The ubiquitin-proteasome system (UPS) controls the stability, activity and localisation of most of the proteome and regulates virtually all cellular processes through modification of proteins with ubiquitin. Ubiquitin conjugation is mediated by a conserved enzymatic cascade composed of E1, E2 and E3 enzymes, which cooperate to activate and transfer ubiquitin to substrate proteins. Dysfunction of the UPS is implicated in many disease states, including cancer, neurodegeneration, immune and cardiovascular disorders. Despite the central role of the UPS in cellular regulation, our understanding of the function, interactions and specificity of proteins that comprise the UPS is still limited. One approach to dissect and to study the UPS is to identify molecular probes, which can be used to specifically interrogate catalytic mechanisms and can be potentially considered as entry points for drug discovery. This work focuses on developing novel high-throughput screening methods for inhibitors of the ubiquitin-conjugating enzymes (E2s), using a unicellular organism Saccharomyces cerevisiae and in vitro technologies. S. cerevisiae is a model organism, commonly used in research as a valuable tool for genetic investigations and other high-throughput studies. In this work, we evaluated the toxicity of exogenously expressed human E2s on yeast cells and discovered that one of the E2s, Ube2U, significantly inhibited yeast growth. This inhibition was dependent on the Ube2U ubiquitin-conjugation activity, as demonstrated with a catalytically inactive Ube2U C89A control, which did not affect yeast growth. The growth defect induced by Ube2U allowed us to develop a screening setup for inhibitors of Ube2U, where the enzyme activity was coupled to cell growth readout. Potential Ube2U inhibitors would be identified as rescuers of the slow growing Ube2U-expressing yeast phenotype. Although screening methods in yeast are relatively straightforward to set up and run, the advantages of this system, namely simplicity of the detection signal and high-throughput, are limited by the fact that yeast is not a recognised large scale screening system in pharmaceutical industry, and that it is difficult to identify the target in a complex pathway such as the UPS. In vitro technologies are needed to provide the necessary structure-activity relationship for chemical optimisation. Therefore, we developed a novel, fluorescence-based, miniaturised assay technology, suitable for biochemical investigations and screening for inhibitors of a wide range of specific ubiquitination reactions within the UPS.

In cryptographic processor design, the selection of functional primitives and connection structures between these primitives are extremely crucial to maximize throughput and flexibility. Hence, detailed analysis on the specifications and requirements of existing crypto-systems plays a crucial role in cryptographic processor design. This thesis provides the most comprehensive literature review that we are aware of on the widest range of existing cryptographic algorithms, their specifications, requirements, and hardware structures. In the light of this analysis, it also describes a high performance, low power, and highly flexible cryptographic processor, Cryptoraptor, that is designed to support both today's and tomorrow's encryption standards. To the best of our knowledge, the proposed cryptographic processor supports the widest range of cryptographic algorithms compared to other solutions in the literature and is the only crypto-specific processor targeting the future standards as well. Unlike previous work, we aim for maximum throughput for all known encryption standards, and to support future standards as well. Our 1GHz design achieves a peak throughput of 128Gbps for AES-128 which is competitive with ASIC designs and has 25X and 160X higher throughput per area than CPU and GPU solutions, respectively. / text

<p>Recently, in materials innovations, computational methods are used more frequently than in past decades. In this thesis, the materials genome initiative, an advanced new framework, will be introduced. With this blueprint, our efficient high-throughput software, AFLOW, has been implemented with several compatible functions for ma- terials properties investigations, such as prototype searching, phase diagram studying and magnetic properties discovering. With this effective tool, we apply ab initio cal- culations to discover new generation of specific materials properties.</p><p>An efficient algorithm for prototypes comparision has been designed and imple- mented into our high-throughput framework AFLOW. In addition, prototypes clas- sification was utilized to differentiate the our materials database. This classification will accelerate the materials properties searching speed. With respect to structure prototypes, low temperature phase diagrams were used for binary and ternary alloy systems stability investigation. The alogrithms have been integrated into AFLOW. With this tool, we systematically explored the binary Ru systems and Tc systems and predicted new stable compounds.</p> / Dissertation

While tissue-engineering approaches of heart valves have made great strides towards creating functional tissues in vitro, the instruments used, named bioreactors, cannot efficiently integrate multiple stimuli to accurately emulate the physiological microenvironment. To address this, we conceptually designed and built a bioreactor system that applied a range of mechanical tension conditions, modulated matrix stiffness, and introduced biochemical signals in a combinatorial and high-throughput manner. Proof-of-concept experiments on PAVIC-seeded hydrogels were performed to assess the independent and combined effects of tensile strain, matrix stiffness and TGF-β1 on myofibroblast differentiation by measuring α-SMA expression, a marker that indicates a disease-associated phenotype. We found that matrix stiffness and TGF-β1 significantly increased α-SMA levels (p < 0.001), while the effect of mechanical strain was only significant on soft gels (~12 kPa) without TGF-β1. This study therefore demonstrated independent and integrated effects of multiple stimuli in regulating key cellular events in the aortic valve.

University, Diss., 2007--Frankfurt (Main). / Zsfassung in engl. und dt. Sprache.

Universiẗat, Diss., 2007--Frankfurt (Main). / Zsfassung in dt. und engl. Sprache.

Stuttgart, Univ., Diss., 2004.

Stuttgart, Univ., Diss., 2004.

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on July 8, 2009). Includes bibliographical references.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 113-121). Also available in electronic version.