Endothelium in the pharyngeal arches 3, 4 and 6 is derived from the second heart field.

Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium in the pharyngeal arches 1 and 2 is derived from a different source. During the formation of the PAAs 3 - 6, endothelial progenitors in the SHF extend cellular processes toward the pharyngeal endoderm, migrate from the SHF and assemble into a uniform vascular plexus. This plexus then undergoes remodeling, whereby plexus endothelial cells coalesce into a large PAA in each pharyngeal arch. Taken together, our studies establish a platform for investigating cellular and molecular mechanisms regulating PAA formation and alterations that lead to disease

Fibronectin signals through integrin α5β1 to regulate cardiovascular development in a cell type-specific manner.

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in the pharyngeal region may be essential for cardiovascular morphogenesis. To test this hypothesis, we ablated Fn1 using the Isl1(Cre) knock-in strain of mice. Deletion of Fn1 using the Isl1(Cre) strain resulted in defective formation of the 4th pharyngeal arch arteries (PAAs), aberrant development of the cardiac outflow tract (OFT), and ventricular septum defects. To determine the cell types responding to Fn1 signaling during cardiovascular development, we deleted a major Fn1 receptor, integrin α5 using the Isl1(Cre) strain, and observed the same spectrum of abnormalities seen in the Fn1 conditional mutants. Additional conditional mutagenesis studies designed to ablate integrin α5 in distinct cell types within the Isl1(+) tissues and their derivatives, suggested that the expression of integrin α5 in the pharyngeal arch mesoderm, endothelium, surface ectoderm and the neural crest were not required for PAA formation. Our studies suggest that an (as yet unknown) integrin α5-dependent signal extrinsic to the pharyngeal endothelium mediates the formation of the 4th PAAs

Bifurcation of pressurized functionally graded elastomeric hollow cylinders

Various bifurcation behaviors, including asymmetric axial buckling induced by end thrust, bifurcation under external pressure, and eversion without any loading, of a soft circular hollow cylinder (or cylindrical shell) composed of functionally graded incompressible elastomeric material are considered in a unified way. Based on the nonlinear elasticity theory of a deformable continuous body undergoing large deformation and the linearized incremental theory for a superimposed infinitesimal deformation, an efficient approach for buckling analysis is developed and applied to the cylinder subjected to a combination of axial end thrust and internal/external pressure. It is based on the state-space formalism, which naturally avoids the derivatives of instantaneous material constants, enabling a convenient and accurate numerical implementation. Along with the layerwise method, an analytical characteristic equation (i.e. the bifurcation criterion) governing the general asymmetric buckling of the cylinder is derived. Detailed parametric studies are then carried out for a pressurized soft functionally graded hollow cylinder using an incompressible Mooney-Rivlin material model. The effects of material gradient on bifurcation induced either by end thrust or external pressure are discussed through numerical examples. Not only does this study provide an efficient tool for buckling analysis of soft cylinders, some findings that are unique to a functionally graded material are also highlighted. All in all, it is found highly possible to tune the bifurcation behavior of soft elastomeric cylindrical shells by tailoring material composition and/or adjusting the pressures acting on the surfaces of the cylinder

Three-dimensional buckling and free vibration analyses of initially stressed functionally graded graphene reinforced composite cylindrical shell

The buckling and free vibration of initially stressed functionally graded cylindrical shell reinforced with non-uniformly distributed graphene platelets (GPLs) are investigated using the state-space formulation based on three-dimensional elasticity theory. The shell is under an axial initial stress and composed of multilayers with GPLs uniformly dispersed in each individual layer but its weight fraction changing layer-by-layer along the thickness direction. The modified Halpin-Tsai model and rule of mixtures are employed to evaluate the effective elastic properties of the GPL-reinforced shell. Analytical buckling and frequency solutions are obtained for simply supported shells. Numerical results are presented for functionally graded GPL-reinforced cylindrical shells with five GPL dispersion patterns (GPL-UD, GPL-V, GPL-A, GPL-X, and GPL-O). The effects of GPL weight fraction, dispersion pattern, geometry, and size as well as the influence of initial stress on the buckling and free vibration characteristics of the shell are discussed in detail. It is found that the addition of a small amount of GPLs significantly increases the critical buckling stress and natural frequencies. The GPL-X pattern outperforms other patterns for thin composite shells while the uniform pattern GPL-UD works better for thick composite shells

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine.

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related to mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection but did mediate antibody-dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that the SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue to develop a novel bivalent vaccine against both ZIKV and JEV. KEY POINTS: • JEV SA14-14-2 vaccine conferred cross-protection against ZIKV challenge in mice. • T cell immunity rather than antibody mediated the cross-protection. • It provides important information in terms of ZIKV prevention or precaution

Original Article SOD2 rs4880 CT/CC genotype predicts poor survival for Chinese gastric cancer patients received platinum and fluorouracil based adjuvant chemotherapy

Abstract: Adjuvant chemotherapy is a standard therapy for gastric cancer patients, however, treatment response is quite heterogeneous. Molecular biomarkers will be highly valuable to guide the therapy and predict the response and prognosis in these patients. The antioxidant enzymes superoxide dismutase 2 (SOD2) and glutathione S-transferase pi 1 (GSTP1) are involved in oxidative stress and drug detoxification, which modulate the efficacy of anticancer drugs. Here, we investigated the clinical associations of two functional single nucleotide polymorphisms of SOD2 and GSTP1 in stage II-III postoperative gastric cancer patients. SOD2 rs4880 and GSTP1 rs1695 were genotyped in 207 patients received postoperative platinum and fluorouracil based chemotherapy and 304 patients who did not. SOD2 rs4880 CT/CC significantly associated with decreased median overall survival time of 23 months when compared to the TT genotype (mean overall survival time of 65.2 months, P=0.002) only for patients received adjuvant chemotherapy. Stratification analysis showed SOD2 rs4880 C

Cross-Protection Against Four Serotypes of Dengue Virus in Mice Conferred by a Zika DNA Vaccine

Both Zika virus (ZIKV) and four serotypes of dengue virus (DENV1–4) are antigenically related mosquito-borne flaviviruses that co-circulate in overlapping geographic distributions. The considerable amino acid sequence homology and structural similarities between ZIKV and DENV1–4 may be responsible for the complicated immunological cross-reactivity observed for these viruses. Thus, a successful Zika vaccine needs to not only confer protection from ZIKV infection but must also be safe during secondary exposures with other flavivirus, especially DENVs. In this study, we used a Zika DNA vaccine candidate (pV-ZME) expressing the ZIKV premembrane and envelop proteins to immunize BALB/c mice and evaluated the potential cross-reactive immune responses to DENV1–4. We observed that three doses of the pV-ZME vaccine elicited the production of cross-reactive antibodies, cytokines and CD8+ T cell responses and generated cross-protection against DENV1–4. Our results demonstrate a novel approach for design and development of safe Zika and/or dengue vaccines