Adaptive Backstepping Control for Air-Breathing Hypersonic Vehicles with Input Nonlinearities

This paper addresses the control problem of air-breathing hypersonic vehicles subject to input nonlinearities, aerodynamic uncertainties and flexible modes. An adaptive backstepping controller and a dynamic inverse controller are developed for the altitude subsystem and the velocity subsystem, respectively, where the former eliminates the problem of “explosion of terms” inherent in backstepping control. Moreover, a modified smooth inverse of the dead-zone is proposed to compensate for the dead-zone effects and reduce the computational burden. Based on this smooth inverse, an input nonlinear pre-compensator is designed to handle input saturation and dead-zone nonlinearities, which leads to a simpler control design for the altitude subsystem subject to these two input nonlinearities. It is proved that the proposed controllers can guarantee that all closed-loop signals are bounded and the tracking errors converge to an arbitrarily small residual set. Simulation results are carried out to demonstrate the effectiveness of the proposed control scheme

Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells

Background: We previously showed that co-immunization with a protein antigen and a DNA vaccine coding for the same antigen induces CD40(low) IL-10(high) tolerogenic DCs, which in turn stimulates the expansion of antigenspecific CD4(+)CD25(-)Foxp3(+) regulatory T cells (CD25(-) iTreg). However, it was unclear how to choose the antigen sequence to maximize tolerogenic antigen presentation and, consequently, CD25(-) iTreg induction. Results: In the present study, we demonstrated the requirement of highly antigenic epitopes for CD25(-) iTreg induction. Firstly, we showed that the induction of CD25(-) iTreg by tolerogenic DC can be blocked by anti-MHC-II antibody. Next, both the number and the suppressive activity of CD25(-) iTreg correlated positively with the overt antigenicity of an epitope to activate T cells. Finally, in a mouse model of dermatitis, highly antigenic epitopes derived from a flea allergen not only induced more CD25(-) iTreg, but also more effectively prevented allergenic reaction to the allergen than did weakly antigenic epitopes. Conclusions: Our data thus indicate that efficient induction of CD25- iTreg requires highly antigenic peptide epitopes. This finding suggests that highly antigenic epitopes should be used for efficient induction of CD25- iTreg for clinical applications such as flea allergic dermatitis

Increasing a Robust Antigen-Specific Cytotoxic T Lymphocyte Response by FMDV DNA Vaccination with IL-9 Expressing Construct

Various chemokines and cytokines as adjuvants can be used to improve efficacy of DNA vaccination. In this study, we sought to investigate if a DNA construct expressing IL-9 (designed as proV-IL9) as a molecular adjuvant enhance antigen specific immune responses elicited by the pcD-VP1 DNA vaccination. Mice immunized with pcD-VP1 combined with proV-IL9 developed a strong humoral response. In addition, the coinoculation induced significant higher level of antigen-specific cell proliferation and cytotoxic response. This agreed well with higher expression level of IFN-γ and perforin in CD8+ T cells, but not with IL-17 in these T cells. The results indicate that IL-9 induces the development of IFN-γ-producing CD8+ T cells (Tc1), but not the IL-17-producing CD8+ T cells (Tc17). Up-regulated expressions of BCL-2 and BCL-XL were exhibited in these Tc1 cells, suggesting that IL-9 may trigger antiapoptosis mechanism in these cells. Together, these results demonstrated that IL-9 used as molecular adjuvant could enhance the immunogenicity of DNA vaccination, in augmenting humoral and cellular responses and particularly promoting Tc1 activations. Thus, the IL-9 may be utilized as a potent Tc1 adjuvant for DNA vaccines

Praziquantel Facilitates IFN-γ-Producing CD8+ T Cells (Tc1) and IL-17-Producing CD8+ T Cells (Tc17) Responses to DNA Vaccination in Mice

BACKGROUND: CD8(+) cytotoxic T lymphocytes (CTLs) are crucial for eliminating hepatitis B virus (HBV) infected cells. DNA vaccination, a novel therapeutic strategy for chronic virus infection, has been shown to induce CTL responses. However, accumulated data have shown that CTLs could not be effectively induced by HBV DNA vaccination. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that praziquantel (PZQ), an anti-schistoma drug, could act as an adjuvant to overcome the lack of potent CTL responses by HBV DNA vaccination in mice. PZQ in combination with HBV DNA vaccination augmented the induction of CD8(+) T cell-dependent and HBV-specific delayed hypersensitivity responses (DTH) in C57BL/6 mice. Furthermore, the induced CD8(+) T cells consisted of both Tc1 and Tc17 subtypes. By using IFN-γ knockout (KO) mice and IL-17 KO mice, both cytokines were found to be involved in the DTH. The relevance of these findings to HBV immunization was established in HBsAg transgenic mice, in which PZQ also augmented the induction of HBV-specific Tc1 and Tc17 cells and resulted in reduction of HBsAg positive hepatocytes. Adoptive transfer experiments further showed that PZQ-primed CD8(+) T cells from wild type mice, but not the counterpart from IFN-γ KO or IL-17 KO mice, resulted in elimination of HBsAg positive hepatocytes. CONCLUSIONS/SIGNIFICANCE: Our results suggest that PZQ is an effective adjuvant to facilitate Tc1 and Tc17 responses to HBV DNA vaccination, inducing broad CD8(+) T cell-based immunotherapy that breaks tolerance to HBsAg

Use of Praziquantel as an Adjuvant Enhances Protection and Tc-17 Responses to Killed H5N1 Virus Vaccine in Mice

BACKGROUND: H5N1 is a highly pathogenic influenza A virus, which can cause severe illness or even death in humans. Although the widely used killed vaccines are able to provide some protection against infection via neutralizing antibodies, cytotoxic T-lymphocyte responses that are thought to eradicate viral infections are lacking. METHODOLOGY/PRINCIPAL FINDINGS: Aiming to promote cytotoxic responses against H5N1 infection, we extended our previous finding that praziquantel (PZQ) can act as an adjuvant to induce IL-17-producing CD8(+) T cells (Tc17). We found that a single immunization of 57BL/6 mice with killed viral vaccine plus PZQ induced antigen-specific Tc17 cells, some of which also secreted IFN-γ. The induced Tc17 had cytolytic activities. Induction of these cells was impaired in CD8 knockout (KO) or IFN-γ KO mice, and was even lower in IL-17 KO mice. Importantly, the inoculation of killed vaccine with PZQ significantly reduced virus loads in the lung tissues and prolonged survival. Protection against H5N1 virus infection was obtained by adoptively transferring PZQ-primed wild type CD8(+) T cells and this was more effective than transfer of activated IFN-γ KO or IL-17 KO CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that adding PZQ to killed H5N1 vaccine could promote broad Tc17-mediated cytotoxic T lymphocyte activity, resulting in improved control of highly pathogenic avian influenza virus infection

The Relative Body Weight Gain From Early to Middle Life Adulthood Associated With Later Life Risk of Diabetes: A Nationwide Cohort Study

AimTo determine the effect of decade-based body weight gain from 20 to 50 years of age on later life diabetes risk.Methods35,611 non-diabetic participants aged ≥ 50 years from a well-defined nationwide cohort were followed up for average of 3.6 years, with cardiovascular diseases and cancers at baseline were excluded. Body weight at 20, 30, 40, and 50 years was reported. The overall 30 years and each 10-year weight gain were calculated from the early and middle life. Cox regression models were used to estimate risks of incident diabetes.ResultsAfter 127,745.26 person-years of follow-up, 2,789 incident diabetes were identified (incidence rate, 2.18%) in 25,289 women (mean weight gain 20-50 years, 7.60 kg) and 10,322 men (7.93 kg). Each 10-kg weight gain over the 30 years was significantly associated with a 39.7% increased risk of incident diabetes (95% confidence interval [CI], 1.33-1.47); weight gain from 20-30 years showed a more prominent effect on the risk of developing diabetes before 60 years than that of after 60 years (Hazard ratio, HR = 1.084, 95% CI [1.049-1.121], P <0.0001 vs. 1.015 [0.975-1.056], P = 0.4643; PInteraction=0.0293). It showed a stable effect of the three 10-year intervals weight gain on risk of diabetes after 60 years (HR=1.055, 1.038, 1.043, respectively, all P < 0.0036).ConclusionsThe early life weight gain showed a more prominent effect on developing diabetes before 60 years than after 60 years; however, each-decade weight gain from 20 to 50 years showed a similar effect on risk developing diabetes after 60 years

Study on Injection Molding Process Simulation and Process Parameter Optimization of Automobile Instrument Light Guiding Support

In the present study, Moldflow® software is applied to simulate the injection molding of automobile instrument light guide bracket and optimize the injection gate position. In this regard, Taguchi orthogonal experimental design is adopted, and five processing parameters, the mold temperature, melt temperature, cooling time, packing pressure, and packing time, are considered as the test factors. Moreover, volume shrinkage and warping amount are considered as quality evaluation indices. Then range analysis and variance analysis are carried out to obtain the optimal combination of molding parameters with the volume shrinkage rate and the warpage amount. The grey correlation analysis was used to analyze the test results and obtain the optimal combination of volume shrinkage rate and amount of warping. Based on the performed simulations, it is found that the maximum volume shrinkage rate and the maximum amount of warping in the optimal design are 6.753% and 1.999 mm, respectively. According to the optimal process parameters, the injection molding of the automobile instrument light guide bracket meets the quality requirements

Study of the Influences of Transient Crack Propagation in a Pinion on Time-Varying Mesh Stiffness

Cracks in a cracked gear may further propagate by a tiny length in a very short time for several reasons, such as material fatigue and load fluctuations. In this paper, this dynamic process is defined as transient propagation of cracks. This research aims to calculate the time-varying mesh stiffness of gears when transient propagation of cracks arises, which has not been extensively studied in existing literatures. The transient propagation of cracks is modelled. An improved potential energy method is proposed by incorporating the propagation model into the potential energy method. The improved method can also be utilised to calculate the mesh stiffness of gears when transient propagation of cracks arises. Different transient propagation models are considered to simulate the propagation of cracks in a short amount of time. Different deterioration levels of cracks before transient propagation and different lengths and models of transient propagation are also examined. The variation rules of mesh stiffness caused by the transient propagation of cracks are summarised. The influence of the deterioration level of cracks on mesh stiffness variation when transient propagation arises is obtained. Simulation results show that the proposed method accurately calculates time-varying mesh stiffness when transient propagation of cracks arises. Furthermore, the method improves the monitoring of further propagation of cracks in gears from the perspective of time-varying mesh stiffness