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Background Internal ribosome entry sites (IRESs) allow the translation of a transcript independent of its cap structure. They are distributed in some viruses and cellular RNA. The element is applied in dual gene expression in a single vector. Although it appears the lower efficiency of IRES-mediated translation than that of cap-dependent translation, it is with the crucial needs to know the precise differences in translational efficacy between upstream cistrons (cap-dependent) and downstream cistrons (IRES-mediate, cap-independent) before applying the bicistronic vector in biomedical applications. Material and methods This study aimed to provide real examples and showed the precise differences for translational efficiency dependent upon target gene locations. We generated various bicistronic constructs with quantifiable reporter genes as upstream and downstream cistrons of the encephalomyocarditis virus (EMCV) IRES to precisely evaluate the efficacy of IRES-mediated translation in mammalian cells. Results There was no significant difference in protein production when the reporter gene was cloned as an upstream cistron. However, lower levels of protein production were obtained when the reporter gene was located downstream of the IRES. Moreover, in the presence of an upstream cistron, a markedly reduced level of protein production was observed. Conclusion Our findings demonstrate the version of the EMCV IRES that is provided in many commercial vectors is relatively less efficient than cap-dependent translation and provide valuable information regarding the utilization of IRES to facilitate the expression of more than one protein from a transcript.

Interleukin (IL)-17 and the cells that produce it within the tumor microenvironment appear to promote tumor development and are associated with survival in cancer patients. Here we investigated the role of the IL-17/IL-17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (γmIL-17) treatment significantly increased proliferation of mouse B16F10 cells and human A375 and A2058 cells. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the γmIL-17-elicited cell proliferation, migration, and invasion, and significantly reduced vascular endothelial growth factor and matrix metalloproteinase production. Remarkably, knockdown of IL-17RA led to a significantly decreased capability of B16F10 cells to form tumors in vivo, similar to that in IL-17-deficient mice. Finally, local application of an adenovirus delivering a shRNA against IL-17RA mRNA not only significantly suppressed tumor development, but also enhanced antitumor immunity by increasing the interferon γ-expressing T cells and not T regulatory cells. Our results highlight the critical role of the IL-17/IL-17RA pathway in tumor progression and imply that targeting IL-17RA represents a promising therapeutic strategy.

We study group formation in the spatial public goods game with continuous strategies. An active group will become inactive with high (low) probability if the collective contribution is below (above) a threshold value. Meanwhile, an inactive group recovers to be active with some probability. We have found that the cooperation level and the average payoff of players are maximized at moderate values of the threshold and the recovery rate. Spatial distributions of strategies and active groups are plotted to understand the evolution of cooperation.

In this paper, we introduce the swarm intelligence methods into the evolutionary dynamics, and have studied the impact of swarm intelligent algorithm on the evolution of cooperation among selfish individuals in the continuous version of spatial public goods games (PGG). We update an individual’s strategy according to the memory which records the most successful individual strategy in the past (referred to as its personal best strategy) as well as the knowledge of the best current strategy found by its nearest neighbors (referred to as the neighborhood best strategy). Through extensive simulations, we find that the introduction of swarm intelligence into PGG can promote cooperation strongly. Other pertinent quantities such as the time evolution of cooperator density, the spatial distribution of strategies and the updated velocities are also investigated.

The presence and clinical significance of interleukin (IL)-17 and IL-17-expressing cells have recently been studied in several types of cancer, but their correlation to tumor development remains controversial. Additionally, the contribution of peripheral IL-17-expressing cells to head and neck cancer (HNC) progression is still poorly understood. We collected peripheral blood from healthy donors and HNC patients to isolate PBMCs. The percentages of IL-17-expressing cells and the production of inflammatory cytokines in PBMCs were measured to determine their association with clinical outcomes and overall survival in HNC. We evaluated the effect and potential mechanism of IL-17 on human oral squamous carcinomas in vitro using exogenous IL-17 stimulation. In comparison to healthy donors, the PBMCs of HNC patients have a significant accumulation of IL-17-expressing T cells and their frequencies were positively correlated with the disease stage. A significantly higher production of PBMC IL-17, TGF-β and IL-21 and plasma VEGF-A were found in HNC patients. Importantly, the 5-years overall survival of HNC patients with a higher percentage of IL-17-expressing cells is significantly decreased. Furthermore, the addition of IL-17 appeared to promote human oral squamous carcinoma cell proliferation via the production of IL-6 and VEGF-A. Our findings suggest that IL-17 has the potential to mediate pro-tumor immunity in the HNC tumor microenvironment. Enhanced IL-17-expressing cells, including Th17 and Tc17 cells, in the peripheral blood could be a significant predictor of a poor prognosis for HNC patients.

An interesting phenomenon is often observed in realistic systems. In the process of games, if the expected payoff from game interactions is not achieved, players would refuse to participate in the games. Inspired by this fact, we propose an aspiration-induced dormant mechanism, in which players quit the games and become dormant if their payoffs are less than the aspiration level. After a dormant period, they continue to play the game with others. Our results indicate an intermediate aspiration value, leading to the highest cooperation level in the spatial prisoner’s dilemma games. The effects of the dormant period are also studied.

Migration plays an important role in the evolution of cooperation. Previous studies concerning mobile population often assumed that all agents move with the identical velocity. In this paper, we propose a payoff-driven migration in which the velocity of an agent depends on his/her payoff. A parameter α is introduced to adjust the influence of payoff, when α = 0 means that agents all move with the identical velocity while α > 0 means that the lower the payoff is, the faster the moving speed is, and vice versa. For the prisoner’s dilemma game, we find that in comparison with the case that agents all move with the same speed, cooperation could be promoted strongly when payoff-dependent velocity is considered. Remarkably, the cooperation level is not a monotonic function of α , and there exists an optimal value of α which can lead to the maximum cooperation level. For the snowdrift game, the cooperation level increases with α .

Asthma is the result of chronic inflammation of the airways which subsequently results in airway hyper-responsiveness and airflow obstruction. It has been shown that an elicited expression of acidic mammalian chitinase (AMCase) may be involved in the pathogenesis of asthma. Our recent study has demonstrated that the specific suppression of elevated AMCase leads to reduced eosinophilia and Th2-mediated immune responses in an ovalbumin (OVA)-sensitized mouse model of allergic asthma. In the current study, we show that the elicited expression of AMCase in the lung tissues of both ovalbumin- and Der P2-induced allergic asthma mouse models. The effects of allergic mediated molecules on AMCase expression were evaluated by utilizing promoter assay in the lung cells. In fact, the exposure of chitin, a polymerized sugar and the fundamental component of the major allergen mite and several of the inflammatory mediators, showed significant enhancement on AMCase expression. Such obtained results contribute to the basis of developing a promising therapeutic strategy for asthma by silencing AMCase expression.

Impact of aspiration is ubiquitous in social and biological disciplines. In this work, we try to explore the impact of such a trait on voluntary prisoners’ dilemma game via a selection parameter w . w = 0 returns the traditional version of random selection. For positive w , the opponent of high payoff will be selected; while negative w means that the partner of low payoff will be chosen. We find that for positive w , cooperation will be greatly promoted in the interval of small b , at variance cooperation is inhibited with large b . For negative w , cooperation is fully restrained, irrespective of b value. It is found that the positive impact of preferential selection is suppressed by the voluntary strategy in prisoner’s dilemma. These observations can be supported by the spatial patterns. Our work may shed light on the emergence and persistence of cooperation with voluntary participation in social dilemma.

Schizophrenia and other psychiatric disorders are generally diagnosed based on a collection of symptoms defined by a combination of an individual's feelings, perceptions, and behaviors. Many of these disorders are characterized by specific cognitive and social deficits. Although it is nearly impossible to recapitulate the full phenotypic spectrum of schizophrenia in mice, mouse models play an indispensable role in understanding the pathogenesis of this disorder and the development of new therapeutics. Genetic mouse models of schizophrenia and mouse behavioral tests provide a feasible approach for elucidating causal relationships between susceptibility gene(s) and schizophrenia-related symptoms. There has been a proliferation of studies characterizing basic behavioral phenotypes in mice. Since there is no way to completely model human psychiatric symptoms in mice, the major role of behavioral tests is to provide insights into underlying affected circuitry and pathophysiology. Given that the recovery of cognitive and social abilities significantly benefits functional outcomes, there has been an increasing interest in characterizing cognitive and social functions in mutant mice; however, these functions are not easy to measure. In this review, a selection of conventional behavioral tasks was briefly described and three specific behavioral tasks aimed at characterizing social communication, attentional function, and choice behavior in mice were highlighted. The choice of specific behavioral tasks during experimental planning should take into consideration a variety of factors, including their validity, reliability, sensitivity, utility, and specificity. Based upon the hypothetical hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathways in the involvement of cognitive and social impairments in schizophrenia, three NMDAR-related compounds/drugs, D-serine, sarcosine, and D-cycloserine, are discussed as an example.

Aim. The objectives of this study were to evaluate an Internet education programme provided to primigravida in the third trimester of pregnancy with the aim of enhancing mothers’ knowledge about newborn care and increasing their maternal confidence. Background. Shorter hospital stays have had an impact on the traditional role of mother–baby nurses in providing education about parenting to their parturient women. Internet education is an efficient way to provide nursing instruction. Design. A randomised controlled trial was used. A total of 118 women receiving prenatal care in a hospital clinic who met study criteria and who consented were assigned randomly to intervention and control groups. The study was conducted at a hospital in Taiwan. Methods. The target population was women at 32–34 weeks gestation, using the Internet on a regular basis. The primigravida were randomly assigned to either the control group (n = 57) or the experimental group (n = 61). Two primary outcome measures were newborn-care knowledge and maternal confidence. Results. The changes in newborn-care knowledge were 7·21 for the experimental group, compared with 1·95 for the control group; the difference between the least-squares means computed by ancova was 5·73 and statistically significant (p

The evolution of strategies in the iterated prisoner's dilemma on scale-free networks is investigated. It is found that the smaller the average degree is, the easier it is to promote cooperation by natural selection. Cooperation on scale-free networks built upon big clustering coefficients is enhanced and maintained at a high level. The introduction of punishment strategy for unsatisfied agents also increases cooperation and improves its persistence on scale-free networks.

Asthma is a chronic airway inflammatory disease that has a high prevalence nowadays, and seeking the means of relieving asthmatic symptoms is now an issue with increased importance. While mesenchymal stem cells have been demonstrated to display immunomodulatory effects, the effect of fetus-type mesenchymal stem cells (MSCs) on asthmatic symptoms in vivo have not been reported to date. Female BALB/c mice at 8 weeks of age were sensitized by ovalbumin, and MSCs derived from Wharton’s jelly of human umbilical cord mesenchymal stem cells (hUCMSCs) were injected into the asthmatic mice. Airway hyper-responsiveness, lung eosinophil infiltration, cytokine level in splenocyte cultures and serum immunoglobulin level were measured. Enzyme-linked immunosorbent assay was used to determine cytokine and immunoglobulin levels. This current study demonstrated that hUCMSCs attenuated both lung lymphocyte and eosinophil infiltration, and significantly decreased the concentration of Th2 cytokines interleukin-5 in splenocyte cultures. Human umbilical cord mesenchymal stem cells have the advantage of being easily harvested non-invasively and are capable of rapid proliferation, therefore an ideal material for stem cell-based immune therapies. The current study showed that fetal-type MSCs were able to suppress asthmatic symptoms efficiently, and its immunomodulatory effect resulted primarily from suppressing the Th2 pathway in the animal model. This study suggested that hUCMSCs could be an ideal candidate for cell-based therapies of asthma.

Background Membrane-bound phospholipid scramblase 1 (PLSCR1) is involved in both lipid trafficking and cell signaling. Previously, we showed that PLSCR1 is overexpressed in many colorectal carcinomas (CRCs). In the present study, we investigated the tumorigenic role of PLSCR1 in CRC and suggest that it is a potential therapeutic target. Methods To identify PLSCR1 as a therapeutic target, we studied the tumorigenic properties of CRC cell lines treated with a monoclonal antibody (NP1) against the N-terminus of PLSCR1 in vitro and in vivo. We also investigated cell cycle status and epidermal growth factor receptor–related pathways and downstream effectors of PLSCR1 after blocking its function with NP1. Results Treating CRC cells with NP1 in vitro and in vivo decreased cell proliferation, anchorage-independent growth, migration, and invasion. Adding NP1 to the CRC cell line HT29 caused arrest at G1/S. Treating HT29 cells with NP1 significantly decreased the expression of cyclin D1 and phosphorylation levels of Src, the adaptor protein Shc, and Erks. The reduced level of cyclin D1 led to an increase in the activated form of the tumor suppressor retinoblastoma protein via dephosphorylation. These actions led to attenuation of tumorigenesis. Conclusions Therefore, PLSCR1 may serve as a potential therapeutic target for CRC.

Introduction: Interleukin 17 (IL-17), correlating with advanced stage or poor prognosis of cancer patients, appears to contribute to tumor progression. Here we demonstrated the presence of IL-17 receptor A (IL-17RA) on the tumor cells directly promoting tumor growth, angiogenesis and metastasis. Methods: B16F10 and its derived IL-17RA deficient melanoma cells were stimulated with recombinant IL-17 (γmIL-17) or subcutaneously implanted into C57BL/6 mice. Cell proliferation, cell invasion, tumor growth, metastasis and angiogensis were monitored and anti-tumor immunity was also assessed. Results: As compared with those in the control B16F10 cells, the γmIL-17 inducing cell proliferation, migration and invasion were significantly reduced in the derived IL-17RA-deficient cells. The tumor growth and metastasis were also apparently reduced in the mice bearing the IL-17RA deficient tumors. In fact, not ony the expression of MMP2 and MMP9 but also the production of VEGF and HGF were reduced both in vitro and in vivo. Additionally, the increased levels of IFNγ+ and Granzyme B+ immune cells as well as the reduced numbers of Tregs and MDSCs appeared in the mice bearing the IL-17RA deficient tumors, indicating the lack of IL-17 enhancing the CTL activity and other anti-tumor immunity. Conclusion: These findings support the hypothesis that IL-17/IL-17RA signaling directly promotes tumor growth as well as recruits MDSCs and Treg cells, resulting in tumor progression. It suggests IL-17RA on tumors as a potential therapeutic target for cancer therapy. Citation Format: Ya-Shan Chen, Chao-Lin Liu, Hui-Shan Chen, Su-Ting Wu, Chia-Rui Shen. Decreased tumor progression by the knockdown of interleukin 17 receoptor A in the B16F10 melanoma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2015-442