In order to test a mathematical model of G1/S-phase transition, the proliferative response of the murine myeloid interleukin 3 (IL-3) dependent cell line NFS-78 to graded reduction of IL-3 levels was measured. Exponentially growing cells were exposed to bromodeoxyuridine (BUdR), which replaces thymidine (TdR) in the DNA double strands during DNA synthesis. After incubation periods ranging from 3 to 36 h the cells were fixed and stained with a fluorescence dye mixture of Hoechst 33258 and ethidium bromide (EB) and (...) subsequently analyzed in a two-parametrical flow cytometer. The BUdR-quenched TdR-specific Hoechst 33258 fluorescence of each cell provides information on the cell cycle location at the start of incubation and on whether or not a cell has divided. The DNA-specific EB fluorescence provides information on the actual cell cycle location at the end of the incubation period. From the 2-dimensional fluorescence distributions the efflux from G1-phase was calculated. Upon IL-3 reduction the cells showed accumulation in the Gl-phase along with a reduction in the progression rate through the other phases of the cell cycle. By staining with the vital dye Hoechst 33342 as well as with propidium iodide (PI) it was further possible to show that cell death after IL-3 withdrawal occurred in all phases of the cell cycle. (shrink)

Growth factors and the extracellular matrix provide the environmental cues that control the proliferation of most cell types. The binding of growth factors and matrix proteins to receptor tyrosine kinases and integrins, respectively, regulates several cytoplasmic signal transduction cascades, among which activation of the mitogen-activated protein kinase cascade, ras → Raf → MEK → ERK, is perhaps the best characterized. Curiously, ERK activation has been associated with both stimulation and inhibition of cell proliferation. In this review, we summarize recent studies (...) that connect ERK signaling to G1 phase cell cycle control and suggest that the cellular response to an ERK signal depends on both ERK signal intensity and duration. We also discuss studies showing that receptor tyrosine kinases and integrins differentially regulate the ERK signal in G1 phase. BioEssays 22:818–826, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Cell cycle dynamics has emerged as a key regulator of stem cell fate decisions. In particular, differentiation decisions are associated with the G1 phase, and recent evidence suggests that self‐renewal is actively regulated outside of G1. The mechanisms underlying these phenomena are largely unknown, but direct control of gene regulatory programs by the cell cycle machinery is heavily implicated. A recent study sheds important mechanistic insight by demonstrating that in human embryonic stem cells (hESCs) the Cyclin‐dependent kinase CDK2 controls (...) a wide‐spread epigenetic program that drives transcription at differentiation‐related gene promoters specifically in G1. Here, we discuss this finding and explore whether similar mechanisms are likely to function in multipotent stem cells. The implications of this discovery toward our understanding of stem cell‐related disease are discussed, and we postulate novel mechanisms that position the cell cycle as a regulator of cell fate gene networks at epigenetic, transcriptional and post‐transcriptional levels. (shrink)

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are ararrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c‐fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure (...) to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin‐dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactivate the cell cycle machinery. (shrink)

In early embryonic development, the cell cycle is paced by a biochemical oscillator involving cyclins and cyclin-dependent kinases (cdks). Essentially the same machinery operates in all eukaryotic cells, although after the first few divisions various braking mechanisms (the so-called checkpoints) become significant. Haase and Reed have recently shown that yeast cells have a second, independent oscillator which coordinates some of the events of the G1 phase of the cell cycle.(1) Although the biochemical nature of this oscillator is not known,it (...) seems unlikely to be a redundant cyclin/cdk system. BioEssays 22:3–5, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

The eukaryotic helicase is an 11-subunit machine containing an Mcm2-7 motor ring that encircles DNA, Cdc45 and the GINS tetramer, referred to as CMG. CMG is “built” on DNA at origins in two steps. First, two Mcm2-7 rings are assembled around duplex DNA at origins in G1 phase, forming the Mcm2-7 “double hexamer.” In a second step, in S phase Cdc45 and GINS are assembled onto each Mcm2-7 ring, hence producing two CMGs that ultimately form two replication forks (...) that travel in opposite directions. Here, we review recent findings about CMG structure and function. The CMG unwinds the parental duplex and is also the organizing center of the replisome: it binds DNA polymerases and other factors. EM studies reveal a 20-subunit core replisome with the leading Pol ϵ and lagging Pol α-primase on opposite faces of CMG, forming a fundamentally asymmetric architecture. Structural studies of CMG at a replication fork reveal unexpected details of how CMG engages the DNA fork. The structures of CMG and the Mcm2-7 double hexamer on DNA suggest a completely unanticipated process for formation of bidirectional replication forks at origins. Here, we review the structure and function of CMG, the 11 subunit helicase for eukaryotic DNA replication. Two CMGs are assembled at origins starting from two Mcm2-7 hexamers oriented N-to-N. The orientation of CMG at a forked DNA implies that the two CMGs at an origin pass one another. (shrink)

We assume the existence of a specific G1 protein which is an initiator of DNA replication. This initiator is supposed to be synthesized according to Michaelis-Menten kinetics. In order to start DNA replication, it is assumed that this G1 specific protein must be produced in a required amount. Intra-cellular growth inhibitors and extra-cellular growth factors control the production of the initiator. This model allows to calculate the average G1 phase time as a function of the various chemical concentrations of (...) nutrients, enzymes, growth inhibitors and growth factors. This model is compared to cell kinetics experiments on a leukemic cell line responding to Interleukin 3 deprivation. The curves giving the experimental average G1 phase times with respect to Interleukin-3 concentrations are fitted by the mathematical model with a quite good agreement. (shrink)

In their environment, plants are continuously submitted to natural stimuli such as wind, rain, temperature changes, wounding, etc. These signals induce a cascade of events which lead to metabolic and morphogenetic responses. In this paper the different steps are described and discussed starting from the reception of the signal by a plant organ to the final morphogenetic response. In our laboratory two plants are studied: Bryonia dioica for which rubbing the internode results in reduced elongation and enhanced radial expansion and (...) Bidens pilosa for which the response occurs at distance, hence pricking the cotyledon of a plantlet induces the growth inhibition of both the hypocotyl and the axillary bud of the pricked cotyledon. Reception of the signal and transmission of the message. In Bryonia the signal is received by epidermal cells while in Bidens they are the cells adjacent to the midrib of the cotyledon which receive the mechanical signal. In both plants the message is transmitted via a wave of electric depolarization. This latter is composed of an action potential associated with a slow wave whose transmission rates are respectively 1cm s−1 and 1 mm s−1. Recent results have shown the involvement of Ca2+ in the triggering of the slow wave and the role of the H+ pump during the slow wave. Transient and fast biochemical responses. An entry of extraceilular Ca2+ into the cells and a transient increase in IP3 occur within seconds following the mechanical stimulus. At the same time, the membrane becomes more fluid, correlated with qualitative changes in phospholipids. The rapid increase in the concentration of peroxidated lipids may be correlated with ethylene biosynthesis which is stimulated after rubbing. Other parameters such as cytoplasmic pH, relative water content, hydric potential, membrane potential and modifications of K+, Mg2+-ATPase and Ca2+-ATPase activities, play a key role in the early responses induced by the traumatisms. Irreversible-biochemical responses. The mechanical stimulus performed on a Bryonia internode induces an acceleration of: i) enzymatic activities related to the lignification, ii) esterification of phenolic acids in the cell wall. Consequently the lignification process is accelerated. Storage of the information. After being received by the target cells the information can be stored during several days before being expressed. At the level of cotyledonary bud, the first message, previously stored, can be expressed or not by a second treatment. Bidens thus behaves as if it was able to “store” and to “retrieve” morphogenetic messages, using a sort of rudimentary memory. The nuclei of the bud cells of the pricked cotyledon show that these cells, initially in G2 phase, divide and then remain in the G1 phase. In Bryonia, calli derived from young stimulated internodes, keep thigmomorphogenetic characteristics during several weeks. In the last part of this paper the particularity of our plant model which permits a study of the transmission and storage of the message, is underlined. The links between the different steps induced by the stimulus are discussed. Special attention is devoted to second messengers and to the amplification of the message. (shrink)

Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase‐dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M (...) checkpoint activation. Such DDR‐positive telomeres, and those that occur as part of the telomere‐dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR‐positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. (shrink)

Enzymatic misrepair of ionizing‐radiation‐induced DNA damage can produce large‐scale rearrangements of the genome, such as translocations and dicentrics. These and other chromosome exchange aberrations can cause major phenotypic alterations, including cell death, mutation and neoplasia. Exchange formation requires that two (or more) genomic loci come together spatially. Consequently, the surprisingly rich aberration spectra uncovered by recently developed techniques, when combined with biophysically based computer modeling, help characterize large‐scale chromatin architecture in the interphase nucleus. Most results are consistent with a picture (...) whereby chromosomes are mainly confined to territories, chromatin motion is limited, and interchromosomal interactions involve mainly territory surfaces. Aberration spectra and modeling also help characterize DNA repair/misrepair mechanisms. Quantitative results for mammalian cells are best described by a breakage‐and‐reunion model, suggesting that the dominant recombinational mechanism during the G0/G1 phase of the cell cycle is non‐homologous end‐joining of radiogenic DNA double strand breaks. In turn, better mechanistic and quantitative understanding of aberration formation gives new insights into health‐related applications. BioEssays 24:714–723, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Receptor tyrosine kinases and integrins are activated by growth factors and extracellular matrix, respectively. Their activation leads to signal transduction cascades that control many aspects of cell phenotype, including progression through the G1 phase of the cell cycle. However, the signalling cassettes driven by growth factors and matrix do not work independently of each other. Integrin triggering is essential to facilitate kinase‐ and GTPase‐mediated signals and thereby drive efficient transfer of information through the growth factor–cyclin axis. A recent study (...) indicates that an additional type of player has a key role in adhesion‐regulated control of cell cycle, namely ubiquitin ligase.(1) BioEssays 24:17–21, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The studies on the cAMP‐requiring mutants and their suppressors in the yeast, Saccharomyces cerevisiae, revealed that cAMP‐dependent protein phosphorylation is involved in the G1 phase of the cell cycle, in conjugation, and in the post‐meiotic stage of sporulation, and that inhibition of cAMP‐dependent protein phosphorylation is required to induce meiotic division.

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during (...) every cell cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates decline drastically (...) during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

It is widely accepted that there exists a “resting” or “quiescent” state where a growing cell leaves the cell cycle to enter what is often called the “G0‐phase.” I propose that there is no biological reality to the “G0‐phase.” The experimental basis for proposing a G0‐phase is re‐examined and re‐analyzed here showing that the G0‐phase is an anthropomorphic construct with no biological reality.

Three major aspects of G1 regulation acting at START in fission yeast are discussed in this review. Firstly, progression towards S phase in the mitotic cycle. This is controlled by the activation of transcription complexes at START which cause cell cycle‐dependent activation of genes required for DNA synthesis. The second aspect is the regulation of developmental fate occurring during G1. Passage through START appears to inhibit sexual differentiation because the meiotic and mitotic pathways are mutually exclusive. This is brought (...) about because the meiotic pathway is inhibited by the same gene functions that are required for S phase onset. Thirdly, distinct checkpoint, or dependency, controls operate both pre‐ and post‐START in the mitotic cycle to inhibit mitosis in the absence of replicated DNA, and also to limit rounds of DNA replication to one per cell cycle. (shrink)

As cells approach S phase, many changes occur to create an environment conducive for DNA synthesis and commitment to cell division. The transcription rate of many genes encoding enzymes involved in DNA synthesis, including the dihydrofolate reductase (dhfr) gene, increases at the G1/S boundary of the cell cycle. Although a number of transcription factors interact to finely tune the levels of dhfr RNA produced, two families of transcription factors, Sp1 and E2F, play central roles in modulating dhfr levels. A (...) region containing several Sp1‐binding sites is required for both regulated and basal transcription levels. In contrast, the E2F‐binding sites near the transcription start site are required only for regulated transcription. A model is presented for the regulation of the dhfr gene which may also pertain to other cell cycle‐associated genes. (shrink)

Recent work suggests that DNA replication origins are regulated by the number of multiple mini‐chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM – the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained (...) by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research. (shrink)

Mos, a protein kinase, is specifically expressed and functions during meiotic maturation (or G2/M progression) of vertebrate oocytes. When expressed ectopically, however, it can also readily induce oncogenic transformation (or uncontrolled G1/S transitions) in somatic cells. In both of these cell types, Mos activates mitogen‐activated protein kinase (MAPK), which seems largely to mediate its different functions in both oocyte maturation and cellular transformation. In oocyte maturation, the Mos‐MAPK pathway probably serves to activate and stabilize M‐phase promoting factor (MPF) (possibly (...) by inhibiting some negative regulator(s) of this factor), while in cellular transformation, it seems to stabilize and activate the nuclear oncoprotein c‐Fos as well as to induce transcription of its gene. Thus, the different functions of Mos in oocytes and somatic cells may arise chiefly from its different MAPK‐mediated targets in the respective cell types. This review discusses the cellular basis that may enable Mos to act differently in oocytes and somatic cells. (shrink)

The dinoflagellates, a diverse sister group of the malaria parasites, are the major agents causing harmful algal blooms and are also the symbiotic algae of corals. Dinoflagellate nuclei differ significantly from other eukaryotic nuclei by having extranuclear spindles, no nucleosomes and enormous genomes in liquid crystal states. These cytological characteristics were related to the acquisition of prokaryotic genes during evolution (hence Mesokaryotes), which may also account for the biochemical diversity and the relatively slow growth rates of dinoflagellates. The fact that (...) the proliferation of many dinoflagellates is sensitive to turbulence may be due to the physiological requirements of the genome's liquid crystal states. Mechanical stress and anti‐microtubule drugs induce cell cycle arrest mainly in G1, implicating a role for the permanent cortical microtubular cytoskeleton in mechanotransduction. The cell cycles of photosynthetic dinoflagellates are also gated by the circadian rhythm, with cell division occurring mainly at the end of the dark phase. Cell growth and the biosynthesis of many toxins occur during the light phase, corresponding to G1 in the cell cycle. The dinoflagellates also embody several options for coupling cell cycle progression to cell growth, enabling them to make the best use of available resources and possibly preparing them for a symbiotic existence. BioEssays 27:730–740, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild‐type p53, as it is not observed in cells lacking functionally wild‐type protein, and at least some component of S phase and G2/M arrests is also thought to be p53‐dependent. p53 functions as a transcription factor which binds (...) specific DNA sequences, and recently major downstream targets have been identified, including p21Cip1 an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase δ auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle. (shrink)

Two mechanisms are available for the repair of DNA double‐strand breaks (DSBs) in eukaryotic cells: homology directed repair (HDR) and non‐homologous end‐joining (NHEJ). While NHEJ is not restricted to a particular phase of the cell cycle, it is incapable of accurately repairing DBSs that have suffered a loss or gain of nucleotide sequence information. In contrast, HDR achieves accurate repair of such DSBs by use of a sister chromatid as a DNA template, but is restricted to cell cycle phases (...) (S/G2) when such templates are available. In this scheme, G1 cells appear to lack a mechanism for the accurate repair of certain DSBs, and an ability to use alternative templates would be highly advantageous. Considered here, therefore, is the possibility that RNA transcripts are used as templates for HDR. Potential mechanisms for transcript‐templated HDR, and ways in which it might be detected, are presented. BioEssays 28:78–83, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Some theories of personal identity allow some variation in what it takes for a person to survive from context to context; and sometimes this is determined by the desires of person-stages or the practices of communities.This leads to problems for decision making in contexts where what is chosen will affect personal identity.‘Temporal Phase Pluralism’ solves such problems by allowing that there can be a plurality of persons constituted by a sequence of person stages. This illuminates difficult decision making problems (...) when persons have to choose between different life-altering choices. (shrink)

The European Corporate Sustainability Framework (ECSF) is, among other concepts, based on a phase-wise development approach as described by Clare Graves' Levels of Existence Theory. As much as corporate sustainability has a sequence of adequate interpretations, aligned with each development level, also the notion of business excellence can be defined at multiple levels, as this paper demonstrates. Furthermore, the authors analyze the current EFQM Excellence Model for particular biases towards various development levels and suggest a new and innovative two-step (...) approach to assessing organizational performance with respect to organizational excellence (OE) and corporate sustainability. According to the organization's ambition, the assessment is either limited to a shareholder approach, mainly focusing at optimal usage of resources, or it also includes an additional assessment format based on the stakeholder approach, with specific reference to the organization's performance on the financial, social and ecological bottom line. This paper demonstrates the need and feasibility of an EFQM-Based assessment tool with a combined focus on corporate sustainability and OE. (shrink)

Written at an undergraduate mathematical level, this book provides the essential theoretical tools and foundations required to develop basic models to explain collective phase transitions for a wide variety of ecosystems.

I analyze the extent to which classical phase transitions, both first order and continuous, pose a challenge for intertheoretic reduction. My contention is that phase transitions are compatible with a notion of reduction that combines Nagelian reduction and what Thomas Nickles called Reduction2. I also argue that, even if the same approach to reduction applies to both types of phase transitions, there is a crucial difference in their physical treatment: in addition to the thermodynamic limit, in continuous (...) phase transitions there is a second infinite limit involved, which marks an important difference in the reduction of first-order and continuous phase transitions. (shrink)

Most models of response time (RT) in elementary cognitive tasks implicitly assume that the speed-accuracy trade-off is continuous: When payoffs or instructions gradually increase the level of speed stress, people are assumed to gradually sacrifice response accuracy in exchange for gradual increases in response speed. This trade-off presumably operates over the entire range from accurate but slow responding to fast but chance-level responding (i.e., guessing). In this article, we challenge the assumption of continuity and propose a phase transition model (...) for RTs and accuracy. Analogous to the fast guess model (Ollman, 1966), our model postulates two modes of processing: a guess mode and a stimulus-controlled mode. From catastrophe theory, we derive two important predictions that allow us to test our model against the fast guess model and against the popular class of sequential sampling models. The first prediction—hysteresis in the transitions between guessing and stimulus-controlled behavior—was confirmed in an experiment that gradually changed the reward for speed versus accuracy. The second prediction—bimodal RT distributions—was confirmed in an experiment that required participants to respond in a way that is intermediate between guessing and accurate responding. (shrink)

Ethical concerns have been raised about the quality of informed consent by participants in phase 1 oncology trials. Interview surveys indicate that substantial proportions of trial participants do not understand the purpose of these trials—evaluating toxicity and dosing for subsequent efficacy studies—and overestimate the prospect of therapeutic benefit that they offer. In this article we argue that although these data suggest the desirability of enhancing the process of information disclosure and assessment of comprehension of the implications of study participation, (...) they do not necessarily invalidate consent by phase 1 trial participants. (shrink)

In many cases, the “therapeutic misconception” may be an unavoidable part of the imperfect process of recruitment and consent in medical researchPaul Appelbaum, Loren Roth, and Charles Lidz coined the term “therapeutic misconception” in 1982.1 They described it as the misconception that participating in research is the same as receiving individualised treatment from a physician. It referred to the research subject’s failure to appreciate that the aim of research is to obtain scientific knowledge, and that any benefit to the subject (...) is a by-product of that knowledge. More recent studies by Appelbaum and Lidz have shown that this phenomenon is just as pervasive now as it was twenty four years ago.2 The problem pertains not to any duty of care for researchers but to participants’ unfounded belief in the therapeutic potential of research.3 It is especially acute in phase I oncology trials, which aim to test the toxicity and highest tolerable dose of anticancer drugs.To remedy this situation, many have argued that both clinicians and researchers need to do more in explaining to subjects the differences between experimental research and standard care. Clinicians and researchers recruiting potential subjects for research must present information about the expected risks and benefits of participation in research in a more realistic and straightforward way.4 In one recent examination of consent forms for phase I oncology trials, Sam Horng et al found that, in the section on “benefit”, only one of 272 forms stated that the subjects were expected to benefit. They also found that 11 consent forms stated clearly that subjects would not benefit, 25 forms communicated uncertainty about benefit, and 5 forms said nothing about the chance of benefit. Interestingly, 139 forms alluded to the …. (shrink)

We classify the phase transition thresholds from provability to unprovability for certain Friedman-style miniaturizations of Kruskal's Theorem and Higman's Lemma. In addition we prove a new and unexpected phase transition result for ε0. Motivated by renormalization and universality issues from statistical physics we finally state a universality hypothesis.

Vincent Ardourel discusses the eliminability of infinite limits in the explanations of phase transitions—an important point in the debate on the reducibility of thermodynamics to statistical mechanics. To this end, he examines alternative physical theories that deal with phase transitions in finite systems.

Wansing’s extended intuitionistic linear logic with strong negation, called WILL, is regarded as a resource-conscious refinment of Nelson’s constructive logics with strong negation. In this paper, (1) the completeness theorem with respect to phase semantics is proved for WILL using a method that simultaneously derives the cut-elimination theorem, (2) a simple correspondence between the class of Petri nets with inhibitor arcs and a fragment of WILL is obtained using a Kripke semantics, (3) a cut-free sequent calculus for WILL, called (...) twist calculus, is presented, (4) a strongly normalizable typed λ-calculus is obtained for a fragment of WILL, and (5) new applications of WILL in medical diagnosis and electric circuit theory are proposed. Strong negation in WILL is found to be expressible as a resource-conscious refutability, and is shown to correspond to inhibitor arcs in Petri net theory. (shrink)

A predictive model applicable in both neurophysiological and decision-making studies is proposed, bridging the gap between psychological/behavioral and neurophysiological studies. Supposing the electromagnetic waves are carriers of decision-making, and electromagnetic waves with the same frequency, individual amplitude and constant phase triggered by conditions interfere with each other and the resultant intensity determines the probability of the decision. Accordingly, brainwave-interference decision-making model is built mathematically and empirically test with neurophysiological and behavioral data. Event-related potential data confirmed the stability of the (...) phase differences in a given decision context. Behavioral data analysis shows that phase stability exists across categorization-decision, two-stage gambling, and prisoner’s dilemma decisions. Irrational decisions occurring in those experiments are actually rational as their phases could be quantitatively derived from the phases of the riskiest and safest choices. Model fitting result reveals that the root-mean-square deviations between the fitted and actual phases of irrational decisions are less than 10°, and the mean absolute percentage errors of the fitted probabilities are less than 0.06. The proposed model is similar in mathematical form compared with the quantum modeling approach, but endowed with physiological/psychological connection and predictive ability, and promising in the integration of neurophysiological and behavioral research to explore the origin of the decision. (shrink)

The Phaselis decree is our chief piece of evidence for the manner in which the Athenians regulated civil-suits arising between themselves and the allies in the mid-fifth century. It reads as follows.

We elaborate Weiermann-style phase transitions for well-partial-orderings (wpo) determined by iterated finite sequences under Higman-Friedman style embedding with Gordeev’s symmetric gap condition. For every d-times iterated wpo \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\left({\rm S}\text{\textsc{eq}}^{d}, \trianglelefteq _{d}\right)}$$\end{document} in question, d > 1, we fix a natural extension of Peano Arithmetic, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${T \supseteq \sf{PA}}$$\end{document}, that proves the corresponding second-order sentence \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} (...) \begin{document}$${\sf{WPO}\left({\rm S}{\textsc{eq}}^{d}, \trianglelefteq _{d}\right) }$$\end{document}. Having this we consider the following parametrized first-order slow well-partial-ordering sentence \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sf{SWP}\left({\rm S}\text{\textsc{eq}}^{d}, \trianglelefteq _{d}, r\right):}$$\end{document}\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( \forall K > 0 \right) \left( \exists M > 0\right) \left( \forall x_{0},\ldots,x_{M}\in {\rm S}\text{\textsc{eq}}^{d}\right)$$\end{document}\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( \left( \forall i\leq M\right) \left( \left| x_{i}\right| 1}$$\end{document} then \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sf{SWP}\left({\rm S}\text{\textsc{eq}}^{d}, \trianglelefteq _{d},r \right) }$$\end{document} is not provable in T.Moreover, by the well-known proof theoretic equivalences we can just as well replace T by PA or ACA0 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\Delta _{1}^{1}\sf{CA}}$$\end{document}, if d = 2 and d = 3, respectively.In the limit case d → ∞ we replaceEFA-provably computable reals r by EFA-provably computable functions \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${f: \mathbb{N} \rightarrow \mathbb{R}_{+}}$$\end{document} and prove analogous theorems. (In the sequel we denote by \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathbb{R}_{+}}$$\end{document} the set of EFA-provably computable positive reals). In the basic case T = PA we strengthen the basic phase transition result by adding the following static threshold clause\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sf{SWP}\left({\rm S}\text{\textsc{eq}}^{2}, \trianglelefteq _{2}, 1\right)}$$\end{document} is still provable in T = PA (actually in EFA). Furthermore we prove the following dynamic threshold clauses which, loosely speaking are obtained by replacing the static threshold t by slowly growing functions 1α given by \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${1_{\alpha }\left( i\right)\,{:=}\,1+\frac{1}{H_{\alpha }^{-1}\left(i\right) }, H_{\alpha}}$$\end{document} being the familiar fast growing Hardy function and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${H_{\alpha }^{-1}\left( i\right)\,{:=}\,\rm min \left\{ j \mid H_{\alpha } \left ( j\right) \geq i \right\}}$$\end{document} the corresponding slowly growing inversion. If \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\alpha < \varepsilon _{0}}$$\end{document}, then \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sf{SWP}\left({\rm S}\text{\textsc{eq}}^{2}, \trianglelefteq _{2}, 1_{\alpha}\right)}$$\end{document} is provable in T = PA. \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sf{SWP}\left( {\rm S}\text{\textsc{eq}}^{2}, \trianglelefteq _{2},1_{\varepsilon _{0}}\right)}$$\end{document} is not provable in T = PA. We conjecture that this pattern is characteristic for all \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${T\supseteq \sf{PA}}$$\end{document} under consideration and their proof-theoretical ordinals o (T ), instead of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\varepsilon _{0}}$$\end{document}. (shrink)

In this paper, I analyze the extent to which classical phase transitions, especially continuous phase transitions, impose a challenge for reduction- ism. My main contention is that classical phase transitions are compatible with reduction, at least with the notion of limiting reduction, which re- lates the behavior of physical quantities in different theories under certain limiting conditions. I argue that this conclusion follows even after rec- ognizing the existence of two infinite limits involved in the treatment of (...) continuous phase transitions. (shrink)

Gödel’s first incompleteness result from 1931 states that there are true assertions about the natural numbers which do not follow from the Peano axioms. Since 1931 many researchers have been looking for natural examples of such assertions and breakthroughs were obtained in the seventies by Jeff Paris [Some independence results for Peano arithmetic. J. Symbolic Logic 43 725–731] , Handbook of Mathematical Logic, North-Holland, Amsterdam, 1977] and Laurie Kirby [L. Kirby, Jeff Paris, Accessible independence results for Peano Arithmetic, Bull. of (...) the LMS 14 285–293]) and Harvey Friedman [S.G. Simpson, Non-provability of certain combinatorial properties of finite trees, in: Harvey Friedman’s Research on the Foundations of Mathematics, North-Holland, Amsterdam, 1985, pp. 87–117; R. Smith, The consistency strength of some finite forms of the Higman and Kruskal theorems, in: Harvey Friedman’s Research on the Foundations of Mathematics, North-Holland, Amsterdam, 1985, pp. 119–136] who produced the first mathematically interesting independence results in Ramsey theory and well-order and well-quasi-order theory .In this article we investigate Friedman-style principles of combinatorial well-foundedness for the ordinals below ε0. These principles state that there is a uniform bound on the length of decreasing sequences of ordinals which satisfy an elementary recursive growth rate condition with respect to their Gödel numbers.For these independence principles we classify their phase transitions, i.e. we classify exactly the bounding conditions which lead from provability to unprovability in the induced combinatorial well-foundedness principles.As Gödel numbering for ordinals we choose the one which is induced naturally from Gödel’s coding of finite sequences from his classical 1931 paper on his incompleteness results.This choice makes the investigation highly non-trivial but rewarding and we succeed in our objectives by using an intricate and surprising interplay between analytic combinatorics and the theory of descent recursive functions. For obtaining the required bounds on count functions for ordinals we use a classical 1961 Tauberian theorem of Parameswaran which apparently is far remote from Gödel’s theorem. (shrink)

In 1885, during initial discussions of J. C. Maxwell's celebrated thermodynamic demon, Whiting(1) observed that the demon-like velocity selection of molecules can occur in a gravitationally bound gas. Recently, a gravitational Maxwell demon has been proposed which makes use of this observation [D. P. Sheehan, J. Glick, and J. D. Means, Found. Phys. 30, 1227 (2000)]. Here we report on numerical simulations that detail its microscopic phase space structure. Results verify the previously hypothesized mechanism of its paradoxical behavior. This (...) system appears to be the only example of a fully classical mechanical Maxwell demon that has not been resolved in favor of the second law of thermodynamics. (shrink)

Phase-shift analysis is a commonly used technique to extract the scattering amplitudes of a two-body strong-interaction scattering process from the experimentally measured quantities | total cross-section, di erential cross-section, polarization and spin-correlation parameters. However, at a xed energy, all the scattering amplitudes can be multiplied by an arbitrary angle-dep phase-factor without a ecting the measurables. It would seem then that the phase of the..

We classify a sharp phase transition threshold for Friedman’s finite adjacent Ramsey theorem. We extend the method for showing this result to two previous classifications involving Ramsey theorem variants: the Paris–Harrington theorem and the Kanamori–McAloon theorem. We also provide tools to remove ad hoc arguments from the proofs of phase transition results as much as currently possible.

Membranous organelles allow sub‐compartmentalization of biological processes. However, additional subcellular structures create dynamic reaction spaces without the need for membranes. Such membrane‐less organelles (MLOs) are physiologically relevant and impact development, gene expression regulation, and cellular stress responses. The phenomenon resulting in the formation of MLOs is called liquid–liquid phase separation (LLPS), and is primarily governed by the interactions of multi‐domain proteins or proteins harboring intrinsically disordered regions as well as RNA‐binding domains. Although the presence of RNAs affects the formation (...) and dissolution of MLOs, it remains unclear how the properties of RNAs exactly contribute to these effects. Here, the authors review this emerging field, and explore how particular RNA properties can affect LLPS and the behavior of MLOs. It is suggested that post‐transcriptional RNA modification systems could be contributors for dynamically modulating the assembly and dissolution of MLOs. (shrink)

Physician‐investigators face the daunting task of enrolling desperate patients into Phase I cancer trials that are not meant to be therapeutic. Patients doggedly regard the trials as therapeutic, and researchers tend to collaborate in their confusion by glossing the trials’ true purposes and noting the occasional benefit that subjects accidentally receive. The disparity between hope and fact must be redressed by degrees, from many angles at once.

When the COVID-19 surge hit New York City hospitals, the Division of Medical Ethics at Weill Cornell Medical College, and our affiliated ethics consultation services, faced waves of ethical issues sweeping forward with intensity and urgency. In this article, we describe our experience over an eight-week period (16 March through 10 May 2020), and describe three types of services: clinical ethics consultation (CEC); service practice communications/interventions (SPCI); and organizational ethics advisement (OEA). We tell this narrative through the prism of time, (...) describing the evolution of ethical issues and trends as the pandemic unfolded. We delineate three phases: anticipation and preparation, crisis management, and reflection and adjustment. The first phase focused predominantly on ways to address impending resource shortages and to plan for remote ethics consultation, and CECs focused on code status discussions with surrogates. The second phase was characterized by the dramatic convergence of a rapid increase in the number of critically ill patients, a growing scarcity of resources, and the reassignment/ redeployment of staff outside their specialty areas. The third phase was characterized by the recognition that while the worst of the crisis was waning, its medium- and long-term consequences continued to pose immense challenges. We note that there were times during the crisis that serving in the role of clinical ethics consultant created a sense of dis-ease as novel as the coronavirus itself. In retrospect we learned that our activities far exceeded the familiar terrain of clinical ethics consultation and extended into other spheres of organizational life in novel ways that were unanticipated before this pandemic. To that end, we defined and categorized a middle level of ethics consultation, which we have termed service practice communication intervention (SPCI). This is an underappreciated dimension of the work that ethics consult services are capable of in times of crisis. We believe that the pandemic has revealed the many enduring ways that ethics consultation services can more robustly contribute to the ethical life of their institutions moving forward. (shrink)

In 1885, during initial discussions of J. C. Maxwell's celebrated thermodynamic demon, Whiting (1) observed that the demon-like velocity selection of molecules can occur in a gravitationally bound gas. Recently, a gravitational Maxwell demon has been proposed which makes use of this observation [D. P. Sheehan, J. Glick, and J. D. Means, Found. Phys. 30, 1227 (2000)]. Here we report on numerical simulations that detail its microscopic phase space structure. Results verify the previously hypothesized mechanism of its paradoxical behavior. (...) This system appears to be the only example of a fully classical mechanical Maxwell demon that has not been resolved in favor of the second law of thermodynamics. (shrink)