A swarm intelligence approach based on coupled oscillators: an application in demand side management with photovoltaic distributed generation

Esta Tesis aborda los problemas de eficiencia de las redes eléctrica desde el punto de vista del consumo. En particular, dicha eficiencia es mejorada mediante el suavizado de la curva de consumo agregado. Este objetivo de suavizado de consumo implica dos grandes mejoras en el uso de las redes eléctricas: i) a corto plazo, un mejor uso de la infraestructura existente y ii) a largo plazo, la reducción de la infraestructura necesaria para suplir las mismas necesidades energéticas. Además, esta Tesis se enfrenta a un nuevo paradigma energético, donde la presencia de generación distribuida está muy extendida en las redes eléctricas, en particular, la generación fotovoltaica (FV). Este tipo de fuente energética afecta al funcionamiento de la red, incrementando su variabilidad. Esto implica que altas tasas de penetración de electricidad de origen fotovoltaico es perjudicial para la estabilidad de la red eléctrica. Esta Tesis trata de suavizar la curva de consumo agregado considerando esta fuente energética. Por lo tanto, no sólo se mejora la eficiencia de la red eléctrica, sino que también puede ser aumentada la penetración de electricidad de origen fotovoltaico en la red. Esta propuesta conlleva grandes beneficios en los campos económicos, social y ambiental. Las acciones que influyen en el modo en que los consumidores hacen uso de la electricidad con el objetivo producir un ahorro energético o un aumento de eficiencia son llamadas Gestión de la Demanda Eléctrica (GDE). Esta Tesis propone dos algoritmos de GDE diferentes para cumplir con el objetivo de suavizado de la curva de consumo agregado. La diferencia entre ambos algoritmos de GDE reside en el marco en el cual estos tienen lugar: el marco local y el marco de red. Dependiendo de este marco de GDE, el objetivo energético y la forma en la que se alcanza este objetivo son diferentes. En el marco local, el algoritmo de GDE sólo usa información local. Este no tiene en cuenta a otros consumidores o a la curva de consumo agregado de la red eléctrica. Aunque esta afirmación pueda diferir de la definición general de GDE, esta vuelve a tomar sentido en instalaciones locales equipadas con Recursos Energéticos Distribuidos (REDs). En este caso, la GDE está enfocada en la maximización del uso de la energía local, reduciéndose la dependencia con la red. El algoritmo de GDE propuesto mejora significativamente el auto-consumo del generador FV local. Experimentos simulados y reales muestran que el auto-consumo es una importante estrategia de gestión energética, reduciendo el transporte de electricidad y alentando al usuario a controlar su comportamiento energético. Sin embargo, a pesar de todas las ventajas del aumento de auto-consumo, éstas no contribuyen al suavizado del consumo agregado. Se han estudiado los efectos de las instalaciones locales en la red eléctrica cuando el algoritmo de GDE está enfocado en el aumento del auto-consumo. Este enfoque puede tener efectos no deseados, incrementando la variabilidad en el consumo agregado en vez de reducirlo. Este efecto se produce porque el algoritmo de GDE sólo considera variables locales en el marco local. Los resultados sugieren que se requiere una coordinación entre las instalaciones. A través de esta coordinación, el consumo debe ser modificado teniendo en cuenta otros elementos de la red y buscando el suavizado del consumo agregado. En el marco de la red, el algoritmo de GDE tiene en cuenta tanto información local como de la red eléctrica. En esta Tesis se ha desarrollado un algoritmo autoorganizado para controlar el consumo de la red eléctrica de manera distribuida. El objetivo de este algoritmo es el suavizado del consumo agregado, como en las implementaciones clásicas de GDE. El enfoque distribuido significa que la GDE se realiza desde el lado de los consumidores sin seguir órdenes directas emitidas por una entidad central. Por lo tanto, esta Tesis propone una estructura de gestión paralela en lugar de una jerárquica como en las redes eléctricas clásicas. Esto implica que se requiere un mecanismo de coordinación entre instalaciones. Esta Tesis pretende minimizar la cantidad de información necesaria para esta coordinación. Para lograr este objetivo, se han utilizado dos técnicas de coordinación colectiva: osciladores acoplados e inteligencia de enjambre. La combinación de estas técnicas para llevar a cabo la coordinación de un sistema con las características de la red eléctrica es en sí mismo un enfoque novedoso. Por lo tanto, este objetivo de coordinación no es sólo una contribución en el campo de la gestión energética, sino también en el campo de los sistemas colectivos. Los resultados muestran que el algoritmo de GDE propuesto reduce la diferencia entre máximos y mínimos de la red eléctrica en proporción a la cantidad de energía controlada por el algoritmo. Por lo tanto, conforme mayor es la cantidad de energía controlada por el algoritmo, mayor es la mejora de eficiencia en la red eléctrica. Además de las ventajas resultantes del suavizado del consumo agregado, otras ventajas surgen de la solución distribuida seguida en esta Tesis. Estas ventajas se resumen en las siguientes características del algoritmo de GDE propuesto: • Robustez: en un sistema centralizado, un fallo o rotura del nodo central provoca un mal funcionamiento de todo el sistema. La gestión de una red desde un punto de vista distribuido implica que no existe un nodo de control central. Un fallo en cualquier instalación no afecta el funcionamiento global de la red. • Privacidad de datos: el uso de una topología distribuida causa de que no hay un nodo central con información sensible de todos los consumidores. Esta Tesis va más allá y el algoritmo propuesto de GDE no utiliza información específica acerca de los comportamientos de los consumidores, siendo la coordinación entre las instalaciones completamente anónimos. • Escalabilidad: el algoritmo propuesto de GDE opera con cualquier número de instalaciones. Esto implica que se permite la incorporación de nuevas instalaciones sin afectar a su funcionamiento. • Bajo coste: el algoritmo de GDE propuesto se adapta a las redes actuales sin requisitos topológicos. Además, todas las instalaciones calculan su propia gestión con un bajo requerimiento computacional. Por lo tanto, no se requiere un nodo central con un alto poder de cómputo. • Rápido despliegue: las características de escalabilidad y bajo coste de los algoritmos de GDE propuestos permiten una implementación rápida. No se requiere una planificación compleja para el despliegue de este sistema. ABSTRACT This Thesis addresses the efficiency problems of the electrical grids from the consumption point of view. In particular, such efficiency is improved by means of the aggregated consumption smoothing. This objective of consumption smoothing entails two major improvements in the use of electrical grids: i) in the short term, a better use of the existing infrastructure and ii) in long term, the reduction of the required infrastructure to supply the same energy needs. In addition, this Thesis faces a new energy paradigm, where the presence of distributed generation is widespread over the electrical grids, in particular, the Photovoltaic (PV) generation. This kind of energy source affects to the operation of the grid by increasing its variability. This implies that a high penetration rate of photovoltaic electricity is pernicious for the electrical grid stability. This Thesis seeks to smooth the aggregated consumption considering this energy source. Therefore, not only the efficiency of the electrical grid is improved, but also the penetration of photovoltaic electricity into the grid can be increased. This proposal brings great benefits in the economic, social and environmental fields. The actions that influence the way that consumers use electricity in order to achieve energy savings or higher efficiency in energy use are called Demand-Side Management (DSM). This Thesis proposes two different DSM algorithms to meet the aggregated consumption smoothing objective. The difference between both DSM algorithms lie in the framework in which they take place: the local framework and the grid framework. Depending on the DSM framework, the energy goal and the procedure to reach this goal are different. In the local framework, the DSM algorithm only uses local information. It does not take into account other consumers or the aggregated consumption of the electrical grid. Although this statement may differ from the general definition of DSM, it makes sense in local facilities equipped with Distributed Energy Resources (DERs). In this case, the DSM is focused on the maximization of the local energy use, reducing the grid dependence. The proposed DSM algorithm significantly improves the self-consumption of the local PV generator. Simulated and real experiments show that self-consumption serves as an important energy management strategy, reducing the electricity transport and encouraging the user to control his energy behavior. However, despite all the advantages of the self-consumption increase, they do not contribute to the smooth of the aggregated consumption. The effects of the local facilities on the electrical grid are studied when the DSM algorithm is focused on self-consumption maximization. This approach may have undesirable effects, increasing the variability in the aggregated consumption instead of reducing it. This effect occurs because the algorithm only considers local variables in the local framework. The results suggest that coordination between these facilities is required. Through this coordination, the consumption should be modified by taking into account other elements of the grid and seeking for an aggregated consumption smoothing. In the grid framework, the DSM algorithm takes into account both local and grid information. This Thesis develops a self-organized algorithm to manage the consumption of an electrical grid in a distributed way. The goal of this algorithm is the aggregated consumption smoothing, as the classical DSM implementations. The distributed approach means that the DSM is performed from the consumers side without following direct commands issued by a central entity. Therefore, this Thesis proposes a parallel management structure rather than a hierarchical one as in the classical electrical grids. This implies that a coordination mechanism between facilities is required. This Thesis seeks for minimizing the amount of information necessary for this coordination. To achieve this objective, two collective coordination techniques have been used: coupled oscillators and swarm intelligence. The combination of these techniques to perform the coordination of a system with the characteristics of the electric grid is itself a novel approach. Therefore, this coordination objective is not only a contribution in the energy management field, but in the collective systems too. Results show that the proposed DSM algorithm reduces the difference between the maximums and minimums of the electrical grid proportionally to the amount of energy controlled by the system. Thus, the greater the amount of energy controlled by the algorithm, the greater the improvement of the efficiency of the electrical grid. In addition to the advantages resulting from the smoothing of the aggregated consumption, other advantages arise from the distributed approach followed in this Thesis. These advantages are summarized in the following features of the proposed DSM algorithm: • Robustness: in a centralized system, a failure or breakage of the central node causes a malfunction of the whole system. The management of a grid from a distributed point of view implies that there is not a central control node. A failure in any facility does not affect the overall operation of the grid. • Data privacy: the use of a distributed topology causes that there is not a central node with sensitive information of all consumers. This Thesis goes a step further and the proposed DSM algorithm does not use specific information about the consumer behaviors, being the coordination between facilities completely anonymous. • Scalability: the proposed DSM algorithm operates with any number of facilities. This implies that it allows the incorporation of new facilities without affecting its operation. • Low cost: the proposed DSM algorithm adapts to the current grids without any topological requirements. In addition, every facility calculates its own management with low computational requirements. Thus, a central computational node with a high computational power is not required. • Quick deployment: the scalability and low cost features of the proposed DSM algorithms allow a quick deployment. A complex schedule of the deployment of this system is not required.

Assessing construction and demolition waste on masonry works to avoid future generation

The difficulty of dealing with construction and demolition waste (CDW) on construction sites is not new and continues to be a significant environmental problem. Currently the CDW collection system in Spain is done in a decentralized manner by each sub-contracted company, being necessary to implement effective waste management measures ensuring a correct management and minimization. During the last years several measures have been launched in order to improve and encourage the reuse and recycling of CDW. A widespread solution for CDW recovery is using them as a landscaping aggregate or for road bases and sub-bases. However, measures encouraging onsite prevention still need to be enhanced. This paper studies the major work stage generating CDW and analyses the categories of CDW produced during its execution. For this, several real building sites have been analysed in order to quantify the estimation of CDW generated. Results of this study show that a significant contributor to the CDW generation on building construction sites in Spain are the masonry works. Finally, a Best Practices Manual (BPM) is proposed containing several strategies on masonry works aimed not only at CDW prevention, but also at improving their management and minimization. The use of this BPM together with the Study and Plan of CDW management --required by law--, promotes the environmental management of the company, favouring the cohesion of the construction process organization at all stages giving rise to establishing responsibilities in the field of waste and providing a greater control over the process. Keywords: construction and demolition waste, management, masonry works, good practice measures, prevention.

Entanglement generation and routing in optical networks

New telecom wavelength sources of polarization entangled photon pairs allow the distribution of entanglement through metro-access networks using standard equipment. This is essential to ease the deployment of future applications that can profit from quantum entanglement, such as quantum cryptography.

Power-frequency control of hydropower plants with long penstocks in isolated systems with wind generation

In this paper the power-frequency control of hydropower plants with long penstocks is addressed. In such configuration the effects of pressure waves cannot be neglected and therefore commonly used criteria for adjustment of PID governors would not be appropriate. A second-order Π model of the turbine-penstock based on a lumped parameter approach is considered. A correction factor is introduced in order to approximate the model frequency response to the continuous case in the frequency interval of interest. Using this model, several criteria are analysed for adjusting the PI governor of a hydropower plant operating in an isolated system. Practical criteria for adjusting the PI governor are given. The results are applied to a real case of a small island where the objective is to achieve a generation 100% renewable (wind and hydro). Frequency control is supposed to be provided exclusively by the hydropower plant. It is verified that the usual criterion for tuning the PI controller of isolated hydro plants gives poor results. However, with the new proposed adjustment, the time response is considerably improved

Methodology for developing an advanced communications system for the Deaf in a new domain

A methodology for developing an advanced communications system for the Deaf in a new domain is presented in this paper. This methodology is a user-centred design approach consisting of four main steps: requirement analysis, parallel corpus generation, technology adaptation to the new domain, and finally, system evaluation. During the requirement analysis, both the user and technical requirements are evaluated and defined. For generating the parallel corpus, it is necessary to collect Spanish sentences in the new domain and translate them into LSE (Lengua de Signos Española: Spanish Sign Language). LSE is represented by glosses and using video recordings. This corpus is used for training the two main modules of the advanced communications system to the new domain: the spoken Spanish into the LSE translation module and the Spanish generation from the LSE module. The main aspects to be generated are the vocabularies for both languages (Spanish words and signs), and the knowledge for translating in both directions. Finally, the field evaluation is carried out with deaf people using the advanced communications system to interact with hearing people in several scenarios. In this evaluation, the paper proposes several objective and subjective measurements for evaluating the performance. In this paper, the new considered domain is about dialogues in a hotel reception. Using this methodology, the system was developed in several months, obtaining very good performance: good translation rates (10% Sign Error Rate) with small processing times, allowing face-to-face dialogues.

Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow

Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.

Coalescent estimates of HIV-1 generation time in vivo

The generation time of HIV Type 1 (HIV-1) in vivo has previously been estimated using a mathematical model of viral dynamics and was found to be on the order of one to two days per generation. Here, we describe a new method based on coalescence theory that allows the estimate of generation times to be derived by using nucleotide sequence data and a reconstructed genealogy of sequences obtained over time. The method is applied to sequences obtained from a long-term nonprogressing individual at five sampling occasions. The estimate of viral generation time using the coalescent method is 1.2 days per generation and is close to that obtained by mathematical modeling (1.8 days per generation), thus strengthening confidence in estimates of a short viral generation time. Apart from the estimation of relevant parameters relating to viral dynamics, coalescent modeling also allows us to simulate the evolutionary behavior of samples of sequences obtained over time.

Generation of mucosal cytotoxic T cells against soluble protein by tissue-specific environmental and costimulatory signals

We compared peripheral and mucosal primary CD8 T cell responses to inflammatory and noninflammatory forms of antigen in a T cell-adoptive transfer system. Immunization with the soluble antigen, ovalbumin (ova), administered i.p. or orally without adjuvant, activated nonmucosal CD8 T cells but did not induce cytotoxic activity. However, after activation, the transferred cells entered the intestinal mucosa and became potent antigen-specific killers. Thus, exogenous intact soluble protein entered the major histocompatibility complex class I antigen presentation pathway and induced mucosal cytotoxic T lymphocytes. Moreover, distinct costimulatory requirements for activation of peripheral versus mucosal T cells were noted in that the CD28 ligand, B7-1, was critical for activated mucosal T cell generation but not for activation of peripheral CD8 T cells. The costimulator, B7-2, was required for optimum activation of both populations. Infection with a new recombinant vesicular stomatitis virus encoding ovalbumin induced lytic activity in mucosal as well as peripheral sites, demonstrating an adjuvant effect of inflammatory mediators produced during virus infection. Generation of antiviral cytotoxic T lymphocytes was also costimulation-dependent. The results indicated that induction of peripheral tolerance via antigen administration may not extend to mucosal sites because of distinct costimulatory and inflammatory signals in the mucosa.

Verb generation in patients with focal frontal lesions: A neuropsychological test of neuroimaging findings

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.

A new method for generating point mutations in bacterial artificial chromosomes by homologous recombination in Escherichia coli

Bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs), which contain large fragments of genomic DNA, have been successfully used as transgenes to create mouse models of dose-dependent diseases. They are also potentially valuable as transgenes for dominant diseases given that point mutations and/or small rearrangements can be accurately introduced. Here, we describe a new method to introduce small alterations in BACs, which results in the generation of point mutations with high frequency. The method involves homologous recombination between the original BAC and a shuttle vector providing the mutation. Each recombination step is monitored using positive and negative selection markers, which are the Kanamycin-resistance gene, the sacB gene and temperature-sensitive replication, all conferred by the shuttle plasmid. We have used this method to introduce four different point mutations and the insertion of the β-galactosidase gene in a BAC, which has subsequently been used for transgenic animal production.

Transcriptional and posttranslational plasticity and the generation of inflammatory pain

Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain reflects direct activation of specific receptors on nociceptor terminals by inflammatory mediators. Pain hypersensitivity is the consequence of early posttranslational changes, both in the peripheral terminals of the nociceptor and in dorsal horn neurons, as well as later transcription-dependent changes in effector genes, again in primary sensory and dorsal horn neurons. This inflammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathways phosphorylate membrane proteins, changing their function, and activate transcription factors, altering gene expression. Two distinct aspects of sensory neuron function are changed as a result of these processes, basal sensitivity, or the capacity of peripheral stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of certain inputs to generate prolonged alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes both potentiate the system and alter neuronal phenotype. Potentiation occurs as a result of the up-regulation in the dorsal root ganglion of centrally acting neuromodulators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those that induce stimulus-induced hypersensitivity. Alterations in phenotype includes the acquisition by A fibers of neurochemical features typical of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity, something only C fiber inputs normally can do. Elucidation of the molecular mechanisms responsible provides new opportunities for therapeutic approaches to managing inflammatory pain.

Genome projects and gene pools: New germplasm for plant breeding?

Crop gene pools have adapted to and sustained the demands of agricultural systems for thousands of years. Yet, very little is known about their content, distribution, architecture, or circuitry. The presumably shallow elite gene pools often continue to yield genetic gains while the exotic pools remain mostly untapped, uncharacterized, and underutilized. The concept and content of a crop’s gene pools are being changed by advancements in plant science and technology. In the first generation of plant genomics, DNA markers have refined some perceptions of genetic variation by providing a glimpse of a primary source, DNA polymorphism. The markers have provided new and more powerful ways of assessing genetic relationships, diversity, and merit by infusing genetic information for the first time in many scenarios or in a more comprehensive manner for others. As a result, crop gene pools may be supplemented through more rapid and directed methods from a greater variety of sources. Previously limited by the barriers of sexual reproduction, the native gene pools will soon be complemented by another gene pool (transgenes) and perhaps by other native exotic gene pools through comparative analyses of plants’ biological repertoire. Plant genomics will be an important force of change for crop improvement. The plant science community and crop gene pools may be united and enriched as never before. Also, the genomes and gene pools, the products of evolution and crop domestication, will be reduced and subjected to the vagaries and potential divisiveness of intellectual property considerations. Let the gains begin.

Transloading of tumor cells with foreign major histocompatibility complex class I peptide ligand: a novel general strategy for the generation of potent cancer vaccines.

The major hurdle to be cleared in active immunotherapy of cancer is the poor immunogenicity of cancer cells. In previous attempts to overcome this problem, whole tumor cells have been used as vaccines, either admixed with adjuvant(s) or genetically engineered to express nonself proteins or immunomodulatory factors before application. We have developed a novel approach to generate an immunogeneic, highly effective vaccine: major histocompatibility complex (MHC) class I-positive cancer cells are administered together with MHC class I-matched peptide ligands of foreign, nonself origin, generated by a procedure we term transloading. Murine tumor lines of the H2-Kd or the H2-Db haplotype, melanoma M-3 and B16-F10, respectively, as well as colon carcinoma CT-26 (H2-Kd), were transloaded with MHC-matched influenza virus-derived peptides and applied as irradiated vaccines. Mice bearing a deposit of live M-3 melanoma cells were efficiently cured by this treatment. In the CT-26 colon carcinoma and the B16-F10 melanoma, high efficacies were obtained against tumor challenge, suggesting the universal applicability of this new type of vaccine. With foreign peptide ligands adapted to the requirements of a desired MHC class I haplotype, this concept may be used for the treatment of human cancers.

Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subunit (CNTFR alpha) and the signal transducers gp130 and leukemia inhibitory factor receptor-beta (LIFR). The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR. The functional importance of these residues was assessed by alanine mutagenesis. Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130. The resulting variants behaved as partial agonists with varying degrees of residual bioactivity in different cell-based assays. Simultaneous alanine substitution of both F152 and K155 totally abolished biological activity. Combining these mutations with amino acid substitutions in the D-helix, which enhance binding affinity for the CNTFR alpha, gave rise to a potent competitive CNTF receptor antagonist. This protein constitutes a new tool for studies of CNTF function in normal physiology and disease.

A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis.

The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium, with polyneuropathy and cardiomyopathy as major clinical manifestations. So far, more than 40 distinct amino acid substitutions distributed throughout the TTR sequence over 30 positions have been found to be correlated with an increased amyloidogenicity of TTR. Most of these amyloidogenic amino acid substitutions are suspected to alter the conformation and stability of the monomer. Here we identify and characterize by protein and DNA analysis a novel amyloidogenic Val-20 to Ile mutation in a German three-generation family. The index patient suffered from severe amyloid cardiomyopathy at the age of 60. Conformational stability and unfolding behavior of the Ile-20 monomer in urea gradients was found to be almost indistinguishable from that of wild-type TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between the two opposing dimers via the side chain of Ile-20. Our observations provide strong evidence for the view that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into those conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential.