Synthesis, properties and application of polyphenylene phosphonium salts

The central objective of this work was to generate weakly coordinating cations of unprecedented molecular size providing an inherently stable hydrophobic shell around a central charge. It was hypothesized that divergent dendritic growth by means of thermal [4+2] Diels-Alder cycloaddition might represent a feasible synthetic method to circumvent steric constraints and enable a drastic increase in cation size.rnThis initial proposition could be verified: applying the divergent dendrimer synthesis to an ethynyl-functionalized tetraphenylphosphonium derivative afforded monodisperse cations with precisely nanoscopic dimensions for the first time. Furthermore, the versatile nature of the applied cascade reactions enabled a throughout flexible design and structural tuning of the desired target cations. The specific surface functionalization as well as the implementation of triazolyl-moieties within the dendrimer scaffold could be addressed by sophisticated variation of the employed building block units (see chapter 3). rnDue to the steric screening provided by their large, hydrophobic and shape-persistent polyphenylene shells, rigidly dendronized cations proved more weakly coordinating compared to their non-dendronized analogues. This hypothesis has been experimentally confirmed by means of dielectric spectroscopy (see chapter 4). It was demonstrated for a series of dendronized borate salts that the degree of ion dissociation increased with the size of the cations. The utilization of the very large phosphonium cations developed within this work almost achieved to separate the charge carriers about the Bjerrum length in solvents of low polarity, which was reflected by approaching near quantitative ion dissociation even at room temperature. In addition to effect the electrolyte behavior in solution, the steric enlargement of ions could be visualized by means of several crystal structure analyses. Thus an insight into lattice packing under the effect of extraordinary large cations could be gathered. rnAn essential theme of this work focused on the application of benzylphosphonium salts in the classical Wittig reaction, where the concept of dendronization served as synthetic means to introduce an exceptionally large polyphenylene substituent at the -position. The straightforward influence of this unprecedented bulky group on the Wittig stereochemistry was investigated by NMR-analysis of the resulting alkenes. Based on the obtained data a valuable explanation for the origin of the observed selectivity was brought in line with the up-to-date operating [2+2] cycloaddition mechanism. Furthermore, a reliable synthesis protocol for unsymmetrically substituted polyphenylene alkenes and stilbenes was established by the design of custom-built polyphenylene precursors (see chapter 5).rnFinally, fundamental experiments to functionalize a polymer chain with sterically shielded ionic groups either in the pending or internal position were outlined within this work. Thus, inherently hydrophobic polysalts shall be formed so that future research can invesigate their physical properties with regard to counter ion condensation and charge carrier mobility.rnIn summary, this work demonstrates how the principles of dendrimer chemistry can be applied to modify and specifically tailor the properties of salts. The numerously synthesized dendrimer-ions shown herein represent a versatile interface between classic organic and inorganic electrolytes, and defined macromolecular structures in the nanometer-scale. Furthermore the particular value of polyphenylene dendrimers in terms of a broad applicability was illustrated. This work accomplished in an interdisciplinary manner to give answer to various questions such as structural modification of ions, the resulting influence on the electrolyte behavior, as well as the stereochemical control of organic syntheses via polyphenylene phosphonium salts. rn

Species specific nitrogen isotope analysis by NanoSIMS

Der atmosphärische Kreislauf reaktiver Stickstoffverbindungen beschäftigt sowohl die Naturwissenschaftler als auch die Politik. Dies ist insbesondere darauf zurückzuführen, dass reaktive Stickoxide die Bildung von bodennahem Ozon kontrollieren. Reaktive Stickstoffverbindungen spielen darüber hinaus als gasförmige Vorläufer von Feinstaubpartikeln eine wichtige Rolle und der Transport von reaktivem Stickstoff über lange Distanzen verändert den biogeochemischen Kohlenstoffkreislauf des Planeten, indem er entlegene Ökosysteme mit Stickstoff düngt. Die Messungen von stabilen Stickstoffisotopenverhältnissen (15N/14N) bietet ein Hilfsmittel, welches es erlaubt, die Quellen von reaktiven Stickstoffverbindungen zu identifizieren und die am Stickstoffkeislauf beteiligten Reaktionen mithilfe ihrer reaktionsspezifischen Isotopenfraktionierung genauer zu untersuchen. rnIn dieser Doktorarbeit demonstriere ich, dass es möglich ist, mit Hilfe von Nano-Sekundärionenmassenspektrometrie (NanoSIMS) verschiedene stickstoffhaltige Verbindungen, die üblicherweise in atmosphärischen Feinstaubpartikeln vorkommen, mit einer räumlichen Auflösung von weniger als einem Mikrometer zu analysieren und zu identifizieren. Die Unterscheidung verschiedener stickstoffhaltiger Verbindungen erfolgt anhand der relativen Signalintensitäten der positiven und negativen Sekundärionensignale, die beobachtet werden, wenn die Feinstaubproben mit einem Cs+ oder O- Primärionenstrahl beschossen werden. Die Feinstaubproben können direkt auf dem Probenahmesubstrat in das Massenspektrometer eingeführt werden, ohne chemisch oder physikalisch aufbereited zu werden. Die Methode wurde Mithilfe von Nitrat, Nitrit, Ammoniumsulfat, Harnstoff, Aminosären, biologischen Feinstaubproben (Pilzsporen) und Imidazol getestet. Ich habe gezeigt, dass NO2 Sekundärionen nur beim Beschuss von Nitrat und Nitrit (Salzen) mit positiven Primärionen entstehen, während NH4+ Sekundärionen nur beim Beschuss von Aminosäuren, Harnstoff und Ammoniumsalzen mit positiven Primärionen freigesetzt werden, nicht aber beim Beschuss biologischer Proben wie z.B. Pilzsporen. CN- Sekundärionen werden beim Beschuss aller stickstoffhaltigen Verbindungen mit positiven Primärionen beobachtet, da fast alle Proben oberflächennah mit Kohlenstoffspuren kontaminiert sind. Die relative Signalintensität der CN- Sekundärionen ist bei kohlenstoffhaltigen organischen Stickstoffverbindungen am höchsten.rnDarüber hinaus habe ich gezeigt, dass an reinen Nitratsalzproben (NaNO3 und KNO3), welche auf Goldfolien aufgebracht wurden speziesspezifische stabile Stickstoffisotopenverhältnisse mithilfe des 15N16O2- / 14N16O2- - Sekundärionenverhältnisses genau und richtig gemessen werden können. Die Messgenauigkeit auf Feldern mit einer Rastergröße von 5×5 µm2 wurde anhand von Langzeitmessungen an einem hausinternen NaNO3 Standard als ± 0.6 ‰ bestimmt. Die Differenz der matrixspezifischen instrumentellen Massenfraktionierung zwischen NaNO3 und KNO3 betrug 7.1 ± 0.9 ‰. 23Na12C2- Sekundärionen können eine ernst zu nehmende Interferenz darstellen wenn 15N16O2- Sekundärionen zur Messung des nitratspezifischen schweren Stickstoffs eingesetzt werden sollen und Natrium und Kohlenstoff im selben Feinstaubpartikel als interne Mischung vorliegt oder die natriumhaltige Probe auf einem kohlenstoffhaltigen Substrat abgelegt wurde. Selbst wenn, wie im Fall von KNO3, keine derartige Interferenz vorliegt, führt eine interne Mischung mit Kohlenstoff im selben Feinstaubpartikel zu einer matrixspezifischen instrumentellen Massenfraktionierung die mit der folgenden Gleichung beschrieben werden kann: 15Nbias = (101 ± 4) ∙ f − (101 ± 3) ‰, mit f = 14N16O2- / (14N16O2- + 12C14N-). rnWird das 12C15N- / 12C14N- Sekundärionenverhältnis zur Messung der stabilen Stickstoffisotopenzusammensetzung verwendet, beeinflusst die Probematrix die Messungsergebnisse nicht, auch wenn Stickstoff und Kohlenstoff in den Feinstaubpartikeln in variablen N/C–Verhältnissen vorliegen. Auch Interferenzen spielen keine Rolle. Um sicherzustellen, dass die Messung weiterhin spezifisch auf Nitratspezies eingeschränkt bleibt, kann eine 14N16O2- Maske bei der Datenauswertung verwendet werden. Werden die Proben auf einem kohlenstoffhaltigen, stickstofffreien Probennahmesubstrat gesammelt, erhöht dies die Signalintensität für reine Nitrat-Feinstaubpartikel.

Image quality and dose evaluation of filtered back projection versus iterative reconstruction algorithm in multislice computed tomography.

Il presente lavoro di tesi è stato svolto presso il servizio di Fisica Sanitaria del Policlinico Sant'Orsola-Malpighi di Bologna. Lo studio si è concentrato sul confronto tra le tecniche di ricostruzione standard (Filtered Back Projection, FBP) e quelle iterative in Tomografia Computerizzata. Il lavoro è stato diviso in due parti: nella prima è stata analizzata la qualità delle immagini acquisite con una CT multislice (iCT 128, sistema Philips) utilizzando sia l'algoritmo FBP sia quello iterativo (nel nostro caso iDose4). Per valutare la qualità delle immagini sono stati analizzati i seguenti parametri: il Noise Power Spectrum (NPS), la Modulation Transfer Function (MTF) e il rapporto contrasto-rumore (CNR). Le prime due grandezze sono state studiate effettuando misure su un fantoccio fornito dalla ditta costruttrice, che simulava la parte body e la parte head, con due cilindri di 32 e 20 cm rispettivamente. Le misure confermano la riduzione del rumore ma in maniera differente per i diversi filtri di convoluzione utilizzati. Lo studio dell'MTF invece ha rivelato che l'utilizzo delle tecniche standard e iterative non cambia la risoluzione spaziale; infatti gli andamenti ottenuti sono perfettamente identici (a parte le differenze intrinseche nei filtri di convoluzione), a differenza di quanto dichiarato dalla ditta. Per l'analisi del CNR sono stati utilizzati due fantocci; il primo, chiamato Catphan 600 è il fantoccio utilizzato per caratterizzare i sistemi CT. Il secondo, chiamato Cirs 061 ha al suo interno degli inserti che simulano la presenza di lesioni con densità tipiche del distretto addominale. Lo studio effettuato ha evidenziato che, per entrambi i fantocci, il rapporto contrasto-rumore aumenta se si utilizza la tecnica di ricostruzione iterativa. La seconda parte del lavoro di tesi è stata quella di effettuare una valutazione della riduzione della dose prendendo in considerazione diversi protocolli utilizzati nella pratica clinica, si sono analizzati un alto numero di esami e si sono calcolati i valori medi di CTDI e DLP su un campione di esame con FBP e con iDose4. I risultati mostrano che i valori ricavati con l'utilizzo dell'algoritmo iterativo sono al di sotto dei valori DLR nazionali di riferimento e di quelli che non usano i sistemi iterativi.

The creation and use of an international reference glossary specific for horror role-playing games

This thesis focuses on the technical approach to the translation of the Italian horror role-playing game Sine Requie into English. It aims to prove that both the role-playing and horror aspects of the genre are important to convey an enjoyable experience to the players, and that it is possible to create and international reference glossary to better translate the horror genre itself. Following a brief introduction of the history of role-playing games (RPGs), we will look at the RPG technical vocabulary in Sine Requie, and analyze which of these elements can be translated following the great models of the history of role-playing games. A brief introduction will follow regsrding the horror genre and its core characteristics based on the work of worldwide famous horror writer H.P. Lovecraft. Lastly, a description on how the international reference glossary for the horror genre was created will be presented along with a few examples of its practical use.

Strumenti e framework per lo sviluppo di linguaggi di programmazione e linguaggi domain-specific in java

La tesi ha lo scopo di indagare le tecnologie disponibili per la realizzazione di linguaggi di programmazione e linguaggi domain specific in ambiente Java. In particolare, vengono proposti e analizzati tre strumenti presenti sul mercato: JavaCC, ANTLR e Xtext. Al termine dell’elaborato, il lettore dovrebbe avere un’idea generale dei principali meccanismi e sistemi utilizzati (come lexer, parser, AST, parse trees, etc.), oltre che del funzionamento dei tre tools presentati. Inoltre, si vogliono individuare vantaggi e svantaggi di ciascuno strumento attraverso un’analisi delle funzionalità offerte, così da fornire un giudizio critico per la scelta e la valutazione dei sistemi da utilizzare.

Microwave breast imaging reconstruction

In this thesis I analyzed the microwave tomography method to recognize breast can- cer. I study how identify the dielectric permittivity, the Helmoltz equation parameter used to model the real physic problem. Through a non linear least squares method I solve a problem of parameters identification; I show the theoric approach and the devel- opment to reach the results. I use the Levenberg-Marquardt algorithm, applied on COMSOL software to multiphysic models; so I do numerical proofs on semplified test problems compared to the specific real problem to solve.

Set up of a procedure for correlation analysis between current discharge and dose delivery in a pulsed power plasma device for medical application

This thesis work aims to find a procedure for isolating specific features of the current signal from a plasma focus for medical applications. The structure of the current signal inside a plasma focus is exclusive of this class of machines and a specific analysis procedure has to be developed. The hope is to find one or more features that shows a correlation with the dose erogated. The study of the correlation between the current discharge signal and the dose delivered by a plasma focus could be of some importance not only for the practical application of dose prediction but also for expanding the knowledge anbout the plasma focus physics. Vatious classes of time-frequency analysis tecniques are implemented in order to solve the problem.

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Chronic myelogenous leukemia maintains specific CD8(+) T cells through IL-7 signaling

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells. The disease progresses after several years from an initial chronic phase to a blast phase. Leukemia-specific T cells are regularly detected in CML patients and may be involved in the immunological control of the disease. Here, we analyzed the role of leukemia-specific CD8(+) T cells in CML disease control and the mechanism that maintains CD8(+) T-cell immunosurveillance in a retroviral-induced murine CML model. To study antigen-specific immune responses, the glycoprotein of the lymphocytic choriomeningitis virus was used as model leukemia antigen. Leukemia-specific CTL activity was detectable in vivo in CML mice and depletion of CD8(+) T cells rapidly led to disease progression. CML-specific CTL were characterized by the expression of the IL-7 receptor -chain. In addition, leukemia cells produced IL-7 that was crucial for the maintenance of leukemia-specific CTL and for disease control. Therefore, CML cells maintain the specific CD8(+) T-cell-mediated immune control by IL-7 secretion. This results in prolonged control of disease and probably contributes to the characteristic chronic phase of the disease.

Using rapid prototyping molds to create patient specific polymethylmethacrylate implants in cranioplasty

Cranioplasty is a commonly performed procedure. Outcomes can be improved by the use of patient specific implants, however, high costs limit their accessibility. This paper presents a low cost alternative technique to create patient specific polymethylmethacrylate (PMMA) implants using rapid prototyped mold template. We used available patient's CT-scans, one dataset without craniotomy and one with craniotomy, for computer-assisted design of a 3D mold template, which itself can be brought into the operating room and be used for fast and easy building of a PMMA implant. We applied our solution to three patients with positive outcomes and no complications.

High-throughput procedure for tick surveys of tick-borne encephalitis virus and its application in a national surveillance study in Switzerland

Tick-borne encephalitis (TBE), a viral infection of the central nervous system, is endemic in many Eurasian countries. In Switzerland, TBE risk areas have been characterized by geographic mapping of clinical cases. Since mass vaccination should significantly decrease the number of TBE cases, alternative methods for exposure risk assessment are required. We established a new PCR-based test for the detection of TBE virus (TBEV) in ticks. The protocol involves an automated, high-throughput nucleic acid extraction method (QIAsymphony SP system) and a one-step duplex real-time reverse transcription-PCR (RT-PCR) assay for the detection of European subtype TBEV, including an internal process control. High usability, reproducibility, and equivalent performance for virus concentrations down to 5 x 10(3) viral genome equivalents/microl favor the automated protocol compared to the modified guanidinium thiocyanate-phenol-chloroform extraction procedure. The real-time RT-PCR allows fast, sensitive (limit of detection, 10 RNA copies/microl), and specific (no false-positive test results for other TBEV subtypes, other flaviviruses, or other tick-transmitted pathogens) detection of European subtype TBEV. The new detection method was applied in a national surveillance study, in which 62,343 Ixodes ricinus ticks were screened for the presence of TBE virus. A total of 38 foci of endemicity could be identified, with a mean virus prevalence of 0.46%. The foci do not fully agree with those defined by disease mapping. Therefore, the proposed molecular test procedure constitutes a prerequisite for an appropriate TBE surveillance. Our data are a unique complement of human TBE disease case mapping in Switzerland.

The Bern psychopathology scale for the assessment of system-specific psychotic symptoms

The translation from psychiatric core symptoms to brain functions and vice versa is a largely unresolved issue. In particular, the search for disorders of single brain regions explaining classical symptoms has not yielded the expected results. Based on the assumption that the psychopathology of psychosis is related to a functional imbalance of higher-order brain systems, the authors focused on three specific candidate brain circuitries, namely the language, and limbic and motor systems. These domains are of particular interest for understanding the disastrous communication breakdown during psychotic disorders. Core symptoms of psychosis were mapped on these domains by shaping their definitions in order to match the related brain functions. The resulting psychopathological assessment scale was tested for interrater reliability and internal consistency in a group of 168 psychotic patients. The items of the scale were reliable and a principal component analysis (PCA) was best explained by a solution resembling the three candidate systems. Based on the results, the scale was optimized as an instrument to identify patient subgroups characterized by a prevailing dysfunction of one or more of these systems. In conclusion, the scale is apt to distinguish symptom domains related to the activity of defined brain systems. PCA showed a certain degree of independence of the system-specific symptom clusters within the patient group, indicating relative subgroups of psychosis. The scale is understood as a research instrument to investigate psychoses based on a system-oriented approach. Possible immediate advantages in the clinical application of the understanding of psychoses related to system-specific symptom domains are also discussed.

All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study

Objective To examine all cause and disease specific mortality in patients with osteoarthritis of the knee or hip. Design Population based cohort study. Setting General practices in the southwest of England. Participants 1163 patients aged 35 years or over with symptoms and radiological confirmation of osteoarthritis of the knee or hip. Main outcome measures Age and sex standardised mortality ratios and multivariable hazard ratios of death after a median of 14 years’ follow-up. Results Patients with osteoarthritis had excess all cause mortality compared with the general population (standardised mortality ratio 1.55, 95% confidence interval 1.41 to 1.70). Excess mortality was observed for all disease specific causes of death but was particularly pronounced for cardiovascular (standardised mortality ratio 1.71, 1.49 to 1.98) and dementia associated mortality (1.99, 1.22 to 3.25). Mortality increased with increasing age (P for trend <0.001), male sex (adjusted hazard ratio 1.59, 1.30 to 1.96), self reported history of diabetes (1.95, 1.31 to 2.90), cancer (2.28, 1.50 to 3.47), cardiovascular disease (1.38, 1.12 to 1.71), and walking disability (1.48, 1.17 to 1.86). However, little evidence existed for increased mortality associated with previous joint replacement, obesity, depression, chronic inflammatory disease, eye disease, or presence of pain at baseline. The more severe the walking disability, the higher was the risk of death (P for trend <0.001). Conclusion Patients with osteoarthritis are at higher risk of death compared with the general population. History of diabetes, cancer, or cardiovascular disease and the presence of walking disability are major risk factors. Management of patients with osteoarthritis and walking disability should focus on effective treatment of cardiovascular risk factors and comorbidities, as well as on increasing physical activity.