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Biology - Ph.D. / Sc.D.

Mostrando recursos 1 - 20 de 886

  1. AGO2 in overexpression exhibits oncogenic functions KrasG̳1̳2̳D̳ -associated mouse tumor models

    Thai, Kevin K. (Kevin Kinh)
    Cancer is a disease of normal healthy cells that have accumulated genetic aberrations that contribute to uncontrolled cell divisions. Generally, cancer cells have acquired gain of function mutations in oncogenes that positively promote cell proliferation and growth. Simultaneously, mutations in tumor suppressor genes are frequently detected, allowing cells to evade cell cycle checkpoints, resulting in the inhibition of cell death signals. Therefore, identifying genetic abnormalities that promote tumor initiation and progression is imperative in the development of targeted therapeutics. This thesis focuses on the role of Argonaute-2 in promoting cellular transformation in mouse model systems, highlighting novel oncogenic functions associated...

  2. PHF6 modulates the chromatin landscape in B-cell leukemia

    Bartlebaugh, Jordan Michael Elizabeth
    Developmental and lineage plasticity have been observed in numerous malignancies, and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the Plant Homeodomain Finger Protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B- and T-cell specific factors. Additionally, Phf6KO cells show significant down-regulation...

  3. Genome engineering and functional gene regulation tools for the study of malaria parasites

    Falla Castillo, Diana Alejandra
    Plasmodium falciparum is the causative agent of the most severe form of human malaria, a mosquito-borne disease that remains a major global health problem. The efforts to create new antimalarial drugs and effective vaccines have been significantly hindered by the lack of robust tools for performing functional genetics in P. falciparum. The identification and characterization of essential functions for parasite survival are fundamental steps towards the creation of effective antimalarial therapies. In this work, we developed an integrated set of gene editing and functional gene regulation tools that enable the study of essential and non-essential genes in blood stage parasites....

  4. Evolutionary conservation and characterization of the metazoan amino acid response

    Edenius, Maja Lena
    Signaling pathways that respond to stress and sense nutrient availability are highly conserved throughout eukaryotes. In mammalian cells, these pathways have evolved to regulate immune responses, representing important therapeutic targets. Interestingly, components of these pathways can be found in plants, yeast and nematodes, where they also participate in response to abiotic and biotic stress. The Amino Acid Response (AAR) pathway, an ancient response to the cellular accumulation of uncharged tRNA, is part of the larger Integrated Stress Response (ISR) in mammals. The ISR consists of multiple branches, each one triggered by distinct stresses that produce phospho-eIF2x signal generation. Each ISR...

  5. Neoblast specialization during regeneration of the planarian S. mediterranea

    Kravarik, Kellie M. (Kellie Marie)
    Planarians are well known for their ability to regenerate an entire animal from small tissue fragments. Planarian regeneration requires a population of dividing cells called neoblasts that are distributed throughout the body. Historically, neoblasts have been considered a homogeneous population of stem cells capable of differentiating into all cell types. Most studies, however, analyze neoblasts at the population rather than the single cell level, making it difficult to determine how heterogeneous the neoblast population is. A bulk RNA sequencing approach with expression screening identified 33 new transcription factors transcribed in specific differentiated cells that were also expressed in small fractions...

  6. Taking shape : the path to myosin activation in the Drosophila ventral furrow

    Heer, Natalie C. (Natalie Claire)
    Creating biological form requires the generation of forces to rearrange tissues, as well as the patterning and organizational control of those forces to create the correct shapes. Force generation by actomyosin networks is a major driver of morphogenesis across many systems. The organization of actomyosin networks across multiple length scales is critical in generating biological form, including the Drosophila melanogaster ventral furrow. Using quantitative microscopy to measure the pattern of transcription, signaling, myosin activation, and cell shape in the Drosophila mesoderm, I found that cells within the ventral domain accumulate different amounts of active apical non-muscle myosin 2 depending on...

  7. Scalable platforms for computation and memory in living cells

    Farzadfard, Fahim
    Living cells are biological computers - constantly sensing, processing and responding to biological cues they receive over time and space. Devised by evolution, these biological machines are capable of performing many computing and memory operations, some of which are analogous to and some are distinct from man-made computers. The ability to rationally design and dynamically control genetic programs in living cells in a robust and scalable fashion offers unprecedented capacities to investigate and engineer biological systems and holds a great promise for many biotechnological and biomedical applications. In this thesis, I describe foundational platforms for computation and memory in living...

  8. Characterization of influenza A virus evolution in laboratory hosts

    Davis, Kimberly Ryan
    Surveillance of influenza A virus (IAV) is conducted for many different hosts including humans, swine, poultry, and wild birds. The surveillance samples are screened by various methods, but ultimately the isolates that are positive for IAV are propagated in a laboratory host prior to genome sequencing and characterization. Previous research has shown that passaging influenza viruses in laboratory hosts results in changes in viral sequence and receptor binding preferences. These studies have been limited to human IAV strains, and it remains unclear how propagation in laboratory hosts alters viruses isolated from animals. This thesis explores the evolutionary dynamics of IAV...

  9. Cdk12 regulates DNA repair Genes by suppressing intronic polyadenylation

    Dubbury, Sara Jane
    During transcription, cyclin-dependent kinases (CDKs) dynamically phosphorylate the C-terminal domain (CTD) of RNA Polymerase II (RNAPII) to recruit factors that coordinate transcription and mRNA biogenesis. Cdk12 phosphorylates Serine 2 (Ser2) of the RNAPII CTD, a modification associated with the regulation of transcription elongation, splicing, and cleavage/polyadenylation. Unlike other transcriptional CDKs that regulate most expressed genes, Cdk12 depletion abrogates the expression of homologous recombination (HR) genes relatively specifically, suppressing the HR DNA damage repair pathway and sensitizing cells to genotoxic stresses that cause replication fork collapse, such as Parp1 inhibitors. The proposed role for Cdk12 in regulating HR is clinically significant...

  10. The role of respiration in supporting cell proliferation

    Gui, Dan Y. (Dan Yi)
    Compared to non-proliferating cells, proliferating cells such as cancer cells have additional metabolic requirements for generating biomass. However, despite these additional requirements the components of the mammalian metabolic network in both proliferating and non-proliferating cells are largely the same. Thus, in order to balance the competing anabolic and catabolic needs of a proliferating cell, the same metabolic networks components must take on distinct roles. Understanding how the various network components support proliferation may lead to improvements in cancer therapy. It has long been known that mitochondrial respiration is essential for proliferation. However, the precise metabolic role that is filled by...

  11. Prion biology in the context of bacteria

    Yuan, Andy H. (Andy Han)
    Prions are infectious amyloid aggregates first described in the context of mammalian neurodegenerative diseases collectively known as the transmissible spongiform encephalopathies. Prions have also been uncovered in yeast, where they function as protein-based units of heredity that confer unique phenotypic traits on those cells that harbor them. To date, the discovery of prions and prion-like phenomena has been confined to the Eukarya. The work presented in this thesis seeks to explore the possibility that prion-like mechanisms are operative in the bacterial domain of life. In what follows, we demonstrate that Escherichia coli cells can propagate a model yeast prion in...

  12. Systematic determination of a transcription factor/binding site functional interaction landscape

    Moravec, Katie Lynn
    Cells require their genetic information to be expressed appropriately; the ability to modulate gene expression in a proper spatiotemporal response to external and internal signals is central to survival. Transcription factors are a major class of regulatory proteins that specifically bind DNA to modulate the expression of targeted genes. While they have been extensively studied, major questions remain about the protein-DNA interaction underlying this hub of regulation. What binding site sequences functionally interact with a given regulator? How does the regulon sample from available functional sequences? How independent is each half of a two part binding site? How do mutations...

  13. Structural and biochemical characterization of nuclear pore complex structural scaffold sub-complexes

    Kelley, Kotaro
    The nuclear pore complex (NPC) is a large, modular protein assembly that regulates nucleocytoplasmic transport in all eukaryotes. The ~60-120 MDa NPC is a modular assembly of multiple copies of ~30 distinct proteins that are arranged into biochemically distinct sub-complexes. We believe that the structural characterization of the NPC is essential for understanding its transport mechanisms and various pathologies and human diseases associated with deletions or mutations of constituents. To obtain detailed structural information of the NPC, techniques that span several resolution ranges are necessary due to its large size and complexity. For instance, recent progress in the structural characterization...

  14. Insights into microbial community structure from pairwise interaction networks

    Higgins, Logan Massie
    Microbial communities are typically incredibly diverse, with many species contributing to the overall function of the community. The structure of these communities is the result of many complex biotic and abiotic factors. In this thesis, my colleagues and I employ a bottom-up approach to investigate the role of interspecies interactions in determining the structure of multispecies communities. First, we investigate the network of pairwise competitive interactions in a model community consisting of 20 strains of naturally co-occurring soil bacteria. The resulting interaction network is strongly hierarchical and lacks significant non-transitive motifs, a result that is robust across multiple environments. Multispecies...

  15. The regulation of premature termination at divergent promoters

    Chiu, Anthony Chun-yin
    Transcription is one of the most fundamental processes in cells, governing the conversion of genetic information to RNA. Numerous regulatory mechanisms function to ensure that desired transcripts are being expressed. Promoters transcribe divergently, producing low-abundant upstream antisense RNAs (uaRNAs) in addition to a stable downstream RNAs. Thus, a central question is what mechanisms are sense RNAs more stable compared to most transcription events. It is proposed that an asymmetric distribution of Ul snRNP binding sites and polyadenylation site (PAS) motifs known as the UI-PAS axis regulates early termination of RNA Polymerase II. Here, we generated a conditional knockout of the...

  16. Examining the effects of environmental compounds on influenza virus ecology

    Bandoro, Christopher
    Influenza A virus (IAV) is a global threat. Infections in humans and highly-pathogenic IAV outbreaks in livestock substantially burden the economy. All past pandemics of IAV in humans and outbreaks in livestock have origins in viruses that previously circulated among wild aquatic birds, which are the natural reservoir for the virus. IAV can also jump from wild birds into other animals including marine mammals. This thesis explores the effects of environmental compounds, including bacteria and pollutants, on the ecology of IAV. In the first study, I demonstrate that gastrointestinal tract bacterial isolates reduce the thermal stability of IAV. Moreover, bacterial...

  17. Horizontal gene transfer as a cohesive force in microbial populations

    Arevalo, Philip A. (Philip Alexander)
    Populations are the central unit of evolution and ecology. In the context of evolution, populations are commonly defined as groups of organisms with a shared gene pool in which adaptive genes can spread freely through natural selection. Ecology takes a less abstract view of populations and conceives of them as members of a single species that occupy the same geographical area. Among sexual eukaryotes, gene pools are easily defined in terms of reproductive isolation and the geographical scales relevant for populations are well-matched to everyday human experience. Microbiologists, however, have faced a great challenge in applying these concepts to the...

  18. Intra-tumor heterogeneity and evolution

    Mathis, Robert Austin
    Although the treatment of cancer is a major focus of biomedical research, many cancers are extremely hard to treat. Tumors likely resist treatment because each tumor is heterogeneous, and can evolve. Although tumor evolution has long been appreciated, it remains incompletely understood. In this thesis, I will explore two questions related to cancer heterogeneity and evolution: how evolution can affect plastic phenotypes, and the role of purifying selection in cancer evolution. Different cell states or phenotypes have been observed within tumors, and they are associated with treatment resistance and metastasis. The observation that these phenotypes are plastic leads to a...

  19. A deadly hug : contact-dependent killing by Caulobacter crescentus, via cell surface-associated glycine-zipper proteins

    García-Bayona, Leonor
    In the battle for resources within microbial communities, antagonistic interactions between bacterial species are often mediated by diffusible inhibitory compounds, which can be diffusible or delivered in a contact-dependent manner. Bacteriocins are one ubiquitous type of such antimicrobials, and collectively constitute a very diverse group of ribosomally-synthesized diffusible proteinaceous toxins. The majority of well-characterized bacteriocin systems belong to a limited group of bacterial clades and environments. In contrast, interbacterial interactions are poorly characterized in the nutrient-poor aquatic environments where the a-proteobacterium Caulobacter crescentus thrives. Here, I describe the discovery and characterization of a new type of bacteriocin in C. crescentus....

  20. Injectable supramolecular hydrogels for insulin delivery

    Xue, Kun, Ph. D. Massachusetts Institute of Technology
    Treatment of diabetes for Type 1 and subsets of Type 2 diabetes require the delivery of the hormone insulin to maintain appropriate blood glucose concentrations, and current methods involve frequent insulin injections. The key goals for insulin therapy include prolonging release to reduce frequency of injections as well as glucose-responsive release to account for meal-time blood glucose fluctuations. There is a need for injectable carrier systems which can show therapeutically relevant insulin delivery to the body. Here, we develop injectable shear-thinning hydrogel systems as a depot for modulating the release of insulin. We have used supramolecular hydrogels created from cyclodextrin-adamantane...

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