Friedrich Giesel entdeckte im Jahre 1902 das Actinium nach Fällung mit Lanthan aus einer Pechblendelösung. Er hatte den Namen Emanium vorgeschlagen, da es stark emanierte. Lange Zeit wurde nur Andre-Louis Debierne als Entdecker des Actiniums akzeptiert, da er 1904 behauptet hatte, dass die von ihm im Jahr 1900 gefundene von ihm Actinium genannte radioaktive Substanz mit den chemischen Eigenschaften des Thoriums, die hauptsächlich das Thoriumisotop 230Th enthielt, mit dem Emanium von Giesel identisch gewesen sei. In dem Beitrag werden die Entdeckungen von Debierne und Giesel und der Weg bis zur Anerkennung von Giesel als Entdecker vorgestellt. / Friedrich Giesel discovered actinium in 1902 after co precipitation with lanthanum from a solution of pitchblende. He had suggested to name it emanium, because of its emanating properties. But for a long time only Andre-Louis Debierne was accepted as discoverer of actinium, because in 1904 he has explained, that the radioactive substance found by him in 1900, with chemical properties of thorium, named actinium, and mainly consisting of the thorium isotope 230Th, has been identical with the emanium of Giesel. The discoveries of Giesel and Debierne are explained as well as the steps on the way of acceptance of Giesel as discoverer of actinium.

DOCTORAL THESIS Nikola Jajcay Spatial and temporal scales of atmospheric dynamics Abstract Earth climate, in general, varies on many temporal and spatial scales. In particular, climate observables exhibit recurring patterns and quasi- oscillatory phenomena with different periods. Although these oscillations might be weak in amplitude, they might have a non-negligible influence on variability on shorter time-scales due to cross-scale interactions, recently observed by Paluš[1]. This thesis supplies an introductory material for inferring the cross-scale information transfer from observational data, where the time series of interest are obtained using wavelet transform, and possible information transfer is studied using the tools from information theory. Finally, cross- scale interactions are studied in two climate phenomena: air temperature variability in Europe, in which we study phase-amplitude coupling from a slower oscillatory mode with an 8-year period on faster variability and its effects, and El Niño/ Southern Oscillation where we observe a causal chain of phase-phase and phase-amplitude couplings among distinct oscillatory modes. [1] M. Paluš. Multiscale atmospheric dynamics: cross-frequency phase-amplitude coupling in the air temperature. Physical Review Letters, 112(7):078702, 2014.

Live cell imaging has not been an active method of analysis during the drug discovery and development phase due to several limitations. This does not change the fact that it along with its time series data analysis describes an undergoing process better than a conventional study with fixed time points. In this project, I was a part of a team which are currently developing live cell morphological profiling assays which allows measuring cells’ morphology and perturbations caused on it due to toxicity by different treatments. Later, I attempted automating a group of robots to perform these assays automatically. I also developed a few software pipelines which generate quantitative data from live cell images, and performs analysis and data visualization on this quantitative time series data. Later, I implemented these methods on one of the experiment set and displayed importance of time series data by showing different trends displayed by different treatments for different morphology descriptors.

Ziel dieser Arbeit ist die Erarbeitung von effizienten (semi-)automatischen Verfahren zur Verknüpfung von Wissensbasen. Eine Vielzahl von Lösungsklassen können zu diesem Zweck eingesetzt werden. In dieser Arbeit werden ausschließlich deklarative Ansätze erörtert. Deklarative Ansätze gehen davon aus, dass das direkte Errechnen von Mappings zwischen Mengen von Ressourcen in vielen Fällen nur schwer möglich ist oder eines nicht vertretbaren Aufwands bedarf. Diese Ansätze zielen daher darauf ab, eine Ähnlichkeitsfunktion sowie einen Schwellwert zu finden, die zur Approximation eines Mappings genutzt werden können. Zwei Herausforderungen gehen mit dieser Modellierung des Problems einher: (a) Effizienz sowie (b) Genauigkeit und Vollständigkeit. Lösungen zu beiden Herausforderungen sowie auf echten Daten basierende Anwendungen dieser Lösungen werden in der Arbeit vorgestellt.

1. SUMMARYMyeloperoxidase (MPO) which belongs to the peroxidase family, is found in mammalian neutrophils. This heme enzyme contributes to the production of (pseudo)halogenous acid such as HOCl which oxidizes proteins, cell membrane, DNA and RNA causing death for the pathogens. It has an antimicrobial effect due to HOCl secreting inside the phagosomes of the neutrophils, whereas it will be released outside neutrophils causing oxidative damages for the host tissues. Proteins, lipids, lipoproteins, DNA and RNA are potential targets of the MPO resulting in several chronic syndromes. Many researchers have discovered the harmful effects of MPO and its products demonstrating its role in many inflammatory chronic diseases such as: Cardiovascular diseases as in atherosclerosis. MPO contribution in atherosclerosis development has been demonstrated. Neurodegenerative diseases also was related to MPO: such as Alzheimer’s disease (AD), multiple sclerosis (MSc) and Parkinson’s disease The enzyme has been also pointed out in other diseases such as renal disease and cancer.For these reasons, MPO as a target of drug discovery has attracted the attention of many researchers. X-ray 3D structures were resolved for this enzyme, biological activity and mechanism of action were investigated in depth, and many medicinal chemists have investigated and screened for new MPO inhibitors. Indeed, this cumulative work including X-ray data, the role of MPO in different pathologies, MPO inhibitory mechanism of action, screening and various chemical entities that inhibit MPO, provided sufficient elements to start a new drug design and drug discovery process on MPO.The aim of the present study was to apply a rational drug design approach to the myeloperoxidase inhibition: from in silico to pharmacological activity. This includes:─ Conducting high throughput virtual screening in order to find new potential hits to inhibit MPO followed by mechanism of inhibition determination. ─ Selecting one hit and then implementing a whole pharmacomodulation process in order to increase the potency of the inhibition greater than the starting hit and to improve the selectivity.Firstly, a rational drug design process was launched to find new hits using high throughput virtual screening. The chosen database for the screening was ASINEX database published in ZINC.X-ray structure of human peroxidase complexed to cyanide and thiocyanate (PDB 1DNW) was selected to conduct High-Throughput Virtual Screening (HTVS). Three successive protocols with different levels of accuracy in the docking and scoring processes were used starting with HTVS, followed by Standard Precision (SP) and finally with Xtra Precision (XP). The quality of the docking process performed was validated by docking a set of 60 chosen molecules of varying chemical structure and known as MPO inhibitors. From the result of the HTVS conducted on 1,350,000 compounds, the 100 best compounds were selected. Among them, 81 molecules were available for purchase from ASINEX, those compounds were tested with a MPO inhibition assay. Thirty-two compounds (39 %) were active, but only 8 compounds were selected, featuring different chemical structures with IC50 values ranging between 0.46 ± 0.07 and 12 ± 3 μM. Among these molecules, two compounds were the best and considered as hits. One has purinedione structure which is similar with the structure of thioxanthine derivatives (F9, IC50=0.46±0.07μM). The second compound has a hexahydropyrimidine structure (A1, IC50 = 0.5 ± 0.1 μM) The most common interactions found among all 8 docked ligands are the ionic bond with Glu102 and a stacking (shifted or not) with pyrrole ring D of the prosthetic group. Hydrogen bonds with Glu102, Thr100, Gln91, Arg239, or the propionate groups of the heme are also found in several docked geometries of the complexes. Interestingly, interactions with Glu102 and pyrrole ring D of the heme were also seen with fluorotryptamine derivatives and also salicylhydroxamic acid (SHA).For measuring MPO-dependent LDL oxidation, the two best compounds were tested. Compounds A1 and F9 showed good inhibition on MPO-dependent LDL oxidation (62 ± 6, 4.5 ± 0.9, 11 ± 2% and 11 ± 2, 2.6 ± 0.8, 6 ± 4%, respectively).Consequently, in order to determine the mechanism of inhibition transient-state kinetics were further investigated of all the 8 selected compounds.Both new lead compounds (A1 and F9) act as electron donors of both Compound I and Compound II of MPO. The reaction with Compound I was significantly faster (k2 ≫ k3). As a consequence, the enzyme is trapped in the Compound II state. They reversibly inactivated the enzyme blocking the harmful halogenation activity of MPO by transferring it to the MPO peroxidase cycle. In the present study, 8 active and reversible MPO inhibitors were selected. They act as electron donors of the oxidoreductase and efficiently block the halogenation activity with reversible inactivation. Two of the selected compounds have a submicromolar activity and inhibit MPO-dependent LDL oxidation. The high-throughput virtual screening was proved to be a successful tool to find new leads of MPO inhibitors. Conducting HTVS on a large-scale database enabled selection of novel scaffolds of MPO inhibitors never explored before in less time and at less expenses.Finding 8 new different chemical scaffolds through the first step of this drug discovery process led us to choose a new hit, compound A1, which has a hexahydropyrimidine structure, compound F9 was not chosen despite being more active due to its similarity to compounds discovered by AstraZeneca. To conduct pharmacomodulation, a validation of the docking procedure was conducted by comparing the X-ray structures of MPO with 2-(3,5-bistrifluoromethylbenzylamino)-6-oxo-1H-pyrimidine-5- carbohydroxamic acid, HX1, and SHA in the X-ray structures of human MPO in complex with cyanide and thiocyanate (PDB code 1DNW) as well as in complex with HX1 (PDB code 4C1M). Compound A1 was docked into both target structures 1DNW and 4C1M. In both cases, A1 showed almost the same poses.Based on the binding modes of A1, different strategies were developed for the design of derivatives which were mainly focused on the substitution of the aromatic rings A and B, the 2 amino groups and the side chain bridges.Pharmacomodulation was carried out on the hit A1 with different strategies:─ Investigating the role of hydroxyl groups on both aromatic rings─ Shifting the position of the amino groups in the hexahydropyrimidine ring to obtain piperazine derivatives and introduction of fluorine ─ Eliminating of one ring and of an amino group in the hexahydropyrimidine ring leading to piperidine derivatives ─ Opening the hexahydropyrimidine ring while keeping amine function and changing the length of the bridge between this amino group and aromatic ring as well as the impact of substitutions on aromatic rings.─ Hybridization of fluorotryptamine derivatives (effective MPO inhibitors) with hit A1.Based on of the docking experiments, 37 designed compounds were synthesized. The assessment of inhibition of the chlorination activity of MPO was undertaken over the 37 compounds. The hit A1 IC50 = 500 nM. The best compounds inhibiting MPO exhibited the following characteristics:─ One amino group on the bridge between aromatic rings was sufficient for the establishment of binding to Glu102 ─ The presence of three methylene groups between the secondary amine and an aromatic ring improved the inhibition of chlorination and thus decreased the IC50 values. These results showed that the position of the hydroxyl group is important. The distance between the hydrogen bond acceptor (HBA) group of one aromatic ring and the amino group is very important. The docking experiments of bisarylpropylamine derivatives showed ionic and hydrogen bonding interactions between Glu102 and hydroxyl group on aromatic ring linked to the longer side chain.─ Hybridized compounds which carry a fluorotryptamine instead of the phenol ring obtained by hybridization of hit A1 and the potent MPO inhibitors fluorotryptamine derivatives. Actually, compound 38 (which had one aromatic ring and a propyl bridge attached to indole ring) had an IC50 = 54 nM which was 10 times more powerful than the starting hit.The 3 best compounds were tested to examine the transient kinetics. They act as electron donors of the oxidoreductase and efficiently shift MPO from the chlorination cycle to the peroxidase cycle. Due to the similarity of the best compound 38 to serotonin it was tested with the two other best compounds on serotonin transporter (SERT) to examine the selectivity between MPO and SERT.Compound 38 had higher selectivity over MPO but the best selective compound was 28 that contains two aromatic rings carrying one hydroxyl and one fluorine.Electron density maps were conducted to predict the site of oxidation. Results suggested it occurs preferentially at the benzene ring or the indole ring in the best compounds.Determination of redox potentials for the synthesized compounds were tested. Best compounds act as electron donors allowing a one-electron reduction of Compound I.In conclusion, the present study succeeded through rational drug design including structure-based drug design and HTVS to identify new chemical entities for MPO inhibition. Eight compounds were more active than the starting hit A1 with submicromolar inhibition potency. Hybridization and structure based design also gave improvement of selectivity of inhibitors against MPO such as compound 38. Bis-arylalkylamine derivatives are a new group of MPO inhibitors with higher selectivity which could be a new hit for future development. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

This thesis aims to examine the internationalization of Swedish social entrepreneurs, with the purpose to acquire a more profound understanding of how social entrepreneurial supporting institutions influence their discovery of international opportunities, as well as their exploitation of the identified opportunities. The study is conducted with qualitative methodology and was conducted by examining the concept of Swedish social entrepreneurship carried out in an international context.

Ubiquitous computing (Ubicomp) increases in proliferation. Multiple and ever growing in numbers, computational devices are now at the users' disposal throughout the physical environment, while simultaneously being effectively invisible. Consequently, a significant challenge is service discovery. Services may for instance be physical, such as printing a document, or virtual, such as communicating information. The existing solutions, such as Bluetooth and UPnP, address part of the issue, specifically low-level physical interconnectivity. Still absent are solutions for high-level challenges, such as connecting users with appropriate services. In order to provide appropriate service offerings, service discovery in Ubicomp must take the users' context, tasks, goals, intentions, and available resources into consideration. It is possible to divide the high-level service-discovery issue into two parts; inadequate service models, and insufficient common-sense models of human activities. This thesis contributes to service discovery in Ubicomp, by arguing that in order to meet these high-level challenges, a new layer is required. Furthermore, the thesis presents a prototype implementation of this new service-discovery architecture and model. The architecture consists of hardware, ontology-layer, and common-sense-layer. This work addresses the ontology and common-sense layers. Subsequently, implementation is divided into two parts; Oden and Magubi. Oden addresses the issue of inadequate service models through a combination of service-ontologies in concert with logical reasoning engines, and Magubi addresses the issue of insufficient common-sense models of human activities, by using common sense models in combination with rule engines. The synthesis of these two stages enables the system to reason about services, devices, and user expectations, as well as to make suitable connections to satisfy the users' overall goal. Designing common-sense models and service ontologies for a Ubicomp environment is a non-trivial task. Despite this, we believe that if correctly done, it might be possible to reuse at least part of the knowledge in different situations. With the ability to reason about services and human activities it is possible to decide if, how, and where to present the services to the users. The solution is intended to off-load users in diverse Ubicomp environments as well as provide a more relevant service discovery. / <p>Report code: LiU-Tek-Lic-2007:14.</p>

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As mobile phones get increasingly complicated the demands for an effective firmware update service increase. A proposed solution is Firmware Over The Air (FOTA) and the Open Mobile Alliance’s Device Management where mobile phones can be updated and managed via the mobile phone network. However, before these operations can be carried out, all FOTA capable mobile phones that should be served must be discovered and registered with a distributor of updates. The information provided must be sufficient to uniquely identify devices, initiate a Device Management session, and determine if a firmware update is needed. This thesis addresses the problems that a solution in automatically collecting this information. Several solutions are presented and their suitability evaluated on the basis of defined and analyzed requirements. The solutions most thoroughly examined are various manual solutions, retrieval of information from core network nodes, and utilizing the Short Message Service (SMS) or Unstructured Supplementary Service Data (USSD). A phone application has been implemented according to the requirements from the Chinese network operator China Mobile Communications Corporation (CMCC). It is a part of a solution in which the information is delivered via a SMS session. The design and development phase of the application is described, accompanied by a brief description of the Symbian OS and the working environment (tools, devices, etc.) needed to implement this solution. This work took place at the Sony Ericsson office in Beijing, China. The application implemented is robust and it is impossible to avoid registration, furthermore the user can not be exposed to acknowledgement messages. It has been made possible on the cost of decreased phone performance (a few kB of memory) since the application runs all the time. Malfunctioning phone or network may hinder registration. / Mobiltelefoner blir ständigt mer komplicerade vilket medför att efterfrågan av en effektiv lösning för uppdateringar av mjukvaran i mobiltelefonerna ökar. Lösningen är Firmware Over The Air (FOTA) och Device Management; mobiltelefonerna uppdateras och sköts via mobiltelefonnätverket. Men innan förfaranden kan exekveras måste alla mobiltelefoner med FOTA som ska omfattas av tjänsten upptäckas och registreras hos den som distribuerar uppdateringarna. Den information som måste levereras måste vara tillräcklig för att kunna identifiera mobiltelefonen, genomföra en Device Management session och avgöra om en uppdatering av mjukvaran är nödvändig. Detta examensarbete behandlar de problem som en lösning i vilken information tillhandahålls möter. Ett flertal lösningar presenteras och deras lämplighet utvärderas på basis av definierade och analyserade krav. De mest ingående undersökta lösningarna är olika manuella lösningar, insamling av information från noderna av kärnnätverket samt utnyttjande av SMS eller USSD. En telefonapplikation har implementeras enligt krav från den kinesiska operatören CMCC. Applikationen är en del av en lösning i vilken informationen levereras via en SMS-session. Applikationens design och utvecklingsfasen är beskriven, samt en översiktlig beskrivning av Symbian operativsystem och utvecklingsmiljön (verktyg, mobiltelefoner, etc.) som behövdes för att implementera lösningen. Detta arbete genomfördes på Sony Ericssons kontor i Beijing, Kina.