Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Imaging properties of scanning equalization digital radiography: A simulation study

We have developed an empirically based simulation system to create images equivalent in SNR and SPR to those that would be acquired with various possible SEDR configurations. This system uses a collection of spot collimated full-field images (SCFFIs) of an anthropomorphic chest phantom, taken at high exposure levels and rescaled in noise and intensity, then digitally collimated and combined to produce the simulated SEDR images. This system allows for the study of design trade-offs between different equalization feedback schemes and scatter rejection geometries in addition to estimating the clinical benefits of SEDR over traditional imaging techniques. Data from this simulation system has demonstrated that SEDR techniques offer potential significant improvements over currently used digital radiography techniques for chest imaging. ^

Modulation of high voltage -activated calcium channels by phosphorylation

High voltage-activated (HVA) calcium channels from rat brain and rabbit heart are expressed in Xenopus laevis oocytes and their modulation by protein kinases studied. A subtype of the HVA calcium current expressed by rat brain RNA is potentiated by the phospholipid- and calcium-dependent protein kinase (PKC). The calcium channel clone $\alpha\sb{\rm1C}$ from rabbit heart is modulated by the cAMP-dependent protein kinase (PKA), and another factor present in the cytoplasm.^ The HVA calcium channels from rat brain do not belong to the L-type subclass since they are insensensitive to dihydropyridine (DHP) agonists and antagonists. The expressed currents do contain a N-type fraction which is identified by inactivation at depolarized potentials, and a P-type fraction as defined by blockade by the venom of the funnel web spider Agelenopsis Aperta. A non N-type fraction of this current is potentiated, by using phorbol esters to activate PKC. This residual fraction of current resembles the newly described Q-type channel from cerebellar granule cells in its biophysical properties, and potentiation by activation of PKC.^ The $\alpha\sb{\rm1C}$ clone from rabbit heart is expressed in oocytes and single-channel currents are measured using the cell-attached and cell-excised patch clamp technique. The single-channel current runs down within two minutes after patch excision into normal saline bath solution. The catalytic subunit of PKA + MgATP is capable of reversing this rundown for over 15 minutes. There also appears to be an additional factor present in the cytoplasm necessary for channel activity as revealed in experiments where PKA failed to prevent rundown.^ These data are important in that these types of channels are involved in synaptic transmission at many different types of synapses. The mammalian synapse is not accessible for these types of studies, however, the oocyte expression system allows access to HVA calcium channels for the study of their modulation by phosphorylation. ^

Calcium-dependent mechanisms and long-term potentiation: Role of NMDA receptors, voltage -dependent calcium channels and persistent protein kinase activity

Long-term potentiation (LTP) is a rapidly induced and long lasting increase in synaptic strength and is the leading cellular model for learning and memory in the mammalian brain. LTP was first identified in the hippocampus, a structure implicated in memory formation. LTP induction is dependent on postsynaptic Ca2+ increases mediated by N-methyl-D-aspartate (NMDA) receptors. Activation of other postsynaptic routes of Ca2+ entry, such as voltage-dependent Ca2+ channels (VDCCs) have subsequently been shown to induce a long-lasting increase in synaptic strength. However, it is unknown if VDCC-induced LTP utilized similar cellular mechanisms as the classical NMDA receptor-dependent LTP and if these two forms of LTP display similar properties. This dissertation determines the similarities and differences in VDCC and NMDA receptor-dependent LTP in area CA1 of hippocampal slices and demonstrates that VDCCs and NMDA receptors activate similar cellular mechanisms, such as protein kinases, to induce LTP. However, VDCC and NMDA receptor activated LTP induction mechanisms are compartmentalized in the postsynaptic neuron, such that they do not interact. Consistent with activation properties of NMDA receptors and VDCCs, NMDA receptor and VDCC-dependent LTP have different induction properties. In contrast to NMDA-dependent LTP, VDCC-induced potentiation does not require evoked presynaptic stimulation or display input specificity. These results indicate that there are two different routes of postsynaptic Ca2+ which can induce LTP and the compartmentation of VDCCs and NMDA receptors and/or their resulting Ca2+ increases may account for the distinction between these LTP induction mechanisms.^ One of the molecular targets for postsynaptic Ca2+ that is required for the induction of LTP is protein kinases. Evidence for the role of protein kinase activity in LTP expression is either correlational or controversial. We have utilized a broad range and potent inhibitors of protein kinases to systematically examine the temporal requirement for protein kinases in the induction and expression of LTP. Our results indicate that there is a critical period of persistent protein kinase activity required for LTP induction activated by tetanic stimulation and extending until 20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide evidence for persistent and/or Ca2+ independent protein kinase activity involvement in LTP induction. ^

Fiscal Federalism and Tax Equalization: The potential for progressive local taxes

We construct an empirically informed computational model of fiscal federalism, testing whether horizontal or vertical equalization can solve the fiscal externality problem in an environment in which heterogeneous agents can move and vote. The model expands on the literature by considering the case of progressive local taxation. Although the consequences of progressive taxation under fiscal federalism are well understood, they have not been studied in a context with tax equalization, despite widespread implementation. The model also expands on the literature by comparing the standard median voter model with a realistic alternative voting mechanism. We find that fiscal federalism with progressive taxation naturally leads to segregation as well as inefficient and inequitable public goods provision while the alternative voting mechanism generates more efficient, though less equitable, public goods provision. Equalization policy, under both types of voting, is largely undermined by micro-actors' choices. For this reason, the model also does not find the anticipated effects of vertical equalization discouraging public goods spending among wealthy jurisdictions and horizontal encouraging it among poor jurisdictions. Finally, we identify two optimal scenarios, superior to both complete centralization and complete devolution. These scenarios are not only Pareto optimal, but also conform to a Rawlsian view of justice, offering the best possible outcome for the worst-off. Despite offering the best possible outcomes, both scenarios still entail significant economic segregation and inequitable public goods provision. Under the optimal scenarios agents shift the bulk of revenue collection to the federal government, with few jurisdictions maintaining a small local tax.

Temperature and time dependent threshold voltage characterization of AlGaN/GaN high electron mobility transistors

Relacionado con línea de investigación del GDS del ISOM ver http://www.isom.upm.es/dsemiconductores.php

Current Mode with RMS Voltage and Offset Control Loops for a Single-Phase Aircraft Inverter Suitable for Parallel and 3-Phase Operation Modes

Rms voltage regulation may be an attractive possibility for controlling power inverters. Combined with a Hall Effect sensor for current control, it keeps its parallel operation capability while increasing its noise immunity, which may lead to a reduction of the Total Harmonic Distortion (THD). Besides, as voltage regulation is designed in DC, a simple PI regulator can provide accurate voltage tracking. Nevertheless, this approach does not lack drawbacks. Its narrow voltage bandwidth makes transients last longer and it increases the voltage THD when feeding non-linear loads, such as rectifying stages. On the other hand, the implementation can fall into offset voltage error. Furthermore, the information of the output voltage phase is hidden for the control as well, making the synchronization of a 3-phase setup not trivial. This paper explains the concept, design and implementation of the whole control scheme, in an on board inverter able to run in parallel and within a 3-phase setup. Special attention is paid to solve the problems foreseen at implementation level: a third analog loop accounts for the offset level is added and a digital algorithm guarantees 3-phase voltage synchronization.

Signal analysis and feature generation for pattern identification of partial discharges in high-voltage equipment

This paper proposes a method for the identification of different partial discharges (PDs) sources through the analysis of a collection of PD signals acquired with a PD measurement system. This method, robust and sensitive enough to cope with noisy data and external interferences, combines the characterization of each signal from the collection, with a clustering procedure, the CLARA algorithm. Several features are proposed for the characterization of the signals, being the wavelet variances, the frequency estimated with the Prony method, and the energy, the most relevant for the performance of the clustering procedure. The result of the unsupervised classification is a set of clusters each containing those signals which are more similar to each other than to those in other clusters. The analysis of the classification results permits both the identification of different PD sources and the discrimination between original PD signals, reflections, noise and external interferences. The methods and graphical tools detailed in this paper have been coded and published as a contributed package of the R environment under a GNU/GPL license.

Novel Inductor‐less Conversion Strategy Based on Multiphase Transformer‐Coupled Converters: Analysis, Design and Applications

There are many the requirements that modern power converters should fulfill. Most of the applications where these converters are used, demand smaller converters with high efficiency, improved power density and a fast dynamic response. For instance, loads like microprocessors demand aggressive current steps with very high slew rates (100A/mus and higher); besides, during these load steps, the supply voltage of the microprocessor should be kept within tight limits in order to ensure its correct performance. The accomplishment of these requirements is not an easy task; complex solutions like advanced topologies - such as multiphase converters- as well as advanced control strategies are often needed. Besides, it is also necessary to operate the converter at high switching frequencies and to use capacitors with high capacitance and low ESR. Improving the dynamic response of power converters does not rely only on the control strategy but also the power topology should be suited to enable a fast dynamic response. Moreover, in later years, a fast dynamic response does not only mean accomplishing fast load steps but output voltage steps are gaining importance as well. At least, two applications that require fast voltage changes can be named: Low power microprocessors. In these devices, the voltage supply is changed according to the workload and the operating frequency of the microprocessor is changed at the same time. An important reduction in voltage dependent losses can be achieved with such changes. This technique is known as Dynamic Voltage Scaling (DVS). Another application where important energy savings can be achieved by means of changing the supply voltage are Radio Frequency Power Amplifiers. For example, RF architectures based on ‘Envelope Tracking’ and ‘Envelope Elimination and Restoration’ techniques can take advantage of voltage supply modulation and accomplish important energy savings in the power amplifier. However, in order to achieve these efficiency improvements, a power converter with high efficiency and high enough bandwidth (hundreds of kHz or even tens of MHz) is necessary in order to ensure an adequate supply voltage. The main objective of this Thesis is to improve the dynamic response of DC-DC converters from the point of view of the power topology. And the term dynamic response refers both to the load steps and the voltage steps; it is also interesting to modulate the output voltage of the converter with a specific bandwidth. In order to accomplish this, the question of what is it that limits the dynamic response of power converters should be answered. Analyzing this question leads to the conclusion that the dynamic response is limited by the power topology and specifically, by the filter inductance of the converter which is found in series between the input and the output of the converter. The series inductance is the one that determines the gain of the converter and provides the regulation capability. Although the energy stored in the filter inductance enables the regulation and the capability of filtering the output voltage, it imposes a limitation which is the concern of this Thesis. The series inductance stores energy and prevents the current from changing in a fast way, limiting the slew rate of the current through this inductor. Different solutions are proposed in the literature in order to reduce the limit imposed by the filter inductor. Many publications proposing new topologies and improvements to known topologies can be found in the literature. Also, complex control strategies are proposed with the objective of improving the dynamic response in power converters. In the proposed topologies, the energy stored in the series inductor is reduced; examples of these topologies are Multiphase converters, Buck converter operating at very high frequency or adding a low impedance path in parallel with the series inductance. Control techniques proposed in the literature, focus on adjusting the output voltage as fast as allowed by the power stage; examples of these control techniques are: hysteresis control, V 2 control, and minimum time control. In some of the proposed topologies, a reduction in the value of the series inductance is achieved and with this, the energy stored in this magnetic element is reduced; less stored energy means a faster dynamic response. However, in some cases (as in the high frequency Buck converter), the dynamic response is improved at the cost of worsening the efficiency. In this Thesis, a drastic solution is proposed: to completely eliminate the series inductance of the converter. This is a more radical solution when compared to those proposed in the literature. If the series inductance is eliminated, the regulation capability of the converter is limited which can make it difficult to use the topology in one-converter solutions; however, this topology is suitable for power architectures where the energy conversion is done by more than one converter. When the series inductor is eliminated from the converter, the current slew rate is no longer limited and it can be said that the dynamic response of the converter is independent from the switching frequency. This is the main advantage of eliminating the series inductor. The main objective, is to propose an energy conversion strategy that is done without series inductance. Without series inductance, no energy is stored between the input and the output of the converter and the dynamic response would be instantaneous if all the devices were ideal. If the energy transfer from the input to the output of the converter is done instantaneously when a load step occurs, conceptually it would not be necessary to store energy at the output of the converter (no output capacitor COUT would be needed) and if the input source is ideal, the input capacitor CIN would not be necessary. This last feature (no CIN with ideal VIN) is common to all power converters. However, when the concept is actually implemented, parasitic inductances such as leakage inductance of the transformer and the parasitic inductance of the PCB, cannot be avoided because they are inherent to the implementation of the converter. These parasitic elements do not affect significantly to the proposed concept. In this Thesis, it is proposed to operate the converter without series inductance in order to improve the dynamic response of the converter; however, on the other side, the continuous regulation capability of the converter is lost. It is said continuous because, as it will be explained throughout the Thesis, it is indeed possible to achieve discrete regulation; a converter without filter inductance and without energy stored in the magnetic element, is capable to achieve a limited number of output voltages. The changes between these output voltage levels are achieved in a fast way. The proposed energy conversion strategy is implemented by means of a multiphase converter where the coupling of the phases is done by discrete two-winding transformers instead of coupledinductors since transformers are, ideally, no energy storing elements. This idea is the main contribution of this Thesis. The feasibility of this energy conversion strategy is first analyzed and then verified by simulation and by the implementation of experimental prototypes. Once the strategy is proved valid, different options to implement the magnetic structure are analyzed. Three different discrete transformer arrangements are studied and implemented. A converter based on this energy conversion strategy would be designed with a different approach than the one used to design classic converters since an additional design degree of freedom is available. The switching frequency can be chosen according to the design specifications without penalizing the dynamic response or the efficiency. Low operating frequencies can be chosen in order to favor the efficiency; on the other hand, high operating frequencies (MHz) can be chosen in order to favor the size of the converter. For this reason, a particular design procedure is proposed for the ‘inductorless’ conversion strategy. Finally, applications where the features of the proposed conversion strategy (high efficiency with fast dynamic response) are advantageus, are proposed. For example, in two-stage power architectures where a high efficiency converter is needed as the first stage and there is a second stage that provides the fine regulation. Another example are RF power amplifiers where the voltage is modulated following an envelope reference in order to save power; in this application, a high efficiency converter, capable of achieving fast voltage steps is required. The main contributions of this Thesis are the following: The proposal of a conversion strategy that is done, ideally, without storing energy in the magnetic element. The validation and the implementation of the proposed energy conversion strategy. The study of different magnetic structures based on discrete transformers for the implementation of the proposed energy conversion strategy. To elaborate and validate a design procedure. To identify and validate applications for the proposed energy conversion strategy. It is important to remark that this work is done in collaboration with Intel. The particular features of the proposed conversion strategy enable the possibility of solving the problems related to microprocessor powering in a different way. For example, the high efficiency achieved with the proposed conversion strategy enables it as a good candidate to be used for power conditioning, as a first stage in a two-stage power architecture for powering microprocessors.

Voltage recovery in intermediate band solar cells

The intermediate band solar cell (IBSC) is based on a novel photovoltaic concept and has a limiting efficiency of 63.2%, which compares favorably with the 40.7% efficiency of a conventional, single junction solar cell. It is characterized by a material hosting a collection of energy levels within its bandgap, allowing the cell to exploit photons with sub-bandgap energies in a two-step absorption process, thus improving the utilization of the solar spectrum. However, these intermediate levels are often regarded as an inherent source of supplementary recombination, although this harmful effect can in theory be counteracted by the use of concentrated light. We present here a novel, low-temperature characterization technique using concentrated light that reveals how the initially enhanced recombination in the IBSC is reduced so that its open-circuit voltage is completely recovered and reaches that of a conventional solar cell.

High-efficiency voltage regulator and stabilizer for outdoor lighting installations

This paper presents a high performance system of regulation and stabilization of luminous flux for public street lighting installations. Its purpose is to reduce the luminous flux of the luminaries efficiently by reducing their voltage supply, resulting in the improvement of energy efficiency in the installation. The system is basically composed of electromagnetic components which provide robustness and high-performance to the device, as well as minimum maintenance requirements. However, the voltage regulation is based on the application of voltage steps. Aging studies of the luminaries have been carried out to analyze the impact of this discrete voltage regulation. A specific prototype of this voltage and stabilizer regulator have been in operation in a real outdoor lighting installation for more than one year.

Synchronous Buck converter with Output Impedance Correction Circuit

This work is related to the improvement of the output impedance of the Buck converter by means of introducing an additional power path that virtually increases the output capacitance during transients. It is well known that in VRM applications, with wide load steps, voltage overshoots and undershoots may lead to undesired performance of the load. To solve this problem, high-bandwidth high-switching frequency power converters can be applied to reduce the transient time or a big output capacitor can be applied to reduce the output impedance. The first solution can degrade the efficiency by increasing switching losses of the MOSFETS, and the second solution is penalizing the cost and size of the output filter. The Output Impedance Correction Circuit (OICC), as presented here, is used to inject or extract a current n-1 times larger than the output capacitor current, thus virtually increasing n times the value of the output capacitance during the transients. This feature allows the usage of a low frequency Buck converter with smaller capacitor but satisfying the dynamic requirements.

Sensorless explicit model predictive control for multi-phase buck converters with variable output voltage

The purpose of this paper is to use the predictive control to take advantage of the future information in order to improve the reference tracking. The control attempts to increase the bandwidth of the conventional regulators by using the future information of the reference, which is supposed to be known in advance. A method for designing a controller is also proposed. A comparison in simulation with a conventional regulator is made controlling a four-phase Buck converter. Advantages and disadvantages are analyzed based on simulation results.

Improvement of the Dynamic Performance of a Buck Converter using Controlled Current Source as an Additional Energy Path

This work is related to the improvement of the dynamic performance of the Buck converter by means of introducing an additional power path that virtually increase s the output capacitance during transients, thus improving the output impedance of the converter. It is well known that in VRM applications, with wide load steps, voltage overshoots and undershoots ma y lead to undesired performance of the load. To solve this problem, high-bandwidth high-switching frequency power converter s can be applied to reduce the transient time or a big output capacitor can be applied to reduce the output impedance. The first solution can degrade the efficiency by increasing switching losses of the MOSFETS, and the second solution is penalizing the cost and size of the output filter. The additional energy path, as presented here, is introduced with the Output Impedance Correction Circuit (OICC) based on the Controlled Current Source (CCS). The OICC is using CCS to inject or extract a current n - 1 times larger than the output capacitor current, thus virtually increasing n times the value of the output capacitance during the transients. This feature allows the usage of a low frequency Buck converter with smaller capacitor but satisfying the dynamic requirements.