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Genes and Pathways Associated with Skeletal Sagittal Malocclusions: A Systematic Review
Get PDFSkeletal class II and III malocclusions are craniofacial disorders that negatively impact people’s quality of life worldwide. Unfortunately, the growth patterns of skeletal malocclusions and their clinical correction prognoses are difficult to predict largely due to lack of knowledge of their precise etiology. Inspired by the strong inheritance pattern of a specific type of skeletal malocclusion, previous genome-wide association studies (GWAS) were reanalyzed, resulting in the identification of 19 skeletal class II malocclusion-associated and 53 skeletal class III malocclusion-associated genes. Functional enrichment of these genes created a signal pathway atlas in which most of the genes were associated with bone and cartilage growth and development, as expected, while some were characterized by functions related to skeletal muscle maturation and construction. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development. There is no doubt that further investigation is necessary to validate these recognized genes’ and pathways’ specific function(s) related to maxillary and mandibular development. In summary, this systematic review provides initial insight on developing novel gene-based treatment strategies for skeletal malocclusions and paves the path for precision medicine where dental care providers can make an accurate prediction of the craniofacial growth of an individual patient based on his/her genetic profile. © 2021 by the authors. Licensee MDPI, Basel, Switzerland
Herpes Simplex Virus-1 Infection in Human Primary Corneal Epithelial Cells is Blocked by a Stapled Peptide that Targets Processive DNA Synthesis
Get PDFPurpose: Acyclovir is most commonly used for treating ocular Herpes Keratitis, a leading cause of infectious blindness. However, emerging resistance to Acyclovir resulting from mutations in the thymidine kinase gene of Herpes Simplex Virus −1 (HSV-1), has prompted the need for new therapeutics directed against a different viral protein. One novel target is the HSV-1 Processivity Factor which is essential for tethering HSV-1 Polymerase to the viral genome to enable long-chain DNA synthesis. Methods: A series of peptides, based on the crystal structure of the C-terminus of HSV-1 Polymerase, were constructed with hydrocarbon staples to retain their alpha-helical conformation. The stapled peptides were tested for blocking both HSV-1 DNA synthesis and infection. The most effective peptide was further optimized by replacing its negative N-terminus with two hydrophobic valine residues. This di-valine stapled peptide was tested for inhibiting HSV-1 infection of human primary corneal epithelial cells. Results: The stapled peptides blocked HSV-1 DNA synthesis and HSV-1 infection. The unstapled control peptide had no inhibitory effects. Specificity of the stapled peptides was confirmed by their inabilities to block infection by an unrelated virus. Significantly, the optimized di-valine stapled peptide effectively blocked HSV-1 infection in human primary corneal epithelial cells with selectivity index of 11.6. Conclusions: Hydrocarbon stapled peptides that simulate the α-helix from the C-terminus of HSV-1 DNA polymerase can specifically block DNA synthesis and infection of HSV-1 in human primary corneal epithelial cells. These stapled peptides provide a foundation for developing a topical therapeutic for treating human ocular Herpes Keratitis. © 202
Continuation Amidst Constraint: Factors Influencing Retention and Well-Being for Players of Augmented Reality Games
No full textLiterature (Bonetti et al., 2010; Penko & Barkley., 2010; Maddison et al., 2007; Walburton et al., 2007) suggests that exergames can bring about measurable benefits to physical and mental health, though enforced or prescribed play results in play becoming viewed as a burden or chore (Madsen et al., 2007; Heeter et al., 2011), leading to either elimination of benefit from play or discontinuation. The benefits of exergaming are thus contingent on players actively choosing to engage with them, yet there is little research on what drives players to engage, or whether those factors differ across varying populations. With societal changes from COVID-19 possibly rendering many of the traditional avenues and approaches for promoting physical activity either inaccessible or unviable, understanding this becomes critical. This dissertation seeks to addresses this through an investigation of the player bases of Pokémon GO (Niantic, 2016) and Harry Potter: Wizards Unite to expose the factors underlying their continued engagement, as well as players’ experiences of these factors affected any benefit they derived from play. Prior to COVID-19, a demographic questionnaire, physical activity measure, and open-ended proforma were administered to players via four subreddit forums dedicated to the exergames. A total of 1052 participants responded to this survey, with 762 (72%) having played PGO and 691 (66%) having played HPWU. A combination of demographic segmentation and psychographic mapping revealed a number of factors that either constrained or sustained engagement, with players’ experiences with the game and the extent to which factors were important differing based on how they classified themselves as gamers (hardcore, in-between, casual, or no idea). A second survey deployed during COVID-19 (demographic questionnaire, video game use, mental well-being scale, open-ended motivation questions) received responses from 2165 participants across 66 countries. A significant positive relationship between hours of participation in gaming and total hours of exercise per week was noted, coupled with a significant increase in the use of video games, suggesting that AR games continued to promote physical activity during the pandemic. Qualitative results supported this, with achievement, entertainment, exercise and social connection being prominent motivations. Implications for practice and research are discussed
Tracing Cell Type Determination In Directed Differentiation Of Human Induced Pluripotent Stem Cells
No full textVariability in gene expression within isogenic populations of mammalian cells is ubiquitous but can have profound functional consequences. This is an important consideration in stem cell biology, where populations of genetically homogeneous human induced pluripotent stem (hiPS) cells have considerable cell-to-cell expression variability and also differentiate into samples that are too heterogeneous for use in regenerative medical or research applications. An important example explored in this thesis is the cardiac directed differentiation of hiPS cells, which consistently produces a mixed population of cardiomyocytes and non-cardiac cell types even when using very well-characterized protocols. We wondered whether variation in differentiated cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation. By associating individual differentiated cells that share a common hiPS cell precursor, we were able to test whether expression variability in differentiated cells was pre-determined from the hiPS cell state. Although within a single experiment, differentiated cells that shared an hiPS cell progenitor were more transcriptionally similar to each other than to other cells in the differentiated population, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurred during differentiation in a manner that suggested that all cells were equally likely to survive or die, suggesting that there was no intrinsic selection bias for cells descended from particular hiPS cell progenitors. These results led us to inquire how distinct cell types spatially distributed during the directed differentiation process. Labeling cells by their expression of a few canonical cell type marker genes, we showed that cells expressing the same marker tended to occur in patches observable by visual inspection, suggesting that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions. Altogether, our results show that while substantial heterogeneity exists in the initial hiPS cell population, it is not responsible for the variability observed in differentiated outcomes; instead, the window during which cell type specification occurs is likely to begin shortly after the seeding of hiPS cells for differentiation
Mir-34 Regulates Brain Aging And Susceptibility To Neurotoxicity In Drosophila Melanogaster
No full textAging is one of the most prominent risk factors for neurodegenerative disease. As a society, we are facing an exponential growth in our elderly population. With it, we see increased cases of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and ALS. At this time, there are still a variety of unknowns regarding how best to treat these diseases. The use of basic research to study the biology of aging has been an integral source of information when considering how to combat these age-associated diseases. Here, we used the Drosophila melanogaster model system to study brain aging and susceptibility to disease. We focused our attention on studying the microRNA miR-34. MiR-34 has been previously shown to be a potent regulator of brain health and lifespan in the fly model. In the absence of miR-34, animals have reduced lifespans and accelerated brain degeneration. In our studies, we transcriptionally profiled the brains of animals with null mutations for miR-34. From this, we identified a series of protein homeostasis impairments in the mutant brain. In trying to understand a mechanism for this molecular phenotype, we identified Lst8, a subunit of TOR Complex 1 and 2, as a target of miR-34. Lst8 upregulation was capable of recapitulating only a select aspect of the miR-34 mutant phenotype, suggesting that additional targets may contribute to the protein homeostasis impairment. We performed additional studies on the mutant brain to understand the degree to which it promotes age-associated phenotypes at a younger state. From this work, we identified a set of similarities between the younger mutant brain and the older control brain, creating a better understanding of how miR-34 regulates aging in the brain
The Role Of Folliculin In Hepatic Lipid Metabolism And The Pathogenesis Of Nafld And Nash
No full textNonalcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid accumulation in the liver. Steatosis can induce lipotoxicity and subsequent development of nonalcoholic steatohepatitis (NASH), characterized not only by steatosis but also inflammation and fibrosis. The pathophysiology of NAFLD and NASH are complex, with the dysregulation of several hepatic lipid processes, and there is currently no FDA-approved pharmacotherapy. Given the central role of the mechanistic target of rapamycin complex 1 (mTORC1) in lipid homeostasis, mTORC1 has the potential to be a therapeutic target. However, how mTORC1 controls hepatic lipids remains incompletely understood, and multiple studies have yielded seemingly conflicting conclusions. Here, we reconcile these studies by showing that selective inhibition of one arm of mTORC1 signaling, via genetic deletion of the RagC/D GTPase-activating protein FLCN in the mouse liver, promotes activation of the transcription factor TFE3 without affecting other mTORC1 targets. Flcn deletion profoundly protects against NAFLD and NASH in mice, induced by multiple diets, and reverses these processes after they have been established. Mechanistically, disease protection is mediated via TFE3, which simultaneously induces lipid-clearance pathways (such as lysosomal biogenesis), promotes mitochondrial respiratory capacity, suppresses anabolic de novo lipogenesis (DNL). The latter is accomplished by suppressing proteolytic processing of SREBP-1c, the central driver of DNL, and by functional interaction with SREBP-1c on chromatin at DNL genes. Initial data show that Flcn deletion also activates VLDL-TAG secretion, suggesting the contribution of another lipid process for NAFLD/NASH protection. All together, our data illuminate previously conflicting studies, and highlight selective inhibition of mTORC1 via suppression of the FLCN:mTORC1:TFE3 axis as a potentially specific and coordinated therapeutic approach to treat NASH/NAFLD
The Eighteenth Brumaire Of Louis Bonaparte In The United States, Germany, And France, 1852-1932
Get PDFThis dissertation is a political history of The Eighteenth Brumaire of Louis Bonaparte, from its composition by Karl Marx and first publication in New York City in 1852 to the last edition published in the Weimar Republic eighty years later. It studies ten editions published in the United States, Germany, and France, using sources such as the correspondence among those involved in making them to determine the political significance of each edition, explaining why the work survived and how it changed over time. It posits that an original political meaning of the work as a “picture of the land of revolution” was quickly forgotten and new modes of interpretation developed to explain its past and present meaning in different national contexts. In this eighty-year period, the Brumaire rose slowly from near oblivion to be recognized as a prime example of historical materialism and a model of revolutionary political thought, but dilemmas of interpretation already evident in inconspicuous forms in the nineteenth century took drastic political shapes after the First World War. Much of our scholarly knowledge of the Brumaire today remains deeply influenced by its political history before 1933. A history of the text is finally a critical investigation of a large part of this inherited knowledge that aims to inform the future uses of Marx in teaching and research
Vertical Contracting In The Us Health Care Industry
Get PDFThis dissertation studies the economic forces that determine prices in business-to-business health care markets. Health care is a large fraction of the US economy. In US health care markets, consumers are often insured and interact with the health care system through intermediary decision makers (health care providers, insurers, and employers). Prices for the associated goods and services in these markets are typically negotiated in business-to-business transactions, which may have complicated implications for consumers. In this dissertation, I analyze pricing agreements across three vertical channels. First, I document large variation across insurers in the prices paid for the same medical services at the same hospital. This price variation, although difficult for consumers to observe, is driven at least in part by insurers\u27 negotiating effort, and materially impacts the value of the insurance plan. Second, in a retrospective analysis of hospital mergers, I document relatively small cost savings, or ``efficiency\u27\u27 gains post-merger. Where they do exist, cost reductions tend to be concentrated among high-tech implantable devices, and among hospitals for which market concentration in the output market is of the greatest concern. Finally, I study competition in the employer sponsored health insurance market. I estimate a model of supply and demand, which allows me to simulate the introduction of a potential publicly offered insurance plan, or public option, to the employer-sponsored market. I find that a public option has limited competitive impact on competition in the employer sponsored market under most policy scenarios, due to existing price discrimination and wide variation in the cost of providing insurance to different employer groups
Towards The Efficient Use Of Fine-Grained Provenance In Datascience Applications
Get PDFRecent years have witnessed increased demand for users to be able to interpret the results of data science pipelines, locate erroneous data items in the input, evaluate the importance of individual input data items, and acknowledge the contributions of data curators. Such applications often involve the use of the provenance at a fine-grained level, and require very fast response time. To address this issue, my goal is to expedite the use of fine-grained provenance in applications within both the database and machine learning domains, which are ubiquitous in contemporary data science pipelines. In applications from the database domain, I focus on the problem of data citation and provide two different types of solutions, Rewriting-based solutions and Provenance-based solutions, to generate fine-grained citations to database query results by implicitly or explicitly leveraging provenance information. In applications from the ML domain, the first considers the problem of incrementally updating ML models after the deletions of a small subset of training samples. This is critical for understanding the importance of individual training samples to ML models, especially in online pipelines. For this problem, I provide two solutions, PrIU and DeltaGrad, to incrementally update ML models constructed by SGD/GD methods, which utilize provenance information collected during the training phase on the full dataset before the deletion requests. The second application from the ML domain that I focus on is to explore how to clean label uncertainties located in the ML training dataset in a more efficient and cheaper manner. To address this problem, I proposed a solution, CHEF, to reduce the cost and the overhead at each phase of the label cleaning pipeline and maintain the overall model performance simultaneously. I also propose initial ideas for how to remove some assumptions used in these solutions to extend them to more general scenarios
Temporal Analysis Of Neurogenesis And Microglia Changes After Mild Traumatic Brain Injury In The Adult Male C57bl/6j Mouse
Get PDFTraumatic brain injury (TBI) affects millions of people every year. Injuries canhave a range of severities from mild to severe, but all injuries have the potential to result in lasting cognitive deficits. The underlying cause of these deficits is not known, but many of the symptoms people experience is in hippocampal-dependent behavior. One cellular candidate for mediating this hippocampal dysfunction is adult neurogenesis - a process known to be 1) affected by other types of injury, 2) involved in dentate gyrus-dependent cognitive function, and 3) modulated by microglia-mediated inflammation. In this thesis, I investigated how a mild TBI (mTBI) impacts adult neurogenesis and microglia populations in the dentate gyrus. Adult male mice were given lateral fluid percussion injury (LFPI) or Sham surgery and injected with BrdU 3 days post-injury (dpi). Mice were sacrificed 3, 7, or 31 dpi, and brain tissue was stained for Ki67, DCX, BrdU, and Iba1 to examine numbers of proliferating cells, immature neurons, surviving cells, and microglia, respectively. I found that after mild LFPI, there is an increase in Ki67+ cells 3 dpi; DCX+ cells 7 dpi; and BrdU+ cells 31 dpi. There was also an increase in Iba1+ cells 3 dpi. Together, these data suggest a transient increase in proliferation and neurogenesis, leading to increased survival of newborn neurons in injured mice, and this neurogenic increase is accompanied by microglial activation at the short-term time point. These results provide essential spatiotemporal detail to the literature on injury-induced neurogenesis and identify a therapeutically relevant window for immune modulation