Cellular Conference Call: External Feedback Affects Cell-Fate Decisions

Cells often need to respond to multiple opposing signals simultaneously. In this issue of Cell, Janes et al. (2006) show that challenging cells with multiple extracellular signals induces an external feedback that involves the release of and response to additional secreted factors with antagonistic functions. These results suggest that an individual cell's decision to die or survive is not wholly independent but depends, at least in part, on feedback from its neighbors

The p53 response in single cells is linearly correlated to the number of DNA breaks without a distinct threshold

Background: The tumor suppressor protein p53 is activated by cellular stress. DNA double strand breaks (DSBs) induce the activation of the kinase ATM, which stabilizes p53 and activates its transcriptional activity. Single cell analysis revealed that DSBs induced by gamma irradiation trigger p53 accumulation in a series of pulses that vary in number from cell to cell. Higher levels of irradiation increase the number of p53 pulses suggesting that they arise from periodic examination of the damage by ATM. If damage persists, additional pulses of p53 are triggered. The threshold of damage required for activating a p53 pulse is unclear. Previous studies that averaged the response across cell populations suggested that one or two DNA breaks are sufficient for activating ATM and p53. However, it is possible that by averaging over a population of cells important features of the dependency between DNA breaks and p53 dynamics are missed. Results: Using fluorescent reporters we developed a system for following in individual cells the number of DSBs, the kinetics of repair and the p53 response. We found a large variation in the initial number of DSBs and the rate of repair between individual cells. Cells with higher number of DSBs had higher probability of showing a p53 pulse. However, there was no distinct threshold number of breaks for inducing a p53 pulse. We present evidence that the decision to activate p53 given a specific number of breaks is not entirely stochastic, but instead is influenced by both cell-intrinsic factors and previous exposure to DNA damage. We also show that the natural variations in the initial amount of p53, rate of DSB repair and cell cycle phase do not affect the probability of activating p53 in response to DNA damage. Conclusions: The use of fluorescent reporters to quantify DNA damage and p53 levels in live cells provided a quantitative analysis of the complex interrelationships between both processes. Our study shows that p53 activation differs even between cells that have a similar number of DNA breaks. Understanding the origin and consequences of such variability in normal and cancerous cells is crucial for developing efficient and selective therapeutic interventions

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

The Implementation, Interpretation, and Justification of Likelihoods in Cosmology

I discuss the formal implementation, interpretation, and justification of likelihood attributions in cosmology. I show that likelihood arguments in cosmology suffer from significant conceptual and formal problems that undermine their applicability in this context

“Pure People” and “Corrupt Elites:” Corruption Talk in the 2020 Election

The word “corruption” has two separate but interrelated meanings. The first kind of corruption refers specifically to an abuse of public office for private gain; the second is broader and indicates a disjunction between a political reality and the ideal to which that reality ought to conform. This paper explores the role of various forms of “corruption talk” in the 2020 presidential election. The first part of the paper examines the “supply side,” looking at the kinds of “corruption narratives” that politicians offered in 2020. Using natural language processing, I analyze how Joe Biden, Donald Trump, and Bernie Sanders spoke about corruption. I show that while Biden tended to speak about corruption in a manner familiar to political scientists — as an abuse of public office for private gain – Sanders and Trump used “corruption” in a completely different way, referring to it as a quality of social groups, corporate interests, “foreign” values, or even the “system” as such. I then examine the “demand side,” using data from the American National Election Survey (ANES) to demonstrate how various forms of “corruption talk” may have played a role in voting outcomes. Finally, I situate the rise of the anti-establishment appeal in the context of the neoliberal turn and propose that the most powerful tool to fight right-wing populism is a discourse that acknowledges the “corruption” of the status-quo and appeals to the principle of popular sovereignty, thereby providing a liberal and inclusive alternative to populism

Does a computer have an arrow of time?

In [Sch05a], it is argued that Boltzmann's intuition, that the psychological arrow of time is necessarily aligned with the thermodynamic arrow, is correct. Schulman gives an explicit physical mechanism for this connection, based on the brain being representable as a computer, together with certain thermodynamic properties of computational processes. [Haw94] presents similar, if briefer, arguments. The purpose of this paper is to critically examine the support for the link between thermodynamics and an arrow of time for computers. The principal arguments put forward by Schulman and Hawking will be shown to fail. It will be shown that any computational process that can take place in an entropy increasing universe, can equally take place in an entropy decreasing universe. This conclusion does not automatically imply a psychological arrow can run counter to the thermodynamic arrow. Some alternative possible explanations for the alignment of the two arrows will be briefly discussed

The Package Deal Account of Laws and Properties

The package Deal Account of Laws and Properties forthcoming in Synthese This paper develops an account of the metaphysics of fundamental laws I call “the Package Deal Account (PDA)” that is a descendent of Lewis’ BSA but differs from it in a number of significant ways. It also rejects some elements of the metaphysics in which Lewis develops his BSA. First, Lewis proposed a metaphysical thesis about fundamental properties he calls “Humean Supervenience” (HS) according to which all fundamental properties are instantiated by points or point sized individuals and the only fundamental relations are geometrical spatial and temporal relations between these. While the BSA does not require HS Lewis seems to hope that it is true. In contrast, the PDA is not committed to HS or even to the fundamental arena in which fundamental properties are instantiated possessing geometrical structure and thus is able to accommodate relations and structures found in contemporary physics that apparently conflict with HS. Second, although Lewis’ BSA doesn’t require HS his Humeanism does require that fundamental properties are categorical. In contrast, the PDA allows for the possibility that fundamental properties are individuated in terms of laws and so are not categorical. Third, the PDA expands and develops the criteria for what counts in favor of a candidate system with more attention to the criteria employed by physicists in evaluating proposed theories. Fourth and most importantly, unlike Lewis’ BSA, the PDA does not presuppose metaphysically primitive elite properties/quantities that Lewis calls “perfectly natural” properties/quantities or presuppose a metaphysically preferred language whose terms denote such properties/quantities. It replaces Lewis’ account with an account on which natural properties are not metaphysically prior to the laws but are elements of a package that includes a fundamental arena that plays the role of space-time as well as fundamental laws and properties. By doing so it responds to some epistemological and metaphysical issues that have been raised regarding natural properties and their role in the BSA. In sum, the PDA goes further in explicating the notion of laws in terms of the aims and practices of science especially fundamental physics rather than in terms of prior metaphysics. I begin by reviewing Lewis’ account of perfectly natural properties and his Humean BSA of laws

The Package Deal Account of Laws and Properties

The package Deal Account of Laws and Properties forthcoming in Synthese This paper develops an account of the metaphysics of fundamental laws I call “the Package Deal Account (PDA)” that is a descendent of Lewis’ BSA but differs from it in a number of significant ways. It also rejects some elements of the metaphysics in which Lewis develops his BSA. First, Lewis proposed a metaphysical thesis about fundamental properties he calls “Humean Supervenience” (HS) according to which all fundamental properties are instantiated by points or point sized individuals and the only fundamental relations are geometrical spatial and temporal relations between these. While the BSA does not require HS Lewis seems to hope that it is true. In contrast, the PDA is not committed to HS or even to the fundamental arena in which fundamental properties are instantiated possessing geometrical structure and thus is able to accommodate relations and structures found in contemporary physics that apparently conflict with HS. Second, although Lewis’ BSA doesn’t require HS his Humeanism does require that fundamental properties are categorical. In contrast, the PDA allows for the possibility that fundamental properties are individuated in terms of laws and so are not categorical. Third, the PDA expands and develops the criteria for what counts in favor of a candidate system with more attention to the criteria employed by physicists in evaluating proposed theories. Fourth and most importantly, unlike Lewis’ BSA, the PDA does not presuppose metaphysically primitive elite properties/quantities that Lewis calls “perfectly natural” properties/quantities or presuppose a metaphysically preferred language whose terms denote such properties/quantities. It replaces Lewis’ account with an account on which natural properties are not metaphysically prior to the laws but are elements of a package that includes a fundamental arena that plays the role of space-time as well as fundamental laws and properties. By doing so it responds to some epistemological and metaphysical issues that have been raised regarding natural properties and their role in the BSA. In sum, the PDA goes further in explicating the notion of laws in terms of the aims and practices of science especially fundamental physics rather than in terms of prior metaphysics. I begin by reviewing Lewis’ account of perfectly natural properties and his Humean BSA of laws

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

The Consequence Argument Meets the Mentaculus

The “Consequence Argument” has spawned an enormous literature in response. The most notable of these is David Lewis’ based on his account of counterfactuals. My excuse for adding to this literature is while Lewis’ diagnosis of the argument is on the right track the account of counterfactuals he relies on to rebut the argument is, as I will argue, defective. I will develop a response that is in some ways similar to Lewis’ but differs in that it is based on a different and better account of counterfactuals which itself is based on an approach to statistical mechanics that goes back to Boltzmann and has more recently been developed by David Albert in his book Time and Chance. This account, which Albert and I refer to as “the Mentaculus”, provides a framework for explaining and connecting the various so called “arrows of time” including those of thermodynamics, causation, knowledge, and influence. It is the last of these arrows that is key to my response to the consequence argument. If my response is effective, then it will turn out that physics (together with some philosophy) rather than conflicting with freedom is able to rescue it, at least, from the Consequence Argument