The transcription factor AP-2ɛ regulates CXCL1 during cartilage development and in osteoarthritis

SummaryObjectiveRecently, the transcription factor AP-2ɛ was shown to be a regulator of hypertrophy in cartilage and to be differentially expressed in osteoarthritis (OA). However, the only known target gene of AP-2ɛ up to date is integrin alpha10. To better characterize the function of AP-2ɛ in cartilage we screened for additional target genes.DesignPromoter analysis, ChIP-assays and electrophoretic mobility shift assay were used to characterize the regulation of a new AP-2ɛ target gene in detail.ResultsIn this study, we determined the chemokine CXCL1, already known to be important in osteoarthritis (OA), as a new target gene of AP-2ɛ. We could confirm that CXCL1 is expressed in chondrocytes and significantly over-expressed in OA-chondrocytes. Transient transfection of chondrocytes with an AP-2ɛ expression construct led to a significant increase of the CXCL1 mRNA level in these cells. We identified three potential AP-2 binding sites within the CXCL1 promoter and performed luciferase assays, indicating that an AP-2 binding motif (AP-2.2) ranging from position −135 to −144bp relative to the translation start is responsive to AP-2ɛ. This result was further addressed by site-directed mutagenesis demonstrating that activation of the CXCL1 promoter by AP-2ɛ is exclusively dependent on AP-2.2. Chromatin immunoprecipitation and electromobility shift assays confirmed the direct binding of AP-2ɛ to the CXCL1 promoter in OA-chondrocytes at this site.ConclusionThese findings revealed CXCL1 as a novel target gene of AP-2ɛ in chondrocytes and support the important role of AP-2ɛ in cartilage

Analytical calculation of the excess current in the OTBK theory

We present an analytical derivation of the excess current in Josephson junctions within the Octavio-Tinkham-Blonder-Klapwijk theory for both symmetric and asymmetric barrier strengths. We confirm the result found numerically by Flensberg et al. for equal barriers [Phys. Rev. B 38, 8707 (1988)], including the prediction of negative excess current for low transparencies, and we generalize it for differing barriers. Our analytical formulae provide for convenient fitting of experimental data, also in the less studied, but practically relevant case of the barrier asymmetry.Comment: 13 pages, 3 figures, submitted to Superconductor Science and Technolog

Infectious Complications of Ventricular Assist Device Use in Children in the US: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs)

Background Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs. Methods Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan–Meier analysis and competing outcomes analysis. Results There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 ± 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 ± 4 vs 14 ± 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008). Conclusions Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection

Overview of Glacial Atlantic Ocean Mapping (GLAMAP 2000)

GLAMAP 2000 presents new reconstructions of the Atlantic's sea surface temperatures (SST) at the Last Glacial Maximum (LGM), defined at both 21,500–18,000 years B.P. (“Last Isotope Maximum”) and 23,000–19,000 years B.P. (maximum glacial sea level low stand and orbital minimum of solar insolation; EPILOG working group; see Mix et al. [2001]). These reconstructions use 275 sediment cores between the North Pole and 60°S with carefully defined chronostratigraphies. Four categories of core quality are distinguished. More than 100 core sections provide a glacial record with subcentennial- to multicentennial-scale resolution. SST estimates are based on a new set of almost 1000 reference samples of modern planktic foraminifera and on improved transfer-function techniques to deduce SST from census counts of microfossils, including radiolarians and diatoms. New proxies also serve to deduce sea ice boundaries. The GLAMAP 2000 SST patterns differ significantly in crucial regions from the CLIMAP [1981] reconstruction and thus are important in providing updated boundary conditions to initiate and validate computational models for climate prediction

The Atlantic Ocean at the last glacial maximum: 1. Objective mapping of the GLAMAP sea-surface conditions

Recent efforts of the German paleoceanographic community have resulted in a unique data set of reconstructed sea-surface temperature for the Atlantic Ocean during the Last Glacial Maximum, plus estimates for the extents of glacial sea ice. Unlike prior attempts, the contributing research groups based their data on a common definition of the Last Glacial Maximum chronozone and used the same modern reference data for calibrating the different transfer techniques. Furthermore, the number of processed sediment cores was vastly increased. Thus the new data is a significant advance not only with respect to quality, but also to quantity. We integrate these new data and provide monthly data sets of global sea-surface temperature and ice cover, objectively interpolated onto a regular 1°x1° grid, suitable for forcing or validating numerical ocean and atmosphere models. This set is compared to an existing subjective interpolation of the same base data, in part by employing an ocean circulation model. For the latter purpose, we reconstruct sea surface salinity from the new temperature data and the available oxygen isotope measurements

Meridional overturning circulation in the South Atlantic at the last glacial maximum

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 7 (2006): Q10N03, doi:10.1029/2005GC001226.The geostrophic shear associated with the meridional overturning circulation is reflected in the difference in density between the eastern and western margins of the ocean basin. Here we examine how the density difference across 30°S in the upper 2 km of the Atlantic Ocean (and thus the magnitude of the shear associated with the overturning circulation) has changed between the last glacial maximum and the present. We use oxygen isotope measurements on benthic foraminifera to reconstruct density. Today, the density in upper and intermediate waters along the eastern margin in the South Atlantic is greater than along the western margin, reflecting the vertical shear associated with the northward flow of surface and intermediate waters and the southward flowing North Atlantic Deep Waters below. The greater density along the eastern margin is reflected in the higher δ 18O values for surface sediment benthic foraminifera than those found on the western margin for the upper 2 km. For the last glacial maximum the available data indicate that the eastern margin foraminifera had similar δ 18O to those on the western margin between 1 and 2 km and that the gradient was reversed relative to today with the higher δ 18O values in the western margin benthic foraminifera above 1 km. If this reversal in benthic foraminifera δ 18O gradient reflects a reversal in seawater density gradient, these data are not consistent with a vigorous but shallower overturning cell in which surface waters entering the Atlantic basin are balanced by the southward export of Glacial North Atlantic Intermediate Water.This work was supported by NSF award OCE-9984989/OCE-0428803 to J.L.-S., NSF award OCE-9986748 to D.W.O. and W.B.C., NSF OCE-0222111 to C.D.C., and SEGRF fellowship at LLNL to J.M