ENHANCING CONSERVATION WITH HIGH RESOLUTION PRODUCTIVITY DATASETS FOR THE CONTERMINOUS UNITED STATES

Human driven alteration of the earth’s terrestrial surface is accelerating through land use changes, intensification of human activity, climate change, and other anthropogenic pressures. These changes occur at broad spatio-temporal scales, challenging our ability to effectively monitor and assess the impacts and subsequent conservation strategies. While satellite remote sensing (SRS) products enable monitoring of the earth’s terrestrial surface continuously across space and time, the practical applications for conservation and management of these products are limited. Often the processes driving ecological change occur at fine spatial resolutions and are undetectable given the resolution of available datasets. Additionally, the links between SRS data and ecologically meaningful metrics are weak. Recent advances in cloud computing technology along with the growing record of high resolution SRS data enable the development of SRS products that quantify ecologically meaningful variables at relevant scales applicable for conservation and management. The focus of my dissertation is to improve the applicability of terrestrial gross and net primary productivity (GPP/NPP) datasets for the conterminous United States (CONUS). In chapter one, I develop a framework for creating high resolution datasets of vegetation dynamics. I use the entire archive of Landsat 5, 7, and 8 surface reflectance data and a novel gap filling approach to create spatially continuous 30 m, 16-day composites of the normalized difference vegetation index (NDVI) from 1986 to 2016. In chapter two, I integrate this with other high resolution datasets and the MOD17 algorithm to create the first high resolution GPP and NPP datasets for CONUS. I demonstrate the applicability of these products for conservation and management, showing the improvements beyond currently available products. In chapter three, I utilize this dataset to evaluate the relationships between land ownership and terrestrial production across the CONUS domain. The main results of this work are three publically available datasets: 1) 30 m Landsat NDVI; 2) 250 m MODIS based GPP and NPP; and 3) 30 m Landsat based GPP and NPP. My goal is that these products prove useful for the wider scientific, conservation, and land management communities as we continue to strive for better conservation and management practices

An Idh1 Mutation Prevalent In Glioma Confers Deficient Dna Repair And Sensitivity To Parp Inhibition

High-grade gliomas (HGGs) are devastating malignancies of the central nervous system, and few treatment options are available for these tumors. In the most malignant form of the disease, glioblastoma multiforme (GBM), over 90% of patients will succumb to their tumor within 5 years after standard of care treatment, consisting of surgery, radiation therapy, and temozolomide chemotherapy. It is now clear that gliomas are molecularly heterogeneous entities, with mutations in tumor suppressors and oncogenes defining many distinct sub-types with important therapy implications. However, almost all HGGs are treated with a limited array of initial therapies, regardless of these molecular differences. Isocitrate dehydrogenase 1 (IDH1), a gene recently found to be mutated in many gliomas, is involved in the conversion of isocitrate to 2-oxoglutarate in cells. The IDH1 R132H mutant enzyme converts 2-oxoglutarate to the oncometabolite (R)-2- hydroxyglutarate (2HG), which leads to profound metabolic alterations in tumor cells. In addition, recent studies indicate that mutations in IDH1 may also induce altered DSB repair, differential sensitivities to chemo-radiotherapy, and substantial changes in chromatin modifications. Here, we present the creation of a novel HeLa cell line harboring an engineered IDH1 R132H mutation at the endogenous gene locus using CRISPR-Cas9 gene editing. We validated the cell line using a variety of biochemical and functional assays. In particular, we demonstrated that our mutant cell clones secrete high levels of 2HG, and confirmed that the levels of this oncometabolite can be suppressed with small molecule inhibitors of mutant IDH1. We then performed a focused drug screen using select small molecule inhibitors of DNA repair, leveraging our observation that IDH1 mutant cells are more sensitive to radiation. We report that IDH1-R132h confers increased sensitivity to BMN-673, a PARP inhibitor known to preferentially kill cells with decreased homologous recombination (HR) functionality. We also demonstrate synergy between BMN-673 and the platinating agent, cisplatin, that is enriched by the IDH1-R132H mutation. Finally, preliminary gene expression analysis does not identify any significant decreased expression in a panel of DNA repair-related genes, suggesting that some alternative mechanism may be responsible for the drug sensitivity effect we see. Taken together, these findings suggest that IDH1 mutant tumors may be sensitive to PARP inhibition, representing a new treatment strategy for a devastating disease

Exercise Performance and Physiological Responses: The Potential Role of Redox Imbalance

Increases in oxidative stress or decreases in antioxidant capacity, or redox imbalance, are known to alter physiological function and has been suggested to influence performance. To date, no study has sought to manipulate this balance in the same participants and observe the impact on physiological function and performance. Using a single-blind, placebo-controlled, and counterbalanced design, this study examined the effects of increasing free radicals, via hyperoxic exposure (FiO2 = 1.0), and/or increasing antioxidant capacity, through consuming an antioxidant cocktail (AOC; vitamin-C, vitamin-E, α-lipoic acid), on 5-kilometer (km) cycling time-trial performance, and the physiological and fatigue responses in healthy college-aged males. Hyperoxic exposure prior to the 5 km TT had no effect on performance, fatigue, or the physiological responses to exercise. The AOC significantly reduced average power output (222 ± 11 vs. 214 ± 12 W), increased 5 km time (516 ± 17 vs. 533 ± 18 sec), suppressed ventilation (VE; 116 ± 5 vs. 109 ± 13 L/min), despite similar oxygen consumption (VO2; 43.1 ± 0.8 vs. 44.9 ± 0.2 mL/kg per min), decreased VE/VO2 (35.9 ± 2.0 vs. 32.3 ± 1.5 L/min), reduced economy (VO2/W; 0.20 ± 0.01 vs. 0.22 ± 0.01), increased blood lactate (10 ± 0.7 vs. 11 ± 0.7 mmol), and perception of fatigue (RPE; 7.39 ± 0.4 vs. 7.60 ± 0.3) at the end of the TT, as compared to placebo (main effect, placebo vs. AOC, respectively). Our data demonstrate that prior to exercise, ingesting an AOC, but not exposure to hyperoxia, likely disrupts the delicate balance between pro- and antioxidant forces, which negatively impacts ventilation, blood lactate, economy, perception of fatigue, and performance (power output and 5 km time) in young healthy males. Thus, caution is warranted in athletes taking excess exogenous antioxidants

Rotor Fatigue Life Prediction and Design for Revolutionary Vertical Lift Concepts

Despite recent technological advancements, rotorcraft still lag behind their fixed-wing counterparts in the areas of flight safety and operating cost. Competition with fixed-wing aircraft is difficult for applications where vertical takeoff and landing (VTOL) capabilities are not required. Both must be addressed to ensure the continued competitiveness of vertical lift aircraft, especially in the context of new military and civilian rotorcraft programs such as Future Vertical Lift and urban air mobility, which will require orders-of-magnitude improvements in reliability, availability, maintainability, and cost (RAM-C) metrics. Lifecycle costs and accident rates are strongly driven by scheduled replacement or failure of flight-critical components. Rotor blades are life-limited to ensure that they are replaced before fatigue damage exceeds critical levels, but purchasing new blades is extremely costly. Despite aggressive component replacement times, fatigue failure of rotor blades continues to account for a significant proportion of inflight accidents. Fatigue damage in rotorcraft is unavoidable due to the physics of rotary-wing flight, but new engineering solutions to improve fatigue life in the rotor system could improve rotorcraft operating costs and flight safety simultaneously. Existing rotorcraft design methods treat fatigue life as a consequence, rather than a driver, of design. A literature review of rotorcraft design and fatigue design methods is conducted to identify the relevant strengths and weaknesses of traditional processes. In rotorcraft design, physics-based rotor design frameworks are focused primarily on fundamental performance analysis and do not consider secondary characteristics such as reliability or fatigue life. There is a missing link between comprehensive rotor design frameworks and conceptual design tools that prevents physics-based assessment of RAM-C metrics in the early design stages. Traditional fatigue design methods, such as the safe life methodology, which applies the Miner's rule fatigue life prediction model to rotorcraft components, are hindered by a lack of physics-based capabilities in the early design stages. An accurate fatigue life quantification may not be available until the design is frozen and prototypes are flying. These methods are strongly dependent on extrapolations built on historical fatigue data, and make use of deterministic safety factors based on organizational experience to ensure fatigue reliability, which can lead to over-engineering or unreliable predictions when applied to revolutionary vertical lift aircraft. A new preliminary fatigue design methodology is designed to address these concerns. This methodology is based on the traditional safe life methodology, but replaces several key elements with modern tools, techniques, and models. Three research questions are proposed to investigate, refine, and validate different elements of the methodology. The first research question addresses the need to derive physics-based fatigue load spectra more rapidly than modern comprehensive analysis tools allow. The second investigates the application of different probabilistic reliability solution methods to the fatigue life substantiation problem. The third question tests the ability of the preliminary fatigue design methodology to evaluate the relative impact of common preliminary fatigue design variables on the probability of fatigue failure of a conceptual helicopter's rotor blade. Hypotheses are formulated in response to each research question, and a series of experiments are designed to test those hypotheses. In the first experiment, a multi-disciplinary analysis (MDA) environment combining the rotorcraft performance code NDARC, the comprehensive code RCAS, and the beam analysis program VABS, is developed to provide accurate physics-based predictions of rotor blade stress in arbitrary flight conditions. A conceptual single main rotor transport helicopter based on the UH-60A Black Hawk is implemented within the MDA to serve as a test case. To account for the computational expense of the MDA, surrogate modeling techniques, such as response surface equations, artificial neural networks, and Gaussian process models are used to approximate the stress response across the flight envelope of the transport helicopter. The predictive power and learning rates of various surrogate modeling techniques are compared to determine which is the most suitable for predicting fatigue stress. Ultimately, shallow artificial neural networks are found the provide the best compromise between accuracy, training expense, and uncertainty quantification capabilities. Next, structural reliability solution methods are investigated as a means to produce high-reliability fatigue life estimates without requiring deterministic safety factors. The Miner's sum fatigue life prediction model is reformulated as a structural reliability problem. Analytical solutions (FORM and SORM), sampling solutions (Monte Carlo, quasi-Monte Carlo, Latin hypercube sampling, and directional simulation), and hybrid solutions importance sampling) are compared using a notional fatigue life problem. These results are validated using a realistic helicopter fatigue life problem \jnr{which incorporates the fatigue stress surrogate model and is based on a probabilistic definition of the mission spectrum to account for fleet-wide usage variations. Monte Carlo simulation is found to provide the best performance and accuracy when compared to the exact solution. Finally, the capabilities of the preliminary fatigue design methodology are demonstrated using a series of hypothetical fatigue design exercises. First, the methodology is used to predict the impact of rotor blade box spar web thickness on probability of fatigue failure. Modest increases in web thickness are found to reduce probability of failure, but larger increases cause structural instability of the rotor blade in certain flight regimes which increases the fatigue damage rate. Next, a similar study tests the impact of tail rotor cant angle. Positive tail rotor cant is found to improve fatigue life in cases where the center of gravity (CG) of the vehicle is strongly biased towards the tail, but is detrimental if the CG is closer to the main rotor hub station line. Last, the effect of design mission requirements like rate of climb and cruising airspeed is studied. The methodology is not sensitive enough to predict the subtle impact of changes to rate of climb, but does prove that a slower cruising airspeed will decrease probability of fatigue failure of the main rotor blade. The methodology is proven to be capable of quantifying the influence of \jnr{rotor blade design variables, vehicle layout and configuration, and certain design mission requirements}, paving the way for implementation in a rotorcraft design framework. This thesis ends with suggestions for future work to address the most significant limitations of this research, as well as descriptions of the tasks required to apply the methodology to conventional rotorcraft or conceptual revolutionary vertical lift aircraft.Ph.D

Structure-function characterization and engineering of polysaccharides and antibodies with therapeutic activity

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2012.Cataloged from PDF version of thesis.Includes bibliographical references.Proteins and polysaccharides are of growing importance as a source for novel therapeutic compounds and target a range of diseases, from cancer to infections from pathogens. However, owing to their large and complex structures, they face a unique set of challenges, compared to small molecules, in their discovery and development as safe, efficacious drugs. Towards addressing these challenges, we describe in this thesis the implementation of structure-function relationship approaches to characterize and engineer polysaccharides and antibodies to improve their therapeutic profiles. The plant polysaccharide pectin, when modified, has demonstrated significant anticancer activity in animal models and small-scale clinical trials. Its development has been hampered, however, due to its complex structure and lack of structure-activity correlates. Using an integrated approach, we engineer a modified pectin that exhibits significant in vivo anticancer activity, which we link to specific structural attributes and cellular functional mechanisms. These results improve our structure-function understanding of anticancer modified pectin, an important step towards the clinical use of this complex polysaccharide. Applying what we learned from pectin, we develop an integrated framework to identify a contaminant in batches of heparin, a polysaccharide anticoagulant drug, associated with an outbreak of allergic-type reactions in 2007-2008. Employing orthogonal analytical approaches to overcome challenges of characterizing structurally complex pharmaceutical heparin, we determine that the structurally related glycan, oversulfated chondroitin sulfate, is the major contaminant. We link its presence to activation of the contact pathway, thereby establishing a structure-function understanding of contaminated heparin and improving the safety profile of this polysaccharide drug. Transitioning knowledge gained from the structure-function characterization of polysaccharides, we engineer, by structure-based design, a broad spectrum neutralizing antibody to dengue virus, which yearly infects more than 200 million people, causing approximately 21,000 deaths. We incorporate complementary approaches of energetics and empirical informatics methods to rationally redesign an existing antibody for greater breadth and potency, resulting in an engineered antibody with binding to all four virus serotypes and good in vitro potency. Overall, this thesis provides important insights into structure-function approaches through the use of complementary methods to characterize and engineer therapeutic polysaccharides and antibodies.by Luke Robinson.Ph.D

ChatGPT MT: Competitive for High- (but not Low-) Resource Languages

Large language models (LLMs) implicitly learn to perform a range of language tasks, including machine translation (MT). Previous studies explore aspects of LLMs' MT capabilities. However, there exist a wide variety of languages for which recent LLM MT performance has never before been evaluated. Without published experimental evidence on the matter, it is difficult for speakers of the world's diverse languages to know how and whether they can use LLMs for their languages. We present the first experimental evidence for an expansive set of 204 languages, along with MT cost analysis, using the FLORES-200 benchmark. Trends reveal that GPT models approach or exceed traditional MT model performance for some high-resource languages (HRLs) but consistently lag for low-resource languages (LRLs), under-performing traditional MT for 84.1% of languages we covered. Our analysis reveals that a language's resource level is the most important feature in determining ChatGPT's relative ability to translate it, and suggests that ChatGPT is especially disadvantaged for LRLs and African languages.Comment: 27 pages, 9 figures, 14 table