Structural properties of mobile armors formed at different flow strengths in gravel-bed rivers

Differences in the structure of mobile armors formed at three different flow strengths have been investigated in a laboratory flume. The temporal evolution of the bed surfaces and the properties of the final beds were compared using metrics of surface grain size, microtopography, and bed organization at both grain and mesoscales. Measurements of the bed condition were obtained on nine occasions during each experiment to describe the temporal evolution of the beds. Structured mobile armors formed quickly in each experiment. At the grain scale (1–45 mm; 9 ≤ Ds50 ≤ 17 mm where Ds50 is the median surface particle size), surface complexity decreased and bed roughness increased in response to surface coarsening and the development of the mobile armor. Particles comprising the armor also became flow aligned and developed imbrication. At a larger scale (100–200 mm), the surface developed a mesoscale topography through the development of bed patches with lower and higher elevations. Metrics of mobile armor structure showed remarkable consistency over prolonged periods of near-constant transport, demonstrating for the first time that actively transporting surfaces maintain an equilibrium bed structure. Bed structuring was least developed in the experiments conducted at the lowest flow strength. However, little difference was observed in the structural metrics of the mobile armors generated at higher flows. Although the range of transport rates studied was limited, the results suggest that the structure of mobile armors is insensitive to the formative transport rate except when rates are low (τ* ≈ 0.03 where τ* is the dimensionless shear stress)

Storytelling and Young Learners: Translanguaging Facilitates Learning English as a Foreign Language

Abstract for presentation at ALAA2016/ALS2016 joint day

Ischemic Postconditioning Fails to Protect against Neonatal Cerebral Stroke

<div><p>The lack of efficient neuroprotective strategies for neonatal stroke could be ascribed to pathogenic ischemic processes differentiating adults and neonates. We explored this hypothesis using a rat model of neonatal ischemia induced by permanent occlusion of the left distal middle cerebral artery combined with 50 min of occlusion of both common carotid arteries (CCA). Postconditioning was performed by repetitive brief release and occlusion (30 s, 1 and/or 5 min) of CCA after 50 min of CCA occlusion. Alternative reperfusion was generated by controlled release of the bilateral CCA occlusion. Blood-flow velocities in the left internal carotid artery were measured using color-coded pulsed Doppler ultrasound imaging. Cortical perfusion was measured using laser Doppler. Cerebrovascular vasoreactivity was evaluated after inhalation with the hypercapnic gas or inhaled nitric oxide (NO). Whatever the type of serial mechanical interruptions of blood flow at reperfusion, postconditioning did not reduce infarct volume after 72 hours. A gradual perfusion was found during early re-flow both in the left internal carotid artery and in the cortical penumbra. The absence of acute hyperemia during early CCA re-flow, and the lack of NO-dependent vasoreactivity in P7 rat brain could in part explain the inefficiency of ischemic postconditioning after ischemia-reperfusion.</p> </div

Postconditioning did not reduce infarct size. Infarct size was measured 3 days after ischemia.

<p><b>A</b>: Infarct size measured in animals subjected to postconditioning with 3 cycles of occlusion/reperfusion of 1 and 5 min on both CCA. <b>B</b>: Infarct size measured in animals subjected to postconditioning with 3 cycles of occlusion/reperfusion of 30 s on the left CCA. <b>C</b>: Infarct size measured in animals subjected to alternative reperfusion. The median (horizontal bar) and the mean (cross) were indicated. No significant difference was detected in the different groups.</p

Laser Doppler monitoring during reperfusion.

<p><b>A</b>: Representative brain from a pup killed at 48 hours after ischemia showing a pale delineated lesion (white dotted line) and 3 regions of interest (ROI), and representative cresyl violet-stained section showing a cortical infarct and 2 ROI for rCBF measurements in the penumbra with the laser probe. <b>B</b>: Changes in rCBF (mean of 3 ROI ± S.D) in 6 animals subjected to ischemia-reperfusion. Upon MCA occlusion, the rCBF dropped to 55±8% of baseline, and additional bilateral CCA occlusion further decreased rCBF to 18±5%. After CCA release, a gradual reperfusion was observed from 30±11% at 1 min to 44±9% 20 min after. *p<0.05, ** p<0.01 <i>vs</i> basal.</p

Changes in arterial cerebral blood flow in animals subjected to neonatal ischemia.

<p><b>A</b>: spectral analyses of blood-flow velocity waveforms acquired with pulsed Doppler in the left ICA before ischemia (basal, left) and at 3 min after re-flow (right). <b>B</b>: Time course of mBFV in the left ICA and in the basilar trunk (BT) during reperfusion. Mean BFVs were plotted before ischemia, during ischemia (at 40 min) and during the first 15 min of the reperfusion. Note that mBFVs in the left ICA at the reperfusion did not reach the level of its mean value in basal condition. In the BT, mBFVs were increased during ischemia (*p<0.05 <i>vs</i> basal) and returned to basal values at the reperfusion. <b>C–D</b>: Time course of mBFV in the left ICA during reperfusion in animals subjected to neonatal ischemia and/or postconditioning. <b>C</b>: Mean BFVs were plotted before ischemia (basal), during ischemia (at 40 min) and during the first 15 min of the reperfusion after release on both CCA (ischemic controls, red line, n = 5), and after 1/1 min postC (3 cycles, green line, n = 6). <b>D</b>: Mean BFVs were plotted before ischemia (basal), during ischemia (at 40 min) and during the first 15 min of the reperfusion after release on both CCA (ischemic controls, red line, n = 6), after release occlusion on left CCA then right CCA 5 min later (green line, n = 5), and after release on the right then left CCA 5 min later (blue line, n = 5). Data are expressed as mean±SD.</p

Protocols for cerebral ischemia without and with postconditioning.

<p>Animals were divided into three groups. All animals were subjected to MCA electrocoagulation, and bilateral CCA were transiently (50 min) occluded 2 min later. Re-flow was initiated by CCA occlusion release in controls (n = 17 in the first set, n = 11 in the second set and n = 11 in the third set of experiments). Postconditioning with 3 cycles (occlusion/reperfusion) of 30 s (n = 11), 1 (n = 18) or 5 (n = 12) min was performed on both or only left CCA within 15 s after the initial CCA reperfusion. Alternative reperfusion was initiated by first occlusion release of the left (L/R, n = 11) or of the right (R/L, n = 12) CCA followed by occlusion release of the other CCA.</p

Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells

<div><p>Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME <i>in vivo</i> and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures <i>in vitro</i>; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF. In addition, hypoxia downregulated antigen presenting proteins like TAP 1/2 and LMP7 that are known to have a dominant role in surface display of peptide-MHC complexes. Corroborating oxygen-dependent regulation of MHC antigen presentation, hyperoxia (60% oxygen) transcriptionally upregulated MHC expression and increased levels of TAP2, LMP2 and 7. In conclusion, this study reveals a novel mechanism by which intra-tumoral hypoxia and HIF can potentiate immune escape. It also suggests the use of hyperoxia to improve tumor cell-based cancer vaccines and for mining novel immune epitopes. Furthermore, this study highlights the advantage of 3D cell cultures in reproducing hypoxia-dependent changes observed in the TME.</p></div

Hypoxia downregulates and hyperoxia upregulates expression levels of TAPs and LMPs.

<p><b>(A, C)</b> MCA205 tumor cells were cultured <i>in vitro</i> as 3D spheroids for 48h under 1%, 21% or 60% oxygen. <b>(C)</b> Relative band intensity, normalized to the loading control and 21% oxygen samples is shown. <b>(B, D)</b> For <i>in vivo</i> experiments, tumor nodules (MCA205 pulmonary tumors) were harvested from mice exposed to respiratory hypoxia (10% oxygen), normoxia (21% oxygen) or hyperoxia (60% oxygen) for 48h. <b>(D)</b> Relative band intensity, normalized to the loading control and 21% oxygen samples is shown. Protein levels were determined by Western blot. β-actin was used as loading control. Representative blots with samples from 2 independent experiments are shown.</p

Hypoxia downregulates MHC class I expression via HIF transcription factors.

<p><b>(A-C):</b> siRNA mediated knockdown of HIF-1α reversed hypoxic downregulation of MHC class I expression as compared with the scrambled, non-targeting (NT) siRNA control. MCA205 tumor cells were reverse transfected with scrambled siRNA (NT; red histogram) or with HIF-1α specific siRNA (blue histogram) and cultured as 3D spheroids under 1% <b>(A)</b> or 21% <b>(B)</b> oxygen for 48h. Levels of MHC class I surface expression was determined using flow cytometry. Efficacy of gene knockdown was assessed using Western blot <b>(C)</b>. β-Actin was used as the loading control. Representative data of 3 independent experiments shown. <b>(D-F):</b> Flow cytometry assessment of surface expression of HLA-ABC on paired isogenic renal cell carcinoma cell lines RCC4 <b>(D)</b>, UMRC2 <b>(E)</b> and CAKI2 <b>(F)</b>. Each pair had the parental cell line that lacked endogenous wild-type VHL (VHL null, transfected with empty vector) and one with vector stably expressing functional VHL (VHL restored). Restoring VHL function and thereby reducing HIF expression, significantly increased HLA-ABC expression on the cells. Representative histograms of 4 independent experiments are shown. Grey filled: unstained control; red: VHL null genotype; blue: VHL restored genotype. <b>(D1-F1):</b> Inactivation of HIF-1α by restoring VHL expression was verified by Western blotting for RCC4 <b>(D1)</b>, UMRC2 <b>(E1)</b> and CAKI2 <b>(F1)</b> cells. β-Actin was used as the loading control.</p