Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms.

Epigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually maintained throughout the life of the organism despite new environmental cues. The evolutionarily conserved Polycomb group (PcG) proteins form Polycomb Repressive Complexes that help orchestrate these developmental choices. Post-development, these complexes actively maintain the resulting cell fate, even in the face of environmental perturbations. Given the crucial role of these polycomb mechanisms in providing phenotypic fidelity (i.e. maintenance of cell fate), we hypothesize that their dysregulation after development will lead to decreased phenotypic fidelity allowing dysregulated cells to sustainably switch their phenotype in response to environmental changes. We call this abnormal phenotypic switching phenotypic pliancy. We introduce a general computational evolutionary model that allows us to test our systems-level phenotypic pliancy hypothesis in-silico and in a context-independent manner. We find that 1) phenotypic fidelity is an emergent systems-level property of PcG-like mechanism evolution, and 2) phenotypic pliancy is an emergent systems-level property resulting from this mechanism's dysregulation. Since there is evidence that metastatic cells behave in a phenotypically pliant manner, we hypothesize that progression to metastasis is driven by the emergence of phenotypic pliancy in cancer cells as a result of PcG mechanism dysregulation. We corroborate our hypothesis using single-cell RNA-sequencing data from metastatic cancers. We find that metastatic cancer cells are phenotypically pliant in the same manner as predicted by our model.

A Sense of Belonging: Perceptions of the Medical School Learning Environment among URM and Non-URM Students.

Phenomenon: Improving the learning environment (LE), particularly for students underrepresented in medicine (URM), has become an important goal for institutions that provide undergraduate and graduate medical education. Until recently, research and intervention development have been limited by the lack of comprehensive theoretical frameworks. A multi-dimensional conceptual model of the medical school environment, developed by Gruppen and colleagues in 2019, provides a useful framework for guiding research and interventions in this area.Approach: Using Gruppen et al's model, this study investigated experiences of the LE from the perspectives of both URM and non-URM students at a medical school in New York City. In examining experiences of the organizational, social, and physical domains of the LE, we sought to explore the symbolic and experiential links across domains and identify concrete needs for improvement.Findings: Institutional structures and policies, features of the built environment, and social relationships that put learning first and generated a sense of community were highly valued. Although both URM and non-URM students shared many perceptions and experiences, URM students expressed heightened vulnerability to the experiences of devaluation and exclusion.Insights: All participants in the study greatly appreciated aspects of the LE that made them feel like valued members of the community. Medical schools should approach the task of improving the LE for URM students using a comprehensive, multi-dimensional approach.

Emerging Adaptive Strategies Under Temperature Fluctuations in a Laboratory Evolution Experiment of Escherichia Coli.

Generalists and specialists are types of strategies individuals can employ that can evolve in fluctuating environments depending on the extremity and periodicity of the fluctuation. To evaluate whether the evolution of specialists or generalists occurs under environmental fluctuation regimes with different levels of periodicity, 24 populations of Escherichia coli underwent laboratory evolution with temperatures alternating between 15 and 43°C in three fluctuation regimes: two periodic regimes dependent on culture's cell density and one random (non-periodic) regime with no such dependency, serving as a control. To investigate contingencies on the genetic background, we seeded our experiment with two different strains. After the experiment, growth rate measurements at the two temperatures showed that the evolution of specialists was favored in the random regime, while generalists were favored in the periodic regimes. Whole genome sequencing demonstrated that several gene mutations were selected in parallel in the evolving populations with some dependency on the starting genetic background. Given the genes mutated, we hypothesized that the driving force behind the observed adaptations is the restoration of the internal physiology of the starting strains' unstressed states at 37°C, which may be a means of improving fitness in the new environments. Phenotypic array measurements supported our hypothesis by demonstrating a tendency of the phenotypic response of the evolved strains to move closer to the starting strains' response at the optimum of 37°C, especially for strains classified as generalists.