Synthetic and mechanistic studies of polyazole Cyclopeptide natural products: Aurantizolicin and Urukthapelstatin A

This PhD thesis describes the development of an effective total synthesis of the strongly cytotoxic polyazole cyclopeptide natural product aurantizolicin. The synthesis design combined building block synthesis in solution with solid-phase peptide synthesis to enable the rapid diversification of the natural product. Macrothiolactonization and aza-Wittig chemistry allowed the formation of the macrocyclically embedded thiazole. Thereby, the stereochemical assignment of the natural product and the formation of an extensive library of analogs have been achieved. Profiling the analog library for its growth inhibitory effect on human cancer cells revealed crucial structural features and significantly expanded the knowledge of the structure–activity relationships (SAR) of this natural product class. Based on the SAR, chemical probes have been designed and synthesized to enable further investigations towards the elucidation of the mechanism of action of aurantizolicin. These probes included cyclopeptide–dye conjugates, compounds for photoaffinity labeling, and immobilized cyclopeptides. Initial investigations utilizing the immobilized cyclopeptides in compound-centric chemical proteomics experiments suggested an RNA-associated mechanism of action. Beyond natural product chemistry, 5-sulfamoyloxy-oxazoles have been developed as competent C–O electrophiles for Suzuki–Miyaura cross-coupling reactions as well as for aromatic nucleophilic substitutions/conjugate additions of various heteroatom nucleophiles. The reactivity of peptide-integrated oxazolyl-sulfamates has been profiled to allow the divergent synthesis of oxazolyl-arenes, 5-amino-oxazoles, oxazolyl-sulfides, and oxazolyl-aryl ethers. The relevance of the organic synthesis method has been demonstrated by the total synthesis of the natural product almazole D

Leveraging the Cloud for Software Security Services.

This thesis seeks to leverage the advances in cloud computing in order to address modern security threats, allowing for completely novel architectures that provide dramatic improvements and asymmetric gains beyond what is possible using current approaches. Indeed, many of the critical security problems facing the Internet and its users are inadequately addressed by current security technologies. Current security measures often are deployed in an exclusively network-based or host-based model, limiting their efficacy against modern threats. However, recent advancements in the past decade in cloud computing and high-speed networking have ushered in a new era of software services. Software services that were previously deployed on-premise in organizations and enterprises are now being outsourced to the cloud, leading to fundamentally new models in how software services are sold, consumed, and managed. This thesis focuses on how novel software security services can be deployed that leverage the cloud to scale elegantly in their capabilities, performance, and management. First, we introduce a novel architecture for malware detection in the cloud. Next, we propose a cloud service to protect modern mobile devices, an ever-increasing target for malicious attackers. Then, we discuss and demonstrate the ability for attackers to leverage the same benefits of cloud-centric services for malicious purposes. Next, we present new techniques for the large-scale analysis and classification of malicious software. Lastly, to demonstrate the benefits of cloud-centric architectures outside the realm of malicious software, we present a threshold signature scheme that leverages the cloud for robustness and resiliency.Ph.D.Computer Science & EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91385/1/jonojono_1.pd

Loss of the Na(+)/H(+) exchanger NHE8 causes male infertility in mice by disrupting acrosome formation

Mammalian sperm feature a specialized secretory organelle on the anterior part of the sperm nucleus, the acrosome, which is essential for male fertility. It is formed by a fusion of Golgi-derived vesicles. We show here that the predominantly Golgi-resident Na+/H+ exchanger NHE8 localizes to the developing acrosome of spermatids. Similar to wild-type mice, Nhe8-/- mice generated Golgi-derived vesicles positive for acrosomal markers and attached to nuclei, but these vesicles failed to form large acrosomal granules and the acrosomal cap. Spermatozoa from Nhe8-/- mice completely lacked acrosomes, were round-headed, exhibited abnormal mitochondrial distribution and displayed decreased motility, resulting in selective male infertility. Of note, similar features are also found in globozoospermia, one of the causes of male infertility in humans. Germ cell-specific, but not Sertoli cell-specific Nhe8 disruption recapitulated the globozoospermia phenotype, demonstrating that NHE8's role in spermiogenesis is germ cell-intrinsic. Our work has uncovered a crucial role of NHE8 in acrosome biogenesis and suggests that some forms of human globozoospermia might be caused by a loss of function of this Na+/H+ exchanger. It points to NHE8 as a candidate gene for human globozoospermia and a possible drug target for male contraception

Entwicklung eines bildgebenden Verfahrens für die Darstellung biologischen Gewebes basierend auf laserinduziertem Ultraschall

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Divergent Synthesis of C5‐Heteroatom Substituted Oxazoles

5‐Oxazoyl‐sulfamates have been profiled as versatile building blocks for modifications of oxazoles with various nucleophiles. The unified approach provides a diversification platform to directly access 5‐amino‐oxazoles, 5‐oxazolyl‐sulfides, and 5‐oxazoyl‐aryl ethers from a single precursor

EMULATOR vs REAL PHONE: Android Malware Detection Using Machine Learning

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.The Android operating system has become the most popular operating system for smartphones and tablets leading to a rapid rise in malware. Sophisticated Android malware employ detection avoidance techniques in order to hide their malicious activities from analysis tools. These include a wide range of anti-emulator techniques, where the malware programs attempt to hide their malicious activities by detecting the emulator. For this reason, countermeasures against anti-emulation are becoming increasingly important in Android malware detection. Analysis and detection based on real devices can alleviate the problems of anti-emulation as well as improve the effectiveness of dynamic analysis. Hence, in this paper we present an investigation of machine learning based malware detection using dynamic analysis on real devices. A tool is implemented to automatically extract dynamic features from Android phones and through several experiments, a comparative analysis of emulator based vs. device based detection by means of several machine learning algorithms is undertaken. Our study shows that several features could be extracted more effectively from the on-device dynamic analysis compared to emulators. It was also found that approximately 24% more apps were successfully analysed on the phone. Furthermore, all of the studied machine learning based detection performed better when applied to features extracted from the on-device dynamic analysis

Global distribution and interannual variations of mesospheric and lower thermospheric neutral wind diurnal tide: 2. Nonmigrating tide

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94716/1/jgra18976.pd

The geospace response to variable inputs from the lower atmosphere:a review of the progress made by Task Group 4 of CAWSES-II

The advent of new satellite missions, ground-based instrumentation networks, and the development of whole atmosphere models over the past decade resulted in a paradigm shift in understanding the variability of geospace, that is, the region of the atmosphere between the stratosphere and several thousand kilometers above ground where atmosphere-ionosphere-magnetosphere interactions occur. It has now been realized that conditions in geospace are linked strongly to terrestrial weather and climate below, contradicting previous textbook knowledge that the space weather of Earth's near space environment is driven by energy injections at high latitudes connected with magnetosphere-ionosphere coupling and solar radiation variation at extreme ultraviolet wavelengths alone. The primary mechanism through which energy and momentum are transferred from the lower atmosphere is through the generation, propagation, and dissipation of atmospheric waves over a wide range of spatial and temporal scales including electrodynamic coupling through dynamo processes and plasma bubble seeding. The main task of Task Group 4 of SCOSTEP's CAWSES-II program, 2009 to 2013, was to study the geospace response to waves generated by meteorological events, their interaction with the mean flow, and their impact on the ionosphere and their relation to competing thermospheric disturbances generated by energy inputs from above, such as auroral processes at high latitudes. This paper reviews the progress made during the CAWSES-II time period, emphasizing the role of gravity waves, planetary waves and tides, and their ionospheric impacts. Specific campaign contributions from Task Group 4 are highlighted, and future research directions are discussed

Solar Cycle Variability of Nonmigrating Tides in the 5.3 and 15 μm Infrared Cooling of the Thermosphere (100–150 km) from SABER

This paper discusses the solar cycle variation of the DE3 and DE2 nonmigrating tides in the nitric oxide (NO) 5.3 μm and carbon dioxide (CO2) 15 μm infrared cooling between 100 and 150 km altitude and ±40° latitude. Tidal diagnostics of SABER NO and CO2 cooling rate data (2002–2013) indicate DE3 (DE2) amplitudes during solar maximum are on the order of 1 (0.5) nW/m3 in NO near 125 km, and on the order of 60 (30) nW/m3 in CO2 at 100 km, which translates into roughly 15–30% relative to the monthly zonal mean. The NO cooling shows a pronounced (factor of 10) solar cycle dependence (lower during solar minimum) while the CO2 cooling does not vary much from solar min to solar max. Photochemical modeling reproduces the observed solar cycle variability and allows one to delineate the physical reasons for the observed solar flux dependence of the tides in the infrared cooling, particularly in terms of warmer/colder background temperature versus smaller/larger tidal temperatures during solar max/min, in addition to cooling rate variations due to vertical tidal advection and tidal density variations. Our results suggest that (i) tides caused by tropospheric weather impose a substantial—and in the NO 5.3 μm case solar cycle dependent—modulation of the infrared cooling, mainly due to tidal temperature, and (ii) observed tides in the infrared cooling are a suitable proxy for tidal activity including its solar cycle dependence in a part of Earth's atmosphere where direct global temperature observations are lacking