Extracellular Transglutaminase 2 Is Catalytically Inactive, but Is Transiently Activated upon Tissue Injury

Transglutaminase 2 (TG2) is a multifunctional mammalian protein with transamidase and signaling properties. Using selective TG2 inhibitors and tagged nucleophilic amine substrates, we show that the majority of extracellular TG2 is inactive under normal physiological conditions in cell culture and in vivo. However, abundant TG2 activity was detected around the wound in a standard cultured fibroblast scratch assay. To demonstrate wounding-induced activation of TG2 in vivo, the toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly(I:C)), was injected in mice to trigger small intestinal injury. Although no TG2 activity was detected in vehicle-treated mice, acute poly(I:C) injury resulted in rapid TG2 activation in the small intestinal mucosa. Our findings provide a new basis for understanding the role of TG2 in physiology and disease

Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2

Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats

Characteristics of debris avalanche deposits inferred from source volume estimate and hummock morphology around Mt. Erciyes, central Turkey

Debris avalanches caused by volcano sector collapse often form characteristic depositional landforms such as hummocks. Sedimentological and geomorphological analyses of debris avalanche deposits (DADs) are crucial to clarify the size, mechanisms, and emplacement of debris avalanches. We describe the morphology of hummocks on the northeastern flank of Mt. Erciyes in Kayseri, central Turkey, likely formed in the late Pleistocene. Using a remotely piloted aircraft system (RPAS) and the structure-from-motion and multi-view stereo (SfM–MVS) photogrammetry, we obtained high-definition digital elevation model (DEM) and orthorectified images of the hummocks to investigate their geometric features. We estimated the source volume of the DAD by reconstructing the topography of the volcano edifice using a satellite-based DEM. We examined the topographic cross sections based on the slopes around the scar regarded as remnant topography. Spatial distribution of hummocks is anomalously concentrated at a certain distance from the source, unlike those that follow the distance–size relationship. The high-definition land surface data by RPAS and SfM revealed that many of the hummocks are aligned toward the flow direction of the debris avalanche, suggesting that the extensional regime of the debris avalanche was dominant. However, some displaced hummocks were also found, indicating that the compressional regime of the flow contributed to the formation of hummocks. These indicate that the flow and emplacement of the avalanche were constrained by the topography. The existing caldera wall forced the initial eastward flow to move northward, and the north-side caldera wall forced the flow into the narrow and steepened outlet valley where the sliding debris underwent a compressional regime, and out into the unconfined terrain where the debris was most likely emplaced on an extensional regime. Also, the estimated volume of 12–15 × 108 m3 gives a mean thickness of 60–75 m, which is much deeper than the reported cases of other DADs. This suggests that the debris avalanche must have flowed further downstream and beyond the current DAD extent. Assessments of the DAD incorporating the topographic constraints can provide further insights into the risk and mitigation of potential disasters in the study area