Regulating the Pace of von Neumann Correctors

In a celebrated paper published in 1951, von Neumann presented a simple procedure allowing to correct the bias of random sources. This device outputs bits at irregular intervals. However, cryptographic hardware is usually synchronous. This paper proposes a new building block called Pace Regulator, inserted between the randomness consumer and the von Neumann regulator to streamline the pace of random bits

Random Number Generators Can Be Fooled to Behave Badly

In this paper, we extend the work on purely mathematical Trojan horses initially presented by Young and Yung. This kind of mechanism affects the statistical properties of an infected random number generator (RNG) by making it very sensitive to input entropy. Thereby, when inputs have the correct distribution the Trojan has no effect, but when the distribution becomes biased the Trojan worsens it. Besides its obvious malicious usage, this mechanism can also be applied to devise lightweight health tests for RNGs. Currently, RNG designs are required to implement an early detection mechanism for entropy failure, and this class of Trojan horses is perfect for this job

On the development of a GroEL based platform for identifying pharmacological chaperones

Many protein misfolding diseases are due to changes in protein homeostasis. This might lead to protein misfolding and possibly intra- or extracellular aggregation, causing loss of protein function or gain of toxic function. In several cases, the cellular clearance mechanism is sometimes inhibited and unable to degrade the aggregated forms leading to cell injury and death. This is frequently observed in misfolding diseases like Parkinson's disease, Cystic fibrosis, Alzheimer's, etc. These diseases account for nearly 30-50 % of all known human diseases afflicting millions and have a significant economic impact. However, there are currently few treatments to counteract these diseases. Thus, there is a pressing need to develop strategies to treat these diseases. One strategy is to develop small molecule ligand drugs that prevent the initial protein misfolding reaction. Proteins are somewhat metastable and naturally exist in dynamic equilibria between native fold and an ensemble of partially unfolded forms. This makes the misfolded forms moving targets and thus difficult to stabilize. This difficulty is compounded while developing high throughput assays to screen for stabilizing ligands for these moving protein targets. Consequently, these assays depend on detecting secondary misfolding events such as aggregation or removal of misfolded species, thus increasing the duration of the assays (hours-days). Additionally, in most instances specific cell-based assay systems have to be developed for each misfolding protein. This inhibits the development of broad based assays and complicates rapid screening of the huge compound libraries developed by rational drug design and combinatorial chemistry. In this dissertation, the development of a broad based high throughput assay for identifying novel stabilizers for protein misfolding diseases has been presented. The bacterial chaperonin GroEL binds to proteins that are partially unfolded or exist in a folded to partially folded dynamic equilibrium. Based on this property, the development of a generic broad based assay to probe a multitude of protein substrates based on changes in hydrophobic character was hypothesized and carried out. Using the chaperonin as a detection platform will enable the extension of this detection platform to identify potential stabilizers of the native fold that prevent or inhibit protein misfolding

Structural and Biochemical Studies of Membrane Proteins CFTR and GLUT1 Yield New Insights into the Molecular Basis of Cystic Fibrosis and Biology of Glucose Transport

Integral membrane proteins (IMPs) assume critical roles in cell biology and are key targets for drug discovery. Given their involvement in a wide range of diseases, the structural and functional characterization of IMPs are of significant importance. However, this remains notoriously challenging due to the difficulties of stably purifying membrane-bound, hydrophobic proteins. Compounding this, many diseases are caused by IMP mutations that further decrease their stability. One such example is cystic fibrosis (CF), which is caused by misfolding or dysfunction of the epithelial cell chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Roughly 70% of CF patients world-wide harbor the ΔF508-CFTR mutation, which interrupts CFTR’s folding, maturation, trafficking and function. No existing treatment sufficiently addresses the consequences of ΔF508, and the substantial instability that results from this mutation limits our ability to study ΔF508-CFTR in search of better treatments. To that end, my colleagues at Sanofi generated homology models of full-length wild-type and ΔF508-CFTR +/- second-site suppressor mutations (SSSMs) V510D and R1070W, and performed molecular dynamics (MD) simulations for each model. Using information obtained from this analysis, I tested several hypotheses on the mechanism by which ΔF508 destabilizes full-length CFTR and how SSSMs suppress this effect. Leveraging studies of the purified NBD1 subdomain and of full-length CFTR in a cellular context, I confirmed the prediction of a key salt-bridge interaction between V510D and K564 important to second-site suppression. Furthermore, I identified a novel class of SSSMs that support a key prediction from these analyses: that helical unraveling of TM10, within CFTR’s second transmembrane domain, is an important contributor to ΔF508-induced instability. In addition, I developed a detergent-free CFTR purification method using styrene-maleic acid (SMA) copolymer to extract the channel directly from its cell membrane along with the surrounding lipid content. The resulting particles were stable, monodisperse discs containing a single molecule of highly-purified CFTR. With this material, I optimized grid preparation techniques and carried out cryo-EM structural analysis of WT-hCFTR which resulted in 2D particle class averages which were consistent with an ABC transporter shape characteristic of CFTR, and a preliminary 3D reconstruction. This result establishes a foundation for future characterization of ΔF508-CFTR in its native state. I have also applied this SMA-based purification method to the facilitated glucose transporter GLUT1 (SLC2A1). SLC2A1 mutations contribute to a rare and developmentally debilitating disease called GLUT1-deficiency syndrome. Using SMA, I successfully extracted GLUT1 in its native state. With the application of this method, I was able to purify endogenous GLUT1 from erythrocytes, in complex with several associated proteins as well as the surrounding lipids, in its monomeric, dimeric and tetrameric forms without the use of cross-linking or chimeric mutations. These results point to the potential for studying isolated IMPs without the use of destabilizing detergents and thereby offer a pathway to analysis of wild-type and mutant membrane protein structure, function and pharmacodynamics

Security in banking

We examine the security of the Australian card payment system by analysing existing cryptographic protocols. In this analysis, we examine TDES and DES-V key derivation and the use of secure cryptographic devices, then contrast this with alternative mechanisms to enable secure card payments. We compare current Australian cryptographic methods with their international counterparts, such as the ANSI methods, and then motivate alternative methods for authenticated encryption in card payment systems

ABC Transporters in Human Diseases

Mammalian ATP-binding cassette (ABC) transporters constitute a superfamily of proteins involved in many essential cellular processes. Most of these transporters are transmembrane proteins and allow the active transport of solutes, small molecules, and lipids across biological membranes. On the one hand, some of these transporters are involved in drug resistance (also referred to as MDR or multidrug resistance), a process known to be a major brake in most anticancer treatments, and the medical challenge is thus to specifically inhibit their function. On the other hand, molecular defects in some of these ABC transporters are correlated with several rare human diseases, the most well-documented of which being cystic fibrosis, which is caused by genetic variations in ABCC7/CFTR (cystic fibrosis transmembrane conductance regulator). In the latter case, the goal is to rescue the function of the deficient transporters using various means, such as targeted pharmacotherapies and cell or gene therapy. The aim of this Special Issue, “ABC Transporters in Human Diseases”, is to present, through original articles and reviews, the state-of-the-art of our current knowledge about the role of ABC transporters in human diseases and the proposed therapeutic options based on studies ranging from cell and animal models to patients

The Rise of Mitochondria in Medicine

Mitochondria are critical bioenergetic and biosynthetic machines that are essential for normal cell function. Traditionally, mitochondria have been considered the powerhouse of the cell, as they supply most of the cellular energy through oxidative phosphorylation. In addition, they supply the building blocks needed for the synthesis of cellular biomass. More recently, mitochondria have been recognized as signaling hubs that receive and transmit signals throughout the cell, thereby affecting cell functionality and fate. The signals generated by mitochondria include changes in metabolites, the NAD+/NADH ratio, ATP/ADP ratio, Ca2+, and reactive oxygen species (ROS), but our understanding of their nature, dynamics, targets, and roles in different physiopathological contexts is still under development. Mitochondrial dysfunction, which may originate from primary defects within the organelles or from stress conditions in the microenvironment, is a hallmark of many common diseases, including ischaemia–reperfusion injury, cancer, metabolic disease, and neurodegenerative disorders, and has become a major research focus in medicine. Understanding the biology of mitochondrial signaling and the role of mitochondrial dysfunction in the pathogenesis of many metabolic, degenerative, cardiovascular, and neoplastic diseases is crucial for the development of strategies aimed at therapeutically restoring mitochondrial functionality. This Special Issue presents current knowledge in the field of mitochondrial signaling in health and disease, and recent advances in mitochondrial pharmacology

Placing Power: Greek Cities and Roman Governors in Western Asia Minor, 69-235 CE.

My dissertation situates public space at the heart of a Greek city’s efforts to negotiate its position in the networks of power that comprised the Roman Empire. It focuses on the annual assize tours Roman governors conducted through the provinces of Asia and Lycia-Pamphylia, and, drawing on a wide range of literary, epigraphic, and archaeological evidence, shows how, in the cities that hosted them, these tours provided local elites with opportunity to use the spaces in which a governor was welcomed and performed his duties as a means of both modeling his conduct and appropriating his prestige. The exposition is divided into five parts. The first part reviews the imperial policies that environed the dialogue between governor and city, and illustrates how Roman power both shaped and was shaped by the provincial spaces in which it was exercised. The second part explores how mid-imperial Roman governors were conditioned to regard Greek cities as settings in which their authority had special conditions and implications. The third part examines in detail the ideal of the stable, orderly, and cultivated polis that imperial Greek notables sought to convey to important visitors. The fourth part considers how a Greek city could, through the ceremonies surrounding a governor’s arrival, present its built environment as both an index of its status and a template for the legitimate exercise of Roman authority. The fifth and final part investigates the extent to which local elites influenced a visiting governor’s engagement with the sites in which he performed his duties. This research significantly nuances our understanding of how Roman power worked in the provinces. Most immediately, it allows greater appreciation of the leverage civic elites possessed in their dealings with imperial representatives. More generally, by illustrating the extent to which local notables cooperated in both the creation and the presentation of their cities, it outlines a way of understanding the formal public spaces of the imperial period as constructs and instruments of elite political goals. Most broadly, it reveals the intimacy of the connections between imperial policy, the ambitions of local notables, and the appearance of provincial cities.PhDGreek and Roman HistoryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120770/1/garyan_1.pd