Measuring Biomarkers of Friedreich Ataxia: Implications for Clinical Research

Friedreich ataxia (FRDA) is a neurodegenerative disease caused by mutations in the frataxin (FXN) gene, resulting in reduced expression of the mitochondrial protein frataxin. While there currently is no cure for FRDA, our increasing understanding of the pathophysiology of disease has led to a surge in the development of potential treatments. As a result, there is a growing need for biological markers of disease progression and patient response to therapeutic intervention. In this thesis, we developed and validated a lateral flow “dipstick” immunoassay for the measurement of frataxin protein in multiple peripheral cell types. We measured significant differences in frataxin levels between controls, carriers, and FRDA patients, and found correlations between frataxin levels and GAA1 repeat length and age of onset. We then compared the utility of the dipstick assay as a population screening and diagnostic tool to a separate, Luminex xMAP-based immunoassay, and discuss the advantages and disadvantages of each assay in different clinical settings. The dipstick assay showed utility in a variety of clinical applications, including preliminary diagnosis of atypical FRDA patients, analysis of longitudinal frataxin measurements, correlations with changes in neurological severity, patient response to HDAC inhibitor treatment, response to chemotherapy in an FRDA case with comorbid osteosarcoma, and assessment of HDAC and SIRT gene polymorphisms on frataxin protein expression. Finally, we used Stable Isotope Labeling with Essential nutrients in Cell culture (SILEC) methodology to assess metabolic changes in transfected cells as well as primary fibroblasts and platelets isolated from FRDA patients. Using SILEC internal standards, we found that acetyl-CoA:succinyl-CoA ratios were significantly decreased in FRDA patients compared to controls, consistent with in vitro siRNA knockdown models of frataxin. Changes in CoA profiles, coupled with isotopic tracer analysis using [U-13C6]-glucose and [U-13C16]-palmitic acid, provided us with further insight into possible metabolic dysfunction in FRDA. Taken together, the results from this thesis show utility for frataxin measurements from peripheral tissues as a biomarker, and potentially provide researchers with a novel set of markers to assess metabolic dysfunction in unaffected tissues, not just in FRDA, but in any mitochondrial disorder

Non-locality and gauge freedom in Deutsch and Hayden's formulation of quantum mechanics

Deutsch and Hayden have proposed an alternative formulation of quantum mechanics which is completely local. We argue that their proposal must be understood as having a form of `gauge freedom' according to which mathematically distinct states are physically equivalent. Once this gauge freedom is taken into account, their formulation is no longer local.Comment: 3 page

Forging a national diet : beef and the political economy of plenty in postwar America

Few foods items are more associated with the United States than beef yet it was not until the 1950s that Americans ate more beef than any other meat. The triumph of mass beef consumption was not accidental or a preordained event. As this dissertation argues, beef became the most consumed meat in America because of a policy enacted by a succession of presidential administrations and was aided by popular demand. Beef policy, as understood by its enactors, was an attempt at creating a nation undifferentiated by diet and unified by eating a meal fit for the leader of the free world. Drawing on primary research materials found at the National Archives in College Park, MD, and at five presidential archives, along with government publications and beef industry literature, this work shines a light on a policy of domestic security that went unnamed and uncelebrated yet had a profound effect on how Americans ate. Within the five presidential administrations between 1945 and 1974 could be found a dedication to securing economic peace between producers and consumers as each side battled over the shape of the economy after World War II. This work situations beef policy within several historical fields, including the history of policy and politics, food studies, environmental history, social history, and women's history. By drawing on a diverse group of fields, this dissertation uncovers the complex factors that transformed a nation of aspirational beef eaters into literal ones.Includes bibliographical reference

The Voluntary Adjustment of Railroad Obligations

Automatic memory management techniques eliminate many programming errors that are both hard to find and to correct. However, these techniques are not yet used in embedded systems with hard realtime applications. The reason is that current methods for automatic memory management have a number of drawbacks. The two major ones are: (1) not being able to always guarantee short real-time deadlines and (2) using large amounts of extra memory. Memory is usually a scarce resource in embedded applications. In this paper we present a new technique, Real-Time Reference Counting (RTRC) that overcomes the current problems and makes automatic memory management attractive also for hard real-time applications. The main contribution of RTRC is that often all memory can be used to store live objects. This should be compared to a memory overhead of about 500% for garbage collectors based on copying techniques and about 50% for garbage collectors based on mark-and-sweep techniques

A practical scheme for quantum computation with any two-qubit entangling gate

Which gates are universal for quantum computation? Although it is well known that certain gates on two-level quantum systems (qubits), such as the controlled-not (CNOT), are universal when assisted by arbitrary one-qubit gates, it has only recently become clear precisely what class of two-qubit gates is universal in this sense. Here we present an elementary proof that any entangling two-qubit gate is universal for quantum computation, when assisted by one-qubit gates. A proof of this important result for systems of arbitrary finite dimension has been provided by J. L. and R. Brylinski [arXiv:quant-ph/0108062, 2001]; however, their proof relies upon a long argument using advanced mathematics. In contrast, our proof provides a simple constructive procedure which is close to optimal and experimentally practical [C. M. Dawson and A. Gilchrist, online implementation of the procedure described herein (2002), http://www.physics.uq.edu.au/gqc/].Comment: 3 pages, online implementation of procedure described can be found at http://www.physics.uq.edu.au/gqc

Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse

ObjectivesThe aim of this research was to test whether constitutive expression of hypoxia-inducible factor 1-alpha (HIF-1α) influences infarction size and cardiac performance after myocardial infarction.BackgroundA major question in clinical medicine is whether infarction size and border zone remodeling of the heart can be influenced by the overexpression of specific genes in the peri-infarction region.MethodsWe investigated the role of constitutive HIF-1α expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the HIF-1α gene under the control of the α-myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in HIF-1α transgenic mice and control animals. Extent of infarction was then quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathologic analysis of heart samples in infarct, peri-infarct, and remote heart regions at serial time points.ResultsConstitutive overexpression of HIF-1α in the murine heart resulted in attenuated infarct size and improved cardiac function 4 weeks after myocardial infarction. Significantly, we found an increase in both capillary density as well as vascular endothelial growth factor and inducible nitric oxide synthase expression in peri-infarct and infarct regions in the hearts of constitutive HIF-1α–expressing animals compared to control animals.ConclusionsThese observations suggest the involvement of HIF-1α in myocardial remodeling and peri-infarct vascularization. Our results show that supranormal amounts of this peptide protect against extension of infarction and improve border zone survival in myocardial infarction

The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor interacting protein (RIP) lcinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-gamma in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases

Human Performance Models of Pilot Behavior

Five modeling teams from industry and academia were chosen by the NASA Aviation Safety and Security Program to develop human performance models (HPM) of pilots performing taxi operations and runway instrument approaches with and without advanced displays. One representative from each team will serve as a panelist to discuss their team s model architecture, augmentations and advancements to HPMs, and aviation-safety related lessons learned. Panelists will discuss how modeling results are influenced by a model s architecture and structure, the role of the external environment, specific modeling advances and future directions and challenges for human performance modeling in aviation

Extensive hydrogen supersaturations in the western South Atlantic Ocean suggest substantial underestimation of nitrogen fixation

The nitrogen cycle is fundamental to Earth's biogeochemistry. Yet major uncertainties of quantification remain, particularly regarding the global oceanic nitrogen fixation rate. Hydrogen is produced during nitrogen fixation and will become supersaturated in surface waters if there is net release from diazotrophs. Ocean surveys of hydrogen supersaturation thus have the potential to illustrate the spatial and temporal distribution of nitrogen fixation, and to guide the far more onerous but quantitative methods for measuring it. Here we present the first transect of high resolution measurements of hydrogen supersaturations in surface waters along a meridional 10,000 km cruise track through the Atlantic. We compare measured saturations with published measurements of nitrogen fixation rates and also with model-derived values. If the primary source of excess hydrogen is nitrogen fixation and has a hydrogen release ratio similar to Trichodesmium, our hydrogen measurements would point to similar rates of fixation in the North and South Atlantic, roughly consistent with modelled fixation rates but not with measured rates, which are lower in the south. Possible explanations would include any substantial nitrogen fixation by newly discovered diazotrophs, particularly any having a hydrogen release ratio similar to or exceeding that of Trichodesmium; under-sampling of nitrogen fixation south of the equator related to excessive focus on Trichodesmium; and methodological shortcomings of nitrogen fixation techniques that cause a bias towards colonial diazotrophs relative to unicellular forms. Alternatively our data are affected by an unknown hydrogen source that is greater in the southern half of the cruise track than the northern