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De Novo Design of Self-assembling Helical Protein Filaments
No full textThesis (Ph.D.)--University of Washington, 2019There has been some success in designing stable peptide filaments; however, mimicking the controllable and reversible assembly of many natural protein filaments is challenging. We devised a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo-electron microscopy structures of six designs are close to the computational design models. The filament diameter can be tuned by varying the number of repeats in the monomer. Anchor and capping units, built from monomers that lack an interaction interface, can be used to control assembly and disassembly. The filaments provide new phenomena through interactions with cells. We also extended the building blocks to multi-component, pH-responsive and potentially more functional proteins to design more controllable filaments. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials
Developing and Evaluating a Prototype Communicable Disease Web-based Clinical Reporting Tool
No full textThesis (Ph.D.)--University of Washington, 2019Reporting reportable diseases within a timeframe is considered a cornerstone of any public health surveillance system. The purpose of surveillance is to empower decision makers to act by providing timely and accurate data. Conducting surveillance requires a cycle of collecting and reporting individual cases by solo healthcare providers or healthcare facilities to the local/public health department. Healthcare providers are familiar with the requirements to report reportable diseases, but compliance is a challenge. Novel influenza has been a reportable disease since the 2007 legislation. Pandemic influenza is caused by novel influenza that is introduced into a population where some of this population has low immunity to novel influenza, which increases the mortality rate. In the past 120 years, there have been six well-known international novel influenza spread. The deadliest novel influenza epidemic happened in 1918. That year the Spanish Influenza (H1N1) infected about 500 million people and caused the death of an estimated 20 – 50 million. Other novel infections similarly need to be reported and track. Two examples in the last five years are Middle East Respiratory virus and Zika virus. I developed a Web-based reporting tool prototype to help healthcare providers in reporting communicable diseases that are required to be tracked such as novel influenza cases to authorities based on the state’s official case report form. The overarching goal was to develop and evaluate this prototype. My aims were: 1) Understanding the problems within the reportable diseases reporting process from healthcare providers to healthcare authorities, 2) Develop and test a prototype Web-based reporting tool to help to improve the reporting process, and 3) Evaluating the prototype communicable disease Web-based clinical reporting tool. The result of Aim 1 was identifying gaps between states’ reporting guidelines and states’ case report forms at individual state level and across states. The identified gaps helped to generate a collection of all the data fields used in novel influenza states’ reporting guidelines and states’ case report forms. The identified data fields were ranked based on the most used data fields across all the participated states. The ranked data fields across all the participated states helps healthcare providers and policymakers to get insight into other data fields required by other states to develop future guidelines and case report forms. The result of Aim 2 was a tool that maps the required data from a database simulating Electronic Health Records (EHRs) with a different granularity of data to one or more state’s official case report forms. The tool does this through query mapping and pre-population of as much data into a given state’s case report form as the granularity of a given EHR data permit. This feature helps in reducing the manual data entry and increase the accuracy and completeness of submitted data to authorities. The tool converts the submitted case report form into Clinical Document Architecture (CDA) format, which is a recommended standard by Health Level Seven International (HL7). For Aim 3, a combination of usability evaluation methods was implemented to evaluate the Web-based reporting tool from Aim 2. The main objectives of the implemented usability evaluation methods are to measure the usability of the tool. The usability refers to the quality of a user’s experience when interacting with the tool and to measure the user’s overall satisfaction. Aim 3 was designed and performed by the developer due to shortage in resources, which was a limitation. For better results, the evaluation testing process should be conducted by multiple evaluators and coders who have no connection to the project. The Key finding from Aim 3 was that the prototype communicable disease Web-based clinical reporting tool is an acceptable tool by potential users. The evaluation study generated qualitative and quantitative results. Also, the results generated a list of usability problems for future development and considerations
Impact of Databases on Oceanographic Citizen Science
No full textDue to recent advances in low-cost and easily programmable micro-electronic sensors, citizen scientist interested in learning more about their personal connection to the ocean and those aspects of marine waters that they interact with are now able to gather and organize data. They can then visualize that data and draw some basic conclusions about the dynamics of their local marine environment. A key component of this pathway towards citizen science engagement is the implementation of an effective and easy to use database architecture. A database application and user interface was designed, built, and tested to investigate the effectiveness of the application in drawing conclusions regarding marine water dynamics. The application was tested by a small group of undergraduate students who reported strong agreement with positive evaluation statements about the helpfulness of the application. This prototype database development also provides for opportunities to collaboratively investigate with other citizen scientists and archive solutions for long-term data analysis research. The database application is meant for a wide level of expertise as it can be manipulated without novel data but also previous data collected by other scientists
Patient Age and Mobile Home Exercise Program (HEP) Use in Outpatient Physical Therapy
No full textThesis (Master's)--University of Washington, 2019Home Exercise Programs (HEPs) are typically prescribed by physical therapists based on the individual needs of patients, and are a common supplement to outpatient physical therapy1. While adherence to these programs has been associated with improved patient outcomes, nearly 70% of patients do not perform HEPs as prescribed by their physical therapists, and adherence tends to decrease over time2. Given that 77% of adults in the United States own a smartphone, including 42% of adults age 65 and older, smartphone applications (mobile apps) offer an alternative to paper-based programming for delivering and encouraging adherence to HEPs3. MedBridgeGO is a mobile app designed to facilitate individualized home exercise programs as a supplement to physical therapy. The purpose of this research is to examine if older age is associated with lower levels of MedBridgeGO utilization, and what patient factors are associated with utilization. This study involves a sequential mixed-methods analysis of the MedBridgeGO Mobile HEP. Key themes that reflect performance expectancy, effort expectancy, social influence and facilitating conditions of mobile HEP use are identified through an analysis of app store reviews from Google Play and iTunes. Subsequently, the research tests whether older age is associated with lower levels of MedBridgeGO utilization, as well as what patient factors are associated with use through a bivariate and multivariate analysis of MedBridgeGO. Major themes identified in analysis of app store reviews include: t he role of the MedBridgeGO mobile HEP in supporting successful rehabilitation through motivation, compliance with the exercise program, and consistent use of proper exercise form; the role of the MedBridgeGO mobile HEP in supporting patient self-efficacy and ease of adherence to their prescribed home exercise program; and areas for further development of the MedBridgeGO mobile HEP to better meet the needs of the users. When compared with adults aged 18-45, adults older than age 85 had lower odds of mobile HEP utilization in un-adjusted analysis (OR 0.33, 95% CI 0.24, 0.43) and after adjusting for exercise dose, geographic location and median family income (OR 0.33, 95% CI 0.23-0.45). Older age (85+ years) is associated with lower levels of mobile HEP utilization, and MedBridgeGO mobile app utilization did not differ among adults younger than 85. The results of this research provide insight into the use of app-based technology as an alternate to paper-based HEP programming, indicate age-associated societal, health system and individual factors that contribute to use of mobile HEPs, and serve as a resource for the wider healthcare community to design and develop mHealth technologies that meet the needs of a diverse population
Elucidating the Molecular Architecture of the 1D-AR:PDZ-Protein Macromolecular Complex
No full textThesis (Ph.D.)--University of Washington, 2019G Protein-Coupled Receptors (GPCRs) are seven transmembrane proteins that are the targets for over 30% of all medications currently on the market. Adrenergic Receptors (ARs) are one type of GPCR that responds to the endogenous catecholamines norepinephrine (NE) and epinephrine(Epi). In the AR family, there are three types: 1-, 2-, and -ARs. Within each of these subfamilies are three subtypes and the Hague lab focuses one of these receptors: the 1D-AR. The 1D-AR is an interesting receptor in that it is very difficult to study due to its intracellular localization. There are no known cell lines that express endogenous 1D-ARs and within 48 hours after removing epithelial cell expressing the 1D-AR at the membrane, the receptor becomes localized to the endoplasmic reticulum (ER). Studying the 1D-AR is clinically important as there are many disorders that are influenced by this receptor. For example, it can impact urine flow in older males, due to benign prostate hypertrophy (BPH). The 1D-AR is also vital in the circulatory system in repairing blood vessels after injury as well as stimulus-induced movement. Also of note is the role the 1D-AR plays in both schizophrenia and post-traumatic stress disorder (PTSD, Raskind et. al. 2018). It has been noted that treatment with antagonists will decrease the reoccurrence of nightmares in veterans with PTSD. However, most antagonists have major toxic side effects that are associated with taking these medications. Thus, it is vital to determine how the 1D-AR signals with its PDZ and non PDZ proteins as a potential to create new therapeutics for PTSD, schizophrenia, BPH, and cardiovascular disease. Previously, the Hague laboratory determined that there may be a cell line that endogenously expresses the 1D-AR. Through mass spectrometry, it was determined that SW480 cells (a colorectal cancer cell line; CRC) express interacting proteins that have been previously shown to interact with the 1D-AR. Thus, I proposed to determine if this cell line does endogenously express the 1D-AR. Unfortunately, it was determined that the 1D-AR is not present in SW480 cells; instead the most common receptor discovered was the 1B-AR. This was apparently inconsistent with the only other paper (Masur et. al. 2001) that attempted to characterize the ARs present in SW480 cells and their role in cancer. When we attempted to use traditional methods, such as radioligand binding, we were also unable to detect this receptor. Thus, we concluded that the EPIC Dynamic Mass Redistribution (DMR) technology is able to detect previously imperceptible, low density receptors. The Hague laboratory has also determined that the 1D-AR must form a homodimeric macromolecular structure to even retain plasma membrane localization. Specifically, the 1D-AR interacts with the PSD95/DLG1/Zo-1 (PDZ) domain proteins syntrophin and Scribble (SCRIB) via a PDZ-ligand on its C-terminus (CT) in all human cell lines screened to date. This interaction was unique as no other GPCRs interacted with syntrophins or Scribble. Interestingly, in only one of the cell lines screened, it was also discovered that there are three additional proteins that interact with the 1D-AR. These proteins are calcium/calmodulin-dependent protein kinase (CASK), human disks large 1 (hDLG1), and LIN7A. Previous research has shown that hDLG1 and LIN7A can also associate with another membrane-associated guanylate kinase (MAGUK) protein, MPP7. Thus, I proposed to biochemically determine the architecture of the 1D-AR:PDZ protein complex and determine the functional purpose of these PDZ proteins. Based on our data, it appears that SCRIB binds the 1D-AR with the highest affinity (0.07 M), particularly PDZ domains 1/4 (0.78 and 1.38 M, respectively). Syntrophins bound with the next highest affinity (0.56 M) followed by hDLG1 (0.72 M). CASK did bind, but at very low affinity (2.13 M) and neither LIN7A nor MPP7 appeared to bind. It is yet unclear how the hDLG1 tripartite complex interacts with the 1D-AR, whether it be as a transport or scaffolding complex. All the PDZ proteins that seem to interact with the 1D-AR are basolateral proteins and involved in either scaffolding or localization. To determine which membrane the 1D-AR is actually localized to, we needed to find a reliable three-dimensional (3D) methodology to use as a model to conduct our experiments. I proposed to use several different methods; a hydrogel method (such as Corning Life Science’s Matrigel) and a non-adherent method (such as Corning Life Science’s Spheroid Microplate) to find the most consistent methodology for forming our 3D structures. Matrigel proved to be inconsistent for our model cell type; HEK293T cells. This is likely due to the length of time necessary to form the spheroid and lumen. However, the spheroid microplate proved to be efficient and fast in the formation of our spheroids. Interestingly, I noticed the 1D-AR at the surface of the membrane, something that is not seen in two-dimensional (2D) cells. I was determined to see if this correlated to an increase in pharmacodynamic properties, and indeed, it did show a significant increase in both EC50 and Emax. Our data, combined, seems to indicate an intricate macromolecular complex of PDZ and non-PDZ proteins that are vital for polarization of the cells and localization to the proper membrane. These data open a whole new field of questions in fundamental cell biology and open the door to novel therapeutics that can target any number of new sites
Hardening Inline DGA Classifiers Against Adversarial Attacks
No full textThesis (Master's)--University of Washington, 2019Domain Generation Algorithms (DGAs) are widely used by cybercriminals to generate domain names on-the-go for C&C (command-and-control) purposes of establishing communication with the bots and instructing them to perform malicious activities. It is therefore important to detect domains generated by DGAs to block the communication between the bot and C&C. In recent years, Machine Learning based DGA detection systems are widely used to address this problem. However, it is found that classifiers that rely only on the domain name to detect DGAs are highly vulnerable to adversarial attacks. Adversarial attacks are intentionally devised by an attacker to fool a classifier and cause it to produce erroneous results. This is a serious concern as it degrades the performance of DGA detection classifiers. In this thesis, we aim to defend DGA detection classifiers against adversarial attacks, without compromising the performance of existing state-of-the-art classifiers in the literature. One such technique is to use side information features obtained from the DNS query/response that cannot be easily manipulated by the adversary. Although there are past research works that use DNS features for a retrospective analysis of DNS traffic, to the best of our knowledge, there are no studies that leverage such data for inline detection of DGA domains. In our work, we train machine learning models based on tree ensembles and deep learning for DGA detection using side information (in addition to the domain name), which can be easily obtained in practice without relying on external data sources such as WHOIS. Besides, we also disregard methods that analyze past DNS data to extract side information features, thereby resulting in a relatively lightweight computation for detecting DGA domains in real-time DNS applications. In the end, we also perform an empirical evaluation by applying the best performing classifiers trained using side information on one day of passive DNS traffic to compare its performance against well known state-of-the-art classifier that relies only on a domain name for DGA detection. Results show that classifiers trained using a combination of lexical and side information features, not only provide high performance but are also more robust to adversarial attacks than the classifiers that rely only on the domain name for inline DGA detection
Testing the theory of radiation belt electron loss by hiss and electromagnetic ion cyclotron waves
No full textThesis (Ph.D.)--University of Washington, 2019Hiss, chorus and electromagnetic ion cyclotron waves (EMIC wave) are three major wave modes that are widely investigated and included in the radiation belt electron models to explain electron precipitation. The quasi-linear theories of electron loss through pitch angle diffusion by hiss and EMIC waves were proposed in 1970s. Since then the testing of the theories is still going on though some progresses had been made. Comparison of theoretical predictions to electrons distribution at loss cone is one effective way to evaluate the theories. The main obstruction of loss cone testing was from the lack of measurements of the electron loss cone distribution with enough pitch angle and energy resolution and simultaneous wave activities at the heart of radiation belt. This thesis is devoted to testing the hiss and EMIC waves diffusion theories from the perspective of the electron loss cone distribution by utilizing the previously unnoticed overlap of UARS and CRRES missions in 1991. The conclusions are as following: (1) Two cases showing the consistency between quasi-linear theory of hiss diffusion and observed loss cone distribution are found. (2) In 25 out of 38 cases, hiss wave power is far insufficient in precipitating the large amount of electrons observed. Loss mechanisms other than hiss, chorus and EMIC waves are needed to account for the discrepancy. (3) Three EMIC wave events were investigated. In the first case, the isotropic distribution (sign of strong diffusion) is caused by process other than EMIC wave diffusion demonstrating that simultaneous presence of EMIC wave and electron precipitation does not guarantee any connection between the two. Large discrepancy between quasi-linear theory of EMIC wave diffusion and observed electron loss cone distribution is found from the second case. The strong depletion of electrons by EMIC waves predicted by the current theory was not found. In the third case the resonant energy goes beyond the instrument limit of electron detectors thus no conclusion is drawn
Firearm storage practices in households with children: A survey of community-based firearm safety event participants
No full textThesis (Master's)--University of Washington, 2019Background/Purpose: Safe firearm storage is associated with lower risk of unintentional and intentionally self-inflicted firearm injuries among children and adolescents. Ten community-based firearm safety events were conducted across Washington state from 2015-2018. We sought to describe characteristics of event participants and assess whether presence and age of children were associated with firearm locking practices among firearm-owning households. Methods: We assessed demographic characteristics and baseline firearm storage behaviors of participants using a 13-item survey. Multivariable Poisson regression models were used to estimate prevalence ratios (PR) and corresponding confidence intervals (CI) for the association of presence and age of children in households with prevalence of storing a household firearm unlocked. Results/Outcomes: Of 2,956 participants, 58.3% were male and 57.8% lived with an individual under 18 years. Among the 90.5% participants living with firearms, 40.1% stored at least one firearm unlocked and 39.1% stored at least one firearm loaded. In adjusted analyses, there was no statistically significant difference in prevalence of storing a household firearm unlocked between those living with no children and those living with a child <11 years (PR=0.91; 95% CI: 0.80,1.04), or a child aged 11-18 years (PR=0.94; 95% CI: 0.81,1.09). Conclusions: A high proportion of participants stored a firearm unlocked or loaded at home and neither living with young children nor adolescents was associated with safer locking practices. In comparison with evidence-based interventions conducted in clinic settings, these community-based interventions were successful in enrolling a large number of participants who were more likely to be male and own firearms
Estimating the effect of healthcare interventions on the distribution of health state severity for low back pain in the Global Burden of Disease study
No full textThesis (Master's)--University of Washington, 2019Background: Many causes of non-fatal health burden present with varying degrees of severity from asymptomatic to most severe. The severity distribution for diseases amenable to healthcare interventions is expected to vary as function of healthcare access and quality (HAQ). Current methods used in the Global Burden of Disease (GBD) study assume a constant severity distribution over space and time, ignoring any effect of healthcare interventions. This paper presents a method to incorporate information on the effect of healthcare interventions on health state severity and quantify the relationship between health state severity and HAQ in order to generate location-specific estimates of average condition severity. Using low back pain (LBP) as an example condition, estimates of intervention efficacy and utilization are generated and used to estimate averted and avoidable burden. Methods: Healthcare interventions for LBP were identified from the Cochrane Database of Systematic Reviews. Efficacy was assessed in terms of the standardized mean difference in disability relative to some usual care or placebo group. Interventions were grouped into five intervention classes: (1) surgical; (2) behavioral, cognitive, and physical therapies; and three classes of analgesics ((3) NSAID, (4) opioid, and (5) non-opioid non-NSAID analgesics). Effect sizes were pooled across all interventions in a class using a network meta-analysis framework. The overall treatment effect for LBP was calculated as the utilization-weighted sum of the intervention class effect sizes. The effect of treatment for LBP was also calculated assuming an aspirational 100% utilization of the optimal set of interventions among all individuals with LBP. The overall treatment effect was applied to the GBD LPB disability weight distribution generated from the United States based Medical Expenditure Panel Survey in order to estimate the relationship between intervention utilization and average disability. Using the Healthcare Access and Quality Index (HAQI) as a proxy for access to interventions for LBP, the relationship between HAQI and average LBP disability per case was linearly interpolated. For each country in the GBD, current YLDs, averted YLDs, avoidable YLDs, and YLDs for the optimal treatment scenario were calculated. Results: A total of 134 trials representing 160 unique intervention-comparison combinations were analyzed. Surgical interventions and NSAIDs were the most effective interventions (SMDs -0.44 (-0.70, -0.20) and -0.28 (-0.52, -0.04) respectively). The overall effect of healthcare interventions on LBP disability was estimated to be -0.17 (-0.35, 0.01) for LBP without leg involvement and -0.29 (-0.56, -0.01) for LBP with leg involvement. The maximum achievable proportion of LBP burden avoided through use of healthcare interventions under routine health care circumstances was 24.4% (1.4-41.3%) based on the relationship between HAQI and LBP disability. A hypothetical 100% utilization of the optimal treatment could avoid an additional 22.6% (4.1-31.2%) of LBP burden leaving 53.0% (28.0-95.4%) of LBP burden that cannot be addressed using existing healthcare interventions for LBP. Interpretation: Estimation of the relationship between intervention efficacy, utilization, and LBP severity indicates that health interventions impact LBP severity and imply that LBP severity should vary according to health system quality and intervention utilization. The methods presented in this study represent a generalizable approach to estimate location-specific severity distributions. Applied across the GBD, this method would allow for the estimation of averted and avoidable burden which serve as useful benchmarks for funders looking to expand coverage of and access to healthcare interventions. A reduction of the remaining burden which cannot be addressed using current healthcare technologies would require research and development to create novel approaches to treatment
Interviews of Senator Warren Magnuson’s Commerce Committee Staff for When the Senate Worked for Us
No full textWritten transcripts of oral history interviews of Senator Warren G. Magnuson's Commerce Committee staffers. Interviewees include:
Len Bickwit;
Mary McInnis Boies;
Joan Claybrook;
David Cohen;
Ed Cohen;
Stan Cohen;
David Freeman;
Jerry Grinstein;
Terry Lierman;
Ed Merlis;
Morton Mintz;
Ralph Nader;
Sharon Nelson;
Ben Palumbo;
David Price;
Manny Rouvelas;
Lynn Sutcliffe;Between the early 1960s and the late 1970s an impressive number of consumer and environmental protection laws come out of the Senate Committee on Commerce, Science, and Transportation. Michael (Mike) Pertschuk worked for the Committee for thirteen years. The Committee was chaired by Senator Warren G. Magnuson of Washington.
Pertschuk interviewed a representative sampling of the most entrepreneurial of the Magnuson Commerce Committee staffers for his 2017 book When the Senate Worked for Us. Pertschuk donated transcripts of those interviews to the Senator Warren G. Magnuson Archives at the University of Washington Library in Seattle, Washington. These interviews join other materials from Magnuson staffers.
The Magnuson Archives offer a rich history of Washington. Magnuson was elected to the House of Representatives in 1936 and to the Senate in 1944. He served as chairman of the Commerce Committee between 1955 and 1977. Much of the consumer protection and automobile safety legislation was enacted by the Committee during Magnuson’s chairmanship. He was also responsible for significant health care legislation and funding. Magnuson was chairman of the Senate Appropriations Committee from 1977 to 1981. He was President pro tempore of the Senate from 1978 to 1981