LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca2+ entry
Bibliographic record
Abstract
A transient window of uterine receptivity ensures that embryos implant in an optimal endometrial environment [ 1 ]. Failure to establish [ 2 ] or premature closure [ 1 , 3 , 4 ] of the implantation window is thought to be a major cause of infertility, which affects ~ 15% of couples. Conversely, prolonged receptivity may lead to out-of-phase implantation and miscarriage [ 3 , 4 ] or recurrent pregnancy loss [ 1 , 4 , 5 ]. The stromal signals responsible for terminating the window of implantation are not well characterized. A putative candidate is Left-Right Determination Factor 2 (LEFTY2), a cytokine highly expressed by decidualizing stromal cells during the late secretory phase of the menstrual cycle [ 6 ], i.e., following closure of the window of implantation and prior to menstruation [ 7 ]. LEFTY2, initially designated endometrial bleeding associated factor (EBAF), is a secreted ligand of the transforming growth factor-beta (β) superfamily of proteins [ 7 , 8 ]. Following proteolytic processing of the secreted precursor, LEFTY2 acts as an antagonist of the Nodal signaling pathway by interfering both with the binding of NODAL to the activin receptor and the formation of a receptor complex [ 9 ]. During the late luteal phase of the menstrual cycle, strong LEFTY2 immunoreactivity was found in the stroma and to a lesser extent in the endometrial glands [ 10 ]. Furthermore, LEFTY2 has also been detected in the endometrial fluid of fertile women, indicating that LEFTY2 is secreted into the lumen of the uterus. Interestingly, induction of the proprotein convertase (PC) 5/6, which processes LEFTY2, is triggered in the mouse uterus in response to artificial decidualization with oil or upon mechanical injury [ 11 ]. Endometrial LEFTY2 is elevated during the receptive phase in some patients with “unexplained infertility” suggesting that dysregulation of LEFTY2 contributes to infertility [ 12 , 13 ]. Further, in vivo gene transfer of Lefty2 in the mouse uterus leads to implantation failure [ 14 ]. However, the mechanisms underlying the negative impact of LEFTY2 on endometrial receptivity remain largely unknown.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".