Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale: some case studies

Every year, debris flows cause huge damage in mountainous areas. Due to population pressure in hazardous zones, the socio-economic impact is much higher than in the past. Therefore, the development of indicative susceptibility hazard maps is of primary importance, particularly in developing countries. However, the complexity of the phenomenon and the variability of local controlling factors limit the use of processbased models for a first assessment. A debris flow model has been developed for regional susceptibility assessments using digital elevation model (DEM) with a GIS-based approach.. The automatic identification of source areas and the estimation of debris flow spreading, based on GIS tools, provide a substantial basis for a preliminary susceptibility assessment at a regional scale. One of the main advantages of this model is its workability. In fact, everything is open to the user, from the data choice to the selection of the algorithms and their parameters. The Flow-R model was tested in three different contexts: two in Switzerland and one in Pakistan, for indicative susceptibility hazard mapping. It was shown that the quality of the DEM is the most important parameter to obtain reliable results for propagation, but also to identify the potential debris flows sources.

IL-12 controls cytotoxicity of a novel subset of self-antigen-specific human CD28+ cytolytic T cells.

Activated CD8 T cells develop cytotoxicity against autologous cells bearing foreign Ags and self/tumor Ags. However, self-specific cytolysis needs to be kept under control to avoid overwhelming immunopathology. After peptide vaccination of melanoma patients, we studied molecular and functional properties of T cell subsets specific for the self/tumor Ag Melan-A/MART-1. Ex vivo analysis revealed three Ag-specific effector memory (EM) populations, as follows: CD28-negative EM (EM28(-)) T cells strongly expressing granzyme/perforin, and two EM28(+) subsets, one with high and the other with low level expression of these cytotoxic proteins. For further functional characterization, we generated 117 stable CD8 T cell clones by ex vivo flow cytometry-based sorting of these subsets. All EM28(-)-derived clones lysed target cells with high efficacy. In contrast, EM28(+)-derived clones were heterogenous, and could be classified in two groups, one with high and the other with low killing capacity, correlating with granzyme/perforin expression. High and low killer phenotypes remained surprisingly stable for several months. However, strongly increased granzyme expression and cytotoxicity were observed after exposure to IL-12. Thus, the data reveal a newly identified subset of CD28(+) conditional killer T cells. Because CD28 can mediate strong costimulatory signals, tight cytotoxicity control, as shown in this study through IL-12, may be particularly important for subsets of T cells expressing CD28.

Perinatal Hypoxia Enhances Cyclic Adenosine Monophosphate-mediated BKCa Channel Activation in Adult Murine Pulmonary Artery.

Exposure to perinatal hypoxia results in alteration of the adult pulmonary circulation, which is linked among others to alterations in K channels in pulmonary artery (PA) smooth muscle cells. In particular, large conductance Ca-activated K (BKCa) channels protein expression and activity were increased in adult PA from mice born in hypoxia compared with controls. We evaluated long-term effects of perinatal hypoxia on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway-mediated activation of BKCa channels, using isoproterenol, forskolin, and dibutyryl-cAMP. Whole-cell outward current was higher in pulmonary artery smooth muscle cells from mice born in hypoxia compared with controls. Spontaneous transient outward currents, representative of BKCa activity, were present in a greater proportion in pulmonary artery smooth muscle cells of mice born in hypoxia than in controls. Agonists induced a greater relaxation in PA of mice born in hypoxia compared with controls, and BKCa channels contributed more to the cAMP/PKA-mediated relaxation in case of perinatal hypoxia. In summary, perinatal hypoxia enhanced cAMP-mediated BKCa channels activation in adult murine PA, suggesting that this pathway could be a potential target for modulating adult pulmonary vascular tone after perinatal hypoxia.

Analyse fonctionnelle et moléculaire d'un nouveau gène (VIT32) impliqué dans le mécanisme d'action de la vasopressine

Résumé Les mécanismes de régulation de la réabsorption fine du sodium dans la partie distale (tube distal et tube collecteur) du néphron ont un rôle essentiel dans le maintien de l'homéostasie de la composition ionique et du volume des fluides extracellulaires. Ces mécanismes permettent le maintien de la pression sanguine. Dans la cellule principale du tube collecteur cortical (CCD), le taux de réabsorption de sodium dépend essentiellement de l'activité du canal épithélial à sodium (ENaC) à la membrane apicale et de la pompe sodium-potassium-adénosine-triphosphatase (Na+-K±ATPase) à la membrane basolatérale. L'activité de ces deux molécules de transport est en partie régulée par des hormones dont l'aldostérone, la vasopressine et l'insuline. Dans les cellules principales de CCD, la vasopressine régule le transport de sodium en deux étapes : une étape précoce dite « non-génomique » et une étape tardive dite « génotnique ». Durant l'étape précoce, la vasopressine régule l'expression de gènes, dont certains peuvent être impliqués dans le transport de sodium, comme ENaC et la Na+ -K+ATP ase. Le but de mon travail a été d'étudier l'implication d'une protéine appelée VIP32 (vasopressin induced protein : VIP) dans le transport de sodium. L'expression de VIP32 est augmentée par la vasopressine dans les cellules principales de CCD. Dans l'ovocyte de Xenopus laevis utilisé comme système d'expression hétérologue, nous avons montré que l'expression de VIP32 provoque la maturation méiotique de l'ovocyte par l'activation de la voie des MAPK (mitogen-activated protein kinase : MAPK) et du facteur de promotion méiotique (MPF). La co-expression d'ENaC et de VIP32 diminue l'activité d'ENaC de façon sélective, par l'activation de la voie des MAPK, sans affecter l'expression du canal à la surface membranaire. Nous avons également montré que la régulation de l'activité d'ENaC par la voie des MAPK est dépendante du mécanisme de régulation d'ENaC lié à un motif du canal appelé PY. Ce motif est impliqué dans le contrôle de la probabilité d'ouverture ainsi que l'expression à la surface membranaire d'ENaC. Dans les cellules principales, VIP32 par l'activation de la voie des MAPK peut être impliqué dans la régulation négative du transport transépithélial qui a lieu après plusieurs heures de traitement à la vasopressine. Le tube collecteur de reins normaux présente un taux basal significatif d'activité de la voie MAPK MEK1/2-ERK1/2. Dans la lignée mpkCCDc14 de cellules principales de CCD de souris, que nous avons utilisé pour cette partie du travail, nous avons montré la présence d'un taux basal d'activité d'ERK1/2 (pERK1/2). L'aldostérone et la vasopressine, connus pour stimuler le courant sodique transépithélial dans le CCD, ne changeaient pas le taux basal de pERK1/2. Le transport de sodium transépithélial basal, ou stimulé par l'aldostérone ou la vasopressine est diminué par l'effet de PD98059, un inhibiteur de MEK1/2 qui diminue parallèlement le taux de pERK1/2. Nous avons également montré dans des cellules non stimulées, ou stimulées par de l'aldostérone ou de la vasopressine, que l'activité de la Na+-K+ ATPase, mais pas celle d'ENaC est inhibée par des traitements avec différents inhibiteurs de MEK1/2. Par un marquage de la Na±-K+ATPase à la surface membranaire nous avons montré que la voie d'ERK1/2 contrôle l'activité intrinsèque de la Na+-K+ ATPase, plutôt que son expression à la surface membranaire. Ces données ont montré que l'activité de la Na+-K+ATPase et le transport transépithélial de sodium sont contrôlés par l'activité basal et constitutive de la voie d'ERK1/2. Summary The regulation of sodium reabsorption in the distal nephron (distal tubule and cortical collecting duct) in the kidney plays an essential role in the control of extracellular fluids composition and volume, and thereby blood pressure. In the principal cell of the collecting duct (CCD), the level of sodium reabsorption mainlly depends on the activity of both epithlial sodium channel (ENaC) and sodium-potassium-adenosine-triphosphatase (Na+-K+ATPase). The activity of these two transporters is regulated by hormones especially aldosterone, vasopressin and insuline.In the principal cell of the CCD, vasopressin regulates sodium transport via a short-term effect and a late genomic effect. During the genomic effect vasopressin activates a complex network of vasopressin-dependent genes involved in the regulation of sodium transport as ENaC and Na+-K+ATPase. We were interested in the role of a recently identified vasopressin induced protein (VIP32) and its implication in the regulation of sodium transport in principal cell of the CCD. The Xenopus oocyte expression system revealed two functions : expressed alone VIP32 rapidly induces oocyte meiotic maturation through the activation of the mitogen-activated protein kinase (MAPK) pathway and the meiotic promoting factor and when co-expressed with ENaC, V1P32 selectively dowrn-egulates channel activity, but not channel cell surface expression. We have shown that the ENaC downregulation mediated by the activation of the MAPK pathway is related to the PY motif of ENaC. This motif is implicated in ENaC cell surface expression and open probability regulation. In the kidney principal cell, VIP32 through the activation of MAPK pathway may be involved in the downregulation of transepithelial sodium transport observed within a few hours after vasopressin treatment. The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 MAPK pathway. Using in vitro cultured mpkCCDc14 principal cells we have shown a significant basal level of ERK1/2 activity (pERK1/2). Aldosterone and vasopressin, known to upregulate sodium reabsorption in CCDs, did not change ERK1/2 activity. Basal and aldosterone- or vasopressin-stimulated sodium transport were downregulated by the MEK1/2 inhibitor PD98059 in parallel with a decrease in pERK1/2 in vitro. The activity of Na+-K+ATPase but not that of ENaC was inhibited by MEK1/2 inhibitors in both, unstimulated and aldosterone- or vasopressin-stimulated CCDs in vitro. Cell surface labelling showed that intrinsic activity rather than cell surface expression of Na+-K+ATPase was controlled by pERK1/2. Our data demonstrate that basal constitutive activity of ERK1/2 pathway controls Na+-K+ATPase activity and transepithelial sodium transport in the principal cell. Résumé tout public Les mécanismes de régulation de la réabsorption fine du sodium dans la partie distale du néphron (l'unité fonctionnelle du rein) ont un rôle essentiel dans le maintien de l'homéostasie de la composition et du volume des fluides extracellulaires. Ces mécanismes permettent de maintenir une pression sanguine effective. Dans les cellules principales du tube collecteur, une région spécifique du néphron distal, le transport de sodium dépend essentiellement de l'activité de deux transporteurs de sodium : le canal épithélial à sodium (ENaC) et la pompe sodium-potassium-adénosine-triphosphatase (Na+-K+ATPase). Afin de répondre aux besoins de l'organisme, l'activité de ces deux molécules de transport est en partie régulée par des hormones dont l'aldostérone, la vasopressine et l'insuline. Dans les cellules principales du tube collecteur, la vasopressine régule le transport de sodium en deux étapes : une étape rapide et une étape lente dite « génomique ». Durant l'étape lente, la vasopressine régule l'expression de gènes pouvant être impliqués dans le transport de sodium, dont notamment ceux d'ENaC et de la Na+-K+ATPase. Parmi les gènes dont l'expression est augmentée par la vasopressine, celui de VIP32 (vasopressin induced protein : VIP) fait l'objet de cette étude. Le but de mon travail a été d'étudier, dans un système d'expression hétérologue (l'ovocyte de Xenopus leavis), l'implication de VIP32 dans le transport de sodium. Nous avons montré que VIP32 est capable d'activer un mécanisme moléculaire en cascade appelé MAPK (mitogen-activated protein kinase : MAPK) et est aussi capable de diminuer l'activité d'ENaC. Parallèlement, dans une lignée de cellules principales de tube collecteur les mpkCCDc14, nous avons montré que le taux basal d'activité de la cascade MAPK est capable de réguler l'activité de la Na+-K+ATPase, tandis qu'il n'influence pas l'activité d'ENaC.

Increased audiovisual integration in cochlear-implanted deaf patients: independent components analysis of longitudinal positron emission tomography data.

It has been demonstrated in earlier studies that patients with a cochlear implant have increased abilities for audio-visual integration because the crude information transmitted by the cochlear implant requires the persistent use of the complementary speech information from the visual channel. The brain network for these abilities needs to be clarified. We used an independent components analysis (ICA) of the activation (H2 (15) O) positron emission tomography data to explore occipito-temporal brain activity in post-lingually deaf patients with unilaterally implanted cochlear implants at several months post-implantation (T1), shortly after implantation (T0) and in normal hearing controls. In between-group analysis, patients at T1 had greater blood flow in the left middle temporal cortex as compared with T0 and normal hearing controls. In within-group analysis, patients at T0 had a task-related ICA component in the visual cortex, and patients at T1 had one task-related ICA component in the left middle temporal cortex and the other in the visual cortex. The time courses of temporal and visual activities during the positron emission tomography examination at T1 were highly correlated, meaning that synchronized integrative activity occurred. The greater involvement of the visual cortex and its close coupling with the temporal cortex at T1 confirm the importance of audio-visual integration in more experienced cochlear implant subjects at the cortical level.

Vasopressin-dependent coupling between sodium transport and water flow in a mouse cortical collecting duct cell line.

Water balance is achieved through the ability of the kidney to control water reabsorption in the connecting tubule and the collecting duct. In a mouse cortical collecting duct cell line (mCCD(c11)), physiological concentrations of arginine vasopressin increased both electrogenic, amiloride-sensitive, epithelial sodium channel (ENaC)-mediated sodium transport measured by the short-circuit current (Isc) method and water flow (Jv apical to basal) measured by gravimetry with similar activation coefficient K(1/2) (6 and 12 pM, respectively). Jv increased linearly according to the osmotic gradient across the monolayer. A small but highly significant Jv was also measured under isoosmotic conditions. To test the coupling between sodium reabsorption and water flow, mCCD(c11) cells were treated for 24 h under isoosmotic condition with either diluent, amiloride, vasopressin or vasopressin and amiloride. Isc, Jv, and net chemical sodium fluxes were measured across the same monolayers. Around 30% of baseline and 50% of vasopressin-induced water flow is coupled to an amiloride-sensitive, ENaC-mediated, electrogenic sodium transport, whereas the remaining flow is coupled to an amiloride-insensitive, nonelectrogenic sodium transport mediated by an unknown electroneutral transporter. The mCCD(c11) cell line is a first example of a mammalian tight epithelium allowing quantitative study of the coupling between sodium and water transport. Our data are consistent with the 'near isoosmotic' fluid transport model.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale

The development of susceptibility maps for debris flows is of primary importance due to population pressure in hazardous zones. However, hazard assessment by processbased modelling at a regional scale is difficult due to the complex nature of the phenomenon, the variability of local controlling factors, and the uncertainty in modelling parameters. A regional assessment must consider a simplified approach that is not highly parameter dependant and that can provide zonation with minimum data requirements. A distributed empirical model has thus been developed for regional susceptibility assessments using essentially a digital elevation model (DEM). The model is called Flow-R for Flow path assessment of gravitational hazards at a Regional scale (available free of charge under www.flow-r.org) and has been successfully applied to different case studies in various countries with variable data quality. It provides a substantial basis for a preliminary susceptibility assessment at a regional scale. The model was also found relevant to assess other natural hazards such as rockfall, snow avalanches and floods. The model allows for automatic source area delineation, given user criteria, and for the assessment of the propagation extent based on various spreading algorithms and simple frictional laws.We developed a new spreading algorithm, an improved version of Holmgren's direction algorithm, that is less sensitive to small variations of the DEM and that is avoiding over-channelization, and so produces more realistic extents. The choices of the datasets and the algorithms are open to the user, which makes it compliant for various applications and dataset availability. Amongst the possible datasets, the DEM is the only one that is really needed for both the source area delineation and the propagation assessment; its quality is of major importance for the results accuracy. We consider a 10m DEM resolution as a good compromise between processing time and quality of results. However, valuable results have still been obtained on the basis of lower quality DEMs with 25m resolution.

Subtype-specific Modulation of Acid-sensing Ion Channel (ASIC) Function by 2-Guanidine-4-methylquinazoline.

Acid-sensing ion channels (ASICs) are neuronal Na(+)-selective channels that are transiently activated by extracellular acidification. ASICs are involved in fear and anxiety, learning, neurodegeneration after ischemic stroke, and pain sensation. The small molecule 2-guanidine-4-methylquinazoline (GMQ) was recently shown to open ASIC3 at physiological pH. We have investigated the mechanisms underlying this effect and the possibility that GMQ may alter the function of other ASICs besides ASIC3. GMQ shifts the pH dependence of activation to more acidic pH in ASIC1a and ASIC1b, whereas in ASIC3 this shift goes in the opposite direction and is accompanied by a decrease in its steepness. GMQ also induces an acidic shift of the pH dependence of inactivation of ASIC1a, -1b, -2a, and -3. As a consequence, the activation and inactivation curves of ASIC3 but not other ASICs overlap in the presence of GMQ at pH 7.4, thereby creating a window current. At concentrations >1 mm, GMQ decreases maximal peak currents by reducing the unitary current amplitude. Mutation of residue Glu-79 in the palm domain of ASIC3, previously shown to be critical for channel opening by GMQ, disrupted the GMQ effects on inactivation but not activation. This suggests that this residue is involved in the consequences of GMQ binding rather than in the binding interaction itself. This study describes the mechanisms underlying the effects of a novel class of ligands that modulate the function of all ASICs as well as activate ASIC3 at physiological pH.

A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel.

Pseudohypoaldosteronism type 1 (PHA-1) is an inherited disease characterized by severe neonatal salt-wasting and caused by mutations in subunits of the amiloride-sensitive epithelial sodium channel (ENaC). A missense mutation (G37S) of the human ENaC beta subunit that causes loss of ENaC function and PHA-1 replaces a glycine that is conserved in the N-terminus of all members of the ENaC gene family. We now report an investigation of the mechanism of channel inactivation by this mutation. Homologous mutations, introduced into alpha, beta or gamma subunits, all significantly reduce macroscopic sodium channel currents recorded in Xenopus laevis oocytes. Quantitative determination of the number of channel molecules present at the cell surface showed no significant differences in surface expression of mutant compared with wild-type channels. Single channel conductances and ion selectivities of the mutant channels were identical to that of wild-type. These results suggest that the decrease in macroscopic Na currents is due to a decrease in channel open probability (P(o)), suggesting that mutations of a conserved glycine in the N-terminus of ENaC subunits change ENaC channel gating, which would explain the disease pathophysiology. Single channel recordings of channels containing the mutant alpha subunit (alphaG95S) directly demonstrate a striking reduction in P(o). We propose that this mutation favors a gating mode characterized by short-open and long-closed times. We suggest that determination of the gating mode of ENaC is a key regulator of channel activity.

Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance.

Aldosterone promotes electrogenic sodium reabsorption through the amiloride-sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the αENaC subunit in colonic superficial cells (Scnn1a(KO)) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (∆PDamil) than control mice fed a high-salt diet. In Scnn1a(KO) mice, however, this salt restriction-induced increase in ∆PDamil did not occur, and the circadian rhythm of ∆PDamil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a(KO) mice. However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8(KO)) were viable, without fetal or perinatal lethality. Compared with controls, Prss8(KO) mice fed regular or low-salt diets exhibited significantly reduced ∆PDamil in the afternoon, but the circadian rhythm was maintained. Prss8(KO) mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance.

An experimental study of discharge partitioning and flow structure at symmetrical bifurcations

Recent research has examined the factors controlling the geometrical configuration of bifurcations, determined the range of stability conditions for a number of bifurcation types and assessed the impact of perturbations on bifurcation evolution. However, the flow division process and the parameters that influence flow and sediment partitioning are still poorly characterized. To identify and isolate these parameters, three-dimensional velocities were measured at 11 cross-sections in a fixed-walled experimental bifurcation. Water surface gradients were controlled, and systematically varied, using a weir in each distributary. As may be expected, the steepest distributary conveyed the most discharge ( was dominant) while the mildest distributary conveyed the least discharge ( was subordinate). A zone of water surface super-elevation was co-located with the bifurcation in symmetric cases or displaced into the subordinate branch in asymmetric cases. Downstream of a relatively acute-angled bifurcation, primary velocity cores were near to the water surface and against the inner banks, with near-bed zones of lower primary velocity at the outer banks. Downstream of an obtuse-angled bifurcation, velocity cores were initially at the outer banks, with near-bed zones of lower velocities at the inner banks, but patterns soon reverted to match the acute-angled case. A single secondary flow cell was generated in each distributary, with water flowing inwards at the water surface and outwards at the bed. Circulation was relatively enhanced within the subordinate branch, which may help explain why subordinate distributaries remain open, may play a role in determining the size of commonly-observed topographic features, and may thus exert some control on the stability of asymmetric bifurcations. Further, because larger values of circulation result from larger gradient disadvantages, the length of confluence-diffluence units in braided rivers or between diffluences within delta distributary networks may vary depending upon flow structures inherited from upstream and whether, and how, they are fed by dominant or subordinate distributaries. Copyright (C) 2011 John Wiley & Sons, Ltd.

Protonation controls ASIC1a activity via coordinated movements in multiple domains.

Acid-sensing ion channels (ASICs) are neuronal Na(+)-conducting channels activated by extracellular acidification. ASICs are involved in pain sensation, expression of fear, and neurodegeneration after ischemic stroke. Functional ASICs are composed of three identical or homologous subunits, whose extracellular part has a handlike structure. Currently, it is unclear how protonation of residues in extracellular domains controls ASIC activity. Knowledge of these mechanisms would allow a rational development of drugs acting on ASICs. Protonation may induce conformational changes that control the position of the channel gate. We used voltage-clamp fluorometry with fluorophores attached to residues in different domains of ASIC1a to detect conformational changes. Comparison of the timing of fluorescence and current signals identified residues involved in movements that preceded desensitization and may therefore be associated with channel opening or early steps leading to desensitization. Other residues participated in movements intimately linked to desensitization and recovery from desensitization. Fluorescence signals of all mutants were detected at more alkaline pH than ionic currents. Their midpoint of pH dependence was close to that of steady-state desensitization, whereas the steepness of the pH fluorescence relationship was closer to that of current activation. A sequence of movements was observed upon acidification, and its backward movements during recovery from desensitization occurred in the reverse order, indicating that the individual steps are interdependent. Furthermore, the fluorescence signal of some labeled residues in the finger domain was strongly quenched by a Trp residue in the neighboring β-ball domain. Upon channel activation, their fluorescence intensity increased, indicating that the finger moved away from the β ball. This extensive analysis of activity-dependent conformational changes in ASICs sheds new light on the mechanisms by which protonation controls ASIC activity.

Blood flow, flow reserve, and glucose utilization in viable and nonviable myocardium in patients with ischemic cardiomyopathy.

PURPOSE: The aim of the study was to determine whether glucose uptake in viable myocardium of ischemic cardiomyopathy patients depends on rest myocardial blood flow (MBF) and the residual myocardial flow reserve (MFR). METHODS: Thirty-six patients with ischemic cardiomyopathy (left ventricular ejection fraction 25 ± 10 %) were studied with N-ammonia and F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Twenty age-matched normals served as controls. Regional MBF was determined at rest and during dipyridamole hyperemia and regional FDG extraction was estimated from regional FDG to N-ammonia activity ratios. RESULTS: Rest MBF was reduced in viable (0.42 ± 0.18 ml/min per g) and nonviable regions (0.32 ± 0.09 ml/min per g) relative to remote regions (0.68 ± 0.23 ml/min per g, p < 0.001) and to normals (0.63 ± 0.13 ml/min per g). Dipyridamole raised MBFs in controls, remote, viable, and nonviable regions. MBFs at rest (p < 0.05) and stress (p < 0.05) in viable regions were significantly higher than that in nonviable regions, while MFRs did not differ significantly (p > 0.05). Compared to MFR in remote myocardium, MFRs in viable regions were similar (1.39 ± 0.56 vs 1.70 ± 0.45, p > 0.05) but were significantly lower in nonviable regions (1.23 ± 0.43, p < 0.001). Moreover, the FDG and thus glucose extraction was higher in viable than in remote (1.40 ± 0.14 vs 0.90 ± 0.20, p < 0.001) and in nonviable regions (1.13 ± 0.21, p < 0.001). The extraction of FDG in viable regions was independent of rest MBF but correlated inversely with MFRs (r =-0.424, p < 0.05). No correlation between the FDG extraction and MFR was observed in nonviable regions. CONCLUSION: As in the animal model, decreasing MFRs in viable myocardium are associated with increasing glucose extraction that likely reflects a metabolic adaptation of remodeling hibernating myocytes.

The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes.

Cellular directional migration in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC), in addition to its function of regulating sodium transport in kidney, has recently been found to modulate cell locomotory speed. Here we tested whether ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that the channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild-type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC mediates galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing.

Topographic forcing of flow partition and flow structures at river bifurcations

This paper presents the predicted flow dynamics from the application of a Reynolds-averaged NavierStokes model to a series of bifurcation geometries with morphologies measured during previous flume experiments. The topography of the bifurcations consists of either plane or bedform-dominated beds which may or may not possess discordance between the two bifurcation distributaries. Numerical predictions are compared with experimental results to assess the ability of the numerical model to reproduce the division of flow into the bifurcation distributaries. The hydrodynamic model predicts: (1) diverting fluxes in the upstream channel which direct water into the distributaries; (2) super-elevation of the free surface induced at the bifurcation edge by pressure differences; and (3) counter-rotating secondary circulation cells which develop upstream of the apex of the bifurcation and move into the downstream channels, with water converging at the surface and diverging at the bed. When bedforms are not present, weak transversal fluxes characterize the upstream channel for almost its entire length, associated with clearly distinguishable secondary circulation cells, although these may be under-estimated by the turbulence model used in the solution. In the bedform dominated case, the same hydrodynamic conditions were not observed, with the bifurcation influence restricted and depth scale secondary circulation cells not forming. The results also demonstrate the dominant effect bed discordance has upon flow division between the two distributaries. Finally, results indicate that in bedform dominated rivers. Consequently, we suggest that sand-bed river bifurcations are more likely to have an influence that extends much further upstream and have a greater impact upon water distribution. This may contribute to observed morphological differences between sand-bedded and gravel-bedded braided river networks. Copyright (C) 2012 John Wiley & Sons, Ltd.