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The Global ETD Search service is a free service for researchers
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Networked Digital Library of Theses and Dissertations.
Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
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Showing 701 to 706 of 706 (0.127 seconds)| 701 |
Identification and characterization of microRNAs which moderate neutrophil migration and acute inflammationAlan Y Hsu (8912033) 09 September 2022 (has links)
<p>Neutrophils are the first cells recruited to an immune
stimulus stemming from infection or sterile injuries via a mixture of
chemoattractant cues. In addition to eliminating pathogens, neutrophils
coordinate the overall inflammation by activating and producing inflammatory
signals in the tissue while modulating the activation of other immune cells
which in some cases leads to adverse tissue damage. Over amplified or chronic
neutrophil recruitment directly leads to autoimmune diseases including
rheumatic arthritis, diabetes, neurodegenerative diseases, and cancer.
Dampening neutrophil recruitment is a strategy to intervene in
neutrophil-orchestrated chronic inflammation. Despite intensive research over
the past several decades, clinical studies targeting neutrophil migration have
been largely unsuccessful, possibly due to the prominent redundancy of adhesion
receptors and chemokines. Additional challenges lie in the balance of dampening
detrimental inflammation while preserving immunity. Neutrophils are terminally
differentiated cells that are hard to study in cell culture. Mouse models are
often used to study hematopoiesis, migration, and chemotaxis of neutrophils but
is very labor intensive. To discover novel therapeutic targets that modulate
neutrophil migration, we performed a neutrophil-specific microRNA (miRNA)
overexpression screen in zebrafish and identified eight miRNAs as potent
suppressors of neutrophil migration. We have generated transgenic zebrafish
lines that overexpresses these candidate miRNAs where we recapitulated the
mitigation in neutrophil motility and chemotaxis to tissue injury or infection.
Among those we further characterized two miRNAs which have not been reported to
regulate neutrophil migration, namely miR-722 and miR-199.</p>
<p> </p>
<p>MiR-722 downregulates the transcript level of <i>rac2</i> through binding to the <i>rac2</i> 3'UTR. Furthermore, miR-722-overexpressing
larvae display improved outcomes in both sterile and bacterial systemic models,
which correlates with a robust upregulation of the anti-inflammatory cytokines
in the whole larvae and isolated neutrophils. miR-722 protects zebrafish from lethal lipopolysaccharide
challenge. In addition, overexpression of mir-722 reduced chemotaxis of human
neutrophil like cells, indicating that miR-722
is a potential agent to reduce inflammation in humans. </p>
<p>MiR-199<i>,</i> decreases neutrophil chemotaxis in zebrafish
and human neutrophil-like cells. Intriguingly, in terminally differentiated
neutrophils, miR-199 alters the cell cycle-related pathways and
directly suppresses cyclin-dependent kinase 2 (<i>cdk2</i>), whose known
activity is restricted to cell cycle progression and cell differentiation.
Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis
of zebrafish neutrophils without inducing cell death. Human neutrophil-like
cells deficient in CDK2 fail to polarize and display altered signaling
downstream of the formyl peptide receptor. Chemotaxis of primary human
neutrophils is also reduced upon CDK2 inhibition. Furthermore, miR-199 overexpression
or CDK2 inhibition significantly improves the outcome of lethal systemic
inflammation challenges in zebrafish. </p>
<p> </p>
<p>In summary, our results reveal previously unknown functions
of these miRNAs, and
provide potential avenues to modulate neutrophil migration as well as lead to
discoveries of novel factors which can regulate this process. We have also
discovered a non-classical role of CDK2 in regulating neutrophil migration
which provides directions for alleviating systemic inflammation and a better
understanding of neutrophil biology. </p>
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| 702 |
MODELING AND SIMULATION OF OSTEOCYTE-FLUID INTERACTION IN A LACUNO-CANALICULAR NETWORK IN THREE DIMENSIONSNigar Karimli (20372055) 10 January 2025 (has links)
<p dir="ltr">Bone health relies on its cells' ability to sense and respond to mechanical forces, a process primarily managed by osteocytes embedded within the bone matrix. The cells reside in the lacuno-canalicular network (LCN), a complex structure, comprised of lacunae (small cavities) and canaliculi (microscopic channels), through which they communicate and receive nutrients. The mechanotransduction (MT) process, by which osteocytes convert mechanical signals from mechanical loading into biochemical responses, is essential for bone remodeling but remains poorly understood. Both in-vitro and in-vivo studies present challenges in directly measuring the cellular stresses and strains involved, making computational modeling a valuable tool for studying osteocyte mechanics.</p><p> </p><p dir="ltr">In this dissertation, we present a coarse-grained, integrative model designed to simulate stress and strain distributions within an osteocyte and its microenvironment. Our model features the osteocyte membrane represented as a network of viscoelastic springs, with six slender, arm-like osteocytic processes extending from the membrane. The osteocyte is immersed in interstitial fluid and encompassed by the rigid extracellular matrix (ECM). The cytosol and interstitial fluid are both modeled as water-like, viscous incompressible fluids, allowing us to capture the fluid-structure interactions crucial to understanding the MT.</p><p> </p><p dir="ltr">To simulate these interactions, we employ the Lattice Boltzmann - Immersed Boundary (LB-IB) method. This approach couples the Lattice Boltzmann method, which numerically solves fluid equations, with the immersed boundary method, which handles the interactions between the osteocyte structures and the surrounding fluids. This framework consists of a system of integro-partial differential equations describing both fluid and solid dynamics, enabling a detailed examination of force, strain, and stress distribution within the osteocyte. Major results include 1) increased incoming flow routes results in increased stress and strain, 2) regions of higher stress and strain are concentrated near the junctions where the osteocytic processes meet the main body.</p>
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| 703 |
Demography of Birch Populations across ScandinaviaSendrowski, Janek January 2022 (has links)
Boreal forests are particularly vulnerable to climate change, experiencing a much more drastic increase in temperatures and having a limited amount of more northern refugia. The trees making up these vast and important ecosystems already had to adapt previously to environmental pressures brought about by the repeated glaciations during past ice ages. Studying the patterns of adaption of these trees can thus provide valuable insights on how to mitigate future damage. This thesis presents and analyses population structure, demo- graphic history and the distribution of fitness effects (DFE) of the diploid Betula pendula and tetraploid B. pubescens across Scandinavia. Birches–being widespread in boreal forests as well as having great economical importance–constitute superb model species. The analyses of this work confirm the expectations on postglacial population expansion and diploid-tetraploid introgression. They furthermore ascertain the presence of two genetic clusters and a remarkably similar DFE for the species. This work also contributes with a transparent, reproducible and reusable pipeline which facilitates running similar analyses for related species.
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| 704 |
Cis-regulation and genetic control of gene expression in neuroblastomaBurkert, Christian Martin 28 June 2021 (has links)
Genregulation beeinflusst Phänotypen im Kontext von Gesundheit und Krankheit. In Krebszellen regulieren genetische und epigenetische Faktoren die Genexpression in cis. Das Neuroblastom ist eine Krebserkrankung, die häufig im Kindesalter auftritt. Es ist gekennzeichnet durch eine geringe Anzahl exonischer Mutationen und durch häufige Veränderungen der somatischen Kopienzahl, einschließlich Genamplifikationen auf extrachromosomaler zirkulärer DNA. Bisher ist wenig darüber bekannt, wie lokale genetische und epigenetische Faktoren Gene im Neuroblastom regulieren. In dieser Arbeit kombiniere ich die allelspezifische Analyse ganzer Genome (WGS), Transkriptome und zirkulärer DNA von Neuroblastom-Patienten, um genetische und cis-regulatorische Effekte zu charakterisieren. Ich zeige, dass somatische Dosis-Effekte der Kopienzahl andere lokale genetische Effekte dominieren und wichtige Signalwege regulieren. Genamplifikationen zeigen starke Dosis-Effekte und befinden sich häufig auf großen extrachromosomalen zirkulären DNAs. Die vorgestellte Analyse zeigt, dass der Verlust von 11q zu einer Hochregulation von Histonvarianten H3.3 und H2A in Tumoren mit alternativer Verlängerung der Telomere (ALT) führt, und dass erhöhte somatische Kopienzahl die Expression der TERT Gens verstärken können. Weitere Erkenntnisse sind, dass 17p-Ungleichgewichte und die damit verbundene Herunterregulierung neuronaler Gene sowie die Hochregulierung des genomisch geprägten Gens RTL1 durch Kopienzahl-unabhängige allelische Dosis-Effekte mit einer ungünstigen Prognose verbunden sind. Die cis-QTL-Analyse bestätigt eine zuvor beschriebene Regulation des LMO1 Gens durch einen Enhancer-Polymorphismus und charakterisiert das regulatorische Potenzial weiterer GWAS-Risiko-Loci. Die Arbeit unterstreicht die Bedeutung von Dosis-Effekten im Neuroblastom und liefert eine detaillierte Übersicht regulatorischer Varianten, die in dieser Krankheit aktiv sind. / Gene regulation controls phenotypes in health and disease. In cancer, the interplay between germline variation, genetic aberrations and epigenetic factors modulate gene expression in cis. The childhood cancer neuroblastoma originates from progenitor cells of the sympathetic nervous system. It is characterized by a sparsity of recurrent exonic mutations but frequent somatic copy-number alterations, including gene amplifications on extrachromosomal circular DNA. So far, little is known on how local genetic and epigenetic factors regulate genes in neuroblastoma to establish disease phenotypes. I here combine allele-specific analysis of whole genomes, transcriptomes and circular DNA from neuroblastoma patients to characterize genetic and cis-regulatory effects, and prioritize germline regulatory variants by cis-QTLs mapping and chromatin profiles. The results show that somatic copy-number dosage dominates local genetic effects and regulates pathways involved in telomere maintenance, genomic stability and neuronal processes. Gene amplifications show strong dosage effects and are frequently located on large but not small extrachromosomal circular DNAs. My analysis implicates 11q loss in the upregulation of histone variants H3.3 and H2A in tumors with alternative lengthening of telomeres and cooperative effects of somatic rearrangements and somatic copy-number gains in the upregulation of TERT. Both 17p copy-number imbalances and associated downregulation of neuronal genes as well as upregulation of the imprinted gene RTL1 by copy-number-independent allelic dosage effects is associated with an unfavorable prognosis. cis-QTL analysis confirms the previously reported regulation of the LMO1 gene by a super-enhancer risk polymorphism and characterizes the regulatory potential of additional GWAS risk loci. My work highlights the importance of dosage effects in neuroblastoma and provides a detailed map of regulatory variation active in this disease.
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| 705 |
A Novel Approach to Identify Candidate Imprinted Genes in HumansShapiro, Jonathan 21 March 2012 (has links)
Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood.
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| 706 |
A Novel Approach to Identify Candidate Imprinted Genes in HumansShapiro, Jonathan 21 March 2012 (has links)
Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood.
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