Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Vascular responses of the extremities to transdermal application of vasoactive agents in Caucasian and African descent individuals

This is an accepted manuscript of an article published by Springer in European Journal of Applied Physiology on 04/04/2015, available online: https://doi.org/10.1007/s00421-015-3164-2 The accepted version of the publication may differ from the final published version.© 2015, Springer-Verlag Berlin Heidelberg. Purpose: Individuals of African descent (AFD) are more susceptible to non-freezing cold injury than Caucasians (CAU) which may be due, in part, to differences in the control of skin blood flow. We investigated the skin blood flow responses to transdermal application of vasoactive agents. Methods: Twenty-four young males (12 CAU and 12 AFD) undertook three tests in which iontophoresis was used to apply acetylcholine (ACh 1 w/v %), sodium nitroprusside (SNP 0.01 w/v %) and noradrenaline (NA 0.5 mM) to the skin. The skin sites tested were: volar forearm, non-glabrous finger and toe, and glabrous finger (pad) and toe (pad). Results: In response to SNP on the forearm, AFD had less vasodilatation for a given current application than CAU (P = 0.027–0.004). ACh evoked less vasodilatation in AFD for a given application current in the non-glabrous finger and toe compared with CAU (P = 0.043–0.014) with a lower maximum vasodilatation in the non-glabrous finger (median [interquartile], AFD n = 11, 41[234] %, CAU n = 12, 351[451] %, P = 0.011) and non-glabrous toe (median [interquartile], AFD n = 9, 116[318] %, CAU n = 12, 484[720] %, P = 0.018). ACh and SNP did not elicit vasodilatation in the glabrous skin sites of either group. There were no ethnic differences in response to NA. Conclusion: AFD have an attenuated endothelium-dependent vasodilatation in non-glabrous sites of the fingers and toes compared with CAU. This may contribute to lower skin temperature following cold exposure and the increased risk of cold injuries experienced by AFD.Published versio

Incorporating Social Justice into Statistical Instruction: Using Action Research to Impact Pre-Service Teachers

The following action research depicts how two researchers from two universities merged their courses and goals of instruction to impact change in future teachers. Two currently practicing middle school teachers from one university worked with researchers to develop a social justice lesson that had relevance to seventeen K-8 pre-service teachers at another university to promote changes in beliefs about equitable teaching practices and policy. Findings from pre- and post-surveys, field notes during enactment, and reflections teachers found teaching statistics for social justice (TS4SJ) in this setting provided an increased responsiveness to the needs of students and statistical connections while also attending to excuses by those facing dilemmas in belief and racial dominance

Overview of field operations during a 2013 research expedition to the southern Beaufort Sea on the RV Araon

Research experiments conducted and preliminary findings The Expedition ARA04C is a multidisciplinary research program in the Beaufort Sea, carried out in collaboration between the Korea Polar Research Institute (KOPRI), Geological Survey of Canada (GSC), Department of Fisheries and Ocean (DFO), Monterey Bay Aquarium Research Institute (MBARI), and the Alfred Wegener Institute (AWI). The Expedition ARA04C on the IBRV Araon took place from September 6 to September 24, 2013 (Figure 0.1). Multiple research experiments were undertaken to study geological processes related to degrading permafrost, fluid flow and degassing, and associated geohazards, paleo-oceanography of the Beaufort shelf and slope region, as well as physical and chemical oceanography measurement of the Arctic Ocean linked with continuous atmospheric studies. The expedition focused on two main research areas: offshore Barrow, Alaska, from September 7 to September 9, 2013, and the Canadian Beaufort Sea from September 10 to September 24, 2013. Multichannel seismic data, in conjunction with an ocean-bottom-seismometer (OBS) study were collected to support drilling proposals especially IODP pre-proposal #806 (Dallimore et al., 2012), and to verify distribution and internal structures of the offshore permafrost occurrences (Figure 0.2). The multi-channel seismic data were acquired on the outer continental shelf of the Canadian Beaufort Sea, totaling 14 lines with ~435 line-kilometers and ~4,500 shot gathers (Chapter 3). The combined multichannel seismic and OBS data will be processed post-expedition at KOPRI and the GSC, and will allow detailed velocity analyses to investigate the permafrost signature and help mapping zones of high-velocity sediments indicative of the presence of ice (Chapter 4). Individual shot gathers collected during the multichannel seismic program show clear refraction arrivals with velocities around 2000m/s in areas of expected permafrost occurrence, and shot gathers lacked such arrivals in zones where the permafrost was predicted to be absent. It is therefore expected that the OBS data, once processed, will also show clear refracted arrivals for velocity analyses. Continuous sub-bottom profiler (SBP) and multibeam data were collected along all ship tracks for detailed subsurface imaging of sediment structures and permafrost, as well as for core-site location verification (Chapter 5 and 6). During Expedition ARA04C, more than 3000 line-kilometers of SBP data were collected, co-located with multibeam and backscatter data. These data are an essential part of the study of sub-seafloor permafrost distribution and provide insights into sediment dynamics at critical boundaries, such as the shelf edge. Along the shelf edge, the occurrence of pingo-like features (PLFs) result in a rugged landscape with thousands of PLFs piercing through the otherwise laminated sediments. More than 30 crossings of this critical shelf-edge boundary were made during this expedition, which complement data acquired in 2012 with the Huntec system and 3.5 kHz data provided by ArcticNet as part of the regional multibeam map of the study area. High resolution data provided critical new insights in deep-water fluid expulsion zones. Key new data were acquired over the area of the "Gary Knolls", where PLF structures occur at the shelf edge in water depth of only 50 to 60 m. All SBP data from this expedition will be post-processed and analyzed for the presence of sub-seafloor permafrost, occurrence of the PLF structures and indications for fluid and gas migration. Multibeam and backscatter data were collected along all ship tracks, adding to the database of existing information gathered through previous expeditions to the study region. Heat flow measurements were undertaken at eight stations (Figure 0.3) to study the thermal structure of fluid expulsion features, as well as degrading permafrost along a slope-shelf transect in the eastern Mackenzie Trough (Chapter 7). The data provide critical constraints on the distribution of sub-seafloor permafrost as well as the gas hydrate stability zone around fluid expulsion features. A very important finding is the observation made at the mud volcano in 420 m water depth, where seafloor temperatures are the highest in all observed stations, indicating active mud volcanism. Geological sampling using gravity coring and multi-coring tools was performed at strategic sites to support two research objectives. The first objective was to provide key data towards ongoing international research linked to IODP pre-proposals #753 (O'Regan et al., 2010) and #806 (Dallimore et al., 2012). The second objective was to collect core to define key seismo-stratigraphic horizons critical to the understanding of geohazards in the region (Chapter 8). In total, 21 gravity cores and 12 multi-cores were taken (Figure 0.4, Table 8.3). All cores were scanned with a multi-sensor core-logger to measure physical properties (Chapter 9). Most sediment analyses on the cores will be performed post-expedition at KOPRI, GSC, and laboratories of other University-based collaborators in Canada and Germany. Onboard, sub-samples were taken from all shallow multi-cores and selected gravity cores. On selected cores from the Canadian Beaufort study region pore-waters were extracted using rhizones. These samples will be analyzed postexpedition at MBARI. Water sampling and Conductivity-Temperature-Depth (CTD) profiling was undertaken at most core sites to study physical and chemical properties of the seawater (Figure 0.5). These station-measurements were complemented by continuous waterproperty and atmospheric measurements when the Araon was underway. Most samples taken will be analyzed post-expedition at KOPRI for DIC/TA, nutrients, DOC, and POC. The pH of seawater, underway data of pCO2, CH4, and N2O, as well as a variety of subsequent calculations is required for accurate estimates in the above listed parameters. Methane was also measured with a methane sensor attached to the CTD tool and at the mud volcano in 420 m water depth, methane concentrations of more than 100-times ocean background were seen. The methane plume was also acoustically imaged with the echo sounder systems on board the IBRV Araon. Further details on the water sampling and atmospheric measurements are given in Chapter 10 and 11