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Epigenetic Aging of Sperm as a target for Chemical Exposures
No full textEvidence showed that sperm epigenome is affected in similar pattern by various factors such as diets, physical exercise, psychological stress, age, exposure to environmental toxicants. These alterations can impact offspring health leading to impaired metabolic, neurodevelopmental, and psychiatric health. Among all studied factors, aging has the strongest effect on sperm DNA methylation and its effects can be modulated by environmental factors. As an example, studies have shown that chemical exposures can alter the rate of aging of the sperm epigenome. However, the mechanism through which aging, environmental factors, and other stressors affect sperm DNA methylation in similar patterns remains unknown. Therefore, this work tries to understand the possible mechanisms behind this association. Research demonstrates that significant epigenetic reprogramming during spermatogenesis occurs in the biochemical environment regulated by the permeability of the blood-testis barrier (BTB). This permeability is controlled by the balance of the mammalian target of rapamycin (mTOR) complexes (mTORC1 and 2), with mTORC1 promoting disassembly of the BTB and mTORC2 promoting its integrity. Thus, I hypothesized first that the balance between mTOR complexes in the Sertoli cell is responsible for the age dependent changes in sperm epigenome due to diverse stressors. Secondly, the conserved patterns observed in sperm DNA methylation changes by aging and other stressors suggest that these changes are due to the sensitive nature of specific DNA regions.
To test my first hypothesis, mouse model with permanently tight and permanently loose BTB were generated, by carrying out a Sertoli cell-specific inactivation of mTORC1 or mTORC2 via knockout of corresponding components of mTOR complexes, Raptor and Rictor, using Cre-Lox approach. Our findings demonstrate that loosening of the BTB through mTORC2 suppression accelerated sperm epigenetic aging in younger mice while tightening of the BTB through mTORC1 suppression in older mice rejuvenated sperm DNA methylation profile.
The conserved pattern of changes in sperm DNA methylation also suggest that likely there are some DNA methylation regions that are naturally responsive to reprogramming, which make me hypothesize that the common patterns of sperm DNA methylation changes in response to aging and stressors are due to the nature of variable methylation regions (VMRs) sensitive to methylation reprograming, and therefore may support the model of stochastic epigenetic variation. The stochastic epigenetic variation hypothesis predicts that sperm epigenome contains naturally variable methylation regions (VMRs) associated with developmental genes and that sperm methylation changes in response to stressors occur due to the increased methylation variation of these VMRs. Thus, I test predictions from the stochastic epigenetic variation hypothesis using mouse and rat sperm DNA methylation and other -omics data. Results demonstrate that VMRs overlap significantly with stress dependent DMRs and are enriched with similar biological categories, such as embryonic development, neurodevelopment, and metabolism. Increasing methylation variation in VMRs is responsible for the formation of stress-dependent DMRs due to asymmetrical increase in variation of hypo- and hyper-methylated regions. Findings for the second hypothesis, provide for the first time evolutionary and molecular mechanistic explanation of the conserved patterns of DNA methylation change in response to various stressors.
Lastly, based on the findings from the first hypothesis, about the role of the mTOR/BTB cascade in sperm epigenetic aging regulation, I hypothesize that environmental and pharmaceutical interventions targeting mTOR activity and/or BTB permeability will modify rates of epigenetic aging of sperm. Using a sperm epigenetic clock, environmental factors - 34.5°C heat stress (HS) and cadmium exposure resulted in 31.7- and 42.3-days older sperm respectively than same age in controls, while pharmaceutic mTORC1 inhibitors (rapalogs) rejuvenated sperm epigenetic age when compared with the controls. For example, 0.5 and 1 mg/kg body weight of rapamycin administered for the duration of two spermatogenesis cycles resulted in a significant reduction of sperm epigenetic aging by 30 and 41 days respectively.
Findings from this work for the first time identifies the mechanisms responsible for the conserved patterns of sperm DNA methylation changes induced by diverse stressors. This research identifies these mechanisms as a novel adverse outcome pathway, linking xenobiotic exposures and sperm epigenetic aging. Additionally, it opens opportunities for the development of new approaches for sperm epigenome rejuvenation, and develops a mouse sperm epigenetic clock, a tool to be used in future research to evaluate a variety of interventions on sperm epigenetic age. Overall, we identified mechanisms that may be a significant route of transfer of aberrant epigenetic information to the next generation.Doctor of Philosophy (Ph.D.)2030-05-1
Underexplored Molecular Mechanisms of Toxicity
No full textSocial biases may concentrate the attention of researchers on a small number of well-known molecules/mechanisms leaving others underexplored. In accordance with this view, central to mechanistic toxicology is a narrow range of molecular pathways that are assumed to be involved in a significant part of the responses to toxicity. It is unclear, however, if there are other molecular mechanisms which play an important role in toxicity events but are overlooked by toxicology. To identify overlooked genes sensitive to chemical exposures, we used publicly available databases. First, we used data on the published chemical–gene interactions for 17,338 genes to estimate their sensitivity to chemical exposures. Next, we extracted data on publication numbers per gene for 19,243 human genes from the Find My Understudied Genes database. Thresholds were applied to both datasets using our algorithm to identify chemically sensitive and chemically insensitive genes and well-studied and underexplored genes. A total of 1110 underexplored genes highly sensitive to chemical exposures were used in GSEA and Shiny GO analyses to identify enriched biological categories. The metabolism of fatty acids, amino acids, and glucose were identified as underexplored molecular mechanisms sensitive to chemical exposures. These findings suggest that future effort is needed to uncover the role of xenobiotics in the current epidemics of metabolic diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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