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Telomerase ribonucleoprotein is a unique reverse transcriptase that adds telomeric DNA repeats to chromosome ends. Telomerase RNA (TER) is extremely divergent in size, sequence and has to date only been identified in vertebrate, yeast, ciliate and plant species. Herein, the identification and characterization of TERs from an evolutionarily distinct group, filamentous fungi, is presented. Based on phylogenetic analysis of 69 TER sequences and mutagenesis analysis of in vitro reconstituted Neurospora telomerase, we discovered a conserved functional core in filamentous fungal TERs sharing homologous structural features with vertebrate TERs. This core contains the template-pseudoknot and P6/P6.1 domains, essential for enzymatic activity, which retain function in trans. The in vitro reconstituted Neurospora telomerase is highly processive, synthesizing canonical TTAGGG repeats. Similar to Schizosaccharomycetes pombe, filamentous fungal TERs utilize the spliceosomal splicing machinery for 3' processing. Neurospora telomerase, while associating with the Est1 protein in vivo, does not bind homologous Ku or Sm proteins found in both budding and fission yeast telomerase holoenzyme, suggesting a unique biogenesis pathway. The development of Neurospora as a model organism to study telomeres and telomerase may shed light upon the evolution of the canonical TTAGGG telomeric repeat and telomerase processivity within fungal species.
ContributorsQi, Xiaodong (Author) / Chen, Julian (Thesis advisor) / Ghirlanda, Giovanna (Committee member) / Chaput, John (Committee member) / Arizona State University (Publisher)
Created2011
Description
This dissertation creates models of past potential vegetation in the Southern Levant during most of the Holocene, from the beginnings of farming through the rise of urbanized civilization (12 to 2.5 ka BP). The time scale encompasses the rise and collapse of the earliest agrarian civilizations in this region. The archaeological record suggests that increases in social complexity were linked to climatic episodes (e.g., favorable climatic conditions coincide with intervals of prosperity or marked social development such as the Neolithic Revolution ca. 11.5 ka BP, the Secondary Products Revolution ca. 6 ka BP, and the Middle Bronze Age ca. 4 ka BP). The opposite can be said about periods of climatic deterioration, when settled villages were abandoned as the inhabitants returned to nomadic or semi nomadic lifestyles (e.g., abandonment of the largest Neolithic farming towns after 8 ka BP and collapse of Bronze Age towns and cities after 3.5 ka BP during the Late Bronze Age). This study develops chronologically refined models of past vegetation from 12 to 2.5 ka BP, at 500 year intervals, using GIS, remote sensing and statistical modeling tools (MAXENT) that derive from species distribution modeling. Plants are sensitive to alterations in their environment and respond accordingly. Because of this, they are valuable indicators of landscape change. An extensive database of historical and field gathered observations was created. Using this database as well as environmental variables that include temperature and precipitation surfaces for the whole study period (also at 500 year intervals), the potential vegetation of the region was modeled. Through this means, a continuous chronology of potential vegetation of the Southern Levantwas built. The produced paleo-vegetation models generally agree with the proxy records. They indicate a gradual decline of forests and expansion of steppe and desert throughout the Holocene, interrupted briefly during the Mid Holocene (ca. 4 ka BP, Middle Bronze Age). They also suggest that during the Early Holocene, forest areas were extensive, spreading into the Northern Negev. The two remaining forested areas in the Northern and Southern Plateau Region in Jordan were also connected during this time. The models also show general agreement with the major cultural developments, with forested areas either expanding or remaining stable during prosperous periods (e.g., Pre Pottery Neolithic and Middle Bronze Age), and significantly contracting during moments of instability (e.g., Late Bronze Age).
ContributorsSoto-Berelov, Mariela (Author) / Fall, Patricia L. (Thesis advisor) / Myint, Soe (Committee member) / Turner, Billie L (Committee member) / Falconer, Steven (Committee member) / Arizona State University (Publisher)
Created2011
Description
The bleomycins are a family of glycopeptide-derived antibiotics isolated from various Streptomyces species and have been the subject of much attention from the scientific community as a consequence of their antitumor activity. Bleomycin clinically and is an integral part of a number of combination chemotherapy regimens. It has previously been shown that bleomycin has the ability to selectively target tumor cells over their non-malignant counterparts. Pyrimidoblamic acid, the N-terminal metal ion binding domain of bleomycin is known to be the moiety that is responsible for O2 activation and the subsequent chemistry leading to DNA strand scission and overall antitumor activity. Chapter 1 describes bleomycin and related DNA targeting antitumor agents as well as the specific structural domains of bleomycin. Various structural analogues of pyrimidoblamic acid were synthesized and subsequently incorporated into their corresponding full deglycoBLM A6 derivatives by utilizing a solid support. Their activity was measured using a pSP64 DNA plasmid relaxation assay and is summarized in Chapter 2. The specifics of bleomycin—DNA interaction and kinetics were studied via surface plasmon resonance and are presented in Chapter 3. By utilizing carefully selected 64-nucleotide DNA hairpins with variable 16-mer regions whose sequences showed strong binding in past selection studies, a kinetic profile was obtained for several BLMs for the first time since bleomycin was discovered in 1966. The disaccharide moiety of bleomycin has been previously shown to be a specific tumor cell targeting element comprised of L-gulose-D-mannose, especially between MCF-7 (breast cancer cells) and MCF-10A ("normal" breast cells). This phenomenon was further investigated via fluorescence microscopy using multiple cancerous cell lines with matched "normal" counterparts and is fully described in Chapter 4.
ContributorsBozeman, Trevor C (Author) / Hecht, Sidney M. (Thesis advisor) / Chaput, John (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2013
Description
The health benefits of physical activity are widely accepted. Emerging research also indicates that sedentary behaviors can carry negative health consequences regardless of physical activity level. This dissertation explored four projects that examined measurement properties of physical activity and sedentary behavior monitors. Project one identified the oxygen costs of four other care activities in seventeen adults. Pushing a wheelchair and pushing a stroller were identified as moderate-intensity activities. Minutes spent engaged in these activities contribute towards meeting the 2008 Physical Activity Guidelines. Project two identified the oxygen costs of common cleaning activities in sixteen adults. Mopping a floor was identified as moderate-intensity physical activity, while cleaning a kitchen and cleaning a bathtub were identified as light-intensity physical activity. Minutes spent engaged in mopping a floor contributes towards meeting the 2008 Physical Activity Guidelines. Project three evaluated the differences in number of minutes spent in activity levels when utilizing different epoch lengths in accelerometry. A shorter epoch length (1-second, 5-seconds) accumulated significantly more minutes of sedentary behaviors than a longer epoch length (60-seconds). The longer epoch length also identified significantly more time engaged in light-intensity activities than the shorter epoch lengths. Future research needs to account for epoch length selection when conducting physical activity and sedentary behavior assessment. Project four investigated the accuracy of four activity monitors in assessing activities that were either sedentary behaviors or light-intensity physical activities. The ActiGraph GT3X+ assessed the activities least accurately, while the SenseWear Armband and ActivPAL assessed activities equally accurately. The monitor used to assess physical activity and sedentary behaviors may influence the accuracy of the measurement of a construct.
ContributorsMeckes, Nathanael (Author) / Ainsworth, Barbara E (Thesis advisor) / Belyea, Michael (Committee member) / Buman, Matthew (Committee member) / Gaesser, Glenn (Committee member) / Wharton, Christopher (Christopher Mack), 1977- (Committee member) / Arizona State University (Publisher)
Created2012
Description
Cardiovascular disease (CVD) is the number one cause of death in the United States and type 2 diabetes (T2D) and obesity lead to cardiovascular disease. Obese adults are more susceptible to CVD compared to their non-obese counterparts. Exercise training leads to large reductions in the risk of CVD and T2D. Recent evidence suggests high-intensity interval training (HIT) may yield similar or superior benefits in a shorter amount of time compared to traditional continuous exercise training. The purpose of this study was to compare the effects of HIT to continuous (CONT) exercise training for the improvement of endothelial function, glucose control, and visceral adipose tissue. Seventeen obese men (N=9) and women (N=8) were randomized to eight weeks of either HIT (N=9, age=34 years, BMI=37.6 kg/m2) or CONT (N=8, age=34 years, BMI=34.6 kg/m2) exercise 3 days/week for 8 weeks. Endothelial function was assessed via flow-mediated dilation (FMD), glucose control was assessed via continuous glucose monitoring (CGM), and visceral adipose tissue and body composition was measured with an iDXA. Incremental exercise testing was performed at baseline, 4 weeks, and 8 weeks. There were no changes in weight, fat mass, or visceral adipose tissue measured by the iDXA, but there was a significant reduction in body fat that did not differ by group (46±6.3 to 45.4±6.6%, P=0.025). HIT led to a significantly greater improvement in FMD compared to CONT exercise (HIT: 5.1 to 9.0%; CONT: 5.0 to 2.6%, P=0.006). Average 24-hour glucose was not improved over the whole group and there were no group x time interactions for CGM data (HIT: 103.9 to 98.2 mg/dl; CONT: 99.9 to 100.2 mg/dl, P>0.05). When statistical analysis included only the subjects who started with an average glucose at baseline > 100 mg/dl, there was a significant improvement in glucose control overall, but no group x time interaction (107.8 to 94.2 mg/dl, P=0.027). Eight weeks of HIT led to superior improvements in endothelial function and similar improvements in glucose control in obese subjects at risk for T2D and CVD. HIT was shown to have comparable or superior health benefits in this obese sample with a 36% lower total exercise time commitment.
ContributorsSawyer, Brandon J (Author) / Gaesser, Glenn A (Thesis advisor) / Shaibi, Gabriel (Committee member) / Lee, Chong (Committee member) / Swan, Pamela (Committee member) / Buman, Matthew (Committee member) / Arizona State University (Publisher)
Created2013
Description
Purpose: The purpose of this study was to examine the acute effects of two novel intermittent exercise prescriptions on glucose regulation and ambulatory blood pressure. Methods: Ten subjects (5 men and 5 women, ages 31.5 ± 5.42 yr, height 170.38 ± 9.69 cm and weight 88.59 ± 18.91 kg) participated in this four-treatment crossover trial. All subjects participated in four trials, each taking place over three days. On the evening of the first day, subjects were fitted with a continuous glucose monitor (CGM). On the second day, subjects were fitted with an ambulatory blood pressure monitor (ABP) and underwent one of the following four conditions in a randomized order: 1) 30-min: 30 minutes of continuous exercise at 60 - 70% VO2peak; 2) Mod 2-min: twenty-one 2-min bouts of walking at 3 mph performed once every 20 minutes; 3) HI 2-min: eight 2-min bouts of walking at maximal incline performed once every hour; 4) Control: a no exercise control condition. On the morning of the third day, the CGM and ABP devices were removed. All meals were standardized during the study visits. Linear mixed models were used to compare mean differences in glucose and blood pressure regulation between the four trials. Results: Glucose concentrations were significantly lower following the 30-min (91.1 ± 14.9 mg/dl), Mod 2-min (93.7 ± 19.8 mg/dl) and HI 2-min (96.1 ± 16.4 mg/dl) trials as compared to the Control (101.1 ± 20 mg/dl) (P < 0.001 for all three comparisons). The 30-min trial was superior to the Mod 2-min, which was superior to the HI 2-min trial in lowering blood glucose levels (P < 0.001 and P = 0.003 respectively). Only the 30-min trial was effective in lowering systolic ABP (124 ± 12 mmHg) as compared to the Control trial (127 ± 14 mmHg; P < 0.001) for up to 11 hours post exercise. Conclusion: Performing frequent short (i.e., 2 minutes) bouts of moderate or high intensity exercise may be a viable alternative to traditional continuous exercise in improving glucose regulation. However, 2-min bouts of exercise are not effective in reducing ambulatory blood pressure in healthy adults.
ContributorsBhammar, Dharini Mukeshkumar (Author) / Gaesser, Glenn A (Thesis advisor) / Shaibi, Gabriel (Committee member) / Buman, Matthew (Committee member) / Swan, Pamela (Committee member) / Lee, Chong (Committee member) / Arizona State University (Publisher)
Created2013
Description
Surface plasmon resonance (SPR) has emerged as a popular technique for elucidating subtle signals from biological events in a label-free, high throughput environment. The efficacy of conventional SPR sensors, whose signals are mass-sensitive, diminishes rapidly with the size of the observed target molecules. The following work advances the current SPR sensor paradigm for the purpose of small molecule detection. The detection limits of two orthogonal components of SPR measurement are targeted: speed and sensitivity. In the context of this report, speed refers to the dynamic range of measured kinetic rate constants, while sensitivity refers to the target molecule mass limitation of conventional SPR measurement. A simple device for high-speed microfluidic delivery of liquid samples to a sensor surface is presented to address the temporal limitations of conventional SPR measurement. The time scale of buffer/sample switching is on the order of milliseconds, thereby minimizing the opportunity for sample plug dispersion. The high rates of mass transport to and from the central microfluidic sensing region allow for SPR-based kinetic analysis of binding events with dissociation rate constants (kd) up to 130 s-1. The required sample volume is only 1 μL, allowing for minimal sample consumption during high-speed kinetic binding measurement. Charge-based detection of small molecules is demonstrated by plasmonic-based electrochemical impedance microscopy (P-EIM). The dependence of surface plasmon resonance (SPR) on surface charge density is used to detect small molecules (60-120 Da) printed on a dextran-modified sensor surface. The SPR response to an applied ac potential is a function of the surface charge density. This optical signal is comprised of a dc and an ac component, and is measured with high spatial resolution. The amplitude and phase of local surface impedance is provided by the ac component. The phase signal of the small molecules is a function of their charge status, which is manipulated by the pH of a solution. This technique is used to detect and distinguish small molecules based on their charge status, thereby circumventing the mass limitation (~100 Da) of conventional SPR measurement.
ContributorsMacGriff, Christopher Assiff (Author) / Tao, Nongjian (Thesis advisor) / Wang, Shaopeng (Committee member) / LaBaer, Joshua (Committee member) / Chae, Junseok (Committee member) / Arizona State University (Publisher)
Created2013
Description
Two critical limitations for hyperspatial imagery are higher imagery variances and large data sizes. Although object-based analyses with a multi-scale framework for diverse object sizes are the solution, more data sources and large amounts of testing at high costs are required. In this study, I used tree density segmentation as the key element of a three-level hierarchical vegetation framework for reducing those costs, and a three-step procedure was used to evaluate its effects. A two-step procedure, which involved environmental stratifications and the random walker algorithm, was used for tree density segmentation. I determined whether variation in tone and texture could be reduced within environmental strata, and whether tree density segmentations could be labeled by species associations. At the final level, two tree density segmentations were partitioned into smaller subsets using eCognition in order to label individual species or tree stands in two test areas of two tree densities, and the Z values of Moran's I were used to evaluate whether imagery objects have different mean values from near segmentations as a measure of segmentation accuracy. The two-step procedure was able to delineating tree density segments and label species types robustly, compared to previous hierarchical frameworks. However, eCognition was not able to produce detailed, reasonable image objects with optimal scale parameters for species labeling. This hierarchical vegetation framework is applicable for fine-scale, time-series vegetation mapping to develop baseline data for evaluating climate change impacts on vegetation at low cost using widely available data and a personal laptop.
ContributorsLiau, Yan-ting (Author) / Franklin, Janet (Thesis advisor) / Turner, Billie (Committee member) / Myint, Soe (Committee member) / Arizona State University (Publisher)
Created2013
Description
The purpose of this pilot randomized control trial was to test the initial efficacy of a 10 week social cognitive theory (SCT)-based intervention to reduce workplace sitting time (ST). Participants were currently employed adults with predominantly sedentary occupations (n=24) working in the Greater Phoenix area in 2012-2013. Participants wore an activPAL (AP) inclinometer to assess postural allocation (i.e., sitting vs. standing) and Actigraph accelerometer (AG) to assess sedentary time for one week prior to beginning and immediately following the completion of the 10 week intervention. Self-reported measures of sedentary time were obtained via two validated questionnaires for overall (International Physical Activity Questionnaire [IPAQ]) and domain specific sedentary behaviors (Sedentary Behavior Questionnaire [SBQ]). SCT constructs were also measured pre and post via adapted physical activity questionnaires. Participants were randomly assigned to receive either (a) 10 weekly social cognitive-based e-newsletters focused on reducing workplace ST; or (b) similarly formatted 10 weekly e-newsletters focusing on health education. Baseline adjusted Analysis of Covariance statistical analyses were used to examine differences between groups in time spent sitting (AP) and sedentary (AG) during self-reported work hours from pre- to post- intervention. Both groups decreased ST and AG sedentary time; however, no significant differences were observed. SCT constructs also did not change significantly between pretest and post test in either group. These results indicate that individualized educational approaches to decreasing workplace sitting time may not be sufficient for observing long term change in behaviors. Future research should utilize a larger sample, measure main outcomes more frequently, and incorporate more environmental factors throughout the intervention.
ContributorsGordon, Amanda (Author) / Buman, Matthew (Thesis advisor) / Der Ananian, Cheryl (Committee member) / Swan, Pamela (Committee member) / Arizona State University (Publisher)
Created2013
Description
INTRODUCTION: Exercise performed at moderate to vigorous intensities has been shown to generate a post exercise hypotensive response. Whether this response is observed with very low exercise intensities is unclear. PURPOSE: To compare post physical activity ambulatory blood pressure (ABP) response to a single worksite walking day and a normal sedentary work day in pre-hypertensive adults. METHODS: Participants were 7 pre-hypertensive (127 + 8 mmHg / 83 + 8 mmHg) adults (3 male, 4 female, age = 42 + 12 yr) who participated in a randomized, cross-over study that included a control and a walking treatment. Only those who indicated regularly sitting at least 8 hours/day and no structured physical activity were enrolled. Treatment days were randomly assigned and were performed one week apart. Walking treatment consisted of periodically increasing walk time up to 2.5 hours over the course of an 8 hour work day on a walking workstation (Steelcase Company, Grand Rapids, MI). Walk speed was set at 1 mph. Participants wore an ambulatory blood pressure cuff (Oscar 2, SunTech Medical, Morrisville, NC) for 24-hours on both treatment days. Participants maintained normal daily activities on the control day. ABP data collected from 9:00 am until 10:00 pm of the same day were included in statistical analyses. Linear mixed models were used to detect differences in systolic (SBP) and diastolic blood pressure (DBP) by treatment condition over the whole day and post workday for the time periods between 4 -10 pm when participants were no longer at work. RESULTS:BP was significantly lower in response to the walking treatment compared to the control day (Mean SBP 126 +7 mmHg vs.124 +7 mmHg, p=.043; DBP 80 + 3 mmHg vs. 77 + 3 mmHg, p = 0.001 respectively). Post workday (4:00 to 10:00 pm) SBP decreased 3 mmHg (p=.017) and DBP decreased 4 mmHg (p<.001) following walking. CONCLUSION: Even low intensity exercise such as walking on a walking workstation is effective for significantly reducing acute BP when compared to a normal work day.
ContributorsZeigler, Zachary (Author) / Swan, Pamela (Thesis advisor) / Buman, Matthew (Committee member) / Gaesser, Glenn (Committee member) / Arizona State University (Publisher)
Created2013