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)

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)

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)

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)

Eukaryotic mRNAs are monocistronic, and therefore mechanisms exist that coordinate the synthesis of multiprotein complexes in order to obtain proper stoichiometry at the appropriate intracellular locations. RNA‐binding proteins containing low‐complexity sequences are prone to generate liquid droplets via liquid‐liquid phase separation, and in this way create cytoplasmic assemblages of functionally related mRNAs. In a recent iCLIP study, we showed that the Drosophila RNA‐binding protein Imp, which exhibits a C‐terminal low‐complexity sequence, increases the formation of F‐actin (...) by binding to 3′ untranslated regions of mRNAs encoding components participating in F‐actin biogenesis. We hypothesize that phase transition is a mechanism the cell employs to increase the local mRNA concentration considerably, and in this way synchronize protein production in cytoplasmic territories, as discussed in the present review. (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)

Mediator is a coregulatory complex that plays essential roles in multiple processes of transcription regulation. One of the human Mediator subunits, MED26, has a role in recruitment of the super elongation complex (SEC) to polyadenylated genes and little elongation complex (LEC) to non‐polyadenylated genes, including small nuclear RNAs (snRNAs) and replication‐dependent histone (RDH) genes. MED26‐containing Mediator plays a role in 3′ Pol II pausing at the proximal region of transcript end sites in RDH genes through recruitment of Cajal bodies (CBs) (...) to histone locus bodies (HLBs). This finding suggests that Mediator is involved in the association of CBs with HLBs to facilitate 3′ Pol II pausing and subsequent 3′‐end processing by supplying 3′‐end processing factors from CBs. Thus, we argue the possibility that Mediator is involved in the organization of nuclear bodies to orchestrate multiple processes of gene transcription. (shrink)

Eukaryotic genome DNA is wrapped around core histones and forms a nucleosome structure. Together with associated proteins and RNAs, these nucleosomes are organized three‐dimensionally in the cell as chromatin. Emerging evidence demonstrates that chromatin consists of rather irregular and variable nucleosome arrangements without the regular fiber structure and that its dynamic behavior plays a critical role in regulating various genome functions. Single‐nucleosome imaging is a promising method to investigate chromatin behavior in living cells. It reveals local chromatin motion, which reflects (...) chromatin organization not observed in chemically fixed cells. The motion data is like a gold mine. Data analyses from many aspects bring us more and more information that contributes to better understanding of genome functions. In this review article, we describe imaging of single‐nucleosomes and their tracked behavior through oblique illumination microscopy. We also discuss applications of this technique, especially in elucidating nucleolar organization in living cells. (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)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying formation and (...) maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

As a senior physicist colleague and our friend, Robert N. Boyd, wrote in a journal (JCFA, Vol. 1,. 2, 2022), Our universe is but one page in a large book [4]. For example, things and Beings can travel between Universes, intentionally or unintentionally. In this short remark, we revisit and offer short remark to Neil’s ideas and trying to connect them with geometrization of musical chords as presented by D. Tymoczko and others, then to Escher staircase and then to Jacob’s (...) ladder which seems to point to possibility to interpret Jacob’s vision as described in the ancient book of Genesis as inter dimensional or heavenly staircase, e.g. an inter dimensional bridge between heaven and earth (see also classic book: Hofstadter, Godel, Escher, Bach). Jacob’s vision of angels going down to earth from that staircase has been depicted for instance in William Blake art etc. In our communication with others via physics literature and discussions etc, we came to several conclusions as follows: Firstly, possibility of quantum wormhole effect to mirror particle universe, which sometimes it is termed non-orientable wormhole. While such mirror particles effect have been more than 50 years predicted with the so-called parity violation (cf. Lee & Yang, 1950s), and that is called symmetry breaking. Secondly, a series of extended experiments on laser irradiated cold water may suggest possible transition from a phase of water to be at least partially fourth phase of water, which may be composed of crystalline water (see e.g. Gerald Pollack, and also Harold Aspden on liquid crystalline). If we can imagine laser cooling effect can be done in protracted time, then we can achieve a physical representation of Aspden’s liquid crystalline. Therefore, in subsequent article (Part II) we outlined simple model of such an effect of tunneling via quantum liquid crystalline Universe, which may likely be modeled with iced-water. It is interesting to remark here that certain experiments by Stockholm University scientists have shown that X-ray triggered water can exhibit properties just like liquid crystal (cf. PRL, 2020). That is why we consider it possible that there can be quantum phase transition where liquid water (comprised of iced cubes and water) can exhibit effects such as tunneling in quantum liquid crystalline Universe. Last but not least, we admit that what we outlined here is just an initial phase; and if you wish, perhaps we can call such experiments as “wormhole-at-lab” experiments (abbreviated: WHALE). (shrink)

The present article was partly inspired by G. Pollack’s book, and also Dadoloff, Saxena & Jensen (2010). As a senior physicist colleague and our friend, Robert N. Boyd, wrote in a journal (JCFA, Vol. 1, No. 2, 2022), for example, things and Beings can travel between Universes, intentionally or unintentionally [4]. In this short remark, we revisit and offer short remark to Neil Boyd’s ideas and trying to connect them with geometry of musical chords as presented by D. Tymoczko and (...) others, then to Escherian staircase and then to Jacob’s ladder which seems to pointto possibility to interpret Jacob’s vision as described in the ancient book of Genesis as interdimensional staircase, e.g. an interdimensional bridge between heaven and earth (cf. classic book: Hofstadter, Godel, Escher, Bach). Jacob’s vision of angels going down to earth from that staircase has been depicted for instance in William Blake art etc. In our communication with others via physics literature and discussions etc, we came to several conclusions as follows: Firstly, possibility of wormhole effect to mirror particle universe, which sometimes it is termed non-orientable wormhole. While such mirror particles effect have been more than 50 years predicted with the so-called parity violation (cf. Lee & Yang, 1950s), and that is called symmetry breaking. Secondly, a series of extended experiments on laser irradiated cold water may suggest possible transition from a phase of water to be at least partially fourth phase of water, which may be composed of crystalline water (see e.g. Gerald Pollack, and also Harold Aspden on liquid crystalline). If we can imagine laser cooling effect can be done in protracted time, then we can achieve a physical representation of Aspden‘s liquid crystalline. Therefore, in this article we outline a series of simple experiments of laser irradiated iced-water along with beryl and selenite crystals in order to see possibility of such a quantum tunneling via quantum liquid crystalline Universe hypothesis, which may likely be modeled with iced-water. It is interesting to remark here that certain experiments by Stockholm University scientists have shown that X-ray triggered water can exhibit properties just like liquid crystal (cf. PRL, 2020). That is why we consider it possible that there can be quantum phase transition where liquid water (comprised of iced cubes and water) can exhibit effects such as tunneling in quantum liquid crystalline Universe. Last but not least, we admit that what we outlined here is just aninitial phase; and if you wish, perhaps we can call such experiments as “wormhole-at-lab” experiments (abbreviated: WHALE). (shrink)

This paper argues that an exploration of colloids can help us situate human social life within a wider understanding of the sociality and animacy of matter. Colloids are substances such as sols, foams, powders, gels, doughs and pastes that exhibit complex and shifting macroscale physical properties that do not conform to standard conceptions of solids, liquids or gases. Colloids can behave in complex and creative ways because of their topological enfolding of dispersed and continuous matter, in different phases, at a (...) ‘mesoscale’ intermediate between the scale of molecules and that of the macroscale substance. I relate colloids, with their twin phenomena of ‘repetition’ and ‘mediation’, to an understanding of social life as reducible neither to the interaction between separate individuals nor to a transindividual whole. I suggest that human social life participates in a colloidal ‘metapattern’ of repetition and mediation that is manifest across diverse material substrates and spatial scales. (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)

Nous examinons ici un type très caractéristique d'installation artisanale, fréquente dans les habitats ou les bâtiments isolés de l'époque minoenne. Elle est composée, dans sa forme la plus simple et la plus courante, d'un récipient tronconique avec bec verseur placé sur une plate-forme artificielle ou un banc et, en immédiate relation avec lui, d'un grand vase situé à un niveau inférieur, servant à recueillir un liquide. On a donné des interprétations variées de ces installations : servaient-elles à séparer deux liquides (...) (huile et eau), au cours de la production de l'huile? à écraser les raisins pendant la fabrication du vin? à laver les vêtements? Après avoir dressé un catalogue, aussi complet que possible, des installations minoennes de ce type connues à ce jour, on tente de comprendre leur fonctionnement, à l'aide de données comparatives et de parallèles iconographiques diachroniques. Enfin, on examine le rôle de ces installations dans le cadre socio-économique plus large de l'époque minoenne. (shrink)

The first classification of general types of transition between phases of matter, introduced by Paul Ehrenfest in 1933, lies at a crossroads in the thermodynamical study of critical phenomena. It arose following the discovery in 1932 of a suprising new phase transition in liquid helium, the “lambda transition,” when W. H. Keesom and coworkers in Leiden, Holland observed a λhaped “jump” discontinuity in the curve giving the temperature dependence of the specific heat of helium at a critical value. (...) This apparent jump led Ehrenfest to introduce a classification of phase transitions on the basis of jumps in derivatives of the free energy function. This classification was immediately applied by A.J. Rutgers to the study of the transition from the normal to superconducting state in metals. Eduard Justi and Max von Laue soon questioned the possibility of its class of “second-order phase transitions” -- of which the “lambda transition was believed to be the arche type -- but C.J. Gorter and H.B.G. Casimir used an “order parameter to demonstrate their existence in superconductors. As a crossroads of study, the Ehrenfest classification was forced to undergo a slow, adaptive evolution during subsequent decades. During the 1940s the classification was increasingly used in discussions of liquid-gas, order-disorder, paramagnetic-ferromagnetic and normal-super-conducting phase transitions. Already in 1944 however, Lars Onsagers solution of the Ising model for two-dimensional magnets was seen to possess a derivative with a logarithmic divergence rather than a jump as the critical point was approached. In the 1950s, experiments further revealed the lambda transition in helium to exhibit similar behavior. Rather than being a prime example of an Ehrenfest phase transition, the lambda transition was seen to lie outside the Ehrenfest classification. The Ehrenfest scheme was then extended to include such singularities, most notably by A. Brain Pippard in 1957, with widespread acceptance. During the 1960s these logarithmic infinities were the focus of the investigation of “scaling” by Leo Kadanoff, B. Widom and others. By the 1970s, a radically simplified binary classification of phase transitions into “first-order” and “continuous” transitions was increasingly adopted. (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)

Fluid-phase endocytosis (pinocytosis) kinetics were studied inDictyostelium discoideum amoebae from the axenic strain Ax-2 that exhibits high rates of fluid-phase endocytosis when cultured in liquid nutrient media. Fluorescein-labelled dextran (FITC-dextran) was used as a marker in continuous uptake- and in pulse-chase exocytosis experiments. In the latter case, efflux of the marker was monitored on cells loaded for short periods of time and resuspended in marker-free medium. A multicompartmental model was developed which describes satisfactorily fluid-phase endocytosis kinetics. (...) In particular, it accounts correctly for the extended latency period before exocytosis in pulse-chase experiments and it suggests the existence of some sorts of maturation stages in the pathway. (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)

— 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)

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)

After World War II, quite a few mathematicians, including Mark Kac, John von Neumann, and Nobert Wiener, worked on the physical problem of phase transitions, i.e. changes in the state of matter caused by gradual changes of physical parameters such as the condensation of a gas to a liquid and the loss of magnetization of a ferromagnet above a certain temperature. The significance of these mathematicians was not so much that they brought mathematical rigor to the theoretical description (...) of the phenomena,1 but that they applied their mathematical skills and tools to solve concrete mathematical problems encountered in the microscopic modeling of phase transitions. The present paper deals... (shrink)