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    ThomX Technical Design Report

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    Circuit design for low-cost smart sensing applications based on printed flexible electronics

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    Fucosylated and Sulfated Glycans Investigated using Cryogenic Infrared Spectroscopy

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    Unusual monosaccharides (fucose), covalent modifications of glycans (sulfation) and terminal sequences play important biological roles in physiology and pathology of living organisms. Furthermore, in an evolutionary sense, uncommon structures are often the result of selection pressures and can be the source to a deeper understanding of the evolution of glycosylation.157 At the same time, fucosylated glycans and sulfated glycans still challenge standard mass spectrometry (MS)-based analytical workflows in glycan analysis. MS emerged throughout the last decade as the most widely used analytical technique in glycan analysis. As a stand-alone technique, it is limited in glycan analysis due to the presence of isomers. Isomerism in glycans arises from their composition, connectivity, configuration, and branching. Therefore, MS is often coupled to orthogonal techniques such as liquid chromatography (LC) and ion mobility spectrometry (IM-MS). Most recently, the combination of cryogenic IR spectroscopy in the gas phase with MS proved beneficial for the identification of smaller glycans. At low measurement temperatures, the IR spectrum of small glycans provides a unique fingerprint to the underlying chemical structure and conformation.In this thesis, cryogenic IR spectroscopy as an addition to the MS-based analytical toolbox was used to shed light on the migration of fucose residues in MS experiments. This elusive rearrangement reaction is not restricted to tandem MS workflows but is recently found to occur in intact ions without extensive activation. Here, the role of the proton in fucose migration reactions was investigated for the two glycan epitopes Lewis x and blood group H type 2. A systematic study of adduct ions and functional groups with competing proton affinities demonstrated that the proton can be selectively mobilized and demobilized. Planning MS-based experiments of fucosylated glycan cations certainly needs an effective strategy to circumvent the presence of a mobile proton in order to avoid erroneous sequence assignments.In a multidimensional approach, IR spectroscopy, IM-MS, RDD and computational modelling were combined to decode the rearrangement product and the reaction mechanism. The trisaccharides Lewis x and blood group H type 2 were found to migrate to a third chemical structure, in which the fucose moiety is most likely 1,6-linked to galactose. The barrier is much higher for blood group H type 2 compared to Lewis x and it is feasible that the latter is never detected in its original chemical structure in the mass spectrometer. These results generalize fucose migration to a universal issue in any mass spectrometer to which even various orthogonal MS-based techniques can be blind.In the second part of this thesis, cryogenic IR spectroscopy in combination with computational modelling was employed for the structural analysis of sulfated glycosaminoglycans (GAGs). Diversity in the chemical structure of linear and acidic GAGs arises from the GAG class, sulfation, epimerization and acetylation. Using messenger tagging IR spectroscopy, sulfated mono- and disaccharides have been characterized successfully recently. In the present thesis, the prominent anticoagulant pentasaccharide fondaparinux which carries eight sulfate functional groups was investigated using cryogenic IR spectroscopy in helium nanodroplets as a proof-of-concept. The spectroscopic fingerprint features unique absorption bands in the mid-IR range for the sulfate functional groups. With this knowledge, a systematic set of all naturally occurring sulfation variations in chondroitin and dermatan sulfate (CS/DS) further demonstrated the capabilities of cryogenic IR spectroscopy for their differentiation. Moreover, from their IR fingerprints in combination with computational modelling, conformational diversity arising from sulfation and charge density distribution could be derived. In a different study, the IR fingerprints of four heparan sulfate (HS) diastereomers revealed a modularity in their chemical structure which was explained, using computational modelling, from their unique hydrogen bonding patterns. The knowledge of the preferred hydrogen bonding pattern could aid e.g. the development for labelling strategies in IM-MS. The results show that the high resolution in the optical fingerprints of GAGs allows to unambiguously resolve their diversity arising from GAG class, sulfation and epimerization. The results exemplify the importance of gas- phase cryogenic IR spectroscopy to enhance future analytical workflows for GAG sequencing. A fully MS-based workflow could involve the ionization of an intact GAG chain and combine tandem MS with IM-MS and cryogenic IR spectroscopy of respective fragments to unambiguously characterize a GAG chain in a single MS experiment.In the last part, cryogenic IR spectroscopy was combined with random forest modelling to extract vibrational features that are characteristic to structural features in GAGs. The selected structural features included the GAG class and sulfation and therefore, almost fully characterize the underlying chemical structure. In a proof-of-concept study, a prediction score of >97% could be achieved for HS tetra- and hexasaccharides based on a training set of only 21 spectra. Especially for certain marker motifs, such as 3-O-sulfation in cancer cells, this workflow could prove beneficial. With machine learning algorithms, the need for comprehensive spectral databases could be circumvented for the identification of unknowns. Overall, the results show that MS-based IR spectroscopy certainly has the potential to leave the framework of academic basic research and add as a valuable addition to the MS-based analytical toolbox.Weinig voorkomende monosachariden (fucose), covalente modificaties van glycanen (sulfering) en terminale sequenties spelen belangrijke rollen in de fysiologie en pathologie van levende organismen. Weinig voorkomende structuren zijn in evolutionaire zin vaak het resultaat van selectiedruk en kunnen derhalve een dieper inzicht leveren in de evolutie van glycosylering. Gefucosyleerde glycanen en gesulfoneerde glycanen vormen echter nog steeds een uitdaging voor standaard workflows in glycaananalyse. Massaspectrometrie (MS) heeft zich in het laatste decennium ontwikkeld tot de meest gebruikte techniek voor glycaananalyse, maar is beperkt door de aanwezigheid van isomeren. Isomeren van glycanen zijn het gevolg van hun samenstelling, connectiviteit, configuratie en vertakking. MS wordt daarom vaak gekoppeld aan complementaire technieken zoals vloeistofchromatografie (LC) en ion- mobiliteitsspectrometrie (IM-MS). Gedurende de laatste jaren is de combinatie van cryogene infrarood (IR)-spectroscopie in de gasfase met MS van grote waarde gebleken voor de identificatie van kleinere glycanen. Bij lage meettemperaturen geeft het IR spectrum van kleine glycanen een unieke vingerafdruk van de onderliggende chemische structuur en conformatie.In dit proefschrift is cryogene IR-spectroscopie in combinatie met MS- gebaseerde analytische technieken gebruikt om licht te werpen op de migratie van fucose in MS-experimenten. Deze ongrijpbare migratiereactie is niet beperkt tot tandem MS workflows, maar is recentelijk ook waargenomen in intacte ionen zonder uitgebreide activering. De rol van het proton in fucose- migratiereacties is onderzocht voor de twee glycaanepitopen Lewis x en bloedgroep H type 2. In een systematische studie van adductie-ionen en functionele groepen met concurrerende protonaffiniteiten is aangetoond dat het proton selectief gemobiliseerd en gedemobiliseerd kan worden. Het meten van gefucosyleerde glycaan-kationen met MS vereist een effectieve strategie om de aanwezigheid van een mobiel proton te omzeilen om foutieve sequentie- toewijzingen te voorkomen.In een multidimensionele benadering zijn IR spectroscopie, IM-MS, radical- directed dissociation (RDD) MS en computationele modellering gecombineerd om het migratieproduct en het reactiemechanisme te ontcijferen. De trisachariden Lewis x en bloedgroep H type 2 blijken te migreren naar een chemische structuur, waarin fucose hoogstwaarschijnlijk 1,6-gekoppeld is aan galactose. De barriËre is veel hoger voor bloedgroep H type 2 dan voor Lewis x en het is goed mogelijk dat de laatste nooit in zijn oorspronkelijke chemische structuur gedetecteerd is in de massaspectrometer. Uit deze resultaten blijkt dat fucose-migratie een universeel probleem is in elke massaspectrometer en dat ook het gebruik van verschillende complementaire MS-gebaseerde technieken dit probleem niet geheel kan oplossen.In het tweede deel van dit proefschrift is cryogene IR spectroscopie in combinatie met computationele modellering gebruikt voor de structurele analyse van gesulfoneerde glycosaminoglycanen (GAG9s). De verscheidenheid in de chemische structuur van lineaire zure GAG9s komt voort uit de GAG klasse, sulfatie, epimerisatie en acetylatie. Met behulp van messenger tagging IR spectroscopie zijn recentelijk met succes gesulfoneerde mono- en disachariden gekarakteriseerd. In dit proefschrift is het anticoagulant pentasaccharide fondaparinux, dat acht sulfaatgroepen bevat, onderzocht met behulp van cryogene IR spectroscopie in helium nanodruppels om het werkingsprincipe van de meting aan te tonen. De spectroscopische vingerafdruk toont unieke absorptiebanden in het midden-IR bereik voor de sulfaatgroepen. Het meten van een systematische set van alle natuurlijk voorkomende sulfatievariaties in chondroÔtine- en dermatan-sulfaat (CS/DS) heeft de differentiatie mogelijkheden met behulp van cryogene IR spectroscopie verder aangetoond. Uit de IR-vingerafdruk in combinatie met computationele modellering kan bovendien conformationele diversiteit als gevolg van sulfatie en ladingsdichtheidsverdeling worden afgeleid. In een andere studie onthullen de IR-vingerafdrukken van vier heparansulfaat (HS) diastereomeren een modulariteit in hun chemische structuur die verklaard is met behulp van computationele modellering door hun unieke waterstofbrugpatronen. De kennis van het geprefereerde waterstofbindingspatroon zou bijvoorbeeld kunnen helpen bij de ontwikkeling van labelingstrategieÎn in IM-MS. De resultaten laten zien dat de hoge resolutie in de optische vingerafdrukken van GAG9s het mogelijk maakt om eenduidig de diversiteit op te lossen dievoortkomt uit GAG klasse, sulfatie en epimerisatie. De resultaten illustreren het belang van gas-fase cryogene IR spectroscopie om toekomstige analytische workflows voor GAG sequencing te verbeteren. Een volledig op MS gebaseerde workflow zou de ionisatie van een intacte GAG-keten kunnen omvatten en tandem MS met IM-MS en cryogene IR-spectroscopie van de respectieve fragmenten kunnen combineren om een GAG-keten eenduidig te karakteriseren in ÈÈn enkel MS-experiment.In het laatste deel van het proefschrift is cryogene IR-spectroscopie gecombineerd met random forest modellering om vibratie patronen die kenmerkend zijn voor structurele eigenschappen in GAG9s aan te tonen. De geselecteerde structurele eigenschappen omvatten de GAG-klasse en sulfatie en karakteriseren derhalve bijna volledig de onderliggende chemische structuur. In een proof-of-concept studie is een voorspellingsscore van >97% bereikt voor HS tetra- en hexasachariden op basis van een trainingsset van slechts 21 spectra. Vooral voor bepaalde markermotieven, zoals 3-O-sulfatie in kankercellen, zou deze workflow nuttig kunnen blijken. Met algoritmen voor machine learning zou de noodzaak voor het gebruik van uitgebreide spectrale databanken voor de identificatie van onbekende GAG9s kunnen worden omzeild. Concluderend kan gesteld worden dat de resultaten zoals beschreven in dit proefschrift aantonen dat IR-spectroscopie op basis van MS zeker het potentieel heeft om het stadium van het academisch basisonderzoek te verlaten en een waardevolle aanvulling vormt op MS gebaseerde analytische technieken

    Acoustic and Elastic Waves: Recent Trends in Science and Engineering

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    The present Special Issue intends to explore new directions in the field of acoustics and ultrasonics. The interest includes, but is not limited to, the use of acoustic technology for condition monitoring of materials and structures. Topics of interest (among others): ‱ Acoustic emission in materials and structures (without material limitation) ‱ Innovative cases of ultrasonic inspection ‱ Wave dispersion and waveguides ‱ Monitoring of innovative materials ‱ Seismic waves ‱ Vibrations, damping and noise control ‱ Combination of mechanical wave techniques with other types for structural health monitoring purposes. Experimental and numerical studies are welcome

    Technical Design Report EuroGammaS proposal for the ELI-NP Gamma beam System

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    The machine described in this document is an advanced Source of up to 20 MeV Gamma Rays based on Compton back-scattering, i.e. collision of an intense high power laser beam and a high brightness electron beam with maximum kinetic energy of about 720 MeV. Fully equipped with collimation and characterization systems, in order to generate, form and fully measure the physical characteristics of the produced Gamma Ray beam. The quality, i.e. phase space density, of the two colliding beams will be such that the emitted Gamma ray beam is characterized by energy tunability, spectral density, bandwidth, polarization, divergence and brilliance compatible with the requested performances of the ELI-NP user facility, to be built in Romania as the Nuclear Physics oriented Pillar of the European Extreme Light Infrastructure. This document illustrates the Technical Design finally produced by the EuroGammaS Collaboration, after a thorough investigation of the machine expected performances within the constraints imposed by the ELI-NP tender for the Gamma Beam System (ELI-NP-GBS), in terms of available budget, deadlines for machine completion and performance achievement, compatibility with lay-out and characteristics of the planned civil engineering

    Factories of the Future

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    Engineering; Industrial engineering; Production engineerin

    Perspectives of Nuclear Physics in Europe: NuPECC Long Range Plan 2010

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    The goal of this European Science Foundation Forward Look into the future of Nuclear Physics is to bring together the entire Nuclear Physics community in Europe to formulate a coherent plan of the best way to develop the field in the coming decade and beyond.<p></p> The primary aim of Nuclear Physics is to understand the origin, evolution, structure and phases of strongly interacting matter, which constitutes nearly 100% of the visible matter in the universe. This is an immensely important and challenging task that requires the concerted effort of scientists working in both theory and experiment, funding agencies, politicians and the public.<p></p> Nuclear Physics projects are often “big science”, which implies large investments and long lead times. They need careful forward planning and strong support from policy makers. This Forward Look provides an excellent tool to achieve this. It represents the outcome of detailed scrutiny by Europe’s leading experts and will help focus the views of the scientific community on the most promising directions in the field and create the basis for funding agencies to provide adequate support.<p></p> The current NuPECC Long Range Plan 2010 “Perspectives of Nuclear Physics in Europe” resulted from consultation with close to 6 000 scientists and engineers over a period of approximately one year. Its detailed recommendations are presented on the following pages. For the interested public, a short summary brochure has been produced to accompany the Forward Look.<p></p&gt

    Numerical Study For Acoustic Micro-Imaging Of Three Dimensional Microelectronic Packages

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    Complex structures and multiple interfaces of modern microelectronic packages complicate the interpretation of acoustic data. This study has four novel contributions. 1) Contributions to the finite element method. 2) Novel approaches to reduce computational cost. 3) New post processing technologies to interpret the simulation data. 4) Formation of theoretical guidance for acoustic image interpretation. The impact of simulation resolution on the numerical dispersion error and the exploration of quadrilateral infinite boundaries make up the first part of this thesis's contributions. The former focuses on establishing the convergence score of varying resolution densities in the time and spatial domain against a very high fidelity numerical solution. The latter evaluates the configuration of quadrilateral infinite boundaries in comparison against traditional circular infinite boundaries and quadrilateral Perfectly Matched Layers. The second part of this study features the modelling of a flip chip with a 140”m solder bump assembly, which is implemented with a 230MHz virtual raster scanning transducer with a spot size of 17”m. The Virtual Transducer was designed to reduce the total numerical elements from hundreds of millions to hundreds of thousands. Thirdly, two techniques are invented to analyze and evaluate simulated acoustic data: 1) The C-Line plot is a 2D max plot of specific gate interfaces that allows quantitative characterization of acoustic phenomena. 2) The Acoustic Propagation Map, contour maps an overall summary of intra sample wave propagation across the time domain in one image. Lastly, combining all the developments. The physical mechanics of edge effects was studied and verified against experimental data. A direct relationship between transducer spot size and edge effect severity was established. At regions with edge effect, the acoustic pulse interfacing with the solder bump edge is scattered mainly along the horizontal axis. The edge effect did not manifest in solder bump models without Under Bump Metallization (UBM). Measurements found acoustic penetration improvements of up to 44% with the removal of (UBM). Other acoustic mechanisms were also discovered and explored. Defect detection mechanism was investigated by modelling crack propagation in the solder bump assembly. Gradual progression of the crack was found have a predictable influence on the edge effect profile. By exploiting this feature, the progress of crack propagation from experimental data can be interpreted by evaluating the C-Scan image
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