Medicine and Health Sciences Commons^™

The Toxoplasma Gondii Cyst Wall Protein Cst1 Is Critical For Cyst Wall Integrity And Promotes Bradyzoite Persistence, Tadakimi Tomita, David J. Bzik, Yan Fen Ma, Barbara A. Fox

Dartmouth Scholarship

Toxoplasma gondii infects up to one third of the world's population. A key to the success of T. gondii as a parasite is its ability to persist for the life of its host as bradyzoites within tissue cysts. The glycosylated cyst wall is the key structural feature that facilitates persistence and oral transmission of this parasite. Because most of the antibodies and reagents that recognize the cyst wall recognize carbohydrates, identification of the components of the cyst wall has been technically challenging. We have identified CST1 (TGME49_064660) as a 250 kDa SRS (SAG1 related sequence) domain protein with a large …

Divergent Antibody Subclass And Specificity Profiles But Not Protective Hla-B Alleles Are Associated With Variable Antibody Effector Function Among Hiv-1 Controllers, Jennifer I. Lai, Anna F. Licht, Anne-Sophie Dugast, Todd Suscovich, Ickwon Choi, Chris Bailey-Kellogg, Galit Alter, Margaret E. Ackerman

Dartmouth Scholarship

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector …

Use Of Irf-3 And/Or Irf-7 Knockout Mice To Study Viral Pathogenesis: Lessons From A Murine Retrovirus-Induced Aids Model, Megan A. O'Connor, William R. Green

Dartmouth Scholarship

Interferon regulatory factor (IRF) regulation of the type I interferon response has not been extensively explored in murine retroviral infections. IRF-3(-/-) and select IRF-3/7(-/-) mice were resistant to LP-BM5-induced pathogenesis. However, further analyses strongly suggested that resistance could be attributed to strain 129-specific contamination of the known retrovirus resistance gene Fv1. Therefore, caution should be taken when interpreting phenotypes observed in these knockout mice, as strain 129-derived genetic polymorphisms may explain observed differences.

X-Linked Mtmr8 Diversity And Evolutionary History Of Sub-Saharan Populations, Damian Labuda, Vania Yotova, Jean-François Lefebvre, Claudia Moreau, Gerd Utermann, Scott M. Williams

Dartmouth Scholarship

The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary …

Recurrent Tissue-Specific Mtdna Mutations Are Common In Humans, David C. Samuels, Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A. Thornton-Wells, Jason H. Moore, Tia M. Hughes, Robert D. Hoffman, Jonathan L. Haines, Deborah G. Murdock, Douglas P. Mortlock, Scott M. Williams

Dartmouth Scholarship

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in …

Sessile Serrated Adenomas In The Proximal Colon Are Likely To Be Flat, Large And Occur In Smokers, Tarun Rustagi, Priya Rangasamy, Matthew Myers, Melinda Sanders, Haleh Vaziri, George Y. Wu, John W. Birk, Petr Protiva, Joseph C. Anderson

Dartmouth Scholarship

Aim: To examine the epidemiology and the morphology of the proximal sessile serrated adenomas (SSAs).

Methods: We conducted a retrospective study to identify patients with SSAs using a university-based hospital pathology database query from January 2007 to April 2011. Data collected included: age, gender, ethnicity, body mass index, diabetes, smoking, family history of colorectal cancer, aspirin, and statin use. We collected data on morphology of SSAs including site (proximal or distal), size, and endoscopic appearance (flat or protuberant). We also compared proximal SSAs to proximal tubular adenomas detected during same time period.

Bioengineered Lysozyme Reduces Bacterial Burden And Inflammation In A Murine Model Of Mucoid Pseudomonas Aeruginosa Lung Infection, Charlotte C. Teneback, Thomas C. Scanlon, Matthew J. Wargo, Jenna L. Bement, Karl E. Griswold, Laurie W. Leclair

Dartmouth Scholarship

The spread of drug-resistant bacterial pathogens is a growing global concern and has prompted an effort to explore potential adjuvant and alternative therapies derived from nature's repertoire of bactericidal proteins and peptides. In humans, the airway surface liquid layer is a rich source of antibiotics, and lysozyme represents one of the most abundant and effective antimicrobial components of airway secretions. Human lysozyme is active against both Gram-positive and Gram-negative bacteria, ac

Flagellar Motility Is A Key Determinant Of The Magnitude Of The Inflammasome Response To Pseudomonas Aeruginosa, Yash R. Patankar, Rustin R. Lovewell, Matthew E. Poynter, Jeevan Jyot, Barbara I. Kazmierczak, Brent Berwin

Dartmouth Scholarship

We previously demonstrated that bacterial flagellar motility is a fundamental mechanism by which host phagocytes bind and ingest bacteria. Correspondingly, loss of bacterial motility, consistently observed in clinical isolates from chronic Pseudomonas aeruginosa infections, enables bacteria to evade association and ingestion of P. aeruginosa by phagocytes both in vitro and in vivo. Since bacterial interactions with the phagocyte cell surface are required for type three secretion system-dependent NLRC4 inflammasome activation by P. aeruginosa, we hypothesized that reduced bacterial association with phagocytes due to loss of bacterial motility, independent of flagellar expression, will lead to reduced inflammasome activation. Here we report …

Engineering A Bcr-Abl–Activated Caspase For The Selective Elimination Of Leukemic Cells, Manabu Kurokawa, Takahiro Ito, Chih-Sheng Yang, Chen Zhao

Dartmouth Scholarship

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of …

Scfslimb Ubiquitin Ligase Suppresses Condensin Ii–Mediated Nuclear Reorganization By Degrading Cap-H2, Daniel W. Buster, Scott G. Daniel, Huy Q. Nguyen, Sarah L. Windler, Lara C. Skwarek, Maureen Peterson

Dartmouth Scholarship

Condensin complexes play vital roles in chromosome condensation during mitosis and meiosis. Condensin II uniquely localizes to chromatin throughout the cell cycle and, in addition to its mitotic duties, modulates chromosome organization and gene expression during interphase. Mitotic condensin activity is regulated by phosphorylation, but mechanisms that regulate condensin II during interphase are unclear. Here, we report that condensin II is inactivated when its subunit Cap-H2 is targeted for degradation by the SCF(Slimb) ubiquitin ligase complex and that disruption of this process dramatically changed interphase chromatin organization. Inhibition of SCF(Slimb) function reorganized interphase chromosomes into dense, compact domains and disrupted …

Characterization Of Brer Interaction With The Bile Response Promoters Breab And Brer In Vibrio Cholerae, Francisca A. Cerda-Maira, Gabriela Kovacikova, Brooke A. Jude, Karen Skorupski, Ronald Taylor

Dartmouth Scholarship

The Vibrio cholerae BreR protein is a transcriptional repressor of the breAB efflux system operon, which encodes proteins involved in bile resistance. In a previous study (F. A. Cerda-Maira, C. S. Ringelberg, and R. K. Taylor, J. Bacteriol. 190:7441-7452, 2008), we used gel mobility shift assays to determine that BreR binds at two independent binding sites at the breAB promoter and a single site at its own promoter. Here it is shown, by DNase I footprinting and site-directed mutagenesis, that BreR is able to bind at a distal and a proximal site in the breAB promoter. However, only one of …

Inhibition Of The Host Translation Shutoff Response By Herpes Simplex Virus 1 Triggers Nuclear Envelope-Derived Autophagy, Kerstin Radtke, Luc English, Christiane Rondeau, David Leib

Dartmouth Scholarship

Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immunofluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the …