3132Casein Kinase 2 is a critical regulator of platelet Ca2+ signaling and activation in arterial thrombosis
Bibliographic record
Abstract
Background: Platelet adhesion to subendothelial collagen results in platelet activation, aggregation and thrombus formation with consecutive development of acute arterial thrombotic occlusions. The tetrameric protein Casein Kinase 2 (CK2) is expressed in platelets and becomes activated upon platelet stimulation, but the impact of CK2-dependent signaling on platelet (patho-) physiology is unknown. Purpose: The present study aimed to elucidate the impact of the CK2 regulatory β subunit in platelet activation and arterial thrombosis. Methods and results: To circumvent prenatal death and to be able to investigate a platelet-specific effect of CK2β on arterial thrombosis in vivo, mice expressing Ck2β alleles flanked with the loxP-Cre excision sequence (cskn2bfl/fl) were used to achieve platelet-specific deletion of Ck2β (ck2β−/−). Ck2β−/− platelets displayed disrupted tubulin polymerization with impaired clustering of intracellular IP3 receptor (IP3R). As a result from diminished intracellular IP3R activation Fura-2-AM spectrofluorimetric Ca2+ measurements pointed to a defective activation-dependent cytosolic Ca2+ increase in ck2β−/− platelets as compared to wildtype (ck2βfl/fl) platelets upon stimulation with platelet agonists collagen-related peptide (CRP) or thrombin. According to FACS analysis, luminescence measurements and aggregometry activation-dependent platelet alpha and dense granule secretion as well as integrin αIIbβ3 activation and platelet aggregation were severely abrogated in ck2β−/− platelets in response to activation with CRP or thrombin. Consequential, in vitro thrombus formation on a collagen-coated surface under high arterial shear rates (1700 s–1) and thrombotic vascular occlusion in vivo following FeCl3-induced vascular injury of mesenteric arterioles as well as carotid artery were significantly diminished in ck2β−/− mice as compared to ck2βfl/fl mice. Furthermore, we could show that ck2β−/− mice were protected against cerebral ischemia when subjected to transient occlusion of the middle cerebral artery (tMCAO). Ck2β−/− mice displayed drastically reduced cerebral infarct volumes and developed significantly less neurological deficits (grip test, Bederson score) as well as significantly increased survival following tMCAO while primary hemostasis was only slightly affected.
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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 | 0.000 | 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".