Bibliographic record
Abstract
It is increasingly clear that there is an intimate link between cellular metabolism and macrophage function.Several studies in the last decade have established that alterations in cellular metabolism both drive and regulate macrophage function, allowing them to mount a functional immune response against viruses by promoting viral resistance, antigen presentation and the production of inflammatory and antiviral cytokines.As a result, metabolic reprogramming of macrophages allows them to adapt the spectrum and magnitude of their response depending on the microenvironment, stimuli, and stage of infection.Yet, it is unclear how different viral ligands alter metabolism to induce specific immune responses and if specific metabolic components can act as rheostats to amplify these responses based on the microenvironment.The central hypothesis of my thesis is that cellular metabolism is crucial to regulating antiviral immune responses.Specifically, I hypothesized that differential mitochondrial reprogramming allows macrophages to modulate ligand-specific effector response.Moreover, mitochondria further function as rheostats, fine-tuning immune responses based on the microenvironment.First, I used publicly available microarray datasets to develop a metabolic signature associated with early IFN-α responses in mouse BMMs and human MDMs.>500 metabolic genes related to cellular bioenergetics, cellular redox status, amino acid, and lipid metabolism were identified.Next, I show that TLR3 and TLR4 engagement in mouse BMMs drive differential ETC remodeling, linked to differential mitochondrial activity and subsequent ROS generation, to support ligand-specific inflammatory and antiviral profiles.Furthermore, when exploring different types of TLR3 engagement, based on ligand length, they trigger distinct inflammatory and antiviral iii programs, due to unique regulatory mechanisms surrounding HIF-1α function as well as altered ETC architecture and function, respectively.The aim of this thesis is to gain a more thorough understanding of the critical role of cellular metabolism in regulating macrophage antiviral responses.A systematic understanding of these critical processes to regulating effector function under non-diseased conditions can provide critical insights into the dysregulation of metabolic processes during chronic viral infections.The data presented may be the foundation towards the development of new antiviral therapeutics by targeting selective mitochondrial components.iv DEDICATION To HODAN NALAYEH Your legacy lives on through us!To all the dream chasers in the world, keep chasing!This is an important discussion and I'm glad we're having it!v
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".