https://www.selleckchem.com/pharmacological_epigenetics.html A record of this paper's transparent peer review process is included in the supplemental information.Understanding the organization of the cell cycle has been a longstanding goal in cell biology. We combined time-lapse microscopy, highly multiplexed single-cell imaging of 48 core cell cycle proteins, and manifold learning to render a visualization of the human cell cycle. This data-driven approach revealed the comprehensive "structure" of the cell cycle a continuum of molecular states that cells occupy as they transition from one cell division to the next, or as they enter or exit cell cycle arrest. Paradoxically, progression deeper into cell cycle arrest was accompanied by increases in proliferative effectors such as CDKs and cyclins, which can drive cell cycle re-entry by overcoming p21 induction. The structure also revealed the molecular trajectories into senescence and the unique combination of molecular features that define this irreversibly arrested state. This approach will enable the comparison of alternative cell cycles during development, in response to environmental perturbation and in disease. A record of this paper's transparent peer review process is included in the supplemental information.Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered