Effective Neutrophil Activation During Innate Immunity: Understanding the Specific Roles of Rac1 and Rac2
Bibliographic record
Abstract
Neutrophils migrate rapidly towards a site of inflammation and mediate bacterial killing\nthrough highly regulated pathways that involve the phagocytosis of bacteria and the\ngeneration of reactive oxygen species by the NADPH oxidase complex. The Rac small\nGTPases have prominent roles in the regulation of neutrophil signaling pathways but the\nresearch strategies used to analyze their functions in live cells have been limited, since\nneutrophils are terminally differentiated and difficult to manipulate genetically. In this\nthesis, I describe a novel high efficiency protocol for transiently transfecting neutrophils\nthat allowed me to investigate the roles of Rac1 and Rac2 in neutrophils in a completely\nnew way, in real time. Using this technique, I show that a bacterial protein known to\ninhibit chemotaxis in vitro, selectively inhibits Rac1 activation downstream of fMLP\nstimulation and inhibits neutrophils polarization. Further dissecting the roles of Rac\nisoforms, I used various approaches to show that Rac1 and Rac2 differentially regulate\nfree-barbed end (FBE) formation downstream of the fMLP receptor. Rac1 is responsible\nfor ~30% of FBE whereas Rac2 is the regulator of FBE formation (~70%) through the\nactivation of cofilin and Arp2/3. Finally, these observations led to the analysis of the\nmechanisms underlying the Rac1 and Rac2 functions. I show that membrane charge\ndetermines Rac1 and Rac2 differential localization during phagocytosis and chemotaxis\niii\nbased on their different aminoacid residues in the polybasic domain. This mechanism\ndepends on lipid metabolism and the accumulation of negatively charged lipids at cellular\nmembranes. During chemotaxis, neutrophils have a polarized accumulation of negatively\ncharged lipids at the leading edge membrane that selectively recruit Rac1. In contrast, the\nlipid metabolism that occurs at the phagosome membrane decreases its negativity and\nselectively recruits Rac2. All together, this thesis describes the study of primary\nneutrophil functions from a new angle and adds some valuable information to the\ncomprehension of effective neutrophil activation based on the analysis of Rac isoforms.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".