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Background and aim Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) is one of these plants sufficiently exploited in traditional African medicine for its hypotensive effect. However, the pharmacological effects of those plants on cardiac functions are not well known. The potassium currents IKs and IKr, responsible for the repolarization of cardiac cell action potential, strongly influence the human cardiac rhythm. Therefore, modulators of these currents have a beneficial or undesirable medical importance in relation to cardiac arrhythmias. In order to optimize the therapeutic use of this medicinal plant, we studied the effects of hydro-ethanolic leaf extract of Hydrocotyle bonariensis on both potassium currents. Experimental procedure The patch clamp experiments for IK currents recording were performed on the HEK 293 (Human Embryonic Kidney 293) cell line, stably transfected with either KCNQ1 and KCNE1 genes encoding the channel responsible for the "IKs" current (HEK293 IKs), or with hERG (human ether-a-go-go related gene) gene encoding "IKr" current (HEK293 IKr). Results and conclusion This study revealed that the hydro-ethanolic leaf extract of H. bonariensis significantly inhibits the slow potassium component (IKs) without altering the fast potassium component (IKr). The extract at 0.5 mg/ml decreases IKs conductance by 24 ± 4.1% (n = 6) without modifying its activation threshold suggesting a direct blockade of the slow potassium channel. This selective action of the extract on the IKs current reflects a class III anti-arrhythmic effect.

Despite the fact that PolyUnsaturated Fatty Acids (PUFA) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. PUFA are particularly enriched in the membrane Phospholipids (PLs) of selective organs, among which skeletal muscles and the cardiovascular system are prime examples. The fatty acid composition of PLs is known to regulate crucial membrane properties, including rigidity, elasticity and plasticity. Since muscle cells undergo repeated cycles of elongation and relaxation and are constantly exposed to mechanical stress, we postulated in the present study that PUFA-containing PLs could be central players for muscle cell adaptation to mechanical constraints. By a combination of in cellulo and in silico approaches, we show that PUFA, and particularly the ω-3 DocoHexaenoic Acid (DHA), regulate important properties of the plasma membrane that improve muscle cell resilience to mechanical constraints. Thanks to their unique property to contortionate within the bilayer plane, they facilitate the formation of Vacuole-like dilation (VLD) which, in turn, reduce membrane stress and avoid cell breakage under mechanical constraints.

International audience; BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to

The balance within phospholipids (PLs) between saturated fatty acids and monounsaturated or polyunsaturated fatty acids is known to regulate the biophysical properties of cellular membranes. As a consequence, in many cell types, perturbing this balance alters crucial cellular processes, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spread of the Western diet, which is highly enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome known as metabolic syndrome (MetS). MetS is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis; however, no clear correlations have been established between diet-induced fatty acid redistribution within cellular PLs and the severity/chronology of the symptoms associated with MetS or the function of the targeted organs. To address this issue, in this study we analyzed PL remodeling in rats exposed to a high-fat/high-fructose diet (HFHF) over a 15-week period. PL remodeling was analyzed in several organs, including known MetS targets. We show that fatty acids from the diet can redistribute within PLs in a very selective manner, with phosphatidylcholine being the preferred sink for this redistribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the expense of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs. This article has an associated First Person interview with the first author of the paper., Summary: In rats, a high-fat diet induces the selective distribution of fatty acids within phosphatidylcholine in the liver and muscles, in a manner that correlates with organ dysfunction. The cardiovascular system appears to be protected under these conditions.

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB., Graphical Abstract

Engineering low-frequency phonon transport in nanostructures with the phonon resonant mechanism has become an important research direction. On the basis of non-equilibrium molecular dynamics simulations, the thermal transport in pristine and resonant Si-membranes bounded with {100}, {110} and {111} facets is investigated. It is found that the creation of surfaces can introduce anisotropic thermal transport due to the lattice symmetry breaking. Besides, ballistic phonon transport is found in pristine membranes with lengths up to 500 nm at low-frequencies with a critical frequency mainly dependent on the crystallographic orientation. Moreover, although surface resonances can dramatically reduce the thermal conductivity of all membranes, the resonant effect strongly relies on membrane orientation. Among the three studied membrane orientations, the resonant effect is maximized in the {111}-membrane, where the thermal conductivity is tuned from the largest one to the smallest one among the three membrane types by resonant pillars. The large thermal conductivity reduction in the {111}-membranes by resonances originated from the reduced spectral heat flux between 3 and 12 THz. Furthermore, the resonant coupling strength can be tuned by the interface vacancy between resonant pillars and the base material, which can enhance phonon transport at an intermediate frequency range. Our work provides further insights on thermal transport engineering by phonon resonances and could be useful for thermal conductivity engineering with surface orientations and resonances.

The balance within phospholipids (PL) between Saturated Fatty Acids (SFA) and mono- or poly-Unsaturated Fatty Acids (UFA), is known to regulate the biophysical properties of cellular membranes. As a consequence, perturbating this balance alters crucial cellular processes in many cell types, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spreading of the Western-diet, which is specifically enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome, known as the Metabolic Syndrome (MetS), which is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis. However, no clear correlations between diet-induced fatty acid redistribution within cellular PL, the severity/chronology of the symptoms associated to MetS and the function of the targeted organs, particularly in the early onset of the disease, have been established. In an attempt to fill this gap, we analyzed in the present study PL remodeling in rats exposed during 15 weeks to a High Fat/High Fructose diet (HFHF) in several organs, including known MetS targets. We show that fatty acids from the diet can distribute within PL in a very selective way, with PhosphatidylCholine being the preferred sink for this distribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the exception of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs.

Magnetite (Fe3O4) deposits in the secondary circuit of nuclear pressurized water reactors (PWRs), lead to the fouling of the steam generators (SG) which decreases their thermal performances and increases the risk of corrosion of the SG tubes. As a counteraction, preventive and curative chemical cleanings (CCC) are industrially implemented to remove oxides sludges and deposits in SGs. The use of chelating agents in chemical cleaning processes could affect the passive layer of SG tubes, and modify their surface reactivity. In order to better understand these phenomena, two experimental loops have been designed and operated: the FORTRAND loop to perform and investigate SG tube oxidation, fouling and refouling and the ECCLIPS loop used to investigate the effects of the chemical cleanings. A three steps strategy has been implemented as follows: (i) reproducing magnetite deposits on oxidized SG tubes, (ii) applying three different industrial chemical cleaning procedures (a curative and two preventive ones) and (iii) studying the redeposition (refouling) of magnetite. The fluid physico-chemical conditions upon these steps have been thoroughly followed and controlled. Magnetite deposits formed on the SG tubes upon the first fouling have been characterized by scanning and transmission electron microscopies (SEM and TEM) and X-ray diffraction (XRD). They are shown to be composed of a dense layer of small magnetite crystals. Secondly, three different SG industrial cleaning processes were reproduced. Their timing and thermo-chemical conditions were strictly respected and they were found to dissolve most of the fouling deposit. Disperse magnetite crystallites were present on the tube surface. Moreover, TEM cross-section images showed that no general attack of the tube passive layer occurred. Finally, the cleaned tubes were fouled again in the FORTRAND loop using the same experimental conditions as for the first fouling step. It could be concluded that chemical cleanings have no effect on the fouling kinetics of the SG tubes for a short one month period and that the amount of deposit formed before and after the cleanings was identical. The small crystallite dense layer observed before cleaning was not present on refouled tubes and the size of the crystallites was bigger after the cleanings. For a short time period, this morphology could result in the formation of a fouling deposit with more porosity. As the increase of deposit porosity can impact the thermal transfer at the SG tube surface, morphological changes, hardly predictable, could be important for the SG thermal performance after chemical cleaning. For a longer period, frequent SG cleaning applications should prevent the densification of the deposit and thus delay performance loss over time. To the best of our knowledge, this experimental program is the first study of chemical cleaning impacts on SG tubes reactivity.

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1–3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2 . In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.

Rapid progress in high-speed, densely packed electronic/photonic devices has brought unprecedented benefits to our society. However, this technology trend has in reverse led to a tremendous increase in heat dissipation, which degrades device performance and lifetimes. The scientific and technological challenge henceforth lies in efficient cooling of such high-performance devices. Here, we report on evaporative electron cooling in asymmetric Aluminum Gallium Arsenide/Gallium Arsenide (AlGaAs/GaAs) double barrier heterostructures. Electron temperature, Te, in the quantum well (QW) and that in the electrodes are determined from photoluminescence measurements. At 300 K, Te in the QW is gradually decreased down to 250 K as the bias voltage is increased up to the maximum resonant tunneling condition, whereas Te in the electrode remains unchanged. This behavior is explained in term of the evaporative cooling process and is quantitatively described by the quantum transport theory., Designing efficient integrated cooling solutions by controlling heat management in nanodevices remains a challenge. Here, the authors propose evaporative electron cooling in the AlGaAs/GaAs double barrier heterostructures quantum well achieving up to 50 K electron temperature reduction at 300 K.

Electron-phonon coupling limited transport in phosphorene metal oxide semiconductor field effect transistors (MOSFETs) is studied along the armchair (AC) and zigzag (ZZ) directions. In a multiscale approach, the unit cell of phosphorene is first relaxed, and the band structure is calculated using hybrid density functional theory (DFT). The transport equations are then solved quantum mechanically under the nonequilibrium Green’s function formalism using DFT-calibrated two-band k ⋅ p hamiltonian. The treatment of electron-phonon scattering is done under the self-consistent Born approximation in conjunction with deformation potential theory. It is found that optical phonon modes are largely responsible for degradation of ON-current apart from p-channel AC MOSFET where acoustic phonon modes play a stronger role. It is further observed that electron-phonon scattering is more pronounced in the ZZ direction, whereas the diffusive ON-current of p-MOSFET in a given direction is higher than n-MOSFET. Further study on the complex band structure of phosphorene reveals band wrapping within the bandgap region in the AC direction and multiple crossings in the ZZ direction. This signifies strong phonon-assisted tunneling in the ZZ direction in comparison with the AC direction. For completeness, drain current in the AC tunnel field effect transistor is calculated, and electron-phonon scattering is observed only in the near vicinity of the OFF-current.

International audience; Long term and high resolution data on water discharge, suspended particulate matter (SPM) and contaminant concentrations in rivers are required for a better understanding of particulate transfers from the continental areas to the seas. The aim of this study was to provide a novel estimation of annual fluxes of SPM and related pollutants in the Rhône River from Lake Geneva to the Mediterranean Sea by combining high frequency or time-integrative monitoring and novel relations between SPM concentration (Cs) and water discharge (Q). At six stations of the Rhône Sediment Observatory (OSR), SPM fluxes were calculated over the 2000-2016 period by combining observational data and Cs-Q relations. Monthly average concentrations of mercury (Hg) and PCB 180 were obtained by analysis of SPM samples collected in time integrative particle traps between 2011 and 2016. These pollutants were selected because of the well documented contamination of the Rhône watershed by these substances. Inter-annual fluxes at the Rhône River outlet averaged 6.6 Mt yr-1 for SPM, 572 kg yr-1 for Hg and 14 kg yr-1 for PCB 180. The Isère and Durance tributaries were found to be the main contributors of SPM fluxes. Annual SPM budgets were not balanced, suggesting deposition, remobilization of bottom sediments and/or contributions from non-monitored tributaries. The SPM sampled at the outlet was more contaminated than the combined SPM inputs from the monitored tributaries, suggesting that intermediate sources of contamination were not captured in the budget.

We investigate numerically the impact of the electron-phonon scattering on the optical properties of a perovskite material (CH3NH3PbI3). Using non-equilibrium Green functions formalism, we calculate the local density-of-states for several values of the electron-phonon scattering strength as well as in the case of ballistic transport. We report an Urbach-like penetration of the density-of-states in the bandgap due to scattering. The density-of-states expands deeper in the bandgap with the scattering strength. We determine the electronic current contributions relative to photon absorption and photon emission. This allows to estimate the Urbach energy from the absorption coefficient below the bandgap. Values of Urbach energy up to 9.5 meV are obtained, meaning that scattering contribution to the total experimental Urbach energy of 15meV is quite important. The Urbach tail is generally attributed to the disorder of the system, leaving hope for further improvement. Yet, we show in this work that a significant contribution to the Urbach tail comes from carriers-phonon interactions, an intrinsic properties of the material which thus set a lower bound on the improvement margin. Finally, we estimate the open-circuit voltage Voc for a solar cell assuming such a material as an absorber. Voc losses increase with the scattering strength, up to 41 mV. This study then confirms that scattering of electrons in perovskite material modifies the optical behaviour.

This work highlights the intrinsic modification of the electronic density-of-states due to electron-phonon scattering. Using a quantum model we show that, by broadening the density-of-states in the bandgap, the scattering changes the absorption/emission ratio and then some photovoltaic parameters like V oc . For the high mobility GaAs material we obtain a moderate V oc reduction of 4mV. In the highly polar CH 3 NH 3 PbI 3 perovskite material, even through the mobility is low, the broadening in the density-of-states is limited by the small phonon energy and then the V oc reduction remains inferior to 41mV.

We investigate the effect of the geometrical model adopted for the gate electrode and for the insulator enveloping the access regions on the full-quantum simulation of ultrascaled nanowire FETs (NW-FETs). We compare the results obtained in the “minimal” geometry commonly used in simulations with those obtained in a more realistic one, able to fully account for the gate fringing effects. We evaluate the impact of the model geometry on the static performance of NW-FETs and discuss the interplay with the surface roughness and the random distribution of dopants. We find that the ${I}_{ \mathrm{\scriptscriptstyle ON}}/{I}_{ \mathrm{\scriptscriptstyle OFF}}$ ratio evaluated in the minimal geometry can be remarkably underestimated in short devices, notably in the case of small length-to-width ratio. The roughness-induced current degradation and the sensitivity to the surface roughness variability can also suffer from nonnegligible underestimations when evaluated in this geometry. Finally, we point out that an inaccurate description of the device electrostatics is expected to result in an overestimation of the sensitivity to the doping-induced variability.

International audience; Monitoring hydrophobic contaminants in surface freshwaters requires measuring contaminant concentrations in the particulate fraction (sediment or suspended particulate matter, SPM) of the water column. Particle traps (PTs) have been recently developed to sample SPM as cost-efficient, easy to operate and time-integrative tools. But the representativeness of SPM collected with PTs is not fully understood, notably in terms of grain size distribution and particulate organic carbon (POC) content, which could both skew particulate contaminant concentrations. The aim of this study was to evaluate the representativeness of SPM characteristics (i.e. grain size distribution and POC content) and associated contaminants (i.e. polychlorinated biphenyls, PCBs; mercury, Hg) in samples collected in a large river using PTs for differing hydrological conditions. Samples collected using PTs (n = 74) were compared with samples collected during the same time period by continuous flow centrifugation (CFC). The grain size distribution of PT samples shifted with increasing water discharge: the proportion of very fine silts (2-6 µm) decreased while that of coarse silts (27-74 µm) increased. Regardless of water discharge, POC contents were different likely due to integration by PT of high POC-content phytoplankton blooms or low POC-content flood events. Differences in PCBs and Hg concentrations were usually within the range of analytical uncertainties and could not be related to grain size or POC content shifts. Occasional Hg-enriched inputs may have led to higher Hg concentrations in a few PT samples (n = 4) which highlights the time-integrative capacity of the PTs. The differences of annual Hg and PCB fluxes calculated either from PT samples or CFC samples were generally below 20%. Despite some inherent limitations (e.g. grain size distribution bias), our findings suggest that PT sampling is a valuable technique to assess reliable spatial and temporal trends of particulate contaminants such as PCBs and Hg within a river monitoring network.

Recently, a new population of resident cardiac stem cells (CSCs) positive for the W8B2 marker has been identified. These CSCs are considered to be an ideal cellular source to repair myocardial damage after infarction. However, the electrophysiological profile of these cells has not been characterized yet. We first establish the conditions of isolation and expansion of W8B2+ CSCs from human heart biopsies using a magnetic sorting system followed by flow cytometry cell sorting. These cells display a spindle-shaped morphology, are highly proliferative, and possess self-renewal capacity demonstrated by their ability to form colonies. Besides, W8B2+ CSCs are positive for mesenchymal markers but negative for hematopoietic and endothelial ones. RT-qPCR and immunostaining experiments show that W8B2+ CSCs express some early cardiac-specific transcription factors but lack the expression of cardiac-specific structural genes. Using patch clamp in the whole-cell configuration, we show for the first time the electrophysiological signature of BKCa current in these cells. Accordingly, RT-PCR and western blotting analysis confirmed the presence of BKCa at both mRNA and protein levels in W8B2+ CSCs. Interestingly, BKCa channel inhibition by paxilline decreased cell proliferation in a concentration-dependent manner and halted cell cycle progression at the G0/G1 phase. The inhibition of BKCa also decreased the self-renewal capacity but did not affect migration of W8B2+ CSCs. Taken together, our results are consistent with an important role of BKCa channels in cell cycle progression and self-renewal in human cardiac stem cells.

This paper proposes a theoretical analysis of electronic transport in ultrathin (220 nm) single-junction GaAs solar cell. Using an in-house electronic quantum transport model, we shed light on two detrimental phenomena, namely the “back-diffusion” and the “contact-to-contact diffusion.” While the back-diffusion degrades both the short-circuit current and the fill factor, the contact-to-contact diffusion reduces the open-circuit voltage. The so-called window and back-surface-field barriers used to reflect minority carriers away from contacts reduce these two detrimental phenomena. In a second part, we then show a synthesis of performance optimization of window/GaAs/back-surface-field heterojunctions varying thicknesses, materials, and material composition profiles. Our results conclude that the $\mathrm{\text{Al}_{0.4}\text{Ga}_{0.6}\text{As}(10\; nm)/\text{GaAs}/\text{In}_{0.49}\text{Ga}_{0.51}P(10\; nm)}$ structure provides the best output power.

Dodoneine (Ddn) is one of the active compounds identified from Agelanthus dodoneifolius, which is a medicinal plant used in African pharmacopeia and traditional medicine for the treatment of hypertension. In the context of a scientific program aiming at discovering new hypotensive agents through the original combination of natural product discovery and superacid chemistry diversification, and after evidencing dodoneine’s vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III) and L-type Ca2+ current inhibition. These derivatives can now be considered as new lead compounds for vasorelaxant therapeutics targeting these two proteins.

International audience; There has been significant work investigating the use of self assembled monolayers (SAMs) made of ferrocenyl terminated alkanethiols for realizing molecular diodes, leading to remarkably large forward-to-reverse current rectification ratios. In this study, we use a multiband barrier tunneling model to examine the electrical properties of SAM-based molecular diodes made of HSC 9 Fc, HSC 11 Fc, and HSC i FcC 13Ài (0 i 13). Using our simple physical model, we reproduce the experimental data of charge transport across various ferrocenyl substituted alkanethiols performed by Nijhuis, Reus, and Whitesides [J. Am. Chem. Soc. 132, 18386–184016 (2010)] and Yuan et al. [Nat. Commun. 6, 6324 (2015)]. Especially, the model allows predicting the rectification direction in HSC i FcC 13Ài (0 i 13) based molecular diodes depending on the position of the ferrocenyl (Fc) moiety within the molecules. We show that the asymmetry of the barrier length at both sides of the Highest Occupied Molecular Orbital of the ferrocenyl moiety strongly contributes to the rectifying properties of ferrocenyl-alkanethiol based molecular junctions. Furthermore, our results reveal that bound and quasi-bound states play an important role in the charge transport.

International audience; In photovoltaic, multi quantum wells (MQW) allow to tailor the optical absorption. This is particularly interesting in multijunction solar cells [1] but it also permits to improve the efficiency of a single junction solar cell [2]. This approach is efficient thanks to the strain-balanced materials which, at a well under compressive strain, associates a barrier under tensile strain. This permits to consider a large number of wells while preventing the formation of dislocations during crystal growth. On the other hand, the use of barriers is a drawback for the collection of the photo-generated carriers and more generally for the electronic transport quality in the MQW. Indeed, since transport is a succession of thermal escape, assisted tunnel escape and, at best, direct tunneling across a barrier, the average carrier velocity is low (of about 104 cm s(-1)) [3]. Finally the recombination rate is large and impacts both open-circuit voltage and short-circuit current. Furthermore, thanks to barriers some minibands can occur [4]. The wave functions of carriers in minibands are Bloch waves, meaning that propagation is efficient. Our theoretical study, based on quantum simulation (Green functions formalism) in InGaAs/GaAs/GaAsP cells, sheds light on minibands in which the average velocity of carriers is around 107 cm s-1. However, we also show that, without an adapted design, such minibands are inefficient since they connect only a few wells. We will present some improvements related to the distance between barriers and the positioning of the MQW inside the cell.

Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat.

A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development.

International audience; To improve the optical diagnostics of soot particles and gain an increased comprehension of the soot formation and aging mechanisms requires a better understanding of the soot refractive index. The present study evaluated the refractive index of soot generated by a miniCAST, an ethylene diffusion flame, and a PALAS GFG by interpreting specific extinction measurements in the near-UV spectrum with the help of an improved RDG-FA theory. Soot's morphology, size distribution, and bulk densities were determined and taken into account for the inversion process. Findings indicate that absorption and scattering capacities of the considered soot were strongly dependent on the amount of organic or volatile carbons and the degree of graphitization of the carbon atoms in the primary sphere (amorphous to graphitic arrangement). The proposed speciation of particles according to these properties is based on the spectral dependence of the determined refractive index for three reference aerosols representative of organic, amorphous, and ordered soot particles. Results show that by combining the refractive indices of these three aerosols it is possible to explain the high variability of most of the optical properties of soot, paving the way for a simple optical technique that permits the speciation of soot particles. (C) 2016 Elsevier Ltd. All rights reserved.

A new three-component system for photoassisted oxypolymerization of alkyd resins containing a drier, a photosensitizer and a radical generator was investigated. Polymerization profiles were recorded by real-time infrared spectroscopy for a thin film exposed for 1 h to simulated sunlight radiation. The kinetic results showed that the system follows complex kinetics. Multiple regression analysis was used to model the influence of the drier, the photosensitizer and the radical generator on the final conversion and total polymerization rate during photooxidation. The mechanisms involved were studied through laser spectroscopies. Laser flash photolysis was used to measure the rate constants of reaction between the radicals formed from the photodissociation of the radical generator and the model compounds of alkyd resins, leading to the rapid formation of hydroperoxides. The photosensitizer was expected to produce singlet state molecular oxygen that reacts on the alkyd resin, and time-resolved chemiluminescence technique was used to determine the quenching rate constant of singlet oxygen by model compounds. On the basis of these results, a mechanism for the photoassisted oxypolymerization of alkyd resins is proposed that account for the all the different reaction pathways.

IF (2,26); International audience; Aim of the study: Effects of the different fractions obtained by partition of ethanolic extract (EE) of Agelanthus dodoneifolius through column chromatography were investigated on rat blood pressure and aortic relaxation and compared to those observed in the presence of crude EE. Materials and methods: The acute hypotensive activity of EE, fractions and dodoneine, administrated intravenously, was evaluated in anaesthetized rats using the invasive method of blood pressure recording. Bioassay-guided fractionation using rat aorta pre-contracted by norepinephrine to monitor the relaxant activity led to the isolation of dodoneine. Results: In normotensive rats, injection of EE (0.01–10 mg/kg) produced a dose-dependent decrease in both systolic and diastolic blood pressure without any significant change in heart rate. In a similar way, the EE (0.001–3 mg/mL) caused relaxation of rat pre-contracted aorta in a concentration-dependent manner. Fractionation of the EE afforded 14 fractions, F1–F14, that were tested on rat precontracted aortic rings. At the concentration level of 1 mg/mL, a maximum relaxation effect was observed for fractions F2–F5. F4 was the most effective to elicit a concentration-dependent relaxation effect with an ED50 = 160±1.1 g/mL (n = 5) and to decreased systolic and diastolic control pressure by 56.9% and 81.6% respectively. F4 contains most of the dihydropyranone dodoneine, with 93% of the sample mass. Dodoneine separated from this fraction was also able to decrease both systolic and diastolic arterial pressure by 32.5% and 38.7% at 100g/kg, respectively. Conclusion: For the first time, this study demonstrates the hypotensive property of the dodoneine present in Agelanthus dodoneifolius.

(IF : 5,246); International audience; The present work is aimed at identifying and characterizing, at a molecular and functional level, new ionic conductances potentially involved in the excitation–secretion coupling and proliferation of cardiac ventricular fibroblasts. Among potassium channel transcripts which were screened by high-throughput real-time PCR, SUR2 and Kir6.1 mRNAs were found to be the most abundant in ventricular fibroblasts. The corresponding proteins were not detected by western blot following 5 days of cell culture, but had appeared at 7 days, increasing with extended cell culture duration as the fibroblasts differentiated into myofibroblasts. Using the inside-out configuration of the patch-clamp technique, single potassium channels could be recorded. These had properties similar to those reported for SUR2/Kir6.1 channels, i.e. activation by pinacidil, inhibition by glibenclamide and activation by intracellular UDP. As already reported for this molecular signature, they were insensitive to intracellular ATP. In the whole-cell configuration, these channels have been shown to be responsible for a glibenclamide-sensitive macroscopic potassium current which can be activated not only by pinacidil, but also by nanomolar concentrations of the sphingolipid sphingosine- 1-phosphate (S1P). The activation of this current resulted in an increase in cell proliferation and a decrease in IL-6 secretion, suggesting it has a functional role in situations where S1P increases. Overall, this work demonstrates for the first time that SUR2/Kir6.1 channels represent a significant potassium conductance in ventricular fibroblasts which may be activated in physio-pathological conditions and which may impact on fibroblast proliferation and function.

A method for simultaneous nondestructive evaluation of WC-Co coating thickness, elastic moduli, and density is presented. The technique, known as laser-ultrasonics, is used to generate and detect surface acoustic waves in a noncontact and nondestructive manner. The surface acoustic wave velocity dependence on frequency is compared to a model and an optimization procedure is used to evaluate the coating properties. The results obtained demonstrate the ability of the technique to simultaneously determine such properties with a single and possibly in situ measurement.

We theoretically investigate the impact of uniaxial strain in extremely thin Si and Ge p-type double gate transistors. Quantum transport modeling is treated using a 6-band k.p Hamiltonian and the non-equilibrium Green's function formalism including hole-phonon scattering. Based on this framework we analyze the influence of strain on current characteristics considering different transport directions and gate length's. The results first confirm the dominance of Ge in long devices (15 nm gate length) for which best electrical performances are obtained for channels along with a uniaxial compressive strain. Situation is reversed for shorter devices (7 nm gate length) where the small effective masses of Ge deteriorate the off-regime of transistors regardless the considered strain. Due to weaker hole-phonon scattering, Si devices with a tensile strain are interestingly found to be more competitive than their -compressive counterparts.

This theoretical work analyzes the photogeneration and the escape of carrier in InGaN/GaN core-shell nanowires. Our electronic transport model considers quantum behaviors such as confinement, tunneling, electron-phonon scattering and electron-photon interactions. The large lattice mismatch between InN and GaN requires the use of multiple quantum well design, in which either In content or well thickness is limited. Since thick GaN barriers are required in these stressed devices, we show that tunneling has a negligible impact on carrier escape, which is mostly achieved by the phonon scattering. Our conclusions demonstrate that a thick quantum well with a low In content, in which the confinement is moderate, is more efficient.

International audience; Ethnopharmacological relevance: Dodoneine (Ddn) is one of the active compounds identified from Agelanthus dodoneifolius (DC.) Polhill and Wiens, a medicinal plant used in traditional medicine for the treatment of hypertension. This dihydropyranone exerts hypotensive and vasorelaxant effects on rats, and two molecular targets have been characterized: the carbonic anhydrase and the L-type calcium channel in cardiomyocytes with biochemical and electrophysiological techniques, respectively. To further evaluate the involvement of these two molecular targets in vasorelaxation, the effect of Ddn on rat vascular smooth muscle was investigated. Material and methods: The effects of Ddn on L-type calcium current and on resting membrane potential were characterized in A7r5 cell line using the whole-cell patch-clamp configuration. The molecular identities of carbonic anhydrase isozymes in smooth muscle cells were examined with RT-PCR. Vascular response was measured on rat aortic rings in an organ bath apparatus and the effect of Ddn on intracellular pH was determined by flow cytometry using the pH-sensitive fluorescent probe BCECF-AM [2,7-Bis-(2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester]. Results: 100 mu M Ddn reduced calcium current density of about 30%. In addition, carbonic anhydrase II, III, XIII and XIV were shown to be expressed in rat aorta and inhibited in smooth muscle cells by Ddn. This inhibition resulted in a rise in pH(i) of about 0.31, leading to K-ca channel activation, thereby inducing membrane hyperpolarization and vasorelaxation. The results of vascular reactivity experiments obtained with pharmacological tools acting on the L-type calcium current and carbonic anhydrase suggest that Ddn produces its vasorelaxant effect via the inhibition of these two molecular targets. Conclusion: This study demonstrates that Ddn induced vasorelaxation by targeting two proteins involved in the modulation of excitation-contraction coupling: L-type calcium channels and carbonic anhydrase.

This theoretical work analyzes the photo-generation and the escape of carrier in InGaN/GaN core-shell nanowires. Our electronic transport model considers quantum behaviors such as confinement, tunneling, electron-phonon scattering and electron-photon interactions. The large lattice mismatch between InN and GaN requires the use of multiple quantum well design, in which either In content or well thickness is limited. Since thick GaN barriers are required in these stressed devices, we show that tunneling has a negligible impact on carrier escape, which is mostly achieved by the phonon absorption. This thermionic escape strongly depends on the quantum confinement. Our conclusions demonstrate that a thick quantum well with a low In content, in which the confinement is moderate, is more efficient.

Genistein is a tyrosine kinase inhibitor which interferes with the activity of several ionic channels either by altering modulatory phosphorylating processes or by direct binding. In whole-cell conditions, genistein induces a partial inhibition of the pacemaker (If) current recorded in cardiac sinoatrial and ventricular myocytes. We investigated the mechanism of action of genistein (50 μM) on the If current in whole-cell, cell-attached, and inside-out configurations, and the measured fractional inhibitions were similar: 26.6, 27.2, and 33.6%, respectively. When ATP was removed from the whole-cell pipette solution no differences were revealed in the effect of the drug when compared to metabolically active cells. Genistein fully maintained its blocking ability even when herbimycin, a tyrosine kinase inhibitor, was added to the whole-cell ATP-free pipette solution. Genistein-induced block was independent of the gating state of the channel and did not display voltage or current dependence; this independence distinguishes genistein from all other f-channel blockers. When inside-out experiments were performed to test for a direct interaction with the channel, genistein, superfused on the intracellular side of the membrane, decreased the maximal If conductance, and slightly shifted the current–activation curve to the left. Furthermore, the effect of genistein was independent of cAMP modulation. We conclude that, in addition to its tyrosine kinase-inhibitory properties, genistein also blocks If by directly interacting with the channel, and thus cannot be considered a valuable pharmacological tool to investigate phosphorylation-dependent modulatory pathways of the If current and of cardiac rhythm. British Journal of Pharmacology (2006) 147, 36–44. doi:10.1038/sj.bjp.0706433

As reported for cyclic nucleotide-gated channels in sensory neurons, we investigated the action of Ca 2+ –calmodulin and calmodulin antagonist (W7) on the apparent affinity of pacemaker ( I f ) channels for cAMP. In this study, we used the patch-clamp technique in inside–out macro-patch configuration in rabbit sino-atrial cells. Intracellular calmodulin perfusion had no effect on f-channel activity and did not change the cAMP-induced I f activation shift. Nevertheless, W7 decreased maximal conductance and induced a voltage shift of the current activation curve towards negative potentials. W7 did not modify the positive shift caused by cAMP, and cAMP did not prevent the effects of W7. Contrary to the cyclic nucleotide-gated channel, the f-channel is not directly modulated by Ca 2+ –calmodulin. The data suggest that W7 alters the voltage-dependent properties of I f independent of cAMP binding. This agent opens the pathway for a new family of bradycardic drugs.

The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 microM trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by approximately 30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.

Metal oxide semiconductor field-effect transistors with channel lengths in the nanometer range have recently been the subject of many new modeling and simulation approaches. Unfortunately, semi-classical methods currently used in microelectronics are not suitable to describe accurately all physical effects when device integration approaches atomic scale. The aim of this study is to compare theoretical results obtained from different atomistic approaches with those classically deduced with the effective mass approximation. We calculated the transmission coefficient in the simple case of linear atomic chains or of several coupled chains by successively considering: (i) the effective mass approximation, (ii) a direct calculation of semi-infinite chains transmission using a simple one band tight binding approximation, (iii) the diffusion theory in the Green’s functions formalism expressed in the frame of tight binding. This last method offers several advantages since it is able to capture the essential physics of nanoscale devices (electron–electron and electron–phonon interactions). Finally, we summarize the discussion of the extension of this last approach to realistic devices.

This theoretical work analyzes photovoltaic effect in InGaN/GaN solar cells. Our electronic transport model considers intrinsic quantum behaviors like confinement, tunneling, electron-phonon scattering and electron-photon interactions. Based on this model we compare performances of Multiple Quantum Wells (MQW) structure with those of thick-layer device. We show that MQW is a promising candidate that provides better current characteristics. This work sheds light on the importance of finding a good balance between photon-absorption efficiency and transport properties. We also show the unintuitive influence of electron-phonon scattering.

International audience; Cardiac fibroblasts are an integral part of the myocardial tissue and contribute to its remodelling. This study characterises for the first time the calcium-dependent chloride channels (CaCC) in the plasma membrane of primary human atrial cardiac fibroblasts by means of the iodide efflux and the patch clamp methods. The calcium ionophore A23187 and Angiotensin II (Ang II) activate a chloride conductance in cardiac fibroblasts that shares pharmacological similarities with calcium-dependent chloride channels. This chloride conductance is depressed by RNAi-mediated selective Anoctamine 1 (ANO1) but not by Anoctamine 2 (ANO2) which has been revealed as CaCC and is inhibited by the selective ANO1 inhibitor, T16inh-A01. The effect of Ang II on anion efflux is mediated through AT1 receptors (with an EC50 = 13.8 ± 1.3 nM). The decrease of anion efflux by calphostin C and bisindolylmaleimide I (BIM I) suggests that chloride conductance activation is dependent on PKC. We conclude that ANO1 contributes to CaCC current in human cardiac fibroblasts and that this is regulated by Ang II acting via the AT1 receptor pathway.

EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1 Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.

Increased levels of the physiological amino acid homocysteine (Hcy) are considered a risk factor for vascular disease. Hyperhomocysteinemia causes an intense remodelling of the extracellular matrix in arterial walls, particularly an elastolysis involving metalloproteinases. We investigated the activation of the latent elastolytic metalloproteinase proMMP-2 (72 kDa) by Hcy. Hcy was proved to exert a dual effect, activating proMMP-2 at low molar ratio (MR 10:1) and inhibiting active MMP2 at high molar ratio (MR > 1000:1). Methionine and the disulphide homocystine did not activate nor inhibit MMP-2, showing that the activation as well as the inhibition requires the thiol group to be free. The activation of proMMP-2 by Hcy is in accordance with the "cysteine-switch" mechanism, but occurs without further autoproteolysis of the enzyme molecule. In contrast with Hcy, the other physiological thiol compounds cysteine and reduced glutathione did not activate proMMP-2. These results suggest that the direct activation of proMMP2 by Hcy could be one of the mechanisms involved in the extracellular matrix deterioration in hyperhomocysteinemia-associated arteriosclerosis.

Aqueous-ethanolic extract ofCassia alata(AECal) and its derived fractions obtained through liquid-liquid fractionation were evaluated for their bronchorelaxant, genotoxic, and antigenotoxic effects. Contractile activity of rats’ tracheas in the presence of tested materials, as well as its modifications with different inhibitors and blockers, was isometrically recorded. The antigenotoxic potential of AECal was evaluated on cyclophosphamide- (CP-) induced genotoxicity in the rat. Animals were pretreated with the extract, then liver comet assay was performed. AECal and its chloroformic fractions (CF-AECal) relaxed the contraction induced by Ach, but both were significantly less potent in inhibiting contraction induced by KCl (30 mM; 80 mM). Propranolol, indomethacin, L-NAME, methylene blue, and glibenclamide did not modify the relaxant effect of CF-AECal. TEA altered the response of trachea to CF-AECal. CF-AECal caused a rightward shift without affecting theEmaxin cumulative concentration-response curves of Ach only at low concentrations. In animals pretreated with the extract, the percentage of CP-induced DNA damage decreased. Our results suggest that (1) muscarinic receptors contribute at least in part to the relaxant effects of CF-AECal; (2) CF-AECal interferes with membrane polarization; and (3) AECal is not genotoxicin vivoand contains chemopreventive phytoconstituents offering protection against CP-induced genotoxicity.

The natural product dodoneine (a dihydropyranone phenolic compound), extracted from African mistletoe Agelanthus dodoneifolius, has been investigated as inhibitor of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. By using superacid chemistry, analogues of the lactone phenolic hybrid lead compound have been synthesized and tested as CA inhibitors. Small chemical modifications of the basic scaffold revealed strong changes in the selectivity profile against different CA isoforms. These new compounds selectively inhibited isoforms CA I (KIs in the range of 0.13–0.76 μM), III (KIs in the range of 5.13–10.80 μM), XIII (KIs in the range of 0.34–0.96 μM) and XIV (KIs in the range of 2.44–7.24 μM), and can be considered as new leads, probably acting as non-zinc-binders, similar to other phenols/lactones investigated earlier.

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.

International audience; Junctionless transistors are being considered as one of the alternatives to conventional metal-oxide field-effect transistors. In this work, it is then presented a simulation study of silicon double-gated p-type junctionless transistors compared with its inversion-mode counterpart. The quantum transport problem is solved within the non-equilibrium Green's function formalism, whereas holephonon interactions are tackled by means of the self-consistent Born approximation. Our findings show that junctionless transistors should perform as good as a conventional transistor only for ultra-thin channels, with the disadvantage of requiring higher supply voltages in thicker channel configurations. (C) 2016 AIP Publishing LLC.

The current produced by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (termed I f, cardiac pacemaker “funny” current, and I h in neurons) is also considered a “pacemaker current” because it plays a key role in controlling the rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. The pacemaker current is an inward current activated by voltage hyperpolarization and modulated by intracellular cAMP. Voltage-dependent opening of these pacemaker channels is directly regulated by the binding of cAMP. The f-channels are encoded by four genes (HCN1–4) and are widely expressed throughout the heart and central nervous system. This article summarizes the structure, function, and regulation of these channels. Because of their relevance to cardiac pacemaker activity, f-channels are a natural target of drugs aimed at the pharmacological control of heart rate. In this regard, several agents developed for their capacity to selectively reduce heart rate act by specifically inhibiting f-channel function. Related compounds that could potentially be used for the treatment of diseases such as angina and heart failure are also discussed.

The mechanism of the action of acetylcholine (ACh) on the L-type calcium current (ICa,L) was examined using a whole-cell voltage-clamp technique in single sino-atrial myocytes from the rabbit heart. ACh depressed basal ICa,L at concentrations in the range 0.05-10 microM, without previous beta-adrenergic stimulation. The ACh-induced reduction of ICa,L was reversed by addition of atropine, indicating that muscarinic receptors mediate it. Incubation of cells with a solution containing pertussis toxin led to abolition of the ACh effect, suggesting that this effect is mediated by G proteins activated by muscarinic receptors. Dialysis of cells with protein kinase inhibitor or 5'-adenylyl imidodiphosphate, inhibitors of the cAMP-dependent protein kinase, decreased basal ICa,L by about 85% and suppressed the effect of ACh. The ACh effect was also absent in cells dialysed with a non-hydrolysable analogue of cAMP, 8-bromo-cAMP. The results suggest that, in basal conditions, a large part of the L-type calcium channels should be phosphorylated by protein kinase A stimulated by a high cAMP level correlated with a high adenylate cyclase activity. The depressing effect of ACh on ICa,L may occur via inhibition of the high basal adenylate cyclase activity leading to a decrease of cAMP-dependent protein kinase stimulation and thus to a dephosphorylation of calcium channels.

We reconsider spin-orbit contribution to strain effects in semiconductors within six-valence-band k · p model. We demonstrate that standard procedure for including that contribution is generally wrong. Indeed, we show that taking into account the spin-orbital strain term of the effective hamiltonian does not modify the matrix form of the strain model in terms of deformation components. Consequently, part of the spin-orbital strain interaction is formally included in the a, b and d deformation potential parameters of the conventional Bir-Pikus matrix. This result brings into question the parameter values: do they or not take into account that spin-orbital strain contribution? Moreover, the remaining part, which involves the split-off valence band, is included in a form similar to that of Pidgeon-Brown (set up for P i P j products) using three additional parameters a Δ , b Δ and d Δ (in place of γ1Δ, γ2Δ and γ3Δ). Following this original approach, we propose new parametrized models for Si, Ge, GaAs and InAs materials. Impacts of spin-orbit contribution are presented for Si, Ge, GaAs and InAs bulk and [001] quantum wells.

We have developed a ballistic self-consistent code which couples the six-band k.p Hamiltonian to the Green function formalism. We investigate the influence of channel material (Si, Ge, SiGe and GaAs), crystallographic orientation ([100] and [110]) and strain (biaxial and uniaxial) on the ultimate double-gate pMOSFET performances. The results show that the best configuration is obtained with strained [100]-oriented Si devices.

This study presents ionized impurity impacts on silicon nanowire MOS transistors. We first calculate the current characteristics with a self-consistent three-dimensional (3D) Green's function approach and show the effects of both acceptor and donor impurities on the physical electron properties. In particular, we emphasize that the presence of a donor induces different transport phenomena according to the applied gate bias. Considering an attractive Coulomb potential, we then evaluate the effective mass validity by comparing the localized states of cubic dots with those obtained through a sp 3 third-neighbor tight-binding model. Our results show that in first approximation, the effective mass is still adapted to treat ionized impurities.