Doctor of Philosophy

dissertationThe MondoA/TXNIP axis controls glucose homeostasis. The transcription factor MondoA senses glucose-6-phosphate (G6P) and responds by driving expression of thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake. The transcriptional activity of MondoA requires oxidative phosphorylation, yet the mechanism is unknown. We studied nutrient sensing by MondoA in the context of acidosis treatment and protein synthesis inhibition, both of which drive MondoA transcriptional activity and TXNIP expression. Both acidosis and protein synthesis inhibition converge on increased synthesis of mitochondrial-ATP (mtATP). Intracellular acidification leads to mitochondrial hyperpolarization and mtATP production through the ATP synthase. Protein synthesis inhibitors also drive mtATP production, likely through increased TCA cycle flux. As mtATP is exported from the mitochondria, it is consumed by mitochondria-bound hexokinase in a reaction that produces G6P. The localized production of G6P drives MondoA transcriptional activity. Thus, by simultaneously sensing glucose and mtATP via production of G6P, MondoA acts as a coincidence detector of the cells primary energy sources. We further show that MondoA drives an adaptive transcriptional response to intracellular acidification and protein synthesis inhibition, of which increased TXNIP is a predominant feature. By characterizing the transcriptional consequences of MondoA and TXNIP loss, we show that TXNIP supports MondoA-dependent transcription. Because TXNIP loss causes a shift away from oxidative metabolism toward aerobic glycolysis, we propose that loss of TXNIP leads to decreased mtATP production, thus restricting MondoA transcriptional activity. Finally, MondoA loss sensitizes cells to Myc-driven cell death. Together these findings further our knowledge of 1) metabolic rewiring during acidosis treatment and protein synthesis inhibition, 2) mtATP and glucose sensing by MondoA, and 3) the biological impacts of MondoA transcriptional activity. Thus, we propose that the MondoA/TXNIP axis is a fundamental attribute of central carbon metabolism and homeostasis

Enumerating and indexing many-body intramolecular interactions:a graph theoretic approach

The central idea observes a recursive mapping of -body intramolecular interactions to -body terms that is consistent with the molecular topology. Iterative application of the line graph transformation is identified as a natural and elegant tool to accomplish the recursion. The procedure readily generalizes to arbitrary -body potentials. In particular, the method yields a complete characterization of -body interactions. The hierarchical structure of atomic index lists for each interaction order is compactly expressed as a directed acyclic graph. A pseudo-code description of the generating algorithm is given. With suitable data structures (e.g., edge lists or adjacency matrices), automatic enumeration and indexing of -body interactions can be implemented straightforwardly to handle large bio-molecular systems. Explicit examples are discussed, including a chemically relevant effective potential model of taurocholate bile salt

Assessment of Orthodontic Patients\u27 Preferences Regarding Treatment from General Dentists or Orthodontists

This study evaluated how parents of prospective orthodontic patients choose between taking their child to a general dentist or an orthodontist for orthodontic treatment. It also looked at which factors influence patients’ satisfaction with the progress of treatment and likelihood to refer other patients to the practice. This study included two phases. The first phase was a qualitative assessment of the decision making process through conducting and analyzing focus groups. The second phase was the development and administration of a nationwide online survey regarding the topics covered in the focus groups. Influential factors in the decision making process fell into 6 major themes: providers’ personal characteristics, office management, referrals, location/physical environment of the office, financial considerations, and training/experience of the provider. The focus groups suggest that parents almost always prefer orthodontists over general dentists for orthodontic treatment, however if there was a substantial price difference parents would consider a general dentist. Approximately 19% of the respondents were currently in treatment with a general dentist. Factors involving communication of the provider were considered most important followed by financial considerations and office management issues. Social media had relatively little influence on the decision compared to a referral from a friend or family member. Analysis of variants showed significant differences within the major themes between males and females, household income levels, insurance status, and treatment from a general dentist or orthodontist. Satisfaction with treatment was higher with orthodontists. While factors involving communication of the provider were most important for selecting a provider, the provider developing a relationship with the parent and patient were more influential in satisfaction with the progress of treatment

Seasonal and spatial heterogeneity in the limnetic zooplankton community of Lake Mead

Zooplankton samples collected from throughout Lake Mead, in 1981-1982, demonstrate the presence of a statistically significant seasonal and spatial heterogeneity in zooplankton densities. Seasonally, the major zooplankton groups were most abundant in the spring and fall, coincident with maxima in chlorophyll-a concentrations. Successions among the various rotifers, cladocerans and copepods present in the reservoir were influenced by food availability, diapause, predation by planktivorous fish and, possibly, water temperatures. Spatial heterogeneity in zooplankton densities was unrelated to water temperature, pH, conductivity and dissolved oxygen concentrations, but was related to the abundance of phytoplankton (chlorophyll-a concentrations) and fish. Statistical analyses indicate that a direct relationship between phytoplankton and zooplankton standing crops exists in Lake Mead. This relationship is clearly evident in the coincidence of seasonal and spatial maxima of chlorophyll-a concentrations and zooplankton densities. Comparison of the results of this study with other studies on Lake Mead zooplankton indicate that since 1971, the density of zooplankton in limnetic areas has declined by over 90%. This decline parallels decreases in chlorophyll-a concentrations which have occurred during this same period

The European Commission’s Green Deal is an opportunity to rethink harmful practices of research and innovation policy

The European Union’s Green Deal and associated policies, aspiring to long-term environmental sustainability, now require economic activities to ‘do no significant harm’ to EU environmental objectives. The way the European Commission is enacting the do no significant harm principle relies on quantitative tools that try to identify harm and adjudicate its significance. A reliance on established technical approaches to assessing such questions ignores the high levels of imprecision, ambiguity, and uncertainty—levels often in flux—characterizing the social contexts in which harms emerge. Indeed, harm, and its significance, are relational, not absolute. A better approach would thus be to acknowledge the relational nature of harm and develop broad capabilities to engage and ‘stay with’ the harm. We use the case of European research and innovation activities to expose the relational nature of harm, and explore an alternative and potentially more productive approach that departs from attempts to unilaterally or uniformly claim to know or adjudicate what is or is not significantly harmful. In closing, we outline three ways research and innovation policy-makers might experiment with reconfiguring scientific and technological systems and practices to better address the significant harms borne by people, other-than-human beings, and ecosystems

Demographic correlations for 100 most-cited authors in ophthalmic research; a bibliometric study

Background: To analyze the academic characteristics, career trajectory, scholarly publications, and demographic background of the 100 most-cited authors in ophthalmic literature. Methods: In this observational cross-sectional study, a database containing every ophthalmology journal article from 1967 to 2018 was built using Scopus journal article information. The 100 authors with the most citations were identified, along with a control group of authors with at least five publications. Information about each author, such as gender, institution, and educational degrees were found from online web searches. Intra- and inter-group analyses were performed to identify correlations that may lead to having a high level of impact in ophthalmology literature. Results: Of the 100 most-cited ophthalmologists, 56 practice in the United States (US) and only 12 are female. In an odds ratio (OR) analysis, highly-cited researchers more often lived in the US (OR, 2.97; P < 0.001), were male (OR, 2.4; P = 0.02), and graduated from an elite medical school (OR, 3.89; P = 0.02) and/or residency (OR, 3.67; P = 0.02), but were not from an undergraduate institution (P = 0.75). There was no difference in citation numbers between different ophthalmology subspecialties (P = 0.22) or advanced degrees (PhD, MPH in addition to MD). Women among the top-100-cited authors were more likely to author high impact journal articles (P < 0.05). Conclusions: Among highly-cited ophthalmologists, practicing in the US and attending a top medical school or residency program may provide training for a successful research career in ophthalmology. Additionally, top female ophthalmologists participate in more influential research

Man-made Fibres? The Split Personalities of Victorian Manliness

This essay investigates the textual traces of a split that was central to the Victorian conception of manliness: the contradiction of gentlemanliness which demanded both the capacity to commit violence and the requirement to be ‘civilized’. It suggests that there is a fault line running through the fabric of masculinity which can be seen in the texts which train boys to become men, which remember and reconstruct that training and which consider manliness in its mature forms. A man is a subject who acts; he is also subjected to forces which he does not control. In fiction, long and short, and in poetry, masculinity is repeatedly shown to be both contested and constructed – a man-made fibre, not a natural or god-given status. From Tennyson to Wilde, there is a tear in the cloth. Keywords: Victorian manliness and masculinity; gentlemanliness; Alfred Tennyson; Charles Dickens; Rudyard Kipling; Saki (H. H. Munro); Oscar Wilde; Robert Louis Stevenson