Rationale: Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown. Objective: To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms. Methods and Results: Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs. Conclusions: The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.

This paper studies the event-triggered receding horizon control (RHC) of continuous-time nonlinearsystems. An integral-type event-triggered mechanism is proposed to save the communicational resource, and a less conservative robustness constraint is introduced to the RHC scheme for compensating the additive disturbance. Based on these formulations, the designed event-triggered algorithm is shown to have better performance on avoiding unnecessary communication. Furthermore, the feasibility of the integral-type event-triggered RHC scheme and the stability of the closed-loop system are rigorously investigated. Several sufficient conditions to guarantee these properties are established, which indicate that a trade-off exists for designing parameters such as the prediction horizon, the disturbance bound, the triggering level, and the contraction rate for the robustness constraint. The effectiveness of the proposed algorithm is illustrated by a numerical example.

No abstract

Ethyl carbamate (EC) is a naturally occurring component in the fermented products, especially the Chinese yellow rice wine. EC has been found showing a potential for carcinogenity and causing food safety problems. This study is to investigate the application of the existing HPLC-FLD method to the analysis of EC in Chinese yellow rice wine, and to validate it for EC analysis with high through-out and applicability in Chinese yellow rice wine sample. The parameters examined in this study were fully evaluated. Results indicated that good linearity was obtained with a correlation coefficient exceeding 0.9990, the limit of detection and quantification was 73.2 and 243.9 lg L )1 , respectively. Recoveries ranged between 98.30% and 101.30%, and the precision of this method was lower than 5% (RSD). The method conducted in this work was successfully applied to determine EC concentration in Chinese yellow rice wine samples from different origins. The negative correlation between EC formation and urea level in yellow rice wine samples is evaluated with the developed HPLC-FLD method.

No abstract

Hypoxia and inflammation often develop concurrently in numerous diseases, and the influence of hypoxia on natural evolution of inflammatory responses is widely accepted. Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory cytokines IL-1β, IL-6, and TNF-α under normoxic and hypoxic conditions. We found that hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ small interfering RNA led to a significant increase in mRNA production and protein secretion of IL-1β and IL-6 in hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and IL-6 in hypoxia. We also found that adrenal hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.

We have fabricated high-T(c) nanoscale superconducting quantum interference devices (nanoSQUIDs) with a hole size of 250 nm × 250 nm based on a 100 nm bridge at 77 K by focused ion beam milling and ion implantation. At 78 K, the curve of the voltage branch became roughly linear and agreed with the Josephson-like behavior. The sample exhibited strong flux flow behavior at temperatures under 76 K. The voltage flux characteristic curves, V -I(mod), of the nanoSQUID at different bias currents at 78 K were observed. Typically, critical currents of 15 µA and peak-to-peak values of the voltage flux transfer function of 3.7 µV were measured. The measured data strongly suggest that the weak link structure could be a superconducting metal with a critical temperature T(c)' smaller than that (T(c)) of other YBa(2)Cu(3)O(7-x) (YBCO) films. This fabrication method of combining a nanobridge and ion implantation can improve the yield of nanojunctions and nanoSQUIDs.

Whether porcine cytokines are induced after pig-to-primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL-6, IFN-γ, IL-1β, and TNF-α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro-inflammatory cytokines (IL-6, IFN-γ, and IL-1β) and chemokines (IL-8, MCP-1, and CXCL2) were upregulated in the both cell types. TNF-α was induced 10-fold in PAECs, but not in PBMCs. Then, we assessed the role of porcine IL-6, IFN-γ, IL-1β, and TNF-α in xenotransplantation using western blotting and real-time PCR. Human umbilical vein endothelial cells (HUVECs) were selected as the target cells. Signaling pathways and downstream genes, such as those related to adhesion, inflammation, and coagulation, and chemokines were investigated. Porcine IL-1β and TNF-α significantly activated NF-κB and P38, and STAT3 was activated by porcine IL-6 in HUVECs. The adhesion genes (E-selectin, VCAM-1, and ICAM-1), inflammatory cytokines (IL-6, IL-1β, and TNF-α), chemokines (MCP-1 and IL-8), and the pro-coagulation gene (tissue factor) were upregulated by porcine IL-1β and TNF-α. Porcine IL-6 increased the expression of ICAM-1, IL-6, MCP-1, and tissue factor, but decreased IL-8 expression slightly. Surprisingly, porcine IFN-γ could not activate STAT1 or regulate the expression of any of the above genes in HUVECs. In conclusion, these findings suggest that porcine IL-6, IL-1β, and TNF-α activate HUVECs and regulate downstream genes expression, which may promote inflammation and coagulation response after xenotransplantation.