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

3D Airway changes using cone beam computed tomography in patients following mandibular advancement surgery with and without constriction

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149306/1/ocr12292.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149306/2/ocr12292_am.pd

A 12-month follow-up of a mobile-based (mHealth) obesity prevention intervention in pre-school children: the MINISTOP randomized controlled trial

Background: To date, few mobile health (mHealth) interventions aimed at changing lifestyle behaviors have measured long term effectiveness. At the 6-month follow-up the MINISTOP trial found a statistically significant intervention effect for a composite score comprised of fat mass index (FMI) as well as dietary and physical activity variables; however, no intervention effect was observed for FMI. Therefore, the aim of this study was to investigate if the MINISTOP intervention 12-months after baseline measurements: (i) improved FMI and (ii) had a maintained effect on a composite score comprised of FMI and dietary and physical activity variables. Methods: A two-arm parallel randomized controlled trial was conducted in 315 healthy 4.5 year old children between January 2014 and October 2015. Parents’ of the participating children either received the MINISTOP intervention or a basic pamphlet on dietary and physical activity behaviors (control group). After 6 months, participants did not have access to the intervention content and were measured again 6 months later (i.e. the 12-month follow-up). The Wilcoxon rank-sum test was then used to examine differences between the groups. Results: At the 12-month follow-up, no statistically significant difference was observed between the intervention and control groups for FMI (p = 0.57) and no maintained effect for the change in composite score was observed (mean ± standard deviation for the intervention and control group: + 0.53 ± 1.49 units and + 0.35 ± 1.27 units respectively, p = 0.25 between groups). Conclusions: The intervention effect observed at the 6-month follow-up on the composite score was not maintained at the 12-month follow-up, with no effect on FMI being observed at either follow-up. Future studies using mHealth are needed to investigate how changes in obesity related markers in young children can be maintained over longer time periods.The MINISTOP project was funded by the Swedish Research Council (project no. 2012–2883), the Swedish Research Council for Health, Working Life and Welfare (2012–0906), Bo and Vera Axson Johnsons Foundation, and Karolinska Institutet (M.L.). C.D.N was supported by the Swedish Nutrition Foundation and S.S was funded by the Seaver Foundation. None of the funding bodies had any contributions or influence in the design of the study, data collection, analysis, interpretation of the data, or the writing of the manuscript

Numerical and experimental analysis of wrinkling during the cup drawing of an AA5042 aluminium alloy

The recent trend to reduce the thickness of metallic sheets used in forming processes strongly increases the likelihood of the occurrence of wrinkling. Thus, in order to obtain defect-free components, the prediction of this kind of defect becomes extremely important in the tool design and selection of process parameters. In this study, the sheet metal forming process proposed as a benchmark in the Numisheet 2014 conference is selected to analyse the influence of the tool geometry on wrinkling behaviour, as well as the reliability of the developed numerical model. The side-wall wrinkling during the deep drawing process of a cylindrical cup in AA5042 aluminium alloy is investigated through finite element simulation and experimental measurements. The material plastic anisotropy is modelled with an advanced yield criterion beyond the isotropic (von Mises) material behaviour. The results show that the shape of the wrinkles predicted by the numerical model is strongly affected by the finite element mesh used in the blank discretization. The accurate modelling of the plastic anisotropy of the aluminium alloy yields numerical results that are in good agreement with the experiments, particularly the shape and location of the wrinkles. The predicted punch force evolution is strongly influenced by the friction coefficient used in the model. Moreover, the two punch geometries provide drawn cups with different wrinkle waves, mainly differing in amplitude.The authors gratefully acknowledge the financial support of the Portuguese Foundation for Science and Technology (FCT) under project PTDC/EMS-TEC/1805/2012. The first author is also grateful to the FCT for the Postdoctoral grant SFRH/BPD/101334/2014 and P.D. Barros is grateful to the FCT for the PhD Grant SFRH/BD/98545/2013info:eu-repo/semantics/publishedVersio

Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts

In this work, we demonstrate that that both human whole skin and freshly isolated skin fibroblasts are productively infected with Dengue virus (DENV). In addition, primary skin fibroblast cultures were established and subsequently infected with DENV-2; we showed in these cells the presence of the viral antigen NS3, and we found productive viral infection by a conventional plaque assay. Of note, the infectivity rate was almost the same in all the primary cultures analyzed from different donors. The skin fibroblasts infected with DENV-2 underwent signaling through both TLR3 and RIG-1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 IRF7, when compared with mock-infected fibroblasts. Our data suggest that fibroblasts might even participate producing mediators involved in innate immunity that activate and contribute to the orchestration of the local innate responses. This work is the first evaluating primary skin fibroblast cultures obtained from different humans, assessing both their susceptibility to DENV infection as well as their ability to produce molecules crucial for innate immunity

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Intra-arterial delivery of triolein emulsion increases vascular permeability in skeletal muscles of rabbits

<p>Abstract</p> <p>Background</p> <p>To test the hypothesis that triolein emulsion will increase vascular permeability of skeletal muscle.</p> <p>Methods</p> <p>Triolein emulsion was infused into the superficial femoral artery in rabbits (triolein group, n = 12). As a control, saline was infused (saline group, n = 18). Pre- and post-contrast T1-weighted MR images were obtained two hours after infusion. The MR images were qualitatively and quantitatively evaluated by assessing the contrast enhancement of the ipsilateral muscles. Histologic examination was performed in all rabbits.</p> <p>Results</p> <p>The ipsilateral muscles of the rabbits in the triolein group showed contrast enhancement, as opposed to in the ipsilateral muscles of the rabbits in the saline group. The contrast enhancement of the lesions was statistically significant (p < 0.001). Histologic findings showed that most examination areas of the triolein and saline groups had a normal appearance.</p> <p>Conclusion</p> <p>Rabbit thigh muscle revealed significantly increased vascular permeability with triolein emulsion; this was clearly demonstrated on the postcontrast MR images.</p