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Full-Text Articles in Medicine and Health Sciences

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster Aug 2017

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster

GSBS Dissertations and Theses

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...


Genetic Approaches To Study Transcriptional Activation And Tumor Suppression: A Dissertation, Ling Lin May 2012

Genetic Approaches To Study Transcriptional Activation And Tumor Suppression: A Dissertation, Ling Lin

GSBS Dissertations and Theses

The development of methods and techniques is the driving force of scientific research. In this work, we described two large-scale screens in studying transcriptional activation and tumor suppression.

In Part I, we studied transcriptional activation mechanisms by deriving and characterizing activation defective mutants. Promoter-specific transcriptional activators stimulate transcription through direct interactions with one or more components of the transcription machinery, termed the “target.” The identification of direct in vivo targets of activators has been a major challenge. We perform a large-scale genetic screen to derive and characterize tra1 alleles that are selectively defective for interaction with Gal4 in vivo. Utilizing ...


Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra Feb 2012

Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra

GSBS Dissertations and Theses

T lymphocytes are distinguished by the expression of αβ TCR or γδ TCR on their cell surface. The kinetic differences in the effector functions classifies γδ T cells as innate-like lymphocytes and αβ T cells as adaptive lymphocytes. Although distinct, αβ and γδ T cell lineages produce a common array of cytokines to mount an effective immune response against a pathogen. The production of cytokine IL-17 is a shared characteristic between the γδ T (Tγδ17) cells and the CD4 T (Th17) cells. γδ T cells develop into Tγδ17 cells in the thymus whereas CD4 T cells differentiate into Th17 cells ...


Intestine Homeostasis And The Role Of Tumor Suppressor Gene 101 In Drosophila Melanogaster: A Dissertation, Madhurima Chatterjee Dec 2011

Intestine Homeostasis And The Role Of Tumor Suppressor Gene 101 In Drosophila Melanogaster: A Dissertation, Madhurima Chatterjee

GSBS Dissertations and Theses

Tissue homeostasis in the adult Drosophila melanogaster intestine is maintained by controlling the proper balance of stem cell self-renewal and differentiation. In the adult fly midgut, intestinal stem cells (ISCs) are the only dividing cells and their identity maintenance is crucial to the proper functioning of the fly gut. Various pathways such as Notch, JAK-STAT and Wingless are known to regulate ISC division and differentiation.

Here I used a pathogen feeding model to study conditions that accelerate ISC division and guide intestinal cell differentiation favoring enterocyte development. I also examined the role of Tumor Suppressor Gene 101 (TSG101) in ISC ...


Conformational Lability In Mhc Ii Proteins: A Dissertation, Corrie A. Painter May 2011

Conformational Lability In Mhc Ii Proteins: A Dissertation, Corrie A. Painter

GSBS Dissertations and Theses

MHC II proteins are heterodimeric glycoproteins that form complexes with antigenic peptides in order to elicit a CD4+ adaptive immune response. Even though there have been numerous MHC II-peptide crystal structures solved, there is little insight into the dynamic process of peptide loading. Through biochemical and biophysical studies, it has been shown that MHC II adopt multiple conformations throughout the peptide loading process. At least one of these conformations is stabilized by the MHC II-like homologue, HLA-DM. The main focus of this thesis is to elucidate alternate conformers of MHC II in an effort to better understand the structural features ...


The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan Mar 2011

The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan

GSBS Dissertations and Theses

The immune system generates discrete lineages of cells that are designed to respond optimally to environmental cues and infectious agents. Two distinct lineages of T cells, distinguished by expression of either an αβ or γδ T cell receptor (TCR), arise from a common progenitor in the thymus. The type of pathogen and the cytokine milieu directs effector differentiation of αβ T cells in the periphery through the induction of specific transcriptional networks. γδ T cell development is distinct from that of αβ T cells in its ordered rearrangement of TCR genes and the pairing of Vγ and Vδ chains to ...


Structural And Functional Studies Of Proteins Involved In Antigen Processing: A Dissertation, Tina T. Nguyen Aug 2010

Structural And Functional Studies Of Proteins Involved In Antigen Processing: A Dissertation, Tina T. Nguyen

GSBS Dissertations and Theses

This thesis is comprised of studies of proteins involved in class I and class II major histocompatibility complex (MHC) antigen procressing. In class I MHC processing, structural and functional studies were conducted of an aminopeptidase, ERAP1, that mediates the final step in antigen processing to understand how it is particularly suitable for cleavage of antigenic peptides for class I MHC presentation. In the class II MHC antigen presentation pathway, structural studies were conducted to characterize a fluorogenic peptide that can be used to understand peptide loading events in vivo and in real time. Also structural studies of class II MHC ...


A Novel Motif In Hiv-1 Nef That Regulates Mip-1Β Chemokine Release In Macrophages: A Dissertation, Lue Dai Jun 2010

A Novel Motif In Hiv-1 Nef That Regulates Mip-1Β Chemokine Release In Macrophages: A Dissertation, Lue Dai

GSBS Dissertations and Theses

Nef is an accessory protein encoded by human and simian immunodeficiency viruses (HIV and SIV), and is critical for viral pathogenicity in vivo.The structure of Nef has been resolved and the major cellular activities of Nef are generally described as down-regulation of cell surface molecules, enhancement of virus infectivity and regulation of cell signaling and activation. Macrophages represent a key target of HIV-1 infection and may contribute significantly to viral pathogenesis by facilitating viral propagation, maintaining a viral reservoir and regulating viral replication. During HIV-1 infection, various cytokines and chemokines are induced for viral advantages more than for host ...


Identification And Characterization Of Snapin As A Novel Antagonist Of Hiv-1 Egress: A Dissertation, Patrick Younan Apr 2010

Identification And Characterization Of Snapin As A Novel Antagonist Of Hiv-1 Egress: A Dissertation, Patrick Younan

GSBS Dissertations and Theses

Vpu has been shown to possess two distinct roles in the pathogenesis of HIV. First, Vpu has been shown to down-regulate the expression of CD4 molecules at the plasma membrane of infected cells by targeting CD4 molecules for degradation in the endoplasmic reticulum. Second, Vpu promotes viral egress in specific cell lines termed non-permissive cells by mechanism that remain relatively unclear.

Therefore, experiments were conducted in order to identify cellular factors involved in the Vpu-dependent phenotype. Using full-length Vpu as bait in yeast two-hybrid experiments, several candidate cellular factors were identified. One protein, SNAPIN, was identified as a cellular factor ...


Defining The Roles Of P300/Cbp (Creb Binding Protein) And S5a In P53 Polyubiquitination, Degradation And Dna Damage Responses: A Dissertation, Dingding Shi Jan 2010

Defining The Roles Of P300/Cbp (Creb Binding Protein) And S5a In P53 Polyubiquitination, Degradation And Dna Damage Responses: A Dissertation, Dingding Shi

GSBS Dissertations and Theses

p53, known as the “guardian of the genome”, is the most well-characterized tumor suppressor gene. The central role of p53 is to prevent genome instability. p53 is the central node in an incredibly elaborate genome defense network for receiving various input stress signals and controlling diverse cellular responses. The final output of this network is determined not only by the p53 protein itself, but also by other p53 cooperating proteins.

p300 and CBP (CREB-Binding Protein) act as multifunctional regulators of p53 via acetylase and ubiquitin ligase activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 ...


Defining The Role Of Ctbp2 In P53-Independent Tumor Suppressor Function Of Arf: A Dissertation, Ramesh C. Kovi Jun 2009

Defining The Role Of Ctbp2 In P53-Independent Tumor Suppressor Function Of Arf: A Dissertation, Ramesh C. Kovi

GSBS Dissertations and Theses

ARF, a potent tumor suppressor, positively regulates p53 by antagonizing MDM2, a negative regulator of p53, which in turn, results in either apoptosis or cell cycle arrest. ARF also suppresses the proliferation of cells lacking p53, and loss of ARF in p53-null mice, compared with ARF-null or p53-null mice, results in a broadened tumor spectrum and decreased tumor latency. This evidence suggests that ARF exerts both p53-dependent and p53-independent tumor suppressor activity. However, the molecular pathway and mechanism of ARF’s p53-independent tumor suppressor activity is not understood.

The antiapoptotic, metabolically regulated, transcriptional corepressor C-terminal binding protein 2 (CtBP2) has ...


Delineating The C. Elegans Microrna Regulatory Network: A Dissertation, Natalia Julia Martinez Apr 2009

Delineating The C. Elegans Microrna Regulatory Network: A Dissertation, Natalia Julia Martinez

GSBS Dissertations and Theses

Metazoan genomes contain thousands of protein-coding and non-coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans-regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis-regulatory DNA elements that are often located in or near their target genes, while microRNAs hybridize to cis-regulatory RNA elements mostly located in the 3’ untranslated region (3’UTR) of their target mRNAs.

My work in the ...


The Role Of The Mrn Complex In The S-Phase Dna Damage Checkpoint: A Dissertation, Mary Elizabeth Porter-Goff Jan 2009

The Role Of The Mrn Complex In The S-Phase Dna Damage Checkpoint: A Dissertation, Mary Elizabeth Porter-Goff

GSBS Dissertations and Theses

The main focus of my work has been the role of the MRN in the S-phase DNA damage checkpoint. The MRN plays many roles in cellular metabolism; some are checkpoint dependent and some are checkpoint independent. The multiple roles in cellular metabolism complicate study of the role of the MRN in the checkpoint. MRN mutations in budding yeast and mammals may display separation of function. Mechanistically, MRN, along with its cofactor Ctp1, is involved in 5’ resection to create single stranded DNA that is required for both signaling and homologous recombination. However, it is unclear if resection is essential for ...


Dna Damage-Induced Apoptosis In The Presence And Absence Of The Tumor Suppressor P53: A Dissertation, Laura Michelle Mcnamee Oct 2008

Dna Damage-Induced Apoptosis In The Presence And Absence Of The Tumor Suppressor P53: A Dissertation, Laura Michelle Mcnamee

GSBS Dissertations and Theses

A key regulator of DNA damage-induced apoptosis is the tumor suppressor gene, p53. p53 is a transcription factor that upregulates genes involved in cell cycle arrest, apoptosis, and senescence. How p53 decides to activate one of these responses in response to DNA damage is largely unanswered. Many have hypothesized it is due to interaction with various signaling pathways and post-translational modification. The p53 tumor suppressor can be modified by SUMO-1 in mammalian cells, but the functional consequences of this modification are unclear. Conjugation to SUMO is a reversible post-translational modification that regulates several transcription factors involved in cell proliferation, differentiation ...


Characterization Of The Bach1 Helicase In The Dna Damage Response Pathway: A Dissertation, Rachel Litman Feb 2007

Characterization Of The Bach1 Helicase In The Dna Damage Response Pathway: A Dissertation, Rachel Litman

GSBS Dissertations and Theses

DNA damage response pathways are a complicated network of proteins that function to remove and/or reverse DNA damage. Following genetic insult, a signal cascade is generated, which alerts the cell to the presence of damaged DNA. Once recognized, the damage is either removed or the damaged region is excised, and the original genetic sequence is restored. However, when these pathways are defective the cell is unable to effectively mediate the DNA damage response and the damage persists unrepaired. Thus, the proteins that maintain the DNA damage response pathway are critical in preserving genomic stability.

One essential DNA repair protein ...


Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar May 2006

Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar

GSBS Dissertations and Theses

Mature αβ and γδ T cells arise from a common precursor population in the thymus. Much debate has focused on the mechanism of T cell lineage choice made by these multi-potential precursor cells. It is widely believed that the decision of these precursor cells to commit to the γδ or αβ T cell lineages is regulated primarily by a specific instructive signal relayed through the appropriate T cell receptor. Contrary to this model, we present evidence for a TCR-independent lineage commitment process. Comparison of global gene expression profiles from immature αβ and γδ lineage thymocytes identified Sox13, an HMG-box transcription ...


Rb Inactivation Leads To E2f1-Mediated Dna Double Strand Break Accumulation: A Dissertation, Mary Theresa Pickering Apr 2006

Rb Inactivation Leads To E2f1-Mediated Dna Double Strand Break Accumulation: A Dissertation, Mary Theresa Pickering

GSBS Dissertations and Theses

Although it is unclear which cellular factor(s) is responsible for the genetic instability associated with initiating and sustaining cell transformation, it is known that most, if not all, cancers have mutations that inactivate the Rb-mediated growth control pathway. We show here that acute inactivation of Rb by RNA interference or expression of the E7 viral oncoprotein from human papillomavirus (HPV), and the resultant deregulation of one E2F family member, E2F1, leads to DNA double strand break (DSB) accumulation. These DSBs occur independent of apoptosis induction, and activation of ATM, NBS1, p53, or MAD2, and generation of reactive oxygen species ...


Cd4+ T Cell Responses: A Complex Network Of Activating And Tolerizing Signals As Revealed By Gene Expression Analysis: A Dissertation, David Spaulding Brown Sep 2005

Cd4+ T Cell Responses: A Complex Network Of Activating And Tolerizing Signals As Revealed By Gene Expression Analysis: A Dissertation, David Spaulding Brown

GSBS Dissertations and Theses

Immunologic self-tolerance is maintained by both central and peripheral mechanisms. Furthermore, regulation of mature lymphocyte responses is governed by inhibitory as well as stimulatory signals. TCR recognition of cognate peptide bound to MHC molecules provides the initial stimulus leading to T lymphocyte activation and determines the antigen specificity of any subsequent response. However, lymphocytes must discriminate between foreign and self antigens presented by self-MHC molecules to maintain self tolerance and avoid pathological autoimmunity. Consequently, TCR ligation alone is reported to result in abortive activation, T cell anergy, apoptosis, and tolerance. Under normal physiological conditions, costimulatory signals modify lymphocyte responsiveness to ...


Functions Of The Cdc14-Family Phosphatase Clp1p In The Cell Cycle Regulation Of Schizosaccharomyces Pombe: A Dissertation, Susanne Trautmann May 2005

Functions Of The Cdc14-Family Phosphatase Clp1p In The Cell Cycle Regulation Of Schizosaccharomyces Pombe: A Dissertation, Susanne Trautmann

GSBS Dissertations and Theses

In order to generate healthy daughter cells, nuclear division and cytokinesis need to be coordinated. Premature division of the cytoplasm in the absence of chromosome segregation or nuclear proliferation without cytokinesis might lead to aneuploidy and cancer.

The cyclin dependent kinases, CDKs, are a main regulator of the cell cycle. Timely increase and decrease in their activity is required for cell cycle progression. To enter mitosis, mitotic CDK activity needs to rise. CDK activity stays elevated until chromosome segregation is completed and exit from mitosis requires decrease in CDK activity.

Observations in several experimental systems suggest that coordination of cytokinesis ...


Mhc Class I Antigen Presentation Is Regulated By The Sumo-Conjugating Enzyme Ubc9: A Dissertation, Yuelei Shen Jun 2003

Mhc Class I Antigen Presentation Is Regulated By The Sumo-Conjugating Enzyme Ubc9: A Dissertation, Yuelei Shen

GSBS Dissertations and Theses

CD8 T cells recognize complexes of MHC class I and peptide on the surface of target cells. MHC class I antigen presentation is a long pathway, in which proteins are degraded by proteasomes to generating oligopeptides, which may be further trimmed by aminopeptidases in the cytosol. Peptides are transported into the ER, where they may be further trimmed by ER lumenal aminopeptidases and bind to newly-synthesized MHC class I complexes. Proteins degraded by the proteasome are generally tagged with ubiquitin by a combination of ubiquitin-conjugating enzymes and ubiquitin ligases. UBC9 is one ubiquitin conjugating enzyme, which does not conjugate ubiquitin ...


Role Of C-Jun Nh-Terminal Kinase In Bcr/Abl Induced Cell Transformation: A Dissertation, Patricia M. Hess Apr 2003

Role Of C-Jun Nh-Terminal Kinase In Bcr/Abl Induced Cell Transformation: A Dissertation, Patricia M. Hess

GSBS Dissertations and Theses

The c-Jun NH2-terminal kinase (JNK) group of kinases include ten members that are created by alternative splicing of transcripts derived from Jnk1, Jnk2 and Jnk3 genes. The JNK1 and JNK2 protein kinases are ubiquitously expressed while JNK3 is expressed in a limited number of tissues. The JNK signaling pathway is implicated in multiple physiological processes including cell transformation. There is growing evidence that JNK signaling is involved in oncogenesis. Nevertheless, the role that JNK plays in malignant transformation is still unclear. The aim of this thesis is to examine the role of JNK in malignant transformation. For this ...


The Role Of The Swi/Snf Component Ini1 In Mammalian Development And Tumorigenesis: A Dissertation, Cynthia J. Guidi Feb 2003

The Role Of The Swi/Snf Component Ini1 In Mammalian Development And Tumorigenesis: A Dissertation, Cynthia J. Guidi

GSBS Dissertations and Theses

In vivo DNA is compacted tightly, via its association with histones and non-histone proteins, into higher-order chromatin structure. In this state, the DNA is refractory to the cellular factors that require access to DNA. The repressive nature of chromatin is alleviated in part by the action enzymes that modify chromatin structure. There are two major groups of chromatin modifying enzymes: those that post-translationally modify histones by the addition of small chemical moieties and those that utilize the energy derived from ATP hydrolysis to physically disrupt chromatin structure. The SWI/SNF enzyme belongs to this latter group.

The SWI/SNF complex ...


Regulation Of Transcription Of Mouse Immunoglobulin Germ-Line Γ1 Rna: Structural Characterization Of Germ-Line Γ1 Rna And Molecular Analysis Of The Promoter: A Dissertation, Minzhen Xu May 1991

Regulation Of Transcription Of Mouse Immunoglobulin Germ-Line Γ1 Rna: Structural Characterization Of Germ-Line Γ1 Rna And Molecular Analysis Of The Promoter: A Dissertation, Minzhen Xu

GSBS Dissertations and Theses

The antibody class switch is achieved by DNA recombination between the sequences called switch (S) regions located 5' to immunoglobulin (Ig) heavy chain constant (CH) region genes. This process can be induced in cultured B cells by polyclonal stimulation and switching can be directed to specific antibody classes by certain lymphokines. These stimuli may regulate the accessibility of CH genes and their S regions to a recombinase as indicated by hypomethylation and transcriptional activity. For example, RNAs transcribed from specific unrearranged (germ-line) CH genes are induced prior to switching under conditions that promote subsequent switching to these ...