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Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

This dissertation examines a number of aspects of the history of the Venetian villa. In particular, it documents Andrea Navagero's influence on the nature of villeggiatura in the sixteenth-century Veneto. Although the initial impetus for this study was the evaluation of Navagero's descriptions of Islamic Spanish gardens and their influence on the Renaissance garden, aspects of his work, letters, and villas have forced a further reevaluation of Venetian villa life and its sources. Among the more significant results of my research on their impact are: a recasting of the early modern Venetian approach to the past, a recognition of a scientific component in villa agriculture, a discussion of the importance of a rustic vocabulary for certain villas, a transmission of the ideal of learned farming to provincial nobles, and a subsequent exercise of villa ideology in the service of the Counter-Reformation in Verona. The powerful image Navagero created of a fruitful and refreshing Moorish landscape did, indeed, reinforce the importance of water within the garden. More importantly, his firm belief that a profusion of ideas about gardens and agriculture offered by these and other sources could be integrated by him and his colleagues into the tradition of villa patronage. In his letters from Spain, Navagero praised the “Moors” gardens and their scientific approach to agriculture. Similarly, while there, Navagero received and recounted news of discoveries in the Americas and carried home to Venice exotic specimens and wonderful tales of the New World. His receptive attitude indicates that Venetian intellectuals were increasingly willing to expand the realm of authorities, mainly the autori antichi, beyond its traditional classical boundaries. In the case of his villas, Navagero's interest in the historical world beyond Greece and Rome supported his transformation of the villa garden into a locus for learned farming. Navagero's adept synthesis of this expanded antique with villa c

The report presents the details of the computational algorithm for a novel three-dimensional variational dynamic analysis approach developed in computational algorithm of impact contact problem based on variational mosaic model and numerical examples. The analysis approach is aimed at solving a variety of stress analysis problems of composite structural parts under the effect of impulsive and impact loads. Some specific applications of the developed analysis are shown on the examples of transverse dynamic bending of simply supported laminated plate and 3D contact analysis for a multi-brick structure under longitudinal and transverse longitudinal rigid body impact. Numerical results clearly show dynamic effects in response of simply supported laminated plate at high rate of transverse dynamic bending. As the rate of transverse dynamic bending decreases the response of simply supported laminated plate reduces to the corresponding benchmark static solution tensile response of 3D woven fabrics. This example shows the capability of the developed computer code to solve 3D dynamic problems for a wide range of dynamic loading rate. Numerical results for the 3D impact contact problem illustrate time variations of the target displacements, strains and stresses as well as the time variations of the projectile displacement and velocity and impact contact pressure obtained from solution of the coupled problem for mechanical system "projectile-target". Considered numerical examples validate applicability and verify accuracy of the developed computational algorithm and computer code.