Parameter selection for model updating with global sensitivity analysis

National Science Foundation of China (NSFC) under Grant No. 11372084 Sem PDF conforme despacho.The problem of selecting parameters for stochastic model updating is one that has been studied for decades, yet no method exists that guarantees the ‘correct’ choice. In this paper, a method is formulated based on global sensitivity analysis using a new evaluation function and a composite sensitivity index that discriminates explicitly between sets of parameters with correctly-modelled and erroneous statistics. The method is applied successfully to simulated data for a pin-jointed truss structure model in two studies, for the cases of independent and correlated parameters respectively. Finally, experimental validation of the method is carried out on a frame structure with uncertainty in the position of two masses. The statistics of mass positions are confirmed by the proposed method to be correctly modelled using a Kriging surrogate.authorsversionpublishe

Requisite Roles of A 2A Receptors, Nitric Oxide, and K ATP Channels in Retinal Arteriolar Dilation in Response to Adenosine

PURPOSE. Adenosine is a potent vasodilator of retinal microvessels and is implicated to be a major regulator of retinal blood flow during metabolic stress. However, the receptor subtypes and the underlying signaling mechanism responsible for the dilation of retinal microvessels in response to adenosine remain unclear. In the present study, the roles of specific adenosine receptor subtypes, nitric oxide (NO), and adenosine triphosphate (ATP)-sensitive K ϩ (K ATP ) channels in adenosineinduced dilation of retinal arterioles in vitro were examined. METHODS. Porcine second-order retinal arterioles (40 -70 m in internal diameter) were isolated, cannulated, and pressurized to 55 cmH 2 O luminal pressure without flow. Diameter changes in response to agonists were recorded by using videomicroscopic techniques. RESULTS. All vessels exhibited basal tone and dilated dose dependently in reaction to adenosine, N 6 -cyclopentyladenosine (an adenosine A 1 receptor agonist), and 2-[p-(2-carboxyethyl)]phenylethyl-amino-5Ј-N-ethylcarboxamidoadenosine (CGS21680; an adenosine A 2A receptor agonist). These responses were not altered by the selective adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but were significantly attenuated by the selective adenosine A 2A receptor antagonist 4-(2-{7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a] [1,3,5]triazin-5-ylamino}ethyl)phenol. Blockade of NO synthase, but not of cyclooxygenase or cytochrome P-450 epoxygenase, significantly attenuated the vasodilations in response to adenosine and CGS21680. The residual vasodilative reactions to both agonists was nearly abolished by the K ATP channel inhibitor glibenclamide. CONCLUSIONS. These data suggest that adenosine evokes retinal arteriolar dilation via activation of A 2A receptors and subsequent production of NO and opening of K ATP channels. A better understanding of the fundamental signaling pathways responsible for adenosine-induced dilation of retinal arterioles may help shed light on the possible mechanisms contributing to impaired retinal blood flow regulation in patients after retinal ischemia. (Invest Ophthalmol Vis Sci. 2005;46:2113-211

Identification of biomarkers for the diagnosis of chronic kidney disease (CKD) with non-alcoholic fatty liver disease (NAFLD) by bioinformatics analysis and machine learning

BackgroundChronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) are closely related to immune and inflammatory pathways. This study aimed to explore the diagnostic markers for CKD patients with NAFLD.MethodsCKD and NAFLD microarray data sets were screened from the GEO database and analyzed the differentially expressed genes (DEGs) in GSE10495 of CKD date set. Weighted Gene Co-Expression Network Analysis (WGCNA) method was used to construct gene coexpression networks and identify functional modules of NAFLD in GSE89632 date set. Then obtaining NAFLD-related share genes by intersecting DEGs of CKD and modular genes of NAFLD. Then functional enrichment analysis of NAFLD-related share genes was performed. The NAFLD-related hub genes come from intersection of cytoscape software and machine learning. ROC curves were used to examine the diagnostic value of NAFLD related hub genes in the CKD data sets and GSE89632 date set of NAFLD. CIBERSORTx was also used to explore the immune landscape in GSE104954, and the correlation between immune infiltration and hub genes expression was investigated.ResultsA total of 45 NAFLD-related share genes were obtained, and 4 were NAFLD-related hub genes. Enrichment analysis showed that the NAFLD-related share genes were significantly enriched in immune-related pathways, programmed cell death, and inflammatory response. ROC curve confirmed 4 NAFLD-related hub genes in CKD training set GSE104954 and other validation sets. Then they were used as diagnostic markers for CKD. Interestingly, these 4 diagnostic markers of CKD also showed good diagnostic value in the NAFLD date set GSE89632, so these genes may be important targets of NAFLD in the development of CKD. The expression levels of the 4 diagnostic markers for CKD were significantly correlated with the infiltration of immune cells.Conclusion4 NAFLD-related genes (DUSP1, NR4A1, FOSB, ZFP36) were identified as diagnostic markers in CKD patients with NAFLD. Our study may provide diagnostic markers and therapeutic targets for CKD patients with NAFLD

Divergent Roles of Nitric Oxide and Rho Kinase in Vasomotor Regulation of Human Retinal Arterioles

Isolated and pressurized human retinal arterioles in vitro dilated to bradykinin, adenosine, and increased flow, in part through nitric oxide synthase activation, whereas Rho kinase activation mediated myogenic tone and endothelin-1–induced vasoconstriction. Similarities in vasoreactivity and underlying signaling mechanisms were demonstrated between human and porcine retinal arterioles, supporting the latter as a viable experimental model of the human retinal microcirculation

A Rapid Self-Assembly Peptide Hydrogel for Recruitment and Activation of Immune Cells

Self-assembly peptide nanotechnology has attracted much attention due to its regular and orderly structure and diverse functions. Most of the existing self-assembly peptides can form aggregates with specific structures only under specific conditions and their assembly time is relatively long. They have good biocompatibility but no immunogenicity. To optimize it, a self-assembly peptide named DRF3 was designed. It contains a hydrophilic and hydrophobic surface, using two N-terminal arginines, leucine, and two c-terminal aspartate and glutamic acid. Meanwhile, the c-terminal of the peptide was amidated, so that peptide segments were interconnected to increase diversity. Its characterization, biocompatibility, controlled release effect on antigen, immune cell recruitment ability, and antitumor properties were examined here. Congo red/aniline blue staining revealed that peptide hydrogel DRF3 could be immediately gelled in PBS. The stable β-sheet secondary structure of DRF3 was confirmed by circular dichroism spectrum and IR spectra. The observation results of cryo-scanning electron microscopy, transmission electron microscopy, and atomic force microscopy demonstrated that DRF3 formed nanotubule-like and vesicular structures in PBS, and these structures interlaced with each other to form ordered three-dimensional nanofiber structures. Meanwhile, DRF3 showed excellent biocompatibility, could sustainably and slowly release antigens, recruit dendritic cells and promote the maturation of dendritic cells (DCs) in vitro. In addition, DRF3 has a strong inhibitory effect on clear renal cell carcinoma (786-0). These results provide a reliable basis for the application of peptide hydrogels in biomedical and preclinical trials

Acute Retinal Ischemia Inhibits Endothelium-Dependent Nitric Oxide–Mediated Dilation of Retinal Arterioles via Enhanced Superoxide Production

In this report it is demonstrated that retinal ischemia elicited by 90-minute elevation of intraocular pressure impairs endothelium-dependent nitric oxide-mediated dilation of isolated porcine retinal arterioles. The inhibitory mechanism of retinal ischemia involves enhanced levels of superoxide in arterioles