Pluripotency factors in embryonic stem cells regulate differentiation into germ layers.

Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.

Feasibility of an Adaptive E-Learning Environment to Improve Provider Proficiency in Essential and Sick Newborn Care in Mwanza, Tanzania.

Introduction: To improve healthcare provider knowledge of Tanzanian newborn care guidelines, we developed adaptive Essential and Sick Newborn Care (aESNC), an adaptive e-learning environment (AEE). The objectives of this study were to 1) assess implementation success with use of in-person support and nudging strategy and 2) describe baseline provider knowledge and metacognition. Methods: 6-month observational study at 1 zonal hospital and 3 health centers in Mwanza, Tanzania. To assess implementation success, we used the RE-AIM framework and to describe baseline provider knowledge and metacognition we used Howell's conscious-competence model. Additionally, we explored provider characteristics associated with initial learning completion or persistent activity. Results: aESNC reached 85% (195/231) of providers: 75 medical, 53 nursing, and 21 clinical officers; 110 (56%) were at the zonal hospital and 85 (44%) at health centers. Median clinical experience was 4 years [IQR 1,9] and 45 (23%) had previous in-service training for both newborn essential and sick newborn care. Efficacy was 42% (SD±17%). Providers averaged 78% (SD±31%) completion of initial learning and 7%(SD±11%) of refresher assignments. 130 (67%) providers had ≥1 episode of inactivity >30 day, no episodes were due to lack of internet access. Baseline conscious-competence was 53% [IQR:38-63%], unconscious-incompetence 32% [IQR:23-42%], conscious-incompetence 7% [IQR:2-15%], and unconscious-competence 2% [IQR:0-3%]. Higher baseline conscious-competence (OR 31.6 [95%CI:5.8, 183.5) and being a nursing officer (aOR: 5.6 [95%CI:1.8, 18.1]), compared to medical officer) were associated with initial learning completion or persistent activity. Conclusion: aESNC reach was high in a population of frontline providers across diverse levels of care in Tanzania. Use of in-person support and nudging increased reach, initial learning, and refresher assignment completion, but refresher assignment completion remains low. Providers were often unaware of knowledge gaps, and lower baseline knowledge may decrease initial learning completion or activity. Further study to identify barriers to adaptive e-learning normalization is needed.