Stern, C. | Search bioRxiv

bioRxiv2022

Disturbed trophoblast transition links preeclampsia progression from placenta to the maternal syndrome

Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications1. We currently lack efficient screening tools2, 3 and early therapies4, 5 to address PE. To investigate the early stages of early onset PE, and identify candidate markers and pathways, we performed spatio-temporal multi-omics profiling of human PE placentae and healthy controls and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-seq approach combined with spatial proteo- and transcriptomics and mechanistic in vitro signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts. We found a significant increase in the senescence marker activin A in preeclamptic maternal serum in early gestation, before the development of clinical symptoms, indicating a translation of the placental syndrome to the maternal side. Our work describes a new disease progression, starting with a disturbed transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.

systems biology↗

bioRxiv2022

Multisensory learning binds modality-specific neurons into a cross-modal memory engram

Withdrawal StatementThe authors have withdrawn this manuscript. After conducting replication experiments and reanalysing the original data, the authors discovered that the voltage imaging results are not reproducible. Additional voltage imaging work by the authors and their collaborators has not produced robust signals. Furthermore, errors in the pipeline originally used for data analysis could have led to the contamination of data. A complete reanalysis by the authors of the voltage imaging data independently from the original pipeline did not replicate the original analysis. Although the authors have replicated the behavioural and connectomic data and consider that the general conclusions of the article are substantiated, the authors have no confidence in the voltage imaging data. The authors would like to apologize for any inconvenience caused to their scientific colleagues and the readers of the journal. The authors would like to thank Waddell lab members, A. Cook, A. Miriyala and M. Klappenbach, who were involved in the replication experiments but are not authors of the original paper and M. Hoffmann, S. Thornquist and G. Maimon of Rockefeller University for identifying possible errors in the voltage data processing. All authors agree with the withdrawal, with the exception of P. F. Jacob who did not respond to correspondence. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗