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    Amyotrophic lateral sclerosis (ALS) induced changes in basigin expression patterns
    Chakravarti, Leela; Rothstein, Jeffrey; Lee, Youngjin (Office of the Provost, Johns Hopkins University, 2011)
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor function due to premature spinal and cortical motor neuron degeneration and death. Mutations in the superoxide dismutase 1 (SOD1) gene cause approximately 20% of inherited cases of ALS. Overexpression of a mutant form of SOD1 (G93A) in mice appears to produce disease progression through an unknown gain of toxicity. To further elucidate mechanisms of neurodegeneration in ALS, we examined expression patterns of the transmembrane glycoprotein, basigin (CD147, Emmprin) in end-stage of the SOD1 G93A mouse model. Basigin, a member of the immunoglobulin superfamily, has various physiological roles including trafficking of monocarboxylate transporters (MCTs) to the plasma membrane, induction of matrix metalloproteinases (MMPs), and leukocyte activation. We focused on interactions of basigin with MCTs and implications for energy-metabolism in the disease state. The astrocyte-neuron lactate shuttle hypothesis states that lactate release from glucose metabolism in glia fuels neuronal metabolism, particularly in states of oxidative stress. Previous studies have shown that inhibition or down-regulation of MCTs leads to impaired lactate transport and neuronal degeneration, likely due to a lack of energy resources. Basigin is essential for localization of MCT1 and MCT4 to the plasma membrane, and inhibition of basigin has been shown to prevent lactate release by astrocytes. Additionally, basigin has been implicated in several other neurological diseases, including roles in leukocyte transmigration in multiple sclerosis and regulation of the γ-secretase complex in Alzheimer's disease. Interactions with MCT isoforms and implication in related diseases make basigin a viable candidate for study in ALS. We show that basigin co-localizes with MCT1 at the plasma membrane and is well-expressed in myelin-rich areas. We also show that basigin mRNA levels are reduced in brain and spinal cord in SOD1 end-stage disease. Basigin protein levels show differential expression, but not uniform down-regulation. These preliminary results indicate that basigin is likely involved in ALS- related neurodegeneration. Further investigation of the role of basigin in disease and normal states may provide insights regarding pathological changes in ALS.
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    Neuronal Differentiation of Human Embryonic Stem Cell-Derived Neural Crest Stem Cells by Pulsed Electrical Field
    Wach, Zachary; Zhang, Shuming; Ren, Yongiuan; Liu, Xingyu; Lee, Gabsang; Studer, Lorenz; Mao, Hai-Quan (Office of the Provost, Johns Hopkins University, 2011)
    This work surveyed the potential of using exogenous pulsed electrical field stimuli to guide the differentiation of human embryonic stem cell (hESC) derived-neural crest stem cells (NCSCs) towards their neuronal lineage. A vertical electrode bioreactor able to vary the parameters of direct current pulse frequency, width and intensity was fabricated for this purpose. Dendritic morphology was observed for hNCSCs cultured on cathodes subject to 1 Hz, 50 ms pulse at 150mV/mm and 200mV/mm for 24 hours. The morphological phenomena were observed in a dosage and polarity orientation dependent manner; however, significant apoptosis was observed post stimulation. hNCSCs and hESCs were then cultured on cathodes and subject to 1Hz, 50ms pulse at 150mV/mm and 200mV/mm for 1.5 hours/day and 3 hours/day for 8 days. The expression of neuron-specific class III beta tubulin (Tuj1) was observed through immunofluorescence post stimulation and the expression levels of Tuj1 were qualitatively higher for the stimulated hNCSCs and hESCs as compared to the controls. Apoptosis was only observed in hNCSCs subject to the harshest condition. Ethylene glycol tetraacetic acid (EGTA) was used to sequester extracellular Ca2+ in the media during the stimulation of hNCSCs on cathodes subject to 1Hz, 50ms pulse at 200mV/mm for 24 hours. As EGTA concentrations were increased from 0mM to 2mM, dendritic morphology was reduced. Thus, the morphological phenomena were correlated to the available free extracellular calcium concentrations. Further investigation into the intracellular calcium concentrations in stimulated hNCSCs and hESCs was accomplished through the Fluo-4 assay. hNCSCs and hESCs were stimulated on cathodes subject to 2Hz, 50ms pulse at 200mV/mm for 5 hours. Increased chronic levels of intracellular calcium were observed for hNCSC and hESC samples post stimulation.
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    Neuromechanical Control of Paddle Juggling
    De, Avik (2010-05-14)
    The objective of this research is to discover the rules by which the human nervous system controls the cyclic task of paddle juggling. The existence of separate feedforward and feedback control signals is hypothesized, and the feedforward control system is completely identified using tools from dynamical systems theory. Using this knowledge progress is made in identifying the feedback control system, with some interesting findings. The author believes that the data analysis methods in this work are novel and can be applied in the study of other hybrid dynamical cyclic tasks such as walking and running.
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    The Identification of Epigenetic Biomarkers for Myeloid Malignancies
    McDevitt, Michael A.; Moliterno, Alison R.; Herman, James G.; Carraway, Hetty E.; Prebet, Thomas; Dilley, Robert L. (Office of the Provost, Johns Hopkins University, 2011)
    Myeloid malignancies comprise a heterogeneous group of blood cancers that arise from abnormal stem or progenitor cells of the bone marrow and often portend a poor prognosis. The major disorders can be divided into four subsets based on clinical and genetic analyses: myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), mixed MPN/MDS, and acute myeloid leukemias (AML). Assigning accurate diagnosis can be quite challenging, and few reliable biomarkers are available for diagnostic, prognostic, and therapeutic purposes. As such, the purpose of this study was to elucidate useful biomarkers in various subsets of myeloid malignancies. It is now well established that epigenetic changes, such as aberrant DNA methylation, underlie all stages of cancer evolution. Epigenetic changes are reversible, so, in theory, cancer cells may be “reset” by targeted treatment with drugs that modulate the epigenetic system. Furthermore, clinical trials using demethylating agents such as azacytidine and decitabine have yielded promising results in hematopoietic malignancies. Intriguingly, acquired chromosomal lesions, primarily large genomic deletions have major clinical prognostic value at diagnosis, and appear to predict response to epigenetic therapies, but the mechanisms are completely unknown. Using microsatellites and SNP arrays, we identified common regions of loss, gain, uniparental disomy (UPD), and loss of heterozygosity (LOH) in subsets of myeloid malignancy patient samples. Common regions of LOH were found on chromosome 7 in AML and MDS and common regions of loss were found on chromosomes 13 and 20 in the classical myeloproliferative disorder myelofibrosis (MF). As shown in other studies, we also found common UPD on chromosome 9, including the JAK2 locus in MPDs. We have interrogated these global regions of change, analyzing the common genes through rigorous bioinformatic analyses to find candidate tumor suppressor genes. We focused on functional pathways that were connected to genes in the common genomic regions, including Wnt, Ras, Jak/STAT, and DNA repair. We reasoned that one gene abnormality may only define a small subset of patients; however, alterations in a common pathway may accurately define the majority of a disease subset. This represents the hypothesis generation component of our analysis. We present early validation studies of our candidate genes. We have preliminary evidence that SOCS family members are methylated in MPNs, offering an explanation for cases with no JAK2 mutation. Additional results investigating signaling, DNA repair, and cell cycle regulatory pathways will be presented across multiple myeloid malignancy samples. Further studies and collaborations are required to validate these targets and pathways in large numbers of patient samples. Common pathway analysis of epigenetic alterations, in concert with genetic alterations, will undoubtedly lead to a better understanding of the pathogenesis of cancers and provide useful biomarkers for diagnosis, prognostic stratification, and drug studies, with the ultimate goal of improving patient survival.
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    Understanding Cancer Cell Motility and Interactions with the Extracellular Matrix
    Wirtz, Denis; Fraley, Stephanie; Krishnamurthy, Ranjini (2009-11)
    The enzyme Transglutaminase is used as a novel method of increasing the stiffness of collagen gel without affecting other characteristics. This discovery has allowed for a more accurate analysis of cancer cell motility in a stiffer ECM leading to a potential understanding of the mechanism behind tumor metastasis.
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    Dynamics of magnetic monopoles in artificial spin ice
    Shen, Yichen (Office of the Provost, Johns Hopkins University, 2011-05)
    While finding the elementary magnetic monopole seems not an easy task, recently, scientists have come out an alternative approach by studying emergent particles in spin systems. Spin ice is a magnet with frustrated interactions from which we ob- serve emergent magnetic charges. Two typical spin ice materials are Dy2Ti2O7, with tetrahedral lattice structure. Artificial spin ice is an array of magnetic nano-wires with similar frustrated interactions as spin ice. In this Senior Thesis Project, I studied both meso-scopic behavior and microscopic behavior of the dynamics of artificial spin ice in a honeycomb network of magnetic nanowires made with permalloy. The concept of magnetic charges is introduced for better visualization and interpretation of the magnetization behavior. Microscopic simulations on a single wire and on a honeycomb junction with high damping are presented in this thesis. The dynamics of magnetic charges is observed in our simulation. By finding the critical field that triggers the reversal process on a junction with respect to the angle of external field, an offset angle α is defined in the system to better estimate the critical field at different angle. This thesis also includes a detailed discussion on the avalanche length distribution when an external field is applied to a uniformly magnetized honeycomb lattice sheet. We found when external angle θ ∈ (90, 131), the avalanche length distribution decays exponentially; and when θ ∈ (132, 180), the avalanche length distribution decays as a power law. This work concludes with the introduction of inertia and its characteristic pa- rameter ε that helped us deal with the case when magnetic charges travels in low damping system.
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    Abuse during Pregnancy among African American & Afro-Caribbean Women
    Chappell, Ashley (The Johns Hopkins University, Office of the Provost, 2011)
    Intimate Partner Violence (IPV) occurs in a relationship where one partner uses physical, emotional, or sexual abuse to control the other. IPV is “a serious criminal, social, and medical problem that has profound effects on a person’s health, wellbeing, and development,” (Morgan 2005 p 176). Moreover, evidence indicates that women are particularly vulnerable to domestic violence during pregnancy (O’Reilly 2007). The goal of this study is (1) to determine what factors place African American women at risk for IPV during pregnancy (2) to identify pregnancy outcomes related to IPV and (3) to compare the results between Afro-Caribbean women residing in the U.S. Virgin Islands (USVI).
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    Exploring Transcriptional Silencing of Transposons in Zebrafish
    Halpern, Marnie E.; Goll, Mary G.; Broache, Molly B. (2010)
    DNA methylation plays a critical role as an epigenetic modifier in plants and mammals, however it is absent from many invertebrate genomes. Although DNA methylation is known to be present in zebrafish, there is limited research on its function. In plants and mammals, one critical function of DNA methylation is the repression of transposable elements, parasitic elements that can be detrimental to the host genome. While it is known that transposons are present in the zebrafish genome, it is unknown whether their expression is dependent on methylation. I examined expression of two transposons, dirs and bhikhari, in wild type embryos and in embryos with hypomethylated genomes. Preliminary data show the unexpected result that expression of some transposons is not regulated by DNA methylation in the zebrafish larva.
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    Technological Innovation and the Status of Modern Civil Legal Aid in the U.K.
    Park, Kevin (2010-04-20)
    The status of technology used in the English legal aid system has previously been studied only in a limited manner. The Legal Services Research Centre (LSRC) has conducted civil justice surveys in 2001, 2004, 2006, and 2007. Outside of those studies, however, relatively little data exists on either government agencies other than the LSC and non-governmental legal aid providers. Thus the purpose of this study is to analyze the existing data for LSC use of technology, and collect new data on the use of technology by non-governmental legal aid providers. In particular, data will be collected on the Citizen’s Advice Bureaus and London-based solicitors firms. It would appear that the use of technology, primarily telephone lines and internet, has increased since the reform of the English legal aid system in 2000. LSC data demonstrates that the government-funded technology experiments have allowed for more efficient provision of legal aid services without significant increases in funding for civil legal aid projects. CAB data also demonstrates a regular increase in the use of their website for legal advice, although no financial comparison is available. In contrast, no definitive trend claim can be made regarding solicitors firms because this study marks the first instance in which data of this nature was collected from solicitors. In addition, the limited number of participants may not permit the findings of this study to be representative of all London-based solicitors firms. As a result, more research is required on this topic, especially with regard to civil legal aid providing solicitors.