Stimulus-dependent dynamics of p53 in single cells

Many biological networks respond to various inputs through a common signaling molecule that triggers distinct cellular outcomes. One potential mechanism for achieving specific input-output relationships is to trigger distinct dynamical patterns in response to different stimuli. Here we focused on the dynamics of p53, a tumor suppressor activated in response to cellular stress. We quantified the dynamics of p53 in individual cells in response to UV and observed a single pulse that increases in amplitude and duration in proportion to the UV dose. This graded response contrasts with the previously described series of fixed pulses in response to γ-radiation. We further found that while γ-triggered p53 pulses are excitable, the p53 response to UV is not excitable and depends on continuous signaling from the input-sensing kinases. Using mathematical modeling and experiments, we identified feedback loops that contribute to specific features of the stimulus-dependent dynamics of p53, including excitability and input-duration dependency. Our study shows that different stresses elicit different temporal profiles of p53, suggesting that modulation of p53 dynamics might be used to achieve specificity in this network

Hyper-activation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage

A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double strand breaks. It is mainly coordinated by the kinases ATM, ATR and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay, where loss of DNA-PKcs function leads to hyper-activation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatments regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner

Subjective probability and quantum certainty

In the Bayesian approach to quantum mechanics, probabilities--and thus quantum states--represent an agent's degrees of belief, rather than corresponding to objective properties of physical systems. In this paper we investigate the concept of certainty in quantum mechanics. Particularly, we show how the probability-1 predictions derived from pure quantum states highlight a fundamental difference between our Bayesian approach, on the one hand, and Copenhagen and similar interpretations on the other. We first review the main arguments for the general claim that probabilities always represent degrees of belief. We then argue that a quantum state prepared by some physical device always depends on an agent's prior beliefs, implying that the probability-1 predictions derived from that state also depend on the agent's prior beliefs. Quantum certainty is therefore always some agent's certainty. Conversely, if facts about an experimental setup could imply agent-independent certainty for a measurement outcome, as in many Copenhagen-like interpretations, that outcome would effectively correspond to a preexisting system property. The idea that measurement outcomes occurring with certainty correspond to preexisting system properties is, however, in conflict with locality. We emphasize this by giving a version of an argument of Stairs [A. Stairs, Phil. Sci. 50, 578 (1983)], which applies the Kochen-Specker theorem to an entangled bipartite system.Comment: 20 pages RevTeX, 1 figure, extensive changes in response to referees' comment

Realism about the Wave Function

A century after the discovery of quantum mechanics, the meaning of quantum mechanics still remains elusive. This is largely due to the puzzling nature of the wave function, the central object in quantum mechanics. If we are realists about quantum mechanics, how should we understand the wave function? What does it represent? What is its physical meaning? Answering these questions would improve our understanding of what it means to be a realist about quantum mechanics. In this survey article, I review and compare several realist interpretations of the wave function. They fall into three categories: ontological interpretations, nomological interpretations, and the \emph{sui generis} interpretation. For simplicity, I will focus on non-relativistic quantum mechanics.Comment: Penultimate version for Philosophy Compas