One year of measurements in Alderney Race: preliminary results from database analysis.

The Alderney Race is assumed to have the largest tidal-stream energy potential in the north-western European coastal seas. Interaction of the powerful tidal stream with strong wind, high waves and irregular bathymetry creates hydrodynamic conditions of extreme complexity, with high levels of turbulence. A comprehensive dataset has been created to improve the understanding of physical processes, turbulence, tidal stream and resource variability at the site. The database contains a large amount of oceanographic and meteorological measurements acquired in Alderney Race in 2017-2018. This exceptionally long period of observations (nearly one year) became possible due to modern tools and strategies of data acquisition. The paper presents some significant results from the database analysis. Among many results, we would like to underline the following: (i) a wide range of variability of mean flow and sea state parameters was documented; (ii) exceptionally large values of current velocity (7 m s-1) and significant wave height (8 m) were measured during extreme meteorological conditions; (iii) high-frequency variability of current speed during storm events was also found to be very large, with the standard deviation of velocity reaching 0.3 m s-1 in the bottom boundary layer, and 0.6 m s-1 in the surface layer; and (iv) predominant wind and wave direction relative to the flow impacts the wave height and significantly increases the turbulence kinetic energy of the flow. To our knowledge, this is the largest multi-variable database available on potential tidal energy sites. The results of database analysis can represent a significant advance in environmental conditions and resource characterization and provide advanced information to turbine developers. This article is part of the theme issue 'New insights on tidal dynamics and tidal energy harvesting in the Alderney Race'.

Sodium Channel Trafficking.

Voltage-gated sodium channels (VGSC) are critical determinants of cellular electrical activity through the control of initiation and propagation of action potential. To ensure this role, these proteins are not consistently delivered to the plasma membrane but undergo drastic quality controls throughout various adaptive processes such as biosynthesis, anterograde and retrograde trafficking, and membrane targeting. In pathological conditions, this quality control could lead to the retention of functional VGSC and is therefore the target of different pharmacological approaches. The present chapter gives an overview of the current understanding of the facets of VGSC life cycle in the context of both cardiac and neuronal cell types.

Impacts of operational conditions on oxygen transfer rate, mixing characteristics and residence time distribution in a pilot scale high rate algal pond.

Different combinations of operational parameters including water level, paddle rotational speed and influent flow rate were applied to investigate their impacts on mixing characteristics, residence time distribution and gas transfer rate in a pilot-scale high rate algal pond. In closed condition, the paddle rotational speed had a positive correlation with the Bodenstein number (Bo), water velocity and oxygen volumetric mass transfer coefficient (kLaO2) while increasing water level generated a negative impact on these parameters, although the impact of water level on water linear velocity was small. The amplification effect of water level and paddle rotational speed on the sensitivity of Bo and kLaO2 should be noticed. Moreover, paddle rotational speed had more impact on kLaO2 than on Bo. The study in open condition indicated that effective volume fraction had a positive correlation with inlet flow rate and negative correlation with paddle rotation, while the opposite was observed in the case of Peclet number. The impact of water level variation on these parameters was unclear. Both water level and paddle rotational speed had negative impacts on the short-circuiting index, while no correlation was observed when varying inlet flow rate. In this study, the optimal operational conditions included low water level (0.1 m) and medium paddle rotational speed (11.6 rpm).

Flux of tritium from the sea to the atmosphere around a nuclear reprocessing plant: Experimental measurements and modelling for the Western English channel.

Tritium is released to the environment by nuclear industries in various forms, mainly HTO. In impact studies leading to estimated doses for the population, atmospheric discharges are mainly taken into consideration because they generally lead to values higher than those related to liquid discharges. However, the tritium released in liquid environments can be transferred to the atmosphere by evaporation and then be transported to terrestrial ecosystems by wind. This study was carried out in France near a fuel reprocessing plant (RP) which discharges tritium into the western English Channel. We highlighted the influence of a mass of water enriched with tritium on the HTO levels in atmospheric water vapour downwind through 18 field campaigns. A hydrodynamic model able to simulate tritium activity in the water was coupled with an evaporation an atmospheric transport model. It allows to reconstitute variations in atmospheric tritium on the coast, depending on liquid discharges of tritium from the reprocessing plant. On this basis, when seawater containing 20-100 Bq.L-1 of tritium flows between 0 and 10 km off the coast, variations in atmospheric activity onshore can increase of 2-15 Bq.L-1. Mean tritium quantities released by the sea into the atmosphere in the Western English Channel reached 130 TBq.y-1 over the 2017-2020 period. Emissions were estimated at 0.9-11.3 GBq km-2.y-1 and depends principally on the distance from the liquid discharge point. If we compare the "marine" source term, in HTO form, with the direct source term for gaseous discharges, the marine source term is one order of magnitude greater for the marine region affected by liquid discharges. Finally, we estimate that approximately 1.1% of tritium stock discharged at sea (regulated and controlled) return to the atmosphere each year at the scale of the Western English Channel.

9-phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels.

BACKGROUND AND PURPOSE: TRPM4 and TRPM5 are calcium-activated non-selective cation channels with almost identical characteristics. TRPM4 is detected in several tissues including heart, kidney, brainstem, cerebral artery and immune system whereas TRPM5 expression is more restricted. Determination of their roles in physiological processes requires specific pharmacological tools. TRPM4 is inhibited by glibenclamide, a modulator of ATP binding cassette proteins (ABC transporters), such as the cystic fibrosis transmembrane conductance regulator (CFTR). We took advantage of this similarity to investigate the effect of hydroxytricyclic compounds shown to modulate ABC transporters, on TRPM4 and TRPM5. EXPERIMENTAL APPROACH: Experiments were conducted using HEK-293 cells permanently transfected to express human TRPM4 or TRPM5. Currents were recorded using the whole-cell and inside-out variants of the patch-clamp technique. KEY RESULTS: The CFTR channel activator benzo[c]quinolizinium MPB-104 inhibited TRPM4 current with an IC(50) in the range of 2 x 10(-5) M, with no effect on single-channel conductance. In addition, 9-phenanthrol, lacking the chemical groups necessary for CFTR activation, also reversibly inhibited TRPM4 with a similar IC(50). Channel inhibition was voltage independent. The IC(50) determined in the whole-cell and inside-out experiments were similar, suggesting a direct effect of the molecule. However, 9-phenanthrol was ineffective on TRPM5, the most closely related channel within the TRP protein family. CONCLUSIONS AND IMPLICATIONS: We identify 9-phenanthrol as a TRPM4 inhibitor, without effects on TRPM5. It could be valuable in investigating the physiological functions of TRPM4, as distinct from those of TRPM5.

Urban stormwater treatment by a constructed wetland: Seasonality impacts on hydraulic efficiency, physico-chemical behavior and heavy metal occurrence.

Urban stormwater affects the general quality of water bodies because of their hydraulic and pollution impacts. Stormwater discharges modify stream water flow and are reported as major source of heavy metals (HMs) in urban streams. Stormwater Constructed Wetlands (SCWs) have been built worldwide to manage stormwater before it is released into hydrosystems. In SCWs, stormwater is stored, evaporated and sometimes infiltrated. Subsequently, the HMs in stormwater can be settled, filtered and bioassimilated by microorganisms. Hence, the efficiency of SCWs in managing stormwater depends on climatic conditions, which change with season. The aim of this study was to investigate the impacts of seasonality on the performance of a 6-year-old constructed wetland made with a pond followed by a vertical flow filter. Hydraulic performance of, physico-chemical behaviour of, and HM mitigation via the SCW were evaluated using over 3 years of monitoring (2015-2017) data. Only 35% of the rain events that occurred in the studied catchment caused a discharge into the pond and 17% into the filter. The SCW was mostly supplied with stormwater in spring and summer and provided peak flow attenuation from 97 to 100% in all seasons. Variations in physico-chemical parameters (temperature, dissolved oxygen, pH, and redox potential) were caused by seasonal and dry/wet weather changes. They were greater in the pond than in the filter, which buffers these variations. The high physico-chemical variations in the pond probably had a deleterious effect on HM storage in the pond sediments. Finally, hydrologic and physico-chemical conditions (antecedent dry period length, pH, redox potential) affected the HM concentrations along the SCW. However, HM removal efficiencies were >97% in all seasons.

Micropollutants removal and storage efficiencies in urban stormwater constructed wetland.

Stormwaters is identified as a major source of pollution in waterbodies. Particularly, heavy metals (HMs) and Polycyclic Aromatic Hydrocarbons (PAHs) in stormwater are highly toxic compounds for living organisms. To limit the impact of these micropollutants on hydrosystems quality, stormwater constructed wetlands (SCWs) have been built worldwide. This study aims to i) assess the efficiency of a SCW that combines a sedimentation pond followed by a vertical flow sand filter in urban area (Strasbourg 67, France) and ii) determine micropollutants storage in water and soils during dry periods. Stormwater quality was analysed during 13 sampling sessions and the SCW storage ability during dry period was highlighted. The rainfall events sampled are characterized by very high variability: dry periods lasted from 5 h to 10 d, rain durations varied from 15 min to 22 h and the return periods were between 2 and 4 wk. and 3-6 mo. The inflow stormwater included a high amount of Zn and a variety of PAHs. Cu, Zn and some PAHs concentrations are impacted by hydrological characteristics. During a rain event, the filter catches the majority of both dissolved and particulate micropollutants and the mobilization of particulate micropollution by incoming flow decreases pond removal efficiency. The treatment removal efficiency varied from 50% (naphthalene) to 100% (particulate Zn). Four HMs (Co, Cu, Pb, Zn) were found in the pond and seven (Cd, Cr, Co, Cu, Ni, Pb, Zn) in the filter during a dry period at high concentrations compared to their occurrence in rainfall. A release of HMs from the filter sand to the interstitial water is highlighted. In water and the soil matrix, PAHs occurrence was consistent with their water solubility, logKow and logKoc.

Effects of atrial natriuretic peptide on rat ventricular fibroblasts during differentiation into myofibroblasts.

Atrial natriuretic peptide antifibrotic properties are mainly described in cardiac myocytes or in induced cardiac myofibroblasts (Angiotensin II or TGF-beta induced differentiation). In the present work, we investigate the effects of ANP/NPRA/cGMP system in modulating rat cardiac fibroblasts function. Cardiac fibroblasts were isolated from adult Wistar male rats and cultured in the presence of serum in order to induce fibroblasts differentiation. Cultures were then treated with ANP (1 microM), 8-Br-cGMP (100 microM) or IBMX (100 microM), a non-specific phosphodiesterases inhibitor. ANP significantly decreased proliferation rate and collagen secretion. Its effect was mimicked by the cGMP analog, while combining ANP with 8-Br-cGMP did not lead to additional effects. Moreover intracellular cGMP levels were elevated when cells were incubated with ANP confirming that ANP intracellular pathway is mediated by cGMP. Additionally, immunoblotting and immunofluorescence were used to confirm the presence of guanylyl cyclase specific natriuretic peptide receptors A and B. Finally we scanned specific cGMP dependent PDEs via RT-qPCR, and noticed that inhibiting all PDEs led to an important decrease in proliferation rate. Effect of ANP became more prominent after 10 culture days, confirming the importance of ANP in fibroblasts to myofibroblasts differentiation. Uncovering cellular aspects of ANP/NPRA/cGMP signaling system provided more elements to help understand cardiac fibrotic process.

Remediation of sediment and water contaminated by copper in small-scaled constructed wetlands: effect of bioaugmentation and phytoextraction.

The use of plants and microorganisms to mitigate sediment contaminated by copper was studied in microcosms that mimic the functioning of a stormwater basin (SWB) connected to vineyard watershed. The impact of phytoremediation and bioaugmentation with siderophore-producing bacteria on the fate of Cu was studied in two contrasted (batch vs. semi-continuous) hydraulic regimes. The fate of copper was characterised following its discharge at the outlet of the microcosms, its pore water concentration in the sediment, the assessment of its bioaccessible fraction in the rhizosphere and the measurement of its content in plant tissues. Physico-chemical (pH, redox potential) and biological parameters (total heterotrophic bacteria) were also monitored. As expected, the results showed a clear impact of the hydraulic regime on the redox potential and thus on the pore water concentration of Cu. Copper in pore water was also dependent on the frequency of Cu-polluted water discharges. Repeated bioaugmentation increased the total heterotrophic microflora as well as the Cu bioaccessibility in the rhizosphere and increased the amount of Cu extracted by Phragmites australis by a factor of ~2. Sugar beet pulp, used as a filter to avoid copper flushing, retained 20% of outcoming Cu and led to an overall retention of Cu higher than 94% when arranged at the outlet of microcosms. Bioaugmentation clearly improved the phytoextraction rate of Cu in a small-scaled SWB designed to mimic the functioning of a full-size SWB connected to vineyard watershed. Highlights: Cu phytoextraction in constructed wetlands much depends on the hydraulic regime and on the frequency of Cu-polluted water discharges. Cu phytoextraction increases with time and plant density. Cu bioaccessibility can be increased by bioaugmentation with siderophore-producing bacteria.

Phenytoin preferentially inhibits L-type calcium currents in whole-cell patch-clamped cardiac and skeletal muscle cells.

The effect of the anticonvulsant diphenylhydantoin (phenytoin) was tested on the inward calcium currents of whole-cell patch-clamped cells from rat and human muscles and from frog atrium. A concentration of 10 microM phenytoin was required to obtain a threshold inhibitory effect and, even with high concentrations (100 microM), the inhibition was not complete. In skeletal muscle (rat and human cells in culture), phenytoin (30 microM) exerted a more potent effect on the high-threshold calcium current (ICa,L inhibition: 53 +/- 6% mean +/- SDn-1) rather than on the low-threshold one (ICa,T inhibition: 16 +/- 10%). Similar results were obtained on dissociated frog atrial cells. These data are to be contrasted with those previously reported on neuronal cells, where specific inhibition of ICa,T was reported. Thus, the action of phenytoin appears to be different in muscle and nerve so that phenytoin does not appear to be a specific inhibitor of ICa,T.

Calcium and melatonin production in dissociated trout pineal photoreceptor cells in culture.

Trout pineal cells maintained in primary culture produce melatonin in high amounts during night time and low amounts during daytime. The dark-induced increase in melatonin production was enhanced, in a dose-dependent manner, by elevating extracellular calcium concentration. Low external calcium concentration reduced nocturnal and diurnal melatonin production. Bay K 8644 increased, in a dose-dependent manner, the dark-induced rise in melatonin output, and this effect was antagonized by nifedipine and verapamil. This suggests a role for the dihydropyridine calcium channels in the regulation of the melatonin output. To confirm this, patch-clamp recordings (whole-cell perforated) were run in a 20 mmol/l barium medium at different holding potentials from -80 mV. A voltage-dependent inward current was activated from -30 mV to +40 mV with a maximal amplitude being observed at 0 mV. This current was drastically increased in the presence of Bay K 8644. Nifedipine inhibited the current both in the absence or in the presence of Bay K 8644. Our results are consistent with the idea that extracellular calcium participates in the control of melatonin secretion by photoreceptor cells. It is suggested that activation of the voltage-dependent L-type channel may modulate this secretion.

Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells.

1. The effect of the bradycardic agent S 16257 on the main ionic mechanisms of diastolic depolarization in sinoatrial node cells isolated from rabbit heart, was investigated by the patch-clamp technique in whole-cell and macro-patch recordings. 2. In whole-cell conditions, S 16257 induced a marked exponential use-dependent blockade of the hyperpolarization-activated I(f) current, without shift of the voltage range of its activation curve. The rate of block increased with the drug concentration. The IC50 for the block of I(f) was 2.8 x 10(-6) M. 3. A similar use-dependent decline of I(f) was obtained with 3 microM S 16257, in cell-attached and in inside out macro-patch configurations, suggesting that the bradycardic agent interacts with I(f) channels from the inside of the cell. 4. A high concentration of S 16257 (10 microM) had no detectable effect on T-type calcium current and slightly decreased L-type calcium current (-18.12 +/- 0.66%), without significant use-dependent blockade. 5. S 16257 had no effect on the delayed outward potassium current Ik at 3 microM and slightly decreased it only at high concentrations, -16.3 +/- 1.2% at 10 microM. In contrast, zatebradine, another bradycardic agent, reduced I k by 20.3 +/- 2.5% at 3 microM. 6. In conclusion, S 16257 may lower heart rate without significant negative inotropic action. In comparison with zatebradine, S 16257 had less effect on Ik suggesting less prolongation of repolarization time.

Effect of human chorionic gonadotrophin on chloride current in human syncytiotrophoblasts in culture.

Human trophoblast differentiates in vivo and in vitro by the fusion of cytotrophoblastic cells to form syncytiotrophoblasts. A large amount of human chorionic gonadotrophin (hCG) is produced by the syncytiotrophoblasts, which express hCG luteinizing hormone (LH) receptors. Since recent investigations with electrophysiological techniques support the conclusion that hormonal effects can be mediated by modulations of the membrane ionic conductances of the cells, a perforated patch-clamp technique was used to investigate the possible presence of a chloride current evoked by hCG. The perifusion of hCG (500 mIU/ml) activated a time-independent current, which presents a linear current-voltage (I/V) relationship in symmetrical chloride concentrations. The reversal potential was -1.8 mV with 142 mM Cl- external solution and 134 mM cl- internal solution. This reversal potential shifted with changes in the transmembrane Cl- gradient. Moreover, this hCG-induced current was sensitive to 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) (50 microM), to diphenylalamine-2-carboxylic acid (DPC) (0.5 mM) and to 9-AC (1 mM), three known chloride channel blockers. These results confirm the autocrine action of hCG in the physiology of the trophoblast.

Effects of two chemically related new Ca2+ channel antagonists, SR33557 (fantofarone) and SR33805, on the L-type cardiac channel.

Fantofarone (SR33557) is a substituted indolizine and SR33805 is a substituted indole. These drugs have been shown to specifically bind to the alpha 1 subunit of the L-type Ca2+ channel at the same site, distinct from those of the classical 1,4-dihydropyridine, phenylalkylamine or benzothiazepine Ca2+ antagonists, but in negative allosteric interaction with them. The present work shows that fantofarone and SR33805 block L-type but not T-type Ca2+ channels in mouse cardiac cells in primary culture. This block is voltage-dependent. Fantofarone and SR33805 are potent Ca2+ channel blockers in depolarized conditions (i.e. at a holding potential of -40 mV) with an EC50 = 1.4 and 4.1 nM, respectively. In polarized conditions (i.e. at a holding potential of -80 mV), SR33805 is a better Ca2+ channel blocker (EC50 = 33 nM) than fantofarone (EC50 = 0.15 microM). Therefore differences in their chemical structures make the blocking action of fantofarone more sensitive to voltage than that of SR33805.

Current and future contributions of transgenic mice to the analysis of germline toxicology.

Evermore sophisticated tests are need to study germline toxicology. The gene conversion-based systems developed in Leicester and in the USA are steps in the right direction, but a lot of validation both in vivo and in vitro is required. Transgenic technology can also be used to research the biology of testis, so that we know more how to make it more human-like. If you talk to toxicologists, they always complain: 'but it 's only a rat, it's only a mouse, it's not a man'. In future, once we understand more biology--it might be possible to make the toxicological response of a transgenic mouse more human-like. As we all know, the testis is a complex biological system and it is only when we get a better understanding of what is going on to the fundamental level are such developments possible. Indeed, it might be possible to do even more exciting things, such as taking mitotic human tissue culture cells and to inducing them to enter meiosis in vitro. Such a system would be a natural complement to the in vitro tests widely used in industry.

The voltage-dependent effect of Agauria salicifolia leaf extract on the sodium current of isolated frog skeletal and cardiac muscle cells.

An ethanolic extract of leaves of Agauria salicifolia was tested on voltage-clamped isolated skeletal and cardiac frog muscle cells using the double sucrose-gap (skeletal) and the whole-cell patch-clamp (cardiac) methods, at concentrations ranging from 10(-8) to 5 x 10(-5) g/l. At 10(-6) g/l a progressive and limited decrease was observed in resting membrane potential (approximately 5 mV). On normally polarized cells (-90 mV) the extract induced a dose- and use-dependent increase in the transient inward current which is accounted for by an increase in the sodium membrane conductance and an opposite shift of the activation and inactivation curves vs. potential. This agonistic effect on INa is fully reversed when the holding potential is maintained depolarized above -80 mV as a result of an actual decrease in the sodium conductance and a reversal of the shifts of activation and activation curves. The inhibitory effect observed on depolarized fibres can be partially relieved by a subsequent repolarization. It is concluded that the extract acts on the sodium channel regardless of its state (resting, activated and inactivated) on at least two different sites.

The effects of Agauria salicifolia leaf extract on calcium current and excitation-contraction coupling of isolated frog muscle cells.

The effects of the ethanolic extract of Agauria salicifolia (AS) previously tested on sodium currents of normal and TTX-treated voltage-clamped skeletal and cardiac muscle cells was investigated on mechanisms involved in the excitation-contraction coupling of the same biological preparations. AS (10(-6) g/l) prolonged the action potential duration whereas the associated contraction was depressed. This is not due to the blocking action of AS on the tubular sodium current since similar results were obtained in the presence of high tetrodotoxin (TTX) concentrations. This is not due to some blocking action of AS on the L-type calcium current since this type of calcium current was enhanced by the extract. In contrast, the cardiac T-type calcium current was decreased by 10(-6) g/l AS. AS exerted a dose-dependent (tested for concentrations ranging from 5 x 10(-10) to 5 x 10(-5) g/l) inhibition of the two components of the contractile response elicited by durable depolarizations, with a prominent effect on the tonic phase. This effect was partially relieved by increasing the external divalent cation (Ca2+ or Cd2+) concentration. At the same concentration it shifted the inactivation/potential relationship for tension by 20 mV towards negative potentials. It is concluded that the inhibitory action of AS on excitation-contraction coupling is partly or completely due to the enhancement of the voltage- and Ca(2+)-dependent inactivation processes of the voltage-sensor.

Uranium-thorium disequilibrium in north-east Atlantic waters.

In this paper we report and compare the concentrations of 234Th and 238U measured in surface and subsurface waters collected in the course of a sampling campaign in the north east Atlantic in June-July 1998. Dissolved 234Th concentrations in surface waters ranged from 5 to 20 Bq m(-3), showing a large deficiency relative to 238U concentrations (typically 42 Bq m-3). This disequilibrium is indicative of active 234Th scavenging from surface waters. Observed 234Th/238U activity ratios, together with corresponding 234Th particulate concentrations, were used to calculate mean residence times for 234Th with respect to scavenging onto particles (tau(diss)) and subsequent removal from surface waters (tau(part)). Residence times in the range 5-30 days were determined for tau(diss) and 4-18 days for tau(part) (n=14). In addition, ultrafiltration experiments at six stations in the course of the same expedition revealed that in north-east Atlantic surface waters a significant fraction (46+/-17%; n=6) of the thorium in the (operationally-defined) dissolved phase (<0.45 microm) is in colloidal form. These observations are consistent with the 'colloidal pumping' model in which it is assumed that 234Th is rapidly absorbed by colloidal particles, which then aggregate, albeit at a slower rate, into larger filterable particles. In essence, colloids act as intermediaries in the transition from the fully dissolved to the filter-retained (>0.45 microm) phase. Thus, the time (tau(c)) for fully dissolved 234Th to appear in the filter-retained fraction is dependent on the rate of colloidal aggregation. Here, we determined tau(c) values in the range 3-17 days.

Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism.

BACKGROUND AND PURPOSE: The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF. EXPERIMENTAL APPROACH: Human CF airway epithelial cells were treated with roscovitine 100 µM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca(2+) on the F508del-CFTR/calnexin interaction and by measuring proteasome activity. KEY RESULTS: Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca(2+) and (ii) to directly inhibit the proteasome activity in a Ca(2+) -independent manner. CONCLUSIONS AND IMPLICATIONS: Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF.

Sarcoplasmic reticulum: a key factor in cardiac contractility of sea bass Dicentrarchus labrax and common sole Solea solea during thermal acclimations.

This study investigated the effects of acclimation temperature upon (i) contractility of ventricular strips (ii) calcium movements in ventricular cardiomyocytes during excitation-contraction coupling (ECC), and (iii) the role of the sarcoplasmic reticulum (SR) in myocardial responses, in two marine teleosts, the sea bass (Dicentrarchus labrax) and the common sole (Solea solea). Because of the different sensitivities of their metabolism to temperature variation, both species were exposed to different thermal ranges. Sea bass were acclimated to 10, 15, 20, and 25 °C, and common sole to 6, 12, 18, and 24 °C, for 1 month. Isometric tension developed by ventricular strips was recorded over a range of physiological stimulation frequencies, whereas the depolarization-induced calcium transients were recorded on isolated ventricular cells through hyperpotassic solution application (at 100 mM). The SR contribution was assessed by ryanodine (RYAN) perfusion on ventricular strips and by caffeine application (at 10 mM) on isolated ventricular cells. Rates of contraction and relaxation of ventricular strip, in both species, increased with increasing acclimation temperature. At a low range of stimulation frequency, ventricular strips of common sole developed a positive force-frequency relationship at high acclimation temperature. In both the species, SR Ca(2+)-cycling was dependent on fish species, acclimation temperature and pacing frequency. The SR contribution was more important to force development at low acclimation temperatures in sea bass but at high acclimation temperatures in common sole. The results also revealed that high acclimation temperature causes an increase in the maximum calcium response amplitude on ventricular cells in both the species. Although sea bass and common sole occupy similar environments and tolerate similar environmental temperatures, this study indicated that sea bass and common sole can acclimatize to new thermal conditions, adjusting their cellular process in a different manner.