"Prescription for Health Care Policy, The Case for Retargeting Tax Subsidies to Health Care"

With health care delivery increasingly shaped by market and budgetary discipline, the provision of health care for all seems an ever-more-distant goal.The high cost of American health care is the inevitable by-product of its method of financing. Cadette proposes shifting the tax subsidies to health care from the tax exclusion of employment-based health insurance to an income-scaled tax credit for the individual purchase of basic health insurance. This plan holds out promise of improving the operation of the health insurance market, making the labor market more efficient, reducing overall health care costs, and providing protection for the unemployed.

Saliency-based image enhancement

Ph.DDOCTOR OF PHILOSOPH

Computational Media Aesthetics for Media Synthesis

Ph.DDOCTOR OF PHILOSOPH

Structure-aware content creation : detection, retargeting and deformation

Nowadays, access to digital information has become ubiquitous, while three-dimensional visual representation is becoming indispensable to knowledge understanding and information retrieval. Three-dimensional digitization plays a natural role in bridging connections between the real and virtual world, which prompt the huge demand for massive three-dimensional digital content. But reducing the effort required for three-dimensional modeling has been a practical problem, and long standing challenge in compute graphics and related fields. In this thesis, we propose several techniques for lightening up the content creation process, which have the common theme of being structure-aware, ie maintaining global relations among the parts of shape. We are especially interested in formulating our algorithms such that they make use of symmetry structures, because of their concise yet highly abstract principles are universally applicable to most regular patterns. We introduce our work from three different aspects in this thesis. First, we characterized spaces of symmetry preserving deformations, and developed a method to explore this space in real-time, which significantly simplified the generation of symmetry preserving shape variants. Second, we empirically studied three-dimensional offset statistics, and developed a fully automatic retargeting application, which is based on verified sparsity. Finally, we made step forward in solving the approximate three-dimensional partial symmetry detection problem, using a novel co-occurrence analysis method, which could serve as the foundation to high-level applications.Jetzt hat die Zugang zu digitalen Informationen allgegenwärtig geworden. Dreidimensionale visuelle Darstellung wird immer zum Einsichtsverständnis und Informationswiedergewinnung unverzichtbar. Dreidimensionale Digitalisierung verbindet die reale und virtuelle Welt auf natürliche Weise, die prompt die große Nachfrage nach massiven dreidimensionale digitale Inhalte. Es ist immer noch ein praktisches Problem und langjährige Herausforderung in Computergrafik und verwandten Bereichen, die den Aufwand für die dreidimensionale Modellierung reduzieren. In dieser Dissertation schlagen wir verschiedene Techniken zur Aufhellung der Erstellung von Inhalten auf, im Rahmen der gemeinsamen Thema der struktur-bewusst zu sein, d.h. globalen Beziehungen zwischen den Teilen der Gestalt beibehalten wird. Besonders interessiert sind wir bei der Formulierung unserer Algorithmen, so dass sie den Einsatz von Symmetrische Strukturen machen, wegen ihrer knappen, aber sehr abstrakten Prinzipien für die meisten regelmäßigen Mustern universell einsetzbar sind. Wir stellen unsere Arbei aus drei verschiedenen Aspekte in dieser Dissertation. Erstens befinden wir Räume der Verformungen, die Symmetrien zu erhalten, und entwickelten wir eine Methode, diesen Raum in Echtzeit zu erkunden, die deutlich die Erzeugung von Gestalten vereinfacht, die Symmetrien zu bewahren. Zweitens haben wir empirisch untersucht dreidimensionale Offset Statistiken und entwickelten eine vollautomatische Applikation für Retargeting, die auf den verifizierte Seltenheit basiert. Schließlich treten wir uns auf die ungefähre dreidimensionalen Teilsymmetrie Erkennungsproblem zu lösen, auf der Grundlage unserer neuen Kookkurrenz Analyseverfahren, die viele hochrangige Anwendungen dienen verwendet werden könnten

Paracrine Adenoviral Delivery of Therapeutic Payloads for Cancer Therapy

Adenoviral vectors are the most commonly used delivery vectors for clinical gene therapy due to their favorable characteristics: (i) they do not integrate into the host cell genome and thus harbor a reduced risk of insertional mutagenesis, (ii) they efficiently transduce dividing and non-dividing cells, and (iii) they have a large packaging capacity allowing large and/or multiple cargo delivery. However, site-specific gene delivery in vivo is still compromised because of the endogenous adenoviral tropism and interactions with the host immune system. To overcome this limitation, our research group developed a generic adenoviral de-/retargeting system consisting of a designed ankyrin repeat protein (DARPin)-based adapter mediating cell-specific transduction and a single-chain variable fragment (scFv)-based vector shield. In an autocrine delivery approach, efficient cancer drug delivery to tumor cells could previously be demonstrated in vivo by applying tumor cell marker-specific DARPin adapters to the adenoviral vector. Building on this approach, we then aimed to expand our system and enable alternative targeting strategies to further improve the efficacy of targeted vector delivery. The aim of this thesis was to retarget a human adenovirus serotype 5 (HAdV5)-derived vector to stromal cells in the tumor microenvironment in order to deliver therapeutic biomolecules to the tumor microenvironment (TME). The therapeutic biomolecules, initially encoded by the adenoviral vector, would thus be produced by the transduced stromal cells and locally secreted into the TME, where they could exert their anti-tumorigenic effect. This should increase the therapeutic efficacy, reduce off-target effects, and prevent systemic toxicities. Since stromal cells are genetically more stable than tumor cells, in some cancers also more abundant than tumor cells, and theoretically not affected by the vector-encoded cancer drug, we anticipated this paracrine delivery approach to harbor several advantages over the existing, tumor cell- targeted autocrine delivery approach. In the main part of this thesis (presented in chapter three and Hartmann et al., 2023), the stromal cell-targeted paracrine adenoviral delivery of cancer therapeutics to the TME is presented. To realize the project, a suitable stromal target for adenoviral retargeting, namely fibroblast activation protein (FAP) on cancer-associated fibroblasts (CAFs), was first identified. Aiming to generate FAP-specific adenoviral retargeting adapters, ribosome display selections were performed to obtain FAP-specific DARPins, which were then utilized as targeting domain in the previously developed bispecific modular adapter. Biologically functional adapters capable to successfully mediate retargeting of HAdV5 to CAFs via FAP were subsequently selected in a cell-based screening approach. These adapters were characterized in great detail for several binding characteristics (including binding kinetics, potential binding epitopes, and cross-reactivity to human/mouse FAP), and tested in vitro for specificity and selectivity using various target and non-target cell lines. HAdV5-based vector retargeting to CAFs was furthermore investigated in vivo using a selected, human/mouse FAP cross-reactive adapter and a suitable mouse model of cancer which had been established before. In these in vivo studies, efficient vector retargeting to CAFs by the FAP-specific adapter was demonstrated. Using the same mouse model of cancer, adenoviral delivery of a therapeutic monoclonal antibody with anti-tumor activity to CAFs could subsequently be investigated in vivo, and showed to be successful as evidenced by reduced tumor growth. Importantly, the therapeutic effect of the monoclonal antibody was superior when encoded and delivered by the FAP- retargeted adenoviral vector than when administered directly as recombinant protein. Altogether, it was thus demonstrated that retargeting of HAdV5-based vectors via FAP-specific adapters enables an efficient, stromal cell-targeted paracrine delivery of anti-cancer therapeutics to the TME. In addition to developing the stromal cell-targeted adenoviral vector for a paracrine cancer drug delivery, it was also possible to contribute to other research projects dealing with the retargeting of HAdV5-based vectors for cancer therapeutic applications. In one collaboration project (presented in chapter four and Freitag et al., 2023), it was intended to retarget HAdV5 to T cells and achieve an efficient transduction of these immune cells, which are naturally not susceptible to an HAdV5 infection. This goal was achieved using the adapter- based retargeting strategy in combination with the experimental finding that T cells ought to be activated to be adenovirally transduced. As a result, novel scFv-based adapters targeting the T cell co-receptor CD3, the co-stimulatory receptor CD28, and the interleukin (IL)-2 receptor were developed and deployed concurrently to promote cell specificity for adenoviral retargeting while providing T cell activation stimuli. Cell-specific retargeting of HAdV5-based vectors to human T cells and efficient human T cell transduction was shown in vitro as well as in vivo in relevant humanized mouse models. This T cell-retargeted adenoviral vector could now be used to engineer T cells in vivo in order to improve chimeric antigen receptor (CAR)-T cell therapy for cancer treatment. In two other collaboration projects, the adenoviral delivery of cancer therapeutics to the TME via the previously established, tumor cell-targeted autocrine approach was investigated in vivo. In both these projects the HAdV5-based vector was retargeted to tumor cells via the human epidermal growth factor receptor 2 (HER2) using specific DARPin adapters. However, different therapeutic biomolecules, including the cytokine IL-12 or a bispecific T cell engager (BiTE) aiming to enhance anti-tumor NK cell (presented in chapter six and Kirchhammer et al., 2022) or T cell activity (presented in chapter five and Freitag and Kolibius et al., manuscript in preparation for publication), were encoded by the adenoviral vector. Targeted payload delivery as well as therapeutic effects were investigated in vivo in relevant tumor mouse models. In both projects, target-specific adenovirus-mediated payload delivery with great therapeutic efficacy could be successfully demonstrated

Management and communication of archaeological artefacts and architectural heritage using digital IS. What today? What next?

In this paper, we reviewed 20 years of development of 3D based IS to support archaeological and AH artefact knowledge, management and communication and their theoretical work basis. In detail, we illustrated our experiences showing the advantages and limits we had observed after extensive use. In conclusion, we have illustrated a new paradigm based on IoT-related technologies, potentially able to overcome existing problems, and the theoretical foundation of the new framework that has been designed, the concept of the Smart Cultural Object, sources and recipients of advanced information and related technological underpinning

HRS: Rover Technologies

No abstract availabl