The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5.

Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that the Rb concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5. UBR5 knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.

Statistical mechanics of thermostatically controlled multizone buildings.

We study the collective phenomena and constraints associated with the aggregation of individual cooling units from a statistical mechanics perspective. These units are modeled as thermostatically controlled loads (TCLs) and represent zones in a large commercial or residential building. Their energy input is centralized and controlled by a collective unit-the air handling unit (AHU)-delivering cool air to all TCLs, thereby coupling them together. Aiming to identify representative qualitative features of the AHU-to-TCL coupling, we build a simple but realistic model and analyze it in two distinct regimes: the constant supply temperature (CST) and the constant power input (CPI) regimes. In both cases, we center our analysis on the relaxation dynamics of individual TCL temperatures to a statistical steady state. We observe that while the dynamics are relatively fast in the CST regime, resulting in all TCLs evolving around the control set point, the CPI regime reveals the emergence of a bimodal probability distribution and two, possibly strongly separated, timescales. We observe that the two modes in the CPI regime are associated with all TCLs being in the same low or high airflow states, with an occasional collective transition between the modes akin to Kramer's phenomenon in statistical physics. To the best of our knowledge, this phenomenon has been overlooked in building energy systems despite its direct operational implications. It highlights a trade-off between occupational comfort-related to zonal temperature variations-and energy consumption.