Digital Commons Network^™

A Microrna Profile Associated With Opisthorchis Viverrini-Induced Cholangiocarcinoma In Tissue And Plasma., Jordan Plieskatt, Gabriel Rinaldi, Yanjun Feng, Jin Peng, Samantha Easley, Xinying Jia, Jeremy Potriquet, Chawalit Pairojkul, Vajarabhongsa Bhudhisawasdi, Banchob Sripa, Paul J Brindley, Jeffrey Bethony, Jason Mulvenna

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive tumor of the bile duct, and a significant public health problem in East Asia, where it is associated with infection by the parasiteOpisthorchis viverrini. ICC is often detected at an advanced stage and with a poor prognosis, making a biomarker for early detection a priority.

Methods

We have comprehensively profiled miRNA expression levels in ICC tumor tissue using small RNA-Seq and validated these profiles using quantitative PCR on matched plasma samples.

Results

Distinct miRNA profiles were associated with increasing histological differentiation of ICC tumor tissue. We also observed that histologically …

The Plight Of The Lucluc: Examining The Deadly Mystery Of Nodding Syndrome, Ethan K. Mcgann

Senior Honors Theses

Nodding syndrome (NS) is an emerging epidemic neurological disease that is shrouded in mystery. It is currently only found in the post-conflict regions of South Sudan, northern Uganda, and Tanzania. NS occurs in children from the ages of five to fifteen and is characterized by a loss of motor control in the neck muscles. Seizure episodes can range in intensity from atonic to tonic-clonic, and the onset of the first episode generally marks the beginning of a decline in the child’s physical and mental health. NS is a progressive disease that generally results in physical wasting, stunted growth, behavioral difficulties, …

Antimicrobial Activity Of Thymoquinone, Alya A. Almatrafi

MSMLS Capstone Projects

Abstract

With the increase in resistance to traditional antibiotics displayed by microbial agents, efforts have been devoted to the explorations of naturally derived antimicrobial compounds.

One such compound is thymoquinone (TQ), derived from Nigella Sativa (black seeds). This compound has been known for its anti-inflammatory and antioxidant properties (Ahmad et al., 2013); however, other healing properties may also be attributed to this compound. Nigella Sativa (NS), an herb, is a member of the Ranunculaceae family. Nigella Sativa has been used to treat different diseases since the ancient era. Extracts from the seeds have been used to treat bacterial infections such …

Subacute Bacterial Endocarditis Secondary To Lactobacillus Species, Shreemayee De Do

Department of Medicine

No abstract provided.

Opisthorchiasis: An Overlooked Danger, Ludmila M. Ogorodova, Olga S. Fedorova, Banchob Sripa, Viatcheslav A. Mordvinov, Aleksei V. Katokhin, Paul J. Brindley, The Topic Consortium

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Opisthorchiasis: An Overlooked Danger., Ludmila M Ogorodova, Olga S Fedorova, Banchob Sripa, Viatcheslav A Mordvinov, Aleksei V Katokhin, Jennifer Keiser, Peter Odermatt, Paul J. Brindley, Oleg A Mayboroda, Thirumalaisamy P Velavan, Maxim B Freidin, Alexey E Sazonov, Irina V Saltykova, Mariya Y Pakharukova, Yulia V Kovshirina, Kostas Kaloulis, Olga Y Krylova, Maria Yazdanbakhsh

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin Activates The Nlrp3 Inflammasome In Human Macrophages Leading To The Release Of Pro-Inflammatory Cytokines, Bruce J. Shenker, David M. Ojcius, Lisa P. Walker, Ali Zekavat, Monika Damek Scuron, Kathleen Boesze-Battaglia

All Dugoni School of Dentistry Faculty Articles

The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies with Actinobacillus actinomycetemcomitans Cdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive …

Relationship Between Heat-Labile Enterotoxin Secretion Capacity And Virulence In Wild Type Porcine-Origin Enterotoxigenic Escherichia Coli Strains, Prageeth Wijemanne, Jun Xing, Emil M. Berberov, David B. Marx, David H. Francis, Rodney A. Moxley

School of Veterinary and Biomedical Sciences: Faculty Publications

Heat-labile enterotoxin (LT) is an important virulence factor secreted by some strains of enterotoxigenic Escherichia coli (ETEC). The prototypic human-origin strain H10407 secretes LT via a type II secretion system(T2SS). We sought to determine the relationship between the capacity to secrete LT and virulence in porcine-origin wild type (WT) ETEC strains. Sixteen WT ETEC strains isolated from cases of severe diarrheal disease were analyzed by GM1ganglioside enzyme- linked immunosorbent assay tomeasure LT concentrations in culture supernatants. All strains had detectable LT in supernatants by 2 h of culture and 1 strain, which was particularly virulent in gnotobiotic piglets (3030-2), had …

Vertebral Sarcoidosis Presenting As Herniated Disk Disease Refractory To Epidural Steroid Treatment, Dhwani Pandya Md, Michael Kalil Do, Stacey Smith Md

Department of Medicine

No abstract provided.

Prolonged-Acting, Multi-Targeting Gallium Nanoparticles Potently Inhibit Growth Of Both Hiv And Mycobacteria In Co-Infected Human Macrophages., Prabagaran Narayanasamy, Barbara L. Switzer, Bradley E. Britigan

Journal Articles: Pathology and Microbiology

Human immunodeficiency virus (HIV) infection and Mycobacterium tuberculosis (TB) are responsible for two of the major global human infectious diseases that result in significant morbidity, mortality and socioeconomic impact. Furthermore, severity and disease prevention of both infections is enhanced by co-infection. Parallel limitations also exist in access to effective drug therapy and the emergence of resistance. Furthermore, drug-drug interactions have proven problematic during treatment of co-incident HIV and TB infections. Thus, improvements in drug access and simplified treatment regimens are needed immediately. One of the key host cells infected by both HIV and TB is the mononuclear phagocyte (MP; monocyte, …

Environmental Microbes And Uveitis: Is Microbial Exposure Always Bad?, Chandirasegaran Massilamany, A. Gangaplara, J. Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

The eye generally is considered to be an immune-privileged organ, but this notion is being increasingly challenged as ocular antigens can be expressed in the generative lymphoid organs, resulting in attainment of self-tolerance. What triggers a break in this tolerant state is a fundamental question in autoimmunity research. The general belief is that exposure to environmental microbes can break self-tolerance in genetically susceptible individuals, leading to the induction of autoimmune responses. The molecular mimicry hypothesis has been proposed as one major mechanistic, pathway through which microbes, by generating crossreactive immune responses, can induce ocular damage of the kind that might …

The Role Of Il-27 In Susceptibility To Post-Influenza Staphylococcus Aureus Pneumonia, Keven M. Robinson, Benjamin Lee, Erich V Scheller, Sivanarayana Mandalapu, Richard I. Enelow

Dartmouth Scholarship

Influenza is a common respiratory virus and Staphylococcus aureus frequently causes secondary pneumonia during influenza infection, leading to increased morbidity and mortality. Influenza has been found to attenuate subsequent Type 17 immunity, enhancing susceptibility to secondary bacterial infections. IL-27 is known to inhibit Type 17 immunity, suggesting a potential critical role for IL-27 in viral and bacterial co-infection.

Tcr Alpha Lcr And Non-Lcr Cis-Elements Contributing To Tissue Specific Expression Of The Tcr Alpha Gene In Thymic And Peripheral T Cells, Martina Kucerova-Levisohn

Dissertations, Theses, and Capstone Projects

Orchestrated expression of multiple genes residing in the complex TCRα/δ/Dad1 locus requires tight control from multiple cis-acting elements. The TCRα locus control region (LCR), is positioned between TCRα and Dad1 gene, and has been implicated in the differential expression of both genes. In this study, we focus our work on the hypersensitive site (HS)1 prime (HS1'), located 3' of the classical Eα enhancer, within the TCRα LCR. We investigated its non- redundant role in TCRα expression in thymic and peripheral T cells as assayed by in vivo and in vitro studies. Furthermore, formation of HS1' in both lymphoid and …

The Onchocerciasis Vaccine For Africa-Tova-Initiative., Peter J Hotez, Maria Elena Bottazzi, Bin Zhan, Benjamin L Makepeace, Thomas R Klei, David Abraham, David W Taylor, Sara Lustigman

Department of Microbiology and Immunology Faculty Papers

No abstract provided.

Il-1Α Signaling Is Critical For Leukocyte Recruitment After Pulmonary Aspergillus Fumigatus Challenge, Alayna K. Caffrey, Margaret M. Lehmann, Julianne M. Zickovich, Vanessa Espinosa, Kelly M. Shepardson, Christopher P. Watschke, Kimberly M. Hilmer, Arsa Thammahong, Bridget M. Barker, Amariliz Rivera, Robert A. Cramer, Joshua J. Obar

Dartmouth Scholarship

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines …

Two Potential Hookworm Daf-16 Target Genes, Snr-3 And Lpp-1: Gene Structure, Expression Profile, And Implications Of A Cis-Regulatory Element In The Regulation Of Gene Expression, Xin Gao, Kevin Goggin, Camille Dowling, Jason Qian, John Hawdon

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Hookworms infect nearly 700 million people, causing anemia and developmental stunting in heavy infections. Little is known about the genomic structure or gene regulation in hookworms, although recent publication of draft genome assemblies has allowed the first investigations of these topics to be undertaken. The transcription factor DAF-16 mediates multiple developmental pathways in the free living nematode Caenorhabditis elegans, and is involved in the recovery from the developmentally arrested L3 in hookworms. Identification of downstream targets of DAF-16 will provide a better understanding of the molecular mechanism of hookworm infection.

Methods

Genomic Fragment 2.23 containing a DAF-16 binding …

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes …

Metabolic Resting-State Brain Networks In Health And Disease, P. G. Spetsieris, J. H. Ko, C. C. Tang, A. Nazem, W. Sako, S. Peng, Y. Ma, V. Dhawan, D. Eidelberg

Journal Articles

The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood …

Dna-Containing Immunocomplexes Promote Inflammasome Assembly And Release Of Pyrogenic Cytokines By Cd14+ Cd16+ Cd64high Cd32low Inflammatory Monocytes From Malaria Patients, I. C. Hirako, C. Gallego-Marin, M. A. Ataide, W. A. Andrade, H. Gravina, B. C. Rocha, R. B. De Oliveira, D. B. Pereira, B. Diamond, R. T. Gazzinelli, +3 Additional Authors

Journal Articles

High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) …

Intake Of Erythrocytes Required For Reproductive Development Of Female Schistosoma Japonicum., Jipeng Wang, Shuqi Wang, Xiufeng Liu, Bin Xu, Riyi Chai, Pan Zhou, Chuan Ju, Jun Sun, Paul J. Brindley, Wei Hu

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The reproductive development and maturation of female schistosomes are crucial since their released eggs are responsible for the host immunopathology and transmission of schistosomiasis. However, little is known about the nutrients required by female Schistosoma japonicum during its sexual maturation. We evaluated the promoting effect of several nutrients (calf serum, red blood cells (RBCs), ATP and hypoxanthine) on the reproductive development of pre-adult females at 18 days post infection (dpi) from mixed infections and at 50 dpi from unisexual infections of laboratory mice in basic medium RPMI-1640. We found RBCs, rather than other nutrients, promoted the female sexual maturation and …

An Improved Method For Generating Axenic Entomopathogenic Nematodes., Shruti Yadav, Upasana Shokal, Steven Forst, Ioannis Eleftherianos

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: Steinernema carpocapsae are parasitic nematodes that invade and kill insects. The nematodes are mutualistically associated with the bacteria Xenorhabdus nematophila and together form an excellent model to study pathogen infection processes and host anti-nematode/antibacterial immune responses. To determine the contribution of S. carpocapsae and their associated X. nematophila to the successful infection of insects as well as to investigate the interaction of each mutualistic partner with the insect immune system, it is important to develop and establish robust methods for generating nematodes devoid of their bacteria.

FINDINGS: To produce S. carpocapsae nematodes without their associated X. nematophila bacteria, we …

Of Monkeys And Men: Immunomic Profiling Of Sera From Humans And Non-Human Primates Resistant To Schistosomiasis Reveals Novel Potential Vaccine Candidates., Mark S Pearson, Luke Becker, Patrick Driguez, Neil D Young, Soraya Gaze, Jeffrey M. Bethony, +12 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosoma haematobium affects more than 100 million people throughout Africa and is the causative agent of urogenital schistosomiasis. The parasite is strongly associated with urothelial cancer in infected individuals and as such is designated a group I carcinogen by the International Agency for Research on Cancer. Using a protein microarray containing schistosome proteins, we sought to identify antigens that were the targets of protective IgG1 immune responses in S. haematobium-exposed individuals that acquire drug-induced resistance (DIR) to schistosomiasis after praziquantel treatment. Numerous antigens with known vaccine potential were identified, including calpain (Smp80), tetraspanins, glutathione-S-transferases, and glucose transporters (SGTP1), as well …

Age-Dependent Alterations In The Inflammatory Response To Pulmonary Challenge, H. M. Linge, K. Ochani, K. Lin, J. Y. Lee, E. J. Miller

Journal Articles

The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 …

Antibodies As Mediators Of Brain Pathology, L. Brimberg, S. Mader, Y. Fujieda, Y. Arinuma, C. Kowal, B. T. Volpe, B. Diamond

Journal Articles

No abstract provided.

The Brighter (And Evolutionarily Older) Face Of The Metabolic Syndrome: Evidence From Trypanosoma Cruzi Infection In Cd-1 Mice, W. Brima, D. J. Eden, S. F. Mehdi, M. Bravo, M. M. Wiese, J. Stein, V. Almonte, D. Zhao, J. Roth, F. Nagajyothi, +5 Additional Authors

Journal Articles

BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 …

Md-2 Is Required For Disulfide Hmgb1-Dependent Tlr4 Signaling, H. Yang, H. Wang, Z. Ju, A. A. Ragab, W. Long, S. I. Valdes-Ferrer, M. He, J. Li, B. Lu, J. Roth, S. S. Chavan, K. J. Tracey, Y. Al-Abed, +10 Additional Authors

Journal Articles

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. …

Modular Analysis Of Peripheral Blood Gene Expression In Rheumatoid Arthritis Captures Reproducible Gene Expression Changes In Tumor Necrosis Factor Responders, M. Oswald, M. E. Curran, S. L. Lamberth, R. M. Townsend, J. D. Hamilton, D. N. Chernoff, M. Kern, C. M. Pond, A. Lee, P. K. Gregersen, +3 Additional Authors

Journal Articles

Objective. To establish whether the analysis of whole-blood gene expression is useful in predicting or monitoring response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). Methods. Whole-blood RNA (using a PAXgene system to stabilize whole-blood RNA in the collection tube) was obtained at baseline and at 14 weeks from 3 independent cohorts, consisting of a combined total of 240 RA patients who were beginning therapy with anti-TNF. We used an approach to gene expression analysis that is based on modular patterns of gene expression, or modules. Results. Good and moderate responders according to the European League …

Randomized, Double-Blind, Placebo-Controlled Trial Of The Effect Of Vitamin D3 On The Interferon Signature In Patients With Systemic Lupus Erythematosus, C. Aranow, D. L. Kamen, M. Dall'era, E. M. Massarotti, M. C. Mackay, F. Koumpouras, A. Coca, W. W. Chatham, M. E. Clowse, L. G. Criscione-Schreiber, S. Callahan, E. A. Goldmuntz, L. Keyes-Elstein, M. Oswald, P. K. Gregersen, B. Diamond

Journal Articles

OBJECTIVE: Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. METHODS: SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level/=30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, …

International Genome-Wide Meta-Analysis Identifies New Primary Biliary Cirrhosis Risk Loci And Targetable Pathogenic Pathways, H. J. Cordell, Y. Han, G. F. Mells, Y. Li, G. M. Hirschfield, C. S. Greene, G. Xie, B. D. Juran, K. A. Siminovitch, P. Gregersen, +14 Additional Authors

Journal Articles

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Widespread Non-Additive And Interaction Effects Within Hla Loci Modulate The Risk Of Autoimmune Diseases, T. Lencz, A. J. Deutsch, B. Han, X. Hu, Y. Okada, S. Eyre, M. Knapp, A. Zhernakova, P. K. Gregersen, S. Raychaudhuri, +27 Additional Authors

Journal Articles

Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, …