The asset/liability structure of the Philippine banks and non-bank financial institutions in 2000s : a preliminary study for financial access analyses

Based on the consolidated statements data of the universal/commercial banks (UKbank) and non-bank financial institutions with quasi-banking licenses, this paper presents a keen necessity of obtaining data in detail on both sides (assets and liabilities) of their financial conditions and further analyses. Those would bring more adequate assessments on the Philippine financial system, especially with regard to each financial subsector's financing/lending preferences and behavior. The paper also presents a possibility that the skewed locational and operational distribution exists in the non-UKbank financial subsectors. It suggests there may be a significant deviation from the authorities' (the BSP, SEC and others) intended/anticipated financial system in the banking/non-bank financial institutions' real operations.

Speaker Diarization Based on Intensity Channel Contribution

The time delay of arrival (TDOA) between multiple microphones has been used since 2006 as a source of information (localization) to complement the spectral features for speaker diarization. In this paper, we propose a new localization feature, the intensity channel contribution (ICC) based on the relative energy of the signal arriving at each channel compared to the sum of the energy of all the channels. We have demonstrated that by joining the ICC features and the TDOA features, the robustness of the localization features is improved and that the diarization error rate (DER) of the complete system (using localization and spectral features) has been reduced. By using this new localization feature, we have been able to achieve a 5.2% DER relative improvement in our development data, a 3.6% DER relative improvement in the RT07 evaluation data and a 7.9% DER relative improvement in the last year's RT09 evaluation data.

An Efficient Multiple Object Detection and Tracking Framework for Automatic Counting and Video Surveillance Applications

Automatic visual object counting and video surveillance have important applications for home and business environments, such as security and management of access points. However, in order to obtain a satisfactory performance these technologies need professional and expensive hardware, complex installations and setups, and the supervision of qualified workers. In this paper, an efficient visual detection and tracking framework is proposed for the tasks of object counting and surveillance, which meets the requirements of the consumer electronics: off-the-shelf equipment, easy installation and configuration, and unsupervised working conditions. This is accomplished by a novel Bayesian tracking model that can manage multimodal distributions without explicitly computing the association between tracked objects and detections. In addition, it is robust to erroneous, distorted and missing detections. The proposed algorithm is compared with a recent work, also focused on consumer electronics, proving its superior performance.

Broadband access in complex environments: LTE on railway

This paper assesses the main challenges associated with the propagation and channel modeling of broadband radio systems in a complex environment of high speed and metropolitan railways. These challenges comprise practical simulation, modeling interferences, radio planning, test trials and performance evaluation in different railway scenarios using Long Term Evolution (LTE) as test case. This approach requires several steps; the first is the use of a radio propagation simulator based on ray-tracing techniques to accurately predict propagation. Besides the radio propagation simulator, a complete test bed has been constructed to assess LTE performance, channel propagation conditions and interference with other systems in real-world environments by means of standard-compliant LTE transmissions. Such measurement results allowed us to evaluate the propagation and performance of broadband signals and to test the suitability of LTE radio technology for complex railway scenarios.

Sophisticated security verification on routing repaired balanced cell-based dual-rail logic against side channel analysis

Conventional dual-rail precharge logic suffers from difficult implementations of dual-rail structure for obtaining strict compensation between the counterpart rails. As a light-weight and high-speed dual-rail style, balanced cell-based dual-rail logic (BCDL) uses synchronised compound gates with global precharge signal to provide high resistance against differential power or electromagnetic analyses. BCDL can be realised from generic field programmable gate array (FPGA) design flows with constraints. However, routings still exist as concerns because of the deficient flexibility on routing control, which unfavourably results in bias between complementary nets in security-sensitive parts. In this article, based on a routing repair technique, novel verifications towards routing effect are presented. An 8 bit simplified advanced encryption processing (AES)-co-processor is executed that is constructed on block random access memory (RAM)-based BCDL in Xilinx Virtex-5 FPGAs. Since imbalanced routing are major defects in BCDL, the authors can rule out other influences and fairly quantify the security variants. A series of asymptotic correlation electromagnetic (EM) analyses are launched towards a group of circuits with consecutive routing schemes to be able to verify routing impact on side channel analyses. After repairing the non-identical routings, Mutual information analyses are executed to further validate the concrete security increase obtained from identical routing pairs in BCDL.

Entanglement Distribution in Quantum Metropolitan Optical Networks

The ability to generate entangled photon-pairs over a broad wavelength range opens the door to the simultaneous distribution of entanglement to multiple users of a network using a single source and wavelength-division multiplexing technologies. Here we show the design of a metropolitan optical network made of tree-type access networks where entangled photon-pairs are distributed to any pair of users, independently of their location. The resulting network improves the reach, number of users and capabilities of existing proposals. Moreover, it is made up of typical commercial components and uses the existing infrastructure, which allows for moderate deployment costs. Finally, we develop a channel plan and a network design that allow direct optical communications, quantum and classical, between any pair of users. Therefore, multiple quantum information technologies can make use of this network.

Entanglement distribution in optical networks

The ability to generate entangled photon pairs over a broad wavelength range opens the door to the simultaneous distribution of entanglement to multiple users in a network by using centralized sources and flexible wavelength-division multiplexing schemes. Here, we show the design of a metropolitan optical network consisting of tree-type access networks, whereby entangled photon pairs are distributed to any pair of users, independent of their location. The network is constructed employing commercial off-the-shelf components and uses the existing infrastructure, which allows for moderate deployment costs. We further develop a channel plan and a network-architecture design to provide a direct optical path between any pair of users; thus, allowing classical and one-way quantum communication, as well as entanglement distribution. This allows the simultaneous operation of multiple quantum information technologies. Finally, we present a more flexible backbone architecture that pushes away the load limitations of the original network design by extending its reach, number of users and capabilities.

Contribución a la caracterización espacial de canales con sistemas MIMO-OFDM en la banda de 2,45 Ghz

La tecnología de múltiples antenas ha evolucionado para dar soporte a los actuales y futuros sistemas de comunicaciones inalámbricas en su afán por proporcionar la calidad de señal y las altas tasas de transmisión que demandan los nuevos servicios de voz, datos y multimedia. Sin embargo, es fundamental comprender las características espaciales del canal radio, ya que son las características del propio canal lo que limita en gran medida las prestaciones de los sistemas de comunicación actuales. Por ello surge la necesidad de estudiar la estructura espacial del canal de propagación para poder diseñar, evaluar e implementar de forma más eficiente tecnologías multiantena en los actuales y futuros sistemas de comunicación inalámbrica. Las tecnologías multiantena denominadas antenas inteligentes y MIMO han generado un gran interés en el área de comunicaciones inalámbricas, por ejemplo los sistemas de telefonía celular o más recientemente en las redes WLAN (Wireless Local Area Network), principalmente por la mejora que proporcionan en la calidad de las señales y en la tasa de transmisión de datos, respectivamente. Las ventajas de estas tecnologías se fundamentan en el uso de la dimensión espacial para obtener ganancia por diversidad espacial, como ya sucediera con las tecnologías FDMA (Frequency Division Multiplexing Access), TDMA (Time Division Multiplexing Access) y CDMA (Code Division Multiplexing Access) para obtener diversidad en las dimensiones de frecuencia, tiempo y código, respectivamente. Esta Tesis se centra en estudiar las características espaciales del canal con sistemas de múltiples antenas mediante la estimación de los perfiles de ángulos de llegada (DoA, Direction-of- Arrival) considerando esquemas de diversidad en espacio, polarización y frecuencia. Como primer paso se realiza una revisión de los sistemas con antenas inteligentes y los sistemas MIMO, describiendo con detalle la base matemática que sustenta las prestaciones ofrecidas por estos sistemas. Posteriormente se aportan distintos estudios sobre la estimación de los perfiles de DoA de canales radio con sistemas multiantena evaluando distintos aspectos de antenas, algoritmos de estimación, esquemas de polarización, campo lejano y campo cercano de las fuentes. Así mismo, se presenta un prototipo de medida MIMO-OFDM-SPAA3D en la banda ISM (Industrial, Scientific and Medical) de 2,45 Ghz, el cual está preparado para caracterizar experimentalmente el rendimiento de los sistemas MIMO, y para caracterizar espacialmente canales de propagación, considerando los esquemas de diversidad espacial, por polarización y frecuencia. Los estudios aportados se describen a continuación. Los sistemas de antenas inteligentes dependen en gran medida de la posición de los usuarios. Estos sistemas están equipados con arrays de antenas, los cuales aportan la diversidad espacial necesaria para obtener una representación espacial fidedigna del canal radio a través de los perfiles de DoA (DoA, Direction-of-Arrival) y por tanto, la posición de las fuentes de señal. Sin embargo, los errores de fabricación de arrays así como ciertos parámetros de señal conlleva un efecto negativo en las prestaciones de estos sistemas. Por ello se plantea un modelo de señal parametrizado que permite estudiar la influencia que tienen estos factores sobre los errores de estimación de DoA, tanto en acimut como en elevación, utilizando los algoritmos de estimación de DOA más conocidos en la literatura. A partir de las curvas de error, se pueden obtener parámetros de diseño para sistemas de localización basados en arrays. En un segundo estudio se evalúan esquemas de diversidad por polarización con los sistemas multiantena para mejorar la estimación de los perfiles de DoA en canales que presentan pérdidas por despolarización. Para ello se desarrolla un modelo de señal en array con sensibilidad de polarización que toma en cuenta el campo electromagnético de ondas planas. Se realizan simulaciones MC del modelo para estudiar el efecto de la orientación de la polarización como el número de polarizaciones usadas en el transmisor como en el receptor sobre la precisión en la estimación de los perfiles de DoA observados en el receptor. Además, se presentan los perfiles DoA obtenidos en escenarios quasiestáticos de interior con un prototipo de medida MIMO 4x4 de banda estrecha en la banda de 2,45 GHz, los cuales muestran gran fidelidad con el escenario real. Para la obtención de los perfiles DoA se propone un método basado en arrays virtuales, validado con los datos de simulación y los datos experimentales. Con relación a la localización 3D de fuentes en campo cercano (zona de Fresnel), se presenta un tercer estudio para obtener con gran exactitud la estructura espacial del canal de propagación en entornos de interior controlados (en cámara anecóica) utilizando arrays virtuales. El estudio analiza la influencia del tamaño del array y el diagrama de radiación en la estimación de los parámetros de localización proponiendo, para ello, un modelo de señal basado en un vector de enfoque de onda esférico (SWSV). Al aumentar el número de antenas del array se consigue reducir el error RMS de estimación y mejorar sustancialmente la representación espacial del canal. La estimación de los parámetros de localización se lleva a cabo con un nuevo método de búsqueda multinivel adaptativo, propuesto con el fin de reducir drásticamente el tiempo de procesado que demandan otros algoritmos multivariable basados en subespacios, como el MUSIC, a costa de incrementar los requisitos de memoria. Las simulaciones del modelo arrojan resultados que son validados con resultados experimentales y comparados con el límite de Cramer Rao en términos del error cuadrático medio. La compensación del diagrama de radiación acerca sustancialmente la exactitud de estimación de la distancia al límite de Cramer Rao. Finalmente, es igual de importante la evaluación teórica como experimental de las prestaciones de los sistemas MIMO-OFDM. Por ello, se presenta el diseño e implementación de un prototipo de medida MIMO-OFDM-SPAA3D autocalibrado con sistema de posicionamiento de antena automático en la banda de 2,45 Ghz con capacidad para evaluar la capacidad de los sistemas MIMO. Además, tiene la capacidad de caracterizar espacialmente canales MIMO, incorporando para ello una etapa de autocalibración para medir la respuesta en frecuencia de los transmisores y receptores de RF, y así poder caracterizar la respuesta de fase del canal con mayor precisión. Este sistema incorpora un posicionador de antena automático 3D (SPAA3D) basado en un scanner con 3 brazos mecánicos sobre los que se desplaza un posicionador de antena de forma independiente, controlado desde un PC. Este posicionador permite obtener una gran cantidad de mediciones del canal en regiones locales, lo cual favorece la caracterización estadística de los parámetros del sistema MIMO. Con este prototipo se realizan varias campañas de medida para evaluar el canal MIMO en términos de capacidad comparando 2 esquemas de polarización y tomando en cuenta la diversidad en frecuencia aportada por la modulación OFDM en distintos escenarios. ABSTRACT Multiple-antennas technologies have been evolved to be the support of the actual and future wireless communication systems in its way to provide the high quality and high data rates required by new data, voice and data services. However, it is important to understand the behavior of the spatial characteristics of the radio channel, since the channel by itself limits the performance of the actual wireless communications systems. This drawback raises the need to understand the spatial structure of the propagation channel in order to design, assess, and develop more efficient multiantenna technologies for the actual and future wireless communications systems. Multiantenna technologies such as ‘Smart Antennas’ and MIMO systems have generated great interest in the field of wireless communications, i.e. cellular communications systems and more recently WLAN (Wireless Local Area Networks), mainly because the higher quality and the high data rate they are able to provide. Their technological benefits are based on the exploitation of the spatial diversity provided by the use of multiple antennas as happened in the past with some multiaccess technologies such as FDMA (Frequency Division Multiplexing Access), TDMA (Time Division Multiplexing Access), and CDMA (Code Division Multiplexing Access), which give diversity in the domains of frequency, time and code, respectively. This Thesis is mainly focus to study the spatial channel characteristics using schemes of multiple antennas considering several diversity schemes such as space, polarization, and frequency. The spatial characteristics will be study in terms of the direction-of-arrival profiles viewed at the receiver side of the radio link. The first step is to do a review of the smart antennas and MIMO systems technologies highlighting their advantages and drawbacks from a mathematical point of view. In the second step, a set of studies concerning the spatial characterization of the radio channel through the DoA profiles are addressed. The performance of several DoA estimation methods is assessed considering several aspects regarding antenna array structure, polarization diversity, and far-field and near-field conditions. Most of the results of these studies come from simulations of data models and measurements with real multiantena prototypes. In the same way, having understand the importance of validate the theoretical data models with experimental results, a 2,4 GHz MIMO-OFDM-SPAA2D prototype is presented. This prototype is intended for evaluating MIMO-OFDM capacity in indoor and outdoor scenarios, characterize the spatial structure of radio channels, assess several diversity schemes such as polarization, space, and frequency diversity, among others aspects. The studies reported are briefly described below. As is stated in Chapter two, the determination of user position is a fundamental task to be resolved for the smart antenna systems. As these systems are equipped with antenna arrays, they can provide the enough spatial diversity to accurately draw the spatial characterization of the radio channel through the DoA profiles, and therefore the source location. However, certain real implementation factors related to antenna errors, signals, and receivers will certainly reduce the performance of such direction finding systems. In that sense, a parameterized narrowband signal model is proposed to evaluate the influence of these factors in the location parameter estimation through extensive MC simulations. The results obtained from several DoA algorithms may be useful to extract some parameter design for directing finding systems based on arrays. The second study goes through the importance that polarization schemes can have for estimating far-field DoA profiles in radio channels, particularly for scenarios that may introduce polarization losses. For this purpose, a narrowband signal model with polarization sensibility is developed to conduct an analysis of several polarization schemes at transmitter (TX) and receiver (RX) through extensive MC simulations. In addition, spatial characterization of quasistatic indoor scenarios is also carried out using a 2.45 GHz MIMO prototype equipped with single and dual-polarized antennas. A good agreement between the measured DoA profiles with the propagation scenario is achieved. The theoretical and experimental evaluation of polarization schemes is performed using virtual arrays. In that case, a DoA estimation method is proposed based on adding an phase reference to properly track the DoA, which shows good results. In the third study, the special case of near-field source localization with virtual arrays is addressed. Most of DoA estimation algorithms are focused in far-field source localization where the radiated wavefronts are assume to be planar waves at the receive array. However, when source are located close to the array, the assumption of plane waves is no longer valid as the wavefronts exhibit a spherical behavior along the array. Thus, a faster and effective method of azimuth, elevation angles-of-arrival, and range estimation for near-field sources is proposed. The efficacy of the proposed method is evaluated with simulation and validated with measurements collected from a measurement campaign carried out in a controlled propagation environment, i.e. anechoic chamber. Moreover, the performance of the method is assessed in terms of the RMSE for several array sizes, several source positions, and taking into account the effect of radiation pattern. In general, better results are obtained with larger array and larger source distances. The effect of the antennas is included in the data model leading to more accurate results, particularly for range rather than for angle estimation. Moreover, a new multivariable searching method based on the MUSIC algorithm, called MUSA (multilevel MUSIC-based algorithm), is presented. This method is proposed to estimate the 3D location parameters in a faster way than other multivariable algorithms, such as MUSIC algorithm, at the cost of increasing the memory size. Finally, in the last chapter, a MIMO-OFDM-SPAA3D prototype is presented to experimentally evaluate different MIMO schemes regarding antennas, polarization, and frequency in different indoor and outdoor scenarios. The prototype has been developed on a Software-Defined Radio (SDR) platform. It allows taking measurements where future wireless systems will be developed. The novelty of this prototype is concerning the following 2 subsystems. The first one is the tridimensional (3D) antenna positioning system (SPAA3D) based on three linear scanners which is developed for making automatic testing possible reducing errors of the antenna array positioning. A set of software has been developed for research works such as MIMO channel characterization, MIMO capacity, OFDM synchronization, and so on. The second subsystem is the RF autocalibration module at the TX and RX. This subsystem allows to properly tracking the spatial structure of indoor and outdoor channels in terms of DoA profiles. Some results are draw regarding performance of MIMO-OFDM systems with different polarization schemes and different propagation environments.

Securing implementations of feedback-shift-register-based ciphers using compiler optimizations and co-processors

Los algoritmos basados en registros de desplazamiento con realimentación (en inglés FSR) se han utilizado como generadores de flujos pseudoaleatorios en aplicaciones con recursos limitados como los sistemas de apertura sin llave. Se considera canal primario a aquel que se utiliza para realizar una transmisión de información. La aparición de los ataques de canal auxiliar (en inglés SCA), que explotan información filtrada inintencionadamente a través de canales laterales como el consumo, las emisiones electromagnéticas o el tiempo empleado, supone una grave amenaza para estas aplicaciones, dado que los dispositivos son accesibles por un atacante. El objetivo de esta tesis es proporcionar un conjunto de protecciones que se puedan aplicar de forma automática y que utilicen recursos ya disponibles, evitando un incremento sustancial en los costes y alargando la vida útil de aplicaciones que puedan estar desplegadas. Explotamos el paralelismo existente en algoritmos FSR, ya que sólo hay 1 bit de diferencia entre estados de rondas consecutivas. Realizamos aportaciones en tres niveles: a nivel de sistema, utilizando un coprocesador reconfigurable, a través del compilador y a nivel de bit, aprovechando los recursos disponibles en el procesador. Proponemos un marco de trabajo que nos permite evaluar implementaciones de un algoritmo incluyendo los efectos introducidos por el compilador considerando que el atacante es experto. En el campo de los ataques, hemos propuesto un nuevo ataque diferencial que se adapta mejor a las condiciones de las implementaciones software de FSR, en las que el consumo entre rondas es muy similar. SORU2 es un co-procesador vectorial reconfigurable propuesto para reducir el consumo energético en aplicaciones con paralelismo y basadas en el uso de bucles. Proponemos el uso de SORU2, además, para ejecutar algoritmos basados en FSR de forma segura. Al ser reconfigurable, no supone un sobrecoste en recursos, ya que no está dedicado en exclusiva al algoritmo de cifrado. Proponemos una configuración que ejecuta múltiples algoritmos de cifrado similares de forma simultánea, con distintas implementaciones y claves. A partir de una implementación sin protecciones, que demostramos que es completamente vulnerable ante SCA, obtenemos una implementación segura a los ataques que hemos realizado. A nivel de compilador, proponemos un mecanismo para evaluar los efectos de las secuencias de optimización del compilador sobre una implementación. El número de posibles secuencias de optimizaciones de compilador es extremadamente alto. El marco de trabajo propuesto incluye un algoritmo para la selección de las secuencias de optimización a considerar. Debido a que las optimizaciones del compilador transforman las implementaciones, se pueden generar automáticamente implementaciones diferentes combinamos para incrementar la seguridad ante SCA. Proponemos 2 mecanismos de aplicación de estas contramedidas, que aumentan la seguridad de la implementación original sin poder considerarse seguras. Finalmente hemos propuesto la ejecución paralela a nivel de bit del algoritmo en un procesador. Utilizamos la forma algebraica normal del algoritmo, que automáticamente se paraleliza. La implementación sobre el algoritmo evaluado mejora en rendimiento y evita que se filtre información por una ejecución dependiente de datos. Sin embargo, es más vulnerable ante ataques diferenciales que la implementación original. Proponemos una modificación del algoritmo para obtener una implementación segura, descartando parcialmente ejecuciones del algoritmo, de forma aleatoria. Esta implementación no introduce una sobrecarga en rendimiento comparada con las implementaciones originales. En definitiva, hemos propuesto varios mecanismos originales a distintos niveles para introducir aleatoridad en implementaciones de algoritmos FSR sin incrementar sustancialmente los recursos necesarios. ABSTRACT Feedback Shift Registers (FSR) have been traditionally used to implement pseudorandom sequence generators. These generators are used in Stream ciphers in systems with tight resource constraints, such as Remote Keyless Entry. When communicating electronic devices, the primary channel is the one used to transmit the information. Side-Channel Attack (SCA) use additional information leaking from the actual implementation, including power consumption, electromagnetic emissions or timing information. Side-Channel Attacks (SCA) are a serious threat to FSR-based applications, as an attacker usually has physical access to the devices. The main objective of this Ph.D. thesis is to provide a set of countermeasures that can be applied automatically using the available resources, avoiding a significant cost overhead and extending the useful life of deployed systems. If possible, we propose to take advantage of the inherent parallelism of FSR-based algorithms, as the state of a FSR differs from previous values only in 1-bit. We have contributed in three different levels: architecture (using a reconfigurable co-processor), using compiler optimizations, and at bit level, making the most of the resources available at the processor. We have developed a framework to evaluate implementations of an algorithm including the effects introduced by the compiler. We consider the presence of an expert attacker with great knowledge on the application and the device. Regarding SCA, we have presented a new differential SCA that performs better than traditional SCA on software FSR-based algorithms, where the leaked values are similar between rounds. SORU2 is a reconfigurable vector co-processor. It has been developed to reduce energy consumption in loop-based applications with parallelism. In addition, we propose its use for secure implementations of FSR-based algorithms. The cost overhead is discarded as the co-processor is not exclusively dedicated to the encryption algorithm. We present a co-processor configuration that executes multiple simultaneous encryptions, using different implementations and keys. From a basic implementation, which is proved to be vulnerable to SCA, we obtain an implementation where the SCA applied were unsuccessful. At compiler level, we use the framework to evaluate the effect of sequences of compiler optimization passes on a software implementation. There are many optimization passes available. The optimization sequences are combinations of the available passes. The amount of sequences is extremely high. The framework includes an algorithm for the selection of interesting sequences that require detailed evaluation. As existing compiler optimizations transform the software implementation, using different optimization sequences we can automatically generate different implementations. We propose to randomly switch between the generated implementations to increase the resistance against SCA.We propose two countermeasures. The results show that, although they increase the resistance against SCA, the resulting implementations are not secure. At bit level, we propose to exploit bit level parallelism of FSR-based implementations using pseudo bitslice implementation in a wireless node processor. The bitslice implementation is automatically obtained from the Algebraic Normal Form of the algorithm. The results show a performance improvement, avoiding timing information leakage, but increasing the vulnerability against differential SCA.We provide a secure version of the algorithm by randomly discarding part of the data obtained. The overhead in performance is negligible when compared to the original implementations. To summarize, we have proposed a set of original countermeasures at different levels that introduce randomness in FSR-based algorithms avoiding a heavy overhead on the resources required.

“You Can't Always Get What You Want” : A Novel Research Paradigm to Explore the Relationship between Multiple Intentions and Behaviours

Funded by •Centre for Translational Research in Public Health •United Kingdom Clinical Research Collaboration Public Health Research Centre •British Heart Foundation •Cancer Research United Kingdom •Economic and Social Research Council •Medical Research Council •National Institute for Health

Permeant ion regulation of N-methyl-d-aspartate receptor channel block by Mg2+

Block of the channel of N-methyl-d-aspartate (NMDA) receptors by external Mg2+ (Mgo2+) has broad implications for the many physiological and pathological processes that depend on NMDA receptor activation. An essential property of channel block by Mgo2+ is its powerful voltage dependence. A widely cited explanation for the strength of the voltage dependence of block is that the Mgo2+-binding site is located deep in the channel of NMDA receptors; Mgo2+ then would sense most of the membrane potential field during block. However, recent electrophysiological and mutagenesis studies suggest that the blocking site cannot be deep enough to account for the voltage dependence of Mgo2+ block. Here we describe the basis for this discrepancy: the magnitude and voltage dependence of channel block by Mgo2+ are strongly regulated by external and internal permeant monovalent cations. Our data support a model in which access to the channel by Mgo2+ is prevented when permeant ion-binding sites at the external entrance to the channel are occupied. Mgo2+ can block the channel only when the permeant ion-binding sites are unoccupied and then can either unblock back to the external solution or permeate the channel. Unblock to the external solution is prevented if external permeant ions bind while Mg2+ blocks the channel, although permeation is still permitted. The model provides an explanation for the strength of the voltage dependence of Mgo2+ block and quantifies the interdependence of permanent and blocking ion binding to NMDA receptors.

Sec61p Serves Multiple Roles in Secretory Precursor Binding and Translocation into the Endoplasmic Reticulum Membrane

The evolutionarily conserved Sec61 protein complex mediates the translocation of secretory proteins into the endoplasmic reticulum. To investigate the role of Sec61p, which is the main subunit of this complex, we generated recessive, cold-sensitive alleles of sec61 that encode stably expressed proteins with strong defects in translocation. The stage at which posttranslational translocation was blocked was probed by chemical crosslinking of radiolabeled secretory precursors added to membranes isolated from wild-type and mutant strains. Two classes of sec61 mutants were distinguished. The first class of mutants was defective in preprotein docking onto a receptor site of the translocon that included Sec61p itself. The second class of mutants allowed docking of precursors onto the translocon but was defective in the ATP-dependent release of precursors from this site that in wild-type membranes leads to pore insertion and full translocation. Only mutants of the second class were partially suppressed by overexpression of SEC63, which encodes a subunit of the Sec61 holoenzyme complex responsible for positioning Kar2p (yeast BiP) at the translocation channel. These mutants thus define two early stages of translocation that require SEC61 function before precursor protein transfer across the endoplasmic reticulum membrane.

Sodium channel selectivity filter regulates antiarrhythmic drug binding

Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel’s selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (μ1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment.