Three methods for claims reserving are compared on two data sets. The first two methods are the commonly used chain ladder method that uses aggregated payments and the relatively new method, double chain ladder, that apart from the payments data also uses the number of reported claims. The third method is more advanced, data on micro-level is needed such as the reporting delay and the number of payment periods for every single claim. The two data sets that are used consist of claims with typically shorter and longer settlement time, respectively. The questions considered are if you can gain anything from using a method that is more advanced than the chain ladder method and if the gain differs from the two data sets. The methods are compared by simulating the reserves distributions as well as comparing the point estimates of the reserve with the real out-of-sample reserve. The results show that there is no gain in using the micro-level method considered. The double chain lad- der method on the other hand performs better than the chain ladder method. The difference between the two data sets is that the reserve in the data set with longer settlement times is harder to estimate, but no difference can be seen when it comes to method choice. / Tre reservsättningsmetoder jämförs på två dataset. De första två metoderna är den välkända chain ladder-metoden som använder sig av aggregerade utbetalningar samt den relativt nya metoden double chain ladder som förutom utbetalningarna använder sig av antalet anmälda skador. Den tredje metoden baseras på mikro-nivå och kräver information om varje enskild skada, såsom anmälningstid och antalet utbetalningsperioder. De två dataseten som används är ett som innehåller skador med typiskt kortare avvecklingstider och ett som innehåller skador med typiskt längre avvecklingstider. Frågorna som behandlas är om man vinner något på att använda en mer avancerad metod än chain ladder och om det skiljer sig åt mellan dataseten. Metoderna jämförs genom simulering av reserven, men också genom att jämföra punktskattningar med den verkliga reserven. Resultaten visar att man I detta fall inte vinner något på att använda mikro-metoden. Double chain ladder å andra sidan presterar bättre än chain ladder. Skillnaden mellan de två dataseten är att det är svårare att estimera reserven när avvecklingstiden är längre, men ingen skillnad ses när det gäller val av metod

<p>Dissociation dynamics of the ionized molecules HCl and the deuterated system DCl has been studied in gas-phase using synchrotron based photoelectron spectroscopy (PES).</p><p>The inner-valence "(4σ)^-1" photoionization band for DCl and HCl was recorded using maximum resolution in order to probe an interference pattern between a dissociative and a bound electronic state. For HCl⁺, we clearly observed distorted Fano-type peaks even for modest resolution, whereas for DCl⁺, the pattern was hardly discernible. The observation in HCl⁺ has been explained by a coupling between two adiabatic electronic states, where the bound state was populated through non-adiabatic curve-crossing. The nuclear motion of HCl⁺ is too fast for the Born-Oppenheimer approximation to be fully valid in this case. Whereas for DCl⁺, with larger reduced mass and therefore slower nuclear motion, the non-adiabatic coupling is less pronounced, and the vibrational progression vanishes.</p><p>A comparative study between PES and threshold photoelectron spectra (TPES) of the inner-valence bands of HCl and DCl has been performed, showing differences in intensities and shapes of the vibrational bands. These differences were attributed to the fact that the sudden approximation, which can be assumed to be valid for PES, is violated in the case of TPES.</p><p>A resonant Auger electron spectroscopy study of HCl and DCl has been performed, which shows an interference pattern between atomic and molecular Auger- and photoelectron channels. The atomic features are associated with ultra-fast dissociation of the molecules, on the same time scale as the Auger decay. The observation shows that the excited molecular system has to be regarded as a superposition of fragmented and molecular states.</p><p>A study of the <i>X</i>-state of HCl⁺, populated via a core-excited state, shows a selective population of the final state. The explanation was shown to be that the magnetic orientation of the core-hole is transferred to the final state of the molecule.</p><p>A setup for data acquisition of Photo-Electron Photo-Ion Photo-Ion COincidence (PEPIPICO) measurements using a Time-Of-Flight (TOF) spectrometer has been developed. A Time-to-Digital Converter (TDC) card has been linked together with the data treatment program Igor as a user interface. Furthermore, the PEPIPICO spectrometer has been characterized to provide a solid basis for the analysis of experimental data.</p>

Dissociation dynamics of the ionized molecules HCl and the deuterated system DCl has been studied in gas-phase using synchrotron based photoelectron spectroscopy (PES). The inner-valence "(4σ)-1" photoionization band for DCl and HCl was recorded using maximum resolution in order to probe an interference pattern between a dissociative and a bound electronic state. For HCl+, we clearly observed distorted Fano-type peaks even for modest resolution, whereas for DCl+, the pattern was hardly discernible. The observation in HCl+ has been explained by a coupling between two adiabatic electronic states, where the bound state was populated through non-adiabatic curve-crossing. The nuclear motion of HCl+ is too fast for the Born-Oppenheimer approximation to be fully valid in this case. Whereas for DCl+, with larger reduced mass and therefore slower nuclear motion, the non-adiabatic coupling is less pronounced, and the vibrational progression vanishes. A comparative study between PES and threshold photoelectron spectra (TPES) of the inner-valence bands of HCl and DCl has been performed, showing differences in intensities and shapes of the vibrational bands. These differences were attributed to the fact that the sudden approximation, which can be assumed to be valid for PES, is violated in the case of TPES. A resonant Auger electron spectroscopy study of HCl and DCl has been performed, which shows an interference pattern between atomic and molecular Auger- and photoelectron channels. The atomic features are associated with ultra-fast dissociation of the molecules, on the same time scale as the Auger decay. The observation shows that the excited molecular system has to be regarded as a superposition of fragmented and molecular states. A study of the X-state of HCl+, populated via a core-excited state, shows a selective population of the final state. The explanation was shown to be that the magnetic orientation of the core-hole is transferred to the final state of the molecule. A setup for data acquisition of Photo-Electron Photo-Ion Photo-Ion COincidence (PEPIPICO) measurements using a Time-Of-Flight (TOF) spectrometer has been developed. A Time-to-Digital Converter (TDC) card has been linked together with the data treatment program Igor as a user interface. Furthermore, the PEPIPICO spectrometer has been characterized to provide a solid basis for the analysis of experimental data.

Dynamic combinatorial chemistry (DCC) is a powerful tool to identify new ligands for biological targets. In the technique, library synthesis and hit identification are neatly combined into a single step. A labile functionality between fragments allows the biological target to self-select binders from a dynamic combinatorial library (DCL) of interconverting building blocks. The scope of suitable reversible reactions that proceed under thermodynamic control in physiological conditions has been gradually expanded over the last decades, however DCC has thus far failed to gain traction as a technique appropriate for drug discovery in the pharmaceutical industry. The constraints placed on library size by validated analytical techniques, and the effort-intensive reality of this academically elegant concept have not allowed DCC to develop into a broad-platform technique to compete with the high-throughput screening campaigns favoured by medicinal chemists. This thesis seeks to develop DCL analysis techniques, in an effort to increase the library size and accelerate the analysis of DCC experiments. Using a 19F-labelled core scaffold, we constructed a DCL that could be monitored non-invasively by 19F NMR. Building on NMR techniques developed by fragment screening and non-biological DCC campaigns, the method was developed to circumvent the undesired equilibrium-perturbing side effects arising from sample-consuming analytical methods. The N-acylhydrazone (NAH) DCL equilibrated rapidly at pH 6.2 using 4-amino-L-phenylalanine (4-APA) as a novel, physiologically benign, nucleophilic catalyst. The DCL was designed to target b-ketoacyl-ACP synthase III (FabH), an essential bacterial enzyme and antibiotic target. From the 5-membered DCL, a single combination was identified as a privileged structure by our 19F NMR method. The result correlated well with an in vitro assay, validating 19F NMR as a tool for DCL screening. During the 19F NMR study we identified an established antimicrobial compound, 4,5- dichloro-1,2-dithiole-3-one (HR45), to have potential as a core scaffold from which to develop future DCLs targeting FabH. Despite the potentially tractable chemistry of HR45 for DCC, lack of knowledge around the inhibitory mechanism of the compound prevented us from proceeding. Thus, we used mass spectrometry, NMR and molecular modelling to show that HR45 acts by forming a covalent adduct with S. aureus FabH. The 5-chloro substituent directs attack from the nucleophilic thiol side chain of the essential active site cysteine-112 residue via a Michael-type addition elimination mechanism. Although interesting, this mechanism disfavoured the use of HR45 as a core scaffold for NAH exchange in a DCC campaign. Electrospray ionisation mass spectrometry (ESI-MS) is a powerful technique that allows for larger DCLs by eliminating the size-limitations imposed by the need for spectral or chromatographic resolution of DCL members. We developed a 4-APAcatalysed NAH library targeting the pyridoxal 5’-phosphate (PLP) dependent enzyme 7,8-diaminopelargonic acid synthase (BioA), an essential enzyme in the biotin biosynthesis pathway. We exploited the aldehyde moiety of PLP to form an NAH DCL with a panel of hydrazides, and used the BioA isozymes from M. tuberculosis (Mtb) and E. coli to template the library. A combination of buffer exchange and denaturing ESI-MS allowed us to conduct a DCC experiment with a 29-member DCL. Hits from the DCC experiment correlated well with differential scanning fluorimetry (DSF) results. Of these hits, 5 compounds were selected for further study. In vivo activity was displayed by 2 compounds against E. coli and the ESKAPE pathogen A. baumannii. The identification of compounds with antibacterial activity from a DCL further validates ESI-MS as a platform technology for drug discovery.

Introducción: El conocimiento de los mecanismos neuroinflamatorios y neurodegenerativos que acontecen en la enfermedad de Alzheimer es aún limitado y la utilidad diagnóstica, pronóstica o de seguimiento del proceso, tanto en la fase DCL como en la EA establecida, de los diferentes marcadores moleculares es controvertida cuando no directamente contradictoria. La teoría patogénica más aceptada hoy en día es que las moléculas centrales de la vía amiloidea pondrían en marcha un proceso inflamatorio crónico, responsable del daño celular, en el que las citocinas tendría un papel preponderante a través de distintas vía de señalización. Objetivos: El objetivo primario comprende la evaluación de la síntesis de una amplia variedad de citocinas (CQs) dentro del SNC en pacientes con deterioro cognitivo leve (DCL) y Enfermedad de Alzheimer (EA), utilizando una técnica más sensible que la tradicional con el propósito de identificar si alguna o algunas CQs o ratio derivada de ellas tienen posibilidades de servir como marcadores diagnósticos de DCL y estudiar si estos mediadores solubles pueden utilizarse como elementos pronósticos/predictivos de evolución a EA desde el estado de DCL. Métodos: Se estudiaron los niveles de diferentes citocinas en LCR y suero mediante tecnología Luminex de 37 pacientes diagnosticados de DCL en la consulta de deterioro cognitivo del Hospital General Universitario de Alicante. Por otro lado, se estudió una cohorte de 24 controles sin quejas subjetivas u objetivas de alteraciones de su capacidad cognitiva. A los 12 meses y tras una nueva punción lumbar, los pacientes se clasificaron como DCL-E (estable, no evolucionados a EA) y DCL-EA (que habían desarrollado EA), volviendo a medir las concentraciones de citocinas en LCR y suero. Se realizó estudio estadístico de estos marcadores y sus ratios en ambos grupos. Resultados: Los dos resultados mayores de este proyecto ha sido la detección de un índice IL6/IL10 en LCR, para los pacientes DCL, con un VPN del 80% a la hora de descartar la presencia de deterioro cognitivo y, en segundo lugar el hallazgo de otro índice IL10S/L, al comparar los valores de esa citocina en suero y LCR de pacientes evolucionados a EA con los del grupo control, con una sensibilidad del 80% para seleccionar pacientes sin riesgo de desarrollar EA. La significación estadística de este segundo índice es independiente de la representada por ßA lo que apunta a mecanismos de acción distintos o bien a momentos de actuación diferentes. Conclusiones: Nuestros resultados apoyan la participación de las citocinas en el proceso inflamatorio de la EA y su valor como marcadores secundarios, con valor diagnóstico/pronóstico, en esto pacientes. Su aplicación puede tener sentido en aquellos casos en los que la clasificación de un paciente es dudosa mediante los métodos diagnósticos habituales.

DCL-1 (CD302) is a type I transmembrane C-type lectin receptor, which is expressed on monocytes, macrophages, granulocytes and dendritic cells. However, its extracellular domain lacks the amino acids motives essential for carbohydrate binding in the presence of calcium ions, suggesting that it does not have the classic binding capacity found in other C-type lectin receptors such as the mannose receptor. No exogenous or endogenous ligands have been identified yet, though. Due to internal colocalization with F-actin we can assume, that this unconventional lectin receptor plays a role not only in endocytosis and phagocytosis but also in the cell adhesion and migration. The receptor DCL-1 was first identified as a genetic fusion partner of human DEC-205 multilectin receptor in Hodgkin's lymphoma cell lines. The experimental part of this thesis deals with the characterization of disulfide bonds and data acquisition for validation of DCL-1 crystal structure. First the production and refolding conditions were optimized to obtain the highest amount of DCL-1 protein, precisely its extracellular domain. These optimal conditions were used to prepare the protein for in-gel digestion using specific endopeptidases in the presence of cystamine followed by LC-MS analysis. DCL-1 disulfide bonds were determined by comparing...

Η διπλωματική αυτή εργασία εκπονήθηκε με σκοπό την δημιουργία ενός προγράμματος για τη διαχείριση του δικτύου Δομημένης Καλωδίωσης. Μέσω της εφαρμογής αυτής, δίνεται η δυνατότητα στον χρήστη να έχει μία πλήρη εικόνα της εγκατεστημένης δομημένης καλωδίωσης του κτηρίου και να μπορεί να παρέμβει άμεσα και αποτελεσματικά σε κάθε περίπτωση τροποποίησης ή δυσλειτουργίας. Το πρόγραμμα υλοποιήθηκε στη γλώσσα προγραμματισμού AutoLISP, που λειτουργεί μέσα από την πλατφόρμα του σχεδιαστικού προγράμματος AutoCAD. Χρησιμοποιήθηκαν τα σχέδια των ορόφων του κτηρίου των Ηλεκτρολόγων Μηχανικών του Πανεπιστημίου Πατρών, όπου, στα πλαίσια της επίτευξης του στόχου, σχεδιάστηκε το σύστημα δομημένης καλωδίωσης. Στην εργασία αυτή, παρουσιάζονται τα βασικά στοιχεία ενός συστήματος δομημένης καλωδίωσης, καθώς και τα εργαλεία υλοποίησης του προγράμματος όπως το σχεδιαστικό πρόγραμμα AutoCAD, η γλώσσα προγραμματισμού AutoLISP, και η γλώσσα σήμανσης Dialog Control Language (DCL). Αρχικά, παρουσιάζεται η διαδικασία σχεδίασης του συστήματος δομημένης καλωδίωσης στο AutoCAD. Μετέπειτα, δίδεται μια περιγραφή του προγράμματος και των λειτουργιών του, και ο πηγαίος κώδικας που αναπτύχθηκε, σε συνδυασμό με λογικά διαγράμματα για την καλύτερη κατανόηση του. Στο παράρτημα, αναλύονται τα υποπρογράμματα που σχεδιάστηκαν για να προσφέρουν επιπλέον δυνατότητες, και το εγχειρίδιο χρήσης της εφαρμογής. / The aim of this thesis is to create an application software for the management of a Structured Cabling System (SCS). Through this application, the user is able to have a complete picture of the installed structured cabling network of the building and be able to intervene quickly and effectively in any case of modification or malfunction. The program was implemented using the programming language AutoLISP, which operates through the CAD software platform of AutoCAD. The architectural floor plans used were those of the building of Electrical Engineering Department, at the University of Patras, where, in the context of achieving the target, the structured cabling system was designed. This thesis presents the basic elements of a structured cabling system, and the tools for implementing the program, i.e. the CAD program AutoCAD, the programming language AutoLISP, and the markup language Dialog Control Language (DCL). The design process of the structured cabling system in AutoCAD is presented initially. Thereafter, a description of the program and its features are presented, as well as the source code that was developed, in conjunction with logic diagrams for clarity. In the Annexes, the subroutines designed to offer additional features are analyzed and the manual of the application is included.