Medicine and Health Sciences | Open Access Articles

Triterpenoid Modulation Of Il-17 And Nrf-2 Expression Ameliorates Neuroinflammation And Promotes Remyelination In Autoimmune Encephalomyelitis, Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio

Dartmouth Scholarship

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of …

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Chromosome Missegregation In Human Cells Arises Through Specific Types Of Kinetochore–Microtubule Attachment Errors, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN). CIN reflects the erosion of mitotic fidelity, and it correlates with poor patient prognosis and drug resistance. The most common mechanism causing CIN is the persistence of improper kinetochore–microtubule attachments called merotely. Chromosomes with merotelic kinetochores often manifest as lagging chromosomes in anaphase, suggesting that lagging chromosomes fail to segregate properly. However, it remains unknown whether the lagging chromosomes observed in anaphase segregate to the correct or incorrect daughter cell. To address this question, we tracked the segregation of a single …

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Coordinated Regulation By Agra, Sara, And Sarr To Control Agr Expression In Staphylococcus Aureus, Dindo Reyes, Diego O. Andrey, Antoinette Monod, William L. Kelley, Gongyi Zhang, Ambrose L. Cheung

Dartmouth Scholarship

The agr locus of Staphylococcus aureus is composed of two divergent transcripts (RNAII and RNAIII) driven by the P2 and P3 promoters. The P2-P3 intergenic region comprises the SarA/SarR binding sites and the four AgrA boxes to which AgrA binds. We reported here the role of AgrA, SarA, and SarR on agr P2 and P3 transcription. Using real-time reverse transcription (RT)-PCR and promoter fusion studies with selected single, double, triple, and complemented mutants, we showed that AgrA is indispensable to agr P2 and P3 transcription, whereas SarA activates and SarR represses P2 transcription. In vitro runoff transcription assays revealed that …

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Protoporphyrin Ix Fluorescence Contrast In Invasive Glioblastomas Is Linearly Correlated With Gd Enhanced Magnetic Resonance Image Contrast But Has Higher Diagnostic Accuracy, Kimberley S. Samkoe, Summer L. Gibbs-Strauss, Harold H. Yang, S. Khan Hekmatyar, P. Jack Hoopes, Julia A. O'Hara, Risto A. Kauppinen, Brian W. Pogue

Dartmouth Scholarship

The sensitivity and specificity of in vivo magnetic resonance (MR) imaging is compared with production of protoporphyrin IX (PpIX), determined ex vivo, in a diffusely infiltrating glioma. A human glioma transfected with green fluorescent protein, displaying diffuse, infiltrative growth, was implanted intracranially in athymic nude mice. Image contrast from corresponding regions of interest (ROIs) in in vivo MR and ex vivo fluorescence images was quantified. It was found that all tumor groups had statistically significant PpIX fluorescence contrast and that PpIX contrast demonstrated the best predictive power for tumor presence. Contrast from gadolinium enhanced T1-weighted (T1W+Gd) and absolute T2 …

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Step-Wise Loss Of Bacterial Flagellar Torsion Confers Progressive Phagocytic Evasion, Rustin R. Lovewell, Ryan M. Collins, Julie L. Acker, George A. O'Toole, Matthew J. Wargo, Brent Berwin, Craig R. Roy

Dartmouth Scholarship

Phagocytosis of bacteria by innate immune cells is a primary method of bacterial clearance during infection. However, the mechanisms by which the host cell recognizes bacteria and consequentially initiates phagocytosis are largely unclear. Previous studies of the bacterium Pseudomonas aeruginosa have indicated that bacterial flagella and flagellar motility play an important role in colonization of the host and, importantly, that loss of flagellar motility enables phagocytic evasion. Here we use molecular, cellular, and genetic methods to provide the first formal evidence that phagocytic cells recognize bacterial motility rather than flagella and initiate phagocytosis in response to this motility. We demonstrate …

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Alpha-Defensins 1-3 Release By Dendritic Cells Is Reduced By Estrogen, Maria M. Escribese, Marta Rodríguez-García, Rhoda Sperling, Stephanie M. Engel

Dartmouth Scholarship

During pregnancy the immune system of the mother must protect any activation that may negatively affect the fetus. Changes in susceptibility to infection as well as resolution of some autoimmune disorders represent empirical evidence for pregnancy related alterations in immunity. Sex hormones reach extremely high levels during pregnancy and have been shown to have direct effects on many immune functions including the antiviral response of dendritic cells. Among the immunologically active proteins secreted by monocyte derived DCs (MDDC) are the alpha-defensins 1-3. This family of cationic antimicrobial peptides has a broad spectrum of microbicidal activity and has also been shown …

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Systematic Analysis Of Diguanylate Cyclases That Promote Biofilm Formation By Pseudomonas Fluorescens Pf0-1, Peter D. Newell, Shiro Yoshioka, Kelli L. Hvorecny, Russell D. Monds, George A. O'Toole

Dartmouth Scholarship

Cyclic di-GMP (c-di-GMP) is a broadly conserved, intracellular second-messenger molecule that regulates biofilm formation by many bacteria. The synthesis of c-di-GMP is catalyzed by diguanylate cyclases (DGCs) containing the GGDEF domain, while its degradation is achieved through the phosphodiesterase activities of EAL and HD-GYP domains. c-di-GMP controls biofilm formation by Pseudomonas fluorescens Pf0-1 by promoting the cell surface localization of a large adhesive protein, LapA. LapA localization is regulated posttranslationally by a c-di-GMP effector system consisting of LapD and LapG, which senses cytoplasmic c-di-GMP and modifies the LapA protein in the outer membrane. Despite the apparent requirement for c-di-GMP for …

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Mediator Influences Telomeric Silencing And Cellular Life Span, Xuefeng Zhu, Beidong Liu, Jonas O. P. Carlsten, Jenny Beve, Thomas Nyström, Lawrence C. Myers, Claes M. Gustafsson

Dartmouth Scholarship

The Mediator complex is required for the regulated transcription of nearly all RNA polymerase II-dependent genes. Here we demonstrate a new role for Mediator which appears to be separate from its function as a transcriptional coactivator. Mediator associates directly with heterochromatin at telomeres and influences the exact boundary between active and inactive chromatin. Loss of the Mediator Med5 subunit or mutations in Med7 cause a depletion of the complex from regions located near subtelomeric X elements, which leads to a change in the balance between the Sir2 and Sas2 proteins. These changes in turn result in increased levels of H4K16 …

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Variations In Mre11/Rad50/Nbs1 Status And Dna Damage-Induced S-Phase Arrest In The Cell Lines Of The Nci60 Panel, Kristen M. K. Garner, Alan Eastman

Dartmouth Scholarship

The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity.

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Autoimmune Melanocyte Destruction Is Required For Robust Cd8+ Memory T Cell Responses To Mouse Melanoma, Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk

Dartmouth Scholarship

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8⁺ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4⁺ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8⁺ memory T cells specific for shared melanoma/melanocyte antigens. CD8 …

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Non-Identity-Mediated Crispr-Bacteriophage Interaction Mediated Via The Csy And Cas3 Proteins, Kyle C. Cady, George A. O'Toole

Dartmouth Scholarship

Studies of the Escherichia, Neisseria, Thermotoga, and Mycobacteria clustered regularly interspaced short palindromic repeat (CRISPR) subtypes have resulted in a model whereby CRISPRs function as a defense system against bacteriophage infection and conjugative plasmid transfer. In contrast, we previously showed that the Yersinia-subtype CRISPR region of Pseudomonas aeruginosa strain UCBPP-PA14 plays no detectable role in viral immunity but instead is required for bacteriophage DMS3-dependent inhibition of biofilm formation by P. aeruginosa. The goal of this study is to define the components of the Yersinia-subtype CRISPR region required to mediate this bacteriophage-host interaction. We show that the Yersinia-subtype-specific CRISPR-associated (Cas) proteins …

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Rho Activation Of Mdia Formins Is Modulated By An Interaction With Inverted Formin 2 (Inf2), Hua Sun, Johannes S. Schlondorff, Elizabeth J. Brown, Henry N. Higgs, Martin R. Pollak

Dartmouth Scholarship

Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these …

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A Retinoic Acid–Dependent Checkpoint In The Development Of Cd4+ T Cell–Mediated Immunity, Karina Pino-Lagos, Yanxia Guo, Chrysothemis Brown, Matthew P. Alexander, Raúl Elgueta, Kathryn A. Bennett, Victor De Vries, Elizabeth Nowak, Rune Blomhoff, Shanthini Sockanathan, Roshantha A. Chandraratna, Ethan Dmitrovsky, Randolph J. Noelle

Dartmouth Scholarship

It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4⁺ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of …

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Full-Text Articles in Medicine and Health Sciences

Dartmouth Scholarship

Chromosome Missegregation In Human Cells Arises Through Specific Types Of Kinetochore–Microtubule Attachment Errors, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Coordinated Regulation By Agra, Sara, And Sarr To Control Agr Expression In Staphylococcus Aureus, Dindo Reyes, Diego O. Andrey, Antoinette Monod, William L. Kelley, Gongyi Zhang, Ambrose L. Cheung

Dartmouth Scholarship

Dartmouth Scholarship

Step-Wise Loss Of Bacterial Flagellar Torsion Confers Progressive Phagocytic Evasion, Rustin R. Lovewell, Ryan M. Collins, Julie L. Acker, George A. O'Toole, Matthew J. Wargo, Brent Berwin, Craig R. Roy

Dartmouth Scholarship

Alpha-Defensins 1-3 Release By Dendritic Cells Is Reduced By Estrogen, Maria M. Escribese, Marta Rodríguez-García, Rhoda Sperling, Stephanie M. Engel

Dartmouth Scholarship

Systematic Analysis Of Diguanylate Cyclases That Promote Biofilm Formation By Pseudomonas Fluorescens Pf0-1, Peter D. Newell, Shiro Yoshioka, Kelli L. Hvorecny, Russell D. Monds, George A. O'Toole

Dartmouth Scholarship

Mediator Influences Telomeric Silencing And Cellular Life Span, Xuefeng Zhu, Beidong Liu, Jonas O. P. Carlsten, Jenny Beve, Thomas Nyström, Lawrence C. Myers, Claes M. Gustafsson

Dartmouth Scholarship

Variations In Mre11/Rad50/Nbs1 Status And Dna Damage-Induced S-Phase Arrest In The Cell Lines Of The Nci60 Panel, Kristen M. K. Garner, Alan Eastman

Dartmouth Scholarship

Autoimmune Melanocyte Destruction Is Required For Robust Cd8+ Memory T Cell Responses To Mouse Melanoma, Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk

Dartmouth Scholarship

Non-Identity-Mediated Crispr-Bacteriophage Interaction Mediated Via The Csy And Cas3 Proteins, Kyle C. Cady, George A. O'Toole

Dartmouth Scholarship

Rho Activation Of Mdia Formins Is Modulated By An Interaction With Inverted Formin 2 (Inf2), Hua Sun, Johannes S. Schlondorff, Elizabeth J. Brown, Henry N. Higgs, Martin R. Pollak

Dartmouth Scholarship

Dartmouth Scholarship