Renal Thrombotic Microangiopathy in Mice with Combined Deletion of Endocytic Recycling Regulators EHD3 and EHD4

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3–/– mice and assessed renal development and pathology. Ehd3–/– animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3–/– mice and suggested functional compensation, we generated and analyzed Ehd3–/–; Ehd4–/– mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3–24 weeks of age. Detailed analyses of Ehd3–/–; Ehd4–/– kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3–/–; Ehd4–/– mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases

The Overseeing Mother: Revisiting the Frontal-Pose Lady in the Wu Family Shrines in Second Century China

Located in present-day Jiaxiang in Shandong province, the Wu family shrines built during the second century in the Eastern Han dynasty (25–220) were among the best-known works in Chinese art history. Although for centuries scholars have exhaustively studied the pictorial programs, the frontal-pose female image situated on the second floor of the central pavilion carved at the rear wall of the shrines has remained a question. Beginning with the woman’s eyes, this article demonstrates that the image is more than a generic portrait (“hard motif ”), but rather represents “feminine overseeing from above” (“soft motif ”). This synthetic motif combines three different earlier motifs – the frontal-pose hostess enjoying entertainment, the elevated spectator, and the Queen Mother of the West. By creatively fusing the three motifs into one unity, the Jiaxiang artists lent to the frontal-pose lady a unique power: she not only dominated the center of the composition, but also, like a divine being, commanded a unified view of the surroundings on the lofty building, hence echoing the political reality of the empress mother’s “overseeing the court” in the second century during Eastern Han dynasty

Exponential attractors and inertial manifolds for the higher-order nonlinear Kirchhoff-type equation

Volume 4 Issue 11 (November 2016

Assessing Similarity to Existing Drugs to Decide Whether to Continue Drug Development

Developing a drug requires large investments, over many years, with dramatic increases in development costs at later stages. Thus, one wants to make a No Go decision on a compound early, unless evidence continues to suggest that the project will ultimately be successful, so that resources can be focused on the most promising compounds to benefit patients. Instead of predicting the probability of success of a Phase III study, our approach to this decision uses the Phase II study results to assess similarity of the novel compound to existing drugs that are classified by different decision categories, such as a clear Go decision (e.g., a clearly effective drug), a (unfortunately common) Not Sure decision (e.g., a potentially useful but not outstanding drug), and a clear No Go decision (e.g., a clearly not effective drug). We describe how this modeling can be done using both individual and binary endpoints and how results can be combined for several different endpoints. Potential extensions of the method are also discussed

Uniform postglacial slip-rate along the central 600km of the Kunlun Fault (Tibet), from <SUP>26</SUP> Al, <SUP>10</SUP> Be, and <SUP>14</SUP> C dating of riser offsets, and climatic origin of the regional morphology

International audienceLate Pleistocene-Holocene sinistral slip-rates on several segments of the Kunlun Fault in northeastern Tibet have been determined. These determinations are based on the measured displacement of alluvial surfaces whose surface ages were determined by cosmogenic 26 Al and 10 Be dating of quartz pebbles, and by 14 C dating of charcoal. In the west, at three sites along the Xidatan-Dongdatan segment of the fault, near 94°E, terrace riser offsets ranging from 24 to 110m, with cosmogenic ages ranging from ~1800 to ~8200yr, yield a mean left-lateral slip-rate of 11.7+/-1.5mmyr-1 . Field observations indicate minimum offsets of 9-12m this offset, when combined with the long-term slip-rate, indicates that great earthquakes (M ~8) rupture this segment of the fault with a recurrence interval of 800-1000yr. At two sites along the Dongxi-Anyemaqin segment of the fault, near 99°E, terrace riser offsets ranging from 57 to 400 m with 14 C ages ranging from 5400 to 37000yr BP yield a minimum slip-rate of ~10mmyr-1 . At one site, the 1937 January 7, M =7.5 and the penultimate earthquakes produced 4 m of left-slip and 0.4 m of reverse-slip. The maximum recurrence interval of earthquakes with such characteristic slip is thus ~400yr. Farther east, near 100.5°E, along the Maqen segment of the fault, the 180moffset of a lateral moraine, emplaced between the last glacial maximum (20ka) and 11100yr BP, yields a mean slip-rate of 12.5+/-2.5mmyr-1 . The slip-rates are constant, within uncertainty, throughout the 600km of the Kunlun Fault that we studied. The average slip-rate is 11.5+/-2.0mmyr-1 . Extrapolating this rate to the reminder of the fault, we conclude that most (80 per cent) of the 300 morphological offsets measured in the field or on SPOT satellite images post-date the Last Glacial Maximum. Most of the terraces we studied were deposited during the humid period of the Early Holocene Optimum (9-5ka) the formation of younger terraces reflects Late Holocene climate change