Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

Learning mixtures of structured distributions over discrete domains

Let $\mathfrak{C}$ be a class of probability distributions over the discrete domain $[n] = \{1,...,n\}.$ We show that if $\mathfrak{C}$ satisfies a rather general condition -- essentially, that each distribution in $\mathfrak{C}$ can be well-approximated by a variable-width histogram with few bins -- then there is a highly efficient (both in terms of running time and sample complexity) algorithm that can learn any mixture of $k$ unknown distributions from $\mathfrak{C}.$ We analyze several natural types of distributions over $[n]$, including log-concave, monotone hazard rate and unimodal distributions, and show that they have the required structural property of being well-approximated by a histogram with few bins. Applying our general algorithm, we obtain near-optimally efficient algorithms for all these mixture learning problems.Comment: preliminary full version of soda'13 pape

Aramid Nanofiber Composites for Energy Storage Applications

Lithium ion batteries and non-aqueous redox flow batteries represent two of the most important energy storage technologies to efficient electric vehicles and power grid, which are essential to decreasing U.S. dependence on fossil fuels and sustainable economic growth. Many of the developmental roadblocks for these batteries are related to the separator, an electrically insulating layer between the cathode and anode. Lithium dendrite growth has limited the performance and threatened the safety of lithium ion batteries by piercing the separator and causing internal shorts. In non-aqueous redox flow batteries, active material crossover through microporous separators and the general lack of a suitable ion conducting membrane has led to low operating efficiencies and rapid capacity fade. Developing new separators for these batteries involve the combination of different and sometimes seemingly contradictory properties, such as high ionic conductivity, mechanical stability, thermal stability, chemical stability, and selective permeability. In this dissertation, I present work on composites made from Kevlar-drived aramid nanofibers (ANF) through rational design and fabrication techniques. For lithium ion batteries, a dendrite suppressing layer-by-layer composite of ANF and polyethylene oxide is present with goals of high ionic conductivity, improved safety and thermal stability. For non-aqueous redox flow batteries, a nanoporous ANF separator with surface polyelectrolyte modification is used to achieve high coulombic efficiencies and cycle life in practical flow cells. Finally, manufacturability of ANF based separators is addressed through a prototype machine for continuous ANF separator production and a novel separator coated on anode assembly. In combination, these studies serve as a foundation for addressing the challenges in separator engineering for lithium ion batteries and redox flow batteries.PHDMacromolecular Science & EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/138543/1/situng_1.pd

On Extracting Common Random Bits From Correlated Sources on Large Alphabets

Suppose Alice and Bob receive strings X=(X1,...,Xn) and Y=(Y1,...,Yn) each uniformly random in [s]n, but so that X and Y are correlated. For each symbol i, we have that Yi=Xi with probability 1-ε and otherwise Yi is chosen independently and uniformly from [s]. Alice and Bob wish to use their respective strings to extract a uniformly chosen common sequence from [s]k, but without communicating. How well can they do? The trivial strategy of outputting the first k symbols yields an agreement probability of (1-ε+ε/s)k. In a recent work by Bogdanov and Mossel, it was shown that in the binary case where s=2 and k=k(ε) is large enough then it is possible to extract k bits with a better agreement probability rate. In particular, it is possible to achieve agreement probability (kε)-1/2·2-kε/(2(1-ε/2)) using a random construction based on Hamming balls, and this is optimal up to lower order terms. In this paper, we consider the same problem over larger alphabet sizes s and we show that the agreement probability rate changes dramatically as the alphabet grows. In particular, we show no strategy can achieve agreement probability better than (1-ε)k(1+δ(s))k where δ(s)→ 0 as s→∞. We also show that Hamming ball-based constructions have much lower agreement probability rate than the trivial algorithm as s→∞. Our proofs and results are intimately related to subtle properties of hypercontractive inequalities

On relationship of Z-curve and Fourier approaches for DNA coding sequence classification

Z-curve features are one of the popular features used in exon/intron classification. We showed that although both Z-curve and Fourier approaches are based on detecting 3-periodicity in coding regions, there are significant differences in their spectral formulation. From the spectral formulation of the Z-curve, we obtained three modified sequences that characterize different biological properties. Spectral analysis on the modified sequences showed a much more prominent 3-periodicity peak in coding regions than the Fourier approach. For long sequences, prominent peaks at 2Π/3 are observed at coding regions, whereas for short sequences, clearly discernible peaks are still visible. Better classification can be obtained using spectral features derived from the modified sequences

Convergence, unanimity and disagreement in majority dynamics on unimodular graphs and random graphs

In majority dynamics, agents located at the vertices of an undirected simple graph update their binary opinions synchronously by adopting those of the majority of their neighbors. On infinite unimodular transitive graphs (e.g., Cayley graphs), when initial opinions are chosen from a distribution that is invariant with respect to the graph automorphism group, we show that the opinion of each agent almost surely either converges, or else eventually oscillates with period two; this is known to hold for finite graphs, but not for all infinite graphs. On Erdős-Rényi random graphs with degrees Ω(n√), we show that when initial opinions are chosen i.i.d. then agents all converge to the initial majority opinion, with constant probability. Conversely, on random 4-regular finite graphs, we show that with high probability different agents converge to different opinions