysis and numerical simulations.

In this paper, we analyze the effect of environment noise on the transmission dynamics of a stochastic hepatitis B virus (HBV) infection model with intervention strategies. By using the Markov semigroups theory, we define the stochastic basic reproduction number and find it can be used to govern disease extinction or persistence. When it is less than one, under a mild extra condition, the stochastic system has a disease-free equilibrium and the disease is predicted to die out with probability one. When it is greater than one, under mild extra conditions, the model admits a stationary distribution which means the persistence of the disease. Thus, we observe that larger intensity of noise (resulting in a smaller stochastic basic reproduction number) can suppress the emergence of hepatitis B outbreak. Numerical simulations are also carried out to investigate the influence of information intervention strategies that may change individual behavior and protect the susceptible from infection. Our analysis shows that the environmental noise can greatly a ect the long-term behavior of the system, highlighting the importance of the role of intervention strategies in the control of hepatitis B.

Markovian switching for near-optimal control of a stochastic SIV epidemic model.

As it is known that environmental perturbation is a key component of epidemic models, and Markov process reveals how the noise affects epidemic systems. The paper introduces Markov chain into a stochastic susceptible-infected-vaccination(SIV) epidemic model composed of vaccination and saturated treatment to analyze the near-optimal control. Based on Pontryagin stochastic maximum principle, the paper gives adequate and all necessary conditions for near-optimal control. Numerical simulations are presented to display the theoretical results and verify the effect of treatment control on epidemic diseases.

Value of CNRIP1 promoter methylation in colorectal cancer screening and prognosis assessment and its influence on the activity of cancer cells.

INTRODUCTION: The aim of the study was to investigate the effect of CNRIP1 promoter methylation on the proliferative, invasive and migration potential of colorectal cancer cells, including its potential use for the early detection and prognostic assessment of colorectal cancer. MATERIAL AND METHODS: Quantitative methylation-specific PCR (qMSP) was used to detect the methylation status of the CNRIP1 promoter region in peripheral blood samples drawn from patients with colorectal adenocarcinoma, benign colorectal adenoma, and matched healthy controls. Putative CpG methylation sites were then pyrosequenced. We subsequently suppressed CNRIP1 methylation within colon cancer cells via treatment with 5-azacytidine and overexpressed colon cancer cells by transfection with a CNRIP1-overexpression pcDNA3.0 plasmid. Thereafter, the CNRIP1 methylation status and mRNA and protein expressions levels were determined. Finally, the proliferative, invasive and migration abilities of cell lines were determined with the CCK-8 and Transwell cell assays. RESULTS: There were differences in the methylation status at loci 2216, 2226, 2231, 2245, and 2254 within the promoter region of CNRIP1 between patients with colorectal adenocarcinoma, colorectal adenoma, and healthy volunteers. The methylation status of CpG sequence 2245 significantly correlated with tumor diameter, invasion depth, TNM stage, grade, and lymph node metastasis (p < 0.05). The proliferative, invasive and migration abilities of colon cancer cells treated with 5-azaC or transfected with a CNRIP1-overexpression plasmid were significantly impaired relative to negative controls (p < 0.05). CONCLUSIONS: The methylation status at locus 2245 within the CNRIP1 promoter region has potential value for the early detection and prognostic evaluation of colorectal cancers. Demethylation of the CNRIP1 promoter or overexpression of CNRIP1 can reduce the proliferative and migration abilities of colon cancer cells.

Inhibition of Nonsmall Cell Lung Cancer Cell Migration by Protein Arginine Methyltransferase 1-small Hairpin RNA Through Inhibiting Epithelial-mesenchymal Transition, Extracellular Matrix Degradation, and Src Phosphorylation In Vitro.

BACKGROUND: Protein arginine methyltransferases 1 (PRMT1) is over-expressed in a variety of cancers, including lung cancer, and is correlated with a poor prognosis of tumor development. This study aimed to investigate the role of PRMT1 in nonsmall cell lung cancer (NSCLC) migration in vitro. METHODS: In this study, PRMT1 expression in the NSCLC cell line A549 was silenced using lentiviral vector-mediated short hairpin RNAs. Cell migration was measured using both scratch wound healing and transwell cell migration assays. The mRNA expression levels of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 1, 2 (TIMP1, 2) were measured using quantitative real-time reverse transcription-polymerase chain reaction. The expression levels of protein markers for epithelial-mesenchymal transition (EMT) (E-cadherin, N-cadherin), focal adhesion kinase (FAK), Src, AKT, and their corresponding phosphorylated states were detected by Western blot. RESULTS: Cell migration was significantly inhibited in the PRMT1 silenced group compared to the control group. The mRNA expression of MMP-2 decreased while TIMP1 and TIMP2 increased significantly. E-cadherin mRNA expression also increased while N-cadherin decreased. Only phosphorylated Src levels decreased in the silenced group while FAK or AKT remained unchanged. CONCLUSIONS: PRMT1-small hairpin RNA inhibits the migration abilities of NSCLC A549 cells by inhibiting EMT, extracellular matrix degradation, and Src phosphorylation in vitro.

Expansion of NK cells by engineered K562 cells co-expressing 4-1BBL and mMICA, combined with soluble IL-21.

NK cells hold promise for protecting hosts from cancer and pathogen infection through direct killing and expressing immune-regulatory cytokines. In our study, a genetically modified K562 cell line with surface expression of 4-1BBL and MICA was constructed to expand functional NK cells in vitro for further adoptive immunotherapy against cancer. After a long-term up to 21 day co-culture with newly isolated peripheral blood mononuclear cells (PBMCs) in the presence of soluble IL-21 (sIL-21), notable increase in proportion of expanded NK cells was observed, especially the CD56(bright)CD16(+) subset. Apparent up-regulation of activating receptors CD38, CD69 and NKG2D was detected on expanded NK cells, so did inhibitory receptor CD94; the cytotoxicity of expanded NK cells against target tumor cells exceeded that of NK cells within fresh PBMCs. The intracellular staining showed expanded NK cells produced immune-regulatory IFN-γ. Taken together, we expanded NK cells with significant up-regulation of activating NKG2D and moderate enhancement of cytotoxicity, with IFN-γ producing ability and a more heterogeneous population of NK cells. These findings provide a novel perspective on expanding NK cells in vitro for further biology study and adoptive immunotherapy of NK cells against cancer.

Role of unfolded protein response in affecting osteoblast differentiation induced by fluoride.

The objective of this study was to determine the expression of classic bone markers and unfolded protein response (UPR) signaling factors through MC3T3-E1 cells exposed to varying concentrations of fluoride. Excessive fluoride exposure caused the skeletal disease. During this process, osteoblasts played a critical role in the advanced skeletal fluorosis. Recent literature showed that endoplasmic reticulum (ER) stress and UPR were involved in numerous aspects of bone biology. Our results indicated that co-exposure of low-dose fluoride and mineral induction medium stimulated the expression of alkaline phosphatase, runt-related transcription factor 2 (Runx2), and osterix in MC3T3-E1 cells. Accordingly, the expression of double-stranded RNA-activated protein kinase (PKR)-like ER kinase, activating transcription factor 6, and X-box binding protein 1 also increased under the same fluoride exposure condition. The upregulation of three UPR factors was similar with osteogenic differentiation markers and transcription factors, which implied the relation between osteoblast differentiation and UPR pathways. Moreover, the role of UPR affecting osteoblast differentiation was investigated by decreasing the expression of binding immunoglobulin protein (BiP) mRNA through small interfering RNA (siRNA) technique. BiP knockdown led to suppress activation of UPR pathways. The deletion of BiP expression hardly stimulated the osteogenic cells differentiation but inhibited cell function under fluoride and mineralization induction exposure. In conclusion, fluoride had dual effect on osteogenic action. The UPR possibly involved in the mechanism of osteoblasts differentiation induced by fluoride.

Role of endoplasmic reticulum stress in aberrant activation of fluoride-treated osteoblasts.

The aberrant activation of osteoblasts in the early stage is one of the critical steps during the pathogenesis of skeletal fluorosis. The endoplasmic reticulum (ER) stresses and unfolded protein response (UPR) are initiated to alleviate the accumulation of unfolded proteins against cell injury. The previous researches had demonstrated that fluoride induced ER stress in other cells or tissues. In this study, we determined the ER stress and UPR to investigate their roles in aberrant activation of fluoride-treated osteoblasts. The gene expression of bone markers and UPR factors in MC3T3-E1 cells treated with varying doses of fluoride administration was analyzed. Meantime, levels of glutathione and glutathione disulfide were tested by the ultraperformance liquid chromatography-tandem mass spectrometry applications. Our results indicated that a certain dose and period of fluoride administration induced cell proliferation and differentiation, and Runx2 was involved in the regulation of osteoblastic differentiation of MC3T3-E1 cells. Increase trend of Runx2 expression was consistent with change of marker of ER stress. Fluoride caused ER stress and stimulated UPR during the process of osteoblast maturation, while oxidative stress was also active in the occurrence of ER stress. These data indicated that ER stress and UPR were possibly involved in the action of fluoride on osteoblasts.

Effect of fluoride on insulin level of rats and insulin receptor expression in the MC3T3-E1 cells.

Studies on the role of insulin and insulin receptor (InsR) in the process of skeletal fluorosis, especially in osteogenic function, are rare. We evaluated the effect of increasing F⁻ doses on the marker of bone formation, serum insulin level and pancreatic secretion changes in vivo and mRNA expression of InsR and osteocalcin (OCN) in vitro. Wistar rats (n = 50) were divided into two groups, i.e. a control group and fluoride group. The fluoride groups were treated with fluoride by drinking tap water containing 100 mg F⁻/L. The fluoride ion-selective electrode measured the fluoride concentrations of femurs. The alkaline phosphatase (ALP), OCN, insulin and glucagon of serum were tested to observe the effect of fluoride action on them. Meantime, the pancreas pathological morphometry analysis via ß cells stained by aldehyde fuchsin showed the action of fluoride on pancreas secretion. MC3T3-E1 cells (derived from newborn mouse calvaria) were exposed to varying concentrations and periods of fluoride. The mRNA expression of InsR and OCN was quantified with real-time PCR. Results showed that 1-year fluoride treatment obviously stimulated ALP activity and OCN level along with increase of bone fluoride concentration of rats, which indicated that fluoride obviously stimulated osteogenic action of rats. In vitro study, the dual effect of fluoride on osteoblast function is shown. On the other hand, there was a significant increase of serum insulin level and a general decrease of glucagon level, and the histomorphometry analysis indicated an elevated insulin-positive area and increase in islet size in rats treated with fluoride for 1 year. In addition, fluoride obviously facilitated the mRNA expression of InsR in vitro. To sum up, there existed a close relationship between insulin secretion and fluoride treatment. The insulin signal pathway might be involved in the underlying occurrence or development of skeletal fluorosis.

Comparative proteomic analysis in left ventricular remodeling following myocardial infarction in rats.

OBJECTIVE: Left ventricular remodeling (LVR) following myocardial infarction (MI) is a key pathophysiological process in which MI develops into heart failure. The exact mechanism of LVR remains unclear. We performed differential proteomic analysis on the myocardia of rats with LVR after MI, to explore the mechanism of ventricular remodeling after MI. METHODS: In the LVR group (n = 12), after the anterior descending coronary artery was ligated, the rats were fed for four weeks before the LVR models were established. Rats in the sham-operated group (n = 11) underwent thread-drawing without ligation. The hemodynamic parameters, pathological findings, and proteomics were compared between the two groups. RESULTS: In the LVR group, the left ventricular end-diastolic pressure increased, the maximal left ventricular pressure increase/decrease ratio decreased significantly, and the left ventricular systolic pressure decreased. H-E staining and Masson staining of cardiac muscle tissues of the LVR group showed myocytolysis, disarray, and collagen proliferation. Twenty-one differentially expressed proteins were detected by proteomic analysis. We validated two proteins using western blot analysis. The differentially expressed proteins could be divided into six categories: energy metabolism-related proteins, cytoskeletal proteins, protein synthesis-related proteins, channel proteins, anti-oxidation- related proteins, and immune-related proteins. CONCLUSION: These differentially expressed proteins might play key roles in LVR following MI.