The central role of calcium dysregulation in a primary cell culture model of amyotrophic lateral sclerosis
Bibliographic record
Abstract
Amyotrophic lateral sclerosis (ALS; aka Lou Gehrig Disease) is an adult-onset, rapidly progressing motor neuron disease for which there is currently very little treatment. Glutamate excitoxicity, formation of proteinaceous inclusions, proteasome impairment, and mitochondrial dysfunction have been associated with both sporadic and familial ALS, but there are many questions about how these events fit together to cause motor neuron dysfunction and death. In culture models of familial ALS due to mutations in the enzyme Cu/Zn-superoxide dismutase (SOD1), treatments that reduce intracellular Ca2+ prolong viability and prevent formation of mutant SOD1 inclusions. Motor neurons are vulnerable to Ca2+ overload due to poor Ca2+ buffering and high glutamatergic input. Thus, disruption of calcium homeostasis may play an early and key role in ALS. The goal of this thesis was to investigate how levels of Ca2+ in cytosol and calcium-buffering organelles (mitochondria and endoplasmic reticulum) change in motor neurons in an experimental model of ALS and how these changes relate to other hallmarks of ALS pathogenesis (impaired mitochondrial and proteasome function). To achieve this goal, ALS-causing G93A-SOD1 was expressed in motor neurons of dissociated murine spinal cord-dorsal root ganglia cultures. Using microfluorometric techniques, increases in mitochondrial Ca2+ ([Ca2+]m) and endoplasmic reticular Ca2+ ([Ca2+]ER) were observed prior to an increase in cytosolic Ca2+ ([Ca2+]c). Decrease in mitochondrial membrane potential and rounding of their shape was observed concomitant with the early increase in [Ca2+]m. A further increase in [Ca2+]c was observed in motor neurons with mutant
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".