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Exhaustion Renders Cd8 T Cells Unresponsive To Antigen-Independent Activation And Is Characterized By Il-18 Receptor Downregulation, Jennifer T. Ingram Jan 2011

Exhaustion Renders Cd8 T Cells Unresponsive To Antigen-Independent Activation And Is Characterized By Il-18 Receptor Downregulation, Jennifer T. Ingram

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During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of interleukin (IL)-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of IFN-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce interferon-gamma (IFN-γ) and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. This unresponsiveness was associated with downregulation of the IL-18 receptor …


Substance-Dependent Tasc Offenders Taking Psychotropic Pharmacotherapy--Associated Factors, Substance Use Outcomes, And Criminal Diversion Outcomes, Dorothy Octavia Jackson Jan 2011

Substance-Dependent Tasc Offenders Taking Psychotropic Pharmacotherapy--Associated Factors, Substance Use Outcomes, And Criminal Diversion Outcomes, Dorothy Octavia Jackson

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Current evidence suggests that persons with co-occurring disorders (COD) are at risk for poorer treatment outcomes in terms of substance use and recidivism. Studies have examined this trend in incarcerated individuals, but few have examined COD offenders under community supervision. The purpose of this study was to develop a predictive model to identify offenders under community corrections supervision with substance use diagnoses who were actively taking psychotropic medications (SUPM) as an index of COD and to compare demographics, social histories, and sexual risk behaviors for SUPM offenders to offenders with a substance use disorder (SUD) only and those who met …


Human Cytomegalovirus Ul97 Kinase Activity Modifies Cell Cycle Checkpoint Regulators, Rachel Brooke Gill Jan 2011

Human Cytomegalovirus Ul97 Kinase Activity Modifies Cell Cycle Checkpoint Regulators, Rachel Brooke Gill

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Human cytomegalovirus (CMV) infection results in destructive infections in neonates and immunocompromised individuals. Being the primary congenital infection in the United States, it can often result in permanent neurological deficits in infants. The current therapies for CMV infections all target the viral DNA polymerase and also have dose-limiting toxicities. Isolates resistant to ganciclovir (GCV), the therapy of choice, can sometimes overwhelm immunocompromised hosts. Better therapies for this infection are required. The CMV UL97 kinase is a key enzyme in the treatment of CMV infection because it phosphorylates GCV. Additionally, maribavir (MBV) specifically inhibits UL97 kinase activity and inhibits viral replication. …


Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall Jan 2011

Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall

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Tuberculosis (TB) is one of the leading infectious diseases in the world. An estimated one third of the world's population is infected with Mycobacterium tuberculosis, the causative pathogen of TB. With the emergence of drug resistant strains of the mycobacterium, and the HIV-TB coinfection epidemic, TB remains a global health emergency. Purine metabolism is an essential cellular component to all living cells. Previous studies have shown that differences exist between mycobacterial and human purine metabolism. One of the differences was in the metabolism of adenosine (Ado), whose cleavage was observed in mycobacterial cells whereas Ado cleavage is inefficient in human …


Elucidation Of The Elongated Fibrillar Structure Of Streptococcus Mutans Antigen I/Ii, Matthew Rodney Larson Jan 2011

Elucidation Of The Elongated Fibrillar Structure Of Streptococcus Mutans Antigen I/Ii, Matthew Rodney Larson

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Streptococcus mutans (S. mutans) is the causative agent behind dental caries, an infectious disease also known as tooth decay or dental cavities. S. mutans has a cell wall-attached protein known as Antigen I/II (AgI/II) utilized for bacterial adhesion to the tooth surface. Here we have solved the structures of both amino- and carboxy-terminal regions of the AgI/II molecule using X-ray crystallography. Using this structural information we have now built a tertiary model for AgI/II as a fibrillar protein. Further, we have functionally characterized AgI/II and determined minimal regions of AgI/II that are implicated in its adherence to the salivary agglutinin …


Developing A Screen To Identify Small Molecule Inhibitors That Disrupt Protein-Protein Interactions In Mycobacteria, Deborah Mai Jan 2010

Developing A Screen To Identify Small Molecule Inhibitors That Disrupt Protein-Protein Interactions In Mycobacteria, Deborah Mai

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Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and infects nearly one-third of the world's population. The same TB chemotherapeutic regimen has been administered for more than 50 years, and can be improved by developing innovative methods to discover new anti-TB drugs. This work describes a newly established high-throughput screen (HTS) platform technology based on Mycobacterial-Protein Fragment Complementation (M-PFC) to identify small molecule inhibitors of protein-protein interactions in mycobacteria. M-PFC HTS employs both whole cell and target-based approaches, and offers flexibility in selecting an appropriate protein interaction target for HTS. Selectable drug targets can include interactions of essential …


Identification And Validation Of Biodosimetry Markers In Multiple Models Of Radiation Exposure, Ashley Nicole Filiano Jan 2010

Identification And Validation Of Biodosimetry Markers In Multiple Models Of Radiation Exposure, Ashley Nicole Filiano

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Following a radiological or nuclear disaster, radiation dose assessment is imperative to minimize morbidity and mortality through rationally directed medical intervention. Current methods of retrospective dosimetry are not amenable to mass exposure scenarios and remain limited to monitoring of clinical symptoms (nausea/vomiting and lymphocyte depletion) and cytogenetic analysis. The goal of this study was to identify radiation biomarkers capable of qualitative (non-irradiated/irradiated) and quantitative (dose) assessment of radiation exposure. Initial analyses revealed 17 radiation-responsive cytokine/chemokine genes in blood samples from 6 pediatric cancer patients undergoing fractionated total body irradiation (TBI). These 17 genes were combined with 29 additional IR-inducible genes …


Prevalence And Susceptibility Of Cryptococcus Neoformans To Fluconazole In Hiv Patients In Kenya, Rennatus Magina Mdodo Jan 2010

Prevalence And Susceptibility Of Cryptococcus Neoformans To Fluconazole In Hiv Patients In Kenya, Rennatus Magina Mdodo

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In an applied analysis, examining the association between log transformed C-reactive


The Development Of Humoral And Cellular Responses To Plasmodium Falciparum Malaria In The Hypoendemic Peruvian Amazon And Potential Clinical Protection, Eva Helen Clark Jan 2010

The Development Of Humoral And Cellular Responses To Plasmodium Falciparum Malaria In The Hypoendemic Peruvian Amazon And Potential Clinical Protection, Eva Helen Clark

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Each year 300-500 million cases of Plasmodium falciparum malaria occur, leading to more than 1 million deaths. In high malaria transmission regions, development of immunity from severe infection requires 2-10 years of persistent parasitemia. This delay has been attributed to difficulties in the development of protective humoral responses. Indeed, anti-malarial antibody responses tend to be short-lived, and immunologic memory seems to be dysfunctional in high-transmission regions. In contrast, in the low-transmission Peruvian Amazon >60% of infections are asymptomatic, suggesting that clinical immunity occurs despite low parasite exposure. To analyze more precisely the naturally-acquired humoral responses to malarial antigens and their …


Association Between Birth Outcomes And Aflatoxin B1-Biomarker Levels Among Pregnant Women In Kumasi, Ghana, Faisal Mohammed Barbas Shuaib Jan 2010

Association Between Birth Outcomes And Aflatoxin B1-Biomarker Levels Among Pregnant Women In Kumasi, Ghana, Faisal Mohammed Barbas Shuaib

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Aflatoxins are fungal metabolites that contaminate staple food crops in many developing countries. Although studies have linked these toxins to adverse health outcomes, few studies have investigated the association between birth outcomes and aflatoxin B1-lysine adduct levels among pregnant women. The objective of this dissertation was to investigate the association between birth outcomes and aflatoxin B1- lysine adduct levels among pregnant women in Kumasi, Ghana. In a cross-sectional study of 755 pregnant women, Aflatoxin B1-lysine adduct (AF-ALB) levels were determined by High Performance Liquid Chromatography. AF-ALB associations were assessed as both continuous and categorical values. Analysis of variance (ANOVA) was …


Hypothesis Testing Based On Pool Screening With Unequal Pool Sizes, Hongjiang Gao Jan 2010

Hypothesis Testing Based On Pool Screening With Unequal Pool Sizes, Hongjiang Gao

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Pool screening is a widely applied technique to estimate the prevalence of a rare event. This focus of this research is on developing statistical test of hypothesis procedures under the assumption that pool sizes are unequal but known. One of the proposed test procedures is , an exact test based on the number of positive pools (denoted by T). Another set of proposed test procedures is a modification of the likelihood ratio, Wald's and Score tests which are commonly-used likelihood-based tests. In paper 1, we derive the distribution of T which will be the basis of the exact test. Other …


Project-Induced Displacement, Secondary Stressors, And Health, Yue Cao Jan 2010

Project-Induced Displacement, Secondary Stressors, And Health, Yue Cao

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It is estimated that 15 million migrants displaced by development projects every year in the world. However, research on health impacts of project-induced displacement is insufficient. The existing literature concerning the causal effect of migration on health is inconclusive due to the selective nature of migration and other methodological problems. This study employs the stress process model as the major theoretical framework, components from Cernea's IRR model as well as Scudder and Colson's framework are also incorporated to examine the short-term health impact of the displacement resulting from China's Three Gorges Dam Project. I also explore whether the displacement's effect …


Determinants Of Self-Efficacy To Seek Care For Tuberculosis And Complete Tuberculosis Treatment Among Hiv-Positive Patients Attending Government Hiv/Aids Clincis In Honduras, Mayra Silvana Arias Jan 2010

Determinants Of Self-Efficacy To Seek Care For Tuberculosis And Complete Tuberculosis Treatment Among Hiv-Positive Patients Attending Government Hiv/Aids Clincis In Honduras, Mayra Silvana Arias

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control


Development Of A Mucosal Vaccine Protective Against Francisella Tularensis Infection, Amit R. Ashtekar Jan 2010

Development Of A Mucosal Vaccine Protective Against Francisella Tularensis Infection, Amit R. Ashtekar

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Francisella tularensis, a facultative intracellular, gram-negative coccobacillus, is the causative agent of tularemia and has been classified as a category A biological agent. Since there currently is no licensed vaccine available, in this study, we assessed the potential of a bivalent subunit vaccine comprising of DnaK and Tul4 to protect against respiratory tularemia. Intranasal immunization of C57BL/6 mice with DnaK, Tul4, and the adjuvant GPI-0100 resulted in mucosal and systemic antibody responses to DnaK and Tul4. In addition to antibody responses, this immunization regimen also induced both Th1 and Th2 cell-mediated immune responses specific for DnaK and Tul4. Finally, more …


Host Preference Profile In An Area Of Eastern Equine Encephalitis (Eee) Virus Transmission In Alabama, Ana Lucia Oliveira Jan 2010

Host Preference Profile In An Area Of Eastern Equine Encephalitis (Eee) Virus Transmission In Alabama, Ana Lucia Oliveira

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osteoporosis susceptibility, perceived osteoporosis severity, perceived barriers to


Pneumococcal Vaccine Response And Aging In Human, Saeyoung Park Jan 2010

Pneumococcal Vaccine Response And Aging In Human, Saeyoung Park

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Streptococcus pneumoniae is a major human pathogen, especially for young children and older adults. To protect from pneumococcal diseases, 23-valent pneumococcal polysaccharide vaccine (PPV23) has been used clinically since 1983. However, PPV23 is not so effective among old adults with its protective efficacy diminishing with age. We confirmed that young and old adults, who were immunized with PPV23, have comparable pneumococcal polysaccharide (PS) specific IgG levels. Interestingly, we found that old adults had lower IgA and IgM antibody levels than young adults for three serotypes (serotype 14, 18C and 23F). Consistent with the previous results, opsonic capacities of immune sera …


The Role Of Socioeconomic Factors In Racial And Ethnic Disparities Among Child And Adult Tuberculosis Cases, Spatial And Non-Spatial Analysis: Alabama 1993-2007, Sharada Adolph Jan 2010

The Role Of Socioeconomic Factors In Racial And Ethnic Disparities Among Child And Adult Tuberculosis Cases, Spatial And Non-Spatial Analysis: Alabama 1993-2007, Sharada Adolph

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This study aimed to evaluate the role of individual and community/population level socioeconomic factors on racial/ethnic disparities among children and adults with TB, and used area-based socioeconomic measures (ABSMs) for the identification of high-risk geographic areas for populations-at-risk. Joinpoint, multivariable and Poisson regression, and spatial methods were used to determine the trends and risks of disease in a low TB incidence state. General disease trends declined significantly by factors of -0.044838 from 1993-1998, and -0.061821 from 2001-2007; but, were disparate and increased for the foreign-born, African Americans (AA) and Latinos, and in long-term care settings. The average annual percentage change …


The Role Of Toll-Like Receptors 2 And 4 In Helicobacter Felis Infections And Asthma, Carolyn Durham Jan 2010

The Role Of Toll-Like Receptors 2 And 4 In Helicobacter Felis Infections And Asthma, Carolyn Durham

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The inverse correlation between the industrialization and disease prevalence is termed the "hygiene hypothesis." Supporting this, immunological studies show Th1 cytokines modulate Th2 immune responses. Because the mucosa is essential in antigenic exposure, understanding bacterial sensing here is critical to addressing three foundations of this hypothesis: the role of bacterial exposure, relevance of noninvasive bacterial exposure, and influence of these exposures on immune responses. Key components of antigen sensing in the mucosa are toll-like receptors (TLRs) 2 and 4, which have been implicated in disease. The hypothesis of this thesis is, by globally knocking out one or both of these …


An Assessment Of The Factors That Affect The Self-Care Behaviors Of Diabetics, Gregory Ellis Jan 2010

An Assessment Of The Factors That Affect The Self-Care Behaviors Of Diabetics, Gregory Ellis

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various heteroskedastic analysis of covariance (ANCOVA) models with orthogonal


Cellular Mechanisms Involved In Host Responses To Porphyromonas Gingivalis And Its Virulence Factor Hemagglutinin B, Dalia Emil Gaddis Jan 2010

Cellular Mechanisms Involved In Host Responses To Porphyromonas Gingivalis And Its Virulence Factor Hemagglutinin B, Dalia Emil Gaddis

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Porphyromonas gingivalis is a main causative agent for adult chronic periodontitis and immunization with its virulence factor Hemagglutinin B (HagB) provides protection against infection. Toll-like receptors (TLRs) recognize various microbial products and are crucial in eliciting and regulating the innate and adaptive immune responses to infections. The objective of this dissertation was to investigate the cellular mechanisms that influence the innate and adaptive immune response to HagB and P. gingivalis, focusing on the role of TLR signaling in the response. We started with investigating the ability of HagB to activate dendritic cells (DC), the most efficient antigen-presenting cell in priming …


Characterization Of The Oligosaccharides Of B. Anthracis Exosporium, Shengli Dong Jan 2010

Characterization Of The Oligosaccharides Of B. Anthracis Exosporium, Shengli Dong

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Fatal systemic anthrax is caused by exposure to spores of Bacillus anthracis. The outermost layer of the B. anthracis spore is called the exosporium. It consists of a paracrystalline basal layer and an external hair-like nap. The filaments of the hair-like nap are primarily composed of the glycoprotein BclA. Our previous studies showed that a 715-Da tetrasaccharide and a 324-Da disaccharide are attached to BclA through GalNAc. We named the novel nonreducing terminal sugar of the 715-Da tetrasaccharide anthrose. We subsequently proposed a plausible anthrose biosynthetic pathway and identified a gene cluster of four continuous genes that appeared to encode …


Exosomal Curcumin: Its Bioavailability And Potential Anti-Inflammation Activity, Dongmei Sun Jan 2010

Exosomal Curcumin: Its Bioavailability And Potential Anti-Inflammation Activity, Dongmei Sun

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Curcumin, a pleiotropic polyphenol derived from turmeric plants Curcuma Longa with rhizome, exhibits strong evidence as an anti-inflammation, anti-oxidant and anti-cancer reagent both in vitro and in vivo. Due to its low stability and systemic bioavailability, a large amount of curcumin has to be administrated to achieve therapeutic effects both in animal and in human. The major effort to overcome this barrier is making by encapsulation of curcumin into nanoparticles such as polymers and liposomes; some promising data have demonstrated the effectiveness of such method. Exosomes are vesicle-like nanoparticles secreted by living cells. Exosomes contain both cell surface molecules and …


Genotyping Of Streptococcus Mutans Using Multilocus Sequence Typing, Stephanie Momeni Jan 2010

Genotyping Of Streptococcus Mutans Using Multilocus Sequence Typing, Stephanie Momeni

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ABSTRACT The role of Streptococcus mutans has been extensively studied using a variety of genotyping techniques. Repetitive extragenic palindromic polymerase chain reaction (rep-PCR) is an effective tool for screening large-scale epidemiological studies with high discriminatory power and reproducibility. For this study, multilocus sequence typing (MLST) analysis is used to evaluate genotypes previously identified as unique using rep-PCR. Twenty-two unique S. mutans rep- PCR genotypes were selected from a longitudinal study. Four additional isolates were selected from each genotype group of the 6 most commonly occurring genotypes (n=30) for further analysis. Real-time PCR was performed using eight housekeeping S. mutans gene …


Examination Of The Capacity Of The Cathelicidins To Control Bacillus Anthracis Pathogenesis, Mark W. Lisanby Jan 2009

Examination Of The Capacity Of The Cathelicidins To Control Bacillus Anthracis Pathogenesis, Mark W. Lisanby

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cillus anthracis is a gram-positive, spore forming bacterium that causes infection through three routes: cutaneous, gastrointestinal and pulmonary. Historically, anthrax pathogenesis was thought to be initiated via the uptake of spores by resident macrophages, which then transited to the regional lymph nodes. While en-route, the spores germinated and developed into bacilli within the phagolysosome, escaped into the cytoplasm, killed the cell and eventually the host. Following the recent use of B. anthracis as a biological weapon, researchers began to reevaluate anthrax pathogenesis in order to develop novel treatments. One aspect of anthrax pathogenesis that saw renewed interest was the intracellular …


Immunotherapy Of Cancer Employing Γδ-T Cells: A Study Examining Their Utility And Feasibility, Benjamin Hester Beck Jan 2009

Immunotherapy Of Cancer Employing Γδ-T Cells: A Study Examining Their Utility And Feasibility, Benjamin Hester Beck

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Unlike antigen-specific alpha beta-T cells, gamma delta-T cells can recognize and lyse cancerous cells rapidly upon encounter in a manner that does not require the recognition of tumor-specific antigens. Given the well-documented capacity of gamma delta-T cells to innately kill malignant cells, efforts are now underway to exploit the antitumor properties of gamma delta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gamma delta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively-transferred gamma delta-T cells would be employed therapeutically against breast …


The Significance Of Heavy Chain Cdr3 Diversity In The Antibody Response To Polysaccharides, Tamer Mahmoud Jan 2009

The Significance Of Heavy Chain Cdr3 Diversity In The Antibody Response To Polysaccharides, Tamer Mahmoud

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An understanding of the molecular mechanisms involved in the generation of protective antibody responses to polysaccharides associated with pathogenic microorganisms is of importance for improving vaccine design. The heavy chain third complementarity-determining region (HCDR3) of an antibody molecule is at the center of its antigen-binding site and plays a determinative role in antigen recognition. The goal of this dissertation was to investigate the role of HCDR3 diversity and composition on the antibody response to the polysaccharide α 1→3 Dextran (DEX). In the first study, we investigated the role of TdT, a DNA polymerase that plays a major role in generating …


Analysis Of The Malaria Vaccine Potential Of Plasmodium Falciparum Merozoite Surface Protein-3, Stephen James Jordan Jan 2009

Analysis Of The Malaria Vaccine Potential Of Plasmodium Falciparum Merozoite Surface Protein-3, Stephen James Jordan

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Malaria causes an estimated 1-3 million deaths each year, with the majority of deaths being a result of infection with Plasmodium falciparum. No commercially available vaccine currently exists, but multiple subunit-based vaccines are in development including one based on the promising vaccine candidate P. falciparum Merozoite Surface Protein-3 (PfMSP3). PfMSP3 varies in sequence between P. falciparum isolates, but all variation is restricted to the N-terminal domain. This observation has lead to the development of a PfMSP3-based vaccine comprised solely of the highly conserved, yet poorly immunogenic, C-terminal domain. The rationale for supporting the C-terminal domain relies entirely on its conserved …


The Cultural Worldview Of Allopthic And Naturopathic Physicians, Cullen Clark Jan 2009

The Cultural Worldview Of Allopthic And Naturopathic Physicians, Cullen Clark

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Worldview is the socio-cultural compass with which we navigate the existential mysteries of life. It is our way of seeing – and being in – the world. As such it influences every aspect of culture from art to medicine. This exploratory study uses a sequential design combining quantitative and qualitative methodology to explore the worldview of allopathic and naturopathic physicians. Using survey research, the study identifies five basic components of competing worldviews among allopathic (n = 550) and naturopathic physicians (n = 399). It measures agreement among the two groups with these components and explores their influence upon support for …


Protein Trafficking And 4.1r Relocalization In Plamodium Falciparum-Infected Erythrocytes, Lindsay A. Parish Jan 2009

Protein Trafficking And 4.1r Relocalization In Plamodium Falciparum-Infected Erythrocytes, Lindsay A. Parish

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Malaria is a mosquito-borne infectious disease that is caused by parasites in the genus Plasmodium. There are four species of malaria that routinely infect humans, but it is P. falciparum that is responsible for the majority of the severe and fatal cases of malaria. P. falciparum has a complex life cycle involving a mosquito vector and intracellular stages in both hepatocytes and erythrocytes; however, it is only the intraerythrocytic stages that are the cause of the pathology associated with malaria. This pathology is largely due to the ability of infected erythrocytes to cytoadhere to host microvasculature. After invasion, the parasite …


Late Development Plasticity In The T Helper 17 Lineage, Yun Kyung Lee Jan 2009

Late Development Plasticity In The T Helper 17 Lineage, Yun Kyung Lee

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CD4 T cells are a principal component of the adaptive immune system that is required for the efficient elimination of foreign antigens, but dysregulated CD4 T cells responses may result in autoimmune and chronic inflammatory diseases. The differentiation of effector CD4 T cells is directed by cytokines elicited by pathogendriven innate immune responses. Therefore the coordinated innate and adaptive immune responses provide an efficient system for host protection. Our understanding of distinct differentiated CD4 T cells has recently expanded with the discovery of the Th17 lineage, a new subset of effector CD4 T cells that has been implicated in chronic …