Matching Items (129)
Description
The majority of chronic myeloid leukemia (CML) and some of acute lymphocytic leukemia (ALL) cases are associated with possessing the BCR-Abl fusion protein from an oncogenic translocation, resulting in a constantly active form of Abl and rapid proliferation. CML and ALL cells that possess the BCR-Abl fusion protein are known as Philadelphia chromosome positive (Ph+). Currently, Imatinib (selective Abl inhibitor) is used as therapy against CML and ALL. However, some patients may have malignancies which show resistance to Imatinib. Previous work displays that the transformation of progenitor B cells with the v-Abl oncogene of Abelson murine leukemia virus results in cell cycle progression, rapid proliferation, and potentially malignant transformation while preventing any further differentiation. Progenitor B cells transformed with the temperature-sensitive form of the v-Abl oncogene have served as a model to study cellular response to Imatinib treatment. After some manipulation, very few cells were forced to progress to malignancy, forming tumor in vivo. These cells were no long sensitive to v-Abl inactivation, resembling the Imatinib resistant ALL. Autophagy is the process by which proteins and organelles are broken-down and recycled within the eukaryotic cell and has been hypothesized to play a part in cancer cell survival and drug-resistance. LC3 processing is a widely accepted marker of autophagy induction and progression. It has also been shown that Imatinib treatment of Ph+ leukemia can induce autophagy. In this study, we examined the autophagy induction in response to v-Abl inactivation in a Ph+-B-ALL cell model that shows resistance to Imatinib. In particular, we wonder whether the tumor cell line resistant to v-Abl inactivation may acquire a high level of autophagy to become resistant to apoptosis induced by v-Abl inactivation, and thus become addicted to autophagy. Indeed, this tumor cell line displays a high basal levels of LC3 I and II expression, regardless of v-Abl activity. We further demonstrated that inhibition of the autophagy pathway enhances the tumor line's sensitivity to Imatinib, resulting in cell cycle arrest and massive apoptosis. The combination of autophagy and Abl inhibitions may serve as an effective therapy for BCR-Abl positive CML.
ContributorsArkus, Nohea (Author) / Chang, Yung (Thesis advisor) / Kusumi, Kenro (Committee member) / Lake, Douglas (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2011
Description
Nonlinear dispersive equations model nonlinear waves in a wide range of physical and mathematics contexts. They reinforce or dissipate effects of linear dispersion and nonlinear interactions, and thus, may be of a focusing or defocusing nature. The nonlinear Schrödinger equation or NLS is an example of such equations. It appears as a model in hydrodynamics, nonlinear optics, quantum condensates, heat pulses in solids and various other nonlinear instability phenomena. In mathematics, one of the interests is to look at the wave interaction: waves propagation with different speeds and/or different directions produces either small perturbations comparable with linear behavior, or creates solitary waves, or even leads to singular solutions. This dissertation studies the global behavior of finite energy solutions to the $d$-dimensional focusing NLS equation, $i partial _t u+Delta u+ |u|^{p-1}u=0, $ with initial data $u_0in H^1,; x in Rn$; the nonlinearity power $p$ and the dimension $d$ are chosen so that the scaling index $s=frac{d}{2}-frac{2}{p-1}$ is between 0 and 1, thus, the NLS is mass-supercritical $(s>0)$ and energy-subcritical $(s<1).$ For solutions with $ME[u_0]<1$ ($ME[u_0]$ stands for an invariant and conserved quantity in terms of the mass and energy of $u_0$), a sharp threshold for scattering and blowup is given. Namely, if the renormalized gradient $g_u$ of a solution $u$ to NLS is initially less than 1, i.e., $g_u(0)<1,$ then the solution exists globally in time and scatters in $H^1$ (approaches some linear Schr"odinger evolution as $ttopminfty$); if the renormalized gradient $g_u(0)>1,$ then the solution exhibits a blowup behavior, that is, either a finite time blowup occurs, or there is a divergence of $H^1$ norm in infinite time. This work generalizes the results for the 3d cubic NLS obtained in a series of papers by Holmer-Roudenko and Duyckaerts-Holmer-Roudenko with the key ingredients, the concentration compactness and localized variance, developed in the context of the energy-critical NLS and Nonlinear Wave equations by Kenig and Merle. One of the difficulties is fractional powers of nonlinearities which are overcome by considering Besov-Strichartz estimates and various fractional differentiation rules.
ContributorsGuevara, Cristi Darley (Author) / Roudenko, Svetlana (Thesis advisor) / Castillo_Chavez, Carlos (Committee member) / Jones, Donald (Committee member) / Mahalov, Alex (Committee member) / Suslov, Sergei (Committee member) / Arizona State University (Publisher)
Created2011
Description
Surveys have shown that several hundred billion weather forecasts are obtained by the United States public each year, and that weather news is one of the most consumed topics in the media. This indicates that the forecast provides information that is significant to the public, and that the public utilizes details associated with it to inform aspects of their life. Phoenix, Arizona is a dry, desert region that experiences a monsoon season and extreme heat. How then, does the weather forecast influence the way Phoenix residents make decisions? This paper aims to draw connections between the weather forecast, decision making, and people who live in a desert environment. To do this, a ten-minute survey was deployed through Amazon Mechanical Turk (MTurk) in which 379 respondents were targeted. The survey asks 45 multiple choice and ranking questions categorized into four sections: obtainment of the forecast, forecast variables of interest, informed decision making based on unique weather variables, and demographics. This research illuminates how residents in the Phoenix metropolitan area use the local weather forecast for decision-making on daily activities, and the main meteorological factors that drive those decisions.
ContributorsMarturano, Julia (Author) / Middel, Ariane (Thesis director) / Schneider, Florian (Committee member) / School of Geographical Sciences and Urban Planning (Contributor, Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Infertility has become an increasing problem in developed countries and in many cases can be attributed to compromised sperm quality. Assessment of male fertility typically utilizes semen analysis which mainly examines sperm morphology, however many males whose sperm appear normal are sub- or infertile, suggesting that sperm from these males may be deficient in a protein or suite of proteins. To date, very little is known about the composition of sperm or the complex maturation process that confers motility and fertilization competency to sperm. Chapter 1 discusses the use of whole cell mass spectrometry to identify 1247 proteins comprising the Rhesus macaque (Macaca mulatta) sperm proteome, a commonly used model of human reproduction. This study provides a more robust proxy of human sperm composition than was previously available and facilitates studies of sperm using the rhesus macaque as a model. Chapters 2 & 3 provide a systems level overview of changes in sperm proteome composition that occurs during epididymal transit. Chapter 2 reports the proteomes of sperm collected from the caput, corpus and cauda segments of the mouse epididymis, identifying 1536, 1720 and 1234 proteins respectively. Chapter 3 reports the sperm proteome from four distinct segments of the Rhesus macaque epididymis, including the caput, proximal corpus, distal corpus and cauda, identifying 1951, 2014, 1764 and 1423 proteins respectively. These studies identify a number of proteins that are added and removed from sperm during epididymal transit which likely play an important role in the sperm maturation process. To date no comparative evolutionary studies of sperm proteomes have been undertaken. Chapter 4 compares four mammalian sperm proteomes including the human, macaque, mouse and rat. This study identified 98 proteins common to all four sperm proteomes, 82 primate and 90 rodent lineage-specific proteins and 494, 467, 566, and 193 species specific proteins in the human, macaque, mouse and rat sperm proteomes respectively and discusses how differences in sperm composition may ultimately lead to functional differences across species. Finally, chapter 5 uses sperm proteome data to inform the preliminary design of a rodent contraceptive vaccine delivered orally using recombinant attenuated Salmonella vaccine vectors.
ContributorsSkerget, Sheri Jo (Author) / Karr, Timothy L. (Thesis advisor) / Lake, Douglas (Committee member) / Petritis, Konstantinos (Committee member) / Arizona State University (Publisher)
Created2013
Description
This thesis outlines the development of a vector retrieval technique, based on data assimilation, for a coherent Doppler LIDAR (Light Detection and Ranging). A detailed analysis of the Optimal Interpolation (OI) technique for vector retrieval is presented. Through several modifications to the OI technique, it is shown that the modified technique results in significant improvement in velocity retrieval accuracy. These modifications include changes to innovation covariance portioning, covariance binning, and analysis increment calculation. It is observed that the modified technique is able to make retrievals with better accuracy, preserves local information better, and compares well with tower measurements. In order to study the error of representativeness and vector retrieval error, a lidar simulator was constructed. Using the lidar simulator a thorough sensitivity analysis of the lidar measurement process and vector retrieval is carried out. The error of representativeness as a function of scales of motion and sensitivity of vector retrieval to look angle is quantified. Using the modified OI technique, study of nocturnal flow in Owens' Valley, CA was carried out to identify and understand uncharacteristic events on the night of March 27th 2006. Observations from 1030 UTC to 1230 UTC (0230 hr local time to 0430 hr local time) on March 27 2006 are presented. Lidar observations show complex and uncharacteristic flows such as sudden bursts of westerly cross-valley wind mixing with the dominant up-valley wind. Model results from Coupled Ocean/Atmosphere Mesoscale Prediction System (COAMPS®) and other in-situ instrumentations are used to corroborate and complement these observations. The modified OI technique is used to identify uncharacteristic and extreme flow events at a wind development site. Estimates of turbulence and shear from this technique are compared to tower measurements. A formulation for equivalent wind speed in the presence of variations in wind speed and direction, combined with shear is developed and used to determine wind energy content in presence of turbulence.
ContributorsChoukulkar, Aditya (Author) / Calhoun, Ronald (Thesis advisor) / Mahalov, Alex (Committee member) / Kostelich, Eric (Committee member) / Huang, Huei-Ping (Committee member) / Phelan, Patrick (Committee member) / Arizona State University (Publisher)
Created2013
Description
Coccidioidomycosis, also known as Valley Fever, is a disease caused by the dimorphic soil-dwelling fungus, Coccidioides sp. Coccidioidomycosis is difficult to diagnose because symptoms are similar to community-acquired pneumonia. Current diagnostic tests rely on antibody responses, but immune responses can be delayed and aberrant, resulting in false negative diagnoses. Unlike serology, detection of coccidioidal proteins or other fungal components in blood could distinguish valley fever from other pulmonary infections and provide a definitive diagnosis. Using mass spectrometry (LC-MS/MS) we examined the plasma peptidome from patients with serologically confirmed coccidioidomycosis. Mass spectra were searched using the protein database from the Coccidioides species, generated and annotated by the Broad Institute. 15 of 20 patients with serologically confirmed coccidioidomycosis demonstrated the presence of a peptide in plasma, "PGLDSKSLACTFSQV" (PGLD). The peptide is derived from an open reading frame from a "conserved hypothetical protein" annotated with 2 exons, and to date, found only in the C. posadasii strain Silviera RMSCC 3488 genomic sequence. In this thesis work, cDNA sequence analysis from polyadenylated RNA confirms the peptide sequence and genomic location of the peptide, but does not indicate that the intron in the gene prediction of C. posadasii strain Silviera RMSCC 3488 is present. A monoclonal antibody generated against the peptide bound to a 16kDa protein in T27K coccidioidal lysate. Detecting components of the fungus plasma could be a useful diagnostic tool, especially when serology does not provide a definitive diagnosis.
ContributorsDuffy, Stacy Leigh (Author) / Lake, Douglas (Thesis advisor) / Magee, Dewey Mitch (Committee member) / Antwi, Kwasi (Committee member) / Arizona State University (Publisher)
Created2013
Description
This dissertation investigates the condition of skeletal muscle insulin resistance using bioinformatics and computational biology approaches. Drawing from several studies and numerous data sources, I have attempted to uncover molecular mechanisms at multiple levels. From the detailed atomistic simulations of a single protein, to datamining approaches applied at the systems biology level, I provide new targets to explore for the research community. Furthermore I present a new online web resource that unifies various bioinformatics databases to enable discovery of relevant features in 3D protein structures.
ContributorsMielke, Clinton (Author) / Mandarino, Lawrence (Committee member) / LaBaer, Joshua (Committee member) / Magee, D. Mitchell (Committee member) / Dinu, Valentin (Committee member) / Willis, Wayne (Committee member) / Arizona State University (Publisher)
Created2013
Description
While exercising mammalian muscle increasingly relies on carbohydrates for fuel as aerobic exercise intensity rises above the moderate range, flying birds are extraordinary endurance athletes and fuel flight, a moderate-high intensity exercise, almost exclusively with lipid. In addition, Aves have long lifespans compared to weight-matched mammals. As skeletal muscle mitochondria account for the majority of oxygen consumption during aerobic exercise, the primary goal was to investigate differences in isolated muscle mitochondria between these species and to examine to what extent factors intrinsic to mitochondria may account for the behavior observed in the intact tissue and whole organism. First, maximal enzyme activities were assessed in sparrow and rat mitochondria. Citrate synthase and aspartate aminotransferase activity were higher in sparrow compared to rat mitochondria, while glutamate dehydrogenase activity was lower. Sparrow mitochondrial NAD-linked isocitrate dehydrogenase activity was dependent on phosphate, unlike the mammalian enzyme. Next, the rate of oxygen consumption (JO), electron transport chain (ETC) activity, and reactive oxygen species (ROS) production were assessed in intact mitochondria. Maximal rates of fat oxidation were lower than for carbohydrate in rat but not sparrow mitochondria. ETC activity was higher in sparrows, but no differences were found in ROS production between species. Finally, fuel selection and control of respiration at three rates between rest and maximum were assessed. Mitochondrial fuel oxidation and selection mirrored that of the whole body; in rat mitochondria the reliance on carbohydrate increased as the rate of oxygen consumption increased, whereas fat dominated under all conditions in the sparrow. These data indicate fuel selection, at least in part, can be modulated at the level of the mitochondrial matrix when multiple substrates are present at saturating levels. As an increase in matrix oxidation-reduction potential has been linked to a suppression of fat oxidation and high ROS production, the high ETC activity relative to dehydrogenase activity in avian compared to mammalian mitochondria may result in lower matrix oxidation-reduction potential, allowing fatty acid oxidation to proceed while also resulting in low ROS production in vivo.
ContributorsKuzmiak, Sarah (Author) / Willis, Wayne T (Thesis advisor) / Mandarino, Lawrence (Committee member) / Sweazea, Karen (Committee member) / Harrison, Jon (Committee member) / Gadau, Juergen (Committee member) / Arizona State University (Publisher)
Created2012
Description
It is possible in a properly controlled environment, such as industrial metrology, to make significant headway into the non-industrial constraints on image-based position measurement using the techniques of image registration and achieve repeatable feature measurements on the order of 0.3% of a pixel, or about an order of magnitude improvement on conventional real-world performance. These measurements are then used as inputs for a model optimal, model agnostic, smoothing for calibration of a laser scribe and online tracking of velocimeter using video input. Using appropriate smooth interpolation to increase effective sample density can reduce uncertainty and improve estimates. Use of the proper negative offset of the template function has the result of creating a convolution with higher local curvature than either template of target function which allows improved center-finding. Using the Akaike Information Criterion with a smoothing spline function it is possible to perform a model-optimal smooth on scalar measurements without knowing the underlying model and to determine the function describing the uncertainty in that optimal smooth. An example of empiric derivation of the parameters for a rudimentary Kalman Filter from this is then provided, and tested. Using the techniques of Exploratory Data Analysis and the "Formulize" genetic algorithm tool to convert the spline models into more accessible analytic forms resulted in stable, properly generalized, KF with performance and simplicity that exceeds "textbook" implementations thereof. Validation of the measurement includes that, in analytic case, it led to arbitrary precision in measurement of feature; in reasonable test case using the methods proposed, a reasonable and consistent maximum error of around 0.3% the length of a pixel was achieved and in practice using pixels that were 700nm in size feature position was located to within ± 2 nm. Robust applicability is demonstrated by the measurement of indicator position for a King model 2-32-G-042 rotameter.
ContributorsMunroe, Michael R (Author) / Phelan, Patrick (Thesis advisor) / Kostelich, Eric (Committee member) / Mahalov, Alex (Committee member) / Arizona State University (Publisher)
Created2012
Description
Background: Coccidioidomycosis (Valley Fever) is a respiratory disease that is caused by the soil-dwelling fungi Coccidioides immitis and Coccidioides posadasii. Because fungal glycosylation patterns are distinct from mammalian glycosylation patterns, we hypothesized that certain lectins (carbohydrate-binding proteins) might have differential binding properties to coccidioidal glycoproteins, and therefore serve as a tool for the purification and characterization of these glycoproteins from patient specimens. Materials and Methods: To identify potential Coccidioides-binding lectins, lectin-based immunohistochemistry was performed using a panel of 21 lectins on lung tissue from human patients infected with Coccidioides. Enzyme-Linked Immunosorbent Assays (ELISAs) were used to confirm and test candidate Coccidioides-binding lectins for their ability to bind to proteins from antigen preparations of laboratory-grown Coccidioides. Inhibition IHC and ELISAs were used to confirm binding properties of these lectins. SDS-PAGE and mass spectrometry were performed on eluates from coccidioidal antigen preparations run through lectin-affinity chromatography columns to characterize and identify lectin-binding coccidioidal glycoproteins. Results: Two GlcNAc-binding lectins, GSLII and sWGA, bound specifically to spherules and endospores in infected human lung tissue, and not to adjacent lung tissue. The binding of these lectins to both Coccidioides proteins in lung tissue and to coccidioidal antigen preparations was confirmed to have lectin-like characteristics. SDS-PAGE analysis of eluates from lectin-affinity chromatography demonstrated that GSLII and sWGA bind to coccidioidal glycoproteins. Mass spectrometric identification of the top ten lectin affinity-purified glycoproteins demonstrated that GSLII and sWGA share affinity to a common set of coccidioidal glycoproteins. Conclusion: This is the first report of lectins that bind specifically to Coccidioides spherules and endospores in infected humans. These lectins may have the potential to serve as tools for a better method of detection and diagnosis of Valley Fever.
ContributorsChowdhury, Yasmynn (Author) / Lake, Douglas (Thesis director) / Grys, Thomas (Committee member) / Magee, Mitchell (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor)
Created2015-05