the larger cations tetramethylammonium, tetraethylammonium, or N-methyl-D-glucamine (Figure 1E). This size-selective permeability increase is characteristic of claudin-2 channel activity (14-16, 48-50), but does not exclude the possibility that other cation-selective pore-forming claudins, e.g., claudin-15 (10, 13, 22), contribute to IL-13-induced barrier loss in vivo. We therefore asked if claudin-2 was required for IL-13-induced barrier loss. Prior to IL-13 treatment, paracellular permeability was similar in Cldn2 +/+ and Cldn2-/mice, consistent with limited claudin-2 expression in adults. IL-13 treatment was not, however, able to increase paracellular permeability of small cations, including Na + and methylamine in Cldn2-/mice (Figure 1F). Claudin-2 is therefore necessary for IL-13-induced increases in intestinal pore pathway permeability. In order to determine if claudin-2 upregulation is sufficient to mediate the effects of IL-13 on intestinal cation permeability, transgenic mice expressing GFP-tagged mouse claudin-2 from the intestinal epithelium-specific villin (Vil1) promoter (Cldn2 Tg) were characterized (29). Total claudin-2 expression (the sum of endogenous and GFP-claudin-2) in these Cldn2 Tg mice was similar in distribution (Figure 1G) to that of IL-13-treated Cldn2 +/+ mice (Figure 1B) and increased 3.3-fold relative to Cldn2 +/+ mice that did not receive IL-13 (Figure 1, H and I). Moreover, transgenic GFPclaudin-2 expression selectively increased paracellular permeability of Na + , methylamine, and, to a lesser extent, ethylamine, in a manner that recapitulated the effect of IL-13 on Cldn2 +/+ mice (Figure 1J). Claudin-2 is, therefore, both necessary and sufficient to mediate IL-13-induced barrier loss in vivo. Transgenic claudin-2 expression exacerbates immune-mediated colitis. We have found that severity and duration of infectious colitis are reduced in these GFP-Cldn2 Tg mice (29). A study of similar transgenic mice expressing human claudin-2 from the same Vil1 promoter demonstrated that claudin-2 overexpression was also protective in DSS-induced, chemical colitis (41). Conversely, claudin-2 knockout exacerbated infectious and chemical colitis (29, 42). These data suggest that claudin-2-mediated pore pathway permeability increases may be adaptive, i.e., beneficial in IBD. To test this hypothesis, we compared severity of experimental IBD in immunodeficient Cldn2 Tg Rag1-/and Cldn2 +/+ Rag1-/mice using the well-established T cell transfer model (33, 51). Unexpectedly, disease was significantly more severe in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice. This was demonstrated by more extensive weight loss (Figure 2A) and greater disease activity (Figure 2B). Consistent with increased disease severity, leak (macromolecular) and unrestricted (epithelial damage) pathway permeabilities, measured as 4-kDa and 70-kDa dextran flux, respectively, were markedly greater in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice (Figure 2C and ref. 29). Colitis was associated with increased claudin-2 exp...

No abstract

Applying the concept of cluster entropy, we demonstrate that the primary P-to-s (Ps) conversions originating from the well-recognized seismological boundaries (Moho, 410 km, and 660 km depth interfaces) in Earth's interior and multiple refl ections (reverberations) between the surface and the Moho-the prominent crust-mantle boundary of Earth-can be unambiguously identifi ed. Their attendant information dimension can act as a discriminant. Documentation of shallow mantle stratifi cation at depths ~150-300 km (L/X layers) using Ps signals is scarce and is sometimes attributed to their weak registration in the seismograms together with interference by reverberations from shallow structure. The slopes of best fi ts to mean cluster information dimension (as function of epicentral distance) of Ps signals from target boundaries such as the Moho, 410 km, and L/X discontinuities are consistently gentle with a slight negative character. In contrast, those related to multiples show a steep positive behavior. This opposite nature can potentially discriminate between reverberations and direct converted waves, even when they tend to arrive in overlapping time windows. Our approach thus enables unequivocal identifi cation of shallow mantle layering from Ps data recorded at diverse tectonic provenances of wide antiquity.