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Description
Solution conformations and dynamics of proteins and protein-DNA complexes are often difficult to predict from their crystal structures. The crystal structure only shows a snapshot of the different conformations these biological molecules can have in solution. Multiple different conformations can exist in solution and potentially have more importance in the biological activity. DNA sliding clamps are a family of proteins with known crystal structures. These clamps encircle the DNA and enable other proteins to interact more efficiently with the DNA. Eukaryotic PCNA and prokaryotic β clamp are two of these clamps, some of the most stable homo-oligomers known. However, their solution stability and conformational equilibrium have not been investigated in depth before. Presented here are the studies involving two sliding clamps: yeast PCNA and bacterial β clamp. These studies show that the β clamp has a very different solution stability than PCNA. These conclusions were reached through various different fluorescence-based experiments, including fluorescence correlation spectroscopy (FCS), Förster resonance energy transfer (FRET), single molecule fluorescence, and various time resolved fluorescence techniques. Interpretations of these, and all other, fluorescence-based experiments are often affected by the properties of the fluorophores employed. Often the fluorescence properties of these fluorophores are influenced by their microenvironments. Fluorophores are known to sometimes interact with biological molecules, and this can have pronounced effects on the rotational mobility and photophysical properties of the dye. Misunderstanding the effect of these photophysical and rotational properties can lead to a misinterpretation of the obtained data. In this thesis, photophysical behaviors of various organic dyes were studied in the presence of deoxymononucleotides to examine more closely how interactions between fluorophores and DNA bases can affect fluorescent properties. Furthermore, the properties of cyanine dyes when bound to DNA and the effect of restricted rotation on FRET are presented in this thesis. This thesis involves studying fluorophore photophysics in various microenvironments and then expanding into the solution stability and dynamics of the DNA sliding clamps.
ContributorsRanjit, Suman (Author) / Levitus, Marcia (Thesis advisor) / Lindsay, Stuart (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2013
Description
Transfer learning is a sub-field of statistical modeling and machine learning. It refers to methods that integrate the knowledge of other domains (called source domains) and the data of the target domain in a mathematically rigorous and intelligent way, to develop a better model for the target domain than a model using the data of the target domain alone. While transfer learning is a promising approach in various application domains, my dissertation research focuses on the particular application in health care, including telemonitoring of Parkinson’s Disease (PD) and radiomics for glioblastoma.
The first topic is a Mixed Effects Transfer Learning (METL) model that can flexibly incorporate mixed effects and a general-form covariance matrix to better account for similarity and heterogeneity across subjects. I further develop computationally efficient procedures to handle unknown parameters and large covariance structures. Domain relations, such as domain similarity and domain covariance structure, are automatically quantified in the estimation steps. I demonstrate METL in an application of smartphone-based telemonitoring of PD.
The second topic focuses on an MRI-based transfer learning algorithm for non-invasive surgical guidance of glioblastoma patients. Limited biopsy samples per patient create a challenge to build a patient-specific model for glioblastoma. A transfer learning framework helps to leverage other patient’s knowledge for building a better predictive model. When modeling a target patient, not every patient’s information is helpful. Deciding the subset of other patients from which to transfer information to the modeling of the target patient is an important task to build an accurate predictive model. I define the subset of “transferrable” patients as those who have a positive rCBV-cell density correlation, because a positive correlation is confirmed by imaging theory and the its respective literature.
The last topic is a Privacy-Preserving Positive Transfer Learning (P3TL) model. Although negative transfer has been recognized as an important issue by the transfer learning research community, there is a lack of theoretical studies in evaluating the risk of negative transfer for a transfer learning method and identifying what causes the negative transfer. My work addresses this issue. Driven by the theoretical insights, I extend Bayesian Parameter Transfer (BPT) to a new method, i.e., P3TL. The unique features of P3TL include intelligent selection of patients to transfer in order to avoid negative transfer and maintain patient privacy. These features make P3TL an excellent model for telemonitoring of PD using an At-Home Testing Device.
The first topic is a Mixed Effects Transfer Learning (METL) model that can flexibly incorporate mixed effects and a general-form covariance matrix to better account for similarity and heterogeneity across subjects. I further develop computationally efficient procedures to handle unknown parameters and large covariance structures. Domain relations, such as domain similarity and domain covariance structure, are automatically quantified in the estimation steps. I demonstrate METL in an application of smartphone-based telemonitoring of PD.
The second topic focuses on an MRI-based transfer learning algorithm for non-invasive surgical guidance of glioblastoma patients. Limited biopsy samples per patient create a challenge to build a patient-specific model for glioblastoma. A transfer learning framework helps to leverage other patient’s knowledge for building a better predictive model. When modeling a target patient, not every patient’s information is helpful. Deciding the subset of other patients from which to transfer information to the modeling of the target patient is an important task to build an accurate predictive model. I define the subset of “transferrable” patients as those who have a positive rCBV-cell density correlation, because a positive correlation is confirmed by imaging theory and the its respective literature.
The last topic is a Privacy-Preserving Positive Transfer Learning (P3TL) model. Although negative transfer has been recognized as an important issue by the transfer learning research community, there is a lack of theoretical studies in evaluating the risk of negative transfer for a transfer learning method and identifying what causes the negative transfer. My work addresses this issue. Driven by the theoretical insights, I extend Bayesian Parameter Transfer (BPT) to a new method, i.e., P3TL. The unique features of P3TL include intelligent selection of patients to transfer in order to avoid negative transfer and maintain patient privacy. These features make P3TL an excellent model for telemonitoring of PD using an At-Home Testing Device.
ContributorsYoon, Hyunsoo (Author) / Li, Jing (Thesis advisor) / Wu, Teresa (Committee member) / Yan, Hao (Committee member) / Hu, Leland S. (Committee member) / Arizona State University (Publisher)
Created2018
Description
Nonalcoholic Steatohepatitis (NASH) is a severe form of Nonalcoholic fatty liverdisease, that is caused due to excessive calorie intake, sedentary lifestyle and in the
absence of severe alcohol consumption. It is widely prevalent in the United States
and in many other developed countries, affecting up to 25 percent of the population.
Due to being asymptotic, it usually goes unnoticed and may lead to liver failure if
not treated at the right time.
Currently, liver biopsy is the gold standard to diagnose NASH, but being an
invasive procedure, it comes with it's own complications along with the inconvenience
of sampling repeated measurements over a period of time. Hence, noninvasive
procedures to assess NASH are urgently required. Magnetic Resonance Elastography
(MRE) based Shear Stiffness and Loss Modulus along with Magnetic Resonance
Imaging based proton density fat fraction have been successfully combined to predict
NASH stages However, their role in the prediction of disease progression still remains
to be investigated.
This thesis thus looks into combining features from serial MRE observations to
develop statistical models to predict NASH progression. It utilizes data from an experiment
conducted on male mice to develop progressive and regressive NASH and
trains ordinal models, ordered probit regression and ordinal forest on labels generated
from a logistic regression model. The models are assessed on histological data collected
at the end point of the experiment. The models developed provide a framework
to utilize a non-invasive tool to predict NASH disease progression.
ContributorsDeshpande, Eeshan (Author) / Ju, Feng (Thesis advisor) / Wu, Teresa (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2021
Description
Functional regression models are widely considered in practice. To precisely understand an underlying functional mechanism, a good sampling schedule for collecting informative functional data is necessary, especially when data collection is limited. However, scarce research has been conducted on the optimal sampling schedule design for the functional regression model so far. To address this design issue, efficient approaches are proposed for generating the best sampling plan in the functional regression setting. First, three optimal experimental designs are considered under a function-on-function linear model: the schedule that maximizes the relative efficiency for recovering the predictor function, the schedule that maximizes the relative efficiency for predicting the response function, and the schedule that maximizes the mixture of the relative efficiencies of both the predictor and response functions. The obtained sampling plan allows a precise recovery of the predictor function and a precise prediction of the response function. The proposed approach can also be reduced to identify the optimal sampling plan for the problem with a scalar-on-function linear regression model. In addition, the optimality criterion on predicting a scalar response using a functional predictor is derived when the quadratic relationship between these two variables is present, and proofs of important properties of the derived optimality criterion are also provided. To find such designs, an algorithm that is comparably fast, and can generate nearly optimal designs is proposed. As the optimality criterion includes quantities that must be estimated from prior knowledge (e.g., a pilot study), the effectiveness of the suggested optimal design highly depends on the quality of the estimates. However, in many situations, the estimates are unreliable; thus, a bootstrap aggregating (bagging) approach is employed for enhancing the quality of estimates and for finding sampling schedules stable to the misspecification of estimates. Through case studies, it is demonstrated that the proposed designs outperform other designs in terms of accurately predicting the response and recovering the predictor. It is also proposed that bagging-enhanced design generates a more robust sampling design under the misspecification of estimated quantities.
ContributorsRha, Hyungmin (Author) / Kao, Ming-Hung (Thesis advisor) / Pan, Rong (Thesis advisor) / Stufken, John (Committee member) / Reiser, Mark R. (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2020
Description
Acoustic emission (AE) signals have been widely employed for tracking material properties and structural characteristics. In this study, the aim is to analyze the AE signals gathered during a scanning probe lithography process to classify the known microstructure types and discover unknown surface microstructures/anomalies. To achieve this, a Hidden Markov Model is developed to consider the temporal dependency of the high-resolution AE data. Furthermore, the posterior classification probability and the negative likelihood score for microstructure classification and discovery are computed. Subsequently, a diagnostic procedure to identify the dominant AE frequencies that were used to track the microstructural characteristics is presented. In addition, machine learning methods such as KNN, Naive Bayes, and Logistic Regression classifiers are applied. Finally, the proposed approach applied to identify the surface microstructures of additively manufactured Ti-6Al-4V and show that it not only achieved a high classification accuracy (e.g., more than 90\%) but also correctly identified the microstructural anomalies that may be subjected to further investigation to discover new material phases/properties.
ContributorsSun, Huifeng (Author) / Yan, Hao (Thesis advisor) / Fricks, John (Thesis advisor) / Cheng, Dan (Committee member) / Arizona State University (Publisher)
Created2020
Description
High-dimensional data is omnipresent in modern industrial systems. An imaging sensor in a manufacturing plant a can take images of millions of pixels or a sensor may collect months of data at very granular time steps. Dimensionality reduction techniques are commonly used for dealing with such data. In addition, outliers typically exist in such data, which may be of direct or indirect interest given the nature of the problem that is being solved. Current research does not address the interdependent nature of dimensionality reduction and outliers. Some works ignore the existence of outliers altogether—which discredits the robustness of these methods in real life—while others provide suboptimal, often band-aid solutions. In this dissertation, I propose novel methods to achieve outlier-awareness in various dimensionality reduction methods. The problem is considered from many different angles depend- ing on the dimensionality reduction technique used (e.g., deep autoencoder, tensors), the nature of the application (e.g., manufacturing, transportation) and the outlier structure (e.g., sparse point anomalies, novelties).
ContributorsSergin, Nurettin Dorukhan (Author) / Yan, Hao (Thesis advisor) / Li, Jing (Committee member) / Wu, Teresa (Committee member) / Tsung, Fugee (Committee member) / Arizona State University (Publisher)
Created2021
Description
Deoxyribonucleic acid (DNA), a biopolymer well known for its role in preserving genetic information in biology, is now drawing great deal of interest from material scientists. Ease of synthesis, predictable molecular recognition via Watson-Crick base pairing, vast numbers of available chemical modifications, and intrinsic nanoscale size makes DNA a suitable material for the construction of a plethora of nanostructures that can be used as scaffold to organize functional molecules with nanometer precision. This dissertation focuses on DNA-directed organization of metallic nanoparticles into well-defined, discrete structures and using them to study photonic interaction between fluorophore and metal particle. Presented here are a series of studies toward this goal. First, a novel and robust strategy of DNA functionalized silver nanoparticles (AgNPs) was developed and DNA functionalized AgNPs were employed for the organization of discrete well-defined dimeric and trimeric structures using a DNA triangular origami scaffold. Assembly of 1:1 silver nanoparticle and gold nanoparticle heterodimer has also been demonstrated using the same approach. Next, the triangular origami structures were used to co-assemble gold nanoparticles (AuNPs) and fluorophores to study the distance dependent and nanogap dependencies of the photonic interactions between them. These interactions were found to be consistent with the full electrodynamic simulations. Further, a gold nanorod (AuNR), an anisotropic nanoparticle was assembled into well-defined dimeric structures with predefined inter-rod angles. These dimeric structures exhibited unique optical properties compared to single AuNR that was consistent with the theoretical calculations. Fabrication of otherwise difficult to achieve 1:1 AuNP- AuNR hetero dimer, where the AuNP can be selectively placed at the end-on or side-on positions of anisotropic AuNR has also been shown. Finally, a click chemistry based approach was developed to organize sugar modified DNA on a particular arm of a DNA origami triangle and used them for site-selective immobilization of small AgNPs.
ContributorsPal, Suchetan (Author) / Liu, Yan (Thesis advisor) / Yan, Hao (Thesis advisor) / Lindsay, Stuart (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2012