Prediction of failure mechanisms in concrete is a fairly complex task due to heterogeneous concrete microstructure, localization process triggered by cracks, multiple crack interactions during their growth and coalescence, and different dissipative mechanisms in a fracture process zone prior to localized failure and in a localization zone during the failure. None of the currently used phenomenological models can represent the full set of 3D failure modes. This work presents an attempt to solve this with the 3D meso-scale model based on discrete lattice approach. In particular we show that we can capture such complexities at the meso-scale, which is able to represent microcracks in fracture process zone along with the localized failure represented in terms of embedded strong discontinuity and accompanied with softening constitutive law. The model can also successfully simulate salient features of concrete response, such as order of magnitude of reduction in strength in uniaxial tension versus compression, strength increase in biaxial loading or hydrostatic tension. Moreover, macro-scale representation of failure surfaces obtained with presented model for different loading programs confirms the need for failure concrete criterion of multi-surface kind. Part I of this work presents the proposed meso-scale based on extensive number of numerical simulations with multiple realizations of different concrete specimens, along as the optimal deterministic fit for several common concrete failure models. The ultimate interest of the work is to provide detailed data set for different failure modes which can be used for identification of probability distribution of material parameters for different criteria. Such task is carried in Part II of this work. c
p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC min or APC min /PAK1 À/À mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six-to 8-week-old PAK1 À/À and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC min mice. IHC revealed that PAK1 deletion reduced p-AKT, b-catenin, and c-Myc expression in APC min adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked b-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.
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