Studies to localize and characterize the isoform specific functional differences between cardiac and skeletal troponin C

Thin filament regulation of muscle contraction is a calcium dependent process mediated by the Tn complex. Calcium is released into the sarcomere and is bound by TnC. The subsequent conformation change in TnC is thought to begin a cascade of events that result in the activation of the actin-myosin ATPase. While the general events of this cascade are known, the molecular mechanisms of this signal transduction event are not. Recombinant DNA techniques, physiological and biochemical studies have been used to localize and characterize the structural domains of TnC that play a role in the calcium dependent signal transduction event that serves to trigger muscle contraction. The strategy exploited the observed functional differences between the isoforms of TnC to map regions of functional significance to the proteins. Chimeric cardiac-skeletal TnC proteins were generated to localize the domains of TnC that are required for maximal function in the myofibrilar ATPase assay. Characterization of these regions has yielded information concerning the molecular mechanism of muscle contraction. ^

Unnatural Narration beyond Postmodernist Alterities

Postmodernism has frequently employed unnatural narration with the aim to disturb and subvert conventionalized reading practices. Postmodernist discourses thus widely associate the unnatural with alterity, marginality and the suppressed. In this paper, I caution against such a perspective, which threatens to unduly limit our understanding of the broad variety of relations between natural and unnatural narrative on the one hand, and of the multiple possible functions of unnatural narratives on the other. Taking my cue from the use of unnatural narration in a number of recent novels, like Mark Z. Danielewski’s House of Leaves (2000), Michael Chabon’s Amazing Adventures of Kavalier & Clay (2000), or Yann Martel’s Life of Pi (2001), I will argue that a postmodernist approach which foregrounds ontological and epistemological questions and emphasizes alterity and subversion remains blind to some of the pragmatic implications that are the main concern of the unnatural narratives under consideration. This not only begs the question whether and in how far such a shift from ontological and epistemological towards pragmatic concerns constitutes a move beyond postmodernism, but also calls for a reconsideration of some of our widely established theories and assumptions about unnatural narratives.

Promising anchoring groups for single-molecule conductance measurements

The understanding of the charge transport through single molecule junctions is a prerequisite for the design and building of electronic circuits based on single molecule junctions. However, reliable and robust formation of such junctions is a challenging task to achieve. In this topical review, we present a systematic investigation of the anchoring group effect on single molecule junction conductance by employing two complementary techniques, namely scanning tunneling microscopy break junction (STM-BJ) and mechanically controllable break junction (MCBJ) techniques, based on the studies published in the literature and important results from our own work. We compared conductance studies for conventional anchoring groups described earlier with the molecular junctions formed through π-interactions with the electrode surface (Au, Pt, Ag) and we also summarized recent developments in the formation of highly conducting covalent Au–C σ-bonds using oligophenyleneethynylene (OPE) and an alkane molecular backbone. Specifically, we focus on the electron transport properties of diaryloligoyne, oligophenyleneethynylene (OPE) and/or alkane molecular junctions composed of several traditional anchoring groups, (dihydrobenzo[b]thiophene (BT), 5-benzothienyl analogue (BTh), thiol (SH), pyridyl (PY), amine (NH2), cyano (CN), methyl sulphide (SMe), nitro (NO2)) and other anchoring groups at the solid/liquid interface. The qualitative and quantitative comparison of the results obtained with different anchoring groups reveals structural and mechanistic details of the different types of single molecular junctions. The results reported in this prospective may serve as a guideline for the design and synthesis of molecular systems to be used in molecule-based electronic devices.

Pestiviruses.

Pestiviruses cause economically important diseases among domestic ruminants and pigs, but they may also infect a wide spectrum of wild species of even-toed ungulates (Artiodactyla). Bovine viral diarrhea virus (BVDV) and Border disease virus of sheep infect their hosts either transiently or persistently. Cellular and humoral immunotolerance to the infecting strain is a unique feature of persistent infection (PI) by ruminant pestiviruses. Persistence, caused by transplacental infection early in fetal development, depends on virally encoded interferon antagonists that inactivate the host's innate immune response to the virus without globally interfering with its function against other viruses. At epidemiological equilibrium, approximately 1-2% of animals are PI. Successful BVDV control programs show that removal of PI animals results in viral extinction in the host population. The nucleotide sequences of ruminant pestiviruses change little during persistent infection. Nevertheless, they display large heterogeneity, pointing to a long history of virus-host coevolution in which avirulent strains are more successful.

Protease inhibitors to treat hepatitis C in the Swiss HIV Cohort Study: high efficacy but low treatment uptake

OBJECTIVES Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs. METHODS Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs. RESULTS Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs. CONCLUSIONS The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Can ancient colour polymorphisms explain why some cichlid lineages speciate rapidly under disruptive sexual selection?

It is not sufficiently understood why some lineages of cichlid fishes have proliferated in the Great Lakes of East Africa much more than anywhere else in the world, and much faster than other cichlid lineages or any other group of freshwater fish. Recent field and experimental work on Lake Victoria haplochromines suggests that mate choice-mediated disruptive sexual selection on coloration, that can cause speciation even in the absence of geographical isolation, may explain it. We summarize the evidence and propose a hypothesis for the genetics of coloration that may help understand the phenomenon. By detl ning colour patterns by hue and arrangement of hues on the body, we could assign almost all observed phenotypes of Lake Victoria cichlids to one of three female («plain», «orange blotched», «black and white») and three male («blue», «red-ventrum», «reddorsum») colour patterns. These patterns diagnose species but frequently eo-occur also as morphs within the same population, where they are associated with variation in mate preferences, and appear to be transient stages in speciation. Particularly the male patterns occur in almost every genus of the species flock. We propose that the patterns and their association into polymorphisms express an ancestral trait that is retained across speciation. Our model for male colour pattern assumes two structural loci. When both are switched off, the body is blue. When switched on by a cascade of polymorphic regulatory genes, one expresses a yellow to red ventrum, the other one a yellow to red dorsum. The expression of colour variation initiates speciation. The blue daughter species will inherit the variation at the regulatory genes that can, without new mutational events, purely by recombination, again expose the colour polymorphism, starting the process anew. Very similar colour patterns also dominate among the Mbuna of Lake Malawi. In contrast, similar colour polymorphisms do not exist in the lineages that have not proliferated in the Great Lakes. The colour pattern polymorphism may be an ancient trait in the lineage (or lineages) that gave rise to the two large haplochromine radiations. We propose two tests of our hypothesis.

Binary recombinase systems for high-resolution conditional mutagenesis.

Conditional mutagenesis using Cre recombinase expressed from tissue specific promoters facilitates analyses of gene function and cell lineage tracing. Here, we describe two novel dual-promoter-driven conditional mutagenesis systems designed for greater accuracy and optimal efficiency of recombination. Co-Driver employs a recombinase cascade of Dre and Dre-respondent Cre, which processes loxP-flanked alleles only when both recombinases are expressed in a predetermined temporal sequence. This unique property makes Co-Driver ideal for sequential lineage tracing studies aimed at unraveling the relationships between cellular precursors and mature cell types. Co-InCre was designed for highly efficient intersectional conditional transgenesis. It relies on highly active trans-splicing inteins and promoters with simultaneous transcriptional activity to reconstitute Cre recombinase from two inactive precursor fragments. By generating native Cre, Co-InCre attains recombination rates that exceed all other binary SSR systems evaluated in this study. Both Co-Driver and Co-InCre significantly extend the utility of existing Cre-responsive alleles.

The differential staurosporine mediated G1 arrest in normal versus tumor cells is dependent on the retinoblastoma and Chk1 proteins

The ability to regulate cell cycle progression is one of the differences that separates normal from tumor cells. A protein, which is frequently mutated or deleted in a majority of tumor cells, is the retinoblastoma protein (pRb). Previously, we reported that normal cells, which have a wild-type Rb pathway, can be reversibly arrested in the G1 phase of the cell cycle by staurosporine (ST), while tumor cells were unaffected by this treatment. As a result, ST may be used to protect normal cells against the toxic affects of chemotherapy. Here we set out to determine the mechanism(s) by which ST can mediate a reversible G1 arrest in pRb positive cells. To this end, we used an isogenic cell model system of normal human mammary epithelial cells (HMEC) with either intact pRb+ (p53-) or p53+ (pRb-) treated with ST. Our results show that pRb+ cells treated with low concentrations of ST, arrested in the G1 phase of the cell cycle; however, in pRb - cells there was no response. This was verified as a true G 1 arrest in pRb+ cells by two different methods for monitoring cell cycle kinetics and in two additional model systems for Rb (i.e. pRb -/- mouse embryo fibroblasts, and downregulation of RB with siRNA). Our results indicated that ST-mediated G1 arrest required pRb, which in turn initiated a cascade of events leading to inhibition of CDK4 and CDK2 activities and up-regulation of p21 protein. Further assessment of this pathway revealed the novel finding that Chk1 expression and activity were required for the Rb-dependent, ST-mediated G1 arrest. In fact, overexpression of Chk1 facilitated recovery from ST-mediated G1 arrest, an effect only observed in RB+ cells. Collectively, our data suggest pRb is able to cooperate with Chk1 to mediate a G1 arrest in pRb+ cells, but not in pRb- cells. The elucidation of this pathway can help identify novel agents that can be used to protect cancer patients against the debilitating affects of chemotherapy, by targeting only the normal proliferating cells in the body that are otherwise destroyed. ^

Dynamic population coding in primary visual cortex

More than a century ago Ramon y Cajal pioneered the description of neural circuits. Currently, new techniques are being developed to streamline the characterization of entire neural circuits. Even if this 'connectome' approach is successful, it will represent only a static description of neural circuits. Thus, a fundamental question in neuroscience is to understand how information is dynamically represented by neural populations. In this thesis, I studied two main aspects of dynamical population codes. ^ First, I studied how the exposure or adaptation, for a fraction of a second to oriented gratings dynamically changes the population response of primary visual cortex neurons. The effects of adaptation to oriented gratings have been extensively explored in psychophysical and electrophysiological experiments. However, whether rapid adaptation might induce a change in the primary visual cortex's functional connectivity to dynamically impact the population coding accuracy is currently unknown. To address this issue, we performed multi-electrode recordings in primary visual cortex, where adaptation has been previously shown to induce changes in the selectivity and response amplitude of individual neurons. We found that adaptation improves the population coding accuracy. The improvement was more prominent for iso- and orthogonal orientation adaptation, consistent with previously reported psychophysical experiments. We propose that selective decorrelation is a metabolically inexpensive mechanism that the visual system employs to dynamically adapt the neural responses to the statistics of the input stimuli to improve coding efficiency. ^ Second, I investigated how ongoing activity modulates orientation coding in single neurons, neural populations and behavior. Cortical networks are never silent even in the absence of external stimulation. The ongoing activity can account for up to 80% of the metabolic energy consumed by the brain. Thus, a fundamental question is to understand the functional role of ongoing activity and its impact on neural computations. I studied how the orientation coding by individual neurons and cell populations in primary visual cortex depend on the spontaneous activity before stimulus presentation. We hypothesized that since the ongoing activity of nearby neurons is strongly correlated, it would influence the ability of the entire population of orientation-selective cells to process orientation depending on the prestimulus spontaneous state. Our findings demonstrate that ongoing activity dynamically filters incoming stimuli to shape the accuracy of orientation coding by individual neurons and cell populations and this interaction affects behavioral performance. In summary, this thesis is a contribution to the study of how dynamic internal states such as rapid adaptation and ongoing activity modulate the population code accuracy. ^

Estradiol and insulin cross -talk in breast cancer

Approximately 33% of clinical breast carcinomas require estrogens to proliferate. Epidemiological data show that insulin resistance and diabetes mellitus is 2–3 times more prevalent in women with breast cancer than those with benign breast lesions, suggesting a clinical link between insulin and estradiol. Insulin and estradiol have a synergistic effect on the growth of MCF7 breast cancer cells, and long-term estradiol treatment upregulates the expression of the key insulin signaling protein IRS-1. The goal of this study was to further define the mechanism(s) of cross-talk between insulin and estradiol in regulating the growth of breast cancer. Using MCF7 cells, acute treatment with insulin or estradiol alone was found to stimulate two activities associated with growth: Erk MAP kinase and PI 3-kinase. However, combined acute treatment had an antagonistic effect on both activities. Acute estradiol treatment inhibited the insulin-stimulated tyrosine phosphorylation of IRS-1 while increasing its serine phosphorylation; the serine phosphorylation was attenuated by the PI 3-kinase inhibitor wortmannin. The acute antagonism observed with combined estradiol and insulin are not consistent with the long-term synergistic effect on growth. In contrast, chronic estradiol treatment enhanced the insulin-sensitivity of breast cancer cells as measured by increases in total cellular insulin-stimulated tyrosine phosphorylation of IRS-1 and activation of PI 3-kinase. Estradiol stimulation of gene transcription was found to require PI 3-kinase activity but not MAP kinase activity. Insulin alone had no effect on ER transcriptional activity, but chronic treatment in combination with estradiol resulted in synergism of ER transcription. The synergistic effect of insulin and estradiol on MCF7 cell growth was also found to require PI 3-kinase but not MAP kinase activity. Therefore, chronic estradiol treatment increases insulin stimulation of PI 3-kinase, and PI 3-kinase is required for estradiol stimulation of gene transcription alone and in combined synergy with insulin. These data demonstrate that PI 3-kinase is the locus for the cross-talk between insulin and estradiol which results in enhanced breast cancer growth with long-term exposure to both hormones. This may have important clinical implications for women with high risk for breast cancer and/or diabetes mellitus. ^

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

On-chip Monitoring: A Light-Weight Interconnection Network Approach

Current nanometer technologies are subjected to several adverse effects that seriously impact the yield and performance of integrated circuits. Such is the case of within-die parameters uncertainties, varying workload conditions, aging, temperature, etc. Monitoring, calibration and dynamic adaptation have appeared as promising solutions to these issues and many kinds of monitors have been presented recently. In this scenario, where systems with hundreds of monitors of different types have been proposed, the need for light-weight monitoring networks has become essential. In this work we present a light-weight network architecture based on digitization resource sharing of nodes that require a time-to-digital conversion. Our proposal employs a single wire interface, shared among all the nodes in the network, and quantizes the time domain to perform the access multiplexing and transmit the information. It supposes a 16% improvement in area and power consumption compared to traditional approaches.

Criterios de optimización de los incentivos en contratos de concesión ligados a indicadores de calidad de servicio para firmes bituminosos

Actualmente se está empezando a consolidar una nueva forma de gestionar la conservación y mantenimiento de la red viaria de las Administraciones Públicas, basándose en contratos de colaboración público-privadas (PPP). Las motivaciones que están provocando este movimiento son de diversa índole. Por un lado, en el seno de la Unión Europea, existen serias restricciones presupuestarias debido al alto endeudamiento del sector público, lo que está llevando a buscar la forma óptima de disminuir el endeudamiento público, sin dejar de prestar servicios a la sociedad como la conservación y mantenimiento de las redes viarias. Por esta vertiente, se trata de convertir contratos convencionales de conservación viaria a esquemas de colaboración público-privada, donde se transferiría al sector privado el riesgo de disponibilidad de la vía mediante el uso de indicadores de calidad y servicio. Con esta transferencia de riesgo, junto con la transferencia del riesgo de demanda/construcción, no consolidaría la deuda de la sociedad de propósito específico constituida para la gestión del contrato de colaboración público-privada dentro de las cuentas públicas, con lo que se conseguiría no aumentar el déficit público, permitiendo continuar ofreciendo el servicio demandado por la sociedad. Por otro lado, la segunda motivación del desarrollo de este tipo de contratos, no tan economicista como la anterior y más enfocada a la gestión, se trata de utilizar los contratos de gestión basados en el uso de indicadores de calidad de servicio para mejorar las prestaciones de la red viaria competencia de una Administración. Con el uso de estos indicadores, el gestor tiene una herramienta muy útil para controlar la actividad del sector privado y asegurar que se ofrece un buen servicio. En la presente tesis, la investigación se ha centrado más en la vertiente de los indicadores de calidad relacionados con la gestión eficiente de las vías objeto de conservación y mantenimiento mediante el empleo de contratos de gestión privada que utilicen este tipo de herramientas de control, monitorización y gestión. En una primera parte, la presente tesis estudia el estado de la red de carreteras, referido principalmente a España, comparando su estado con el resto de redes de carreteras de Europa, detectando las principales carencias de la misma, sobre todo en cuanto a la gestión y conservación de firmes. En un segundo bloque, la tesis analiza el estado del arte de los nuevos procedimientos de gestión de la conservación y mantenimiento basados en indicadores de calidad del servicio en el mundo, destacándose que se trata de un tema relativamente reciente, con gran interés para el sector de la gestión y financiación de infraestructuras viarias. Al ser tan novedoso, por la falta de experiencias previas, las distintas Administración, tanto propias como foráneas, han pecado de un exceso de celo a la hora de establecer los umbrales sobre los que giran los distintos indicadores de calidad de servicio que permiten controlar la gestión de la conservación y mantenimiento de la vía. Partiendo de la labor de análisis descrita, la tesis realiza una investigación más detallada de los indicadores de calidad de servicio correspondientes a firmes bituminosos, debido a que estos indicadores son los más delicados y decisivos a la hora de realizar una correcta gestión de la vía a largo plazo. Dentro de los indicadores de firmes bituminosos, se ha realizado un modelo específico de evolución de comportamiento a lo largo del tiempo de la regularidad superficial, parámetro básico para numerosas Administraciones y organismos investigadores para poder conocer la evolución de un firme a lo largo del tiempo. A esta metodología se le ha dado el nombre de Modelo JRB para evaluar la racionalidad económica de indicadores de calidad asociados a parámetros de firmes. El modelo propuesto básicamente evalúa el valor óptimo desde la perspectiva económica que ha de tener el parámetro técnico que defina alguna propiedad del firme, aplicado a la definición de los indicadores de calidad de servicio. Esta visión del valor umbral del indicador deja a un lado consideraciones de equidad o de cualquier otra índole, basándose más en una visión económica. La metodología del Modelo JRB se puede aplicar a cualquier indicador de calidad relacionado con firmes, ya que lo que se obtiene es el valor óptimo económico que debería tener el umbral del indicador de calidad. El Modelo JRB consta de varias fases. En las primeras etapas el Modelo realiza el cálculo de los costes totales de transporte utilizando como herramienta el software HDM-IV desarrollado por el Banco Mundial. En etapas posteriores, el Modelo realiza análisis de sensibilidad para distintas propuestas de sección de firme, intensidades de tráfico y restricciones al parámetro técnico que define el indicador de calidad de servicio. Como ejercicio práctico de cara a contrastar la metodología del Modelo JRB se ha realizado un Caso de Estudio. Se ha tomado un tramo teórico, con características similares a la red de carreteras española, y con una flota vehicular similar a la española, donde se ha elegido como indicador de calidad la regularidad superficial (IRI). Con las sensibilidades realizadas con el Modelo JRB, se ha determinado el rango de valores que debería tener un indicador de calidad basado en el IRI para que dichos valores fueran óptimos desde la perspectiva económica Nowadays is becoming a new way to manage O&M (operation and maintenance) in public road networks, based on PPP contracts (public-private partnership). There are several issues which are driving this trend. On the one hand, EU (European Union) has serious budgetary constraints due to the high public sector borrowing. EU politicians are looking for the best way to reduce public debt, keeping services to society such as O&M of road networks. For this aspect, conventional O&M contracts are switching to PPP scenarios, where availability risk would be transfer to private sector using PI (performance indicators), along with demand risk transfer With this risk transference, along with the transfer of demand/construction risk, SPV (specific purpose vehicle) debt doesn’t consolidate in public accounts, so deficit wouldn’t increase, allowing the continuation of services demanded by society. On the other hand, the second motivation for developing this kind of contracts, not so economist as above and more focused to management, it is about using O&M contracts based on the use of PI to improve road network maintenance. Using these indicators, manager has a very useful tool to monitor private sector activity and ensure that it is provided a good service. In this thesis, the research has been focused on PI quality aspect, related with efficient management of PPP contracts for roads, which use these tools for control, monitoring and management. In the first part, this thesis examines the state of road network, based mainly in Spain, comparing with other road networks in Europe, identifying the main gaps in it, especially with regard to the management and maintenance of pavements. In a second block, the thesis analyzes the state of art of new O&M contracts based on PI in the world, emphasizing that they are relatively recent. These kinds of contracts have a great interest in road management and financing sector. Administrations all around the world have launch tenders with very exigent PI thresholds due to several factors: this knowledge is a new area, the lack of previous experiences and the variety of Administrations which have bid these contracts. Building on the described analysis, thesis develops a more detailed research about PI for bituminous pavements, because these PI are the most delicate and decisive in making a proper long term road management. Among bituminous pavements PI, IRI (International Roughness Index) has been analyzed with more detail and has been developed a specific model of behaviour evolution over time for evenness (IRI), basic parameter for many administrations and research departments in order to know the evolution of a pavement over time. This methodology has been given the name of JRB Model to evaluate the economic rationality of performance indicators associated with pavements parameters. The proposed model basically evaluates the optimal value from an economic perspective it must have the technical parameter which defines some pavement characteristic applied to the definition of performance indicators. This point of view of indicator value threshold sets aside justice considerations or otherwise, based more on an economic perspective. JRB Model methodology can be applied to any performance indicator associated to pavements, because what you get is the economic optimum threshold should have the performance indicator. JRB Model consists of several phases. In the early stages, the Model calculates transport total cost using HDM-IV software, developed by the World Bank, as a tool. In later stages, the Model performs sensitivity analyzes for different pavement section, AADT and restrictions to the technical parameter which defines the performance indicator. As a practical exercise to test JRB Model methodology, it has done a Case Study. It has taken a theoretical section, with similar characteristics to Spanish road network, and a vehicles fleet similar to Spanish. Evenness (IRI) was chosen as a performance indicator. JRB Model calculated some sensitivities, which were useful to determined thresholds range for pavement performance indicators based on IRI to be optimal from an economic perspective.