TRANSGENE IL-21-ENGINEERED ANTIGEN-SPECIFIC EXOSOME TARGETED T CELL-BASED VACCINE POTENTLY CONVERTS CTL EXHAUSTION IN CHRONIC INFECTION

CD8+ cytotoxic T lymphocytes (CTLs), the potent effector T cells, capable of directly destroying virus-infected cells, correlate with acute viral control and long-term non-progression in virus-mediated infectious diseases, play an important role in controlling viral infections. However, CD8+ CTLs due to persistent viral stimulation showed functional exhaustion in virally induced chronic infections, which expressed inhibitory molecules such as inhibitory programmed death (PD)-1, programmed death ligand (PDL)-1, T-cell Ig and mucin protein-3 (TIM3) and lymphocyte-activation gene 3 (LAG-3), and were functionally exhausted such as defect in effector cytokine IFN- production, lack of cytolytic effect and reduction of recall responses upon the pathogen reencounter. Therefore, CTL exhaustion has become one of the major obstacles for the ineffectiveness of viral control in chronic infectious diseases such as human immunodeficiency virus (HIV)-1. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and HIV-1 Gag-specific Gag-TEXO vaccines inducing therapeutic immunity in B6 mice and converting CTL exhaustion via its CD40L signaling activation of the PI3K-Akt-mTORC1 pathway in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. In AdVOVA-B6 mice, OVA-specific CTLs expressing IL-7R, IL-21R and inhibitory PD-1, PDL-1 and LAG-3 were inflated and functionally exhausted. Cytokine IL-21, a member of the common -chain cytokine family, produced by CD4+ helper T cells, plays an important role in controlling chronic infections. IL-21 promotes CTL activation and survival by activation of the phosphatidylinositol-3 kinase (PI3K) and the mTORC1-regulated T-bet pathway. In this study, we constructed recombinant transgene IL-21-expressing AdVIL-21 by recombinant DNA technology, generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines or the control OVA-TEXO/Null and Gag-TEXO/Null vaccines by infection of OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull without transgene, and assessed their stimulatory immunogenicity in wild-type B6 or AdVOVA-B6 mice, respectively. We demonstrate that both OVA-TEXO/IL-21 and the control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, IL-21-expressing OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs through increasing CTL proliferation and effector cytokine IFN-ɤ expression by 6-fold than the 3-fold in OVA-TEXO/Null-vaccinated AdVOVA-B6 mice, though these two vaccines stimulated comparable OVA-specific responses and immunity against OVA-expressing BL6-10OVA melanoma in B6 mice. In vivo OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-regulated EIF4E and expression of mTORC1-controlled T-bet molecules as well as Ki67 (a protein associated with cell-cycle progression) than the control OVA-TEXO/Null-stimulated CTLs, indicating that enhancement of converting CTL exhaustion in chronic infection by OVA-TEXO/IL-21 vaccination is mostly through the stronger activation of the PI3K-Akt-mTORC1 pathway derived from both its endogenous CD40L and transgenic IL-21 signaling. Importantly, Gag-TEXO/IL21 vaccine also induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for chronic infectious diseases such as HIV-1 infection

Time-dependent adjoint-based optimization of photonic crystals and metamaterials using a stabilized finite element method

In the current research, a time-dependent discrete adjoint algorithm for optimization of electromagnetic problems is developed. The proposed algorithm improves the efficiency for gradient-based optimization. The time-dependent Maxwell equations are discretized using a semi-discrete Petrov-Galerkin method, and time advancement is accomplished with an implicit, second-order backward differentiation formulation (BDF2). Utilizing the developed capability, two gradient-based shape design optimizations are conducted. In the first optimization an optical waveguide is designed with photonic crystals, and in the second an all-dielectric metamaterial is designed. A motivation for optimizing photonic crystals is due to their use as multi-band optical waveguides for telecommunication applications. For this design optimization, to ensure smooth surfaces, Bezier curves are employed to parametrically represent the shape. To reflect the design changes on the mesh, linear elasticity is used to adapt interior mesh points to boundary modifications. The cost function used in this design attempts to shift the band gap of the photonic crystals to desired frequency ranges. Results demonstrate a band gap shift from one single band gap to multiple band gaps is achievable. The motivation for optimizing broadband metamaterials is for their use as dielectric mirrors for applications where high power reflection is required. In this optimization, Hicks-Henne functions are utilized for shape parameterization and linear elasticity used once again for mesh adaptation. The cost function used attempts to widen the bandwidth of the metamaterial over a desired frequency range. Results demonstrate an increase of the full width at half maximum (FWHM) of reflection from 111THz to 303THz

Finite-size analysis of continuous-variable measurement-device-independent quantum key distribution

We study the impact of the finite-size effect on the continuous-variable measurement-device-independent quantum key distribution (CV-MDI QKD) protocol, mainly considering the finite-size effect on the parameter estimation procedure. The central-limit theorem and maximum likelihood estimation theorem are used to estimate the parameters. We also analyze the relationship between the number of exchanged signals and the optimal modulation variance in the protocol. It is proved that when Charlie's position is close to Bob, the CV-MDI QKD protocol has the farthest transmission distance in the finite-size scenario. Finally, we discuss the impact of finite-size effects related to the practical detection in the CV-MDI QKD protocol. The overall results indicate that the finite-size effect has a great influence on the secret key rate of the CV-MDI QKD protocol and should not be ignored.Comment: 9 pages, 9 figure

Moral Hazard Effects of Corporate Bond Guarantee Purchases: Empirical Evidence from China

This study examines corporate bond guarantees by developing a theoretical model that decomposes the overall impact of a guarantee into signalling and incentive effects and presenting empirical evidence based on data from China’s corporate bond market. Our empirical research yields considerable evidence for the effects we posit in the model and provides some important insights into the problems of adverse selection and moral hazard in China’s bond market. The empirical evidence shows that the bond issuer with lower credit rating are more willing to purchase a bond guarantee and guaranteed bonds have a higher issue spread yield than those non-guaranteed bonds, even though both have the same bond credit rating. Our findings suggest that moral hazard would be better than adverse selection to explain the self- selection of bond guarantees. Prior to bond issuance credit rating signal provides a mechanism to mitigate information inequality, while bond guarantees relieve information asymmetry afterwards.&nbsp