Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease

In this thesis is described the design and synthesis of potential agents for the treatment of the multifactorial Alzheimer’s disease (AD). Our multi-target approach was to consider cannabinoid system involved in AD, together with classic targets. In the first project, designed modifications were performed on lead molecule in order to increase potency and obtain balanced activities on fatty acid amide hydrolase and cholinesterases. A small library of compounds was synthesized and biological results showed increased inhibitory activity (nanomolar range) related to selected target. The second project was focused on the benzofuran framework, a privileged structure being a common moiety found in many biologically active natural products and therapeutics. Hybrid molecules were designed and synthesized, focusing on the inhibition of cholinesterases, Aβ aggregation, FAAH and on the interaction with CB receptors. Preliminary results showed that several compounds are potent CB ligands, in particular the high affinity for CB2 receptors, could open new opportunities to modulate neuroinflammation. The third and the fourth project were carried out at the IMS, Aberdeen, under the supervision of Prof. Matteo Zanda. The role of the cannabinoid system in the brain is still largely unexplored and the relationship between the CB1 receptors functional modification, density and distribution and the onset of a pathological state is not well understood. For this reasons, Rimonabant analogues suitable as radioligands were synthesized. The latter, through PET, could provide reliable measurements of density and distribution of CB1 receptors in the brain. In the fifth project, in collaboration with CHyM of York, the goal was to develop arginine analogues that are target specific due to their exclusively location into NOS enzymes and could work as MRI contrasting agents. Synthesized analogues could be suitable substrate for the transfer of polarization by p-H2 molecules through SABRE technique transforming MRI a more sensitive and faster technique.

Persistent infections after natural transmission of bovine viral diarrhoea virus from cattle to goats and among goats

Bovine viral diarrhoea virus (BVDV) is an economically important pathogen of cattle worldwide. Infection of a pregnant animal may lead to persistent infection of the foetus and birth of a persistently infected (PI) calf that sheds the virus throughout its life. However, BVD viruses are not strictly species specific. BVDV has been isolated from many domesticated and wild ruminants. This is of practical importance as virus reservoirs in non-bovine hosts may hamper BVDV control in cattle. A goat given as a social companion to a BVDV PI calf gave birth to a PI goat kid. In order to test if goat to goat infections were possible, seronegative pregnant goats were exposed to the PI goat. In parallel, seronegative pregnant goats were kept together with the PI calf. Only the goat to goat transmission resulted in the birth of a next generation of BVDV PI kids whereas all goats kept together with the PI calf aborted. To our knowledge, this is the first report which shows that a PI goat cannot only transmit BVD virus to other goats but that such transmission may indeed lead to the birth of a second generation of PI goats. Genetic analyses indicated that establishment in the new host species may be associated with step-wise adaptations in the viral genome. Thus, goats have the potential to be a reservoir for BVDV. However, the PI goats showed growth retardation and anaemia and their survival under natural conditions remains questionable.

The VLT/NaCo large program to probe the occurrence of exoplanets and brown dwarfs at wide orbits II. Survey description, results, and performances

Context. Young, nearby stars are ideal targets for direct imaging searches for giant planets and brown dwarf companions. After the first-imaged planet discoveries, vast efforts have been devoted to the statistical analysis of the occurence and orbital distributions of giant planets and brown dwarf companions at wide (>= 5-6 AU) orbits. Aims. In anticipation of the VLT/SPHERE planet-imager, guaranteed-time programs, we have conducted a preparatory survey of 86 stars between 2009 and 2013 to identify new faint comoving companions to ultimately analyze the occurence of giant planets and brown dwarf companions at wide (10-2000 AU) orbits around young, solar-type stars. Methods. We used NaCo at VLT to explore the occurrence rate of giant planets and brown dwarfs between typically 0.1 and 8 ''. Diffraction-limited observations in H-band combined with angular differential imaging enabled us to reach primary star-companion brightness ratios as small as 10(-6) at 1.5 ''. Repeated observations at several epochs enabled us to discriminate comoving companions from background objects. Results. During our survey, twelve systems were resolved as new binaries, including the discovery of a new white dwarf companion to the star HD8049. Around 34 stars, at least one companion candidate was detected in the observed field of view. More than 400 faint sources were detected; 90% of them were in four crowded fields. With the exception of HD8049 B, we did not identify any new comoving companions. The survey also led to spatially resolved images of the thin debris disk around HD61005 that have been published earlier. Finally, considering the survey detection limits, we derive a preliminary upper limit on the frequency of giant planets for the semi-major axes of [10, 2000] AU: typically less than 15% between 100 and 500 AU and less than 10% between 50 and 500 AU for exoplanets that are more massive than 5 M-Jup and 10 M-Jup respectively, if we consider a uniform input distribution and a confidence level of 95%. Conclusions. The results from this survey agree with earlier programs emphasizing that massive, gas giant companions on wide orbits around solar-type stars are rare. These results will be part of a broader analysis of a total of similar to 210 young, solar-type stars to bring further statistical constraints for theoretical models of planetary formation and evolution.

New methods for the estimation of Takagi-Sugeno model based extended Kalman filter and its applications to optimal control for nonlinear systems

This paper describes new approaches to improve the local and global approximation (matching) and modeling capability of Takagi–Sugeno (T-S) fuzzy model. The main aim is obtaining high function approximation accuracy and fast convergence. The main problem encountered is that T-S identification method cannot be applied when the membership functions are overlapped by pairs. This restricts the application of the T-S method because this type of membership function has been widely used during the last 2 decades in the stability, controller design of fuzzy systems and is popular in industrial control applications. The approach developed here can be considered as a generalized version of T-S identification method with optimized performance in approximating nonlinear functions. We propose a noniterative method through weighting of parameters approach and an iterative algorithm by applying the extended Kalman filter, based on the same idea of parameters’ weighting. We show that the Kalman filter is an effective tool in the identification of T-S fuzzy model. A fuzzy controller based linear quadratic regulator is proposed in order to show the effectiveness of the estimation method developed here in control applications. An illustrative example of an inverted pendulum is chosen to evaluate the robustness and remarkable performance of the proposed method locally and globally in comparison with the original T-S model. Simulation results indicate the potential, simplicity, and generality of the algorithm. An illustrative example is chosen to evaluate the robustness. In this paper, we prove that these algorithms converge very fast, thereby making them very practical to use.

A New Multidisciplinary Home Care Telemedicine System to Monitor Stable Chronic Human Immunodeficiency Virus-Infected Patients: A Randomized Study

BACKGROUND: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. METHODOLOGY: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. FINDINGS: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4+ T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels >90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. CONCLUSIONS: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection. TRIAL REGISTRATION: Clinical-Trials.gov: NCT01117675.

A new method for the identification of old-growth trees in National Forest Inventories: Application to Pinus halepensis Mill. stands in Spain

Old-growth trees play a very important role in the maintenance of biodiversity in forests. However, no clear definition is yet available to help identify them since tree age is usually not recorded in National Forest Inventories. To develop and test a new method to identify old-growth trees using a species-specific threshold for tree diameter in National Forest Inventories. Different nonlinear mixed models for diameter ? age were generated using data from the Spanish Forest Inventory in order to identify the most appropriate one for Aleppo pine in its South-western distribution area. The asymptote of the optimal model indicates the threshold diameter for defining an old-growth tree. Additionally, five site index curves were examined to analyze the influence of site quality on these models.

A new dominance intensity method to deal with ordinal information about a DM's preferences within MAVT

Dominance measuring methods are a new approach to deal with complex decision-making problems with imprecise information. These methods are based on the computation of pairwise dominance values and exploit the information in the dominance matrix in dirent ways to derive measures of dominance intensity and rank the alternatives under consideration. In this paper we propose a new dominance measuring method to deal with ordinal information about decision-maker preferences in both weights and component utilities. It takes advantage of the centroid of the polytope delimited by ordinal information and builds triangular fuzzy numbers whose distances to the crisp value 0 constitute the basis for the de?nition of a dominance intensity measure. Monte Carlo simulation techniques have been used to compare the performance of this method with other existing approaches.

New methodology for the integration of biometric features in speaker recognition systems applied to security environments

La cuestión principal abordada en esta tesis doctoral es la mejora de los sistemas biométricos de reconocimiento de personas a partir de la voz, proponiendo el uso de una nueva parametrización, que hemos denominado parametrización biométrica extendida dependiente de género (GDEBP en sus siglas en inglés). No se propone una ruptura completa respecto a los parámetros clásicos sino una nueva forma de utilizarlos y complementarlos. En concreto, proponemos el uso de parámetros diferentes dependiendo del género del locutor, ya que como es bien sabido, la voz masculina y femenina presentan características diferentes que deberán modelarse, por tanto, de diferente manera. Además complementamos los parámetros clásicos utilizados (MFFC extraídos de la señal de voz), con un nuevo conjunto de parámetros extraídos a partir de la deconstrucción de la señal de voz en sus componentes de fuente glótica (más relacionada con el proceso y órganos de fonación y por tanto con características físicas del locutor) y de tracto vocal (más relacionada con la articulación acústica y por tanto con el mensaje emitido). Para verificar la validez de esta propuesta se plantean diversos escenarios, utilizando diferentes bases de datos, para validar que la GDEBP permite generar una descripción más precisa de los locutores que los parámetros MFCC clásicos independientes del género. En concreto se plantean diferentes escenarios de identificación sobre texto restringido y texto independiente utilizando las bases de datos de HESPERIA y ALBAYZIN. El trabajo también se completa con la participación en dos competiciones internacionales de reconocimiento de locutor, NIST SRE (2010 y 2012) y MOBIO 2013. En el primer caso debido a la naturaleza de las bases de datos utilizadas se obtuvieron resultados cercanos al estado del arte, mientras que en el segundo de los casos el sistema presentado obtuvo la mejor tasa de reconocimiento para locutores femeninos. A pesar de que el objetivo principal de esta tesis no es el estudio de sistemas de clasificación, sí ha sido necesario analizar el rendimiento de diferentes sistemas de clasificación, para ver el rendimiento de la parametrización propuesta. En concreto, se ha abordado el uso de sistemas de reconocimiento basados en el paradigma GMM-UBM, supervectores e i-vectors. Los resultados que se presentan confirman que la utilización de características que permitan describir los locutores de manera más precisa es en cierto modo más importante que la elección del sistema de clasificación utilizado por el sistema. En este sentido la parametrización propuesta supone un paso adelante en la mejora de los sistemas de reconocimiento biométrico de personas por la voz, ya que incluso con sistemas de clasificación relativamente simples se consiguen tasas de reconocimiento realmente competitivas. ABSTRACT The main question addressed in this thesis is the improvement of automatic speaker recognition systems, by the introduction of a new front-end module that we have called Gender Dependent Extended Biometric Parameterisation (GDEBP). This front-end do not constitute a complete break with respect to classical parameterisation techniques used in speaker recognition but a new way to obtain these parameters while introducing some complementary ones. Specifically, we propose a gender-dependent parameterisation, since as it is well known male and female voices have different characteristic, and therefore the use of different parameters to model these distinguishing characteristics should provide a better characterisation of speakers. Additionally, we propose the introduction of a new set of biometric parameters extracted from the components which result from the deconstruction of the voice into its glottal source estimate (close related to the phonation process and the involved organs, and therefore the physical characteristics of the speaker) and vocal tract estimate (close related to acoustic articulation and therefore to the spoken message). These biometric parameters constitute a complement to the classical MFCC extracted from the power spectral density of speech as a whole. In order to check the validity of this proposal we establish different practical scenarios, using different databases, so we can conclude that a GDEBP generates a more accurate description of speakers than classical approaches based on gender-independent MFCC. Specifically, we propose scenarios based on text-constrain and text-independent test using HESPERIA and ALBAYZIN databases. This work is also completed with the participation in two international speaker recognition evaluations: NIST SRE (2010 and 2012) and MOBIO 2013, with diverse results. In the first case, due to the nature of the NIST databases, we obtain results closed to state-of-the-art although confirming our hypothesis, whereas in the MOBIO SRE we obtain the best simple system performance for female speakers. Although the study of classification systems is beyond the scope of this thesis, we found it necessary to analise the performance of different classification systems, in order to verify the effect of them on the propose parameterisation. In particular, we have addressed the use of speaker recognition systems based on the GMM-UBM paradigm, supervectors and i-vectors. The presented results confirm that the selection of a set of parameters that allows for a more accurate description of the speakers is as important as the selection of the classification method used by the biometric system. In this sense, the proposed parameterisation constitutes a step forward in improving speaker recognition systems, since even when using relatively simple classification systems, really competitive recognition rates are achieved.

New methodology for describing the equilibrium beach profile applied to the Valencia's beaches

Mathematical models used for the understanding of coastal seabed morphology play a key role in beach nourishment projects. These projects have become the fundamental strategy for coastal maintenance during the last few years. Accordingly, the accuracy of these models is vital to optimize the costs of coastal regeneration projects. Planning of such interventions requires methodologies that do not generate uncertainties in their interpretation. A study and comparison of mathematical simulation models of the coastline is carried out in this paper, as well as elements that are part of the model that are a source of uncertainty. The equilibrium profile (EP) and the offshore limit corresponding to the depth of closure (DoC) have been analyzed taking into account different timescale ranges. The results have thus been compared using data sets from three different periods which are identified as present, past and future. Accuracy in data collection for the beach profiles and the definition of the median grain size calculation using collected samples are the two main factors that have been taken into account in this paper. These data can generate high uncertainties and can produce a lack of accuracy in nourishment projects. Together they can generate excessive costs due to possible excess or shortage of sand used for the nourishment. The main goal of this paper is the development of a new methodology to increase the accuracy of the existing equilibrium beach profile models, providing an improvement to the inputs used in such models and in the fitting of the formulae used to obtain seabed shape. This new methodology has been applied and tested on Valencia's beaches.

New Approaches, Alternative Avenues and Means of Access to Asylum Procedures for Persons Seeking International Protection. CEPS Liberty and Security in Europe No. 77/ January 2015

This study examines the workings of the Common European Asylum System (CEAS), in order to assess the need and potential for new approaches to ensure access to protection for people seeking it in the EU, including joint processing and distribution of asylum seekers. Rather than advocating the addition of further complexity and coercion to the CEAS, the study proposes a focus on front-line reception and streamlined refugee status determination, in order to mitigate the asylum challenges facing Member States, and vindicate the rights of asylum seekers and refugees according to the EU acquis and international legal standards. Joint processing could contribute to front-line reception and processing capacity, but is no substitute for proper investment in national systems. The Dublin system as currently configured leads inexorably to increasing coercion and detention, and must thus be reconfigured to remove coercion as a principle and ensure consistency with human rights and other fundamental values of the EU.

Michigan Union corridor to new dormitory

Irving Kane and Allen B. Pond, architects. Plans for the Union were on a scale unknown at the time for "club houses" in American colleges and universities: 250 feet long and 200 feet wide. Construction began in 1916 and owing to war time difficulties was not ready to be used by students until 1919. Two new wings to the south were completed in 1936 and 1938. Another addition was begun 1954-55. Verso: 7631 MICHIGAN UNION BLDG., University of Mich., Ann Arbor. Corridor in new dormitory addition. Magnesium Oxychloride tiles, put down in 1937. The floor base is black Hubbellite. On image: 7631.

The 'parallel bridge' and its relevance to biotechnology new ventures

A firm's competitive strategy and innovation processes are strongly influenced by, and must be responsive to, its competitive environment. This is nowhere more strongly evident than in the high technology industries. In the present work, case studies of biotechnology new ventures are presented. These studies illustrate how an initial market entry strategy of parallel competition (through creative imitation) has enabled several biotechnology start-ups to reduce their mortality risk. We coin the term ''parallel bridge'' to describe this strategy. The parallel bridge provides early cash flows which support research and development and provide time for new ventures to develop core competencies, including a capacity to produce second and third horizon products that will sustain longer term competitiveness.

Tifones y gigantes en el mundo macedonio: el rey como símbolo del orden cósmico

Este artículo analiza la existencia de un posible ritual en la antigua Macedonia que fuese similar al Akîtu babilonio. Pensamos que la victoria de Zeus sobre sus enemigos en la gigantomaquia y tifonomaquia fue celebrada por los reyes macedonios para fortalecer su posición en el poder. Aunque no hay evidencias directas de ello, tenemos una serie de diferentes fuentes en las cuales los macedonios están relacionados directa o indirectamente con Tifón y los gigantes. Además, la estratégica importancia del monte Olimpo para los macedonios nos hace pensar que la victoria de Zeus sobre las fuerzas del mal fue conmemorada de alguna forma por ellos.

State-Selective Attachment of Helium to Molecular Ions in a New Cryogenic Ion Trap

Light is the main information about the interstellar medium accessible on Earth. Based on this information one can conclude on the composition of the region where the light originates from, as well as on its history. The requirement for this is that it is possible to identify the different absorption and emission features in the spectrum and assign them to certain molecules, atoms or ions. To enable the identification of the different species, precise spectroscopic investigations of the species in the laboratory are necessary. In this work a new spectroscopic method is presented, which can be used to record pure rotational spectra of mass selected, cold, stored molecular ions. It is based on the idea of state specific attachment of helium atoms to the stored molecular ions. The new technique has been made possible through the development and recent completion of two new 22-pole ion trap instruments in the work group of Laboratory Astrophysics at the University of Cologne. These new instruments have the advantage to reach temperatures as low as 4K compared to the 10K of the predecessor instrument. These low temperatures enable the ternary attachment of helium atoms to the stored molecular ions and by this make it possible to develop this new method for pure rotational spectroscopy. According to this, this work is divided into two parts. The first part deals with the new FELion experiment that was build and characterized in the first part of the thesis. FELion is a cryogenic 22-pole ion trap apparatus, allowing to generate, mass select, store and cool down, and analyze molecular ions. The different components of the instrument, e.g. the Storage Ion Source for generating the ions or the first quadrupole mass filter, are described and characterized in this part. Besides this also the newly developed control and data acquisitions system is introduced. With this instrument the measurements presented in the second part of the work were performed. The second part deals with the new action spectroscopic method of state-selective helium attachment to the stored molecular ions. For a deeper analysis of the new technique the systems of CD+ and helium and HCO+ and helium are investigated in detail. Analytical and numerical models of the process are presented and compared to experimental results. The results of these investigations point to a seemingly very general applicability of the new method to a wide class of molecular ions. In the final part of the thesis measurements of the rotational spectrum of l-C3H+ are presented. These measurements have to be high-lighted, since it was possible for the first time in the laboratory to unambiguously measure four low-lying rotational transitions of l-C3H+. These measurements (Brünken et al. ApJL 783, L4 (2014)) enabled the reliable identification of so far unidentified emision lines observed in several regions of the interstellar medium (Pety et al. Astron. Astrophys. 548, A68 (2012), McGuire et al. The Astrophysical Journal 774, 56 (2013) and McGuire et al. The Astrophysical Journal 783, 36 (2014)).

Two roads to planet detection

One of the most exciting discoveries in astrophysics of the last last decade is of the sheer diversity of planetary systems. These include "hot Jupiters", giant planets so close to their host stars that they orbit once every few days; "Super-Earths", planets with sizes intermediate to those of Earth and Neptune, of which no analogs exist in our own solar system; multi-planet systems with planets smaller than Mars to larger than Jupiter; planets orbiting binary stars; free-floating planets flying through the emptiness of space without any star; even planets orbiting pulsars. Despite these remarkable discoveries, the field is still young, and there are many areas about which precious little is known. In particular, we don't know the planets orbiting Sun-like stars nearest to our own solar system, and we know very little about the compositions of extrasolar planets. This thesis provides developments in those directions, through two instrumentation projects.

The first chapter of this thesis concerns detecting planets in the Solar neighborhood using precision stellar radial velocities, also known as the Doppler technique. We present an analysis determining the most efficient way to detect planets considering factors such as spectral type, wavelengths of observation, spectrograph resolution, observing time, and instrumental sensitivity. We show that G and K dwarfs observed at 400-600 nm are the best targets for surveys complete down to a given planet mass and out to a specified orbital period. Overall we find that M dwarfs observed at 700-800 nm are the best targets for habitable-zone planets, particularly when including the effects of systematic noise floors caused by instrumental imperfections. Somewhat surprisingly, we demonstrate that a modestly sized observatory, with a dedicated observing program, is up to the task of discovering such planets.

We present just such an observatory in the second chapter, called the "MINiature Exoplanet Radial Velocity Array," or MINERVA. We describe the design, which uses a novel multi-aperture approach to increase stability and performance through lower system etendue, as well as keeping costs and time to deployment down. We present calculations of the expected planet yield, and data showing the system performance from our testing and development of the system at Caltech's campus. We also present the motivation, design, and performance of a fiber coupling system for the array, critical for efficiently and reliably bringing light from the telescopes to the spectrograph. We finish by presenting the current status of MINERVA, operational at Mt. Hopkins observatory in Arizona.

The second part of this thesis concerns a very different method of planet detection, direct imaging, which involves discovery and characterization of planets by collecting and analyzing their light. Directly analyzing planetary light is the most promising way to study their atmospheres, formation histories, and compositions. Direct imaging is extremely challenging, as it requires a high performance adaptive optics system to unblur the point-spread function of the parent star through the atmosphere, a coronagraph to suppress stellar diffraction, and image post-processing to remove non-common path "speckle" aberrations that can overwhelm any planetary companions.

To this end, we present the "Stellar Double Coronagraph," or SDC, a flexible coronagraphic platform for use with the 200" Hale telescope. It has two focal and pupil planes, allowing for a number of different observing modes, including multiple vortex phase masks in series for improved contrast and inner working angle behind the obscured aperture of the telescope. We present the motivation, design, performance, and data reduction pipeline of the instrument. In the following chapter, we present some early science results, including the first image of a companion to the star delta Andromeda, which had been previously hypothesized but never seen.

A further chapter presents a wavefront control code developed for the instrument, using the technique of "speckle nulling," which can remove optical aberrations from the system using the deformable mirror of the adaptive optics system. This code allows for improved contrast and inner working angles, and was written in a modular style so as to be portable to other high contrast imaging platforms. We present its performance on optical, near-infrared, and thermal infrared instruments on the Palomar and Keck telescopes, showing how it can improve contrasts by a factor of a few in less than ten iterations.

One of the large challenges in direct imaging is sensing and correcting the electric field in the focal plane to remove scattered light that can be much brighter than any planets. In the last chapter, we present a new method of focal-plane wavefront sensing, combining a coronagraph with a simple phase-shifting interferometer. We present its design and implementation on the Stellar Double Coronagraph, demonstrating its ability to create regions of high contrast by measuring and correcting for optical aberrations in the focal plane. Finally, we derive how it is possible to use the same hardware to distinguish companions from speckle errors using the principles of optical coherence. We present results observing the brown dwarf HD 49197b, demonstrating the ability to detect it despite it being buried in the speckle noise floor. We believe this is the first detection of a substellar companion using the coherence properties of light.