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)

It is proposed that the multiple enhancer elements associated with locus control regions and super‐enhancers recruit RNA polymerase II and efficiently assemble elongation competent transcription complexes that are transferred to target genes by transcription termination and transient looping mechanisms. It is well established that transcription complexes are recruited not only to promoters but also to enhancers, where they generate enhancer RNAs. Transcription at enhancers is unstable and frequently aborted. Furthermore, the Integrator and WD‐domain containing protein 82 mediate transcription termination at (...) enhancers. Abortion and termination of transcription at the multiple enhancers of locus control regions and super‐enhancers provide a large pool of elongation competent transcription complexes. These are efficiently captured by strong basal promoter elements at target genes during transient looping interactions. -/- . (shrink)

Liquid‐liquid phase separation (LLPS) has recently emerged as a possible mechanism that enables ubiquitin‐binding shuttle proteins to facilitate the degradation of ubiquitinated substrates via distinct protein quality control (PQC) pathways. Shuttle protein LLPS is modulated by multivalent interactions among their various domains as well as heterotypic interactions with polyubiquitin chains. Here, the properties of three different shuttle proteins (hHR23B, p62, and UBQLN2) are closely examined, unifying principles for the molecular determinants of their LLPS are identified, and how LLPS (...) is connected to their functions is discussed. Evidence supporting LLPS of other shuttle proteins is also found. In this review, it is proposed that shuttle protein LLPS leads to spatiotemporal regulation of PQC activities by mediating the recruitment of PQC machinery (including proteasomes or autophagic components) to biomolecular condensates, assembly/disassembly of condensates, selective enrichment of client proteins, and extraction of ubiquitinated proteins from condensates in cells. (shrink)

The intracellular multiprotein complex β‐catenin destruction complex plays a key role in Wnt/β‐catenin signaling. Wnt stimulation induces the assembly of the receptor‐associated signalosome and the inactivation of the destruction complex, leading to β‐catenin accumulation and transcriptional activation of the target genes. The core components of the destruction complex include Axin, APC, GSK3β, CK1α and other proteins. Recent studies demonstrated that Axin and APC undergo liquid–liquid phase separation (LLPS), which is critical for their function to regulate Wnt/β‐catenin signaling. Here, (...) we discuss the possible roles of LLPS in Wnt/β‐catenin signaling and regulation of Axin LLPS by post‐translational modifications. (shrink)

Cells contain a myriad of membraneless ribonucleoprotein (RNP) condensates with distinct compositions of proteins and RNAs. RNP condensates participate in different cellular activities, including RNA storage, mRNA translation or decay, stress response, etc. RNP condensates are assembled via liquid‐liquid phase separation (LLPS) driven by multivalent interactions. Transition of RNP condensates into bodies with abnormal material properties, such as solid‐like amyloid structures, is associated with the pathogenesis of various diseases. In this review, we focus on how RNAs regulate multiple (...) aspects of RNP condensates, such as dynamic assembly and/or disassembly and biophysical properties. RNA properties – including concentration, sequence, length and structure – also determine the phase behaviors of RNP condensates. RNA is also involved in specifying autophagic degradation of RNP condensates. Unraveling the role of RNA in RNPs provides novel insights into pathological accumulation of RNPs in various diseases. This new understanding can potentially be harnessed to develop therapeutic strategies. (shrink)

New concepts, or new and better formulations of old concepts, are essential for scientific progress. This paper is intended to focus attention on two phases of natural processes and human activities which have a variety of names, and by giving them neutral names, to deprive them of their emotional flavour. As a result I hope that two evolutionary principles of some generality will become apparent.

Phase separation underlies the formation of biomolecular condensates. We hypothesize the cellular processes that occur within condensates shape their structural features. We use the example of transcription to discuss structure–function relationships in condensates. Various types of transcriptional condensates have been reported across the evolutionary spectrum in the cell nucleus as well as in mitochondrial and bacterial nucleoids. In vitro and in vivo observations suggest that transcriptional activity of condensates influences their supramolecular structure, which in turn affects their function. (...) Condensate organization thus becomes driven by differences in miscibility among the DNA and proteins of the transcription machinery and the RNA transcripts they generate. These considerations are in line with the notion that cellular processes shape the structural properties of condensates, leading to a dynamic, mutual interplay between structure and function in the cell. (shrink)

— We prescnt here a comparative study on the decay of chlorophyll a fluorescence yield in thylakoid membranes and photosystem 11 ‐enriched samples, measured with multifrequency cross‐correlation phase fluorometry. These measurements confirm the general conclusions of Van Mieghem ef al., obtained with a flash method, on the effects of reduction of the primary quinone acceptor on ChI a fluorescence yield of PSI. Different states of the reaction centers of PSII were produced by: pretreatment with sodium dithionite and mcthyl viologen (...) followed by laser illumination: the doubly reduced QA centers: with laser illumination or pretreatment with diuron: QA‐ centers; and the addition of micromolar concentration of dichlorobenzoquinonc : oxidized QA centers. The data were analyzed with Lorentzian distribution as well as with multiexponential fluorescence decay functions. The analysis with Lorcntzian distribution function showed that upon formation of QA. the major lifetime distribution peak shifted to longer lifetimes: from 0.25 ns to 1.66 ns and from 0.24 ns to 1.31 ns. However, when QAHZ was formed, the lifetime distribution peaks shifted back to shorter lifetimes both in thylakoids and PSIl membranes. Multiexponential analysis showed three lifetime components: fast, middle and slow. When QA was formed in PS11 centers, the amplitude of the fast Component decreased, but both thc amplitude and the lifetime of the middle component increased severalfold. However, when QA was doubly reduccd, the amplitude of the fast component increased and the amplitude of the middle component decreased: in addition, the lifetime of the slow component increased. All of the above results are consistent with the conclusions that PS11 charge separation is decreased when QA is formed and increased when doubly reduced QA is formed. Copyright © 1993, Wiley Blackwell. All rights reserved. (shrink)

The Leibniz Center for Law is involved in the project Digitale Uitwisseling Ruimtelijke Plannen [DURP (http://www.vrom.nl/durp); digital exchange of spatial plans] which develops a XML-based digital exchange format for spatial regulations. Involvement in the DURP project offers new possibilities to study a legal area that hasn’t yet been studied to the extent it deserves in the field of Computer Science & Law. We studied and criticised the work of the DURP project and the Dutch Ministry of internal affairs on metadata (...) for regulatory documents, and made an inventory of issues related to legal knowledge representation that it felt were not sufficiently covered by current initiatives in the Geographic Information Systems (GIS) field. This inventory was an input to the DURP standardisation effort. In a second phase of the project we extended the METALex XML schema (cf. Boer et al. 2002; Boer et al. 2003) for ‚regular’ legal sources that we developed in the past for geospatial regulatory information, in order to support exchange of spatial regulations, including the associated geospatial information in the form of maps. We developed a prototype application and demonstrated how the spatial planning information in GML can be combined with XML with only minimal changes, using the Web Ontology Language (OWL). This paper describes our experiences. (shrink)

With the present paper I maintain that the group field theory (GFT) approach to quantum gravity can help us clarify and distinguish the problems of spacetime emergence from the questions about the nature of the quanta of space. I will show that the mechanism of phase transition suggests a form of indifference between scales (or phases) and that such an indifference allows us to black-box questions about the nature of the ontology of the fundamental levels of the theory. I (...) consider the GFT approach to quantum gravity which derives spacetime as an emergent property from abstract non-geometrical tetrahedra through a processes of phase transition. Because the physical interpretation of the tetrahedra is problematic in view of their (non)-spatiotemporal nature, I will apply the considerations about phase transitions to GFT and conclude that the fundamental ontology of the theory and the mechanism of spacetime emergence can and should be treated separately. (shrink)

In this paper, we outline a new method for evaluating the human impact of machine-learning applications. In partnership with Underwriters Laboratories Inc., we have developed a framework to evaluate the impacts of a particular use of machine learning that is based on the goals and values of the domain in which that application is deployed. By examining the use of artificial intelligence in particular domains, such as journalism, criminal justice, or law, we can develop more nuanced and practically relevant understandings (...) of key ethical guidelines for artificial intelligence. By decoupling the extraction of the facts of the matter from the evaluation of the impact of the resulting systems, we create a framework for the process of assessing impact that has two distinctly different phases. (shrink)

The Communist Party of Germany (KPD) first coined the united-front policy in 1921, representing a promising effort to bolster Communist influence in the workers’ movement of that country. As the first part of the article shows, the KPD recruited large numbers of new members and significantly improved its electoral returns as a result. Despite this success, however, the party only pursued the united-front policy in two phases (1921–3 and 1926). As illustrated in the second part of the article, the KPD (...) bid farewell to the united front as ‘Stalinisation’ began to set in during the Weimar Republic’s final years – with lethal consequences, as its abandonment decisively abetted the victory of German fascism. (shrink)

The rapidly growing research on hybrid organizations in recent years suggests that these organizations may have particular abilities to facilitate institutional change. This article contributes to our understanding of change and, in particular, sustainable transformation in society by highlighting the importance of organizational forms. Looking more closely at the role of hybrid organizations in processes of path generation, we analyze the conditions under which hybrid organizations may enable path generation. A retrospective exploratory case study of the Swedish hybrid organization The (...) Natural Step confirms how hybrids can take part in- and may facilitate the early phases of path generation: assimilation and coalescence. The conclusion drawn is that hybrids have multivocal abilities that enable them to earn trust and authority to open up “neutral” spaces for orientation and connection between actors in separated sub-paths, and that this in turn may ease tensions and trigger dialogue and exchange, also between former opponents. Yet, as also seen in the case, this enabling position of the hybrid may be both fragile and temporary. (shrink)

On the 25th anniversary of Berry’s historic papers on the geometric phase, I discuss here our neutron interferometry experiment in which this phase is clearly separated from the dynamical phase. The connection of this experiment to the observation of the sign reversal of the wave function of a fermion during a 2π precession in a magnetic field by three groups independently in 1975 is discussed.

This paper aims to focus on the concept of experience and reconstruct its evolutions within Royce’s thought. To do so, I divide this paper in three parts. I begin by analysing Royce’s concept of experience, which takes roots in his interpretation of the British empiricists, such as Locke, Berkeley and Hume, in The Spirit of Modern Philosophy (1892). In the second part I outline Royce’s theory of experience from a philosophical and psychological point of view. My claim is that, in (...) his philosophical writings, Royce argues that cognitions are not abstract ideas but plans of actions: meanings and concepts are embodied, situated and time-oriented. I refer also to Royce’s contribution to the psychological field, with regard to embodied aspects of cognitions. According to Royce, cognitions are enriched with elements related to sensorimotor, imaginative and perceptual faculties. Action and perception are no separated aspects of cognitions, because perception implies sensorimotor dynamics. At the same time, the perception of the object is entangled with the imagination of the would be, i.e., the result of doing different actions with the object. (shrink)

In this paper I attempt to trace the development of Gottfried Leibniz’s early thought on the status of the actually infinitely small in relation to the continuum. I argue that before he arrived at his mature interpretation of infinitesimals as fictions, he had advocated their existence as actually existing entities in the continuum. From among his early attempts on the continuum problem I distinguish four distinct phases in his interpretation of infinitesimals: (i) (1669) the continuum consists of assignable points separated (...) by unassignable gaps; (ii) (1670-71) the continuum is composed of an infinity of indivisible points, or parts smaller than any assignable, with no gaps between them; (iii) (1672-75) a continuous line is composed not of points but of infinitely many infinitesimal lines, each of which is divisible and proportional to a generating motion at an instant (conatus); (iv) (1676 onward) infinitesimals are fictitious entities, which may be used as compendia loquendi to abbreviate mathematical reasonings; they are justifiable in terms of finite quantities taken as arbitrarily small, in such a way that the resulting error is smaller than any pre-assigned margin. Thus according to this analysis Leibniz arrived at his interpretation of infinitesimals as fictions already in 1676, and not in the 1700's in response to the controversy between Nieuwentijt and Varignon, as is often believed. (shrink)

Cellular events must be executed in a certain sequence during the cell division in order to maintain genome integrity and hence ensure a cell's survival. In M phase, for instance, chromosome segregation always precedes mitotic exit (characterized by mitotic kinase inactivation via cyclin destruction); this is then followed by cytokinesis. How do cells impose this strict order? Recent findings in budding yeast have suggested a mechanism whereby partitioning of chromosomes into the daughter cell is a prerequisite for the activation (...) of mitotic exit network (MEN). So far, however, a regulatory scheme that would temporally link the initiation of cytokinesis to the execution of mitotic exit has not been determined. We propose that the requirement of MEN components for cytokinesis, their translocation to the mother–daughter neck and triggering of this translocation by inactivation of the mitotic kinase may be the three crucial elements that render initiation of cytokinesis dependent on mitotic exit. BioEssays 24: 659–666, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The gravitational waves from a binary black hole with masses \ can be detected with the Laser Interferometer Space Antenna once their orbital frequency exceeds 10\–10\ Hz. The binary separation at this stage is \R_{\mathrm{g}}\), and the orbital speed is \\). I argue that at this stage, the binary will be producing bright electromagnetic radiation via gas bound to the individual BHs. Both BHs will have their own photospheres in X-ray and possibly also in optical bands. Relativistic Doppler modulations (...) and lensing effects will inevitably imprint periodic variability in the EM light-curve, tracking the phase of the orbital motion, and serving as a template for the GW inspiral waveform. Advanced localization of the source by LISA weeks to months prior to merger will enable a measurement of this EM chirp by wide-field X-ray or optical instruments. A comparison of the phases of the GW and EM chirp signals will help break degeneracies between system parameters, and probe a fractional difference difference \ in the propagation speed of photons and gravitons as low as \. (shrink)

A century after the advent of quantum mechanics and general relativity, both theories enjoy incredible empirical success, constituting the cornerstones of modern physics. Yet, paradoxically, they suffer from deep-rooted, so-far intractable, conflicts. Motivations for violations of the notion of relativistic locality include the Bell’s inequalities for hidden variable theories, the cosmological horizon problem, and Lorentz-violating approaches to quantum geometrodynamics, such as Horava–Lifshitz gravity. Here, we explore a recent proposal for a “real ensemble” non-local description of quantum mechanics, in which “particles” (...) can copy each others’ observable values AND phases, independent of their spatial separation. We first specify the exact theory, ensuring that it is consistent and has quantum mechanics as a fixed point, where all particles with the same values for a given observable have the same phases. We then study the stability of this fixed point numerically, and analytically, for simple models. We provide evidence that most systems are locally stable to small deviations from quantum mechanics, and furthermore, the phase variance per value of the observable, as well as systematic deviations from quantum mechanics, decay as \ time)\, where \. Interestingly, this convergence is controlled by the absolute value of energy, suggesting a possible connection to gravitational physics. Finally, we discuss different issues related to this theory, as well as potential novel applications for the spectrum of primordial cosmological perturbations and the cosmological constant problem. (shrink)

Recent double-slit type neutron experiments (1) and their theoretical implications (2) suggest that, since one can tell through which slit the individual neutrons travel, coherent wave packets remain nonlocally coupled (with particles one by one), even in the case of wide spatial separation. Following de Broglie's initial proposal, (3) this property can be derived from the existence of the persisting action of real superluminal physical phase waves considered as building blocks of the real subluminal wave field packets which (...) surround individual particle paths in the Einstein-de Broglie-Bohm interpretation of quantum mechanics. (shrink)

Variants of classical linear logics are presented based on the modal version of new structural rule !?mingle instead of the known rules !weakening and ?weakening. The cut-elimination theorems, the completeness theorems and a characteristic property named the mix separation principle are proved for these logics.

Freely falling point-like objects converge toward the center of the Earth. Hence the gravitational field of the Earth is inhomogeneous, and possesses a tidal component. The free fall of an extended quantum mechanical object such as a hydrogen atom prepared in a high principal-quantum-number state, i.e. a circular Rydberg atom, is predicted to fall more slowly than a classical point-like object, when both objects are dropped from the same height above the Earth’s surface. This indicates that, apart from transitions between (...) quantum states, the atom exhibits a kind of quantum mechanical incompressibility during free fall in inhomogeneous, tidal gravitational fields like those of the Earth.A superconducting ring-like system with a persistent current circulating around it behaves like the circular Rydberg atom during free fall. Like the electronic wavefunction of the freely falling atom, the Cooper-pair wavefunction is quantum mechanically incompressible. The ions in the lattice of the superconductor, however, are not incompressible, since they do not possess a globally coherent quantum phase. The resulting difference during free fall in the response of the nonlocalizable Cooper pairs of electrons and the localizable ions to inhomogeneous gravitational fields is predicted to lead to a charge separation effect, which in turn leads to a large Coulomb force that opposes the convergence caused by the tidal gravitational force on the superconducting system.A “Cavendish-like” experiment is proposed for observing the charge separation effect induced by inhomogeneous gravitational fields in a superconducting circuit. The charge separation effect is determined to be limited by a pair-breaking process that occurs when low frequency gravitational perturbations are present. (shrink)

Santayana argues that instinct and imagination are crucial to the emergence of reason from chaos. Santayana's Life of Reason, published in five books from 1905 to 1906, ranks as one of the greatest works in modern philosophical naturalism. Acknowledging the natural material bases of human life, Santayana traces the development of the human capacity for appreciating and cultivating the ideal. It is a capacity he exhibits as he articulates a continuity running through animal impulse, practical intelligence, and ideal harmony in (...) reason, society, art, religion, and science. The work is an exquisitely rendered vision of human life lived sanely. In this first book of the work, Santayana provides an account of how the human animal develops instinct, passion, and chaotic experience into rationality and ideal life. Inspired by Aristotle's De Anima, Darwin's evolutionary theory, and William James's The Principles of Psychology, Santayana contends that the requirements of action in a hazardous and uncertain environment are the sources of the development of mind. More specifically, instinct and imagination are crucial to the emergence of reason from chaos. Separating himself from the typical thought of the time by his recognition of the imagination, Santayana in this volume offers extensive critiques of various philosophies of mind, including those of Kant and the British empiricists. This Critical Edition, volume VII of The Works of George Santayana, includes a chronology, notes, bibliography, textual commentary, lists of variants, and other tools useful to Santayana scholars. The other four books of the volume include Reason in Society, Reason in Religion, Reason in Art, and Reason in Science. (shrink)

Santayana's Life of Reason, published in five books from 1905 to 1906, ranks as one of the greatest works in modern philosophical naturalism. Acknowledging the natural material bases of human life, Santayana traces the development of the human capacity for appreciating and cultivating the ideal. It is a capacity he exhibits as he articulates a continuity running through animal impulse, practical intelligence, and ideal harmony in reason, society, art, religion, and science. The work is an exquisitely rendered vision of human (...) life lived sanely. In this first book of the work, Santayana provides an account of how the human animal develops instinct, passion, and chaotic experience into rationality and ideal life. Inspired by Aristotle's De Anima, Darwin's evolutionary theory, and William James's The Principles of Psychology, Santayana contends that the requirements of action in a hazardous and uncertain environment are the sources of the development of mind. More specifically, instinct and imagination are crucial to the emergence of reason from chaos. Separating himself from the typical thought of the time by his recognition of the imagination, Santayana in this volume offers extensive critiques of various philosophies of mind, including those of Kant and the British empiricists. This Critical Edition, volume VII of The Works of George Santayana, includes a chronology, notes, bibliography, textual commentary, lists of variants, and other tools useful to Santayana scholars. The other four books of the volume include Reason in Society, Reason in Religion, Reason in Art, and Reason in Science. (shrink)

J. S. Bell's argument that only “nonlocal” hidden variable theories can reproduce the quantum statistical correlations of the singlet spin state in the case of two separated spin-1/2 particles is examined in terms of Wigner's formulation. It is shown that a similar argument applies to a single spin-1/2 particle, and that the exclusion of hidden variables depends on an obviously untenable assumption concerning conditional probabilities. The problem of completeness is discussed briefly, and the grounds for rejecting a phase-space reconstruction (...) of the quantum statistics are clarified. (shrink)

Homologous recombination (HR) is required to protect and restart stressed replication forks. Paradoxically, the Mrc1 branch of the S phase checkpoints, which is activated by replicative stress, prevents HR repair at breaks and arrested forks. Indeed, the mechanisms underlying HR can threaten genome integrity if not properly regulated. Thus, understanding how cells avoid genetic instability associated with replicative stress, a hallmark of cancer, is still a challenge. Here I discuss recent results that support a model by which HR responds (...) to replication stress through replicative and repair activities that operate at different stages of the cell cycle (S and G2, respectively) and in distinct subnuclear structures. Remarkably, the replication checkpoint appears to control this scenario by inhibiting the assembly of HR repair centers at stressed forks during S phase, thereby avoiding genetic instability. (shrink)

Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe (...) the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0. (shrink)

Paraspeckles are nuclear condensates, or membranelees organelles, that are built on the long noncoding RNA, NEAT1, and have been linked to many diseases. Although originally described as constitutive structures, here, in reviewing this field, we develop the hypothesis that cells increase paraspeckle abundance as part of a general stress response, to aid pro‐survival pathways. Paraspeckles increase in many scenarios: when cells transform from one state to another, become infected with viruses and bacteria, begin to degenerate, under inflammation, in aging, and (...) in cancer. Cells increase paraspeckles by increasing transcription of NEAT1 and adjusting its RNA processing. These increases in NEAT1 are driven by numerous stress‐sensing signaling pathways, including signaling to mitochondria and stress granules, revealing crosstalk between the cytoplasm and nucleoplasm in the stress response. Thus, paraspeckles are an important piece of the puzzle in cellular homeostasis, and could be considered RNA‐scaffolded nuclear equivalents of dynamic stress‐induced structures that form in the cytoplasm. We speculate that, in general, cells rely on phase‐separated paraspeckles to transiently tweak gene regulation in times of cellular flux. (shrink)

Environmental, physiological, and pathological stimuli induce the misfolding of proteins, which results in the formation of aggregates and amyloid fibrils. To cope with proteotoxic stress, cells are equipped with adaptive mechanisms that are accompanied by changes in gene expression. The evolutionarily conserved mechanism called the heat shock response is characterized by the induction of a set of heat shock proteins (HSPs), and is mainly regulated by heat shock transcription factor 1 (HSF1) in mammals. We herein introduce the mechanisms by which (...) HSF1 tightly controls the transcription of HSP genes via the regulation of pre‐initiation complex recruitment in their promoters under proteotoxic stress. These mechanisms involve the stress‐induced regulation of HSF1‐transcription complex formation with a number of coactivators, changes in chromatin states, and the formation of phase‐separated condensates through post‐translational modifications. (shrink)