Environmental and Occupational Health Sciences Institute
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Genetic diversity of degradation pathways for monocyclic aromatics hydrocarbons
No full textChemicals can be released into the environment from various industrial practices and later can be exposed to different biotic and abiotic weathering reactions, such as biochemical and physical modification. Synthetic chemicals are essential to our lives, but their continuous production and release are increasing. Chemical pollutants can alter the composition of the environment's water, air, and soil and cause toxicity, also influencing their fate and biodegradation. They are harmful not just to the environment but also to human health; they can reach the human body via inhalation, oral absorption, and ingestion and cause various diseases depending on the exposure duration and the intensity of pollutants. Many physical and chemical techniques have been used to reduce the release of various toxic chemical pollutants into the environment, including bioremediation. Bioremediation uses different microorganisms to break down environmental pollutants, which can be less expensive, can propagate and adapt quickly to different conditions, and requires simple growth conditions. Many microorganisms possess oxygenase enzymes that have a broad specificity against different types of chemical pollutants. Microbial oxygenases oxidize the substrate by transferring oxygen from molecular oxygen using FADH/NADH/NADPH as a co-substrate. They are divided into monooxygenases and dioxygenases based on the number of oxygen atoms used for oxygenation. The first goal of this work was to study the aerobic biodegradation of benzoate by Sphingomonas wittichii RW1. Benzoate is the simplest compound that is produced from industrial activities and is an intermediate in the biodegradation of many aromatic compounds. When benzoate is degraded aerobically, it will produce catechol as the last intermediate for the upper degradation pathway. Once catechol is produced, it will enter two different routes using two different ring cleavage enzymes, and both pathways are found in Sphingomonas wittichii RW1. The first goal of this study was to identify the role of the catA gene encoding catechol 1,2-dioxygenase in the ortho-pathway in benzoate metabolism. The catA gene was identified by the similarity of the encoded protein to known catechol 1,2-dioxygenase enzymes. A clone carrying a knockout of the catA gene was constructed in Sphingomonas wittichii RW1 and tested using 5 mM benzoate. The growth curve result showed that there was no difference between the wild type and the knockout strain. Next, the role of two different catechol 2,3-dioxygenase mutants in the meta-pathway of benzoate metabolism was identified. Construction of double and triple knockout strains was prepared by combining the knockout catA gene with the two previously prepared meta-cleavage strains. These two strains involved RW1ΔdbfB (Swit_4902) and RW1Δ3046 (Swit_3046), in addition to the double knockout strain RW1ΔdbfBΔ3046. Growth curve results showed that the double mutant strain ΔcatAΔ3046 and the triple mutant strain ΔcatAΔdbfBΔ3046 did not grow on 5 mM benzoate. Results also indicated that mutant strain ΔcatAΔ3046 was able to grow when complemented by either the cloned catA gene or the cloned 3046 gene. In addition, results also showed that the double mutant strain ΔcatAΔdbfB grew well with benzoate, indicating that dbfB is not involved in metabolizing catechol. Growth curve results showed that catechol can be metabolized through the ortho pathway with the catA gene or the meta pathway with the 3046 gene.
The second goal of this study was to analyze the genome of new Burkholderia strains that were isolated in our lab by a visiting Fulbright professor Habiba Atta. These strains were collected from a contaminated wetland area near an oil refinery in Delta state, south-south region, Nigeria. The strains were tested on some selected aromatic substrates such as o-xylene, m-xylene, p-xylene, ethylbenzene, dibenzofuran, biphenyl, naphthalene, toluene, o-cresol, m-cresol, p-cresol, and phenol. The growth tests showed a variation of the growth on different aromatic substrates suggesting that these strains do not have the same degradation pathways towards these substrates. The initial screening involved checking the existence of the three essential genes in Burkholderia strains genomes, the xylM, xylE, and tmo. The xylM is a gene for the toluene monooxygenase enzyme that attacks the methyl group, a gene for the TOL plasmid pathway, xylE is a gene for the ring cleavage enzyme, and tmo is a gene for the toluene monooxygenase enzyme. Furthermore, whole genome sequencing was performed to analyze the genome of the Burkholderia strains and verify the presence of these essential genes for aerobic aromatic degradation. The analysis showed that all strains had a highly similar but not identical phenol/toluene dmp/tmo operon, except strain 20Lm, which was missing the genes for the initial phenol hydroxylase. The strains 26mm, 5mx, and 20Lm have genes for a TOL plasmid type pathway, with 26mm and 20Lm having nearly identical operons but 5mx having more distantly related genes in a different arrangement. Furthermore, strain 7to did not have genes for a TOL plasmid pathway, and strain 12mnd may have genes for a TOL plasmid pathway. The variation showed in the genetic analysis of the isolated strains explained the evolution that happened with time, even though they were isolated from one location.
The third goal of this study was to identify which aromatic degradation pathway(s) our Nigerian strains are using. The strain 12mnd was chosen for cloning the initial monooxygenase and later in testing the monooxygenase enzyme activity using three different chemicals: o-cresol, p-cresol, or m-cresol. Following the cloning of the monooxygenase enzyme, heterologous gene expression was performed, and the results indicated that the biotransformation media changed from noncolored solutions to dark brown with o-cresol and m-cresol, and light brown with p-cresol reflecting the oxidation of all three cresols to methylcatechol and confirming the catalytic activity of the monooxygenase enzyme in these cells. Furthermore, a clone carrying the ring cleavage enzyme gene was constructed, and the gene expression of monooxygenase and ring cleavage enzymes against the same three chemicals was performed, the analysis showed that the biotransformation media changed faster from noncolored solutions to a darker color with o-cresol but lighter with m-cresol and p-cresol explaining that once catechol was formed, it was metabolized through the ring cleavage enzyme to the meta-cleavage product. In addition, plasposon mutagenesis was used to identify which aromatic degradation pathway(s) the isolated Nigerian strains are using. The strain 26mm was used as a test strain since it has genes for both the monooxygenase and TOL-type pathways. In addition, the strain showed the best and the fastest growth in 24 hours among the other strains. Rescue cloning, which involves digestion of the total genomic DNA, self-ligation, and transformation into highly competent E. coli cells, was used. Subsequently, the transposon was isolated and used in a sequence reaction with designed primers facing outward from the transposon, and the strains were tested after the transposon mutagenesis on MSB media supplemented with m-xylene. Results showed two strains only lost the ability to grow on m-xylene. Further sequencing and genomic analysis were performed for the two mutant strains, which showed a deletion in the mutant strains of degradation genes in addition to a transposon insertion, and this deletion prevented the mutant strains from growing on m-xylene. Also, the analysis showed that neither of the transposon insertions in the mutants were in genes involved in the degradation of aromatic hydrocarbons. The results also showed that the wild type of strain 26mm metabolizes m-xylene through a TOL plasmid-type pathway and additionally contains a phenol/cresol degradation pathway. By inference, the other Nigerian Burkholderia strains metabolize monocyclic compounds in the same way.Ph.D.Includes bibliographical reference
Contrapuntos nacionales: sonic identities and reimagining nationhood in the River Plate Region
No full text“Contrapuntos nacionales: sonic identities and reimagining nationhood in the River Plate Region” investigates the role of music and sound in performances that reject unifying hegemonic identity discourses in Argentina and Uruguay. I argue that sound's ephemeral mobility and generative nature create new possibilities for (re)envisioning exclusionary constructions of race and gender in Argentina and Uruguay. Expanding upon Benedict Anderson’s idea of the nation as a socially constructed “imagined community,” I employ a sound-based methodology that draws on the works of sound studies scholars such as Brandon LaBelle and Salomé Voegelin, performance scholars such as Diana Taylor and Judith Butler, and media scholars such as Caroline Vernallis to illustrate how historically uncounted individuals, underrepresented, and silenced individuals to fashion acquire agency through “sonic selfhood:” alternative constructions of identity that rearranges habitual assemblages of national culture to foster social empowerment. My first chapter, “Aquí me pongo a cantar: Echoes of Foundational Fictions in Twenty-First-Century Popular Music (2017-2019),” emphasizes how the gaucho’s transformation in popular music reflects the River Plate region’s tradition of self-reflexive critique and scrutiny. I argue that the gaucho’s sudden reappearance into twenty-first-century Argentine and Uruguayan popular music signals a decolonial form of resistance to cultural tropes and identity markers by destabilizing national resistance to acculturation pressures and foregrounding instances of social justice issues amid globalized capitalism. Music and sound allow these groups to create political and social “voices” within exclusionary constructions of nationhood, paving the way for alternative identitarian models that reflect the complex history of the nation and the multi-faceted subjectivities of its inhabitants. Chapter Two, “No tengo la culpa de las cosas malas de este país: Sound, Racial Anxieties, and Redefining National Identity,” investigates how two racialized groups in Argentina—Japanese-Argentines and Venezuelan migrants—negotiate representation by questioning the demarcations of culture and identity around increasingly fluid circulations of capital, media, and people. The Japanese-Argentine band Los Parraleños employs parodic distorsión in their 2002 music video “Megadeth,” undermining the “fixity” of an essentialized, mass-produced Japanese identity by promoting integration and belonging through cultural hybridity rather than as a divisive cultural “remix.” My analysis of the volunteer orchestra Latin Vox Machine investigates print and film portrayals of “sonic encounters” that legitimize Venezuelan migrants’ presence in their host country by establishing their cultural capital. Chapter Three, “Mi cuerpo no es un objeto de consumo: #NiUnaMenos and Audible Activism in Argentina,” explores instances of sonic protest in the recent Argentine feminist #NiUnaMenos movement. Under the collective emblem of el grito, activists’ performances, marches, and digital campaigns complicate a neoliberal post-feminist tendency of reducing Argentina’s femicides to political and social capital by transforming formerly silenced sounds and feelings of grief into resistance. Audible activism invites listeners to think precisely about opening the political imaginary to begin to unpack how, where, and why that gendered violence is structured in Argentina.Ph.D.Includes bibliographical reference
Unfolding the Globalized City: Urban Space and Media in Italy, 1961-2023
No full textIn my dissertation, I examine works of fiction, TV series, and photographs from 1992 to the present day that portray the margins of Italian cities from a social, spatial, racial, and architectural perspective. I argue that the literary and visual display of urban margins threatens established notions of identity set by the media’s commodification and homogenization of the Italian urban space: The city is the locus where subjective perceptions and mediatized images clash. I examine texts of second-generation Indian-Italian and Somali-Italian authors (Kuruvilla, Scego), Elena Ferrante’s novels and their screen adaptations, and a range of works from the visual arts (Antonioni, Basilico, Spada) to place them in conversation with biopolitical theories (Foucault), theories of media and space (Benjamin, Kracauer), and urban theory (Lefebvre, Harvey). All the primary texts I analyze release the Italian city from its iconic renditions by unfolding multiple spatial, social, and cultural perspectives over the urban layout. They adopt narrative and rhetorical strategies that preclude an easy schematization of Italian history, society, and politics. More important, they suggest a networked, rhizomatic reading of Italian space, which counteracts hegemonic narratives of that environment. My work additionally disputes the role Italian intellectuals, publishers, and streaming media play in promoting Italy’s image throughout the global market. I discuss the tactics that authors employ to shield the country from the external gaze and how, conversely, they ply to the global market demands of a commodified vision of the Italian space. From the experience of being both “global” and “local” artists, narrating one’s own individual marginality often becomes the tool to be admitted to the very social environment from which they feel excluded. In Chapter One, I explore the transformations to the Milanese urban layout in the works of Michelangelo Antonioni, Marina Spada, Gabriele Basilico, and Gabriella Kuruvilla. Chapter Two examines the correlation between the city of Naples and instability in Elena Ferrante’s texts. Chapter Three focuses on Rome as a space of transit in the works of Michelangelo Antonioni and Igiaba Scego.Ph.D.Includes bibliographical referencesIncludes vit
On the super tree property and on large cardinals in HOD
No full textThis thesis is divided into two parts.
The first part is a work on the super tree property, a strengthening of the tree property. From Specker's theorem, the continuum hypothesis must fail at if we want the tree property at . Following up on Honzik and Stejskalov'a's theorem on tree property, we show that under a large cardinal assumption, it is consistent that the super tree property holds at all even together with any given Easton's function under as long as the function violates at all :
Theorem
Assume holds. Let be an -sequence of supercompact cardinals with limit . Let . Let , and let be an Easton function which respects the 's. Then there is a forcing such that in :
1. Cardinals in are preserved, and all other cardinals below are collapsed; in particular, for all , , and .
2. For all , holds.
3. The continuum function on is controlled by , i.e.
The second part is the forcing part of a joint work "On -strongly measurable cardinals in Pmax extensions" with Takehiko Gappo, James Holland, and Grigor Sargsyan. This is a work toward refuting the Woodin's conjecture by making three successors cardinals of -strongly measurable in . This work answered Question 4.11 of "On -strongly measurable cardinals" raised by Ben-Neria and Hayut. We showed that under a large cardinal assumption, it is consistent that , , and of satisfy a strengthening of -strongly measurable in : Theorem[A.-Gappo-Holland-Sargsyan]It is consistent relative to a Woodin limit of Woodin cardinals that holds and if , then is -strongly measurable in , i.e. the restriction of the club filter on to is an ultrafilter in .Ph.D.Includes bibliographical reference
Low-cost machine learning of fused filament fabrication extrusion dynamics
No full textFused filament fabrication (FFF) is a widely used additive manufacturing process. FFF involves melting and extrusion of a polymer filament, which involves complex dynamics. It also is subject to many different process parameters which often change from one manufacturing process or machine to another. Current models of these dynamics do not explore the full breadth of process parameters and are either complex, computationally expensive simulations or simplified analytical and machine learning models that rely on large amounts of expensive experimental data and have limited predictive power. Additionally, few of these models include the effects of a dynamically varying extrusion rate, which is necessary for the use of more advanced FFF strategies. The objective of this work is to model the dynamics of the FFF extrusion process for time-varying extrusion rates over multiple process parameters while ensuring low cost by minimizing the amount of experimental data required to develop the model. In the proposed approach, a Long Short-Term Memory neural network (LSTM) is trained on experimental data to predict printed line width for the FFF extrusion process based on the observed line widths and input extrusion speed trajectory. Transfer learning is used to learn the dynamics across different sets of process parameters using a small amount of additional experimental data. This approach does not rely on complex, expensive simulations limited to a small number of process parameters to learn dynamics accurately. It also is not based on a simplified analytical model, allowing it to learn the complex relationships present in their totality. The use of transfer learning also improves upon existing machine learning models by greatly reducing data requirements. Additionally, the proposed approach models the dynamics of the extrusion process for time-varying extrusion speed trajectories, unlike most existing models which only include the effects of a static extrusion speed. The new approach is shown to accurately predict printed line widths for extrusion speed trajectories and various process parameters while requiring 62% fewer experimental data points when compared to purely data-driven machine learning methods. It can also be extended to include the effects of more process parameters and even be applied to different manufacturing processes.M.S.Includes bibliographical reference
Impact of pesticides on Apis mellifera (hymenoptera: apidae) health and performance in blueberries
No full textHoney bee (Apis mellifera L.; Hymenoptera: Apidae) health is a global concern due to the negative impacts of agricultural intensification and pest management practices. While insecticide toxicity to honey bees is well document, the impact of fungicides on honey bees has received less attention. This research investigated the historical use of fungicides in New Jersey (USA) highbush blueberry (Vaccinium corymbosum L.) farms, the impacts of farm size and multiple crop pollination on colony health and pesticide residues found in pollen, and the effects of fungicides on forager behavior and larval toxicity. By extracting fungicide spray record data from seven farms, I found an increase in fungicide applications, fungicide active ingredients, fungicide mode of actions, and a change in the types of fungicides used between 1995 and 2020. After investigating the impacts of farm size and multiple crop pollination in a 3-year study, I found colonies pollinating small blueberry farms exhibited higher weight gain and brood compared to those pollinating large blueberry farms, despite having similar pesticide residues detected in pollen. Moreover, the highest fungicide quantities were detected in pollen collected during multiple crop pollination and these colonies consistently resulted in the lowest weight gain and brood coverage. When examining the most used fungicides during New Jersey blueberry bloom (Abound, Quash, Pristine, Switch, and Ziram), I found that neither wet nor dry applications of these fungicides impacted forager behavior or colony health when provided a choice between blueberry bushes sprayed with water or sprayed with fungicide in flight tunnels. In laboratory studies, honey bee larvae were fed diet incorporated with different doses of the active ingredients found in the same five fungicides. I found a dose-dependent effect of metconazole (the active ingredient in Quash) and zinc dimethyldithiocarbamate (the active ingredient in Ziram) on honey bee larval toxicity. The most toxic to larvae was zinc dimethyldithiocarbamate, with an LC50 of 18 ppm. This research documents fungicide use changes in New Jersey highbush blueberries over the last 25 years. Farm size and the number of pollinating crops can negatively affect colony health, highlighting the potential for certain fungicides, such as Ziram, to adversely affect honey bee brood survival. Future research should focus on identifying the impacts of fungicides on honey bees under field conditions and developing methods to mitigate their impact, which could help improve the overall health in pollinating colonies.Ph.D.Includes bibliographical reference
Essays on the economics of juvenile crime
No full textThis dissertation contributes to our understanding of the benefits and harms associated with diversionary reforms in the juvenile justice system. Since the 1990s, there has been a notable transition from a punitive 'Get tough' approachon juvenile crime to strategies that emphasize rehabilitation. I examine two major juvenile reforms that were implemented with this intent and measure their impact on juvenile arrest and recidivism rates. I explore whether the
diversion of juveniles from more severe to lenient judicial conditions potentially contributes to higher rates of reoffending or conversely, if it facilitates their escape from the perpetual cycle of incarceration. In Chapter 1, I explore the causal relationship between the ‘Close to Home’ reform and juvenile recidivism (subsequent contact with justice system). The 'Close to Home' initiative mandated the placement of city juveniles in local facilities within New York City rather than sending them to distant state facilities in upstate New York, as was previously customary. I assess whether proximity to home and community connections contribute to reduced recidivism rates among juveniles, or on the other hand, if it enables them to maintain ties with their peer networks, potentially increasing recidivism due to reduced deterrence and incapacitation (as posited by behavioral choice theories in criminal justice). The findings indicate a substantial decrease in the likelihood of escalated criminal behavior among juveniles, with significant reductions in recidivism rates among female and Black city juveniles. Chapter 2 examines the causal effect of Florida’s Juvenile Civil Citation Program on recidivism rates. Implemented in a staggered manner across Florida counties, this program diverts first-time misdemeanants from formal judicialproceedings by issuing a civil citation, similar to a traffic ticket, instead of an arrest. Upon successful completion of the citation requirements, the juvenile’s citation history is expunged, ensuring that the events do not appear on their
criminal records. I investigate whether this form of diversion, which prevents initial contact with the justice system, influences recidivism rates among juveniles. The civil citation program is associated with a 15-57% decline in the
recidivism rates of juveniles eligible for citation after the implementation of the program in their county, among which juveniles receiving citations are 32-38% less likely to recidivate compared to those who were eligible but did not receive
the citation. Chapter 3 investigates whether Florida’s civil citation program inadvertently exacerbates the school-to-prison pipeline, a phenomenon in which stricter school policies result in pushing marginalized students out of school and intothe justice system. Using multiple data sources such as Florida Department of Juvenile Justice and Annie E. Casey Foundation and using synthetic difference-in-differences as the main identification strategy, I find that the reform is not
associated with any statistically significant changes in the school referral rates of Miami Dade County, thereby not contributing to the pipeline. Additionally, I also do not find any statistically significant changes in the graduation or drop
out rates of students enrolled in school in Miami-Dade County after the reform implementation.Ph.D.Includes bibliographical reference
Prosecutors: discretion, distrust, and corrective transparency
No full textThis project consists of three related chapters that argue the following. Prosecutors (as public fiduciaries) have a duty to counteract public distrust through acts of unilateral transparency and institutional reform. Prosecutors are the focus of this project because they are understood to have significant discretion within the criminal-legal system. Their ability to indict a suspect serves as a gate-keeping function for the criminal legal system and is largely unreviewable by other officials. Discretion (or ‘discretionary authority’) is a crucial aspect of governance that provides an agent with a set of options to achieve the purpose of his role. My view, the fiduciary theory of discretion, argues that the discretion of prosecutors, along with all public officials, is circumscribed by the purpose of their institution and their role within it, the legal limits placed on the use of public power, and the duty of loyalty owed to their jurisdiction. This set of options is the result of a trust-based relationship that the state has with the public. Distrust is the foreclosure of trust, and so threatens trust-based relationships (including the state-subject relationship). Public distrust results from the actions of government agents that demonstrate an incapacity or unwillingness to insulate the public’s interest while performing state functions. For example, brutal, mendacious, or exploitative policies and practices generate public distrust. This form of distrust threatens a state’s legitimacy; in other words, public distrust undermines the moral permission of government agents to create, apply, and enforce rules for a jurisdiction. To counteract distrust, public officials must take action that can undermine their distrustworthiness and demonstrate trustworthiness to the public. I offer corrective transparency, which is a combination of unilateral transparency with third-party mediators and policy reform, as an effective and appropriate means of counteracting distrust. This form of transparency is conditioned on public distrust and is different from standard accounts of democratic transparency, where transparency is an ongoing feature of a democratic society. Therefore, my conclusion is conditional: If public distrust can be shown to exist within a jurisdiction, then public officials have a strong reason to adopt corrective transparency. For prosecutors, I argue that a prosecutor who is in a distrusting jurisdiction must release grand jury records in cases where police officers kill in the line of duty. Due to the difficulty of legal interpretation, disclosure is made to the grand jury oversight committee, which is a panel of legal experts who regularly report their findings to the public.The three chapters are the following: “Prosecutors, Discretion, and Democracy: A Theory of Prosecutorial Ethics”, “Distrustworthy Authority: Public Distrust, Prosecutors, and the Grand Jury”, and “Corrective Transparency: How should public fiduciaries respond to public distrust?”. The first chapter introduces the reader to the fiduciary theory of discretion and applies it to prosecutors. The second chapter introduces the concept of public distrust and its impact on the normative legitimacy of government institutions. The final chapter combines the two preceding chapters into an argument for corrective transparency, which is a conditional form of transparency aimed at countering public distrust.Ph.D.Includes bibliographical reference
General Control Non-Derepressible 2 is a Homeostatic Regulator of Thermogenesis and Biological Rhythms
No full textMammals adapt to changes in their environment such as temperature, light exposure and food availability by engaging a variety of homeostatic mechanisms. The integrated stress response (ISR) is an intracellular signaling network that functions to maintain homeostatic control of the proteome. The ISR activates adaptation following a variety of environmental threats such as nutrient scarcity, misfolded protein, viral infection and oxygen deprivation and serves as a key survival mechanism for cells to adapt changes in their intracellular environment. Activation of the ISR triggers phosphorylation of the translation factor, eukaryotic initiation factor 2 (eIF2) on its alpha subunit by a family of four protein kinases. Phosphorylated eIF2 slows cap-dependent translation while at the same time promotes the preferential synthesis of ATF4 and other stress-responsive DNA binding proteins function to realign the transcriptome towards survival and adaptation.The eIF2 kinase, general control non-derepressible 2 (GCN2) is a primary sensor of amino acid insufficiency. However, evidence for GCN2 activation in response to other forms of stress such as cold stress adaptation and the maintenance of the circadian clock are present in the literature. At this time, these insights are limited to either invitro models or have only been demonstrated in a single tissue. The objective of this dissertation was twofold: 1) to understand the functional role of GCN2 in response to acute cold stress 2) explore how activation of GCN2 by amino acid insufficiency impacts diurnal rhythms in the liver.
The first thesis objective was addressed with an experimental design that examined the role of GCN2 in maintaining core body temperature under acute cold exposure. The results showed that cold exposure increases GCN2 and eIF2 phosphorylation in the BAT of male mice and corresponded with an increase in the transcript abundance of SLC transmembrane transporters and intracellular amino acid levels. Loss of GCN2 activity impaired ISR activation and SLC transporter expression in brown adipose resulting in acute cold intolerance independent of sex.
The second thesis objective was addressed using two different experimental designs. In the first study, I examined the role of GCN2 and dietary leucine intake on the maintenance of circadian rhythms in whole body metabolism and peripheral tissues. In WT mice, hepatic GCN2 phosphorylation displayed a diurnal pattern which strongly correlated with diurnal changes in intracellular branched chain amino acid levels. Although global loss of Gcn2 did not alter circadian rhythms in whole body calorimetry measures, diurnal changes in hepatic ISR signaling, transcriptome and triglyceride content were lost. Similarly, in wildtype (WT) mice, leucine devoid diet (Leu D) feeding did not alter circadian rhythms in whole body calorimetry measures but altered diurnal rhythms in ISR activation and transcriptional execution in a time dependent manner. Lastly, global loss of Gcn2 under Leu D feeding impaired circadian rhythms in whole body metabolism and altered the transcripts in the liver changing over a diurnal cycle. Taken together, the results demonstrate a role for GCN2 in the maintenance of diurnal changes in ISR transcriptional execution in peripheral tissues which is likely driven by changes in intracellular branched chain amino acid levels.
A second study examined how the ISR and mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways are coordinated over a feeding-fasting cycle and the impact of acute dietary amino acid insufficiency (AAI) on diurnal rhythms in these signaling pathways and the circadian clock in the liver. Control-fed mice displayed diurnal rhythms in both ISR and mTORC1 signaling, with ISR activity antiphase to mTORC1. TrpD feeding disrupted these rhythms, and lead to significant changes in the identity and the temporal profile of the diurnal hepatic transcriptome, particularly in genes involved in amino acid metabolism and stress responses. Furthermore, TrpD feeding impacted the diurnal expression and ribosome association of clock genes. These findings demonstrate that acute changes in dietary amino acid intake significantly alters diurnal rhythms in hepatic ISR and mTORC1 signaling, affecting transcriptional and translational regulation. This study illustrates the diurnal relationship between GCN2 and mTORC1 in the liver and provides insights into the interplay between nutrient sensing and circadian regulation.
The data within this dissertation expands our understanding of the physiological role of GCN2 in relaying changes in the intracellular environment to physiological outputs in the BAT and liver. The insights provided within this work highlight new functional outcomes of ISR signaling which hold broader implications for how to target this signaling pathway therapeutically can be leveraged to combat obesity and metabolic disorders.Ph.D.Includes bibliographical referencesIncludes vit