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Inflammation is part of the body’s response to invading pathogens, injury, and a wide range of diseases. Although inflammation is paramount to maintain a healthy immune system, unregulated inflammation can aggravate chronic conditions or cause severe, acute pathologies. Pyroptosis, a caspase-1-dependent, pro-inflammatory cell death that results in the release of IL-1β and IL-18, has been implicated in propagating an inflammatory response in the body. Pyroptosis has been shown to result from the activation of the NLRP3 inflammasome. Furthermore, multiple reports have demonstrated that intracellular potassium efflux and spleen tyrosine kinase (Syk) activity are both essential for facilitating the assembly of the NLRP3 inflammasome and proper processing and release of IL-1β and IL-18. The focus of this thesis was to determine the relationship between intracellular potassium efflux and Syk during key regulatory events in the activation of the NLRP3 inflammasome by identifying their effect on pro-inflammatory cytokine release, inflammasome assembly, mitochondrial reactive oxygen species (mROS) generation, and cell death. Both inhibiting potassium efflux from occurring and deactivating Syk significantly reduced the amount of pro-inflammatory cytokine released (70-100% reduction), the number of inflammasomes assembled (60-80% reduction), the amount of mROS generation, and the quantity of cell death (50-90% reduction). Moreover, it was discovered that potassium efflux was required for Syk activation, but Syk activation had no effect on potassium efflux. Their relationship proved to be unidirectional. This study provides the first demonstration of ion flux-dependent regulation of kinase activation in the NLRP3 inflammasome pathway and provides support for targeting ion regulation mechanisms and Syk kinase activity to manipulate macrophage-mediate inflammatory processes.
ContributorsRao, Mounica Yarlagadda (Author) / Meldrum, Deirdre R. (Thesis director) / Ankeny, Casey (Committee member) / Glenn, Honor (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2015-05
Description
A major goal of the Center for Biosignatures Discovery Automation (CBDA) is to design a diagnostic tool that detects novel cancer biosignatures at the single-cell level. We designed the Single-cell QUantitative In situ Reverse Transcription-Polymerase Chain Reaction (SQUIRT-PCR) system by combining a two-photon laser lysis (2PLL) system with a microfluidic reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) platform. It is important to identify early molecular changes from intact tissues as prognosis for premalignant conditions and develop new molecular targets for prevention of cancer progression and improved therapies. This project analyzes RNA expression at the single-cell level and presents itself with two major challenges: (1) detecting low levels of RNA and (2) minimizing RNA absorption in the polydimethylsiloxane (PDMS) microfluidic channel. The first challenge was overcome by successfully detecting picogram (pg) levels of RNA using the Fluidigm (FD) BioMark™ HD System (Fluidigm Corporation, South San Francisco, CA) for RT-qPCR analysis. This technology incorporates a highly precise integrated fluidic circuit (IFC) that allows for high-throughput genetic screening using microarrays. The second challenge entailed collecting data from RNA flow-through samples that were passed through microfluidic channels. One channel was treated with a coating of polyethylene glycol (PEG) and the other remained untreated. Various flow-through samples were subjected to RT-qPCR and analyzed using the FD FLEXsix™ Gene Expression IFC. As predicted, the results showed that the treated PDMS channel absorbed less RNA than the untreated PDMS channel. Once the optimization of the PDMS microfluidic platform is complete, it will be implemented into the 2PLL system. This novel technology will be able to identify cell populations in situ and could have a large impact on cancer diagnostics.
ContributorsBlatt, Amy Elissa (Author) / Meldrum, Deirdre R. (Thesis director) / Tran, Thai (Committee member) / Chao, Joseph (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
Intracranial aneurysms are blood \u2014filled sacs along the blood vessels in the brain. These aneurysms can be particularly dangerous due to difficulty in detection and potential lifethreatening outcome. When these aneurysms are detected, there are few treatment options to prevent rupture, one of which is endovascular stents. By placing a stent across the parent vessel, blood flow can be diverted from the aneurysm. Reduced flow reduces the chance of rupture and promotes clotting within the aneurysm. In this study, hemodynamics in idealized basilar tip aneurysm models were investigated at three flow rates using particle imaging velocimetry (PIV). Two models were created with increasing dome size (4mm vs 6mm), and constant dome-to-neck ratio (3:2) and parent vessel contact angle to represent growing aneurysm. With the pulsatile flow, data is acquired at three separate points in the cardiac cycle. Both of the models were studied untreated, treated with Enterprise stent and treated with Pipeline stent. Enterprise stent was developed mainly for structural support while the Pipeline stent was developed as a flow diverter. Due to target functions of the stents, Enterprise stent is more porous than the Pipeline stent. Hemodynamics were studied using a stereo particle image velocimetry technique. The flow in models was characterized by neck and aneurysmal RMS velocity, neck and aneurysm kinetic energy, cross neck flow. It was found that both of the stents are capable diverting flow. Enterprise reduced aneurysmal RMS velocity in model 1 by 38.7% and in model 2 by 76.2%. Pipeline stent reduced aneurysmal RMS velocity in model 1 by 71.4% and in model 2 by 88.1%. Both reductions are data for 3ml/s at peak systole pulsatile flow. Data shows that the Pipeline stent is better than Enterprise stent at reducing flow to the aneurysm.
ContributorsChung, Hanseung (Author) / Frakes, David (Thesis director) / Caplan, Michael (Committee member) / Babiker, Haithem (Committee member) / Barrett, The Honors College (Contributor) / Economics Program in CLAS (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
The goal of this project was to explore biomimetics by creating a jellyfish flying device that uses propulsion of air to levitate while utilizing electromyography signals and infrared signals as mechanisms to control the device. Completing this project would require knowledge of biological signals, electrical circuits, computer programming, and physics to accomplish. An EMG sensor was used to obtain processed electrical signals produced from the muscles in the forearm and was then utilized to control the actuation speed of the tentacles. An Arduino microprocessor was used to translate the EMG signals to infrared blinking sequences which would propagate commands through a constructed circuit shield to the infrared receiver on jellyfish. The receiver will then translate the received IR sequence into actions. Then the flying device must produce enough thrust to propel the body upwards. The application of biomimetics would best test my skills as an engineer as well as provide a method of applying what I have learned over the duration of my undergraduate career.
ContributorsTsui, Jessica W (Author) / Muthuswamy, Jitteran (Thesis director) / Blain Christen, Jennifer (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
DescriptionMy main goal for my thesis is in conjunction with the research I started in the summer of 2010 regarding the creation of a TBI continuous-time sensor. Such goals include: characterizing the proteins in sensing targets while immobilized, while free in solution, and while in free solution in the blood.
ContributorsHaselwood, Brittney (Author) / LaBelle, Jeffrey (Thesis director) / Pizziconi, Vincent (Committee member) / Cook, Curtiss (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2011-12
Description
Breast and other solid tumors exhibit high and varying degrees of intra-tumor heterogeneity resulting in targeted therapy resistance and other challenges that make the management and treatment of these diseases rather difficult. Due to the presence of admixtures of non-neoplastic cells with polyclonal cell populations, it is difficult to define cancer genomes in patient samples. By isolating tumor cells from normal cells, and enriching distinct clonal populations, clinically relevant genomic aberrations that drive disease can be identified in patients in vivo. An in-depth analysis of clonal architecture and tumor heterogeneity was performed in a stage II chemoradiation-naïve breast cancer from a sixty-five year old patient. DAPI-based DNA content measurements and DNA content-based flow sorting was used to to isolate nuclei from distinct clonal populations of diploid and aneuploid tumor cells in surgical tumor samples. We combined DNA content-based flow cytometry and ploidy analysis with high-definition array comparative genomic hybridization (aCGH) and next-generation sequencing technologies to interrogate the genomes of multiple biopsies from the breast cancer. The detailed profiles of ploidy, copy number aberrations and mutations were used to recreate and map the lineages present within the tumor. The clonal analysis revealed driver events for tumor progression (a heterozygous germline BRCA2 mutation converted to homozygosity within the tumor by a copy number event and the constitutive activation of Notch and Akt signaling pathways. The highlighted approach has broad implications in the study of tumor heterogeneity by providing a unique ultra-high resolution of polyclonal tumors that can advance effective therapies and clinical management of patients with this disease.
ContributorsLaughlin, Brady Scott (Author) / Ankeny, Casey (Thesis director) / Barrett, Michael (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor) / School for the Science of Health Care Delivery (Contributor)
Created2015-05
Description
Motor behavior is prone to variable conditions and deviates further in disorders affecting the nervous system. A combination of environmental and neural factors impacts the amount of uncertainty. Although the influence of these factors on estimating endpoint positions have been examined, the role of limb configuration on endpoint variability has been mostly ignored. Characterizing the influence of arm configuration (i.e. intrinsic factors) would allow greater comprehension of sensorimotor integration and assist in interpreting exaggerated movement variability in patients. In this study, subjects were placed in a 3-D virtual reality environment and were asked to move from a starting position to one of three targets in the frontal plane with and without visual feedback of the moving limb. The alternating of visual feedback during trials increased uncertainty between the planning and execution phases. The starting limb configurations, adducted and abducted, were varied in separate blocks. Arm configurations were setup by rotating along the shoulder-hand axis to maintain endpoint position. The investigation hypothesized: 1) patterns of endpoint variability of movements would be dependent upon the starting arm configuration and 2) any differences observed would be more apparent in conditions that withheld visual feedback. The results indicated that there were differences in endpoint variability between arm configurations in both visual conditions, but differences in variability increased when visual feedback was withheld. Overall this suggests that in the presence of visual feedback, planning of movements in 3D space mostly uses coordinates that are arm configuration independent. On the other hand, without visual feedback, planning of movements in 3D space relies substantially on intrinsic coordinates.
ContributorsRahman, Qasim (Author) / Buneo, Christopher (Thesis director) / Helms Tillery, Stephen (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
The purpose of this project was to examine the viability of protein biomarkers in pre-symptomatic detection of lung cancer. Regular screening has been shown to vastly improve patient survival outcome. Lung cancer currently has the highest occurrence and mortality of all cancers and so a means of screening would be highly beneficial. In this research, the biomarker neuron-specific enolase (Enolase-2, eno2), a marker of small-cell lung cancer, was detected at varying concentrations using electrochemical impedance spectroscopy in order to develop a mathematical model of predicting protein expression based on a measured impedance value at a determined optimum frequency. The extent of protein expression would indicate the possibility of the patient having small-cell lung cancer. The optimum frequency was found to be 459 Hz, and the mathematical model to determine eno2 concentration based on impedance was found to be y = 40.246x + 719.5 with an R2 value of 0.82237. These results suggest that this approach could provide an option for the development of small-cell lung cancer screening utilizing electrochemical technology.
ContributorsEvans, William Ian (Author) / LaBelle, Jeffrey (Thesis director) / Spano, Mark (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
Cerebral aneurysms, also known as intracranial aneurysms, are sac-like lesions in the arteries of the brain that can rupture to cause subarachnoid hemorrhaging, damaging and killing brain cells. Metal coil embolization has been traditionally used to occlude and treat cerebral aneurysms to limited success, but polymer embolization has been suggested, because it can provide a greater fraction of occlusion. One such polymer with low cytotoxicity is poly(propylene glycol)diacrylate (PPODA) crosslinked via Michael-type addition with pentaerythritol tetrakis(3-mercaptopropionate) (QT). This study was performed to examine the behavior of PPODA-QT gel in vitro under pulsatile flow emulating physiological conditions. An idealized cerebral aneurysm flow model was designed based on geometries associated with an increase in rupture risk. Pressure was monitored at the apex of the aneurysm dome for varied flow rates and polymer filling fractions of 32.4, 78.2, and 100%. The results indicate that the amount of PPODA-QT deployed into the aneurysm decreases the peak-to-peak oscillation in pressure at the aneurysm wall by an inverse proportion. The 32.4 and 78.2% treatments did not significantly decrease the mean pressure applied to the aneurysm dome, but the 100% treatment greatly reduced it by diverting flow. This study indicates that the maximum filling fraction after swelling of PPODA-QT polymer should be deployed into the aneurysmal sac for treatment.
ContributorsWorkman, Christopher David (Author) / Vernon, Brent (Thesis director) / Frakes, David (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
This thesis explores the task of creating industry-based marketing materials to assist academic programs in their recruitment of high school and community college students. With consistent reductions to public university budgets there is an increasing pressure on academic programs to raise their student enrollment figures, as student count is often cited as one of the most important statistics when making budget decisions. Many academic programs are ill-equipped to perform this task, however, as their personnel are not trained as recruiters, but rather as professors and industry professionals; furthermore, the university-level recruitment staff faces the impossible task of advertising every department's recruitment message. The Del E. Webb School of Construction has embarked upon a journey to create industry-based marketing materials to aid them in their recruitment efforts. Construction management (CM) has traditionally been viewed as a technology major relegated to vocational students and those not fit for baccalaureate programs. In recent years that perception has changed, however, as the industry has become increasingly complex and CM programs actively work to recruit students. In an attempt to increase that recruitment, the Del E. Webb School has created marketing materials that are signature to the program featuring the world's most widely-used building material, concrete, to create a keepsake for prospective students. This keepsake comes in the form of concrete replicas of the new ASU Pitchfork logo. These pitchforks are small and designed to be mass produced so that they can be handed out at recruitment events either on campus or in local schools. The Del E. Webb School had previously experimented with flexible rubber molds and flowable mixtures, such that the models could be easily cast and rapidly demolded and reset for casting. There were issues, however, as those pitchforks did not meet desired level of quality and were difficult to reproduce. This thesis thus describes an experimental program examining different casting and demolding regimens in an attempt to find the optimal way to create the pitchforks on a consistent basis. Following this, an operations manual for how to create the pitchforks was created in order to ensure that successive cohorts of construction students can reproduce the pitchforks in preparation for the School's annual recruitment events.
ContributorsErnzen, John Alexander (Author) / Wiezel, Avi (Thesis director) / Rogers, James (Committee member) / Barrett, The Honors College (Contributor) / Division of Educational Leadership and Innovation (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05