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Aberrations Of A Putative Tumor Suppressor Gene Sel1l In Pancreatic Ductal Adenocarcinoma, Qian Liu

Dissertations and Theses (Open Access)

Introduction: Pancreatic cancer is the fourth leading cause of cancer-related death among males and females in the United States. Sel-1-like (SEL1L) is a putative tumor suppressor gene that is downregulated in a significant proportion of human pancreatic ductal adenocarcinoma (PDAC). It was hypothesized that SEL1L expression could be down-modulated by somatic mutation, loss of heterozygosity (LOH), CpG island hypermethylation and/or aberrantly expressed microRNAs (miRNAs).

Material and methods: In 42 PDAC tumors, the SEL1L coding region was amplified using reverse transcription polymerase chain reaction (RT-PCR), and analyzed by agarose gel electrophoresis and sequenced to search for mutations. Using fluorescent …

Lentiviral-Mediated Rnai Knockdown Yields A Novel Mouse Model For Studying Cyp2b Function, Basma Damiri

All Dissertations

The Cyp2b subfamily contains five members (Cyp2b9, Cyp2b10, Cyp2b13, Cyp2b19, and Cyp2b23) of which three (Cyp2b9, Cyp2b10, Cyp2b13) are hepatic enzymes involved in xenobiotic detoxification. In this study, we made a Cyp2b-knockdown mouse using lentiviral-promoted shRNA homologous to all five Cyp2b subfamily members in FVB/NJ mouse to characterize Cyp2b's role in xenobiotic detoxification. We assessed the in vivo function of Cyp2bs in the toxicity from pesticides (i.e. parathion) and drugs (i.e. zoxazolamine). We demonstrated that Cyp2b isoforms play a key role in parathion and Zoxazolamine metabolism and toxicity. In addition, we in partially phenotyped and characterized Cyp2b-KD model and assessed …

Anticancer Effects Of Red Raspberries On Immune Cells And Blood Parameters, Jannet Romero

All Dissertations

There is an abundance of research correlating diets rich in fruits and vegetables to the reduction or prevention of chronic diseases such as cancer and cardiovascular disease. Plants extracts have also been claimed to possess antiviral, antibacterial, and immunological properties. This study focused on the in vitro and in vivo effects of a water extract from lyophilized Meeker red raspberries on tumor cell viability and immune parameters. A large number of studies have demonstrated the cytotoxic effect of different fruit juices and extracts against tumor cell lines in vitro. However, studies also show that the blood plasma levels of berry …

Augmented Cocaine Seeking In Response To Stress Or Crf Delivered Into The Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated By Crf Receptor Type 1 But Not Crf Receptor Type 2, Jordan M. Blacktop, Chad Seubert, David A. Baker, Nathan Ferda, Geng Lee, Evan N. Graf, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. …

Natural And Synthetic Corticosteroids Inhibit Uptake2-Mediated Transport In Cns Neurons, Jonathan E. Hill, Khadijah Makky, Lalita Shrestha, Cecilia J. Hillard, Paul J. Gasser

Biomedical Sciences Faculty Research and Publications

In addition to exerting actions via mineralocorticoid and glucocorticoid receptors, corticosteroids also act by inhibiting uptake₂, a high-capacity monoamine transport system originally described in peripheral tissues. Recent studies have demonstrated that uptake₂ transporters are expressed in the brain and play roles in monoamine clearance, suggesting that they mediate some corticosteroid effects on physiological and behavioral processes. However, the sensitivity of brain uptake₂ to many natural and synthetic corticosteroids has not been characterized. Cultured rat cerebellar granule neurons (CGNs) were previously shown to exhibit corticosterone-sensitive accumulation of the uptake₂ substrate1-methyl-4-phenylpyridinium (MPP⁺). We examined the …

Creation Of Multilinage Adult Stem-Like Cells From Terminally Differentiatied Fibroblasts, John Moore

Theses and Dissertations

Induced Pluripotent Stem cells (iPScs) are artificially generated cells that demonstrate multilineage differentiation potential. These cells demonstrate similar morphology and high differentiation potential to Embryonic Stem Cells (ESCs). Generation of these cells from a terminally differentiated cell line requires activation of the core pluripotency genes Nanog, Oct4, and Sox2 as well as an oncogenic stimulus such as c-Myc. Here we examine the effect of the Human Pappiloma Virus derived proteins E6 and E7 on the ability of a terminally differentiated fibroblast cell line to a more primitive state and examine its multilineage differentiation capacity. In this paper, we attempt to …

Protection And Attachment Of Vibrio Cholerae Mediated By The Toxin-Coregulated Pilus In The Infant Mouse Model, Shelly J. Krebs, Ronald K. Taylor

Dartmouth Scholarship

Colonization of the human small intestine by Vibrio cholerae is an essential step in pathogenesis that requires the type IV toxin-coregulated pilus (TCP). To date, three functions of TCP have been characterized: it serves as the CTXΦ receptor, secretes the colonization factor TcpF, and functions in microcolony formation by mediating bacterium-bacterium interactions. Although type IV pili in other pathogenic bacteria have been characterized as playing a major role in attachment to epithelial cells, there are very few studies to suggest that TCP acts as an attachment factor. Taking this into consideration, we investigated the function of TCP in attachment to …

The Levels Of Analysis Revisited., Scott A Macdougall-Shackleton

Brain and Mind Institute Researchers' Publications

The term levels of analysis has been used in several ways: to distinguish between ultimate and proximate levels, to categorize different kinds of research questions and to differentiate levels of reductionism. Because questions regarding ultimate function and proximate mechanisms are logically distinct, I suggest that distinguishing between these two levels is the best use of the term. Integrating across levels in research has potential risks, but many benefits. Consideration at one level can help generate novel hypotheses at the other, define categories of behaviour and set criteria that must be addressed. Taking an adaptationist stance thus strengthens research on proximate …

Expression Profiling And Functional Validation Of Micrornas Involved In Schizophrenia And Bipolar Disorder, Albert H. Kim

Theses and Dissertations

MicroRNAs (miRNAs) are a family of small non-coding RNAs that regulate gene expression at both the mRNA and protein levels. MiRNAs have been shown to affect neuronal differentiation, synaptosomal complex localization and synapse plasticity, all functions thought to be disrupted in schizophrenia. We investigated the expression of 667 miRNAs (miRBase v.13) in the prefrontal cortex of individuals with schizophrenia (SZ, N = 35) and bipolar disorder (BP, N =35) using a real-time PCR-based Taqman Low Density Array (TLDA). After extensive QC steps, 441 miRNAs were included in the final analyses. At a FDR of 10%, 22 miRNAs were identified as …

Na/K-Atpase Mimetic Pnaktide Peptide Inhibits The Growth Of Human Cancer Cells, Zhichuan Li, Zhongbing Zhang, Joe X. Xie, Xin Li, Jiang Tian, Ting Cai, Hongaun Cui, Hanfei Ding, Joseph I. Shapiro Md, Zijian Xie

Biochemistry and Microbiology

Cells contain a large pool of non-pumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of α1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/K-ATPase to regulate Src-related signaling processes. Supplement of pNaKtide, a peptide derived from α1 Na/K-ATPase, reduces activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness …

Upregulation Of Cathepsin D In The Caudate Nucleus Of Primates With Experimental Parkinsonism., Sowmya V. Yelamanchili, Amrita Datta Chaudhuri, Claudia T. Flynn, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease.

RESULTS: Using chronic 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in …

Intracellular Signaling Contributions To Behaviors Relevant To Nicotine Addiction, Lauren Thompson

Theses and Dissertations

Nicotine is the primary addictive substance in tobacco, and most smokers who quit will relapse within a year. Evidence shows that cigarette craving increases over time, termed “incubation.” The purpose of these studies was to see if protracted abstinence from chronic nicotine increases rat self-administration, an animal model with good face validity for human tobacco use, and if nicotine self-administration during daily exposure/after 8+ days of abstinence is regulated by extracellular signal-regulated kinase (ERK) signaling in the nucleus accumbens (NAc) shell or anterior cingulate cortex (PFC). ERK kinase inhibitor U0126 was infused in the NAc shell or PFC of Long …

Comparison Of Adenoviruses As Oncolytics And Cancer Vaccines In An Immunocompetent B Cell Lymphoma Model, Eric A. Weaver, Christopher Y. Chen, Shannon M. May, Mary E. Barry, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

We have screened human adenoviruses (Ads) for oncolytic activity against a variety of mouse and hamster cell lines and have found a number that are susceptible to a variety of Ad serotypes. A20 lymphoma is derived from BALB/c mice and is susceptible to infection and killing by a variety of human Ads. A20 is also a suitable cancer vaccine model, because these cells express a unique immunoglobulin variable region that can be targeted by vaccination. To compare Ads as cancer vaccines versus Ads as oncolytics, A20 tumors were initiated in immunocompetent BALB/c mice. Mice immunized with first-generation Ad5 expressing the …

Racial Differences In The Genetics Of Preeclampsia, Lori Hill

Theses and Dissertations

Preeclampsia (PE), characterized by hypertension and proteinuria after 20 weeks of gestation, affects 5-8% of pregnancies worldwide. Although preeclampsia is a significant cause of maternal and perinatal mortality and morbidity, its etiology remains to be elucidated. Racial differences have been observed for preeclampsia, with U.S. Blacks having higher rates and more severe disease, compared to U.S. Whites and Hispanics. One potential source of racial differences in preeclampsia is genetic variation between populations. Genetic susceptibility to preeclampsia is well established, but the specific contributions of maternal vs. fetal genes, and how these vary among racial groups is poorly understood. This dissertation …

Emotional Reactivity And Regulation In Current And Remitted Depression: An Event Related Potential Study, Lauren M. Bylsma

USF Tampa Graduate Theses and Dissertations

Major Depressive Disorder (MDD) is thought to be characterized by emotion regulation deficits, including decreased use of adaptive strategies such as reappraisal, but little is known about the exact nature of these deficits and whether or not they are specific to the depressed mood state. The late positive potential (LPP) is a sustained positive deflection of the event-related potential (ERP) associated with responding to emotionally-valenced stimuli, and reappraisal strategies have been found to reduce LPP magnitude in response to emotional stimuli in healthy individuals, but this effect has not been examined in MDD. This study utilized ERPs to examine emotional …

Caenorhabditis Briggsae Recombinant Inbred Line Genotypes Reveal Inter-Strain Incompatibility And The Evolution Of Recombination, Joseph A. Ross, Daniel C. Koboldt, Julia E. Staisch, Helen M. Chamberlin, Bhagwati P. Gupta, Raymond D. Miller, Scott Everet Baird, Eric S. Haag

Biological Sciences Faculty Publications

The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains and genotyped at over 1,000 loci. A second set of recombinant inbred lines involving a third strain was also genotyped at lower resolution. The resulting recombination maps exhibit discrete domains of high and low recombination, as in C. elegans, indicating these are a general feature of Caenorhabditis species. The proportion of a chromosome's physical size occupied by …

Emerging Dynamics Of Human Campylobacteriosis In Southern Ireland, Susan Bullman, Daniel Corcoran, James O'Leary, Derry O'Hare, Brigid Lucey, Roy D. Sleator

Department of Biological Sciences Publications

Infections with Campylobacter spp. pose a significant health burden worldwide. The significance of Campylobacter jejuni/Campylobacter coli infection is well appreciated but the contribution of non-C. jejuni/C. coli spp. to human gastroenteritis is largely unknown. In this study, we employed a two-tiered molecular study on 7194 patient faecal samples received by the Microbiology Department in Cork University Hospital during 2009. The first step, using EntericBio® (Serosep), a multiplex PCR system, detected Campylobacter to the genus level. The second step, utilizing Campylobacter species-specific PCR identified to the species level. A total of 340 samples were confirmed as Campylobacter genus positive, 329 of …

Sr-A Ligand And M-Csf Dynamically Regulate Sr-A Expression And Function In Primary Macrophages Via P38 Mapk Activation, Dejan Nikolic, Lindsay Calderon, Liqin Du, Steven R. Post

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Inflammation is characterized by dynamic changes in the expression of cytokines, such as M-CSF, and modifications of lipids and proteins that result in the formation of ligands for Class A Scavenger Receptors (SR-A). These changes are associated with altered SR-A expression in macrophages; however, the intracellular signal pathways involved and the extent to which SR-A ligands regulate SR-A expression are not well defined. To address these questions, SR-A expression and function were examined in resident mouse peritoneal macrophages incubated with M-CSF or the selective SR-A ligand acetylated-LDL (AcLDL).

RESULTS: M-CSF increased SR-A expression and function, and required the specific …

Ceacam1 Separates Graft-Versus-Host-Disease From Graft-Versus-Tumor Activity After Experimental Allogeneic Bone Marrow Transplantation., Sydney X Lu, Lucy W Kappel, Anne-Marie Charbonneau-Allard, Renée Atallah, Amanda M Holland, Claire Turbide, Vanessa M Hubbard, Jimmy A Rotolo, Marsinay Smith, David Suh, Christopher King, Uttam K Rao, Nury Yim, Johanne L Bautista, Robert R Jenq, Olaf Penack, Il-Kang Na, Chen Liu, George Murphy, Onder Alpdogan, Richard S Blumberg, Fernando Macian, Kathryn V Holmes, Nicole Beauchemin, Marcel R M Van Den Brink

Department of Medical Oncology Faculty Papers

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.

METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In …

Clinical Pharmacology As A Foundation For Translational Science., Scott A. Waldman, R J. Hohl, G L. Kearns, S J. Swan, A Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The evolution of enabling technologies and their associated perspectives into molecular mechanisms underlying disease has extended beyond the abilities of scientific and clinical structures to advance their translation into new algorithms that improve the health of patients and populations.¹ Research programs have yielded a vast array of novel molecules related to pathophysiological mechanisms that represent diagnostic and therapeutic targets which have the potential for personalized healthcare management. Yet, despite extraordinary scientific advances, routine successful translation of discovery into new therapeutic tools remains a distant vision. Beyond constraints in bridging discovery science with clinical translation due to obstacles in facilities, …

Prevalencia Del Virus De La Diarrea Viral Bovina Y De Animales Portadores Del Virus En Bovinos En La Provincia De Espinar, Cusco., Cesar Cardenas A., Hermelinda G. Rivera, Mariluz Araínga, Mercy Ramirez V., Jimmy De Paz M.

Journal Articles: Pharmacology & Experimental Neuroscience

The prevalence of bovine viral diarrhea virus (BVDV) in 406 cattle was evaluated of both sexes and older than 6 months. Animals belonged to 114 small farmers from three rural communities of the province of Espinar, Cusco, Peru. Blood samples were collected according to three age groups Ɩ-12, 13-23, >24 months old). Serum samples were tested for antibodies against BVDV using the viral neutralization test. The 56.2 ± 4.8% 鴤/406) of samples had antibodies against BVDV. Persistently infected animals were not detected. Antibodies were present in the three age groups, but the highest prevalence ࿡.4%) was detected in animals older …

Functional Macroautophagy Induction By Influenza A Virus Without A Contribution To Major Histocompatibility Complex Class Ii-Restricted Presentation., Joseph D Comber, Tara M Robinson, Nicholas A Siciliano, Adam E Snook, Laurence C Eisenlohr

Department of Microbiology and Immunology Faculty Papers

Major histocompatibility complex (MHC) class II-presented peptides can be derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Although several endogenous antigen-processing pathways have been reported, little is known about their relative contributions to global CD4(+) T cell responses against complex antigens. Using influenza virus for this purpose, we assessed the role of macroautophagy, a process in which cytosolic proteins are delivered to the lysosome by de novo vesicle formation and membrane fusion. Influenza infection triggered productive macroautophagy, and autophagy-dependent presentation was readily observed with model antigens that naturally traffic to the autophagosome. Furthermore, treatments that enhance or …

Generation Of A Kupffer Cell-Evading Adenovirus For Systemic And Liver-Directed Gene Transfer, Reeti Khare, Shannon M. May, Francesco Vetrini, Eric A. Weaver, Donna Palmer, Amanda Rosewell, Nathan Grove, Philip Ng, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to …

Insulin-Like Growth Factor 1 And Transforming Growth Factor-Β Stimulate Cystine/Glutamate Exchange Activity In Dental Pulp Cells, Katherine Pauly, Kymberly Fritz, Alyssa Furey, Doug Lobner

Biomedical Sciences Faculty Research and Publications

Introduction

The growth factors insulin-like growth factor (IGF-1) and transforming growth factor-β (TGF-β) are protective to dental pulp cells in culture against the toxicity of the composite materials Durafill VS and Flow Line (Henry Schein Inc, New York, NY). Because the toxicity of these materials is mediated by oxidative stress, it seemed possible that the protective effects of IGF-1 and TGF-β were through the enhancement of an endogenous antioxidant mechanism.

Methods

We used cultured dental pulp cells to determine the mechanism of the protective effects of IGF-1 and TGF-β, focusing on the glutathione system and the role of cystine/glutamate exchange …

Tumor-Derived Interleukin-10 As A Prognostic Factor In Stage Iii Patients Undergoing Adjuvant Treatment With An Autologous Melanoma Cell Vaccine., Amit Mahipal, Mizue Terai, David Berd, Inna Chervoneva, Kashyap Patel, Michael Mastrangelo, Takami Sato

Department of Medical Oncology Faculty Papers

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP).

METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind …

Serotonin Mediated Changes In Corticotropin Releasing Factor Mrna Expression And Feeding Behavior Isolated To The Hypothalamic Paraventricular Nuclei, Joanne P. Boisvert, Tyler J. Boschuetz, Jon M. Resch, Christopher R. Mueller, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Fenfluramine reduces hunger and promotes body weight loss by increasing central serotonin (5-HT) signaling. More recently, neuropeptides have been linked to the regulation of feeding behavior, metabolism and body weight. To examine possible interactions between 5-HT and neuropeptides in appetite control, fenfluramine (200 nmol/0.5 μl/side) was administered directly into the hypothalamic paraventricular nuclei (PVN) of male rats. Bilateral fenfluramine produced significant hypophagia and increased expression of PVN corticotropin releasing factor (CRF) mRNA and neuropeptide Y (NPY) mRNA in the arcuate nucleus within the first hour after drug administration. Fenfluramine's effects on feeding behavior and mRNA expression were blocked by PVN …

Oral Administration Of Levo-Tetrahydropalmatine Attenuates Reinstatement Of Extinguished Cocaine Seeking By Cocaine, Stress Or Drug-Associated Cues In Rats, Yazmin Figueroa-Guzman, Christopher R. Mueller, Oliver Vranjkovic, Samantha Wisniewski, Zheng Yang, Shi-Jiang Li, Colin Bohr, Evan N. Graf, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats. This study examined the effects of acute oral (gavage) administration of levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine isoquinoline with a pharmacological profile that includes antagonism of D1, D2 and D3 dopamine receptors, …

Distribution Of Propranolol In Periocular Tissues: A Comparison Of Topical And Systemic Administration, Jinsong Hao, Michael B. Yang, Hongzhou Liu, S. Kevin Li

Pharmaceutical Science and Research

Purpose: Oral propranolol has become a promising treatment of capillary hemangiomas (CHs) despite concerns of side effects associated with systemic beta-blockers. The objective of this study was to investigate the distribution of propranolol in periocular tissues and in plasma after topical application of propranolol as compared with intravenous and oral administration of propranolol.

Methods: Each rabbit received propranolol as ophthalmic solution (1%) in one eye (1.5 mg dose), intravenous injection (1.5 mg dose), or commercially available propranolol oral solution (5 mg dose). The periocular tissues (e.g., eyelids and extraocular muscles) and blood were collected and assayed for propranolol. …

Metagenomic Biomarker Discovery And Explanation, Nicola Segata, Jacques Izard, Levi Waldron, Dirk Gevers, Larisa Miropolsky, Wendy S. Garrett, Curtis Huttenhower

Department of Food Science and Technology: Faculty Publications

This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

Includes supplemental materials.

Caspase-1 Dependent Il-1Β Secretion Is Critical For Host Defense In A Mouse Model Of Chlamydia Pneumoniae Lung Infection, Kenichi Shimada, Timothy R. Crother, Justin Karlin, Shuang Chen, Norika Chiba, V. Krishnan Ramanujan, Laurent Vergnes, David M. Ojcius, Moshe Arditi

All Dugoni School of Dentistry Faculty Articles

Chlamydia pneumoniae (CP) is an important human pathogen that causes atypical pneumonia and is associated with various chronic inflammatory disorders. Caspase-1 is a key component of the ‘inflammasome’, and is required to cleave pro-IL-1β to bioactive IL-1β. Here we demonstrate for the first time a critical requirement for IL-1β in response to CP infection. Caspase-1^−/− mice exhibit delayed cytokine production, defective clearance of pulmonary bacteria and higher mortality in response to CP infection. Alveolar macrophages harbored increased bacterial numbers due to reduced iNOS levels in Caspase-1^−/− mice. Pharmacological blockade of the IL-1 receptor in CP infected wild-type mice …