Bioculture Journal
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The Automated Anatomical Labeling (AAL) Atlas with additional regions of interest for automated white matter segmentation
No full textIntegrating paper fluidic liquid handling and whole blood plasma separation into silicon photonic biosensors.
No full textThesis (Master's)--University of Washington, 2019Silicon photonic biosensors have emerged as a powerful platform for various lab-on-a-chip applications. The technology can miniaturize assays, perform label-free detection, and is capable of rapid multiplexing. These qualities make silicon photonic biosensors a competitive platform to replace conventional clinical tests based on less scalable technologies. Most silicon photonic biosensors rely on external pumps to deliver samples and reagents over the photonic sensors. To increase the clinical viability of this technology, this project seeks to dramatically reduce the complexity of the bio-sensing system by integrating sample processing and fluidics via a capillary driven network. We have previously integrated paper microfluidic liquid handling with our custom silicon photonic test bench. With the work presented in this thesis, we demonstrate the integration of paper microfluidic networks into the Ratner lab’s OEM silicon photonic platform and we increase the complexity of the network to incorporate whole blood plasma separation. The Ratner lab has recently developed an ABO blood typing assay via silicon photonics. Using silicon photonics as the platform has the potential to achieve a higher level of automation than conventional ABO typing agglutination methods, while simultaneously reducing the assay time, and lowering costs. We validated our paper fluidic network with a reverse ABO typing assay based on the patient’s serology. In our system, we need to separate the whole blood sample in order to run the sample without running the risk of stopping the flow in the network. Here we demonstrate capillary network liquid handling and paper-based whole blood separation into our OEM silicon photonic system (i.e. the Genalyte Maverick). This integrated plasma separation and paper fluidic network reagent delivery make the system more suitable for point-of-care and rapid diagnostic testing applications. We hope this work helps bring silicon photonic biosensing closer to clinical adoption and more appropriate for clinical settings
Geomorphic and Atmospheric Investigations on the Habitability of Past and Present Mars
No full textThesis (Ph.D.)--University of Washington, 2019While the current surface of Mars is viewed to be inhospitable to life as we know it, past Mars may have harbored habitable environments though the extent and duration of such environment is still unclear. There are several requirements to make an environment habitable, which include a liquid solvent (e.g. liquid water), a source of energy (e.g. redox gradients), bioimportant major and trace elements (e.g. CHNOPS), and sustained clement conditions for necessary biochemical reactions to take place (e.g. temperature, pH). This dissertation focuses on better constraining these requirements through atmospheric modeling and quantitative surficial geomorphological investigations. The first half of this dissertation explores the habitability of past and present Mars through the lens of atmospheric redox chemistry. The photochemically produced CO-O2 redox pair in the modern atmosphere produces the second largest atmospheric thermodynamic disequilibrium in the solar system (behind Earth’s atmosphere-ocean system), which represents an untapped source of free energy for potential life to exploit. A rigorous upper limit on the possible extant biomass that can be sustained from this free energy is presented. Volcanic outgassing of reducing gases, e.g. CO and H2, can shift the redox state of the atmosphere, changing the surface conditions towards being reducing and anoxic which are more favorable for the formation of prebiotic chemical compounds (e.g. amino acids). The required levels of volcanism needed to create reducing conditions and potential observables of such environments are also presented here. The latter half of this dissertation focuses on assessing the current state of coastal evidence for past liquid water oceans on Mars. While nearly all aspects of these hypothesized oceans are vigorously debated, availability of large sustained bodies of liquid water would be a boon for constraining the past surface habitability. Presented here is a toolkit developed for quantitatively identifying paleoshorelines using topographic, morphological, and spectroscopic investigations. This toolkit is then applied to 40 individual sites across Mars that have been proposed as ancient ocean shorelines and evaluated along with the general mapped contacts on their consistency with such an origin. None of the putative paleoshoreline sites provided compelling evidence nor consistency with a coastal origin and can all be explained through more conservative geological processes. Together, the chapters in this dissertation provide quantitative means of characterizing contributing aspects of potentially habitable environments on past and present Mars
Understanding Residential Patterns across Asian Ethnic Groups and U.S. Metropolitan Areas
No full textThesis (Master's)--University of Washington, 2019This paper explores the residential patterns of the six largest Asian ethnic groups – Chinese, Asian Indian, Filipino, Vietnamese, Korean, and Japanese – across fifty-seven U.S. metropolitan areas, which are categorized into seven types of immigrant gateways. Using 2010 U.S. decennial census data, I discover that the application of multiple residential segregation measures, each of which captures a unique aspect of residential experiences, leads to diverging results across subgroups and across places. On the basis of the dissimilarity index, Vietnamese are the most segregated; Chinese and Asian Indians are the most segregated when using the isolation index; and Filipinos are the most segregated along the clustering dimension. Older and more traditional immigrant gateways experience higher dissimilarity scores than newer gateways, while destinations that have received a high share of the foreign-born population in the second-half of the 20th century, namely after the enactment of the 1965 Immigration and Nationality Act, contain more clusters. These findings underscore the importance of examining residential patterns at a more granular level than the broad, pan-ethnic grouping of Asians; beyond the oft-studied large metropolitan areas; and with more refined differentiation of immigrant gateway types than the dichotomy of new versus traditional immigrant destinations. Importantly, the results reveal that settlement dynamics of Asian groups need to be understood at the intersection of a group’s immigration route and a metropolitan area’s ecological structure as an immigrant destination. Finally, I identify a new neighborhood model, characterized as a “socially constrained resurgent community,” which broadens the role that ethnic neighborhoods play in the settlement experiences of Asian groups and highlights the need to refine traditional theoretical ethnic neighborhood models in the literature
Complete mapping of HIV-1 escape from broadly neutralizing antibodies, vaccines, and drugs
No full textThesis (Ph.D.)--University of Washington, 2019The expansive global diversity of HIV-1 Env presents significant hurdles in developing a broadly protective vaccine. This diversity is a result of HIV Env’s exceptional evolutionary capacity, which allows it to evade the extraordinary diversity of the humoral immune system during infection. However, the evolutionary arms race between Env and humoral immunity occasionally drives the development of broadly neutralizing antibodies (bnAbs) capable of neutralizing diverse strains. Mapping the epitope specificity of bnAbs has revealed conserved regions of Env, which are promising targets for structure-based vaccine design. Additionally, bnAbs’ broad activity and potential to direct the killing of infected cells make them promising antiviral immunotherapeutic drugs for HIV prevention, therapy, and cure strategies. Translating bnAbs into vaccines and therapies will require both a detailed understanding of how bnAbs interact with Env as well as assessing their potential for viral escape. While structural studies provide atomic-level views of HIV-antibody interactions, they fail to reveal the functional interactions necessary for neutralization and the viral mutations that disrupt these interactions. Neutralization and binding assays using mutants can provide such information for specific mutations, but even the largest studies employing one-at-a-time mutagenesis can only assay a small fraction of all possible Env mutations. To overcome these shortcomings, we have developed mutational antigenic profiling, a deep mutational scanning approach that completely maps the functional interface between HIV and an antibody in a single massively parallel experiment. This involves generating libraries of HIV that carry all possible amino-acid mutations to Env (12,730 amino-acid mutations), incubating these viral libraries with or without an antibody, infecting T cells, and using deep sequencing to quantify the enrichment of each mutation in the antibody selected versus non-selected libraries. Profiling escape from bnAb PGT151 identified all previously known and revealed numerous additional escape mutations. Benchmarking these data against traditional neutralization assays further validated that we accurately quantified the effect of all amino-acid mutations to Env. Additionally, evaluating the effect of each amino acid at each site elucidated the biochemical mechanisms of escape throughout the epitope, highlighting the previously unappreciated role for charge-charge repulsions. To gain a broad view of HIV antibody escape, we mapped escape from a panel of nine bnAbs targeting the five best-characterized Env epitopes. Importantly, many of these bnAbs are being clinically developed as immunotherapeutics. While prior studies had defined each of these bnAbs’ structural epitope, our unbiased mapping defined their functional epitopes, or the sites at which mutations mediated escape in the context of replication competent viruses, for the first time. For most bnAbs, mutations at only a small fraction of structurally defined contact sites mediated escape, and escape often occurred at sites that are near but do not directly contact the antibody. Further, these data helped to interpret viral mutations observed in immunotherapy clinical trials—in vivo escape occurred in the functional epitope, some of which was previously missed since it was far from the structural epitope. Additionally, this data allowed for an unbiased quantification of the ease of viral escape for each bnAb, which we found is distinct from antibody breadth. We also mapped escape from a pool of two bnAbs; we found that there were no mutations that robustly escaped both antibodies, agreeing with the results of two recently completed clinical trials that administered this combination. Further, we profiled escape from two antibodies across multiple viral strains, providing the first unbiased quantifications of strain-specific differences in antibody escape. Next, we leveraged mutational antigenic profiling to directly refine structure-based vaccine design. We contrasted escape from bnAb VRC34.01 with escape from two murine antibodies that were elicited with immunogens based on the VRC34.01 epitope. This revealed distinct differences in the recognition of natural and vaccine-elicited antibodies, and provide a template to guide the iterative rounds of vaccine design. We then adapted this approach to better delineate the genotypic determinants of resistance to the only clinically approved HIV fusion inhibitor, enfuvirtide. Again, we identified both previously characterized and novel resistance mutations. Many resistance mutations were allosteric to the drug’s binding site, which shed light on diverse mechanisms of resistance. Further, this complete map of resistance may be of use in the clinical monitoring of resistance during therapy and the genotypic prediction of enfuvirtide sensitivity prior to treatment. Few protein-protein interfaces have been as heavily studied as those between bnAbs and Env, as these interactions provide the motivation for many HIV treatment and prevention efforts. Mutational antigenic profiling yields an unprecedented view of these interfaces, redefining out understanding of an antibody’s functional epitope. The complete maps of viral escape detailed in this thesis provide a mutation-level antigenic atlas for understanding viral immune escape and guiding the development of antibody immunotherapies and vaccines
Modeling the suicidal behavior cycle: Understanding repeated suicide attempts among individuals with borderline personality disorder and a history of attempting suicide
No full textThesis (Master's)--University of Washington, 2019Objective: Suicide remains a leading cause of death in the United States and recent reports have suggested the suicide rate is increasing. One of the most robust predictors of future suicidal behavior is a history of attempting suicide. Despite this, little is known about the factors that reduce the likelihood of a re-attempting suicide. This study compares theoretically-derived suicide risk indicators to determine which factors are most predictive of future suicide attempts. Method: We used data from a randomized controlled trial comparing three forms of Dialectical Behavior Therapy (DBT; Linehan et al., 2015). Participants (N = 99, mean age = 30.3 years, 100% female, 71% White) met criteria for borderline personality disorder and had repeated and recent self-injurious behavior. Assessments occurred at four-month intervals throughout one year of treatment and one year of follow-up. Time-lagged generalized linear mixed models (GLMMs) were used to evaluate relationship satisfaction, emotion dysregulation, and coping styles as predictors of suicide attempts. Results: Both univariate and multivariate models suggested that higher between person variance in problem-focused coping and lack of access to emotion regulation strategies were weakly associated with additional suicide attempts over the two-year study. Within person variance in the time-lagged predictors were not associated with subsequent suicide attempts. Conclusions: Among individuals with a recent suicide attempt, problem-focused coping and specific deficits in emotion regulation may differentiate those likely to re-attempt from those who stop suicidal behavior during and after DBT. These results suggest that treatments for recent suicide attempters should target increasing problem-focused coping and decreasing maladaptive emotion regulation skills
Connecting End Users to Domain Experts With Universal Mobile Phones Services
No full textThesis (Ph.D.)--University of Washington, 2019The potential for communication services available on any mobile phone to engage users, disseminate information, and facilitate behavior change has been well documented. Designing using universal applications based on SMS and voice services enables platforms that reach and empower marginalized segments of the global population. The majority of mobile messaging services for development are either one-way push messaging or use fully automated bi-directional hierarchy based bots. In this thesis, I present the design, deployment and evolution of mWACH – a semi-automated bi-directional SMS platform for global health interventions. This novel system mediates personalized conversations between patients and trained medical professionals through a personalized schedule of automated messages. In collaboration with UW Global Health and Kenyatta National Hospital in Nairobi mWACH has been used in five different projects at seven Kenyan clinics. Since 2013 over 120 thousand automated SMS messages have been sent and we have received over 35 thousand messages from participants with study staff sending an additional 25 thousand messages. This thesis contributes an in depth quantitative analysis of system use and engagement over time and across projects. Results from the system analysis and messaging content will help inform the design of future systems looking to engage patients on health messaging platforms
The Sounds of Silence: Iraq's Missing Voices From the Sanctions Period
No full textThesis (Master's)--University of Washington, 2019Using personal interviews and works of art, I bring into focus the suffering of Iraq’s people who lived through the sanctions period (1990-2003) under the regime of Saddam Hussein. In particular, I examine the effects of the sanctions regime on their everyday lives in regard to family, the economy, medical care, education, and culture. My research centers on the presentation of events from the Iraqi point of view, adding a new perspective to existing articles and books written by non-Iraqis who were not affected by sanctions personally. By providing historical background as a foundation, I demonstrate the ways in which Iraq and its people fell into a downward spiral after Saddam Hussein took control in 1979. Through primary research, I examine corrupt acts committed by the United States and Iraq that began during the presidency of Ronald Reagan and continued throughout the sanctions period. I argue that, in view of this oral history research, the conditions in Iraq during this period were far more devastating than previously acknowledged. Finally, I illustrate how the United States government and the media exacerbated the struggles of the Iraqi people by willfully neglecting them
Keep Your Habitat: Preventing the displacement of vulnerable homeowners in Seattle’s Central District
No full textThesis (Master's)--University of Washington, 2019As housing costs across Seattle steadily rise, both homeowners and renters consider moving outside of the city in search of cheaper housing, often sacrificing convenient access to transit, jobs and amenities. This study utilizes an informal group of homeowners in Seattle’s Central District called “Keep Your Habitat” to understand gentrification-induced displacement pressures and propose options for residents to resist displacement. This study employs a mixed methods approach, combining quantitative analysis of neighborhood demographics and housing market trends with qualitative interviews with neighborhood stakeholders to understand displacement pressures and resistance in the Central District. Finally, this research proposes several options to prevent displacement of vulnerable homeowners in the Central District, including property tax relief, more equitably distributing growth and supports for homeowners seeking to lease space within their home. Keeping residents in neighborhoods that they have called home for decades with good access to amenities and transit is a critical planning goal that strives to prevent displacement and re-segregation as more affluent household move back to inner city neighborhoods
Targeting RNA Structures that Control Protein Synthesis and RNA Stability
No full textThesis (Ph.D.)--University of Washington, 2019RNA structures play a pivotal role in many biological processes and the progression of human disease, making them an unexploited target for therapeutic development. The first chapter of this thesis reviews features related to targeting RNA structures and to the subsequent topics of this thesis: disease-associated RNA classes, advantages and disadvantages of different RNA-binding chemistries (e.g. small molecules, peptides, engineered proteins), NMR-based methods for RNA screening and structure determination, and a future perspective on the field. Chapter 2 describes the results of my research on specialized translation initiation, whereby protein synthesis is controlled by eukaryotic initiation factor 3 (eIF3) recognizing RNA structures within the 5’-untranslated regions of certain genes to regulate translation rates of specific mRNAs. I examined this mechanism by establishing the structural basis for eIF3 recognition of the c-JUN 5’-UTR cis-regulatory element (SL1). SAXS modeling and NMR structure determination identified similarities to the way eIF3 recognizes RNA motifs within internal ribosomal entry sites (IRES) in the Hepatitis C Virus (HCV) RNA, suggesting mechanistic similarities. This work establishes RNA structural features involved in c-JUN specialized translation initiation and provides a foundation to search for small molecules inhibitors of aberrant expression of the proto-oncogenic c-JUN protein. Chapter 3 reviews strategies for designing cyclic β-hairpin peptidomimetics targeting pharmaceutically relevant structured RNAs such as HIV-TAR and pre-microRNA-21 (pre-miR-21). This rational is built into several pre-microRNA targeting projects discussed in chapter 4, where I describe the development of a pre-miR-21 processing assay to characterize inhibitors ranging from cyclic peptides to engineered RNA-binding motifs (RRM*). My results demonstrate that many cyclic peptides disrupt efficient pre-miR-21 processing, as demonstrated by the formation of novel reaction intermediates only produced in the presence of cyclic peptide inhibitors