The Upregulation of α2δ-1 Subunit Modulates Activity-Dependent Ca2+ Signals in Sensory Neurons.

As auxiliary subunits of voltage-gated Ca(2+) channels, the α2δ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α2δ-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of α2δ-1 in rat sensory neurons leads to prolonged Ca(2+) responses evoked by membrane depolarization. This mechanism is coupled to CaV2.2 channel-mediated responses, as it is blocked by a ω-conotoxin GVIA application. Once initiated, the prolonged Ca(2+) transients are not dependent on extracellular Ca(2+) and do not require Ca(2+) release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca(2+) uptake demonstrates that α2δ-1-mediated prolonged Ca(2+) signals are buffered by mitochondria, preferentially activated by Ca(2+) influx through CaV2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the α2δ-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca(2+) signaling in dorsal root ganglion neurons

A Ca(V)2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant

Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide

Combining the Hybrid Functional Method with Dynamical Mean-Field Theory

We present a new method to compute the electronic structure of correlated materials combining the hybrid functional method with the dynamical mean-field theory. As a test example of the method we study cerium sesquioxide, a strongly correlated Mott-band insulator. The hybrid functional part improves the magnitude of the pd-band gap which is underestimated in the standard approximations to density functional theory while the dynamical mean-field theory part splits the 4f-electron spectra into a lower and an upper Hubbard band.Comment: 5 pages, 2 figures, replaced with revised version, published in Europhys. Let

A new classification and clinical predictivity for some naevus variants

Background. The incidence of cutaneous melanoma is rapidly increasing in Europe. Active research is directed toward the identification of naevi as a risk factor. Objective. The aim of our case-control study was to observe different numbers of moles and different mole typology associations in order to evaluate clinical predictivity and to establish a new classification for some naevus variants. Methods. A case-control study was carried out, enrolling 64 cases affected by melanoma and 183 controls, between October 2009 and February 2011. Each patient was interviewed and subjected to clinical examination. The resulting data were analysed using the statistical elaboration program SPSS 16.0. Results. The association of target naevus with other variants increases the degree of risk (target + small brown Odds Ratio 5.25; confidence interval 1.8-15.4); (target + small brown + small black + large brown odds ratio 5.0; confidence interval 1.1-22.4). Therefore, other variants and/or other variant combinations do not significantly increase risk. Conclusion. People presenting two naevus variants in association with other naevus variants seem to run a major risk. The general nonuniformity of the whole naevus panorama should be carefully considered

The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi

BACKGROUND: The role of [(18)F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool

Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acidbase regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients

Open access simulation toolbox for the grid connection of offshore wind farms using multi-terminal HVDC networks

Decarbonisation of the European electricity system can become dauntingly costly due to transmission and distribution network issues arising from the integration of intermittent renewable generation sources. It is expected that wind energy will be the principal renewable source by 2050 and, as such, a number of initiatives in the academia and in the industry are being carried out to propose solutions to best accommodate the wind resource. This paper presents work carried out by DEMO 1 partners within the EU FP7 project BEST PATHS. A MATLAB/Simulink toolbox consisting of the necessary building blocks for the simulation and integration of offshore wind farms using enabling technologies such as multiterminal high-voltage direct-current grids is presented. To illustrate the toolbox capabilities, a number of system topologies is studied. System performance is assessed and measured against a set of key performance indicators. To ensure knowledge dissemination, the toolbox has been made available as open access in the BEST PATHS project website

Design of Self-Healing Key Distribution Schemes

A self-healing key distribution scheme enables dynamic groups of users of an unreliable network to establish group keys for secure communication. In such a scheme, a group manager, at the beginning of each session, in order to provide a key to each member of the group, sends packets over a broadcast channel. Every user, belonging to the group, computes the group key by using the packets and some private information. The group manager can start multiple sessions during a certain time-interval, by adding/removing users to/from the initial group. The main property of the scheme is that, if during a certain session some broadcasted packet gets lost, then users are still capable of recovering the group key for that session simply by using the packets they have received during a previous session and the packets they will receive at the beginning of a subsequent one, without requesting additional transmission from the group manager. Indeed, the only requirement that must be satisfied, in order for the user to recover the lost keys, is membership in the group both before and after the sessions in which the broadcast messages containing the keys are sent. This novel and appealing approach to key distribution is quite suitable in certain military applications and in several Internet-related settings, where high security requirements need to be satisfied. In this paper we continue the study of self-healing key distribution schemes, introduced by Staddon et al. [37]. We analyze some existing constructions: we show an attack that can be applied to one of these constructions, in order to recover session keys, and two problems in another construction. Then, we present a new mechanism for implementing the self-healing approach, and we present an efficient construction which is optimal in terms of user memory storage. Finally, we extend the self-healing approach to key distribution, and we present a scheme which enables a user to recover from a single broadcast message all keys associated with sessions in which he is member of the communication group

A prototype for water content measurement in partially saturated soils

The paper presents the technological set-up and calibration of a system based on impedance spectroscopy for measuring water content in partially saturated soils. The technique adopted is relatively recent in geotechnical practice; it is used herein to characterize the electrical response of a soil specimen among two conducting electrodes upon application of an alternate voltage and the measurement of the current intensity resulting across the specimen, for frequency values in the range [500 Hz - 50 kHz]. The complex impedance of the soil specimen is due to both resistance, i.e. opposition to current, and reactance, i.e. tendency of the system to yield and retrieve energy, and it depends on the specimen water content. An on-purpose experimental plan has been conceived and is presented herein, aimed at building a calibration function for deriving the water content in pyroclastic soils from the impedance measurements. Preliminary results reveal an adequate level of repeatability of the measurements and suggest the existence of a monotonic correlation between the impedance modulus and the gravimetric water content

Design and Control of Hybrid Electric Light Rail Vehicles With Open Ended Winding Machines

Light railways are a low carbon emission form of transport, but it is often difficult to electrify tracks in central urban areas. This limitation can be avoided by integrating an on-board battery storage connected to the dc bus of the traction inverter with a boost dc/dc converter. However, the boost converter requires a bulky inductor and introduces additional power losses that are undesirable. This paper proposes to replace the standard induction motor with an open ended winding induction motor connected at one end to the overhead line with the traction inverter and to the other end to a battery with a second inverter in order to reduce the power losses of the traction drive. The paper addresses design and control aspects for light rail vehicles with open ended winding induction machines when the power supply is partly from the overhead line and partly from the on board battery. Moreover, the paper studies in detail the hybrid operations of the traction system i.e., when the overhead line charges the battery during coasting or at the stops. Finally, numerical simulations for a real use case are presented to quantify the reduction of power losses in comparison to the standard solution