Impairment of ??-Adrenergic Signaling in Healthy Peripheral Blood Mononuclear Cells Exposed to Serum from Patients with Septic Shock: Involvement of the Inhibitory Pathway of Adenylyl Cyclase Stimulation
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Bibliographic record
Abstract
The objective of this study was to determine whether the serum of patients with sepsis could alter the capability of healthy human peripheral blood mononuclear cells (PBMC) to synthesize cAMP in response to beta-adrenergic stimulation and to evaluate the involvement of the inhibitory pathway (Gi) of adenylyl cyclase in the sepsis-induced alteration of beta-adrenergic signaling. First, PBMC from a healthy donor were incubated for 24 h in serum-containing medium according to three culture conditions: serum alone, serum with pertussis toxin, and serum with propranolol. Second, PBMC were stimulated with 10(-5) M isoproterenol or 10(-6) M forskolin, and measurement of cyclic adenosine monophosphate (cAMP) intracellular accumulation was performed. Serum samples were obtained from three groups of subjects: 14 patients with severe sepsis, 21 patients with septic shock, and 10 healthy control subjects. Basal and forskolin-stimulated cAMP levels were similar in PBMC cultured in control or in septic serum. Isoproterenol-stimulated accumulation was reduced in PBMC preincubated in septic serum. The lowest cAMP levels were found after exposure to serum from patients with septic shock. The addition of pertussis toxin in the incubation medium constantly increased cAMP response to isoproterenol, but more significantly in PBMC exposed to septic serum. Incubation in the presence of propranolol had no significant effect. The serum of patients with sepsis contained soluble depressant substances that inhibited adenylyl cyclase activation by beta-adrenergic agonists. Septic shock serum exhibited the most potent inhibitory effect. Hyperactivation of the Gi pathway of adenylyl cyclase was mainly responsible for the altered transmembrane beta-adrenergic signaling.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it